The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar): [structure] wherein Y ar , X 1ar , X 2ar , R 1ar , R 2ar , R 3ar , R 4ar and R 5ar are as defined herein; or a pharmaceutically acceptable salt or prodrug thereof. The compounds of the invention are selective inhibitors of DNMT1 and can be useful in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anemia, and beta thalassemia, and diseases associated with DNMT1 inhibition. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting DNMT1 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

62 parts

›This application is a 371 of International Application…

This application is a 371 of International Application No. PCT/IB2017/053511, filed 13 Jun. 2017, which claims priority to U.S. Provisional 62/349,227, filed 13 Jun. 2016, U.S. Provisional 62/393,256, filed 12 Sep. 2016, and U.S. Provisional 62/412,343, filed 25 Oct. 2016.

›FIELD OF THE INVENTION

The present invention relates to substituted pyridine derivatives that are selective inhibitors of the activity of DNA methyltransferase) (DNMT1). The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of cancer, pre-cancerous syndromes, beta hemoglobinopathy disorders, sickle cell disease, sickle cell anaemia, and beta thalassemia, and other diseases associated with DNMT1 inhibition.

›BACKGROUND OF THE INVENTION

Epigenetics is a way to turn genes on and off independent of the underlaying DNA sequence. DNA methylation occurring in gene promotors is an example of a repressive epigenetic mark resulting in chromatin compaction and gene silencing. DNA methylation is mediated by the DNA methyltransferase (DNMT) family of proteins which is comprised of four family members. Three of the family members, DNMT1, DNMT3A and DNMT3B, contain DNA methyltransferase activity. These three members are responsible for establishing the de novo DNA methylation pattern, while DNMT1 is primarily responsible for maintaining the methylation pattern in daughter strands following DNA replication.

In cancer, DNA methylation patterns become aberrant resulting in global hypomethylation and localized hypermethylation within promoter regions. This can result in downstream silencing of tumor suppressor genes (Ting et al. Genes Dev. 2006; 20:3215-3231). Additionally, silencing of DNMT1 results in DNA demethylation and reexpression of tumor suppressor genes resulting in tumor growth inhibition (Zhou et al. Oncol. Lett. 2014; 5: 2130-2134).

DNA methylation inhibitors (termed DNA hypomethylating agents) are clinically validated anti-cancer therapies utilized for the treatment of MDS, AML and CMML. While these agents are available, there is still significant opportunity for improvement regarding toxicity, utility in solid tumors and oral bioavailability. Hence, a novel DNMT inhibitor would be of interest for the treatment of cancer and/or any disease or condition mediated by DNA methylation. Of particular interest to this invention, is specifically targeting DNMT1 to prevent propagation of abnormal methylation patterns (such as those that occur in cancer) to daughter strands during replication.

US 2008/0132525 and WO 2006/078752 describe inhibitors of DNA methyltransferase. CA 2030875 describes methods and probes for detecting nucleoside transporter and method for producing the probes.

Hemoglobinopathies

Hemoglobin disorders, such as sickle cell anemia and beta-thalassaemia, represent the most common heritable blood diseases in the world. Sickle cell anemia and beta-thalassemia are characterized by disorders of hemoglobin, which is the oxygen carrying protein complex in red blood cells. Structurally, hemoglobin is normally composed of two pairs of proteins plus four molecules of heme. Adults and children older than about four months, express a form of hemoglobin referred to as adult hemoglobin, which predominantly consists of two alpha-globin proteins paired with two beta-globin proteins plus four molecules of heme. However, fetuses and infants typically express mostly fetal hemoglobin, which is composed of two alpha-globin proteins paired with two gamma-globin proteins plus four molecules of heme. Note that there are two forms of gamma-globin, termed G-gamma and A-gamma, that are encoded by two different genes (HBG1 and HBG2) but that are functionally equivalent to a large degree; fetal hemoglobin refers to any combination of a pair of G-gamma and/or A-gamma plus a pair of alpha-globin proteins plus four molecules of heme.

In sickle cell anemia, the gene encoding for beta-globin contains a mutation which results in an abnormal hemoglobin structure and causes red blood cells to adopt a characteristic sickle shape under certain conditions. This sickle shape leads to reduced red cell plasticity, longer capillary transit times, and frequent vaso-occlusive processes that can damage tissues and result in patient morbidity. In contrast, beta-thalassemia is characterized by inadequate beta-globin production to combine with normally produced alpha-globin. The resulting accumulation of alpha globin is toxic to red blood cell precursors, and results in ineffective erythropoiesis and extensive red blood cell hemolysis.

There is currently no approved pharmacologic treatment to cure sickle cell anemia or beta-thalassemia. However, increases in the number of red blood cells that produce fetal hemoglobin, combined with overall increases in the level of fetal hemoglobin per red blood cell have been proven to provide clinical benefit in sickle cell anemia and sickle cell disease patients by reducing the frequency of acute vaso-occlusive crises. Additionally, although not clinically proven, the disease biology of beta-thalassemia suggests that increasing fetal hemoglobin production to high levels may be a viable strategy for the therapy of this disease as well.

The object of this therapeutic approach, the de-repression of the silenced HBG1 and HBG2 genes, may be targeted through intervention in an epigenetic process in erythropoiesis. Changes in DNA methylation are key determining events in the course of hematopoiesis, marking differentiation milestones that result in commitments to various cell lineages. During erythropoiesis, a rapid decrease in global DNA methylation demarks a commitment point toward the expression of erythroid specific regulators GATA1 and KLF1, and suppression of hematopoietic progenitor regulators GATA2 and PU.1 (1, 2). For erythroid progenitor cells in adult bone marrow, DNA in the promoter region of the beta-globin HBB gene becomes unmethylated, corresponding to high level expression of beta-globin protein. In contrast, promoters of the HBG1 and HBG2 loci are highly methylated, resulting in greatly diminished expression of gamma-globin proteins (3). Although DNA methyltransferases DNMT1, DNMT3A, and DNMT3B are each expressed in erythroid progenitors, the relatively greater expression of DNMT1, particularly in the final stages of erythroid differentiation suggests that it plays a dominant role in globin gene regulation (2). 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine) are pan-DNMT inhibitors that are known inducers of fetal hemoglobin in erythroid progenitor cells. In erythroid cell culture and in an in vivo model of fetal hemoglobin induction (4, 5), treatment with these agents causes decreased methylation of CpG sites in the HBG promoters with corresponding increases in the gamma globin protein expression. Moreover, in a limited set of clinical studies, both agents caused increases in fetal hemoglobin in patients with sickle cell anemia, sickle cell disease and beta-thalassemia (6-9). While effective at inducing fetal hemoglobin, these agents have not been widely used to treat sickle cell anemia, sickle cell disease, or beta-thalassemia due to concerns over long-term safety, dose-limiting toxicities, and an unsuitable dosing route.

›REFERENCES

(1) Pop R, Shearstone J R, Shen Q, Liu Y, Hallstrom K, Koulnis M, et al. A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression. 2010; 8.

(2) Shearstone J R, Pop R, Bock C, Boyle P, Meissner A, Socolovsky M. Global DNA demethylation during mouse erythropoiesis in vivo. 2011; 334:799-802.

(3) Mabaera R, Richardson C A, Johnson K, Hsu M, Fiering S, Lowrey C H. Developmental- and differentiation-specific patterns of human +¦- and +¦-globin promoter DNA methylation. 2007; 110:1343-52.

(4) Chin J, Singh M, Banzon V, Vaitkus K, Ibanez V, Kouznetsova T, et al. Transcriptional activation of the +¦-globin gene in baboons treated with decitabine and in cultured erythroid progenitor cells involves different mechanisms. 2009; 37:1131-42.

(5) Akpan I, Banzon V, Ibanez V, Vaitkus K, DeSimone J, Lavelle D. Decitabine increases fetal hemoglobin in Papio anubis by increasing +¦-globin gene transcription. 2010; 38:989-93.

(6) Dover G J, Charache S H, Boyer S H, Talbot J, Smith K D. 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. 1983; 134:475-88.

(7) Saunthararajah Y, Hillery C A, Lavelle D, Molokie R, Dorn L, Bressler L, et al. Effects of 5-aza-2GÇ¦-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. 2003; 102:3865-70.

(8) Ley T J, DeSimone J, Noguchi C T, Turner P H, Schechter A N, Heller P, et al. 5-Azacytidine increases +¦-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. 1983; 62:370-80.

(9) Lowrey C H, Nienhuis A W. Brief report: Treatment with azacitidine of patients with end-stage +¦-thalassemia. 1993; 329:845-8.

It is an object of the present invention to provide novel compounds that are selective inhibitors of DNMT1.

It is also an object of this invention to provide compounds which increase the production of gamma globin, and thereby also increase the production of fetal hemoglobin in human erythroid cells. The compounds of this invention may therefore be useful to treat sickle cell anemia and sickle cell disease. Beta-thalassemia may also be ameliorated by treatment with these compounds.

It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutical excipient and compounds of Formula (I).

It is also an object of the present invention to provide a method for treating cancer, pre-cancerous syndromes, beta hemoglobinopathies, such as sickle cell disease, sickle cell anaemia, and beta thalassemia, that comprises administering novel selective inhibitors of DNMT1 activity.

›SUMMARY OF THE INVENTION · 1 of 2

The invention is directed to substituted pyridine derivatives. Specifically, the invention is directed to compounds according to Formula (Iar):

wherein Y ar , X 1ar , X 2ar , R 1ar , R 2ar , R 3ar , R 4ar and R 5ar are as defined below; or a pharmaceutically acceptable salt or prodrug thereof.

The present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of DNMT1, and selective against DNMT3A and DNMT3B.

This invention also relates to a method of treating cancer, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating pre-cancerous syndromes, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating beta hemoglobinopathies, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating sickle cell disease, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating sickle cell anemia, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating beta thalassemia, which comprises administering to a subject in need thereof an effective amount of a DNMT1 inhibiting compound of Formula (I); or a pharmaceutically acceptable salt thereof.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of pre-cancerous syndromes.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of beta hemoglobinopathies.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of sickle cell disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of sickle cell anemia.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of beta thalassemia.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pre-cancerous syndromes.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of beta hemoglobinopathies.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sickle cell disease.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of sickle cell anemia.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of beta thalassemia.

Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition as defined above for use in therapy.

Also included in the present invention are methods of co-administering the presently invented DNMT1 inhibiting compounds with a further anti-neoplastic agent or agents.

Also included in the present invention are methods of co-administering the presently invented DNMT1 inhibiting compounds with a further fetal hemoglobin inducing agent or agents.

Also included in the present invention are methods of co-administering the presently invented DNMT1 inhibiting compounds with a further agent or agents that lessens the severity of beta hemoglobinopathies.

Also included in the present invention are methods of co-administering the presently invented DNMT1 inhibiting compounds with a further agent or agents that lessens the severity of beta thalassemia.

The invention also relates to a combination for use in therapy which comprises a therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) at least one anti-neoplastic agent.

›SUMMARY OF THE INVENTION · 2 of 2

›BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts the effect of Compound A on erythroid progenitor cells (EPCs). Representative results (n=3 studies each) of 5 day treatment with Compound A on fetal hemoglobin (HbF) ELISA (open circles), and cell growth assay (closed circles).

FIG. 1B depicts the effect of Compound A on HBG1 and HBG2 DNA methylation. Erythroid progenitor cells (EPCs) were treated for 3 days with vehicle (gray bars) or 5 μM Compound A (black bars), genomic DNA was extracted and bisulfite sequenced for nine loci in the promoter regions of HBG1 and HBG2 that were previously described to be sites of DNMT1 cytosine methylation. Sites of methylation are labeled as positions relative to respective start sites

FIG. 2A depicts the effect of Compound A on fetal hemoglobin in the transgenic mouse model. Compound A administered orally to sickle cell disease (SCD) model transgenic mice at 10 or 50 mg/kg, BID daily caused dose dependent increases in % HbF protein, measured by HPLC.

FIG. 2B depicts the effect of Compound A on fetal hemoglobin in the transgenic mouse model. Compound A administered orally to SCD transgenic mice at 10 or 50 mg/kg, BID daily caused dose dependent increases in % F-reticulocytes and % F-RBCs, measured by flow cytometry.

›DETAILED DESCRIPTION OF THE INVENTION · 1 of 41

This invention relates to compounds of Formula (Iar) and to the use of compounds of Formula (Iar) in the methods of the invention:

wherein:

X 1ar and X 2ar are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , —SH, and —SR a ;

Y ar is selected from: S, NH, NR z , O, S(O) and S(O) 2 ; R 1ar is selected from:

amino, —NHR a , —NR b R c , cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

R 2ar is selected from:

hydrogen, C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , —C(O)OR a , —C(O)NHR a , and —C(O)NR b R c ;

R 3ar is selected from:

hydrogen, aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ;

R 4ar is selected from:

R 5ar is selected from:

amino, —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —OC 1-6 alkyl, —OR e , —Oaryl, —Oaryl substituted from 1 to 4 times by R d , —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

where:

each R a is independently selected from

provided that:

at least one of R 2ar , R 3ar and R 4ar , is hydrogen, R 2ar , R 3ar and R 4ar are not all hydrogen, and X 1ar and X 2ar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Iar) R 2ar is —C(O)NH 2 .

Suitably in the compounds of Formula (Iar) R 3ar is aryl optionally substituted from 1 to 4 times by R d .

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (I):

wherein:

X 1 and X 2 are independently selected from:

Y is selected from: S, NH, NR z , O, S(O) and S(O) 2 ; R 1 is selected from:

R 2 is selected from:

R 3 is selected from:

hydrogen, aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ;

R 4 is selected from:

R 5 is selected from:

where:

each R a is independently selected from

provided that:

at least one of R 2 , R 3 and R 4 , is hydrogen, R 2 , R 3 and R 4 are not all hydrogen, and X 1 and X 2 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (II):

wherein:

X 21 and X 22 are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, heterocycloalkyl, and —SH;

Y 1 is selected from: S, NH, NR z , S(O) and S(O) 2 ; R 21 is selected from:

amino, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , —NHR a , —NR b R c , cycloalkyl, cycloalkyl substituted with from 1 to 4 times by R d , heterocycloalkyl, —SH, and —SR a ;

R 22 is selected from:

hydrogen, C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , —C(O)OR a , and —C(O)NHR a ;

R 23 is selected from:

hydrogen, aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ;

R 24 is selected from:

hydrogen, C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , —C(O)OR a , and —C(O)NHR a ;

R 25 is selected from:

amino, —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —OC 1-6 alkyl, —OR e , —Oaryl, —Oheteroaryl, —SH, and —SR a ;

where:

each R a is independently selected from

provided that:

at least one of R 22 , R 23 and R 24 , is hydrogen, R 22 , R 23 and R 24 are not all hydrogen, and X 21 and X 22 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (III):

wherein:

X 31 and X 32 are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, cycloalkyl, and —SH;

Y 2 is selected from: S, NH, NR z and S(O); R 31 is selected from:

C 1-6 alkyl, R e1 , —OC 1-6 alkyl, —OR e1 , —NHR a1 , —NR b1 R c1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , —SH, and —SR a1 ;

›DETAILED DESCRIPTION OF THE INVENTION · 2 of 41

R 32 is selected from:

hydrogen, C 1-6 alkyl, R e1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 ;

R 33 is selected from:

hydrogen, aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d1 ;

R 34 is selected from:

hydrogen, C 1-6 alkyl, R e1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 ;

R 35 is selected from:

amino, —NHR a1 , —NR b1 R c1 , aryl, aryl substituted from 1 to 4 times by R d1 , —OC 1-6 alkyl, —OR e1 , —SH, and —SR a1 ;

where:

each R a1 is independently selected from

provided that:

at least one of R 32 , R 33 and R 34 , is hydrogen, R 32 , R 33 and R 34 are not all hydrogen, and X 31 and X 32 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (III), neither X 31 nor X 32 are hydrogen.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IVar):

wherein:

X 41ar and X 42ar are independently selected from: —CN, fluoro, chloro, bromo and iodo; Y 4ar is selected from: S and NH; R 41ar is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyloxy, —OH, —COOH, —NH 2 —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 and —CN, C 1-4 alkyloxy, C 1-4 alkyloxy substituted from 1 to 4 times by fluoro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, —CN, oxo, —OH, —NO 2 , and —NH 2 ,

heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from:

cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 42ar is selected from:

hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 4 substituents independently selected from:

where R xa1 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, —NO 2 , and —NH 2 ;

R 43ar is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

where R 46 and R 47 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 48 R 49 , where R 48 and R 49 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ; and

R 44ar and R 45ar are independently selected from:

hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, heterocycloalkyl, C 1-4 alkoxy, oxo, —OH, —NH 2 and —CN, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

R 44ar and R 45ar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 3 of 41

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —N(C 1-4 alkyl) 2 , SO 2 NH 2 , SO 2 CH 2 CH 3 , and SO 2 CH 3 ;

provided that:

R 42ar and R 43ar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IVar) neither R 44ar nor R 45ar is hydrogen.

Suitably in the compounds of Formula (IVar) R 42ar is —C(O)NH 2 .

Suitably in the compounds of Formula (IVar) R 43ar is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IV):

wherein:

X 41 and X 42 are independently selected from: —CN, fluoro, chloro, bromo and iodo; Y 4 is selected from: S and NH; R 41 is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyloxy, —OH, —COOH, —NH 2 —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 and —CN, C 1-4 alkyloxy, C 1-4 alkyloxy substituted from 1 to 4 times by fluoro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 42 is selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, —NHC(O)H, —NHC(O)R xa1 , where R xa1 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro, C 1-4 alkoxy, —CN, oxo, —OH, —NO 2 , and —NH 2 ;

R 43 is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ; and

R 44 and R 45 are independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 4 of 41

R 44 and R 45 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

provided that:

R 42 and R 43 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IV) neither R 44 nor R 45 is hydrogen.

This invention relates to novel compounds of Formula (IVaar) and to the use of compounds of Formula (IVaar) in the methods of the invention:

wherein:

X 41aar and X 42aar are independently selected from: —CN, fluoro, chloro, bromo and iodo; Y 4aar is selected from: S and NH; R 41aar is selected from:

heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from:

cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 42aar selected from:

where R xa1 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, —NO 2 , and —NH 2 ;

R 43aar selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ; and

R 44aar and R 45aar are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, heterocycloalkyl, C 1-4 alkoxy, oxo, —OH, —NH 2 and —CN, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 5 of 41

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, aryl, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , and SO 2 NH 2 , or

R 44aar and R 45aar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —N(C 1-4 alkyl) 2 , SO 2 NH 2 , SO 2 CH 2 CH 3 , and SO 2 CH 3 ;

provided that:

R 42aar and R 43aar are not both hydrogen, and R 44aar and R 45aar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IVaar) neither R 44aar nor R 45aar is hydrogen.

Suitably in the compounds of Formula (IVaar) R 42aar is —C(O)NH 2 .

Suitably in the compounds of Formula (IVaar) R 43aar is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

This invention relates to novel compounds of Formula (IVa) and to the use of compounds of Formula (IVa) in the methods of the invention:

wherein:

X 41a and X 42a are independently selected from: —CN, fluoro, chloro, bromo and iodo; Y 4a is selected from: S and NH; R 41a is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyloxy, —OH, —COOH, —NH 2 —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 and —CN, C 1-4 alkyloxy, C 1-4 alkyloxy substituted from 1 to 4 times by fluoro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 42a is selected from:

where R xa1 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, —NO 2 , and —NH 2 ;

R 43a is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

›DETAILED DESCRIPTION OF THE INVENTION · 6 of 41

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ; and

R 44a and R 45a are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, heterocycloalkyl, C 1-4 alkoxy, oxo, —OH, —NH 2 and —CN, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

R 44a and R 45a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —N(C 1-4 alkyl) 2 , SO 2 NH 2 , SO 2 CH 2 CH 3 , and SO 2 CH 3 ;

provided that:

R 42a and R 43a are not both hydrogen, and R 44a and R 45a are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IVa) neither R 44a nor R 45a is hydrogen.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (V):

wherein:

X 51 and X 52 are independently selected from: —CN, fluoro and chloro; Y 5 is selected from: S and NH; R 50 is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, C 1-4 alkyloxy, cycloalkyl, cycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

R 51 is selected from:

hydrogen, C 1-6 alkyl, —C(O)NHR 55 , where R 55 is selected from: hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, bromo, oxo, —OH, —NH 2 and —CN, —NHC(O)H, —NHC(O)R xa2 ,

where R xa2 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, and —NH 2 ;

R 52 is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

where R 56 and R 57 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 58 R 59 , where R 58 and R 59 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

oxo, —CN, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH;

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

where R 56 and R 57 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 58 R 59 , where R 58 and R 59 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-6 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

oxo, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH; and

R 53 and R 54 are independently selected from:

hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, oxo, heterocycloalkyl, C 1-4 alkoxy, —OH and —NH 2 , heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C 1-4 alkoxy, and —OH, or

R 53 and R 54 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 7 of 41

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

provided that:

R 51 and R 52 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (V) neither R 53 nor R 54 is hydrogen.

This invention relates to novel compounds of Formula (Vaar) and to the use of compounds of Formula (Vaar) in the methods of the invention:

wherein:

X 51aar and X 52aar are independently selected from: —CN, fluoro and chloro; Y 5aar is selected from: S and NH; R 50aar is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, C 1-4 alkyloxy, aryl, alkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

heteroaryl, heteroalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

R 51aar is selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, bromo, oxo, —OH, —NH 2 and —CN, —NHC(O)H, —NHC(O)R xa2 ,

where R xa2 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, and —NH 2 ;

R 52aar is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

oxo, —CN, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 , where R 56 and R 57 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 58 R 59 , where R 58 and R 59 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, oxo, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH; and

R 53aar and R 54aar are independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C 1-4 alkoxy, and —OH, or

R 53aar and R 54aar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

›DETAILED DESCRIPTION OF THE INVENTION · 8 of 41

provided that:

R 51aar and R 52aar are not both hydrogen, and R 53aar and R 54aar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Vaar) neither R 53aar nor R 54aar is hydrogen.

Suitably in the compounds of Formula (Vaar) R 51aar is —C(O)NH 2 .

Suitably in the compounds of Formula (Vaar) R 52aar is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro,

chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

This invention relates to novel compounds of Formula (Va) and to the use of compounds of Formula (Va) in the methods of the invention:

wherein:

X 51a and X 52a are independently selected from: —CN, fluoro and chloro; Y 5a is selected from: S and NH; R 50a is selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

R 51a is selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, bromo, oxo, —OH, —NH 2 and —CN, —NHC(O)H, —NHC(O)R xa2 ,

where R xa2 is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, —CN, oxo, —OH, and —NH 2 ;

R 52a is selected from:

hydrogen, C 1-6 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

where R 56 and R 57 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-6 alkyl and C 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and NR 58 R 59 , where R 58 and R 59 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

oxo, —CN, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 59 and —NR 56 R 57 ,

oxo, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —OH; and

R 53a and R 54a are independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C 1-4 alkoxy, and —OH, or

R 53a and R 54a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

provided that:

R 51a and R 52a are not both hydrogen, and R 53a and R 54a are not both hydrogen;

›DETAILED DESCRIPTION OF THE INVENTION · 9 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Va) neither R 53a nor R 54a is hydrogen.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI):

wherein:

Y 6 is selected from: S and NH; R 60 is selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro and chloro, —N(H)C 1-3 alkyl, —N(C 1-3 alkyl) 2 , —SC 1-4 alkyl, C 1-3 alkyloxy, cycloalkyl, cycloalkyl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl;

R 61 is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 4 substituents independently selected from:

oxo, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, and —NH 2 , —NHC(O)H, and —NHC(O)R xa3 ,

where R xa3 is selected from C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro;

R 62 is selected from:

hydrogen, C 1-3 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

where R 66 and R 67 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 68 R 69 , where R 68 and R 69 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

—CN, —S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

hetroaryl, and hetroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

—S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ; and

R 63 and R 64 are independently selected from:

hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, heterocycloalkyl, oxo, —NH 2 , C 1-4 alkoxy, and —OH, heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl, or

R 63 and R 64 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

provided that:

R 61 and R 62 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VI) neither R 63 nor R 64 is hydrogen.

This invention relates to novel compounds of Formula (VIaar) and to the use of compounds of Formula (VIaar) in the methods of the invention:

wherein:

Y 6aar is selected from: S and NH; R 60aar is selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro and chloro, —N(H)C 1-3 alkyl, —N(C 1-3 alkyl) 2 , —SC 1-4 alkyl, C 1-3 alkyloxy, aryl, aryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

heteroaryl, heteroaryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

cycloalkyl, cycloalkyl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl;

R 61aar is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 4 substituents independently selected from:

oxo, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, and —NH 2 , —NHC(O)H, and —NHC(O)R xa3 ,

where R xa3 is selected from C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro;

R 62aar is selected from:

hydrogen, C 1-3 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

›DETAILED DESCRIPTION OF THE INVENTION · 10 of 41

—CN, —S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

hetroaryl, and hetroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

—S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ;

R 63aar and R 64aar are independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl, or

R 63aar and R 64aar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

provided that:

R 61aar and R 62aar are not both hydrogen, and R 63aar and R 64aar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIaar) neither R 63aar nor R 64aar is hydrogen.

Suitably in the compounds of Formula (VIaar) R 61aar is —C(O)NH 2 .

Suitably in the compounds of Formula (VIaar) R 62aar is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

This invention relates to novel compounds of Formula (VIa) and to the use of compounds of Formula (VIa) in the methods of the invention:

wherein:

Y 6a is selected from: S and NH; R 69a is selected from:

fluoro, chloro, —OH, and C 1-3 alkyl;

R 61a is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 4 substituents independently selected from:

oxo, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, and —NH 2 , —NHC(O)H, and —NHC(O)R xa3 ,

where R xa3 is selected from C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro;

R 62a is selected from:

hydrogen, C 1-3 alkyl, aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

—CN, —S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

hetroaryl, and hetroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 69 and —NR 66 R 67 ,

›DETAILED DESCRIPTION OF THE INVENTION · 11 of 41

—S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ;

R 63a and R 64a are independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl, or

R 63a and R 64a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, and —N(C 1-4 alkyl) 2 ;

provided that:

R 61a and R 62a are not both hydrogen, and R 63a and R 64a are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIa) neither R 63a nor R 64a is hydrogen.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VII):

wherein:

Y 7 is selected from: S and NH; R 70 is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, and cyclopropyl;

R 71 is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 77 is selected from:

hydrogen, C 1-3 alkyl, and aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 79 and —NR 76 R 77 ,

where R 76 and R 77 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 78 R 79 , where R 78 and R 79 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

—CN, S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 72 and R 73 are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 72 and R 73 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

pyrrolidinyl, piperidinyl, 1,4diazepanyl, piperazinyl, 2,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, hexahydro-1H-pyrrolo[1,2a][1,4]diazepinyl, morpholinyl, 1-oxa-6-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, azetidinyl, 1,8-diazaspiro[4.5]decanyl, and 5-oxa-2-azaspiro[3.4]octanyl, all of which are optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)CH 2 NH 2 , —NHC(O)CHCH 3 NH 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)aminotetrahydropyranyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —C(O)aminooxetanyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 71 and R 77 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VII) neither R 72 nor R 73 is hydrogen.

This invention relates to novel compounds of Formula (VIIaar) and to the use of compounds of Formula (VIIaar) in the methods of the invention:

wherein:

Y 7aar is selected from: S and NH; R 70aar is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, methoxy, phenyl, furanyl, and cyclopropyl;

R 71aar is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 77aar is selected from:

hydrogen, C 1-3 alkyl, and aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 79a and —NR 76a R 77a ,

where R 76a and R 77a are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 78a R 79a , where R 78a and R 79a are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

›DETAILED DESCRIPTION OF THE INVENTION · 12 of 41

—CN, S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 72aar and R 73aar are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 72aar and R 73aar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)CH 2 NH 2 , —NHC(O)CHCH 3 NH 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)aminotetrahydropyranyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —C(O)aminooxetanyl, —C(O)aminotetrahydropyranyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 72aar and R 73aar are not both hydrogen, and R 71aar and R 77aar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIaar) neither R 72aar nor R 73aar is hydrogen.

Suitably in the compounds of Formula (VIIaar) R 71aar is —C(O)NH 2 .

Suitably in the compounds of Formula (VIIaar) R 77aar is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 79a and —NR 76a R 77a ,

This invention relates to novel compounds of Formula (VIIa) and to the use of compounds of Formula (VIIa) in the methods of the invention:

wherein:

Y 7a is selected from: S and NH; R 70a is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, and cyclopropyl;

R 71a is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 77a is selected from:

hydrogen, C 1-3 alkyl, and aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 79a and —NR 76a R 77a ,

—CN, S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 72a and R 73a are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 72a and R 73a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

pyrrolidinyl, piperidinyl, 1,4diazepanyl, piperazinyl 2,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, hexahydro-1H-pyrrolo[1,2a][1,4]diazepinyl, morpholinyl, 1-oxa-6-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, azetidinyl, 1,8-diazaspiro[4.5]decanyl, and 5-oxa-2-azaspiro[3.4]octanyl, all of which are optionally substituted with from 1 to 5 substituents independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 13 of 41

provided that:

R 72a and R 73a are not both hydrogen, and R 71a and R 77a are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIa) neither R 72a nor R 73a is hydrogen.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VIII):

wherein:

Y 8 is selected from: S and NH; R 80 is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, and cyclopropyl;

R 81 is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 87 is selected from:

hydrogen, CH 3 , phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 89 and —NR 86 R 87 ,

where R 86 and R 87 are independently selected from: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 88 R 89 , where R 88 and R 89 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

—CN, S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 82 and R 83 are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 82 and R 83 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

provided that:

R 81 and R 87 are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIII) neither R 82a nor R 83a is hydrogen.

This invention relates to novel compounds of Formula (VIIIaar) and to the use of compounds of Formula (VIIIaar) in the methods of the invention:

wherein:

Y 8aar is selected from: S and NH; R 80aar is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, methoxy, phenyl, furanyl, and cyclopropyl;

R 81aar is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 87aar is selected from:

hydrogen, CH 3 , phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 89 and —NR 86 R 87 ,

—CN, —S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 82aar and R 83aar are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 82aar and R 83aar are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 NH 2 , —OCH 2 CH 2 OH, —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)CH 2 NH 2 , —NHC(O)CHCH 3 NH 2 , —NHC(O)—CNH 2 (CH 3 ) 2 , —NHC(O)aminotetrahydropyranyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —C(O)aminooxetanyl, —C(O)aminotetrahydropyranyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 14 of 41

provided that:

R 81aar and R 87aar are not both hydrogen, and R 82aar and R 83aar are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIIaar) neither R 82aar nor R 83aar is hydrogen.

Suitably in the compounds of Formula (VIIIaar) R 81aar is —C(O)NH 2 .

Suitably in the compounds of Formula (VIIIaar) R 87aar is phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 89 and —NR 86 R 87 ,

This invention relates to novel compounds of Formula (Villa) and to the use of compounds of Formula (Villa) in the methods of the invention:

wherein:

Y 8a is selected from: S and NH; R 80a is selected from:

ethyl, —CH 2 CF 3 , —NCH 3 , —SCH 3 , ethoxy, and cyclopropyl;

R 81a is selected from:

hydrogen, —C(O)NH 2 , heterocycloalkyl, and heterocycloalkyl substituted by oxo, —C(O)CH 3 or —NHC(O)CH 3 ;

R 87a is selected from:

hydrogen, CH 3 , phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 89 and —NR 86 R 87 ,

—CN, —S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ,

pyridinyl, thiazolyl, and thiazolyl substituted by —C(O)CH 3 or —NHC(O)CH 3 ;

R 82a and R 83a are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: —OH, oxo, —NH 2 , morpholino and methoxy, 5-oxa-2azaspiro[3.4]octanyl, and 8-azabicyclo[3.2.1]octanyl, or R 82a and R 83a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

provided that:

R 81a and R 87a are not both hydrogen, and R 82a and R 83a are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIIa) neither R 82a nor R 83a is hydrogen.

This invention relates to novel compounds of Formula (Q) and to the use of compounds of Formula (Q) in the methods of the invention:

wherein:

Y 7a′ is selected from: S and NH; R 70a′ is selected from:

ethyl, —CH 2 CF 3 , and cyclopropyl;

R 71a′ is selected from:

hydrogen, CH 3 , phenyl, phenyl substituted with chloro, and pyridine,

R 77a′ is selected from:

—C(O)NH 2 , and aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 79a′ and —NR 76a′ R 77a′ ,

where R 76a′ and R 77a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 78a′ R 79a′ , where R 78a′ and R 79a′ are independently selected form: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

S(O) 2 NH 2 , —S(O) 2 NHCH 3 , and

R 72a′ and R 73a′ are independently selected from:

hydrogen, C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: morpholino and methoxy, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or R 72a′ and R 73a′ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 15 of 41

pyrrolidinyl, piperidinyl, 1,4diazepan piperazinyl, 2,9-diazaspiro[5.5]undecan, 2,8-diazaspiro[4.5]decan, octahydro-1H-pyrrolo[1,2a][1,4]diazepin, morpholin, 1-oxa-6-azaspiro[3.4]octan, 1,7-diazaspiro[3.5]nonan, 2,7-diazaspiro[3.5]nonan, 2,6-diazaspiro[3.4]octan, azetidin, 1,8-diazaspiro[4.5]decan, and 5-oxa-2-azaspiro[3.4]octan, all of which are optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 72a′ and R 73a′ are not both hydrogen;

or a pharmaceutically acceptable salts thereof.

Suitably in the compounds of Formula (Q) neither R 72a′ nor R 73a′ is hydrogen.

This invention relates to novel compounds of Formula (T) and to the use of compounds of Formula (T) in the methods of the invention:

wherein:

R 80 is selected from:

ethyl, —CH 2 CF 3 , and cyclopropyl;

R 81 is selected from:

phenyl, and phenyl substituted with chloro or fluoro, and

R 72a′ and R 73a′ are independently selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: oxo, and NH 2 , or R 72a′ and R 73a′ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

pyrrolidinyl, piperidinyl, 1,4diazepan, piperazinyl, 2,9-diazaspiro[5.5]undecan, 2,8-diazaspiro[4.5]decan, octahydro-1H-pyrrolo[1,2a][1,4]diazepin, morpholin, 1-oxa-6-azaspiro[3.4]octan, 1,7-diazaspiro[3.5]nonan, 2,7-diazaspiro[3.5]nonan, 2,6-diazaspiro[3.4]octan, azetidin, 1,8-diazaspiro[4.5]decan, and 5-oxa-2-azaspiro[3.4]octan, all of which are optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 C(CH 3 ) 3 , —N(CH 3 )cyclobutane, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (T), the compounds are in the form of a phosphate prodrug.

This invention relates to novel compounds of Formula (Ta) and to the use of compounds of Formula (Ta) in the methods of the invention:

wherein:

R 80a is selected from:

ethyl, —CH 2 CF 3 , and cyclopropyl;

R 81a is selected from:

phenyl, and phenyl substituted with chloro or fluoro, and

R 82a and R 83a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 C(CH 3 ) 3 , —N(CH 3 )cyclobutane, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Ta), the compounds are in the form of a phosphate prodrug.

This invention relates to novel compounds of Formula (S) and to the use of compounds of Formula (S) in the methods of the invention:

wherein:

R 90 is selected from:

ethyl, —CH 2 CF 3 , and cyclopropyl;

R 91 is selected from:

phenyl, and phenyl substituted with from 1 to 2 substituents independently selected from:

fluoro, chloro, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a′ and —NR 76a′ R 77a′ ,

wherein R 76a′ and R 77a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 78a′ R 79a′ , where R 78a′ and R 79a′ are independently selected form: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

›DETAILED DESCRIPTION OF THE INVENTION · 16 of 41

R 92 and R 93 are independently selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: oxo, —N(CH 2 CH 3 ) 3 , —CH 2 CH 2 piperidinyl, and NH 2 , or R 92 and R 93 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, oxo, —OH, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 C(O)OCH 3 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH(CH 3 ) 2 , —NHC(O)CH(CH 3 )(NH 2 ), —NHC(O)C(CH 3 ) 3 , —N(CH 3 )cyclobutane, —CH 2 NH 2 , —CH 2 pyrrolidinyl, —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, piperidinyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, pyrrolidinyl, pyrrolidinylmethyl, piperazinylmethyl, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (S), the compounds are in the form of a phosphate prodrug.

This invention relates to novel compounds of Formula (Sa) and to the use of compounds of Formula (Sa) in the methods of the invention:

wherein:

R 90a is selected from:

ethyl, —CH 2 CF 3 , and cyclopropyl;

R 91a is selected from:

phenyl, and phenyl substituted with from 1 to 2 substituents independently selected from:

fluoro, chloro, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH b )2, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a′ and —NR 76a′ R 77a′ ,

R 92a and R 93a are independently selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 3 substituents independently selected from: oxo, —N(CH 2 CH 3 ) 3 , —CH 2 CH 2 piperidinyl, and NH 2 , or R 92a and R 93a are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Sa), the compounds are in the form of a phosphate prodrug.

Primary Amide

This invention relates to compounds of Formula (Ibr) and to the use of compounds of Formula (Ibr) in the methods of the invention:

wherein:

X 1br and X 2br are independently selected from:

hydrogen, —CN, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , —SH, and —SR a ;

Y br is selected from: S, NH, NR z , O, S(O), and S(O) 2 ;

R 1br is selected from:

—NH 2 , —NHR a , —NR b R c , —CN, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

R 3br is selected from:

hydrogen, C 1-6 alkyl, R e , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ; and

›DETAILED DESCRIPTION OF THE INVENTION · 17 of 41

R 5br is selected from:

—NH 2 , —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —C 1-6 alkyl, —OC 1-6 alkyl, —OR e , —Oaryl, —Oaryl substituted from 1 to 4 times by R d , —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

where:

each R a is independently selected from

provided that:

X 1br and X 2br are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Ibr) R 3br is aryl optionally substituted from 1 to 4 times by R d .

Suitably in the compounds of Formula (Ibr) neither X 1br nor X 2br are hydrogen.

Suitably in the compounds of Formula (Ibr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Ibr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IIbr):

wherein:

X 21br and X 22br are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, heterocycloalkyl, and —SH;

Y 1br is selected from: S, NH, and NR z ; R 21br is selected from:

amino, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —NHR a , —NR b R c , cycloalkyl, cycloalkyl substituted with from 1 to 4 times by R d , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, —OR e , heteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

R 23br is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, heterocycloalkyl, aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ; and

R 25br is selected from:

amino, —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —OC 1-6 alkyl, —OR e , —Oaryl, —Oheteroaryl, —SH, and —SR a ;

where:

each R a is independently selected from

provided that:

X 21br and X 22br are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IIbr) R 23br is aryl optionally substituted from 1 to 4 times by R d .

Suitably in the compounds of Formula (IIbr) neither X 21br nor X 22br are hydrogen.

Suitably in the compounds of Formula (IIbr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (IIbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IIIbr):

wherein:

X 31br and X 32br are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, cycloalkyl, and —SH;

Y 2br is selected from: S, NH, and NR z ; R 31br is selected from:

C 1-6 alkyl, R e1 , —OC 1-6 alkyl, —OR e1 , —NHR a1 , —NR b1 R c1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d1 , aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, heteroaryl substituted from 1 to 4 times by R d1 , —SH, and —SR a1 ;

R 33br is selected from:

C 1-6 alkyl, heterocycloalkyl, aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, and heteroaryl substituted from 1 to 4 times by Rd 1 ; and

R 35br is selected from:

amino, —NHR a1 , —NR b1 R c1 , aryl, aryl substituted from 1 to 4 times by R d1 , —OC 1-6 alkyl, —OR e1 , —SH, and —SR a1 ;

where:

each R a1 is independently selected from

C 1-6 alkyl, R e1 , aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;

R b1 and R c1 are independently selected from:

C 1-6 alkyl, R e1 , —OR e1 , aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, heteroaryl substituted from 1 to 4 times by R d1 ; cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 , or R b1 and R c1 are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e1 , aryl, aryl substituted from 1 to 4 times by R d1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 , C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)R e1 , —N(C 1-4 alkyl) 2 , —ONHC(NH)NH 2 , —Oheterocycloalkyl, —NHcycloalkyl, —NHheterocycloalkyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —SO 2 NH 2 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropyl methyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

each R d1 is independently selected from:

fluoro,

provided that:

X 31br and X 32br are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IIIbr), neither X 31br nor X 32br are hydrogen.

Suitably in the compounds of Formula (IIIbr) R 33br is aryl optionally substituted from 1 to 4 times by R d1 .

Suitably in the compounds of Formula (IIIbr), the compounds are in the form of a phosphate prodrug.

›DETAILED DESCRIPTION OF THE INVENTION · 18 of 41

Suitably in the compounds of Formula (IIIbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (IVbbr) and to the use of compounds of Formula (IVbbr) in the methods of the invention:

wherein:

X 41bbr and X 42bbr are independently selected from: —CN, methyl, fluoro, chloro, bromo and iodo; Y 4bbr is selected from: S and NH; R 41bbr is selected from:

heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from:

cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 43bbr is selected from:

C 1-4 alkyl, phenyl, phenyl substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , chloro, —C(O)phenyl, pyrrolidinyl, —P(O)(CH 3 ) 2 , —C(O)NH 2 , —S(O) 2 NHCH 3 , —OCH 2 CH 2 N(CH 3 ) 2 and CH 2 C(O)NH 2 , thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , and —OCH 3 ;

R 44bbr and R 45bbr are independently selected from:

hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, pyrrolidinyl, —OC(O)NH 2 , —OCH 2 CH 2 NH 2 , —ONHC(NH 2 )NH 2 , —NHCH 2 C(CH 3 ) 3 , —NOCH 3 , —NHOH, —NHCH 2 CH 2 F, —N(CH 3 )CH 2 CH 2 OCH 3 , —N(CH 2 CH 3 ) 2 , —NCH(CH 2 OH) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —N(CH 3 )C(CH 3 ) 2 CH 2 OH, —NHCH 2 CH 3 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 )CH 2 CH 2 OH, —NHC(O)C(O)NH 2 , —N(CH 3 )CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH(OH)CH 2 OH, —N(CH 3 )CH 2 CH 2 NH 2 , oxo, —NHCH 2 C(CH 3 ) 2 CH 2 OH, —OH, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 CH 2 OH, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHOC(CH 3 ) 2 NH 2 , —N(CH 3 )CH 2 cyclopropyl, —NHCH 2 cyclopropyl, —NHoxetanyl, —NCH 2 CH 2 triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino,

where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, —NH 2 , —N(CH 3 ) 2 , hydroxymethyl, oxo, —OH, and CH 2 NH 2 ,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

R 44bbr and R 45bbr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl-, —OH, —NH 2 , —N(H)C 1-5 alkyl, aminoheterocycloalkyl-, —N(C 1-5 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —OP(O)(OH) 2 , —COOH, —CONH 2 , —NO 2 , —NH 2 , —N(H)C 1-5 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl-, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-5 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —SO 2 NH 2 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, (methyloxetanmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 19 of 41

provided that:

X 41bbr and X 42bbr are not both hydrogen, and R 44bbr and R 45bbr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IVbbr) neither R 44bbr nor R 45bbr is hydrogen.

Suitably in the compounds of Formula (IVbbr) R 43br is phenyl.

Suitably in the compounds of Formula (IVbbr) neither X 41bbr nor X 42bbr are hydrogen.

Suitably in the compounds of Formula (IVbbr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (IVbbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (Vbbr) and to the use of compounds of Formula (Vbbr) in the methods of the invention:

wherein:

Y 5bbr is selected from: S and NH; R 50bbr is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, C 1-4 alkyloxy, aryl, alkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

heteroaryl, heteroalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

R 51bbr is selected from:

—CH 3 , phenyl, phenyl substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , chloro, —C(O)phenyl, pyrrolidinyl, —C(O)NH 2 , —S(O) 2 NHCH 3 , —OCH 2 CH 2 N(CH 3 ) 2 and —CH 2 C(O)NH 2 , thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , and —OCH 3 ;

R 53bbr and R 54bbr are independently selected from:

hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, —CH 2 CH 2 pyrrolidinyl, —OC(O)NH 2 , —OCH 2 CH 2 NH 2 , —ONHC(NH 2 )NH 2 , —NHCH 2 C(CH 3 ) 3 , —NOCH 3 , —NHOH, —NHCH 2 CH 2 F, —N(CH 3 )CH 2 CH 2 OCH 3 , —N(CH 2 CH 3 ) 2 , —NCH(CH 2 OH) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —N(CH 3 )CH 2 (CH 3 ) 2 CH 2 OH, —NHCH 2 CH 3 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 )CH 2 CH 2 OH, —NHC(O)C(O)NH 2 , —N(CH 3 )CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH(OH)CH 2 OH, —N(CH 3 )CH 2 CH 2 NH 2 , oxo, —NHCH 2 C(CH 3 ) 2 CH 2 OH, —OH, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 CH 2 OH, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHOC(CH 3 ) 2 NH 2 , —N(CH 3 )CH 2 cyclopropyl, —NHCH 2 cyclopropyl, —NHoxetanyl, —NCH 2 CH 2 triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino,

where said phenyl, morpholino, triazolyl, imidazolyl, azepinyl, azetidinyl, pyrrolidinyl piperazinyl, piperidinyl, oxetanyl, cyclopropyl, and pyrazolyl are optionally substituted with from 1 to 4 substituents independently selected from: methyl, fluoro, —NH 2 , —N(CH 3 ) 2 , hydroxymethyl, oxo, —OH, and —CH 2 NH 2 ,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C 1-4 alkoxy, and —OH, or

R 53bbr and R 54bbr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-5 alkyl, aminoheterocycloalkyl, —N(C 1-5 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents Independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —OP(O)(OH) 2 , —COOH, —CONH 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-4 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyll pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 20 of 41

provided that:

R 53bbr and R 54bbr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Vbbr) neither R 53bbr nor R 54bbr is hydrogen.

Suitably in the compounds of Formula (Vbbr) R 51bbr is phenyl.

Suitably in the compounds of Formula (Vbbr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Vbbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (VIbbr) and to the use of compounds of Formula (VIbbr) in the methods of the invention:

wherein:

R 60bbr is selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro and chloro, —N(H)C 1-3 alkyl, —N(C 1-3 alkyl) 2 , —SC 1-4 alkyl, C 1-3 alkyloxy, aryl, aryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

heteroaryl, heteroaryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

cycloalkyl, cycloalkyl substituted with from one to three substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl;

R 61bbr is selected from:

R 63bbr and R 64bbr are independently selected from:

hydrogen, C 1-4 alkyl, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, —CH 2 CH 2 pyrrolidinyl, —OC(O)NH 2 , —OCH 2 CH 2 NH 2 , —ONHC(NH 2 )NH 2 , —NHCH 2 C(CH 3 ) 3 , —NOCH 3 , —NHOH, —NHCH 2 CH 2 F, —N(CH 3 )CH 2 CH 2 OCH 3 , —N(CH 2 CH 3 ) 2 , —NCH(CH 2 OH) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —N(CH 3 )CH 2 (CH 3 ) 2 CH 2 OH, —NHCH 2 CH 3 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 )CH 2 CH 2 OH, —NHC(O)C(O)NH 2 , —N(CH 3 )CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH(OH)CH 2 OH, —N(CH 3 )CH 2 CH 2 NH 2 , oxo, —NHCH 2 C(CH 3 ) 2 CH 2 OH, —OH, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 CH 2 OH, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHOC(CH 3 ) 2 NH 2 , —N(CH 3 )CH 2 cyclopropyl, —NHCH 2 cyclopropyl, —NHoxetanyl, —NCH 2 CH 2 triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino,

cycloalkyl, cycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl,

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl, or

R 63bbr and R 64bbr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, —OP(O)(OH) 2 , —CN, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-5 alkyl, aminoheterocycloalkyl, —N(C 1-5 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, —NH 2 , —N(H)C 1-6 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —ONHC(NH)NH 2 , —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-4 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 63bbr and R 64bbr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIbbr) neither R 63bbr nor R 64bbr is hydrogen.

Suitably in the compounds of Formula (VIbbr) R 61bbr is phenyl.

Suitably in the compounds of Formula (VIbbr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (VIbbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (VIIbbr) and to the use of compounds of Formula (VIIbbr) in the methods of the invention:

wherein:

R 70bbr is selected from:

ethyl, ethyl substituted from 1 to 4 times by fluoro, —NCH 3 , —SCH 3 , ethoxy, methoxy, propoxy, phenyl, furanyl, cyclopropyl, and cyclopropyl substituted once or twice by fluoro;

›DETAILED DESCRIPTION OF THE INVENTION · 21 of 41

R 71bbr is selected from:

phenyl, phenyl substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , chloro, —C(O)phenyl, pyrrolidinyl, —C(O)NH 2 , —S(O) 2 NHCH 3 , —OCH 2 CH 2 N(CH 3 ) 2 and CH 2 C(O)NH 2 , thienyl, piperidinyl, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , and —OCH 3 ; and

R 72bbr and R 73bbr are independently selected from:

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or

R 72bbr and R 73bbr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

pyrrolidinyl, pyrrolo[3,4-c]pyrazolyl, piperidinyl, 1,4diazepanyl, piperazinyl, 6,7-dihydro-triazolo[4,5-c]pyridinyl, 2,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, octahydro-1H-pyrrolo[1,2a][1,4]diazepinyl, oxa-diazaspiro[4.5]decanyl, oxazolyl, morpholinyl, 1-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, azetidinyl, hexahydropyrrolo[3,4-b]oxazinyl, dihydronaphthyridinyl, diazabicycloheptanyl, 1,8-diazaspiro[4.5]decanyl, and 5-oxa-2-azaspiro[3.4]octanyl, all of which are optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, oxo, —OH, —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 72bbr and R 73bbr are not both hydrogen,

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIbbr) neither R 72bbr nor R 73bbr is hydrogen.

Suitably in the compounds of Formula (VIIbbr) R 71bbr is phenyl.

Suitably in the compounds of Formula (VIIbbr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (VIIbbr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (Qb) and to the use of compounds of Formula (Qb) in the methods of the invention:

wherein:

R 70a″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 71a″ is selected from:

phenyl, phenyl substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , and chloro, pyridine, and pyridine substituted with 1 or 2 substituents independently selected from: fluoro, —CH 3 , —CF 3 , and —OCH 3 ; and

R 72a″ and R 73a″ are independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 22 of 41

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or

R 72a″ and R 73a″ are taken together with the nitrogen to which they are

attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —OP(O)(OH) 2 , —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 72a″ and R 73a″ are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qb) neither R 72a″ nor R 73a″ is hydrogen.

Suitably in the compounds of Formula (Qb) R 71a″ is phenyl.

Suitably in the compounds of Formula (Qb), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qb), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (Qb1) and to the use of compounds of Formula (Qb1) in the methods of the invention:

wherein:

R 70b″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 71b″ is selected from:

R 72b″ and R 73b″ are independently selected from:

C 1-4 alkyl, C 1-4 alkyl substituted with from 1 to 4 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, —CH 2 CH 2 pyrrolidinyl, —OC(O)NH 2 , —OCH 2 CH 2 NH 2 , —ONHC(NH 2 )NH 2 , —NHCH 2 C(CH 3 ) 3 , —NOCH 3 , —NHOH, —NHCH 2 CH 2 F, —N(CH 3 )CH 2 CH 2 OCH 3 , —N(CH 2 CH 3 ) 2 , —NCH(CH 2 OH) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —N(CH 3 )CH 2 (CH 3 ) 2 CH 2 OH, —NHCH 2 CH 3 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 )CH 2 CH 2 OH, —NHC(O)C(O)NH 2 , —N(CH 3 )CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH(OH)CH 2 OH, —N(CH 3 )CH 2 CH 2 NH 2 , oxo, —NHCH 2 C(CH 3 ) 2 CH 2 OH, —OH, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 CH 2 OH, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHOC(CH 3 ) 2 NH 2 , —N(CH 3 )CH 2 cyclopropyl, —NHCH 2 cyclopropyl, —NHoxetanyl, —NCH 2 CH 2 triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino,

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or

R 72b″ and R 73b″ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 23 of 41

fluoro, chloro, oxo, —OH, —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 72b″ and R 73b″ are not both unsubstituted alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qb1) R 71b″ is phenyl.

Suitably in the compounds of Formula (Qb1), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qb1), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (Qb2) and to the use of compounds of Formula (Qb2) in the methods of the invention:

wherein:

R 70c″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 71c″ is selected from:

R 72c″ and R 73c″ are are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 24 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qb2) R 71c″ is phenyl.

Suitably in the compounds of Formula (Qb2), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qb2), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Non Primary Amide:

This invention relates to compounds of Formula (Icr) and to the use of compounds of Formula (Icr) in the methods of the invention:

wherein:

X 1cr and X 2cr are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycle, heterocycle substituted from 1 to 4 times by R d , —SH, and —SR a ;

Y cr is selected from: S, NH, NR z , O, S(O) and S(O) 2 ; R 1cr is selected from:

amino, —NHR a , —NR b R c , cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycle, heterocycle substituted from 1 to 4 times by R d , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

R 2cr is selected from:

hydrogen, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: halogen, —OH, —COOH;

R 3cr is selected from:

aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ;

R 4cr is selected from:

hydrogen, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: halogen, —OH, —COOH;

R 5cr is selected from:

amino, —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —C 1-6 alkyl, —OC 1-6 alkyl, —OR e , —Oaryl, —Oaryl substituted from 1 to 4 times by R d , —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R d , —SH, and —SR a ;

where:

each R a is independently selected from

provided that:

X 1cr and X 2cr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Icr) neither X 1cr nor X 2cr are hydrogen.

Suitably in the compounds of Formula (Icr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Icr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IIcr):

wherein:

X 21cr and X 22cr are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , cycloalkyl, heterocycle, and —SH;

Y 1cr is selected from: S, NH, and NR z ; R 21cr is selected from:

amino, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e , —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d , cycloalkyl, cycloalkyl substituted with from 1 to 4 times by R d , heterocycle, heterocycle substituted with from 1 to 4 times by R d , —SH, and —SR a ;

R 22cr is selected from:

hydrogen, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, and bromo;

R 23cr is selected from:

aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d ;

R 24cr is selected from:

hydrogen, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, chloro, and bromo;

R 25cr is selected from:

amino, —NHR a , —NR b R c , aryl, aryl substituted from 1 to 4 times by R d , —OC 1-6 alkyl, —Oaryl, —Oheteroaryl, —SH, and —SR a ;

where:

each R a is independently selected from

provided that: X 21cr and X 22cr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IIcr) neither X 21cr nor X 22cr are hydrogen.

Suitably in the compounds of Formula (IIcr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (IIcr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IIIcr):

wherein:

X 31cr and X 32cr are independently selected from:

hydrogen, cyano, fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, cycloalkyl, and —SH;

Y 2cr is selected from: S, NH, and NR z ; R 31cr is selected from:

C 1-6 alkyl, R e , —OC 1-6 alkyl, —OR e1 , —NHR a1 , —NR b1 R c1 , aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, heteroaryl substituted from 1 to 4 times by R d1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R d1 , —SH, and —SR a1 ;

R 32cr is selected from:

hydrogen, C 1-3 alkyl, and C 1-3 alkyl substituted from 1 to 4 times by fluoro;

R 33cr is selected from:

aryl, aryl substituted from 1 to 4 times by R d1 , heteroaryl, and heteroaryl substituted from 1 to 4 times by R d1 ;

R 34cr is selected from:

hydrogen, C 1-3 alkyl, and C 1-3 alkyl substituted from 1 to 4 times by fluoro;

R 35cr is selected from:

amino, —NHR a1 , —NR b1 R c1 , aryl, aryl substituted from 1 to 4 times by R d1 , —OC 1-6 alkyl, —OR e1 , —SH, and —SR a1 ;

where:

each R a1 is independently selected from

provided that:

X 31cr and X 32cr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IIIcr), neither X 31cr nor X 32cr are hydrogen.

Suitably in the compounds of Formula (IIIcr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (IIIcr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (IVccr) and to the use of compounds of Formula (IVccr) in the methods of the invention:

wherein:

X 41ccr and X 42ccr are independently selected from: —CN, methyl, fluoro, chloro, bromo and

›DETAILED DESCRIPTION OF THE INVENTION · 25 of 41

iodo;

Y 4ccr is selected from: S and NH; R 41ccr is selected from:

heteroaryl, heteroaryl substituted with from 1 to 4 substituents independently selected from:

cycloalkyl, cycloalkyl substituted with from 1 to 4 substituents independently selected from:

R 43ccr is selected from:

aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 C 1-4 alkyl, —CN, —OR 49 and —NR 46 R 47 ,

where R 46 and R 47 are independently selected from: hydrogen, —S(O) 2 CH 3 , pyrazole, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 48 R 49 , where R 48 and R 49 are independently selected from: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

—CN, oxo, —OH, heterocycloalkyl, heterocycloalkyl independently substituted once or twice with a substituent selected from: fluoro and oxo, —N(CH 3 )S(O) 2 CFH 2 , —N(CH 3 )S(O) 2 CF 2 H, —N(CH 3 )S(O) 2 CF 3 , —OS(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NR 80a′ R 81a′ where R 80a′ and R 81a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, boronic acid, —NO 2 , and —NH 2 ,

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —CN, —OR 49 and —NR 46 R 47 ,

C 1-4 alkoxy, —CN, oxo, —OH, —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NO 2 , and —NH 2 ; and

R 44ccr and R 45ccr are independently selected from: hydrogen, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: phenyl, morpholino, triazolyl, imidazolyl, pyrrolidinyl, —OC(O)NH 2 , —OCH 2 CH 2 NH 2 , —ONHC(NH 2 )NH 2 , —NHCH 2 C(CH 3 ) 3 , —NOCH 3 , —NHOH, —NHCH 2 CH 2 F, —N(CH 3 )CH 2 CH 2 OCH 3 , —N(CH 2 CH 3 ) 2 , —NCH(CH 2 OH) 2 , —N(CH 2 CH 2 OH) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —N(CH 3 )C(CH 3 ) 2 CH 2 OH, —NHCH 2 CH 3 , —NHCH 2 CH 2 OCH 3 , —N(CH 3 )CH 2 CH 2 OH, —NHC(O)C(O)NH 2 , —N(CH 3 )CH 2 CH 2 CH 2 OH, —N(CH 3 )CH 2 CH(OH)CH 2 OH, —N(CH 3 )CH 2 CH 2 NH 2 , oxo, —NHCH 2 C(CH 3 ) 2 CH 2 OH, —OH, —NH 2 , —NHCH 3 , —NHCH 2 CH 2 CH 2 OH, —N(CH 3 ) 2 , —N(CH 3 )CH 2 CH 3 , —NHOC(CH 3 ) 2 NH 2 , —N(CH 3 )CH 2 cyclopropyl, —NHCH 2 cyclopropyl, —NHoxetanyl, —NCH 2 CH 2 triazole, piperazinyl, piperidinyl, pyrazolyl, azepinyl, azetidinyl, methoxy, and cyclopropylamino,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

R 44ccr and R 45ccr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 26 of 41

fluoro, chloro, bromo, iodo, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl-, —OH, —NH 2 , —N(H)C 1-5 alkyl, aminoheterocycloalkyl-, —N(C 1-5 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, aryl, cycloalkyl, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, bromo, iodo, oxo, —OH, —NH 2 and —CN, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —OP(O)(OH) 2 , —COOH, —NO 2 , —NH 2 , —N(H)C 1-5 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-5 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —SO 2 NH 2 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinlymethyl, oxazolidinyl, (methyloxetanmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that: R 44ccr and R 45ccr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (IVccr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (IVccr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Suitably in the compounds of Formula (IVccr) neither R 44ccr nor R 45ccr is hydrogen.

Suitably in the compounds of Formula (IVccr) R 43ccr is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, bromo, iodo, heterocycloalkyl, heterocycloalkyl independently substituted once or twice a substituent selected from: fluoro and oxo, —OS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 C 1-4 alkyl, —CN, —OR 49 and —NR 46 R 47 ,

This invention relates to novel compounds of Formula (Vccr) and to the use of compounds of Formula (Vccr) in the methods of the invention:

wherein:

Y 5ccr is selected from: S and NH; R 50ccr is selected from:

C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , —SC 1-4 alkyl, C 1-4 alkyloxy, aryl, aryl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

heteroaryl, heteroaryl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro,

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

R 52ccr is selected from:

aryl, aryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 59 and —NR 56 R 57 ,

oxo, —CN, tetrahydroisothiazolyl, tetrahydroisothiazolyl substituted twice by oxo, tetrahydro-1,2-thiazinyl, tetrahydro-1,2-thiazinyl substituted twice by oxo, —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )S(O) 2 CFH 2 , —N(CH 3 )S(O) 2 CF 2 H, —N(CH 3 )S(O) 2 CF 3 , —OS(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —NR 80a′ R 81a′ where R 80a′ and R 81a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, and —OH;

›DETAILED DESCRIPTION OF THE INVENTION · 27 of 41

heteroaryl, and heteroaryl substituted with from 1 to 4 substituents independently selected from:

R 53ccr and R 54ccr are independently selected from:

cycloalkyl, cycloalkyl substituted with from one to five substituents independently selected from:

fluoro, chloro, —OH, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro;

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, C 1-4 alkoxy, and —OH, or

R 53ccr and R 54ccr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-5 alkyl, aminoheterocycloalkyl, —N(C 1-5 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, —C 1-6 alkylNH 2 , chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —OP(O)(OH) 2 , —COOH, —CONH 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-4 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinlyl pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

provided that:

R 53ccr and R 54ccr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Vccr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Vccr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Suitably in the compounds of Formula (Vccr) neither R 53ccr nor R 54ccr is hydrogen.

Suitably in the compounds of Formula (Vccr) R 52ccr is aryl substituted with from 1 to 4 substituents independently selected from:

fluoro,

chloro, tetrahydrothiazolyl, tetrahydrothiazolyl substituted twice by oxo, tetrahydrothiazinyl, tetrahydrothiazinyl substituted twice by oxo, —N(CH 3 )S(O) 2 CH 3 , —OS(O) 2 CH 3 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 59 and —NR 56 R 57 ,

›DETAILED DESCRIPTION OF THE INVENTION · 28 of 41

This invention relates to novel compounds of Formula (VIccr) and to the use of compounds of Formula (VIccr) in the methods of the invention:

wherein:

Y 6ccr is selected from: S and NH; R 60ccr is selected from:

C 1-3 alkyl, C 1-3 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro and chloro, —N(H)C 1-3 alkyl, —N(C 1-3 alkyl) 2 , —SC 1-4 alkyl, C 1-3 alkyloxy, aryl, aryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

heteroaryl, heteroaryl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl,

cycloalkyl, cycloalkyl substituted with from one to 3 substituents independently selected from:

fluoro, chloro, —OH, and C 1-3 alkyl;

R 62ccr is selected from:

phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 69 and —NR 66 R 67 ,

tetrahydroisothiazolyl, tetrahydroisothiazolyl substituted twice by oxo, tetrahydro-1,2-thiazinyl, tetrahydro-1,2-thiazinyl substituted twice by oxo, —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )S(O) 2 CFH 2 , —N(CH 3 )S(O) 2 CF 2 H, —N(CH 3 )S(O) 2 CF 3 , —OS(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , and —NR 80a′ R 81a′ where R 80a′ and R 81a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

hetroaryl, and hetroaryl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 69 and —NR 66 R 67 ,

—S(O) 2 NH 2 , and —S(O) 2 NHCH 3 ; and

R 63ccr and R 64ccr are independently selected from:

cycloalkyl, cycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl,

heterocycloalkyl, and heterocycloalkyl substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, and C 1-6 alkyl, or

R 63ccr and R 64ccr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, —OH, —OP(O)(OH) 2 , —CN, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-6 alkyl, aminoheterocycloalkyl, —N(C 1-6 alkyl) 2 , —CN, —N(C 1-4 alkyl)(CH 2 OCH 3 ), and —NHC 1-4 alkyl substituted by one or two substituents independently selected from oxo, NH 2 , and —OH, heterocycloalkyl, heterocycloalkyl substituted with from 1 to 9 substituents independently selected from: C 1-6 alkyl, —C 1-6 alkylOH, fluoro, chloro, oxo and —OH, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, —NH 2 , —N(H)C 1-4 alkyl, —N(H)C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro, chloro, C 1-4 alkoxy, oxo, phenyl, cycloalkyl, aminoC 1-4 alkoxy, heterocycloalkyl, methylheterocycloalkyl, —OH, —NH 2 , —N(H)C 1-4 alkyl, —N(C 1-4 alkyl) 2 , and —CN, —ONHC(NH)NH 2 , —Ooxetanyl, —ONHC(NH)NH 2 , —NHcyclopropyl, —NHoxetanyl, —N(C 1-4 alkyl) 2 , —S(O) 2 CH 2 CH 3 , S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 phenyl, benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 29 of 41

provided that:

R 63ccr and R 64ccr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIccr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (VIccr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Suitably in the compounds of Formula (VIccr) neither R 63ccr nor R 64ccr is hydrogen.

Suitably in the compounds of Formula (VIccr) R 62ccr is phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, tetrahydroisothiazolyl, tetrahydroisothiazolyl substituted twice by oxo, tetrahydro-1,2-thiazinyl, tetrahydro-1,2-thiazinyl substituted twice by oxo, —N(CH 3 )S(O) 2 CH 3 , —OS(O) 2 CH 3 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 5 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 69 and —NR 66 R 67 ,

This invention relates to novel compounds of Formula (VIIccr) and to the use of compounds of Formula (VIIccr) in the methods of the invention:

wherein:

R 70ccr is selected from:

ethyl, ethyl substituted from 1 to 4 times by fluoro, —NCH 3 , —SCH 3 , ethoxy, methoxy, phenyl, furanyl, cyclopropyl, cyclopropyl substituted once or twice by fluoro;

R 77ccr is selected from:

phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a and —NR 76a R 77a ,

dihydropyridinyl, oxo-dihydropyridinyl, tetrahydroisoquinolinyl, tetrahydroisoquinolinyl substituted by —C(O)CH 3 , thiazolyl, and thiazolyl substituted by a substituent selected from: —C(O)CH 3 and —NHC(O)CH 3 ;

R 72ccr and R 73ccr are independently selected from:

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or R 72ccr and R 73ccr are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —OP(O)(OH) 2 , —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 pyrrolidinyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 3 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 30 of 41

provided that:

R 72ccr and R 73ccr are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (VIIccr), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (VIIccr), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Suitably in the compounds of Formula (VIIccr) neither R 72ccr nor R 73ccr is hydrogen.

Suitably in the compounds of Formula (VIIccr) R 77ccr is phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , tetrahydroisothiazolyl, tetrahydroisothiazolyl substituted twice by oxo, tetrahydro-1,2-thiazinyl, tetrahydro-1,2-thiazinyl substituted twice by oxo, —N(CH 3 )S(O) 2 CH 3 , —OS(O) 2 CH 3 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a and —NR 76a R 77a ,

This invention relates to novel compounds of Formula (Qc) and to the use of compounds of Formula (Qc) in the methods of the invention:

wherein:

R 70ca″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 77ca″ is selected from:

phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a and —NR 76a′ R 77a′ ,

where R 76a and R 77a are independently selected form: hydrogen, —S(O) 2 CH 3 , C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro, —COOH and —NR 78a′ R 79a′ , where R 78a′ and R 79a′ are independently selected form: hydrogen, phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH,

form: hydrogen, —S(O) 2 CH 3 , phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, and

R 72ca″ and R 73ca″ selected from:

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or R 72a″ and R 73a″ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —OP(O)(OH) 2 , —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 pyrrolidinyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 3 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, -propylpyrrolidinyl, -methylcyclopropyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, (methoxypyridinylmethyl)amino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, (methylcyclopropylmethyl)amino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, (fluorophenylmethyl)amino, piperazinylmethyl, oxazolidinyl, (methyloxetanylmethyl)amino, (methylcyclobutylmethyl)amino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 31 of 41

provided that:

R 72a″ and R 73a″ are not both hydrogen;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qc), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qc), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

Suitably in the compounds of Formula (Qc) neither R 72a″ nor R 73a″ is hydrogen.

This invention relates to novel compounds of Formula (Qc1) and to the use of compounds of Formula (Qc1) in the methods of the invention:

wherein:

R 70ca1″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 77ca1″ is selected from:

phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a and —NR 76a′ R 77a′ ,

tetrahydroisothiazolyl, tetrahydroisothiazolyl substituted twice by oxo, tetrahydro-1,2-thiazinyl, tetrahydro-1,2-thiazinyl substituted twice by oxo, —OS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —N(CH 3 )S(O) 2 CFH 2 , —N(CH 3 )S(O) 2 CF 2 H, —N(CH 3 )S(O) 2 CF 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , and —NR 80a′ R 81a′ where R 80a′ and R 81a′ are independently selected form: hydrogen, —S(O) 2 CH 3 , phenyl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —NH 2 , —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, and

R 72ca1″ and R 73ca1″ are independently selected from:

cyclobutyl, aminocyclobutyl, tetrahydrofuran, 5-oxa-2azaspiro[3.4]octan, and 8-azabicyclo[3.2.1]octan, or R 72ca1″ and R 73ca1″ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 pyrrolidinyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 3 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

›DETAILED DESCRIPTION OF THE INVENTION · 32 of 41

provided that:

R 72ca1″ and R 73ca1″ are not both unsubstituted alkyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qc1), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qc1), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

This invention relates to novel compounds of Formula (Qc2) and to the use of compounds of Formula (Qc2) in the methods of the invention:

wherein:

R 70ca2″ is selected from:

ethyl, —OCH 3 , —CH 2 CF 3 , and cyclopropyl;

R 77ca2″ is selected from:

phenyl, phenyl substituted with from 1 to 4 substituents independently selected from:

fluoro, chloro, —CN, oxo, C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, oxo, —OH, —NH 2 , —NHCH 3 , and —N(CH 3 ) 2 , C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 3 substituents independently selected from: fluoro, chloro, bromo, iodo, oxo, —S(O) 2 CH 3 , —CN, —OR 79a′ and —NR 76a′ R 77a′ ,

R 72ca2″ and R 73ca2″ are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl selected from:

fluoro, chloro, oxo, —OH, —CN, —CH 3 , —CH 2 OH, methoxy, —CH 2 CH 3 , —C(O)CH 3 , —C(O)NH 2 , —OCH 2 CH 2 OH, —OCH 2 CH 2 NH 2 , —ONHC(NH)NH 2 , —OC(O)NH 2 , —Ooxetanyl, —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH 2 CH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH 2 OH, —CH 2 C(O)OCH 3 , —CH 2 C(O)NH 2 , —C(O)CH(CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 CH 3 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 CH 2 N(CH 3 )CH 2 OCH 3 , —C(CH 3 ) 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OCH 3 , —C(O)CH 2 OH, —CH 2 isothiazolyl, —CH 2 thiazolyl, —CH 2 pyrazolyl, —CH 2 imidazolyl, —CH 2 pyridinyl, —CH 2 oxazolyl, —CH 2 pyrrolyl, —CH 2 pyrrolidinyl, —CH 2 isoxazoly, —CH 2 furanyl, —CH 2 CH 2 morpholinyl, —CH 2 CH 2 pyrrolidinyl, —CH 2 CH 2 pyrrolidinylCH 3 , —CH 2 CH 2 CH 2 pyrrolidinyl, —C(O)phenyl, —C(O)C(tetrahydropyranyl)NH 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CHF 2 , —NHCH 2 C(CH 3 ) 3 , —NHCH 2 CH(CH 3 ) 2 , —NHCH 2 CH 2 OCH 3 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 NH 2 , —NHCH 2 C(O)OH, —NHC(O)CH 2 NH 2 , —NHC(O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 C(O)NH 2 , —NHCH 2 C(OH)(CH 3 ) 2 , —NHC(O)CH(CH 3 )NH 2 , —NHC(O)OCH(CH 3 )NH 2 , —NHC(O)CH(CH 3 ) 2 , —NHC(O)C(CH 3 ) 3 , —NHC(O)C(CH 3 ) 2 NH 2 , —NHC(O)CH 2 OH, —NHC(O)CH(CH 2 OH)NH 2 , —NHC(O)(oxetanyl)NH 2 , —NHC(O)OC(CH 3 ) 3 , —NHC(CH 3 ) 2 C(O)OCH 3 , —NHcyclopropyl, —NHoxetanyl, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 CH 2 NH 2 , —CH 2 NHCH 2 C(CH 3 ) 3 , —CH 2 NHC(O)C(CH 3 ) 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 2 OH, —CH 2 N(CH 3 ) 2 , —CH 2 NHCH 3 , —CH 2 N(CH 2 CH 3 ) 2 , —CH 2 CH 2 N(CH 3 ) 2 , —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably in the compounds of Formula (Qc2), the compounds are in the form of a phosphate prodrug.

Suitably in the compounds of Formula (Qc2), the compounds are in the form of a —C(O)CH(NH 2 )CH(CH 3 ) 2 prodrug.

In an embodiment, X 51a is selected from: —CN, fluoro and chloro. In an embodiment, X 52a is selected from: —CN, fluoro and chloro. In an embodiment, X 51a is —CN. In an embodiment, X 52a is —CN.

In an embodiment, Y 5a is selected from: S and NH. In an embodiment, Y 5a is S.

In an embodiment, Y 5bbr is S.

In an embodiment, R 50a is selected from: C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an embodiment, R 50a is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an embodiment, R 50a is ethyl.

›DETAILED DESCRIPTION OF THE INVENTION · 33 of 41

In an embodiment, R 50bbr is selected from: C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an embodiment, R 50bbr is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an embodiment, R 50bbr is ethyl.

In an embodiment, R 50aar is selected from: phenyl, furanyl, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an embodiment, R 50aar is selected from phenyl, furanyl, ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an embodiment, R 50aar is ethyl. In an embodiment, R 50aar is phenyl. In an embodiment, R 50aar is furanyl.

In an embodiment R 51a is selected from: hydrogen, C 1-6 alkyl, aryl, chlorophenyl and heteroaryl. In an embodiment R 51a is selected from: hydrogen, methyl, phenyl, chlorophenyl and pyridine. In an embodiment R 51a is phenyl. In an embodiment R 51a is hydrogen.

In an embodiment R 51bbr is selected from: hydrogen, C 1-6 alkyl, aryl, chlorophenyl and heteroaryl. In an embodiment R 51bbr is selected from: hydrogen, methyl, phenyl, chlorophenyl, piperidinyl and pyridinyl. In an embodiment R 51bbr is phenyl. In an embodiment R 51bbr is pyridinyl.

In an embodiment R 52a is selected from: —C(O)NH 2 and -phenylCH 2 NHC(O)CH 3 . In an embodiment R 52a is —C(O)NH 2 . In an embodiment R 52a is -phenylCH 2 NHC(O)CH 3 .

In an embodiment R 53a and R 54a are independently selected from: hydrogen, methyl, morpholinethyl, methoxyethyl, oxaazaspiro[3.4]octan, 5-oxa-2-azaspiro[3.4]octan, aminoethyl, amino-2-oxoethyl and hydroxyethyl.

In an embodiment R 53a and R 54a are taken together with the nitrogen to which they are attached to form: pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, 1,4-diazepanyl, methyl-1,4-diazepanyl, methoxyethyl-1,4-diazepanyl, hydroxypropyl-1,4-diazepanyl, methyl-1,4-diazepanacetate, (methyl)oxo-1,4-diazepanyl, (methyl)oxopiperazinyl, propylpiperazinyl, aminopyrrolidinyl, oxo-1,4-diazepanyl, piperidinylpiperazinyl, hydroxymethylpiperazinyl, oxopiperazinyl, morpholinpiperidinyl, hydroxyethyl 1,4diazepanyl, dimethylaminopropylpiperazinyl, pyrrolidinpiperidinyl, piperidinpiperidinyl, pyrrolidinpropyl-1,4-diazepanyl, methylpiperazinyl, dimethylaminopiperidinyl, dimethylpiperazinyl, dimethylmorpholinyl, (aminomethyl)hydroxypiperidinyl, aminopiperidinyl, methylaminopiperidinyl, piperazinyl, aminoethylpiperazinyl, ethylpiperazinyl, morpholinmethylpiperidinyl, aminopropylpiperazinyl, methylpiperazinmethylpiperidinyl, pyrrolidinmethylpiperidinyl, methylpiperazinpiperidinyl, ethyl1,4diazepanyl, imidazolidinpiperidinyl, oxoimidazolidinpiperidinyl, propy-l1,4-diazepanyl, azetidinyl, methoxyazetidinyl, acetylpiperazinyl, hydroxyethylpiperazinyl, morpholinyl, 2-methylpropanoylpiperazinyl, ethanesulfonylpiperazinyl, methanesulfonylpiperazinyl, benzoylpiperazinyl, oxopiperidinyl, hydroxyethylpiperidinpiperidinyl, hydroxymethylmorpholinyl or difluoropiperidinyl,

In an embodiment R 53 and R 54 are taken together with the nitrogen to which they are attached to form: diazaspiroundecanyl, 2,9-diazaspiro[5.5]undecanyl, diazaspirodecanyl, 2,8-diazaspiro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, methyl-2,9-diazaspiro[5.5]undecanyl, cyclopropylmethyl-2,9-diazaspiro[5.5]undecanyl, oxaazaspirooctanyl, oxaazaspiro[3.4]octanyl, diazaspirononanyl, diazaspiro[3.5]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, diazaspirooctanyl, diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, methanesulfonyl-1,8-diazaspiro[4.5]decanyl, azabicyclooctanyl, 8-azabicyclo[3.2.1]octanyl, 4-amino-4-methylpiperidin-1-yl, NH 2 CH 2 C(O)NH-piperidinyl, NH 2 CH(CH 3 )C(O)NH-piperidinyl, 3-aminooxetane-3-carbonyl)piperazinyl, 4-amino-(piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide, 4-amino-(piperazin-4-yl)tetrahydro-2H-pyran-4-carboxamide, hydroxyethyl-1,4-diazepanyl, aminopiperidinyl, hydroxyazetidinyl, hydroxypyrrolidinyl or hydroxyethoxypiperidinyl.

In an embodiment R 53bbr and R 54bbr are independently selected from: hydrogen, methyl, morpholinethyl, methoxyethyl, oxaazaspiro[3.4]octan, 5-oxa-2-azaspiro[3.4]octan, aminoethyl, amino-2-oxoethyl and hydroxyethyl.

In an embodiment R 53bbr and R 54bbr are taken together with the nitrogen to which they are attached to form: pyrrolidinyl, hydroxypyrrolidinyl, piperidinyl, hydroxypiperidinyl, 1,4-diazepanyl, methyl-1,4-diazepanyl, methoxyethyl-1,4-diazepanyl, hydroxypropyl-1,4-diazepanyl, methyl-1,4-diazepanacetate, (methyl)oxo-1,4-diazepanyl, (methyl)oxopiperazinyl, propylpiperazinyl, aminopyrrolidinyl, oxo-1,4-diazepanyl, piperidinylpiperazinyl, hydroxymethylpiperazinyl, oxopiperazinyl, morpholinpiperidinyl, hydroxyethyl 1,4diazepanyl, dimethylaminopropylpiperazinyl, pyrrolidinpiperidinyl, piperidinpiperidinyl, pyrrolidinpropyl-1,4-diazepanyl, methylpiperazinyl, dimethylaminopiperidinyl, dimethylpiperazinyl, dimethylmorpholinyl, (aminomethyl)hydroxypiperidinyl, aminopiperidinyl, methylaminopiperidinyl, piperazinyl, aminoethylpiperazinyl, ethylpiperazinyl, morpholinmethylpiperidinyl, aminopropylpiperazinyl, methylpiperazinmethylpiperidinyl, pyrrolidinmethylpiperidinyl, methylpiperazinpiperidinyl, ethyl1,4diazepanyl, imidazolidinpiperidinyl, oxoimidazolidinpiperidinyl, propy-l1,4-diazepanyl, azetidinyl, methoxyazetidinyl, acetylpiperazinyl, hydroxyethylpiperazinyl, morpholinyl, 2-methylpropanoylpiperazinyl, ethanesulfonylpiperazinyl, methanesulfonylpiperazinyl, benzoylpiperazinyl, oxopiperidinyl, hydroxyethylpiperidinpiperidinyl, hydroxymethylmorpholinyl or difluoropiperidinyl,

In an embodiment R 53bbr and R 54bbr are taken together with the nitrogen to which they are attached to form: diazaspiroundecanyl, 2,9-diazaspiro[5.5]undecanyl, diazaspirodecanyl, 2,8-diazaspiro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, methyl-2,9-diazaspiro[5.5]undecanyl, cyclopropylmethyl-2,9-diazaspiro[5.5]undecanyl, oxaazaspirooctanyl, oxaazaspiro[3.4]octanyl, diazaspirononanyl, diazaspiro[3.5]nonanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, diazaspirooctanyl, diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.4]octanyl, methanesulfonyl-1,8-diazaspiro[4.5]decanyl, azabicyclooctanyl, 8-azabicyclo[3.2.1]octanyl, 4-amino-4-methylpiperidin-1-yl, NH 2 CH 2 C(O)NH-piperidinyl, NH 2 CH(CH 3 )C(O)NH-piperidinyl, 3-aminooxetane-3-carbonyl)piperazinyl, 4-amino-(piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide, 4-amino-(piperazin-4-yl)tetrahydro-2H-pyran-4-carboxamide, hydroxyethyl-1,4-diazepanyl, aminopiperidinyl, hydroxyazetidinyl, hydroxypyrrolidinyl or hydroxyethoxypiperidinyl.

›DETAILED DESCRIPTION OF THE INVENTION · 34 of 41

In an embodiment, X 41ccr is selected from: —CN, fluoro and chloro. In an embodiment, X 42ccr is selected from: —CN, fluoro and chloro. In an embodiment, X 41ccr is —CN. In an embodiment, X 42ccr is —CN.

In an embodiment, Y 4ccr is selected from: S and NH. In an embodiment, Y 4ccr is S.

In an embodiment, R 41ccr is selected from: C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an embodiment, R 41ccr is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an embodiment, R 41ccr is ethyl.

In an embodiment, R 43ccr is selected from: phenyl, phenyl substituted with 1 or 2 substituents independently selected form: —OS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , —CH 2 NHC(O)CH 3 , —CH 2 NHC(O)CH 2 NH 2 , —CH 2 NHC(O)CH 3 , tetrahydrothiazolyl, tetrehydrothiazolyl substituted once or twice by oxo, tetrahydrothiazinyl, tetrahydrothiazinyl substituted once or twice by oxo, and —CH 2 S(O) 2 CH 3 ,

In an embodiment R 44ccr and R 45ccr are independently selected from: hydrogen, methyl, and C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: —N(CH 2 CH 3 ) 2 , and —NHOC(CH 3 ) 2 NH 2 .

In an embodiment R 44ccr and R 45ccr are taken together with the nitrogen to which they are attached to form: piperidinyl, piperidinyl substituted by one or two substituents independently selected from: amino, —NHCH(CH 3 ), pyrrolidinyl, —NHC(O)C(CH 3 ) 3 , —NH(O)CH(CH 3 )(NH 2 ), fluoro, chloro, and CH 2 N(CH 3 ) 2 , morpholinyl, morpholinyl substituted by CH 2 pyrrolidinyl, 1,4diazepanyl, and methyl1,4diazepanyl.

In an embodiment, X 41bbr is selected from: —CN, fluoro and chloro. In an embodiment, X 42bbr is selected from: —CN, fluoro and chloro. In an embodiment, X 41bbr is —CN. In an embodiment, X 42bbr is —CN.

In an embodiment, Y 4bbr is selected from: S and NH. In an embodiment, Y 4bbr is S.

In an embodiment, R 41bbr is selected from: C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from: fluoro and chloro, and cycloalkyl. In an embodiment, R 41bbr is selected from ethyl, cyclopropyl and 2,2,2,trifluoroethyl. In an embodiment, R 41bbr is ethyl.

In an embodiment, R 43bbr is selected from: phenyl, and phenyl substituted with 1 or 2 substituents independently selected form: fluoro and chloro.

In an embodiment R 44bbr and R 45bbr are independently selected from: methyl, and —CH 2 C(O)NH 2 .

In an embodiment R 44bbr and R 45bbr are taken together with the nitrogen to which they are attached to form: piperidinyl, piperidinyl substituted by one or two substituents independently selected from: amino, —NHCH 2 C(CH 3 ) 3 , flouro, chloro, and —N(CH 3 )cyclobutyl, pyrrolidinyl, and pyrrolidinyl substituted by hydroxy.

Included in the compounds of Formula (I) and in the methods of the invention are:

›DETAILED DESCRIPTION OF THE INVENTION · 35 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Included prodrugs of Formula (I) of the invention are:

1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl dihydrogen phosphate; (2S)-2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl dihydrogen phosphate;

or a pharmaceutically acceptable salt thereof.

Suitably, the presently invented novel compounds of Formula (IVa) are selected from:

›DETAILED DESCRIPTION OF THE INVENTION · 36 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Included prodrugs of Formula (IVa) of the invention are:

or a pharmaceutically acceptable salt thereof.

Primary Amide:

Included in the compounds of Formula (Ibr) and in the methods of the invention are:

2-[(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl]-2-phenylacetamide; (R)-[(6-amino-3,5-dicyano-4-ethylpyridin-2-yl)sulfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-propyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-morpholinopyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-(pyridin-4-yl)acetamide; 2-[(3,5-dicyano-4-ethyl-6-{methyl[2-(morpholin-4-yl)ethyl]amino}pyridin-2-yl)sulfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-propylpiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-ethyl-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[3-(hydroxymethyl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2,6-dimethylmorpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((R)-3-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypiperidin-1-yl)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-ethylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-aminopropyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1,7-diazaspiro[3.5]nonan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)amino)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-[(6-amino-3,5-dicyano-4-cyclopropyl-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-((3,5-Dicyano-4-ethyl-6-(methylamino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-morpholinopyridin-2-yl)thio)-2-phenylacetamide; 2-[[6-(azetidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridyl]sulfanyl]-2-phenyl-acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-oxopiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(1′-(2-hydroxyethyl)-[4,4′-bipiperidin]-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(8-azabicyclo[3.2.1]octan-3-yl(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-[(3,5-Dicyano-4-ethyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-methyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-4-ethyl-6-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxpropyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; Methyl 2-[4-(6-{[carbamoyl(phenyl)methyl]sulfanyl}-3,5-dicyano-4-ethylpyridin-2-yl)-1,4-diazepan-1-yl]acetate; 2-{[3,5-Dicyano-4-cyclopropyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-cyclopropyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-ethyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4-(2,2,2-trifluoroethyl)pyridin-2-yl}sulfanyl)-2-phenylacetamide; (2R)-2-({3,5-Dicyano-4-ethyl-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}amino)-2-phenylacetamide; 2-({6-[(3S)-3-Aminopyrrolidin-1-yl]-3,5-dicyano-4-cyclopropylpyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-9-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-3-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-([4,4′-Bipiperidin]-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(2-Aminoethyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-Aminopropyl)piperazin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Acetylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(4-Chlorophenyl)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-[(3,5-Dicyano-4-cyclopropyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((5S,6S)-6-hydroxy-1-(methylsulfonyl)-1,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4,4-difluoropiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-(furan-2-yl)-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)acetamide; (2S)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(3-Aminooxetane-3-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 2-((6-(4-(4-Aminotetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Aminoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 2-((6-(4-(2-Aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl dihydrogen phosphate; (2S)-2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; 2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(piperidin-4-yl)acetamide; yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(propylsulfonyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(phenylsulfonyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl)amino)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-1-yl)pyridin-2-yl)amino)-2-phenylacetamide; 2-(3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypiperidin-1-yl)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-Dichloro-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(1,1-dioxidothiomorpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(methyl(2-(piperazin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((4-Cyano-3-(1,4-diazepan-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)thio)-2-phenylacetamide; 2-((6-(4-(1H-Imidazol-1-yl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(dimethylamino)ethoxy)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-3-yl)amino)acetic acid; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-2-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Pyrrol-2-yl) methyl) piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(3,4-dihydro-2,7-naphthyridin-2 (1H)-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-3-yl)acetamide; 2-((6-(4-((1H-Pyrrol-3-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazol-3-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-5-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazol-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 3-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxetane-3-carboxamide; 2-((6-(4-((1H-Pyrazol-4-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-5-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-2-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-methoxpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxy-2-methylpropyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isothiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(furan-3-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-morpholinoethyl)thio)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-methyl-1,4-diazepan-1-yl)-4-(methylthio)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dichloro-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; p 2-((3,5-Dicyano-4-ethyl-6-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(5-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(6-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(4-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(2,4-difluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(5-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)propanamide; 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)-4-propoxpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(3,4-difluorophenyl)acetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidine-4-carboxamide; 2-((3,5-Dicyano-6-((2-(dimethylamino)ethyl)thio)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(5-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-(trifluoromethyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethoxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(2-fluoropyridin-3-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(6-fluoropyridin-3-yl)acetamide; 3-((6-(2-Amino-2-oxo-1-phenylethylthio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxetan-3-yloxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-((2,2-difluoroethyl) amino)-4-methylpiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; 2-((6-(4-Aminopiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2-fluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-(hydroxymethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)acetamide; 2-(4-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2-methylpyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-(pyrrolidin-1-yl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-fluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2,5-difluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxoimidazolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-Amino-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) piperidine-4-carboxamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxopyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide (isomer 1); 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide (Isomer 2); 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-4-hydroxy piperidine-4-carboxamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl carbamate; 2-((3,5-Dicyano-6-(4-(2,4-dioxooxazolidin-3-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 3-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-2-hydroxy-2-methylpropanamide; 2-((3,5-Dicyano-4-ethyl-6-(3-(hydroxymethyl)azetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-ylthio)-2-(thiophen-3-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(5-methylpyridin-3-yl)acetamide; 2-((6-(4-(3-Amino-2-oxopyrrolidin-1-yl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl (2S)-2-amino-3-methylbutanoate; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (methyl) amino)ethyl (2S)-2-amino-3-methylbutanoate; 2,2′-((3,5-Dicyano-4-ethylpyridine-2,6-diyl)bis(sulfanediyl))bis(2-phenylacetamide); (2S)-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4 ethylpyridin-2-yl)azetidin-3-yl)methyl 2-amino-3-methylbutanoate; 2-((6-(3-Aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-methylpyridin-2-yl)thio)-2-phenylacetamide; N-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-hydroxyacetamide; N-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl)-2-hydroxyacetamide; 2-((3-Cyano-4-ethyl-5-methyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide-2-d; (R)-2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide-2-d; 2-((6-(4-(4-Bromobenzoyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-cyanopiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (S)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-2-yl)acetamide; 2-((3,5-Dichloro-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)carbamate; 2-((6-(3-(2-Amino-2-oxoethyl)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (2R)-1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl 2-amino-3-methylbutanoate; 2-((3,5-Dicyano-4-ethyl-6-(methyl((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((4H-1,2,4-Triazol-3-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-methylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4,6-diethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-(4H-1,2,4-Triazol-4-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Pyrazol-3-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-2-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-5-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)propanamide; 4-(2-Amino-1-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-oxoethyl)benzamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropyl pyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-((2-Aminoethyl)(methyl)amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 4-(2-Amino-1-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-oxoethyl)benzamide; 2-(6-(4-Aminopiperidin-1-yl)-3-cyano-4-ethyl-5-methylpyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-(N-methylsulfamoyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(6-fluoro-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-3,3-difluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3,3-difluoropiperidin-4-yl) carbamate; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidine-3-carboxamide; 2-((6-((3-Aminopropyl) (methyl) amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino) pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((2-Amino-2-oxoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)ethyl carbamate; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-3-hydroxypropanamide; (2S)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) piperidin-4-yl)-3-hydroxypropanamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-ylthio)acetamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(4-(N-methylsulfamoyl)phenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino-d 6 )-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)-2-(3-(2-(dimethylamino)ethoxy)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-A(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (single enantiomer) (3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) Pyrrolidin-3-yl dihydrogen phosphate; (3R)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; (S)-1-(6-(((S)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; (S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(3-(dimethylphosphoryl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-(3-(dimethylphosphoryl)phenyl)acetamide; (R)-2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(4-methoxyphenyl)acetamide; (R)-2-(4-chlorophenyl)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-(4-fluoro phenyl)acetamide; (S)-1-(6-(((R)-2-amino-1-(4-fluorophenyl)-2-oxoethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl)thio)-2-(4-fluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl)thio)-2-(2,6-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl)thio)-2-(2,3-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl)thio)-2-(2,4-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobutylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((3-methyloxetan-3-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-2-methylpyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-2-methylpyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(6-(4-(benzylamino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((6-methoxpyridin-2-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-((R)-2-methylpyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-((S)-2-methylpyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclobutyl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((6-methoxpyridin-3-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-(ethylamino)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclopropyl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((4-fluorobenzyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-((2-((2S,5R)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((6-((2-(azepan-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(piperidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; methyl 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-2-methylpropanoate; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(neopentylamino)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-(methyl(2-(1-methylcyclopropylamino)ethyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-methoxyethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxy-2-methylpropyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(dimethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-fluoroethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(3,3-difluoropyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)acetic acid; 2-((6-((3-aminocyclobutyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-(3,5-dicyano-4-ethyl-6-(methyl((R)-tetrahydrofuran-3-yl)amino)pyridin-2-ylthio)-2-phenylacetamide; (S)-2-(3,5-dicyano-4-ethyl-6-(methyl((R)-tetrahydrofuran-3-yl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-morpholinopiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-3-oxopiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; rel-2-((6-(trans)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-((2-methoxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(diethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((R)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((S)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3S,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(methylamino)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-(aminomethyl)pyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)-3-fluoropiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((4-((S)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-((R)-3-aminopyrrolidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (S)-2-((6-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; tert-butyl ((3S,4R)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-fluoropiperidin-4-yl)carbamate; 2-((6-((2-((S)-3-aminopyrrolidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; tert-butyl ((3R,4S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-fluoropiperidin-4-yl)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (S)-2-((6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-((2-hydroxy-2-methylpropyl)amino)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; tert-butyl ((3R,4R)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; rel-2-((6-cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(ethyl(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methyl(neopentyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2,2-difluoroethyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((R)-2-((neopentylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((dimethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((diethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((R)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-((methylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methyl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-((methylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-2-((neopentylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-((neopentylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-methylpropanamide; 2-((4-((S)-3-(aminomethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-2-((diethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-methylpropanamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(3-fluoropyridin-2-yl)acetamide; 2-((6-((S)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-3-yl)methyl)-2-methylpropanamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-3-yl)methyl)acetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)acetamide; 2-((6-((R)-3-(aminomethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-((R)-3-((neopentylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)acetamide; N—(((R)-4-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-hydroxyacetamide; (S)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-hydroxyethyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((1-(hydroxymethyl)cyclopropyl)methyl)-N-methylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)acetamide; (2S)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((S)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-3-hydroxpyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide hydrochloride; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N-(2-aminoethyl)acetamide hydrochloride; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-oxo-2-(pyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-oxo-2-(piperazin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-morpholino-2-oxoethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(guanidinooxy)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)-2-methylpropanamide; 2-((6-((2-(2-aminoethoxy)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)butanamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-aminoethyl)acetamide; 2-((6-((2-(azetidin-1-yl)-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(guanidinooxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (single stereoisomer) 2-((3,5-dicyano-4-ethyl-6-((R)-3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N-(1,3-dihydroxypropan-2-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(oxetan-3-ylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N,N-bis(2-hydroxyethyl)acetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)amino)-4-methylpiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(guanidinooxy)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((2-aminoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-2-(hydroxymethyl)morpholino)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((cis)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (2S)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(2-aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-((2-hydroxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(1,3-dihydroxypropan-2-yl)acetamide; 2-((3,5-dicyano-6-((2-((3R,5S)-3,5-dihydroxypiperidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)amino)-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-2-(hydroxymethyl)morpholino)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-methoxyacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxypropyl)-N-methylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((R)-2,3-dihydroxypropyl)acetamide; 2-((6-(4-((2-amino-2-oxoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N,N-bis(2-hydroxyethyl)acetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-hydroxyethyl)acetamide; 2-((6-((3-aminopropyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-(aminomethyl)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((1-(hydroxymethyl)cyclopropyl)methyl)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(2,4-difluorophenyl)acetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-(hydroxymethyl)oxetan-3-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(guanidinooxy)azetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxypropyl)acetamide; 2-((3,5-dicyano-6-(4-(2,3-dihydroxypropyl)-1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-hydroxyacetamide; 3-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)oxetane-3-carboxamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(2-fluorophenyl)acetamide; 2-((3,5-dicyano-6-((S)-3-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide; N-(2-(4H-1,2,4-triazol-4-yl)ethyl)-2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)acetamide; N1-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)oxalamide; 2-((6-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((R)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-((2,2-difluoroethyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-4-hydroxyisoxazolidin-2-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((3-hydroxpropyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-hydroxpyrrolidin-1-yl)-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((R)-3-(aminomethyl)-3-hydroxpyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; and 2-((3,5-dicyano-4-ethyl-6-(methyl(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)thio)-2-phenylacetamide;

›DETAILED DESCRIPTION OF THE INVENTION · 37 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably, presently invented novel compounds of Formula (IVbbr) are selected from:

2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-propyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-morpholinopyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-(pyridin-4-yl)acetamide; 2-[(3,5-dicyano-4-ethyl-6-{methyl[2-(morpholin-4-yl)ethyl]amino}pyridin-2-yl)sulfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-propylpiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-ethyl-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[3-(hydroxymethyl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxmethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2,6-dimethylmorpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((R)-3-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypiperidin-1-yl)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-ethylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-aminopropyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1,7-diazaspiro[3.5]nonan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl) pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)amino)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-morpholinopyridin-2-yl)thio)-2-phenylacetamide; 2-[[6-(azetidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridyl]sulfanyl]-2-phenyl-acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-oxopiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(1′-(2-hydroxyethyl)-[4,4′-bipiperidin]-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(8-azabicyclo[3.2.1]octan-3-yl(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-[(3,5-Dicyano-4-ethyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-methyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-4-ethyl-6-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxpropyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; Methyl 2-[4-(6-{[carbamoyl(phenyl)methyl]sulfanyl}-3,5-dicyano-4-ethylpyridin-2-yl)-1,4-diazepan-1-yl]acetate; 2-{[3,5-Dicyano-4-cyclopropyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-cyclopropyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-ethyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4-(2,2,2-trifluoroethyl)pyridin-2-yl}sulfanyl)-2-phenylacetamide; (2R)-2-({3,5-Dicyano-4-ethyl-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}amino)-2-phenylacetamide; 2-({6-[(3S)-3-Aminopyrrolidin-1-yl]-3,5-dicyano-4-cyclopropylpyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-9-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-3-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-([4,4′-Bipiperidin]-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(2-Aminoethyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-Aminopropyl)piperazin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Acetylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(dimethylamino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(4-Chlorophenyl)-2-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-[(3,5-Dicyano-4-cyclopropyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((5S,6S)-6-hydroxy-1-(methylsulfonyl)-1,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4,4-difluoropiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-(furan-2-yl)-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)acetamide; (2S)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(3-Aminooxetane-3-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 2-((6-(4-(4-Aminotetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Aminoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 2-((6-(4-(2-Aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl dihydrogen phosphate; (2S)-2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; 2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(piperidin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(propylsulfonyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(phenylsulfonyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl)amino)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(3-(pyrrolidin-1-yl)propyl)-1,4-diazepan-1-yl)pyridin-2-yl)amino)-2-phenylacetamide; 2-(3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypiperidin-1-yl)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-Dichloro-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(1,1-dioxidothiomorpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(methyl(2-(piperazin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((4-Cyano-3-(1,4-diazepan-1-yl)-6,7-dihydro-5H-cyclopenta[c]pyridin-1-yl)thio)-2-phenylacetamide; 2-((6-(4-(1H-Imidazol-1-yl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyridin-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(dimethylamino)ethoxy)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-3-yl)amino)acetic acid; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-2-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Pyrrol-2-yl) methyl) piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(3,4-dihydro-2,7-naphthyridin-2 (1H)-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-3-yl)acetamide; 2-((6-(4-((1H-Pyrrol-3-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazol-3-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxazol-5-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isoxazol-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 3-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxetane-3-carboxamide; 2-((6-(4-((1H-Pyrazol-4-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-5-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((1H-Imidazol-2-yl)methyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-methoxpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxy-2-methylpropyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(thiazol-5-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(isothiazol-4-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(furan-3-ylmethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-morpholinoethyl)thio)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-methyl-1,4-diazepan-1-yl)-4-(methylthio)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dichloro-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(5-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(6-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(4-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(2,4-difluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(5-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethoxy-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)propanamide; 2-((3,5-Dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)-4-propoxpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(3,4-difluorophenyl)acetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidine-4-carboxamide; 2-((3,5-Dicyano-6-((2-(dimethylamino)ethyl)thio)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-fluoropyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(5-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(1-hydroxy-2-methylpropan-2-yl)piperazin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-(trifluoromethyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethoxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(2-fluoropyridin-3-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(6-fluoropyridin-3-yl)acetamide; 3-((6-(2-Amino-2-oxo-1-phenylethylthio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(oxetan-3-yloxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-((2,2-difluoroethyl) amino)-4-methylpiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; 2-((6-(4-Aminopiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(pyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-methoxypyridin-2-yl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(5-methylpyridin-2-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2-fluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-3-oxa-1,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-(hydroxymethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)acetamide; 2-(4-Benzoylphenyl)-2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2-methylpyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-(pyrrolidin-1-yl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(3-fluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(2,5-difluoropyridin-4-yl)acetamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxoimidazolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-Amino-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) piperidine-4-carboxamide; 2-((3,5-Dicyano-6-(4-(2,5-dioxopyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide (isomer 1); 2-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide (Isomer 2); 2-((3,5-Dicyano-4-ethyl-6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-4-hydroxy piperidine-4-carboxamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl carbamate; 2-((3,5-Dicyano-6-(4-(2,4-dioxooxazolidin-3-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 3-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-2-hydroxy-2-methylpropanamide; 2-((3,5-Dicyano-4-ethyl-6-(3-(hydroxymethyl)azetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-ylthio)-2-(thiophen-3-yl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl) pyridin-2-yl)thio)-2-(5-methylpyridin-3-yl)acetamide; 2-((6-(4-(3-Amino-2-oxopyrrolidin-1-yl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl (2S)-2-amino-3-methylbutanoate; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) (methyl) amino)ethyl (2S)-2-amino-3-methylbutanoate; 2,2′-((3,5-Dicyano-4-ethylpyridine-2,6-diyl)bis(sulfanediyl))bis(2-phenylacetamide) (2S)-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4 ethylpyridin-2-yl)azetidin-3-yl)methyl 2-amino-3-methylbutanoate; 2-((6-(3-Aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-methylpyridin-2-yl)thio)-2-phenylacetamide; N-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-hydroxyacetamide; N-(1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl)-2-hydroxyacetamide; 2-((3-Cyano-4-ethyl-5-methyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide-2-d; (R)-2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide-2-d; 2-((6-(4-(4-Bromobenzoyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-cyanopiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (S)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-2-yl)acetamide; 2-((3,5-Dichloro-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)carbamate; 2-((6-(3-(2-Amino-2-oxoethyl)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (2R)-1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl 2-amino-3-methylbutanoate; 2-((3,5-Dicyano-4-ethyl-6-(methyl((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((4H-1,2,4-Triazol-3-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethoxy-6-methylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4,6-diethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-(4H-1,2,4-Triazol-4-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Pyrazol-3-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(6,7-dihydro-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-2-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(((1H-Imidazol-5-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)propanamide; 4-(2-Amino-1-((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-oxoethyl)benzamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-((2-Aminoethyl)(methyl)amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 4-(2-Amino-1-((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-oxoethyl)benzamide; 2-(6-(4-Aminopiperidin-1-yl)-3-cyano-4-ethyl-5-methylpyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(4-(N-methylsulfamoyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(6-fluoro-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Amino-3,3-difluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; tert-Butyl (1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3,3-difluoropiperidin-4-yl) carbamate; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 1-(6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidine-3-carboxamide; 2-((6-((3-Aminopropyl) (methyl) amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl) thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino) pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((2-Amino-2-oxoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-Amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)ethyl carbamate; (2R)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-3-hydroxypropanamide; (2S)-2-Amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) piperidin-4-yl)-3-hydroxypropanamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-ylthio)acetamide; 2-(4-(2-Amino-2-oxoethyl)phenyl)-2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)acetamide; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(4-(N-methylsulfamoyl)phenyl)acetamide; 2-((3,5-Dicyano-6-(dimethylamino-d 6 )-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-ylthio)-2-(3-(2-(dimethylamino)ethoxy)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-A(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (single enantiomer) (3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) Pyrrolidin-3-yl dihydrogen phosphate; (3R)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; (S)-1-(6-(((S)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; (S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl) pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)-2-(3-(dimethylphosphoryl)phenyl)acetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-(3-(dimethylphosphoryl)phenyl)acetamide; (R)-2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(4-methoxyphenyl)acetamide; (R)-2-(4-chlorophenyl)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-(4-fluoro phenyl)acetamide; (S)-1-(6-(((R)-2-amino-1-(4-fluorophenyl)-2-oxoethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(4-fluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2,6-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2,3-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl) pyridin-2-yl) thio)-2-(2,4-difluorophenyl) acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobutylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((3-methyloxetan-3-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-2-methylpyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5S)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-2-methylpyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(6-(4-(benzylamino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((6-methoxpyridin-2-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((S)-3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-((R)-2-methylpyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-3-fluoropyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-((S)-2-methylpyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclobutyl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((6-methoxpyridin-3-yl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-(ethylamino)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(((1-methylcyclopropyl)methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((4-fluorobenzyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-6-((2-((2S,5R)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-ylthio)-2-phenylacetamide; 2-((6-((2-(azepan-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(piperidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-2-(hydroxymethyl)pyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-(ethyl(methyl)amino)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-((S)-3-hydroxypyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; methyl 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)-2-methylpropanoate; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(neopentylamino)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-(methyl(2-(1-methylcyclopropylamino)ethyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((2S,5S)-2,5-dimethylpyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-methoxyethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxy-2-methylpropyl)(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(dimethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-ethyl-6-((2-((R)-3-hydroxypyrrolidin-1-yl)ethyl)(methyl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((2-fluoroethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(3,3-difluoropyrrolidin-1-yl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)amino)acetic acid; 2-((6-((3-aminocyclobutyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-(3,5-dicyano-4-ethyl-6-(methyl((R)-tetrahydrofuran-3-yl)amino)pyridin-2-ylthio)-2-phenylacetamide; (S)-2-(3,5-dicyano-4-ethyl-6-(methyl((R)-tetrahydrofuran-3-yl)amino)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-morpholinopiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethyl)-3-oxopiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; rel-2-((6-(trans)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-((2-methoxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methyl)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxy-2-methylpropyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3S,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-(diethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((R)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((S)-3-(dimethylamino)pyrrolidin-1-yl)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3R,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((3S,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(methylamino)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (R)-2-((6-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-(aminomethyl)pyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)-3-fluoropiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((4-((S)-3-aminopyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-((R)-3-aminopyrrolidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; (S)-2-((6-((3S,4R)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-(trifluoromethyl)phenyl)acetamide; tert-butyl ((3S,4R)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-fluoropiperidin-4-yl)carbamate; 2-((6-((2-((S)-3-aminopyrrolidin-1-yl)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; tert-butyl ((3R,4S)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; rel-tert-butyl (cis)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-fluoropiperidin-4-yl)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (S)-2-((6-((3R,4S)-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-((2-hydroxy-2-methylpropyl)amino)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; tert-butyl ((3R,4R)-1-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)-3-hydroxypiperidin-4-yl)carbamate; 2-((3,5-dicyano-6-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; rel-2-((6-cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(ethyl(methyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(methyl(neopentyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-methoxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(4-((2,2-difluoroethyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((R)-2-((neopentylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((dimethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(2-((diethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((R)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2-((methylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-(3-((dimethylamino)methyl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-((methylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-2-((neopentylamino)methyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-((neopentylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-methylpropanamide; 2-((4-((S)-3-(aminomethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((R)-2-((diethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-methylpropanamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(3-fluoropyridin-2-yl)acetamide; 2-((6-((S)-2-(aminomethyl) morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-3-yl)methyl)-2-methylpropanamide; 2-amino-N-(((3S)-1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-3-yl)methyl)acetamide; 2-amino-N-(((2R)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)acetamide; 2-((6-((R)-3-(aminomethyl)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-4-ethyl-6-((R)-3-((neopentylamino)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-amino-N-(((2S)-4-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)acetamide; N-(((R)-4-(6-(((R)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)morpholin-2-yl)methyl)-2-hydroxyacetamide; (S)-2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-hydroxyethyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((1-(hydroxymethyl)cyclopropyl)methyl)-N-methylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)acetamide; (2S)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((S)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (2R)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)-3-hydroxypropanamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)-N-methylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-3-hydroxpyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(aminomethyl)-4-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide hydrochloride; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N-(2-aminoethyl)acetamide hydrochloride; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-oxo-2-(pyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(4-hydroxypiperidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-oxo-2-(piperazin-1-yl)ethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(methyl(2-morpholino-2-oxoethyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((6-((S)-3-(aminomethyl)-3-hydroxypyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(guanidinooxy)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)-2-methylpropanamide; 2-((6-((2-(2-aminoethoxy)ethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)butanamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-aminoethyl)acetamide; 2-((6-((2-(azetidin-1-yl)-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(guanidinooxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-aminoazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (single stereoisomer) 2-((3,5-dicyano-4-ethyl-6-((R)-3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((4-((S)-3-(aminomethyl)-3-fluoropyrrolidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N-(1,3-dihydroxypropan-2-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(oxetan-3-ylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)(methyl)amino)-N,N-bis(2-hydroxyethyl)acetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)amino)-4-methylpiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-(guanidinooxy)ethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-((2-aminoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-2-(hydroxymethyl)morpholino)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((cis)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((S)-3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3S,4S)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-3-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; p (2S)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(2-aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-((2-hydroxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(1,3-dihydroxypropan-2-yl)acetamide; 2-((3,5-dicyano-6-((2-((3R,5S)-3,5-dihydroxypiperidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((2-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)amino)-4-(hydroxymethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((R)-2-(hydroxymethyl)morpholino)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-methoxyacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-((3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-1-yl)-2-oxoethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxypropyl)-N-methylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((R)-2,3-dihydroxypropyl)acetamide; 2-((6-(4-((2-amino-2-oxoethyl)amino)piperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N,N-bis(2-hydroxyethyl)acetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(2-hydroxyethyl)acetamide; 2-((6-((3-aminopropyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-(aminomethyl)azetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-((1-(hydroxymethyl)cyclopropyl)methyl)acetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(2,4-difluorophenyl)acetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-(hydroxymethyl)oxetan-3-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(3-(guanidinooxy)azetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxypropyl)acetamide; 2-((3,5-dicyano-6-(4-(2,3-dihydroxypropyl)-1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-hydroxyacetamide; 3-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-cyclopropylpyridin-2-yl)azetidin-3-yl)oxetane-3-carboxamide; 2-((3,5-dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(2-fluorophenyl)acetamide; 2-((3,5-dicyano-6-((S)-3-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)-N-(3-hydroxy-2,2-dimethylpropyl)acetamide; N-(2-(4H-1,2,4-triazol-4-yl)ethyl)-2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)acetamide; N1-(2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl)oxalamide; 2-((6-(3-(aminomethyl)-3-fluoroazetidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((R)-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-((2,2-difluoroethyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((R)-3-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((S)-4-hydroxyisoxazolidin-2-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((3-hydroxpropyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-6-((S)-3-hydroxpyrrolidin-1-yl)-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; and 2-((3,5-dicyano-4-ethyl-6-(4-(3-methoxyazetidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide;

›DETAILED DESCRIPTION OF THE INVENTION · 38 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably, presently invented novel compounds of Formula (IVbbr) are selected from:

2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((6-((2-Amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; 2-((3,5-dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-fluoro-4-A(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; and 2-((3,5-dicyano-4-ethyl-6-(methyl(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)thio)-2-phenylacetamide;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably, presently invented novel compounds of Formula (IVbbr) are selected from:

(R)-2-((3,5-dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4-(cyclobutyl(methyl)amino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-(4-fluorophenyl)acetamide; and 2-((3,5-dicyano-4-ethyl-6-(methyl(1-methylpyrrolidin-3-yl)amino)pyridin-2-yl)thio)-2-phenylacetamide;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably, presently invented novel compounds of Formula (Vbbr) are selected from:

2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-propyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-ethyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-morpholinopyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-(pyridin-4-yl)acetamide; 2-[(3,5-dicyano-4-ethyl-6-{methyl[2-(morpholin-4-yl)ethyl]amino}pyridin-2-yl)sulfanyl]-2-phenylacetamide; 2-{[3,5-dicyano-4-ethyl-6-(4-propylpiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-ethyl-6-[4-(piperidin-4-yl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[3-(hydroxymethyl)piperazin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-{[3,5-dicyano-4-cyclopropyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-dicyano-4-cyclopropyl-6-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-methylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2,6-dimethylmorpholino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(3-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(Aminomethyl)-4-hydroxypiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(3-(methylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(3-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(4-(dimethylamino)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((R)-3-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-(3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypiperidin-1-yl)pyridin-2-ylthio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-(pyridin-4-yl)acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-ethylpiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-aminopropyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(1,7-diazaspiro[3.5]nonan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-ylmethyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl)amino)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,6-diazaspiro[3.4]octan-6-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-2-yl)thio)propanamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-oxoimidazolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-hydroxypiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((S)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((2-methoxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(3-methoxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-morpholinopyridin-2-yl)thio)-2-phenylacetamide; 2-[[6-(azetidin-1-yl)-3,5-dicyano-4-ethyl-2-pyridyl]sulfanyl]-2-phenyl-acetamide; 2-((3,5-dicyano-4-ethyl-6-(4-oxopiperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(1′-(2-hydroxyethyl)-[4,4′-bipiperidin]-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(8-azabicyclo[3.2.1]octan-3-yl(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(2-(hydroxymethyl)morpholino)pyridin-2-yl)thio)-2-phenylacetamide; (R)-2-[(3,5-Dicyano-4-ethyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; N-(4-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-ylthio)methyl)benzyl)acetamide trifluoroacetate; 2-{[3,5-dicyano-4-ethyl-6-(5-methyl-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-4-ethyl-6-[4-(2-methoxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxpropyl)-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; Methyl 2-[4-(6-{[carbamoyl(phenyl)methyl]sulfanyl}-3,5-dicyano-4-ethylpyridin-2-yl)-1,4-diazepan-1-yl]acetate; 2-{[3,5-Dicyano-4-cyclopropyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-cyclopropyl-6-(5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-4-ethyl-6-(4-methyl-5-oxo-1,4-diazepan-1-yl)pyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-{[3,5-Dicyano-6-(1,4-diazepan-1-yl)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; 2-({3,5-Dicyano-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]-4-(2,2,2-trifluoroethyl)pyridin-2-yl}sulfanyl)-2-phenylacetamide; (2R)-2-({3,5-Dicyano-4-ethyl-6-[4-(2-hydroxyethyl)-1,4-diazepan-1-yl]pyridin-2-yl}amino)-2-phenylacetamide; 2-({6-[(3S)-3-Aminopyrrolidin-1-yl]-3,5-dicyano-4-cyclopropylpyridin-2-yl}sulfanyl)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(hexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(2-methyl-2,9-diazaspiro[5.5]undecan-9-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(2-(cyclopropylmethyl)-2,9-diazaspiro[5.5]undecan-9-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide hydrochloride; 2-((3,5-Dicyano-6-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-3-yl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2,2,2-trifluoroacetic acid; 2-((6-([4,4′-Bipiperidin]-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(2-Aminoethyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-(3-Aminopropyl)piperazin-1-yl)-3,5-dicyano-4-cyclopropylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-cyclopropyl-6-(4-((4-methylpiperazin-1-yl)methyl)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-Acetylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-(4-(2-hydroxyethyl)piperazin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-[(3,5-Dicyano-4-cyclopropyl-6-morpholino-2-pyridyl)sulfanyl]-2-phenyl-acetamide; 2-((6-(4-Benzoylpiperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-4-ethyl-6-((5S,6S)-6-hydroxy-1-(methylsulfonyl)-1,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-Dicyano-6-(4,4-difluoropiperidin-1-yl)-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; (R)-2-((3,5-Dicyano-4-ethyl-6-((R)-3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-(furan-2-yl)-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-amino-4-methylpiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)acetamide; (2S)-2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)propanamide; 2-((6-(4-(3-aminooxetane-3-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 4-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)tetrahydro-2H-pyran-4-carboxamide; 2-((6-(4-(4-aminotetrahydro-2H-pyran-4-carbonyl)piperazin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; p 2-((3,5-dicyano-6-(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)-4-methoxypyridin-2-yl)thio)-2-phenylacetamide; 2-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-aminoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((6-((2-amino-2-oxoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)-2-phenylacetamide; 2-amino-N-(1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 2-((6-(4-(2-aminoethoxy)piperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(3-hydroxpyrrolidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide; 2-((3,5-dicyano-4-ethyl-6-(4-(2-hydroxyethoxy)piperidin-1-yl)pyridin-2-yl)thio)-2-phenylacetamide;

›DETAILED DESCRIPTION OF THE INVENTION · 39 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

Included prodrugs of Formula (Vbbr) of the invention are:

1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl dihydrogen phosphate; (2S)-2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; (S)-1-(6-(((S)-2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; and 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl dihydrogen phosphate;

or a pharmaceutically acceptable salt thereof.

Non Primary Amide:

Suitably, presently invented novel compounds of Formula (Icr) are selected from:

2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; (R)-2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)propanamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-(piperidin-1-yl)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; 2-(4-aminopiperidin-1-yl)-6-((4-(1,1-dioxidoisothiazolidin-2-yl)benzyl)thio)-4-ethylpyridine-3,5-dicarbonitrile; 2-(4-aminopiperidin-1-yl)-6-((4-(1,1-dioxido-1,2-thiazinan-2-yl)benzyl)thio)-4-ethylpyridine-3,5-dicarbonitrile; 2-(4-aminopiperidin-1-yl)-4-ethyl-6-((4-((methylsulfonyl)methyl)benzyl)thio)pyridine-3,5-dicarbonitrile; 4-(((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl methanesulfonate; N-(4-(((3,5-dicyano-4-ethyl-6-(4-(isopropylamino)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-ylthio)methyl)benzyl)acetamide; 2-amino-N-(4-(((3,5-dicyano-6-((2-(diethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; rel-2-amino-N-(4-(((6-(cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; N-(4-(((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)acetamide; and N-(4-(((3,5-dicyano-6-(3-((dimethylamino)methyl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;

or a pharmaceutically acceptable salt or prodrug thereof.

Suitably, presently invented novel compounds of Formula (Icr) are selected from:

N-(4-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-ylthio)methyl)benzyl)acetamide; 2-(4-(Aminomethyl)benzylthio)-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridine-3,5-dicarbonitrile; tert-Butyl 4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzylcarbamate; 4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzamide; 2-((4-(Aminomethyl)benzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 2-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)acetic acid; 4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzoic acid; 2-(Dimethylamino)-4-ethyl-6-(((6-oxo-1,6-dihydropyridin-3-yl)methyl)thio)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)thiazol-2-yl)acetamide; 4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzenesulfonamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)acetamide; tert-Butyl (2-((4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)amino)-2-oxoethyl)carbamate; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)methanesulfonamide; 2-Amino-N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)acetamide; 2-(4-Aminopiperidin-1-yl)-6-(benzylthio)-4-ethylpyridine-3,5-dicarbonitrile; 4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl acetate; 2-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl acetamide; 2-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylacetamide; 4-Ethyl-2-((4-(hydroxymethyl)benzyl)thio)-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)-2-hydroxyacetamide; Example 87N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio) methyl)benzyl)propionamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)isobutyramide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)-3-methylbutanamide; 4-Ethyl-2-((4-(((2-hydroxyethyl)amino)methyl)benzyl)thio)-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-6-(4-methyl-1,4-diazepan-1-yl)-4-(methylamino)pyridin-2-yl)thio)methyl)benzyl)acetamide; 2-(((2-Acetyl-1,2,3,4-tetrahydroisoquinolin-6-yl)methyl)thio)-6-(dimethylamino)-4-ethylpyridine-3,5-dicarbonitrile; 2-((4-Cyanobenzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 2-Amino-N-(1-(6-(benzylthio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)acetamide; 2-Amino-N-(1-(6-(benzylthio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; 3-Amino-N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)propanamide; (S)-2-Amino-N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)propanamide; (R)-2-Amino-N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)propanamide; 1-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)-3-ethylurea; 1-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)-3-phenylurea; N-(4-(((3,5-Dicyano-6-(4-methyl-1,4-diazepan-1-yl)-4-(methylthio)pyridin-2-yl)thio)methyl)benzyl)acetamide; (E)-3-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)acrylic acid; N-(4-(((3,5-Dicyano-4-ethyl-6-((2-hydroxyethyl)(methyl)amino)pyridin-2-yl)thio)methyl)benzyl)acetamide; 4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)-N-methylbenzenesulfonamide; N-(4-(((3,5-Dicyano-4-ethoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)acetamide; N-(4-(((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; (S)-2-((1-(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; (S)-2-((6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl 2-amino-3-methylbutanoate; 2-Amino-N-(4-(((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; 4-Ethyl-2-(4-methyl-1,4-diazepan-1-yl)-6-((4-((2-oxopyrrolidin-1-yl)methyl)benzyl)thio)pyridine-3,5-dicarbonitrile; 2-((4-(Aminomethyl)benzyl)thio)-6-(dimethylamino)-4-ethylpyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio) methyl) phenyl) acetamide; N-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)benzyl)-2-hydroxyacetamide; 3-Amino-N-(4-(((3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)benzyl)propanamide; (S)-1-(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl 2-amino-3-methylbutanoate; N-(4-(((3,5-Dicyano-4-ethyl-6-methylpyridin-2-yl)thio)methyl)benzyl)acetamide; 2-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)-1H-pyrazol-1-yl)acetamide; N-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)phenyl) methanesulfonamide; (S)-1-(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl 2-amino-3-methylbutanoate; N-(1-(6-((4-(Acetamidomethyl)benzyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)acetamide; 2-(4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-(2-hydroxyethyl)acetamide; 4-(((3,5-Dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl)thio) methyl)-N-(2-hydroxyethyl)benzamide; 2-((4-(1H-Imidazol-1-yl)benzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 2-((4-Cyano-3-methylbenzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; tert-Butyl(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)carbamate; 2-((4-Aminobenzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)acetamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl) methanesulfonamide; 2-(((6-Aminopyridin-3-yl)methyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-2-hydroxyacetamide; 2-Amino-N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)acetamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(3-oxopiperazin-1-yl)pyridin-2-yl)thio) methyl) benzyl) acetamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)methyl)benzyl)acetamide; N-(4-(1-(3,5-Dicyano-6-(4-(dimethylamino)piperidin-1-yl)-4-ethylpyridin-2-ylthio)propyl)benzyl)acetamide; N-(5-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)pyridin-2-yl)methanesulfonamide; 2-(6-(4-(Acetamidomethyl)benzylthio)-3,5-dicyano-4-ethylpyridin-2-ylthio)-2-phenylacetamide; 4-Ethyl-2-((4-(pyridin-3-yl)benzyl)thio)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridine-3,5-dicarbonitrile; 4-Ethyl-2-((4-(pyridin-4-yl)benzyl)thio)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridine-3,5-dicarbonitrile; 2-Amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-sulfamoylbenzyl)thio)pyridin-2-yl)piperidin-4-yl)acetamide; 2-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-(2-hydroxyethyl)acetamide; 2-(((1H-Indol-5-yl)methyl)thio)-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridine-3,5-dicarbonitrile; 4-(((6-(4-Aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl) benzenesulfonamide; 2-((Benzo[d][1,3]dioxol-5-ylmethyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 2-(((3,3-Dimethoxy-2-oxoindolin-5-yl)methyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 2-(((2,3-Dioxoindolin-5-yl)methyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((6-(((4H-1,2,4-Triazol-3-yl)methyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; 4-Ethyl-2-((4-(pyridin-2-yl)benzyl)thio)-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylacetamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl) thio)methyl)phenyl)-N-methylmethanesulfonamide; 4-((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-ylthio)methyl)phenylboronic acid; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)benzyl)-2-(methylamino)acetamide; 2-((4-Amino-3-fluorobenzyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)-2-fluorophenyl)methanesulfonamide; N-(4-(((3,5-Dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl) thio)methyl)-2-fluorophenyl)acetamide; 2-(4-Aminopiperidin-1-yl)-4-ethyl-6-(((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methyl)thio)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-Dicyano-4-ethyl-6-(3-hydroxypyrrolidin-1-yl)pyridin-2-yl)thio)methyl)benzyl)-2-hydroxyacetamide; N-(4-(((6-((2-Amino-2-oxoethyl)(methyl) amino)-3,5-dicyano-4-ethylpyridin-2-yl) thio) methyl) benzyl)-2-hydroxyacetamide; 2-(4-(2-(Dimethylamino)ethoxy)benzylthio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 4-Ethyl-2-(4-methyl-1,4-diazepan-1-yl)-6-((4-(methylsulfonyl)benzyl)thio)pyridine-3,5-dicarbonitrile; 2-(4-Aminopiperidin-1-yl)-6-(((1-(2,3-dihydroxpropyl)-1H-pyrazol-4-yl)methyl)thio)-4-ethylpyridine-3,5-dicarbonitrile; 4-Ethyl-2-(4-methyl-1,4-diazepan-1-yl)-6-((4-(4-methylpiperazin-1-yl)benzyl)thio)pyridine-3,5-dicarbonitrile; 4-Ethyl-2-(4-methyl-1,4-diazepan-1-yl)-6-((4-(((2-oxopyrrolidin-3-yl)amino)methyl)benzyl)thio)pyridine-3,5-dicarbonitrile; 2-(((1H-Benzo[d]imidazol-5-yl)methyl)thio)-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridine-3,5-dicarbonitrile; 4-Ethyl-2-(4-methyl-1,4-diazepan-1-yl)-6-(4-(methylsulfonylmethyl)benzylthio)pyridine-3,5-dicarbonitrile; 2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-(neopentylamino)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-((2-((2-methoxyethyl)(methyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-(methylamino)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-((2-((2-methoxyethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-((1-methylcyclopropyl)amino)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-6-((2-(dimethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((6-((2-aminoethyl)(methyl)amino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; 2-(4-aminopiperidin-1-yl)-4-ethyl-6-((4-((methylsulfonyl)methyl)benzyl)thio)pyridine-3,5-dicarbonitrile; N-(4-(((3,5-dicyano-4-ethyl-6-((2-((2-fluoroethyl)amino)ethyl)(methyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; 2-amino-N-(4-(((3,5-dicyano-6-((2-(diethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; 4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)-N-(1H-pyrazol-4-yl)benzamide; rel-2-amino-N-(4-(((6-(cis-4-amino-3-fluoropiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)benzyl)acetamide; N-(4-(((3,5-dicyano-4-ethyl-6-(4-(isopropylamino)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(4-((2-methoxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-6-(2-((dimethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; 2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)-2-methylpropanamide; N-(4-(((3,5-dicyano-6-(4-(cyclopropylamino)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(2-(pyrrolidin-1-ylmethyl)morpholino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(methyl(2-(piperidin-1-yl)ethyl)amino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-6-((2-(diethylamino)ethyl)(methyl)amino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-6-(2-((diethylamino)methyl)morpholino)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; (R)-2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)propanamide; (S)-2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)propanamide; N-(4-(((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; 2-amino-N-(1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)piperidin-4-yl)acetamide; N-(4-(((6-(2-(aminomethyl)morpholino)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-1-fluoro-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-4-ethyl-6-(2-((methylamino)methyl)morpholino)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((3,5-dicyano-6-(3-((dimethylamino)methyl)piperidin-1-yl)-4-ethylpyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; 2-(4-aminopiperidin-1-yl)-6-((4-(1,1-dioxidoisothiazolidin-2-yl)benzyl)thio)-4-ethylpyridine-3,5-dicarbonitrile; 2-(4-aminopiperidin-1-yl)-6-((4-(1,1-dioxido-1,2-thiazinan-2-yl)benzyl)thio)-4-ethylpyridine-3,5-dicarbonitrile; N-(4-(((3,5-dicyano-4-ethyl-6-(4-methyl-1,4-diazepan-1-yl)pyridin-2-yl)thio)methyl)phenyl)-1,1-difluoro-N-methylmethanesulfonamide; 2-((4-(1,1-dioxidoisothiazolidin-2-yl)benzyl)thio)-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridine-3,5-dicarbonitrile; 2-((4-(1,1-dioxido-1,2-thiazinan-2-yl)benzyl)thio)-4-ethyl-6-(4-(neopentylamino)piperidin-1-yl)pyridine-3,5-dicarbonitrile; 4-(((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)methyl)phenyl methanesulfonate; (R)-2-amino-N-((1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)pyrrolidin-3-yl)methyl)acetamide; (S)-2-amino-N-((1-(3,5-dicyano-4-ethyl-6-((4-(N-methylmethylsulfonamido)benzyl)thio)pyridin-2-yl)pyrrolidin-3-yl)methyl)acetamide; N-(4-(1-((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-ethylpyridin-2-yl)thio)ethyl)phenyl)-N-methylmethanesulfonamide; N-(4-(((6-(4-aminopiperidin-1-yl)-3,5-dicyano-4-methoxypyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide; and N-(4-(((3,5-dicyano-4-ethyl-6-(4-((2-hydroxyethyl)amino)piperidin-1-yl)pyridin-2-yl)thio)methyl)phenyl)-N-methylmethanesulfonamide;

›DETAILED DESCRIPTION OF THE INVENTION · 40 of 41

or a pharmaceutically acceptable salt or prodrug thereof.

The skilled artisan will appreciate that pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention pharmaceutically acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to pharmaceutically acceptable salts, of the compounds according to Formula (I). The invention is further directed to free or unsalted compounds of Formula (I).

The pharmaceutically acceptable salts of the compounds of the invention are readily prepared by those of skill in the art.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS, tromethamine), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N′-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-p chlorobenzyl-2-pyrrolildine-1′-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, and zinc.

The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, is not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically enriched mixtures, or as enantiomerically pure individual stereoisomers.

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I.

Isotopically-labelled compounds, for example those into which radioactive isotopes such as 3 H or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and 125 I isotopes are particularly useful in SPECT (single photon emission computerized tomography), both are useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.

The compounds of the invention may exist in solid or liquid form. In solid form, compound of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon the temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterized by a phase change, typically first order (‘melting point’).

›DETAILED DESCRIPTION OF THE INVENTION · 41 of 41

The compounds of the invention may have the ability to crystallize in more than one form, a characteristic, which is known as polymorphism (“polymorphs”). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility and melting point.

The compounds of Formula (I) may exist in solvated and unsolvated forms. As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of Formula (I) or a salt) and a solvent. Such solvents, for the purpose of the invention, may not interfere with the biological activity of the solute. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline compounds wherein solvent molecules are incorporated into the crystalline lattice during crystallization. The incorporated solvent molecules may be water molecules or non-aqueous such as ethanol, isopropanol, DMSO, acetic acid, ethanolamine, and ethyl acetate molecules. Crystalline lattice structures incorporated with water molecules are typically referred to as “hydrates”. Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water.

It is also noted that the compounds of Formula (I) may form tautomers. ‘Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. It is understood that all tautomers and mixtures of tautomers of the compounds of the present invention are included within the scope of the compounds of the present invention.

While aspects for each variable have generally been listed above separately for each variable this invention includes those compounds in which several or each aspect in Formula (I) is selected from each of the aspects listed above. Therefore, this invention is intended to include all combinations of aspects for each variable.

›Definitions · 1 of 14

It will be appreciated that the following definitions apply to each of the aforementioned formulae and to all instances of these terms, unless the context dictates otherwise.

“Alkyl” refers to a hydrocarbon chain having the specified number of “member atoms”. For example, C 1 -C 6 alkyl refers to an alkyl group having from 1 to 6 member atoms. Alkyl groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes but is not limited to: methyl, ethyl, ethylenyl, propyl (n-propyl and isopropyl), butenyl, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.

“Alkoxy” refers to an —O-alkyl group wherein “alkyl” is as defined herein. For example, C 1 -C 4 alkoxy refers to an alkoxy group having from 1 to 4 carbon member atoms. Examples of such groups include but is not limited to: methoxy, ethoxy, propoxy, butoxy, and t-butoxy.

“Aryl” refers to an aromatic hydrocarbon ring system. Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member atoms, such as but no limited to: phenyl, dihydroindene, naphthalene, tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl.

“Cycloalkyl”, unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring or rings having from three to seven carbon atoms. Cycloalkyl groups are monocyclic or spiro ring systems. For example, C 3 -C 7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member atoms. Examples of cycloalkyl as used herein include but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, spiro heptanyl and cycloheptyl. Suitably cycloalkyl is selected from: cyclopropyl, cyclopentyl and cyclohexyl.

“Heteroaryl” refers to a monocyclic aromatic 4 to 8 member ring containing from 1 to 7 carbon atoms and containing from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms, or to such aromatic ring is fused one or more rings, such as heteroaryl rings, aryl rings, heterocyclic rings, or cycloalkyl rings. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms. Heteroaryl includes but is not limited to: benzoimidazolyl, benzothiazolyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1,4]dioxanyl, benzofuranyl, 9H-a-carbolinyl, cinnolinyl, furanyl, imidazolyl, oxazoly, indazolyl, indolizinyl, indolyl, isoindolyl, isothiazolyl, isoquinolinyl, isoxazolyl, indolizinyl, naphthyridinyl, oxazolyl, oxothiadiazolyl, oxadiazolyl, phthalazinyl, pyridyl, pyrrolyl, purinyl, pteridinyl, phenazinyl, pyrazolyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, pyridazyl, pyrazinyl, pyrimidyl, quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolyl and thiazolidinyl. Suitably heteroaryl is selected from: furanyl, pyrazolyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, triazolyl, thiazolyl and thienyl. Suitably heteroaryl is a pyridyl group or an imidazolyl group. Suitably heteroaryl is a pyridyl.

“Heterocyclic” or “heterocycloalkyl”, as used herein, unless otherwise defined, refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 11 are carbon atoms and from 1 to 6 are heteroatoms independently selected from nitrogen, oxygen and sulfur. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Such ring may be optionally fused to one or more other “heterocyclic” rings, aryl rings, heteroaryl rings, or cycloalkyl rings. Such rings may be bridged bicyclic or spiro. Examples of “heterocyclic” groups include, but are not limited to: 1,4diazepanyl, azetidinyl, oxetanyl, 1,4-dioxanyl, 1,3-dioxanyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, piperazinyl, piperazinyl-2,5-dionyl, morpholinyl, dihydropyranyl, dihydrocinnolinyl, dihydropyridinyl, tetrahydropyranyl, 2,3-dihydrofuranyl, 2,3-dihydrobenzofuranyl, dihydroisoxazolyl, tetrahydrooxazolyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydrothiazinyl, tetrahydrothiopyranyl, tetrahydrothiophenyl, dihydroquinoxalinyl, tetrahydroquinoxalinyl, tetrahydroisoquinolinyl, tetrahydropyridinyl, tetrahydrocarbolinyl, 2,9-diazaspiro[5.5]undecanyl, 1,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, 1-oxa-6-azaspiro[3.4]octanyl, 5-oxa-2-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, 1,8-diazaspiro[4.5]decanyl and 8-azabicyclo[3.2.1]octanyl. Suitably heterocyclic is selected from: 1,4-diazepanyl, azetidinyl, oxetanyl, pyrrolidinyl, dihydropyridinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydropyranyl, 2,9-diazaspiro[5.5]undecanyl, 1,8-diazaspiro[4.5]decanyl, 2,8-diazaspiro[4.5]decanyl, hexahydropyrrolo-1,4-diazepanyl, 1-oxa6-azaspiro[3.4]octanyl, 5-oxa-2-azaspiro[3.4]octanyl, 1,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 2,6-diazaspiro[3.4]octanyl, 1,8-diazaspiro[4.5]decanyl and 8-azabicyclo[3.2.1]octanyl.

“Heteroatom” refers to a nitrogen, sulphur or oxygen atom.

“Halogen” and “halo” refers to a fluorine, chlorine, bromine, or iodine atom.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “hydroxy” refers to the group —OH.

As used herein, the term “amino” refers to the group —NH 2 .

As used herein, the term “aminocarbonyl” refers to the group —C(O)NH 2 .

As used herein, the term “guanidino” refers to the group —NHC(═NH)NH 2 .

As used herein, the term “carboxy” refers to the group —C(O)OH.

As used herein, the term “cyano” refers to the group —CN.

›Definitions · 2 of 14

As used herein, the term “prodrug” refers to a compound that is metabolized in the body to produce a biologically active compound. This more biologically active compound is referred to herein as an “active compound”. An example of a prodrug of the invention is the compound of Example 151. An example of the corresponding active compound is the compound of Example 147.

As used herein, the term “active compound” refers to a compound inhibits the activity of DNMT1, suitably a compound that is a selective inhibitor of DNMT1.

As used herein, the term “selective”, when referring to chemical compounds, suitably the active compounds of the present invention, means the compounds exhibit an IC50 over 30 times more active, suitably over 50 times more active, suitably over 100 times more active as an inhibitor against DNMT1, than DNMT3A or DNMT3B in the Breaklight Assay described herein or a similar assay.

As used herein, the term “Compound A” refers to: 2-{[3,5-dicyano-6-(dimethylamino)-4-ethylpyridin-2-yl]sulfanyl}-2-phenylacetamide, the compound of Example 3.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry . Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl); Ac 2 O (acetic anhydride); A-CN (acetonitrile); AlBN (azobis(isobutyronitrile)); BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl); BMS (borane-dimethyl sulphide complex); Bn (benzyl); Boc (tert-Butoxycarbonyl); Boc 2 O (di-tert-butyl dicarbonate); BOP (Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); CAN (cerric ammonium nitrate); Cbz (benzyloxycarbonyl); CSI (chlorosulfonyl isocyanate); CSF (cesium fluoride); DABCO (1,4-Diazabicyclo[2.2.2]octane); DAST (Diethylamino)sulfur trifluoride); DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene); DCC (Dicyclohexyl Carbodiimide); DCE (1,2-dichloroethane); DCM (dichloromethane); DDQ (2,3-Dichloro-5,6-dicyano-1,4-benzoquinone); ATP (adenosine triphosphate); Bis-pinacolatodiboron (4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi-1,3,2-dioxaborolane); BSA (bovine serum albumin); C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase) CH 3 —CN (acetonitrile) Cy (cyclohexyl); DCM (dichloromethane); DIEA (diisopropylethylamine); DIPEA (Hunig's base, N-ethyl-N-(1-methylethyl)-2-propanamine); Dioxane (1,4-dioxane); DMAP (4-dimethylaminopyridine); DME (1,2-dimethoxyethane); DMEDA (N,N′-dimethylethylenediamine); DMF (N,N-dimethylformamide); DMSO (dimethylsulfoxide); DPPA (diphenyl phosphoryl azide); EDC (N-(3-dimethylaminopropyl)-N′ethylcarbodiimide) hydrochloride salt; EDTA (ethylenediaminetetraacetic acid); EtOAc (ethyl acetate); EtOH (ethanol); Et 2 O (diethyl ether); HEPES (4-(2-hydroxyethyl)-1-piperazinyl ethane sulfonic acid); HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole); HOBt (1-hydroxybenzotriazole); HOAc (acetic acid); HPLC (high pressure liquid chromatography); HMDS (hexamethyldisilazide); Hunig's Base (N,N-Diisopropylethylamine); IPA (isopropyl alcohol); Indoline (2,3-dihydro-1H-indole); KHMDS (potassium hexamethyldisilazide); LAH (lithium aluminum hydride); LDA (lithium diisopropylamide); LHMDS (lithium hexamethyldisilazide); MeOH (methanol); MTBE (methyl tert-butyl ether); mcM (micromolar); mCPBA (m-chloroperbezoic acid); NaHMDS (sodium hexamethyldisilazide); NCS (N-chlorosuccinimide); NBS (N-bromosuccinimide); PE (petroleum ether); Pd 2 (dba) 3 (Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl 2 .DCM Complex ([1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).dichloromethane complex); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate); RPHPLC (reverse phase high pressure liquid chromatography); RT (room temperature); Sat. (saturated); SFC (supercritical fluid chromatography); SGC (silica gel chromatography); SM (starting material); TLC (thin layer chromatography); TEA (triethylamine); TEMPO (2,2,6,6-Tetramethylpiperidinyl 1-oxyl, free radical); TFA (trifluoroacetic acid); THF (tetrahydrofuran); and Ts-Cl (p-toluenesulfonyl chloride).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCl.

Compound Preparation

The compounds according to Formula (I) are prepared using conventional organic synthetic methods. Suitable synthetic routes are depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (4th ed.), John Wiley & Sons, NY (2006). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound.

›Definitions · 3 of 14

In some cases intermediate of formula 13, is used to obtain intermediate of formula 4, as shown in Scheme 2, and used in subsequent steps as shown in Scheme 1 and Scheme 2.

In other cases intermediate of formula 13 is used to obtain compound of formula 16, which is used in subsequent steps to give compounds of formula 18 as described in Scheme 3.

In some cases compounds of formula 19 and 20 are used to give the compounds of formula 21 as described in Scheme 4.

Compounds of formula 24 are prepared by the synthetic route shown in Scheme 5. Intermediates of formula 22 are commercially available compounds, that could be or could not be single enantiomers. When compounds of formula 22 are single enantiomers, so are the corresponding compounds of formula 23 and formula 24.

For compounds of formula 26, intermediate of formula 14 and intermediate of formula 25 have been used as shown in Scheme 6. Intermediates of formula 25 are commercially available or are synthesized using conventional organic synthesis procedures that can be reproduced by any skilled artisan.

Alternatively for compounds of formula 26, intermediate of formula 14 and intermediate of formula 27 have been used as in Scheme 7. Intermediates of formula 27 are commercially available or are synthesized using conventional organic synthesis procedures that can be reproduced by any skilled artisan.

Compounds of formulas 33 and 34 have been prepared by the synthetic routes shown in Scheme 8. Intermediates 28 and 29 are commercially available compounds. Intermediates of formula 31 are commercial or are synthesized using conventional organic synthesis procedures that can be reproduced by any skilled artisan.

Compounds of formula 40 have been prepared by the synthetic routes shown in Scheme 9. Intermediates 35 and 36 are commercially available compounds. Intermediates of formula 31 are commercial or are synthesized using conventional organic synthesis procedures that can be reproduced by any skilled artisan.

Compounds of formula 43 have been prepared by the synthetic routes shown in Scheme 10. Intermediate 41 is commercial.

Compounds of formula 48 have been prepared by the synthetic routes shown in scheme 11. Intermediates 1 and 44 are commercially available.

Compounds of formula 52 have been prepared by the synthetic routes shown in scheme 12. Intermediate 49 is commercial and intermediate 46 is shown above in scheme 11.

Compounds of formula 58 have been prepared by the synthetic routes shown in scheme 13. Intermediates 1 and 53 are commercially available.

Methods of Use

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof are selective inhibitors of DNMT1. These compounds are potentially useful in the treatment of conditions that respond to the selective inhibition of DNMT1. These include but are not limited to, cancer and pre-cancerous syndromes and beta hemoglobinopathies such as sickle cell disease, sickle cell anemia, and beta thalassemia. Accordingly, in another aspect the invention is directed to methods of treating such conditions.

Suitably, the present invention relates to a method for treating breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating colon cancer.

Suitably the present invention relates to a method for treating pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.

Suitably the present invention relates to a method for treating skin cancer, including melanoma, including metastatic melanoma.

Suitably the present invention relates to a method for treating lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Suitably the present invention relates to a method for treating cancers selected from the group consisting of: cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid glad, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemagioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary -CNS lymphoma; neoplasms of the -CNS; spinal axis tumours; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hanlartoma; inesothelioma; and Hodgkin's Disease.

Suitably the present invention relates to a method for treating cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilms tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.

›Definitions · 4 of 14

Suitably the present invention relates to a method for treating pre-cancerous syndromes in a mammal, including a human, wherein the pre-cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

In some embodiments, the compounds of the invention can be used to overcome T-cell tolerance.

In some embodiments, the compounds of the invention can be used to treat diabetic nephropathy, diabetes, podocyte injury, atherosclerosis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, liver cirrhosis, rheumatoid arthritis, and Alzheimer's disease.

Compounds of the invention can also be used to increase or enhance an immune response, including increasing the immune response to an antigen; to improve immunization, including increasing vaccine efficacy; and to increase inflammation. In some embodiments, the compounds of the invention can be used to enhance the immune response to vaccines including, but not limited, Listeria vaccines, oncolytic viral vaccines, and cancer vaccines such as GV AX® (granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccine).

Further diseases and disorders treatable with compounds of the invention include, but are not limited to, treating beta hemoglobinopathies, such as sickle cell disease, sickle cell anemia, and beta thalassemia.

The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof.

By the term “treating” and derivatives thereof as used herein, in reference to a condition means: (1) to ameliorate the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The term “treating” and derivatives thereof refers to therapeutic therapy. Therapeutic therapy is appropriate to alleviate symptoms or to treat at early signs of disease or its progression.

The skilled artisan will appreciate that “prevention” is not an absolute term. In medicine, “prevention” is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen or when the subject has a strong family history of a beta-hemoglobinopathy such as sickle cell disease, sickle cell anemia, or beta-thalassemia.

As used herein, the term “effective amount” and derivatives thereof means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” and derivatives thereof means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.

As used herein, “patient” or “subject” refers to a human or other mammal. Suitably the patient or subject is a human.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration and parenteral administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Typical daily dosages may vary depending upon the particular route of administration chosen. Typical dosages for oral administration range from 1 mg to 1000 mg per person per dose. Preferred dosages are 1-500 mg once daily or BID per person.

›Definitions · 5 of 14

Additionally, the compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered as prodrugs. As used herein, a “prodrug” of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Typical functional derivatives used to prepare prodrugs include modifications of the compound that are chemically or enzymatically cleaved in vivo. Such modifications, include the preparation of phosphates, amides, ethers, esters, thioesters, carbonates, and carbamate. Where a —COOH or —OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for —COOH, and acetate maleate and the like for —OH, and those esters known in the art for modifying solubility or hydrolysis characteristics.

Accordingly, the invention is further directed to prodrugs of the compounds according to Formula (I). Suitably, the prodrug is a dihydrogen phosphate. Suitably, the prodrug is a 2-amino-3-methylbutanoate.

Included in the prodrugs of Formula (I) are:

1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)pyrrolidin-3-yl dihydrogen phosphate; 2-((6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)(methyl)amino)ethyl dihydrogen phosphate; 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)azetidin-3-yl dihydrogen phosphate; (2S)-2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl 2-amino-3-methylbutanoate; 2-((1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl)oxy)ethyl dihydrogen phosphate; and 1-(6-((2-amino-2-oxo-1-phenylethyl)thio)-3,5-dicyano-4-ethylpyridin-2-yl)piperidin-4-yl dihydrogen phosphate;

a pharmaceutically acceptable salt thereof.

Prodrugs of the compounds of the invention are readily prepared by those of skill in the art.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.

By the term “co-administration” as used herein is meant either simultaneous administration or any manner of separate sequential administration of an inhibitor of the activity of DMNT1, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented combinations are indicated below. This list is non-limiting. Additional anti-neoplastic agents are contemplated for use with the presently invented compounds.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 6 th edition (Feb. 15, 2001), Lippincott Williams & Wilkins Publishers. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented combinations are chemotherapeutic agents.

Anti-microtubule or anti-mitotic agents are phase specific agents active against the microtubules of tumor cells during M or the mitosis phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids. Diterpenoids, which are derived from natural sources, are phase specific anti-cancer agents that operate at the G 2 /M phases of the cell cycle. It is believed that the diterpenoids stabilize the β-tubulin subunit of the microtubules, by binding with this protein. Disassembly of the protein appears then to be inhibited with mitosis being arrested and cell death following. Examples of diterpenoids include, but are not limited to, paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene product isolated from the Pacific yew tree Taxus brevifolia and is commercially available as an injectable solution TAXOL®. It is a member of the taxane family of terpenes. Paclitaxel has been approved for clinical use in the treatment of refractory ovarian and breast cancer in the United States.

›Definitions · 6 of 14

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine,N-tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially available as an injectable solution as TAXOTERE®. Docetaxel is indicated for the treatment of breast cancer. Docetaxel is a semisynthetic derivative of paclitaxel q.v., prepared using a natural precursor, 10-deacetyl-baccatin III, extracted from the needle of the European Yew tree. The dose limiting toxicity of docetaxel is neutropenia.

Vinca alkaloids are phase specific anti-neoplastic agents derived from the periwinkle plant. Vinca alkaloids act at the M phase (mitosis) of the cell cycle by binding specifically to tubulin. Consequently, the bound tubulin molecule is unable to polymerize into microtubules. Mitosis is believed to be arrested in metaphase with cell death following. Examples of vinca alkaloids include, but are not limited to, vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available as VELBAN® as an injectable solution. Although, it has possible indication as a second line therapy of various solid tumors, it is primarily indicated in the treatment of testicular cancer and various lymphomas including Hodgkin's Disease; and lymphocytic and histiocytic lymphomas. Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commercially available as ONCOVIN® as an injectable solution. Vincristine is indicated for the treatment of acute leukemias and has also found use in treatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects are the most common side effect of vincristine and to a lesser extent myelosupression and gastrointestinal mucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commercially available as an injectable solution of vinorelbine tartrate (NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine is indicated as a single agent or in combination with other chemotherapeutic agents, such as cisplatin, in the treatment of various solid tumors, particularly non-small cell lung, advanced breast, and hormone refractory prostate cancers. Myelosuppression is the most common dose limiting side effect of vinorelbine.

Platinum coordination complexes are non-phase specific anti-cancer agents, which are interactive with DNA. The platinum complexes enter tumor cells, undergo, aquation and form intra- and interstrand crosslinks with DNA causing adverse biological effects to the tumor. Examples of platinum coordination complexes include, but are not limited to, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available as PLATINOL® as an injectable solution. Cisplatin is primarily indicated in the treatment of metastatic testicular and ovarian cancer and advanced bladder cancer. The primary dose limiting side effects of cisplatin are nephrotoxicity, which may be controlled by hydration and diuresis, and ototoxicity.

Carboplatin, platinum, diammine [1,1-cyclobutane-dicarboxylate(2-)-O,O′], is commercially available as PARAPLATIN® as an injectable solution. Carboplatin is primarily indicated in the first and second line treatment of advanced ovarian carcinoma. Bone marrow suppression is the dose limiting toxicity of carboplatin.

Alkylating agents are non-phase anti-cancer specific agents and strong electrophiles. Typically, alkylating agents form covalent linkages, by alkylation, to DNA through nucleophilic moieties of the DNA molecule such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts nucleic acid function leading to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

Cyclophosphamide, 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate, is commercially available as an injectable solution or tablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent or in combination with other chemotherapeutic agents, in the treatment of malignant lymphomas, multiple myeloma, and leukemias. Alopecia, nausea, vomiting and leukopenia are the most common dose limiting side effects of cyclophosphamide.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commercially available as an injectable solution or tablets as ALKERAN®. Melphalan is indicated for the palliative treatment of multiple myeloma and non-resectable epithelial carcinoma of the ovary. Bone marrow suppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, is commercially available as LEUKERAN® tablets. Chlorambucil is indicated for the palliative treatment of chronic lymphatic leukemia, and malignant lymphomas such as lymphosarcoma, giant follicular lymphoma, and Hodgkin's disease. Bone marrow suppression is the most common dose limiting side effect of chlorambucil.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially available as MYLERAN® TABLETS. Busulfan is indicated for the palliative treatment of chronic myelogenous leukemia. Bone marrow suppression is the most common dose limiting side effects of busulfan.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commercially available as single vials of lyophilized material as Bi-CNU®. Carmustine is indicated for the palliative treatment as a single agent or in combination with other agents for brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Delayed myelosuppression is the most common dose limiting side effects of carmustine.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is commercially available as single vials of material as DTIC-Dome®. Dacarbazine is indicated for the treatment of metastatic malignant melanoma and in combination with other agents for the second line treatment of Hodgkin's Disease. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dacarbazine.

›Definitions · 7 of 14

Antibiotic anti-neoplastics are non-phase specific agents, which bind or intercalate with DNA. Typically, such action results in stable DNA complexes or strand breakage, which disrupts ordinary function of the nucleic acids, leading to cell death. Examples of antibiotic anti-neoplastic agents include, but are not limited to, actinomycins such as dactinomycin, anthrocyclins such as daunorubicin and doxorubicin; and bleomycins. Dactinomycin, also know as Actinomycin D, is commercially available in injectable form as COSMEGEN®. Dactinomycin is indicated for the treatment of Wilm's tumor and rhabdomyosarcoma. Nausea, vomiting, and anorexia are the most common dose limiting side effects of dactinomycin.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as a liposomal injectable form as DAUNOXOME® or as an injectable as CERUBIDINE®. Daunorubicin is indicated for remission induction in the treatment of acute nonlymphocytic leukemia and advanced HIV associated Kaposi's sarcoma. Myelosuppression is the most common dose limiting side effect of daunorubicin.

Doxorubicin, (8S, 10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedione hydrochloride, is commercially available as an injectable form as RUBEX® or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatment of acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also a useful component in the treatment of some solid tumors and lymphomas. Myelosuppression is the most common dose limiting side effect of doxorubicin.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus , is commercially available as BLENOXANE®. Bleomycin is indicated as a palliative treatment, as a single agent or in combination with other agents, of squamous cell carcinoma, lymphomas, and testicular carcinomas. Pulmonary and cutaneous toxicities are the most common dose limiting side effects of bleomycin.

Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G 2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA causing DNA strand breaks. The strand breaks accumulate and cell death follows. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin 9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially available as an injectable solution or capsules as VePESID® and is commonly known as VP-16. Etoposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of testicular and non-small cell lung cancers. Myelosuppression is the most common side effect of etoposide. The incidence of leucopenia tends to be more severe than thrombocytopenia.

Teniposide, 4′-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially available as an injectable solution as VUMON® and is commonly known as VM-26. Teniposide is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia in children. Myelosuppression is the most common dose limiting side effect of teniposide. Teniposide can induce both leucopenia and thrombocytopenia.

Antimetabolite neoplastic agents are phase specific anti-neoplastic agents that act at S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting purine or pyrimidine base synthesis and thereby limiting DNA synthesis. Consequently, S phase does not proceed and cell death follows. Examples of antimetabolite anti-neoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is commercially available as fluorouracil. Administration of 5-fluorouracil leads to inhibition of thymidylate synthesis and is also incorporated into both RNA and DNA. The result typically is cell death. 5-fluorouracil is indicated as a single agent or in combination with other chemotherapy agents in the treatment of carcinomas of the breast, colon, rectum, stomach and pancreas. Myelosuppression and mucositis are dose limiting side effects of 5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro deoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, is commercially available as CYTOSAR-U® and is commonly known as Ara-C. It is believed that cytarabine exhibits cell phase specificity at S-phase by inhibiting DNA chain elongation by terminal incorporation of cytarabine into the growing DNA chain. Cytarabine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Other cytidine analogs include 5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine). Cytarabine induces leucopenia, thrombocytopenia, and mucositis.

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, is commercially available as PURINETHOL®. Mercaptopurine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Mercaptopurine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression and gastrointestinal mucositis are expected side effects of mercaptopurine at high doses. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commercially available as TABLOID®. Thioguanine exhibits cell phase specificity at S-phase by inhibiting DNA synthesis by an as of yet unspecified mechanism. Thioguanine is indicated as a single agent or in combination with other chemotherapy agents in the treatment of acute leukemia. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of thioguanine administration. However, gastrointestinal side effects occur and can be dose limiting. Other purine analogs include pentostatin, erythrohydroxynonyladenine, fludarabine phosphate, and cladribine.

›Definitions · 8 of 14

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride (β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibits cell phase specificity at S-phase and by blocking progression of cells through the G1/S boundary. Gemcitabine is indicated in combination with cisplatin in the treatment of locally advanced non-small cell lung cancer and alone in the treatment of locally advanced pancreatic cancer. Myelosuppression, including leucopenia, thrombocytopenia, and anemia, is the most common dose limiting side effect of gemcitabine administration.

Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl) methyl]methylamino] benzoyl]-L-glutamic acid, is commercially available as methotrexate sodium. Methotrexate exhibits cell phase effects specifically at S-phase by inhibiting DNA synthesis, repair and/or replication through the inhibition of dyhydrofolic acid reductase which is required for synthesis of purine nucleotides and thymidylate. Methotrexate is indicated as a single agent or in combination with other chemotherapy agents in the treatment of choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and carcinomas of the breast, head, neck, ovary and bladder. Myelosuppression (leucopenia, thrombocytopenia, and anemia) and mucositis are expected side effect of methotrexate administration.

Camptothecins, including, camptothecin and camptothecin derivatives are available or under development as Topoisomerase I inhibitors. Camptothecins cytotoxic activity is believed to be related to its Topoisomerase I inhibitory activity. Examples of camptothecins include, but are not limited to irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin described below. Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dione hydrochloride, is commercially available as the injectable solution CAMPTOSAR®.

Irinotecan is a derivative of camptothecin which binds, along with its active metabolite SN-38, to the topoisomerase I-DNA complex. It is believed that cytotoxicity occurs as a result of irreparable double strand breaks caused by interaction of the topoisomerase I:DNA:irintecan or SN-38 ternary complex with replication enzymes. Irinotecan is indicated for treatment of metastatic cancer of the colon or rectum. The dose limiting side effects of irinotecan HCl are myelosuppression, including neutropenia, and GI effects, including diarrhea.

Topotecan HCl, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride, is commercially available as the injectable solution HYCAMTIN®. Topotecan is a derivative of camptothecin which binds to the topoisomerase I-DNA complex and prevents religation of singles strand breaks caused by Topoisomerase I in response to torsional strain of the DNA molecule. Topotecan is indicated for second line treatment of metastatic carcinoma of the ovary and small cell lung cancer. The dose limiting side effect of topotecan HCl is myelosuppression, primarily neutropenia.

Also of interest, is the camptothecin derivative of Formula A following, including the racemic mixture (R,S) form as well as the R and S enantiomers:

known by the chemical name “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptothecin (racemic mixture) or “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin (R enantiomer) or “7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin (S enantiomer). Such compound as well as related compounds are described, including methods of making, in U.S. Pat. Nos. 6,063,923; 5,342,947; 5,559,235; and 5,491,237.

Hormones and hormonal analogues are useful compounds for treating cancers in which there is a relationship between the hormone(s) and growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues useful in cancer treatment include, but are not limited to, adrenocorticosteroids such as prednisone and prednisolone which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutethimide and other aromatase inhibitors such as anastrozole, letrazole, vorazole, and exemestane useful in the treatment of adrenocortical carcinoma and hormone dependent breast carcinoma containing estrogen receptors; progestrins such as megestrol acetate useful in the treatment of hormone dependent breast cancer and endometrial carcinoma; estrogens, androgens, and anti-androgens such as flutamide, nilutamide, bicalutamide, cyproterone acetate and 5α-reductases such as finasteride and dutasteride, useful in the treatment of prostatic carcinoma and benign prostatic hypertrophy; anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene, as well as selective estrogen receptor modulators (SERMS) such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and 6,207,716, useful in the treatment of hormone dependent breast carcinoma and other susceptible cancers; and gonadotropin-releasing hormone (GnRH) and analogues thereof which stimulate the release of leutinizing hormone (LH) and/or follicle stimulating hormone (FSH) for the treatment prostatic carcinoma, for instance, LHRH agonists and antagagonists such as goserelin acetate and luprolide.

Signal transduction pathway inhibitors are those inhibitors, which block or inhibit a chemical process which evokes an intracellular change. As used herein this change is cell proliferation or differentiation. Signal tranduction inhibitors useful in the present invention include inhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3 domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth. Such protein tyrosine kinases can be broadly classified as receptor or non-receptor kinases.

›Definitions · 9 of 14

Receptor tyrosine kinases are transmembrane proteins having an extracellular ligand binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell growth and are generally termed growth factor receptors. Inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase growth factor receptor activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth. Accordingly, the aberrant activity of such kinases has been linked to malignant tissue growth. Consequently, inhibitors of such kinases could provide cancer treatment methods. Growth factor receptors include, for example, epidermal growth factor receptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors, and the RET protooncogene. Several inhibitors of growth receptors are under development and include ligand antagonists, antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides. Growth factor receptors and agents that inhibit growth factor receptor function are described, for instance, in Kath, John C., Exp. Opin. Ther. Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and Lofts, F. J. et al, “Growth factor receptors as targets”, New Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David, CRC press 1994, London.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01/49367, having an International filing date of Dec. 19, 2001, International Publication Number WO02/059110 and an International Publication date of Aug. 1, 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.

Suitably, 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is in the form of a monohydrochloride salt. This salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US01/49367, having an International filing date of Dec. 19, 2001.

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide is sold commercially as the monohydrochloride salt and is known by the generic name pazopanib and the trade name Votrient®.

Pazopanib is implicated in the treatment of cancer and ocular diseases/angiogenesis. Suitably the present invention relates to the treatment of cancer and ocular diseases/angiogenesis, suitably age-related macular degeneration, which method comprises the administration of a compound of Formula (I) alone or in combination with pazopanib.

Tyrosine kinases, which are not growth factor receptor kinases are termed non-receptor tyrosine kinases. Non-receptor tyrosine kinases for use in the present invention, which are targets or potential targets of anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents which inhibit non-receptor tyrosine kinase function are described in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; and Bolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15: 371-404.

SH2/SH3 domain blockers are agents that disrupt SH2 or SH3 domain binding in a variety of enzymes or adaptor proteins including, PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs are discussed in Smithgall, T. E. (1995), Journal of Pharmacological and Toxicological Methods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascade blockers which include blockers of Raf kinases (rafk), Mitogen or Extracellular Regulated Kinase (MEKs), and Extracellular Regulated Kinases (ERKs); and Protein kinase C family member blockers including blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase family members, PDK1 and TGF beta receptor kinases. Such Serine/Threonine kinases and inhibitors thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment and Research. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; Pearce, L. R et al. Nature Reviews Molecular Cell Biology (2010) 11, 9-22. and Martinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Suitably, the pharmaceutically active compounds of the invention are used in combination with a MEK inhibitor. Suitably, N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, or a pharmaceutically acceptable salt or solvate, suitably the dimethyl sulfoxide solvate, thereof, which is disclosed and claimed in International Application No. PCT/JP2005/011082, having an International filing date of Jun. 10, 2005; International Publication Number WO 2005/121142 and an International Publication date of Dec. 22, 2005, the entire disclosure of which is hereby incorporated by reference. N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide, can be prepared as described in United States Patent Publication No. US 2006/0014768, Published Jan. 19, 2006, the entire disclosure of which is hereby incorporated by reference.

›Definitions · 10 of 14

Suitably, the pharmaceutically active compounds of the invention are used in combination with a B-Raf inhibitor. Suitably, N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, or a pharmaceutically acceptable salt thereof, which is disclosed and claimed, in International Application No. PCT/US2009/042682, having an International filing date of May 4, 2009, the entire disclosure of which is hereby incorporated by reference. N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide can be prepared as described in International Application No. PCT/US2009/042682.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of Feb. 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of Aug. 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide is the compound of example 224 and can be prepared as described in International Application No. PCT/US2008/053269.

Suitably, the pharmaceutically active compounds of the invention are used in combination with an Akt inhibitor. Suitably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide or a pharmaceutically acceptable salt thereof, which is disclosed and claimed in International Application No. PCT/US2008/053269, having an International filing date of Feb. 7, 2008; International Publication Number WO 2008/098104 and an International Publication date of Aug. 14, 2008, the entire disclosure of which is hereby incorporated by reference. N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide is the compound of example 96 and can be prepared as described in International Application No. PCT/US2008/053269. Suitably, N-{(1S)-2-amino-1-[(3-fluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide is in the form of a hydrochloride salt. The salt form can be prepared by one of skill in the art from the description in International Application No. PCT/US2010/022323, having an International filing date of Jan. 28, 2010.

Inhibitors of Phosphotidylinositol-3 Kinase family members including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be useful in the present invention. Such kinases are discussed in Abraham, R. T. (1996), Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S. (1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), International Journal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545.

Also of interest in the present invention are Myo-inositol signaling inhibitors such as phospholipase C blockers and Myoinositol analogues. Such signal inhibitors are described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitors of Ras Oncogene. Such inhibitors include inhibitors of farnesyltransferase, geranyl-geranyl transferase, and CAAX proteases as well as anti-sense oligonucleotides, ribozymes and immunotherapy. Such inhibitors have been shown to block ras activation in cells containing wild type mutant ras, thereby acting as antiproliferation agents. Ras oncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R., Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligand binding may also serve as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies to the extracellular ligand binding domain of receptor tyrosine kinases. For example Imclone C225 EGFR specific antibody (see Green, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (see Tyrosine Kinase Signalling in Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice, Cancer Res. (2000) 60, 5117-5124).

Non-receptor kinase angiogenesis inhibitors may also be useful in the present invention. Inhibitors of angiogenesis related VEGFR and TIE2 are discussed above in regard to signal transduction inhibitors (both receptors are receptor tyrosine kinases). Angiogenesis in general is linked to erbB2/EGFR signaling since inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression. Accordingly, non-receptor tyrosine kinase inhibitors may be used in combination with the compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosine kinase), but bind to the ligand; small molecule inhibitors of integrin (alpha, beta 3 ) that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds. (See Bruns C J et al (2000), Cancer Res., 60: 2926-2935; Schreiber A B, Winkler M E, and Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000), Oncogene 19: 3460-3469).

›Definitions · 11 of 14

Agents used in immunotherapeutic regimens may also be useful in combination with the compounds of Formula (I). There are a number of immunologic strategies to generate an immune response. These strategies are generally in the realm of tumor vaccinations. The efficacy of immunologic approaches may be greatly enhanced through combined inhibition of signaling pathways using a small molecule inhibitor. Discussion of the immunologic/tumor vaccine approach against erbB2/EGFR are found in Reilly R T et al. (2000), Cancer Res. 60: 3569-3576.

Agents used in proapoptotic regimens (e.g., bcl-2 antisense oligonucleotides) may also be used in the combination of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Upregulation of bcl-2 has therefore been linked to chemoresistance. Studies have shown that the epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e., mcl-1). Therefore, strategies designed to downregulate the expression of bcl-2 in tumors have demonstrated clinical benefit and are now in Phase II/III trials, namely Genta's G3139 bcl-2 antisense oligonucleotide. Such proapoptotic strategies using the antisense oligonucleotide strategy for bcl-2 are discussed in Water J S et al. (2000), J. Clin. Oncol. 18: 1812-1823.

Cell cycle signalling inhibitors inhibit molecules involved in the control of the cell cycle. A family of protein kinases called cyclin dependent kinases (CDKs) and their interaction with a family of proteins termed cyclins controls progression through the eukaryotic cell cycle. The coordinate activation and inactivation of different cyclin/CDK complexes is necessary for normal progression through the cell cycle. Several inhibitors of cell cycle signalling are under development. For instance, examples of cyclin dependent kinases, including CDK2, CDK4, and CDK6 and inhibitors for the same are described in, for instance, Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230. Further, p21WAF1/CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball et al., Progress in Cell Cycle Res., 3: 125 (1997)). Compounds that are known to induce expression of p21WAF1/CIP1 have been implicated in the suppression of cell proliferation and as having tumor suppressing activity (Richon et al., Proc. Nat Acad. Sci. U.S.A. 97(18): 10014-10019 (2000)), and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors are implicated in the transcriptional activation of p21WAF1/CIP1 (Vigushin et al., Anticancer Drugs, 13(1): 1-13 (January 2002)), and are suitable cell cycle signaling inhibitors for use in combination herein.

Examples of Such HDAC Inhibitors Include:

1. Vorinostat, including pharmaceutically acceptable salts thereof. Marks et al., Nature Biotechnology 25, 84 to 90 (2007); Stenger, Community Oncology 4, 384-386 (2007).

Vorinostat has the following chemical structure and name:

N-hydroxy-N-phenyl-octanediamide

2. Romidepsin, including pharmaceutically acceptable salts thereof. Vinodhkumar et al., Biomedicine & Pharmacotherapy 62 (2008) 85-93.

Romidepsin, has the following chemical structure and name:

(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetrazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone

3. Panobinostat, including pharmaceutically acceptable salts thereof. Drugs of the Future 32(4): 315-322 (2007).

Panobinostat, has the following chemical structure and name:

(2E)-N-hydroxy-3-[4-({[2-(2-methyl-1H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylamide

4. Valproic acid, including pharmaceutically acceptable salts thereof. Gottlicher, et al., EMBO J. 20(24): 6969-6978 (2001).

Valproic acid, has the following chemical structure and name:

2-propylpentanoic acid

5. Mocetinostat (MGCD0103), including pharmaceutically acceptable salts thereof. Balasubramanian et al., Cancer Letters 280: 211-221 (2009).

Mocetinostat, has the following chemical structure and name:

N-(2-Aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide

Further examples of such HDAC inhibitors are included in Bertrand European Journal of Medicinal Chemistry 45, (2010) 2095-2116, particularly the compounds of table 3 therein as indicated below.

Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Several proteasome inhibitors are marketed or are being studied in the treatment of cancer. Suitable proteasome inhibitors for use in combination herein include:

1. Bortezomib (Velcade®), including pharmaceutically acceptable salts thereof. Adams J, Kauffman M (2004), Cancer Invest 22 (2): 304-11.

Bortezomib has the following chemical structure and name.

[(1R)-3-methyl-1-({(2S)-3-phenyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoyl}amino)butyl]boronic acid

2. Disulfiram, including pharmaceutically acceptable salts thereof. Bouma et al. (1998). J. Antimicrob. Chemother. 42 (6): 817-20.

Disulfiram has the following chemical structure and name.

1,1′,1″,1′″-[disulfanediylbis(carbonothioylnitrilo)]tetraethane

3. Epigallocatechin gallate (EGCG), including pharmaceutically acceptable salts thereof. Williamson et al., (December 2006), The Journal of Allergy and Clinical Immunology 118 (6): 1369-74.

Epigallocatechin gallate has the following chemical structure and name.

[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate

4. Salinosporamide A, including pharmaceutically acceptable salts thereof. Feling et at, (2003), Angew. Chem. Int. Ed. Engl. 42 (3): 355-7.

Salinosporamide A has the following chemical structure and name.

(4R,5S)-4-(2-chloroethyl)-1-((1S)-cyclohex-2-enyl(hydroxy)methyl)-5-methyl-6-oxa-2-azabicyclo3.2.0 heptane-3,7-dione

5. Carfilzomib, including pharmaceutically acceptable salts thereof. Kuhn D J, et al, Blood, 2007, 110:3281-3290.

Carfilzomib has the following chemical structure and name.

(S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide

›Definitions · 12 of 14

The 70 kilodalton heat shock proteins (Hsp70s) and 90 kilodalton heat shock proteins (Hsp90s) are a family of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are over expressed certain cancer types. Several Hsp70s and Hsp90s inhibitors are being studied in the treatment of cancer. Suitable Hsp70s and Hsp90s inhibitors for use in combination herein include:

1. 17-AAG(Geldanamycin), including pharmaceutically acceptable salts thereof. Jia W et al. Blood. 2003 Sep. 1; 102(5):1824-32.

17-AAG(Geldanamycin) has the following chemical structure and name.

17-(Allylamino)-17-demethoxygeldanamycin

2. Radicicol, including pharmaceutically acceptable salts thereof. (Lee et al., Mol Cell Endocrinol. 2002, 188, 47-54)

Radicicol has the following chemical structure and name.

(1aR,2Z,4E,14R,15aR)-8-chloro-9,11-dihydroxy-14-methyl-15,15a-dihydro-1aH-benzo[c]oxireno[2,3-k][1]oxacyclotetradecine-6,12(7H,14H)-dione

Inhibitors of cancer metabolism—Many tumor cells show a markedly different metabolism from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the pyruvate generated is reduced to lactate, rather than being further oxidized in the mitochondria via the tricarboxylic acid (TCA) cycle. This effect is often seen even under aerobic conditions and is known as the Warburg Effect.

Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a pivotal role in tumor cell metabolism by performing the reduction of pyruvate to lactate, which can then be exported out of the cell. The enzyme has been shown to be upregulated in many tumor types. The alteration of glucose metabolism described in the Warburg effect is critical for growth and proliferation of cancer cells and knocking down LDH-A using RNA-i has been shown to lead to a reduction in cell proliferation and tumor growth in xenograft models.

D. A. Tennant et. al., Nature Reviews, 2010, 267.

P. Leder, et. al., Cancer Cell, 2006, 9, 425.

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance. Alli et al. Oncogene (2005) 24, 39-46. doi:10.1038

Inhibitors of cancer metabolism, including inhibitors of LDH-A and inhibitors of fatty acid biosynthesis (or FAS inhibitors), are suitable for use in combination with the compounds of this invention.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented CD73 inhibiting compounds are anti-PD-L1 agents.

Anti-PD-L1 antibodies and methods of making the same are known in the art.

Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.

Exemplary PD-L1 antibodies are disclosed in:

U.S. Pat. No. 8,217,149; Ser. No. 12/633,339; U.S. Pat. No. 8,383,796; Ser. No. 13/091,936; U.S. Pat. No. 8,552,154; Ser. No. 13/120,406; US patent publication No. 20110280877; Ser. No. 13/068,337; US Patent Publication No. 20130309250; Ser. No. 13/892,671; WO2013019906; WO2013079174; U.S. application Ser. No. 13/511,538 (filed Aug. 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010); and U.S. application Ser. No. 13/478,511 (filed May 23, 2012).

Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for use are disclosed in U.S. Pat. No. 7,943,743; US20130034559, WO2014055897, U.S. Pat. Nos. 8,168,179; and 7,595,048. PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.

In one embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. Pat. No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. Pat. No. 8,217,149.

In another embodiment, the antibody to PD-L1 is an antibody disclosed in U.S. application Ser. No. 13/511,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. application Ser. No. 13/511,538.

In another embodiment, the antibody to PD-L1 is an antibody disclosed in application Ser. No. 13/478,511. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in U.S. application Ser. No. 13/478,511.

In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MED14736.

“PD-1 antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human individual is to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3 and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab′-SH, F(ab′) 2 , scFv and Fv fragments.

›Definitions · 13 of 14

Examples of mAbs that bind to human PD-1, and useful in the vario us aspects and embodiments of the present invention, are described in U.S. Pat. Nos. 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,168,757, WO2004/004771, WO2004/072286, WO2004/056875, and US2011/0271358.

Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized IgG4 mAb with the structure described in WHO Drug Information , Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in FIG. 6; nivolumab, a human IgG4 mAb with the structure described in WHO Drug Information , Vol. 27, No. 1, pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in FIG. 7; the humanized antibodies h409A11, h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune.

Other PD-1 antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesin that specifically binds to PD-1, and preferably specifically binds to human PD-1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

Other examples of mAbs that bind to human PD-L1, and useful in the treatment method, medicaments and uses of the present invention, are described in WO2013/019906, WO2010/077634 A1 and U.S. Pat. No. 8,383,796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MED14736, MSB0010718C.

KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in U.S. Pat. No. 8,168,757.

Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in U.S. Pat. No. 8,008,449.

As used herein “immuno-modulators” refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modulators. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab). Other immuno-modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41BB antibodies and GITR antibodies.

Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in U.S. Pat. Nos. 6,984,720 and 7,605,238.

CD134, also known as ANTIBODIES TO OX40, is a member of the TNFR-superfamily of receptors which is not constitutively expressed on resting nave T cells, unlike CD28. ANTIBODIES TO OX40 is a secondary costimulatory molecule, expressed after 24 to 72 hours following activation; its ligand, ANTIBODIES TO OX40L, is also not expressed on resting antigen presenting cells, but is following their activation. Expression of ANTIBODIES TO OX40 is dependent on full activation of the T cell; without CD28, expression of ANTIBODIES TO OX40 is delayed and of fourfold lower levels. OX-40 antibodies, OX-40 fusion proteins and methods of using them are disclosed in U.S. Pat. Nos. 7,504,101; 7,758,852; 7,858,765; 7,550,140; 7,960,515; WO2012027328; WO2013028231.

Aminoalkyl glucosaminide phosphates (AGPs) are known to be useful as vaccine adjuvants and immunostimulatory agents for stimulating cytokine production, activating macrophages, promoting innate immune response, and augmenting antibody production in immunized animals. Aminoalkyl glucosaminide phosphates (AGPs) are synthetic ligands of the Toll-like Receptor 4 (TLR4). AGPs and their immunomodulating effects via TLR4 are disclosed in patent publications such as WO 2006/016997, WO 2001/090129, and/or U.S. Pat. No. 6,113,918 and have been reported in the literature. Additional AGP derivatives are disclosed in U.S. Pat. Nos. 7,129,219, 6,525,028 and 6,911,434. Certain AGPs act as agonists of TLR4, while others are recognized as TLR4 antagonists.

›Definitions · 14 of 14

CDRs for murine antibodies to human ICOS having agonist activity are shown in PCT/EP2012/055735 (WO 2012/131004). Antibodies to ICOS are also disclosed in WO 2008/137915, WO 2010/056804, EP 1374902, EP1374901, and EP1125585.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented compound of Formula (I) are STING modulating compounds, CD39 inhibitors and A2a and A2a adenosine antagonists.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful for treating beta hemoglobinopathies, such as sickle cell disease, sickle cell anemia, and beta thalassemia.

Examples of a further active ingredient or ingredients for use in combination or co-administered with the presently invented combinations is hydroxyurea.

Compositions

The pharmaceutically active compounds within the scope of this invention are useful as selective DNMT1 inhibitors in mammals, particularly humans, in need thereof.

The present invention provides a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof.

The present invention provides a process for preparing a pharmaceutical composition containing a pharmaceutically acceptable excipient and an effective amount of a compound of Formula (I) as described above or a pharmaceutically acceptable salt thereof, which process comprises bringing the compound of Formula (I) or a pharmaceutically acceptable salt thereof into association with a pharmaceutically acceptable excipient.

The present invention therefore provides a method of treating cancer, pre-cancerous syndromes and other conditions requiring DNMT1 inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide f

›Tables in the description — 7

C 1-6 alkyl, R e , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d ;

R b and R c are independently selected from:

C 1-6 alkyl, R e , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d ; cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d , or R b and R c are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OR e , aryl, aryl substituted from 1 to 4 times by R d , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d , C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)R e , —N(C 1-4 alkyl) 2 , —ONHC(NH)NH 2 , —Oheterocycloalkyl, —NHcycloalkyl, —NHheterocycloalkyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —SO 2 NH 2 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

each R d is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , heteroaryl, heteroaryl substituted from 1 to 4 times by R x ,

where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x ,

heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x ,

aryl, aryl substituted from 1 to 4 times by R x ,

C 1-4 alkoxy, C 1-4 alkoxy substituted from 1 to 4 times by fluoro, —Oaryl, —Oaryl substituted from 1 to 4 times by R x ,

—C(O)H, —C(O)R zz , —C(O)aryl, —C(O)aryl substituted from 1 to 4 times by R zz , —C(O)heteroaryl, —C(O)heteroaryl substituted from 1 to 4 times by R zz , —OC(O)H, —CO(O)R zz , —OC(O)aryl, —CO(O)aryl substituted from 1 to 4 times by R zz , —OC(O)heteroaryl, —OC(O)heteroaryl substituted from 1 to 4 times by R zz , mercapto, —SR x ,

—S(O)H, —S(O)R x ,

—S(O) 2 H, —S(O) 2 R x ,

—S(O) 2 NH 2 , —S(O) 2 NHR x ,

—S(O) 2 NR x1 R x2 ,

where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

—P(O)(CH 3 ) 2 , —NHS(O) 2 H, —NHS(O) 2 R x ,

—NHC(O)H, —NHC(O)R x ,

—C(O)NH 2 , —C(O)NHR x ,

—C(O)NR x1 R x2 ,

—C(O)OH, —C(O)OR x ,

oxo, hydroxy, amino, —NHR x ,

—NR x1 R x2 ,

nitro, cyano, —NHC(O)NH 2 , —NHC(O)NHR x ,

—NHC(O)NR x1 R x2 ,

each R e is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, mercapto, —SR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O)H, —S(O)R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 H, —S(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, hydroxy, amino, —NHR xx , where R xx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OR xy , —COOH, —CN, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and NR xy R xz , where R xy and R xz are independently selected from: hydrogen, aryl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, —NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 Substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, guanidino, —C(O)OH, —C(O)OR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —C(O)NH 2 , —C(O)NHR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —C(O)NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 Substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, aryl, aryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —Oaryl, —Oaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heteroaryl, heteroaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 NH 2 , —S(O) 2 NHR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 Substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —NHS(O) 2 H, —NHS(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —NHC(O)NHR xp , where R xp is selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: —COOH, —NH 2 , and —CN, —NHC(O)NR x3 R x4 , where R x3 and R x4 are each independently selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 6 Substituents independently selected from: —COOH, —NH 2 , and —CN, nitro, and cyano; and

R z is selected from

C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d ;

R zz is selected from

C 1-6 alkyl, and R e ;

R b and R c are independently selected from:

C 1-6 alkyl, R e , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d ; cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d , or R b and R c are taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from:

each R d is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , heteroaryl, heteroaryl substituted from 1 to 4 times by R x ,

cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x ,

heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x ,

where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, fluoro, oxo, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

aryl, aryl substituted from 1 to 4 times by R x ,

C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —CN, —Oaryl, —Oaryl substituted from 1 to 4 times by R x ,

—OR e , —C(O)H, —C(O)R zz , —C(O)aryl, —C(O)aryl substituted from 1 to 4 times by R zz , —C(O)heteroaryl, —C(O)heteroaryl substituted from 1 to 4 times by R zz , —OC(O)H, —CO(O)R zz , —OC(O)aryl, —CO(O)aryl substituted from 1 to 4 times by R zz , —OC(O)heteroaryl, —OC(O)heteroaryl substituted from 1 to 4 times by R zz , mercapto, —SR x ,

—S(O)H, —S(O)R x ,

—S(O) 2 H, —S(O) 2 R x ,

—OS(O) 2 R x ,

—S(O) 2 NH 2 , —S(O) 2 NHR x ,

—S(O) 2 NR x1 R x2 ,

—P(O)(CH 3 ) 2 , —NHS(O) 2 H, —NHS(O) 2 R x ,

—NHC(O)H, —NHC(O)R x ,

—C(O)NH 2 , —C(O)NHR x ,

—C(O)NR x1 R x2 ,

—C(O)OH, —C(O)OR x ,

oxo, hydroxy, amino, —NHR x ,

where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, C 1-6 alkoxy, and C 1-6 alkoxy substituted with from 1 to 6 substituents Independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and CN

—NR x1 R x2 ,

where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, —S(O) 2 C 1-6 alkyl, —S(O) 2 C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

boronic acid, nitro, cyano, —NHC(O)NH 2 , —NHC(O)NHR x ,

—NHC(O)NR x1 R x2 ,

each R e is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

fluoro, chloro, bromo, iodo, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —OC(O)C 1-6 alkyl, —OC(O)C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —ONHC(NH)NH 2 , —OP(O)(OH) 2 , mercapto, —SR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O)H, —S(O)R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 H, —S(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, hydroxy, amino, —NHR xx , where R xx is selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 6 substituents independently selected from: fluoro, triazolyl, cyclopropyl, oxo, —OR xy , —COOH, —CN, and —NR xy R xz , where R xy and R xz are Independently selected from: hydrogen, aryl, C 1-5 alkyl heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OR xy , —COOH, —CN, and —NR xy R xz , where R xy and R xz are Independently selected from: hydrogen, aryl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, triazolyl, cyclopropyl, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, —NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, guanidino, —C(O)OH, —C(O)OR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —C(O)NH 2 , —C(O)NHR x , where R x is selected from aryl, heteroaryl, —OH, C 1-4 alkoxy, cycloalkyl, cycloalkyl substituted with HO—(C 1-4 alkyl)-, heterocyloalkyl, heterocyloalkyl substituted with HO—(C 1-4 alkyl)-, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, heteroaryl, —NH 2 , and —CN, —C(O)NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, cycloalkyl substituted with HO—(C 1-4 alkyl)-, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, or R x1 and R x2 taken together with the nitrogen to which they are attached, and optionally from 1 to 3 additional heteroatoms independently selected from O, N, and S, to form a heterocycloalkyl, which is optionally substituted with from 1 to 5 substituents independently selected from fluoro, oxo, —OH, HO—(C 1-4 alkyl)-, —COOH, —NH 2 , and —CN, aryl, aryl substituted from 1 to 4 times by R x , where R x is selected from fluoro, chloro, bromo, iodo, aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —N(CH 3 ) 2 , —NHC(O)C 1-4 alkyl, and —CN, —Oaryl, —Oaryl substituted from 1 to 4 times by R x , where R x selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heteroaryl, heteroaryl substituted from 1 to 4 times by R x , where R x selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-4 alkoxy C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R x , where R x selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x , where R x selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x , where R x selected from oxo, —OH, —N(C 1-4 alkyl) 2 , aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , —N(CH 3 ) 2 , and —CN, —S(O) 2 NH 2 , —S(O) 2 NHR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —NHS(O) 2 H, —NHS(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —OC(O)NH 2 , —NHC(O)R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN —NHC(O)NHR xp , where R xp is selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: —COOH, —NH 2 , and —CN, —NHC(O)NR x3 R x4 , where R x3 and R x4 are each independently selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: —COOH, —NH 2 , and —CN, —NHC(O)C(O)NH 2 , —NO 2 , and —CN; and

R z is selected from

C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d ; and

R zz is selected from

C 1-6 alkyl, and R e ;

C 1-6 alkyl, R e , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d cycloalkyl, —OR e , cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d ;

R b and R c are independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , —OR e , aryl, aryl substituted from 1 to 4 times by R d , heteroaryl, heteroaryl substituted from 1 to 4 times by R d , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d , C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)R e , —N(C 1-4 alkyl) 2 , —ONHC(NH)NH 2 , —Oheterocycloalkyl, —NHcycloalkyl, —NHheterocycloalkyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropylmethyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methyl piperazinyl, pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

each R d is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e , heteroaryl, heteroaryl substituted from 1 to 4 times by R x ,

cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x ,

heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x ,

aryl, aryl substituted from 1 to 4 times by R x ,

C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected

from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

—Oaryl, —Oaryl substituted from 1 to 4 times by R x ,

—S(O)H, —S(O)R x ,

—S(O) 2 H, —S(O) 2 R x ,

—OS(O) 2 R x ,

—S(O) 2 NH 2 , —S(O) 2 NHR x ,

—S(O) 2 NR x1 R x2 ,

—NH 2 , and —CN, —NHS(O) 2 H, —NHS(O) 2 R x ,

—NHC(O)H, —NHC(O)R x ,

—C(O)NH 2 , —C(O)NHR x ,

—C(O)NR x1 R x2 ,

—C(O)OH, —C(O)OR x ,

oxo, hydroxy, amino, —NHR x ,

—NR x1 R x2 ,

boronic acid, nitro, cyano, —NHC(O)NH 2 , —NHC(O)NHR x ,

—NHC(O)NR x1 R x2 ,

each R e is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, —OC 1-6 alkyl, —OC 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, mercapto, —SR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O)H, —S(O)R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 H, —S(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, oxo, hydroxy, amino, —NHR xx , where R xx is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OR xy , —COOH, —CN, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —NR xy R xz , where R xy and R xz are independently selected from: hydrogen, aryl, C 1-5 alkyl and C 1-5 alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, —OH, —OC 1-5 alkyl, —OC 1-5 alkyl substituted from 1 to 6 times by fluoro and —COOH, —NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, guanidino, —C(O)OH, —C(O)OR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —C(O)NH 2 , —C(O)NHR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —C(O)NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, aryl, aryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —Oaryl, —Oaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heteroaryl, heteroaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —Oheteroaryl, —Oheteroaryl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, cycloalkyl, cycloalkyl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 NH 2 , —S(O) 2 NHR x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —S(O) 2 NR x1 R x2 , where R x1 and R x2 are each independently selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —NHS(O) 2 H, —NHS(O) 2 R x , where R x is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —NHC(O)NHR xp , where R xp is selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 4 substituents independently selected from: —COOH, —NH 2 , and —CN, —NHC(O)NR x3 R x4 , where R x3 and R x4 are each independently selected from heteroaryl, cycloalkyl, heterocyloalkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: —COOH, —NH 2 , and —CN, nitro, and cyano;

R z is selected from

C 1-6 alkyl, R e , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d ;

R zz is selected from

C 1-6 alkyl, and R e ;

C 1-6 alkyl, R e1 , aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 ;

R b1 and R c1 are independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e1 , aryl, aryl substituted from 1 to 4 times by R d1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 , C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN, —CN, oxo, —OH, —COOH, —NO 2 , —NH 2 , —N(H)C 1-4 alkyl, —N(H)R e1 , —N(C 1-4 alkyl) 2 , —ONHC(NH)NH 2 , —Oheterocycloalkyl, —NHcycloalkyl, —NHheterocycloalkyl, —S(O) 2 CH 2 CH 3 , —S(O) 2 CH 2 CH 2 CH 3 , —S(O) 2 phenyl, —S(O) 2 CH 3 , benzoyl, benzylamino, 3-pyrrolidinylpropyl, 2-cyclopropyl methyl, cyclobutylamino, cyclobutyl-N(CH 3 )—, piperidinyl, imidazolyl, morpholinyl, morpholinylmethyl, methylpiperazinylmethyl, methylpiperazinyl pyrrolidinyl, pyrrolidinylmethyl, methoxypyridinylmethylamino, methylpyrrolidinyl, difluoropyrrolidinyl, dimethylpyrrolidinyl, methylcyclopropylmethylamino, hydroxymethylpyrrolidinyl, fluoropyrrolidinyl, fluorophenylmethylamino, piperazinylmethyl, oxazolidinyl, methyloxetanmethylamino, methylcyclobutylmethylamino, oxoimidazolidinyl, and 2-hydroxyethylpiperidinyl;

each R d1 is independently selected from:

fluoro, chloro, bromo, iodo, C 1-6 alkyl, R e1 , heteroaryl, heteroaryl substituted from 1 to 4 times by R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

cycloalkyl, cycloalkyl substituted from 1 to 4 times by R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

heterocycloalkyl, heterocycloalkyl substituted from 1 to 4 times by R x ,

where R x is selected from: fluoro, oxo, C 1-6 alkyl, and C 1-6 alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, —OH, —COOH, —NH 2 , and —CN,

aryl, aryl substituted from 1 to 4 times by R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

C 1-4 alkoxy, C 1-4 alkoxy substituted with from 1 to 4 substituents independently selected from: fluoro and —NH 2 , —Oaryl, —C(O)H, —C(O)R zz , —C(O)aryl, —C(O)heteroaryl, —OC(O)H, —CO(O)R zz , —OC(O)aryl, —OC(O)heteroaryl, mercapto, —SR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—S(O)H, —S(O)R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—S(O) 2 H, —S(O) 2 R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—OS(O) 2 R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—S(O) 2 NH 2 , —S(O) 2 NHR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—NHS(O) 2 H, —NHS(O) 2 R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—NHC(O)H, —NHC(O)R xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—C(O)NH 2 , —C(O)NHR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

—C(O)OH, —C(O)OR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

oxo, hydroxy, amino, —NR x1a R x2a ,

where R x1a and R x2a are each independently selected from —S(O) 2 C 1-6 alkyl, and C 1-6 alkyl,

—NHR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro,

nitro, cyano, boronic acid, —NHC(O)NH 2 , and —NHC(O)NHR xa ,

where R xa is selected from aryl, heteroaryl, cycloalkyl, heterocyloalkyl, C 1-6 alkyl, and C 1-6 alkyl substituted from 1 to 6 times by fluoro;

each R e1 is independently selected from:

C 1-6 alkyl substituted with from 1 to 9 substituents independently selected from:

R z is selected from

C 1-6 alkyl, R e1 , cycloalkyl, cycloalkyl substituted from 1 to 4 times by R d1 , heterocycloalkyl, and heterocycloalkyl substituted from 1 to 4 times by R d1 ;

R zz is selected from

C 1-6 alkyl, and R e1 ;

Ex- *Examples 523 and 542 are deemed to be 3:1 mixtures of diastereomers with the major component as drawn.

am-		LCMS
ple	Structure/Name	m/z	1H NMR
441
505.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.54-7.45 (m, 2H), 7.45-7.34 (m, 3H), 6.64-6.47 (m, 1H), 5.97-5.66 (m, 1H), 5.42-5.34 (m, 1H), 4.79-4.66 (m, 2H), 3.77-3.54 (m, 1H), 3.48-3.35 (m, 1H), 3.26-3.05 (m, 11.2 Hz, 4H), 2.94 (q, J = 7.6 Hz, 3H), 2.73-2.58 (m, 1H), 2.14- 1.98 (m, 2H), 1.98-1.62 (m, 7H), 1.35 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((S)-2-
	(hydroxymethyl)pyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
443
479.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.51-7.45 (m, 2H), 7.44-7.35 (m, 3H), 6.57 (s, 1H), 5.90 (s, 1H), 5.40 (s, 1H), 4.76 (d, J = 13.3 Hz, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.12 (dd, J = 22.3, 11.5 Hz, 2H), 2.94 (q, J = 7.6 Hz, 2H), 2.88-2.61 (m, 4H), 2.38 (s, 3H), 2.01 (d, J = 12.0 Hz, 2H), 1.75-1.57 (m, 2H), 1.35 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-
	hydroxyethyl)(methyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
444
507.0 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.54-7.45 (m, 2H), 7.45- 7.34 (m, 3H), 6.64 (s, 1H), 6.35 (s, 1H), 5.40 (s, 1H), 4.77 (d, J = 13.0 Hz, 2H), 3.23- 3.11 (m, 1H), 3.11-2.98 (m, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.82-2.50 (m, 5H), 2.21- 2.01 (m, 3H), 1.90-1.76 (m, 1H), 1.76-1.61 (m, 1H), 1.39- 1.23 (m, 9H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-hydroxy-2-
	methylpropyl)(methyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
445
488.8 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.52-7.46 (m, 2H), 7.43-7.35 (m, 3H), 6.76 (s, 1H), 5.86 (s, 1H), 5.43 (s, 1H), 4.68 (d, J = 13.4 Hz, 2H), 3.16 (t, J = 13.0 Hz, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.79-2.48 (m, 6H), 2.01-1.89 (m, 7H), 1.43-1.29 (m, 5H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(pyrrolidin-1-ylmethyl)piperidin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
446
506.8 [M + H] +	1 H NMR (400 MHz, DMSO) δ 8.52 (br. s, 1H), 8.03 (br. s, 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.45- 7.31 (m, 4H), 5.59 (s, 1H), 4.66 (s, 2H), 3.17 (s, 6H), 3.05 (s, 2H), 2.78 (q, J = 7.5 Hz, 2H), 2.21 (m, 2H), 1.68 (br. s, 2H), 1.22 (m, 9H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-methoxy-2-
	methylpropyl)amino)piperidin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
447
492.9 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 6.7 Hz, 2H), 7.47- 7.35 (m, 3H), 5.52 (s, 1H), 4.69 (t, J = 12.0 Hz, 2H), 3.27-3.24 (m, 2H), 2.94-2.89 (m, 3H), 2.72 (s, 2H), 2.13-2.10 (m, 2H), 1.57-1.53 (m, 2H), 1.37-1.23 (m, 9H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-hydroxy-2-
	methylpropyl)amino)piperidin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
448
475.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.94 (s, 1H), 7.53-7.51 (m, 2H), 7.41-7.32 (m, 4H), 5.53 (s, 1H), 4.44-4.40 (m, 2H), 3.34-3.26 (m, 3H), 2.76 (s, 1H), 2.73 (q, J = 7.4 Hz, 2H), 2.14 (m, 2H), 1.89-1.64 (m, 6H), 1.35 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-(4-
	(cyclobutylamino)piperidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
449
504.8 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.51-7.44 (m, 2H), 7.45- 7.35 (m, 3H), 6.58 (br. s, 1H), 5.75 (br. s, 1H), 5.39 (s, 1H), 4.59-4.49 (m, 2H), 4.47 (d, J = 5.8 Hz, 2H), 4.40 (d, J = 5.8 Hz, 2H), 3.41-3.35 (m, 2H), 2.99-2.84 (m, 5H), 2.10 (br. s, 2H), 1.62-1.47 (m, 2H), 1.38-1.30 (m, 6H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(((3-methyloxetan-3-
	yl)methyl)amino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
450
503.9 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 6.9 Hz, 2H), 7.42- 7.30 (m, 3H), 6.54 (br. s, 1H), 5.67 (br. s, 1H), 5.40 (s, 1H), 4.71 (d, J = 13.7 Hz, 2H), 3.18 (dd, J = 23.0, 11.3 Hz, 2H), 2.93 (q, J = 7.3 Hz, 2H), 2.86- 2.56 (m, 9H), 2.41 (s, 3H), 2.19-2.02 (m, 2H), 1.73-1.60 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-(4-
	methylpiperazin-1-yl)piperidin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
451
489.0 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 7.2 Hz, 2H),7.47- 7.37 (m, 3H), 5.53 (s, 1H), 4.90-4.80 (m, 2H), 3.92-3.79 (s, 1H), 3.69-3.59 (m, 1H), 3.54-3.42 (m, 1H), 3.31-3.13 (m, 3H), 2.93 (q, J = 7.5 Hz, 2H), 2.36-2.16 (m, 3H), 2.15- 2.02 (m, 2H), 1.88-1.72 (m, 3H), 1.45 (d, J = 5.9 Hz, 3H), 1.32 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((R)-2-methylpyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
452
502.9 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.44-7.29 (m, 4H), 5.56 (s, 1H), 4.77-4.59 (m, 2H), 3.18-2.82 (m, 5H), 2.75 (q, J = 7.4 Hz, 2H), 1.90-1.64 (m, 4H), 1.50-1.30 (m, 4H), 1.21 (t, J = 7.6 Hz, 3H), 1.01 (s, 6H).
	2-((3,5-dicyano-6-(4-((2R,5S)-
	2,5-dimethylpyrrolidin-1-
	yl)piperidin-1-yl)-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
453
489.2 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 6.9 Hz, 2H), 7.47- 7.39 (m, 3H), 5.52 (s, 1H), 4.89- 4.77 (m, 2H), 3.84-3.74 (m, 1H), 3.64-3.54 (m, 1H), 3.49- 3.38 (m, 1H), 3.29-3.16 (m, 3H), 2.92 (q, J = 7.6 Hz, 2H), 2.31-2.16 (m, 3H), 2.10-2.01 (m, 2H), 1.85-1.72 (m, 3H), 1.42 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((S)-2-methylpyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
454
489.0 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 7.1 Hz, 2H), 7.46- 7.39 (m, 3H), 5.52 (s, 1H), 4.90- 4.85 (m, 2H), 3.95-3.91 (m, 1H), 3.65-3.61 (m, 1H), 3.24- 3.19 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.68 (s, 3H), 2.38- 2.29 (m, 4H), 1.95-1.87 (m, 2H), 1.85-1.75 (m, 4H), 1.31 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-(4-
	(cyclobutyl(methyl)amino)
	piperidin-1-yl)-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
455
510.8 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.49-7.09 (m, 10H), 5.54 (s, 1H), 4.41 (d, J = 10.8 Hz, 2H), 3.80 (s, 2H), 3.37 (m, 1H), 3.30 (m, 1H), 2.79-2.73 (m, 3H), 2.04-1.92 (m, 2H), 1.50- 1.32 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	2-(6-(4-(benzylamino)piperidin-
	1-yl)-3,5-dicyano-4-
	ethylpyridin-2-ylthio)-2-
	phenylacetamide
456
542.3 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.43-7.30 (m, 4H), 7.06 (d, J = 7.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 5.54 (s, 1H), 4.49- 4.36 (m, 2H), 3.97-3.73 (m, 5H), 3.33-3.26 (m, 3H), 2.94- 2.81 (m, 1H), 2.76 (q, J = 7.5 Hz, 2H), 2.06-1.93 (m, 2H), 1.51-1.36 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(((6-methoxypyridin-2-
	yl)methyl)amino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
457
492.9 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 6.7 Hz, 2H), 7.47- 7.34 (m, 3H), 5.53 (s, 1H), 5.30 (m, 0.5H), 5.15 (m, 0.5H), 4.75- 4.65 (m, 2H), 3.24 (t, J = 12.9 Hz, 2H), 3.17-3.00 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.80 (ddd, J = 32.1, 12.0, 5.0 Hz, 1H), 2.61-2.45 (m, 2H), 2.23 (dtd, J = 20.7, 14.6, 6.3 Hz, 1H), 2.15-1.98 (m, 3H), 1.67- 1.53 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((S)-3-fluoropyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
458
529.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.47 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.93 (t, J= 7.0 Hz, 2H), 3.43 (s, 3H), 3.31 (s, 3H), 2.99-2.86 (m, 7H), 2.36 (s, 2H), 1.32 (t, J = 7.6 Hz, 3H), 0.88 (s, 9H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(methyl(2-
	(neopentylamino)ethyl)amino)
	pyridin-2-yl)thio)methyl)phenyl)-
	N-methylmethanesulfonamide
459
463.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (t, J = 5.7 Hz, 2H), 7.47- 7.34 (m, 3H), 5.53-5.57 (m, 1H), 4.31-3.99 (m, 2H), 3.98- 3.86 (m, 1H), 3.64-3.35 (m, 5H), 3.13-2.66 (m, 4H), 2.28- 2.08 (m, 1H), 2.05-1.83 (m, 2H), 1.60 (s, 1H), 1.32 (t, J = 7.5 Hz, 6H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-((R)-2-
	methylpyrrolidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
460
493.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.50-7.44 (m, 2H), 7.44-7.35 (m, 3H), 6.60 (s, 1H), 5.62 (br. s, 1H), 5.38 (s, 1H), 5.29-5.15 (m, 1H), 4.69-4.51 (m, 2H), 3.35 (t, J = 11.4 Hz, 2H), 3.13- 2.70 (m, 5H), 2.65-2.38 (m, 2H), 2.25-1.98 (m, 4H), 1.80- 1.61 (m, 2H), 1.35 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((R)-3-fluoropyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
461
531.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.46 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 4.57 (s, 2H), 3.93 (t, J = 7.2 Hz, 2H), 3.47- 3.42 (m, 5H), 3.31 (s, 3H), 3.29 (s, 3H), 2.95-2.87 (m, 5H), 2.76 (t, J = 7.1 Hz, 2H), 2.62 (t, J = 5.5 Hz, 2H), 2.32 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	methoxyethyl)(methyl)amino)
	ethyl)(methyl)amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
462
503.0 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 7.6 Hz, 2H), 7.45- 7.35 (m, 3H), 5.53 (s, 1H), 4.84- 4.70 (m, 2H), 3.64-3.40 (m, 2H), 3.24-3.05 (m, , 3H), 2.91 (q, J = 7.6 Hz, 2H), 2.24-2.07 (m, 4H), 1.76-1.47 (m, 4H), 1.32 (t, J = 7.6 Hz, 3H), 1.19 (s, 6H).
	2-((3,5-dicyano-6-(4-((2S,5S)-
	2,5-dimethylpyrrolidin-1-
	yl)piperidin-1-yl)-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
463
463.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.57 (t, J = 6.6 Hz, 2H), 7.53- 7.25 (m, 3H), 5.52-5.47 (m, 1H), 4.36-3.93 (m, 2H), 3.86- 3.56 (m, 3H), 3.56-3.48 (m, 3H), 3.42-3.16 (m, 2H), 2.96 (q, J = 7.6 Hz, 2H), 2.44-2.29 (m, 1H), 2.24-2.03 (m, 2H), 1.89- 1.67 (m, 1H), 1.51 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-((S)-2-
	methylpyrrolidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
464
505.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.48 (d, J = 6.5 Hz, 2H), 7.45- 7.35 (m, 3H), 6.64-6.53 (m, 1H), 5.90-5.75 (m, 1H), 5.42- 5.35 (m, 1H), 4.80-4.67 (m, 2H), 3.76-3.38 (m, 3H), 3.22- 3.06 (m, 4H), 3.00-2.83 (m, 3H), 2.67-2.62 (m, 1H), 2.11- 1.99 (m, 2H), 1.92-1.68 (m, 6H), 1.35 (t, J = 7.6 Hz, 3H).
	ISOMER 1
	2-((3,5-dicyano-4-ethyl-6-(4-
	((R)-2-
	(hydroxymethyl)pyrrolidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
465
467.1 [M + H] +	1 H NMR (DMSO-d 6 ) δ 9.94 (br. s., 1H), 7.99 (br. s., 1H), 7.57 (dd, J = 8.4, 5.6 Hz, 2H), 7.43 (br. s., 1H), 7.26 (t, J = 8.7 Hz, 2H), 5.58 (s, 1H), 4.73 (d, J = 11.2 Hz, 2H), 3.51 (br. s., 1H), 3.08-3.22 (m, 2H), 2.77 (d, J = 4.6 Hz, 8H), 2.38-2.49 (m, 1H), 2.14 (d, J = 10.6 Hz, 2H), 1.53-1.77 (m, 2H), 1.22 (t, J = 7.5 Hz, 3H)
	2-((3,5-dicyano-6-(4-
	(dimethylamino)piperidin-1-yl)-
	4-ethylpyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide, Formic
	acid salt
466
502.7 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 7.1 Hz, 2H), 7.48- 7.37 (m, 3H), 5.51 (s, 1H), 4.83 (t, J = 15.8 Hz, 2H), 3.51-3.36 (m, 1H), 3.23 (t, J = 13.2 Hz, 2H), 3.12 (s, 2H), 2.94 (q, J = 7.6 Hz, 2H), 2.33-2.26 (m, 2H), 2.11-1.95 (m, 4H), 1.91- 1.82 (m, 2H), 1.79-1.68 (m, 2H), 1.36-1.27 (m, 6H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(((1-
	methylcyclobutyl)methyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-
	2-phenylacetamide
467
542.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.48-7.32 (m, 3H), 6.87 (d, J = 8.6 Hz, 1H), 5.52 (s, 1H), 4.75 (t, J = 13.3 Hz, 2H), 4.04 (s, 2H), 3.94 (s, 3H), 3.29-3.14 (m, 3H), 2.92 (q, J = 7.6 Hz, 2H), 2.23 (d, J = 12.5 Hz, 2H), 1.67- 1.57 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(((6-methoxypyridin-3-
	yl)methyl)amino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
468
422.9 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.50-7.45 (m, 2H), 7.44- 7.37 (m, 3H), 7.23 (s, 1H), 5.86 (s, 1H), 5.38 (s, 1H), 4.02- 3.94 (m, 1H), 3.92-3.84 (m, 1H), 3.51 (S, 3H), 3.05-2.97 (m, 2H), 2.97-2.91 (m, 2H), 2.79 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H).
	2-(3,5-dicyano-4-ethyl-6-((2-
	(ethylamino)ethyl)(methyl)
	amino)pyridin-2-ylthio)-2-
	phenylacetamide
469
517.9 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.49-7.47 (m, 2H), 7.44-7.38 (m, 3H), 6.54 (s, 1H), 5.55 (s, 1H), 5.41 (s, 1H), 4.68 (d, J = 13.4 Hz, 2H), 3.20-3.09 (m, 2H), 2.93 (q, J = 7.6 Hz, 2H), 2.67-2.46 (m, 7H), 2.39 (s, 3H), 2.28 (d, J = 7.0 Hz, 2H), 2.04- 1.79 (m, 4H), 1.36-1.27 (m, 5H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((4-methylpiperazin-1-
	yl)methyl)piperidin-1-yl)pyridin-
	2-yl)thio)-2-phenylacetamide
470
409.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.50-7.45 (m, 2H), 7.44- 7.37 (m, 3H), 7.25 (s, 1H), 6.21 (br. s, 1H), 5.41 (s, 1H), 3.98 (dt, J = 14.0, 6.9 Hz, 1H), 3.83 (dt, J = 14.1, 7.2 Hz, 1H), 3.48? (s, 3H), 2.99-2.86 (m, 4H), 2.54-2.44 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-
	(methylamino)ethyl)amino)
	pyridin-2-yl)thio)-2-phenylacetamide
471
473.2 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.49 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 4.58 (s, 2H), 4.04 (t, J = 6.6 Hz, 2H), 3.50 (s, 3H), 3.32 (s, 3H), 3.24 (t, J = 6.6 Hz, 2H), 2.99-2.90 (m, 5H), 2.67 (s, 3H), 1.33 (t, J = 7.6 Hz, 3H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(methyl(2-
	(methylamino)ethyl)amino)
	pyridin-2-yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
472
502.7 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 7.5 Hz, 2H), 7.46- 7.36 (m, 3H), 5.53 (s, 1H), 4.82- 4.69 (m, 2H), 3.51-3.38 (m, 2H), 3.23-3.12 (m, 2H), 3.08- 2.98 (m, 1H), 2.91 (q, J = 7.6 Hz, 2H), 2.28-2.08 (m, 4H), 1.76-1.62 (m, 2H), 1.55-1.44 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.15 (d, J = 5.8 Hz, 6H).
	2-((3,5-dicyano-6-(4-((2R,5R)-
	2,5-dimethylpyrrolidin-1-
	yl)piperidin-1-yl)-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
473
489.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.56 (d, J = 6.7 Hz, 2H), 7.49- 7.34 (m, 3H), 5.52 (s, 1H), 4.81 (t, J = 13.9 Hz, 2H), 3.51-3.37 (m, 1H), 3.29-3.12 (m, 2H), 3.05-2.84 (m, 4H), 2.27 (d, J = 12.3 Hz, 2H), 1.81-1.64 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.25 (s, 3H), 0.66 (t, J = 5.1 Hz, 2H), 0.56 (t, J = 5.2 Hz, 2H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(((1-
	methylcyclopropyl)methyl)
	amino)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
474
528.8 [M + H] +	1 H NMR (400 MHz, DMSO) δ 9.30 (s, 1H), 8.00 (s, 1H), 7.72- 7.63 (m, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.39-7.29 (m, 6H), 5.58 (s, 1H), 4.65 (d, J = 13.2 Hz, 2H), 4.22 (s, 2H), 3.49- 3.39 (m, 1H), 3.22 (t, J = 12.8 Hz, 2H), 2.78 (q, J = 7.6 Hz, 2H), 2.27-2.24 (m, 2H), 1.73- 1.66 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((4-
	fluorobenzyl)amino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
475
478.8 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 7.1 Hz, 2H), 7.41- 7.37 (m, 3H), 5.63-5.59 (m, 1H), 4.23-3.89 (m, 2H), 3.54- 3.50 (m, 2H), 3.45-3.43 (m, 3H), 3.27-3.15 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.65 (s, 2H), 2.44-2.33 (m, 1H), 1.98-1.90 (m, 1H), 1.83-1.70 (m, 2H), 1.66-1.58 (m, 1H), 1.31 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((S)-2-
	(hydroxymethyl)pyrrolidin-1-
	yl)ethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
476
477.3 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.90 (s, 1H), 7.50 (d, J = 7.3 Hz, 2H), 7.45-7.27 (m, 4H), 5.55 (s, 1H), 3.95-3.76 (m, 2H), 3.38 (s, 3H), 2.85-2.71 (m, 4H), 2.62-2.55 (m, 2H), 1.83-1.70 (m, 2H), 1.28-1.16 (m, 5H), 0.97 (t, J = 5.9 Hz, 6H).
	2-(3,5-dicyano-6-((2-((2S,5R)-
	2,5-dimethylpyrrolidin-1-
	yl)ethyl)(methyl)amino)-4-
	ethylpyridin-2-ylthio)-2-
	phenylacetamide
477
476.9 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.58 (d, J = 7.0 Hz, 2H), 7.47 (s, 1H), 7.45-7.33 (m, 3H), 6.22 (s, 1H), 5.61 (s, 1H), 4.60-4.48 (m, 1H), 4.11 (s, 1H), 3.49 (s, 3H), 3.31 (s, 6H), 2.94 (q, J = 7.5 Hz, 2H), 2.10-1.86 (m, 4H), 1.82-1.62 (m, 4H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((6-((2-(azepan-1-
	yl)ethyl)(methyl)amino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
478
462.8 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 7.0 Hz, 2H), 7.45- 7.29 (m, 4H), 6.05 (br. s, 1H), 5.55 (s, 1H), 4.55-4.45 (m, 1H), 4.07 (br. s, 1H), 3.51 (s, 3H), 3.44-2.52 (m, 8H), 2.05-1.55 (m, 6H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-(piperidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
479
478.8 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 7.0 Hz, 2H), 7.43- 7.37 (m, 3H), 5.61 (s, 1H), 4.24- 3.85 (m, 2H), 3.58-3.48 (m, 2H), 3.47-3.40 (m, 3H), 3.27- 3.22 (m, 2H), 2.91 (q, J = 7.6 Hz, 2H), 2.71 (br. s, 2H), 2.45 (br. s, 1H), 1.98-1.90 (m, 1H), 1.81-1.72 (m, 2H), 1.68-1.58 (m, 1H), 1.31 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((R)-2-
	(hydroxymethyl)pyrrolidin-1-
	yl)ethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
480
517.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 3.86 (t, J = 6.9 Hz, 2H), 3.49 (t, J = 10.0, 5.0 Hz, 2H), 3.42 (s, 3H), 3.36 (s, 3H), 3.33 (s, 3H), 2.99-2.90 (m, 4H), 2.86 (s, 3H), 2.83-2.78 (m, 2H), 1.74 (br. s, 1H), 1.34 (t, J = 7.6 Hz, 3H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	methoxyethyl)amino)ethyl)
	(methyl)amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
481
513.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.42 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.46 (s, 2H), 3.92 (s, 2H), 3.42 (s, 3H), 3.34 (br. s, 3H), 3.10 (t, J = 6.9 Hz, 2H), 2.94 (q, J = 7.6 Hz, 2H), 2.87 (s, 3H), 1.38-1.27 (m, 6H), 0.77-0.62 (m, 2H), 0.46 (s, 2H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(methyl(2-((1-
	methylcyclopropyl)amino)ethyl)
	amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
482
487.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.40 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 4.45 (s, 2H), 3.88 (t, J = 6.6 Hz, 2H), 3.44 (s, 3H), 3.33 (s, 3H), 2.92 (q, J = 7.6 Hz, 2H), 2.86 (s, 3H), 2.62 (t, J = 6.6 Hz, 2H), 2.28 (s, 6H), 1.34 (t, J = 7.6 Hz, 3H).
	N-(4-(((3,5-dicyano-6-((2-
	(dimethylamino)ethyl)(methyl)
	amino)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
483
437.3 [M + H] +	1 H NMR (400 MHz, DMSO) δ ppm 7.96 (s, 1H), 7.53-7.48 (m, 2H), 7.41-7.30 (m, 4H), 5.55 (s, 1H), 4.00-3.91 (m, 1H), 3.86-3.77 (m, 1H), 3.33 (s, 3H), 2.76 (q, J = 7.4 Hz, 2H), 2.56 (t, J = 6.3 Hz, 2H), 2.39- 2.32 (m, 2H), 2.16 (s, 3H), 1.20 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H).
	2-(3,5-dicyano-4-ethyl-6-((2-
	(ethyl(methyl)amino)ethyl)
	(methyl)amino)pyridin-2-ylthio)-2-
	phenylacetamide
484
459.2 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.49 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 4.56 (s, 2H), 4.01 (t, J = 6.7 Hz, 2H), 3.49 (s, 3H), 3.32 (s, 3H), 3.19 (t, J = 6.7 Hz, 2H), 2.99-2.90 (m, 5H), 1.33 (t, J = 7.6 Hz, 3H).
	N-(4-(((6-((2-
	aminoethyl)(methyl)amino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
485
476.8 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.50 (d, J = 5.4 Hz, 2H), 7.45-7.26 (m, 4H), 5.62- 5.51 (m, 1H), 3.99-3.76 (m, 2H), 3.32 (s, 3H), 2.96 (s, 2H), 2.87-2.65 (m, 4H), 1.93-1.67 (m, 2H), 1.32-1.13 (m, 5H), 0.85 (t, J = 6.5 Hz, 6H).
	2-((3,5-dicyano-6-((2-((2R,5R)-
	2,5-dimethylpyrrolidin-1-
	yl)ethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
486
464.8 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.1 Hz, 2H), 7.48- 7.30 (m, 3H), 5.67-5.59 (m, 1H), 4.37 (br. s, 1H), 4.20-4.10 (m, 1H), 3.93-3.79 (m, 1H), 3.46 (s, 3H), 2.98-2.77 (m, 6H), 2.69-2.56 (m, 2H), 2.19, 2.09 (m, 1H), 1.80-1.64 (m, 1H), 1.31 (t, J = 7.6 Hz, 3H).
	2-(3,5-dicyano-4-ethyl-6-((2-
	((S)-3-hydroxypyrrolidin-1-
	yl)ethyl)(methyl)amino)pyridin-
	2-ylthio)-2-phenylacetamide
487
521.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.2 Hz, 2H), 7.45- 7.35 (m, 3H), 5.52 (s, 1H), 4.67- 4.54 (m, 2H), 3.74 (s, 3H), 3.28-3.17 (m, 2H), 2.90 (q, J = 7.6 Hz, 2H), 2.84-2.75 (m, 1H), 1.98 (d, J = 12.4 Hz, 2H), 1.49 (q, J = 24.5, 13.1 Hz, 2H), 1.37 (s, 6H), 1.31 (t, J = 7.6 Hz, 3H).
	methyl 2-((1-(6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)piperidin-4-yl)amino)-2-
	methylpropanoate
488
465.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (dd, J = 7.5, 1.9 Hz, 2H), 7.43-7.36 (m, 3H), 7.04 (s, 1H), 5.35 (s, 1H), 4.07-3.76 (m, 2H), 3.50 (s, 3H), 3.06-2.87 (m, 4H), 2.47 (s, 2H), 1.34 (t, J = 7.6 Hz, 3H), 0.91 (s, 9H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-
	(neopentylamino)ethyl)amino)
	pyridin-2-yl)thio)-2-
	phenylacetamide
489
449.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (dd, J = 6.5, 2.9 Hz, 2H), 7.43-7.36 (m, 3H), 7.21 (s, 1H), 5.25 (s, 1H), 4.30 (br. s, 1H), 4.01-3.91 (m, 1H), 3.55 (s, 3H), 3.29-3.14 (m, 2H), 2.96 (q, J = 7.6 Hz, 2H), 1.50 (s, 3H), 1.36 (t, J = 7.6 Hz, 3H), 1.16 (br. s, 2H), 0.68 (br. s, 2H).
	2-(3,5-dicyano-4-ethyl-6-
	(methyl(2-(1-
	methylcyclopropylamino)ethyl)
	amino)pyridin-2-ylthio)-2-
	phenylacetamide
490
477.3 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.93 (s, 1H), 7.51 (d, J = 7.3 Hz, 2H), 7.46-7.20 (m, 4H), 5.61- 5.52 (m, 1H), 4.00-3.74 (m, 2H), 3.34 (s, 1.5H), 3.33 (s, 1.5H), 2.97 (s, 2H), 2.86-2.62 (m, 4H), 1.91-1.73 (m, 2H), 1.30-1.09 (m, 5H), 0.85 (t, J = 6.3 Hz, 6H).
	2-((3,5-dicyano-6-((2-((2S,5S)-
	2,5-dimethylpyrrolidin-1-
	yl)ethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
491
453.3 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.53-7.46 (m, 2H), 7.45-7.34 (m, 4H), 7.22 (s, 1H), 5.26 (s, 1H), 4.61-4.51 (m, 1H), 3.92- 3.79 (m, 2H), 3.79-3.71 (m, 1H), 3.56 (s, 3H), 3.37 (s, 3H), 3.33-3.13 (m, 4H), 2.96 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((2-
	methoxyethyl)amino)ethyl)
	(methyl)amino)pyridin-2-yl)thio)-2-
	phenylacetamide
492
521.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.55 (d, J = 6.8 Hz, 2H), 7.48- 7.35 (m, 3H), 5.54 (s, 1H), 4.85- 4.74 (m, 2H), 3.25 (S, 3H), 3.13 (t, J = 12.7 Hz, 2H), 2.91 (q, J = 7.5 Hz, 2H), 2.80-2.26 (m, 6H), 2.09-1.88 (m, 2H), 1.71-1.54 (m, 2H), 1.31 (t, J = 7.6 Hz, 3H), 1.22 (s, 6H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-methoxy-2-
	methylpropyl)(methyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
493
422.9 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.57 (d, J = 6.2 Hz, 2H), 7.51 (br. s, 1H), 7.45-7.34 (m, 3H), 5.93 (br. s, 1H), 5.61 (s, 1H), 4.58-4.44 (m, 1H), 4.12 (br. s, 1H), 3.53 (s, 3H), 3.26-3.15 (m, 2H), 2.95 (q, J = 7.5 Hz, 2H), 2.90-2.72 (m, 6H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-((2-
	(dimethylamino)ethyl)(methyl)
	amino)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
494
465.3 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.54 (d, J = 7.2 Hz, 2H), 7.46- 7.34 (m, 3H), 5.66-5.59 (m, 1H), 4.36 (br. s, 1H), 4.24-4.07 (m, 1H), 3.90-3.80 (m, 1H), 3.46 (s, 3H), 2.97-2.76 (m, 6H), 2.69-2.56 (m, 2H), 2.14 (td, J = 14.3, 7.4 Hz, 1H), 1.81- 1.66 (m, 1H), 1.31 (t, J = 7.6 Hz, 3H).
	2-(3,5-dicyano-4-ethyl-6-((2-
	((R)-3-hydroxypyrrolidin-1-
	yl)ethyl)(methyl)amino)pyridin-
	2-ylthio)-2-phenylacetamide
495
440.7 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.61-7.50 (m, 2H), 7.50-7.39 (m, 3H), 5.44 (s, 1H), 4.78 (t, J = 4.6 Hz, 1H), 4.66 (t, J = 4.6 Hz, 1H), 4.18-3.91 (m, 4H), 3.54 (s, 3H), 3.38 (m, 1H), 3.23 (m, 1H), 2.95 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.7 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((2-
	fluoroethyl)amino)ethyl)
	(methyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
496
510.8 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.92 (s, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.39-7.34 (m, 4H), 5.53 (s, 1H), 4.43 (br. s, 2H), 3.32- 3.16 (m, 2H), 2.98 (t, J = 13.8 Hz, 2H), 2.79-2.72 (m, 4H), 2.47 (m, 1H), 2.29-2.20 (m, 2H), 1.92 (d, J = 11.7 Hz, 2H), 1.45-1.39 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-(4-(3,3-
	difluoropyrrolidin-1-yl)piperidin-
	1-yl)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
497
478.7 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.46-7.28 (m, 4H), 5.55 (s, 1H), 4.58 (d, J = 13.4 Hz, 2H), 3.46-3.34 (m, 2H), 3.52 (q, J = 27.4, 14.3 Hz, 5H), 2.83- 2.72 (m, 2H), 2.14-2.04 (m, 2H), 1.62-1.47 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H).
	2-((1-(6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)piperidin-4-
	yl)amino)acetic
	acid
498
421.2 [M + H] +	1 H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 8.03 (br. s, 2H), 7.60 (d, J = 7.2 Hz, 2H), 7.52- 7.24 (m, 4H), 5.77 (s, 1H), 5.60- 5.40 (m, 1H), 3.74 (br. s, 1H), 3.28 (s, 3H), 2.84-2.66 (m, 4H), 2.48-2.39 (m, 2H), 1.22 (t, J = 7.3 Hz, 3H).
	2-((6-((3-
	aminocyclobutyl)(methyl)
	amino)-3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
499
470.2 [M + H] +	1 H NMR (400 MHz, DMSO) δ 7.45 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.1 Hz, 2H), 4.53 (s, 2H), 4.51-4.41 (m, 4H), 3.32-3.15 (m, 5H), 2.90 (s, 3H), 2.78 (q, J = 7.6 Hz, 2H), 2.02-1.91 (m, 2H), 1.60-1.40 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).
	2-(4-aminopiperidin-1-yl)-4-
	ethyl-6-((4-
	((methylsulfonyl)methyl)benzyl)
	thio)pyridine-3,5-dicarbonitrile
500
504.9 [M + H] +	1 H NMR (400 MHz, MeOD) δ 7.50-7.41 (m, 4H), 4.64-4.53 (m, 3H), 4.52-4.44 (m, 1H), 3.92 (t, J = 7.0 Hz, 2H), 3.45 (s, 3H), 3.31 (s, 3H), 3.03-2.87 (m, 9H), 1.34-1.30 (m, 3H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	fluoroethyl)amino)ethyl)
	(methyl)amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
501
422.2 [M + H] +	1 H NMR (400 MHz, CDCl3) δ ppm 7.50-7.45 (m, 2H), 7.45- 7.38 (m, 3H), 6.58 (br. s, 1H), 5.51-5.41 (m, 3H), 4.20-4.14 (m, 1H), 3.98-3.89 (m, 2H), 3.74 (dd, J = 16.7, 8.8 Hz, 1H), 3.34 (s, 3H), 2.96 (q, J = 7.6 Hz, 2H), 2.55-2.46 (m, 1H), 2.05- 1.95 (m, 1H), 1.36 (t, J = 7.6 Hz, 3H).
	(R)-2-(3,5-dicyano-4-ethyl-6-
	(methyl((R)-tetrahydrofuran-3-
	yl)amino)pyridin-2-ylthio)-2-
	phenylacetamide
502
422.2 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.52-7.46 (m, 2H), 7.45- 7.38 (m, 3H), 6.57 (br. s, 1H), 5.52 (br. s, 1H), 5.41-5.36 (m, 2H), 4.20-4.14 (m, 1H), 4.00- 3.95 (m, 1H), 3.89-3.83 (m, 1H), 3.76-3.68 (m, 1H), 3.35 (s, 3H), 2.96 (q, J = 7.6 Hz, 2H), 2.62-2.51 (m, 1H), 2.03-1.93 (m, 1H), 1.36 (t, J = 7.6 Hz, 3H).
	(S)-2-(3,5-dicyano-4-ethyl-6-
	(methyl((R)-tetrahydrofuran-3-
	yl)amino)pyridin-2-ylthio)-2-
	phenylacetamide
503
490.8 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.51-7.45 (m, 2H), 7.43-7.39 (m, 3H), 6.56 (br. s, 1H), 5.70 (br. s, 1H), 5.39 (s, 1H), 4.70 (d, J = 13.7 Hz, 2H), 3.77 (s, 4H), 3.20 (t, J = 12.8 Hz, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.57-2.48 (m, 5H), 2.07 (d, J = 12.4 Hz, 2H), 1.67-1.53 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	morpholinopiperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
504
465.1 [M + H] +	1 H NMR (400 MHz, CDCl 3 ) δ 7.54-7.46 (m, 2H), 7.43-7.33 (m, 3H), 6.90 (s, 1H), 6.17 (s, 1H), 5.42 (s, 1H), 4.53 (dd, J = 39.2, 17.5 Hz, 2H), 4.27-4.17 (m, 1H), 4.14-4.04 (m, 1H), 3.89-3.77 (m, 2H), 3.74-3.52 (m, 4H), 2.95 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-(2-
	hydroxyethyl)-3-oxopiperazin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
505
493.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.59- 7.53 (m, 2H), 7.39 (s, 1H), 7.27-7.20 (m, 2H), 5.55 (s, 1H), 4.47-4.35 (m, 2H), 3.33-3.26 (m, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.58-2.53 (m, 1H, partially obscured by residual solvent signal), 2.40- 2.20 (m, 1H), 1.94 (d, 4H), 1.55-1.35 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(pyrrolidin-1-yl)piperidin-1-
	yl)pyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide
506
439.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.35-8.25 (m, 3H), 7.97 (s, 1H), 7.56-7.50 (m, 2H), 7.45-7.33 (m, 4H), 5.55 (s, 1H), 5.17-4.90 (m, 2H), 4.64 (d, J = 11.4 Hz, 1H), 3.80-3.66 (m, 1H), 3.57 (dd, J = 15.0, 39.4 Hz, 1H), 3.31- 3.21 (m, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.04-1.84 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H).
	(R)-2-((6-((3S,4R)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	2,2,2-trifluoroacetate
507
453.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.96 (br. s., 1H), 7.56-7.49 (m, 2H), 7.44- 7.29 (m, 4H), 5.56-5.52 (m, 1H), 5.01-4.78 (m, 2H), 4.60-4.45 (m, 1H), 3.59- 3.39 (m, 1H), 2.83-2.64 (m, 3H), 2.38-2.32 (m, 3H), 1.94-1.83 (m, 1H), 1.69- 1.50 (m, 1H), 1.31-1.08 (m, 5H)
	2((3,5-dicyano-4-ethyl-6-(3-
	fluoro-4-
	(methylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
508
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.97 (s, 1H), 7.57- 7.50 (m, 2H), 7.42-7.31 (m, 4H), 5.58-5.54 (m, 1H), 4.46-4.21 (m, 2H), 4.16- 4.03 (m, 1H), 3.80-3.66 (m, 1H), 3.64-3.55 (m, 1H), 3.09-2.98 (m, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.02-1.88 (m, 1H), 1.84 (br. s., 2H), 1.50-1.39 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H).
	rel-2-((6-(trans)-4-amino-3-
	fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
509
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.33 (br s, 3H), 7.97 (s, 1H), 7.57-7.46 (m, 2H), 7.44-7.30 (m, 4H), 5.55 (s, 1H), 5.17-4.97 (m, 2H), 4.64 (d, J = 11.9 Hz, 1H), 3.81-3.62 (m, 1H), 3.51 (dd, J = 15.0, 39.2 Hz, 1H), 3.27 (t, J = 11.8 Hz, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.06-1.84 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	(R)-2-((6-((3R,4S)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide •
	(0.67)2,2,2-trifluoroacetate •
	(0.33)methanesulfonate
510
497.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.96 (br. s., 1H), 7.57-7.48 (m, 2H), 7.43- 7.29 (m, 4H), 5.56-5.51 (m, 1H), 5.00-4.77 (m, 2H), 4.59-4.46 (m, 1H), 3.58- 3.43 (m, 1H), 3.41 (t, J = 5.4 Hz, 2H), 3.26 (s, 3H), 2.96- 2.69 (m, 5H), 1.95-1.80 (m, 1H), 1.70-1.50 (m, 1H), 1.25-1.18 (m, 5H).
	2((3,5-dicyano-4-ethyl-6-(3-
	fluoro-4-((2-
	methoxyethyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
511
449.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.97 (s, 1H), 7.52- 7.47 (m, 2H), 7.40-7.30 (m, 4H), 5.55 (s, 1H), 4.03- 3.94 (m, 1H), 3.79 (td, J = 6.8, 14.2 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.69 (t, J = 6.3 Hz, 2H), 2.48-2.41 (m, 4H), 1.68-1.60 (m, 4H), 1.20 (t, J = 7.6 Hz, 3H) (3H obscured).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-(pyrrolidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
512
449.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94-7.87 (m, 1H), 7.51 (dt, J = 2.3, 4.1 Hz, 2H), 7.41-7.25 (m, 4H), 5.62-5.54 (m, 1H), 4.04- 3.87 (m, 2H), 3.87-3.67 (m, 1H), 3.57-3.46 (m, 1H), 2.73 (q, J = 7.5 Hz, 2H), 2.34- 2.20 (m, 2H), 2.19 (s, 6H), 2.10-1.98 (m, 1H), 1.75- 1.59 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H) (1H obscured by DMSO).
	2-((3,5-dicyano-6-(3-
	((dimethylamino)methyl)
	pyrrolidin-1-yl)-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
513
511.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.59- 7.51 (m, 2H), 7.38 (s, 1H), 7.26-7.17 (m, 2H), 5.55 (s, 1H), 4.43-4.32 (m, 2H), 4.20 (s, 1H), 2.80-2.65 (m, 3H), 2.44 (s, 3H), 1.98-1.84 (m, 2H), 1.54 (br. s., 1H), 1.40-1.23 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 1.09 (s, 6H) (1H obscured by residual water peak).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-hydroxy-2-
	methylpropyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide
514
437.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.98 (s, 1H), 7.90 (br. s., 3H), 7.54-7.50 (m, 2H), 7.43-7.34 (m, 4H), 5.68 (d, J = 4.1 Hz, 1H), 5.52 (s, 1H), 4.62 (d, J = 12.7 Hz, 2H), 3.98 (br. s., 1H), 3.56 (d, J = 13.4 Hz, 1H), 3.19 (t, J = 11.5 Hz, 1H), 2.82-2.72 (m, 2H), 2.46 (br. s., 1H), 1.94-1.75 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H)
	(R)-2-((6-((3S,4R)-4-amino-
	3-hydroxypiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide,
	Trifluoroacetic acid salt
515
451.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.51- 7.48 (m, 2H), 7.40-7.30 (m, 4H), 5.54 (s, 1H), 3.97- 3.88 (m, 1H), 3.85-3.76 (m, 1H), 3.34 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 2.62-2.53 (m, 2H), 2.44-2.37 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H), 0.84 (t, J = 7.1 Hz, 6H).
	2-((3,5-dicyano-6-((2-
	(diethylamino)ethyl)(methyl)
	amino)-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
516
492.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 2H), 7.41-7.30 (m, 4H), 5.54 (s, 1H), 4.00- 3.90 (m, 1H), 3.80 (dd, J = 6.3, 14.2 Hz, 1H), 2.80- 2.52 (m, 8H), 2.40-2.31 (m, 1H), 2.05 (s, 6H), 1.83-1.72 (m, 1H), 1.59-1.48 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-6-((2-((R)-3-
	(dimethylamino)pyrrolidin-1-
	yl)ethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
517
492.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.96 (s, 1H), 7.52- 7.48 (m, 2H), 7.41-7.30 (m, 4H), 5.54 (s, 1H), 4.01- 3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.34 (br. s., 3H), 2.79- 2.52 (m, 8H), 2.39-2.29 (m, 1H), 2.07-2.02 (m, 6H), 1.83-1.72 (m, 1H), 1.59- 1.48 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-((2-((S)-3-
	(dimethylamino)pyrrolidin-1-
	yl)ethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
518
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.32 (br s, 3H), 7.98 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.32 (m, 4H), 5.55 (s, 1H), 4.87-4.71 (m, 2H), 4.65 (dt, J = 5.2, 9.6 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1H), 3.41-3.23 (m, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.21-2.11 (m, 1H), 1.73-1.58 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H).
	(R)-2-((6-((3R,4R)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide,
	Trifluoroacetic acid salt
519
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.32 (br. s., 3H), 7.98 (s, 1H), 7.56-7.50 (m, 2H), 7.43-7.32 (m, 4H), 5.55 (s, 1H), 4.87-4.71 (m, 2H), 4.65 (dt, J = 5.2, 9.6 Hz, 1H), 4.50 (d, J = 14.2 Hz, 1H), 3.41-3.23 (m, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.21-2.11 (m, 1H), 1.73-1.58 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H).
	(R)-2-((6-((3S,4S)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide,
	Trifluoroacetic acid salt
520
494.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.31 (br. s., 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 4.48 (s, 2H), 4.31-4.21 (m, 2H), 3.84 (t, J = 6.5 Hz, 2H), 3.36 (s, 3H), 2.76 (q, J = 7.6 Hz, 2H), 2.60 (t, J = 6.5 Hz, 2H), 2.42 (q, J = 7.1 Hz, 4H), 1.26- 1.14 (m, 3H), 0.86 (t, J = 7.1 Hz, 6H)
	2-amino-N-(4-(((3,5-dicyano-
	6-((2-
	(diethylamino)ethyl)(methyl)
	amino)-4-ethylpyridin-2-
	yl)thio)methyl)benzyl)
	acetamide
521
421.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.97-7.88 (m, 1H), 7.56-7.48 (m, 2H), 7.42-7.27 (m, 4H), 5.62- 5.56 (m, 1H), 3.98-3.54 (m, 4H), 3.25 (br. s., 1H), 2.78- 2.70 (m, 2H), 2.32-2.28 (m, 3H), 2.08-1.96 (m, 1H), 1.96-1.79 (m, 1H), 1.25- 1.13 (m, 3H)
	2-((3,5-dicyano-4-ethyl-6-(3-
	(methylamino)pyrrolidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
522
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.09 (br. s., 3H), 8.04 (s, 1H), 7.60-7.54 (m, 2H), 7.39 (s, 1H), 7.26-7.19 (m, 2H), 5.60 (s, 1H), 4.58 (d, J = 13.4 Hz, 2H), 3.43- 3.37 (m, 1H), 3.25 (dt, J = 6.1, 11.8 Hz, 2H), 2.76 (q, J = 7.6 Hz, 2H), 2.13-2.03 (m, 2H), 1.67-1.50 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((6-(4-aminopiperidin-1-
	yl)-3,5-dicyano-4-
	ethylpyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide
	hydrochloride
523
437.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.04 (br. s., 3H), 7.99-7.88 (m, 1H), 7.54- 7.50 (m, 2H), 7.44-7.32 (m, 4H), 5.94 (br. s., 1H), 5.55- 5.52 (m, 1H), 4.69-4.52 (m, 2H), 3.23-3.13 (m, 2H), 3.11-3.01 (m, 1H), 2.78 (q, J = 7.6 Hz, 2H), 2.47-2.39 (m, 1H), 2.12-1.99 (m, 1H), 1.63-1.49 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H)
	(R)-2-((6-((3R,4R)-4-amino-
	3-hydroxypiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	2,2,2-trifluoroacetate*
524
407.0 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.92 (br. s., 1H), 7.54-7.49 (m, 2H), 7.41- 7.29 (m, 4H), 5.61-5.58 (m, 1H), 4.02-3.82 (m, 2H), 3.76 (br. s., 1H), 3.62-3.46 (m, 2H), 2.74 (q, J = 7.5 Hz, 2H), 2.05-1.88 (m, 1H), 1.77 (br. s., 3H), 1.20 (t, J = 7.5 Hz, 3H)
	2-((6-((R)-3-aminopyrrolidin-
	1-yl)-3,5-dicyano-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
525
421.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.91 (br. s., 1H), 7.54-7.49 (m, 2H), 7.41- 7.31 (m, 4H), 5.61-5.56 (m, 1H), 4.00-3.69 (m, 3H), 3.62-3.42 (m, 1H), 2.74 (q, J = 7.5 Hz, 2H), 2.64-2.58 (m, 2H), 2.32-2.22 (m, 1H), 2.12-2.00 (m, 1H), 1.80- 1.64 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((6-(3-
	(aminomethyl)pyrrolidin-1-
	yl)-3,5-dicyano-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
526
453.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.59- 7.51 (m, 2H), 7.37 (s, 1H), 7.26-7.18 (m, 2H), 5.55 (s, 1H), 4.41-4.29 (m, 2H), 3.41-3.35 (m, 1H), 2.74 (q, J = 7.4 Hz, 2H), 2.65-2.56 (m, 1H), 2.30 (s, 3H), 1.94- 1.86 (m, 2H), 1.38-1.24 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(methylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide
527
479.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (br. s., 1H), 7.56-7.50 (m, 2H), 7.43- 7.31 (m, 4H), 5.57-5.52 (m, 1H), 5.04-4.82 (m, 2H), 4.62-4.50 (m, 1H), 3.60- 3.38 (m, 1H), 3.25-3.13 (m, 1H), 3.01-2.85 (m, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.35- 2.14 (m, 2H), 1.93-1.79 (m, 1H), 1.73-1.52 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 0.46- 0.37 (m, 2H), 0.29-0.23 (m, 2H)
	2-((3,5-dicyano-6-(4-
	(cyclopropylamino)-3-
	fluoropiperidin-1-yl)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
528
407.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.92 (br. s., 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.41- 7.29 (m, 4H), 5.61-5.58 (m, 1H), 4.02-3.70 (m, 3H), 3.65-3.46 (m, 3H), 2.74 (d, J = 7.6 Hz, 2H), 2.06-1.95 (m, 1H), 1.84-1.67 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H)
	2-((6-((S)-3-aminopyrrolidin-
	1-yl)-3,5-dicyano-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
529
464.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.98 (s, 1H), 7.54- 7.47 (m, 2H), 7.43-7.29 (m, 4H), 5.55 (s, 1H), 3.95 (td, J = 6.8, 13.8 Hz, 1H), 3.84-3.73 (m, 1H), 3.30- 3.23 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.72-2.54 (m, 4H), 2.48-2.41 (m, 1H), 2.18 (dt, J = 4.8, 9.1 Hz, 1H), 1.99- 1.89 (m, 1H), 1.58 (br. s., 2H), 1.35-1.26 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H) (3H obscured)
	2-((6-((2-((R)-3-
	aminopyrrolidin-1-
	yl)ethyl)(methyl)amino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
530
453.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (br. s., 1H), 7.56 (dd, J = 5.6, 7.9 Hz, 2H), 7.38 (br. s., 1H), 7.26-7.17 (m, 2H), 5.60 (s, 1H), 4.09- 3.86 (m, 2H), 3.84-3.51 (m, 2H), 2.79-2.69 (m, 3H), 2.23 (br. s., 6H), 2.19-2.12 (m, 1H), 1.87-1.74 (m, 1H), 1.20 (t, J = 7.5 Hz, 3H)
	2-((3,5-dicyano-6-((R)-3-
	(dimethylamino)pyrrolidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-
	2-(4-fluorophenyl)acetamide
531
439.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.32 (br. s., 3H), 7.97 (s, 1H), 7.59-7.47 (m, 2H), 7.45-7.31 (m, 4H), 5.55 (s, 1H), 5.19-4.96 (m, 2H), 4.64 (d, J = 11.9 Hz, 1H), 3.81-3.63 (m, 1H), 3.51 (dd, J = 14.7, 38.8 Hz, 1H), 3.27 (t, J = 11.8 Hz, 1H), 2.79 (q, J = 7.5 Hz, 2H), 2.07-1.84 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H)
	(S)-2-((6-((3S,4R)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide •
	(0.67)2,2,2-trifluoroacetate •
	(0.33)methanesulfonate
532
559.3 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.08 (s, 1H), 7.77 (s, 4H), 7.49 (s, 1H), 5.68 (s, 1H), 4.42-4.29 (m, 2H), 3.32-3.24 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 2.70-2.62 (m, 1H), 2.30 (s, 2H), 1.93- 1.86 (m, 2H), 1.39-1.28 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.87 (s, 9H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(neopentylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-(4-
	(trifluoromethyl)phenyl)
	acetamide
533
537.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.92 (s, 1H), 7.52 (d, J = 7.1 Hz, 2H), 7.43-7.31 (m, 4H), 6.42 (d, J = 7.9 Hz, 1H), 5.51 (s, 1H), 4.92 (d, J = 3.8 Hz, 1H), 4.53 (d, J = 13.4 Hz, 2H), 3.82 (br. s., 1H), 3.73-3.61 (m, 1H), 3.53 (d, J = 13.4 Hz, 1H), 3.21 (t, J = 11.8 Hz, 1H), 2.80- 2.69 (m, 2H), 1.84-1.72 (m. 1H). 1 66-1 59 (m, 1H), 1.41 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H)
	tert-butyl ((3S,4R)-1-(6-
	(((R)-2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-yl)-
	3-hydroxypiperidin-4-
	yl)carbamate
534
539.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.93 (s, 1H), 7.54- 7.48 (m, 2H), 7.43-7.30 (m, 4H), 7.17-7.08 (m, 1H), 5.54-5.51 (m, 1H), 4.92- 4.75 (m, 2H), 4.63-4.52 (m, 1H), 3.91-3.72 (m, 1H), 3.59-3.39 (m, 1H), 3.31- 3.21 (m, 1H), 2.77 (q, J = 7.6 Hz, 2H), 1.92-1.70 (m, 2H), 1.41 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H)
	rel-tert-butyl (cis)-1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-yl)-
	3-fluoropiperidin-4-
	yl)carbamate
535
464.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.98 (s, 1H), 7.53- 7.48 (m, 2H), 7.41-7.31 (m, 4H), 5.55 (s, 1H), 4.00- 3.91 (m, 1H), 3.83-3.74 (m, 1H), 3.30-3.23 (m, 1H), 2.76 (q, J = 7.4 Hz, 2H), 2.72- 2.54 (m, 4H), 2.48-2.41 (m, 1H), 2.18 (dt, J = 4.8, 9.0 Hz, 1H), 1.99-1.89 (m, 1H), 1.60 (br. s., 2H), 1.35-1.26 (m, 1H), 1.21 (t, J = 7.5 Hz, 3H)
	2-((6-((2-((S)-3-
	aminopyrrolidin-1-
	yl)ethyl)(methyl)amino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
536
435.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.93 (br. s., 1H), 7.55-7.47 (m, 2H), 7.40- 7.27 (m, 4H), 5.57 (s, 1H), 4.07-3.86 (m, 2H), 3.85- 3.51 (m, 2H), 2.80-2.65 (m, 3H), 2.26-2.10 (m, 7H), 1.87-1.72 (m, 1H), 1.19 (t, J = 7.5 Hz, 3H)
	2-((3,5-dicyano-6-((R)-3-
	(dimethylamino)pyrrolidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
537
537.3 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.91 (s, 1H), 7.54- 7.48 (m, 2H), 7.42-7.31 (m, 4H), 6.37 (d, J = 8.1 Hz, 1H), 5.49 (s, 1H), 4.95 (d, J = 3.8 Hz, 1H), 4.56 (d, J = 13.9 Hz, 1H), 4.48-4.40 (m, 1H), 3.82 (br. s., 1H), 3.72-3.62 (m, 1H), 3.51- 3.45 (m, 1H), 3.22-3.13 (m, 1H), 2.79-2.71 (m, 2H), 1.92-1.80 (m, 1H), 1.67- 1.58 (m, 1H), 1.40 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H)
	tert-butyl ((3R,4S)-1-(6-
	(((R)-2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-yl)-
	3-hydroxypiperidin-4-
	yl)carbamate
538
539.3 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.93 (s, 1H), 7.54- 7.49 (m, 2H), 7.43-7.31 (m, 4H), 7.19-7.08 (m, 1H), 5.54-5.51 (m, 1H), 4.93- 4.74 (m, 2H), 4.63-4.53 (m, 1H), 3.91-3.74 (m, 1H), 3.59-3.41 (m, 1H), 3.31- 3.22 (m, 1H), 2.81-2.73 (m, 2H), 1.91-1.70 (m, 2H), 1.42 (s, 9H), 1.20 (t, J = 7.6 Hz, 3H)
	rel-tert-butyl (cis)-1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-yl)-
	3-fluoropiperidin-4-
	yl)carbamate
539
435.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.54- 7.50 (m, 2H), 7.41-7.31 (m, 4H), 5.58 (s, 1H), 4.10- 3.86 (m, 2H), 3.86-3.69 (m, 1H), 3.62-3.40 (m, 1H), 2.80-2.66 (m, 3H), 2.23 (br. s., 6H), 2.19-2.11 (m, 1H), 1.88-1.75 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-6-((S)-3-
	(dimethylamino)pyrrolidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
540
439.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.39-8.25 (m, 3H), 7.97 (s, 1H), 7.57-7.50 (m, 2H), 7.45-7.33 (m, 4H), 5.55 (s, 1H), 5.19-4.90 (m, 2H), 4.64 (d, J = 11.4 Hz, 1H), 3.81-3.66 (m, 1H), 3.57 (dd, J = 15.0, 39.2 Hz, 1H), 3.25 (t, J = 12.0 Hz, 1H), 2.79 (q, J = 7.6 Hz, 2H), 2.05-1.83 (m, 2H), 1.22 (t, J = 7.6 Hz, 3H)
	(S)-2-((6-((3R,4S)-4-amino-
	3-fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	2,2,2-trifluoroacetate
541
479.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.92 (br. s., 1H), 7.55-7.49 (m, 2H), 7.40- 7.29 (m, 4H), 5.62-5.59 (m, 1H), 4.25-4.22 (m, 1H), 4.05-3.71 (m, 3H), 3.69- 3.48 (m, 1H), 2.73 (q, J = 7.5 Hz, 2H), 2.47-2.39 (m, 2H), 2.04 (dt, J = 4.9, 12.2 Hz, 1H), 1.94-1.69 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H), 1.12- 1.05 (m, 6H)
	2-((3,5-dicyano-4-ethyl-6-
	((S)-3-((2-hydroxy-2-
	methylpropyl)amino)
	pyrrolidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
542
537.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.93 (s, 1H), 7.51 (d, J = 6.8 Hz, 2H), 7.43-7.29 (m, 4H), 6.88 (d, J = 6.6 Hz, 1H), 5.51 (s, 1H), 5.15 (d, J = 4.1 Hz, 1H), 4.34 (d, J = 12.4 Hz, 1H), 4.22 (d, J = 13.7 Hz, 1H), 3.49-3.25 (m, 4H), 2.75 (q, J = 7.4 Hz, 2H), 2.02-1.92 (m, 1H), 1.47- 1.33 (m, 10H), 1.20 (t, J = 7.5 Hz, 3H)
	tert-butyl((3R,4R)-1-(6-(((R)-
	2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-yl)-
	3-hydroxypiperidin-4-
	yl)carbamate*
543
501.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 12.64 (br. s., 1H), 10.41 (s, 1H), 8.01 (br. s., 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.73-7.61 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H), 4.58 (s, 2H), 3.92-3.73 (m, 4H), 2.79 (q, J = 7.6 Hz, 2H), 2.63-2.57 (m, 2H), 2.49-2.45 (m, 2H), 2.22 (s, 3H), 1.96-1.87 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H)
	4-(((3,5-dicyano-4-ethyl-6-
	(4-methyl-1,4-diazepan-1-
	yl)pyridin-2-yl)thio)methyl)-
	N-(1H-pyrazol-4-
	yl)benzamide
544
453.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.59- 7.53 (m, 2H), 7.38 (br. s., 1H), 7.26-7.19 (m, 2H), 5.62-5.58 (m, 1H), 4.08- 3.87 (m, 2H), 3.85-3.65 (m, 1H), 3.62-3.38 (m, 1H), 2.80-2.66 (m, 3H), 2.30- 2.10 (m, 7H), 1.87-1.74 (m, 1H), 1.20 (t. J = 7.6 Hz, 3H)
	2-((3,5-dicyano-6-((S)-3-
	(dimethylamino)pyrrolidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-
	2-(4-fluorophenyl)acetamide
545
439.4 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.96 (s, 1H), 7.55- 7.49 (m, 2H), 7.41-7.30 (m, 4H), 5.56-5.51 (m, 1H), 4.80-4.60 (m, 2H), 4.51- 4.39 (m, 1H), 3.61-3.38 (m, 1H), 3.28-3.15 (m, 1H), 3.04-2.90 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 1.79-1.69 (m, 1H), 1.69-1.56 (m, 3H), 1.20 (t, J = 7.6 Hz, 3H)
	rel-2-((6-cis-4-amino-3-
	fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
546
482.4 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 8.30 (t, J = 6.0 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 4.83- 4.63 (m, 2H), 4.54-4.38 (m, 3H), 4.26 (d, J = 6.1 Hz, 2H), 3.63-3.45 (m, 2H), 3.30-3.21 (m, 2H), 3.11 (s, 2H), 3.02-2.87 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 1.78- 1.54 (m, 4H), 1.20 (t, J = 7.6 Hz, 3H)
	rel-2-amino-N-(4-(((6-(cis-4-
	amino-3-fluoropiperidin-1-
	yl)-3,5-dicyano-4-
	ethylpyridin-2-
	yl)thio)methyl)benzyl)
	acetamide
547
435.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.57- 7.47 (m, 2H), 7.44-7.27 (m, 4H), 5.54 (s, 1H), 4.36 (d, J = 13.4 Hz, 2H), 3.42- 3.29 (m, 2H), 2.75 (q, J = 7.5 Hz, 2H), 2.66-2.55 (m, 1H), 2.30 (s, 3H), 1.91 (d, J = 11.4 Hz, 2H), 1.69 (br. s., 1H), 1.40-1.25 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(methylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
548
449.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.93 (s, 1H), 7.56- 7.46 (m, 2H), 7.43-7.25 (m, 4H), 5.53 (s, 1H), 4.56 (d, J = 12.9 Hz, 2H), 3.23- 3.10 (m, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.46-2.35 (m, 1H), 2.22-2.11 (m, 6H), 1.86 (d, J = 12.2 Hz, 2H), 1.49-1.28 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-6-(4-
	(dimethylamino)piperidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
549
463.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.95 (s, 1H), 7.57- 7.46 (m, 2H), 7.43-7.26 (m, 4H), 5.54 (s, 1H), 4.60 (d, J = 12.7 Hz, 2H), 3.21- 3.07 (m, 2H), 2.82-2.61 (m, 3H), 2.47 (q, J = 7.2 Hz, 2H), 2.15 (s, 3H), 1.81 (d, J = 12.2 Hz, 2H), 1.54-1.30 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(ethyl(methyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
550
491.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.59- 7.49 (m, 2H), 7.44-7.29 (m, 4H), 5.54 (s, 1H), 4.48- 4.33 (m, 2H), 3.44-3.27 (m, 2H) 2.75 (q, J = 7.6 Hz, 2H), 2.73-2.62 (m, 1H), 2.32 (br. s., 2H), 2.00-1.85 (m, 2H), 1.51-1.26 (m, 3H), 1.21 (t, J = 7.6 Hz, 3H), 0.88 (s, 9H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(neopentylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
551
505.2 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.58- 7.48 (m, 2H), 7.44-7.25 (m, 4H), 5.55 (s, 1H), 4.67 (d, J = 13.4 Hz, 2H), 3.15- 2.98 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 2.69-2.57 (m, 1H), 2.25 (s, 3H), 2.16 (s, 2H), 1.80 (d, J = 12.2 Hz, 2H), 1.55-1.34 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H), 0.86 (s, 9H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(methyl(neopentyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-
	2-phenylacetamide
552
461.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.56- 7.49 (m, 2H), 7.43-7.29 (m, 4H), 5.54 (s, 1H), 4.43- 4.32 (m, 2H), 3.39-3.29 (m., 2H), 2.84 (br. s., 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.27 (br. s., 1H), 2.11 (tt, J = 3.5, 6.5 Hz, 1H), 2.00-1.90 (m, 2H), 1.43-126 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.44-0.36 (m, 2H), 0.25-0.18 (m, 2H)
	2-((3,5-dicyano-6-(4-
	(cyclopropylamino)piperidin-
	1-yl)-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
553
479.4 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.57- 7.47 (m, 2H), 7.45-7.28 (m, 4H), 5.53 (s, 1H), 4.46- 4.31 (m, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.33-3.27 (m, 2H), 3.26 (s, 3H), 2.82-2.66 (m, 5H), 1.92 (d, J = 12.9 Hz, 2H), 1.63 (br. s., 1H), 1.39-1.25 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-
	methoxyethyl)amino)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
554
485.3 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.94 (s, 1H), 7.57- 7.47 (m, 2H), 7.44-7.28 (m, 4H), 5.98 (tt, J = 4.6, 56.0 Hz, 1H), 5.53 (s, 1H), 4.49- 4.35 (m, 2H), 3.33-3.24 (m, 2H), 2.94 (t, J = 14.6 Hz, 2H), 2.84-2.70 (m, 3H), 2.08 (br. s., 1H), 1.94 (d, J = 10.9 Hz, 2H), 1.41-1.24 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-6-(4-((2,2-
	difluoroethyl)amino)piperidin-
	1-yl)-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
555
507.4 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.91 (s, 1 H), 7.52 (d, J = 7.1 Hz, 2 H), 7.30-7.43 (m, 4 H), 5.48- 5.55 (m, 1 H), 4.45- 4.62 (m, 2 H), 3.89-4.00 (m, 1 H), 3.44-3.62 (m, 2 H), 3.20- 3.29 (m, 1 H), 3.06-3.16 (m, 1 H), 2.77 (q, J = 7.5 Hz, 2 H), 2.66 (br. s., 2 H), 2.29 (br. s., 2 H), 1.37-1.52 (m, 1 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.81-0.90 (m, 9 H)
	2-((3,5-dicyano-4-ethyl-6-(((R)-
	2-
	((neopentylamino)methyl)
	morpholino)pyridin-2-yl)thio)-2-
	phenylacetamide
556
527.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.42-7.47 (m, 2 H), 7.35- 7.40 (m, 2 H), 4.50 (s, 2 H), 4.35-444 (m, 2 H), 3.25-3.33 (m, 4 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.73-2.80 (m, 2 H), 1.85- 1.95 (m, 2 H), 1.18-1.38 (m, 6 H), 0.97 (d, J = 6.1 Hz, 6 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-(isopropylamino)piperidin-1-
	yl)pyridin-2-yl)
	thio)methyl)phenyl)-N-
	methylmethanesulfonamide
557
543.1 [M + H] +	1 H NMR (400 MHz, DMSO- d 6 ) δ ppm 7.42-7.48 (m, 2 H), 7.34- 7.40 (m, 2 H), 4.50 (s, 2 H), 4.30-4.40 (m, 2 H), 3.28-3 41 (m, 4 H), 3.24 (s, 3 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.67-2.80 (m, 5 H), 1.84-1.95 (m, 2 H), 1.60 (br. s., 1 H), 1.24-1.34 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-((2-
	methoxyethyl)amino)piperidin-
	1-yl)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
558
465.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86-7.96 (m, 1 H), 7.48-7.54 (m, 2 H), 7.31-7.43 (m, 4 H), 5.49-5.55 (m, 1 H), 4.41-4.57 (m, 2 H), 3.89-3.98 (m, 1 H), 3.45-3.69 (m, 2 H), 3.18-3.29 (m, 1 H), 3.00-3.09 (m, 1 H), 2.77 (q, J = 1.4 Hz, 2 H), 2.30-2.44 (m, 2 H), 2.19 (d, J = 4.3 Hz, 6 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-((3,5-dicyano-6-(2-
	((dimethylamino)methyl)
	morpholino)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
559
493.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90 (br. s., 1 H), 7 48- 7.55 (m, 2 H), 7.31-7.43 (m, 4 H), 5.49-5.56 (m, 1 H), 4.46- 4.59 (m, 2 H), 3.88-3.98 (m, 1 H), 3.41-3.63 (m, 2 H), 3.15- 3.25 (m, 1 H), 3.03-3.13 (m, 1 H), 2.77 (q, J = 7.5 Hz, 2 H), 2.40- 2.57 (m, 6 H), 1.21 (t, J = 7.6 Hz, 3H), 0.91-0.97 (m, 6 H)
	2-((3,5-dicyano-6-(2-
	((diethylamino)methyl)
	morpholino)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
560
491.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.93 (br. s., 1 H), 7.48- 7.55 (m, 2 H), 7.31-7.43 (m, 4 H), 5.49-5.56 (m, 1 H), 4.52- 4.63 (m, 1 H), 4.40-4.51 (m, 1 H), 3.90-3 98 (m, 1 H), 3.62- 3.73 (m, 1 H), 3.46-3.62 (m, 1 H), 3.18-3.30 (m, 2 H), 2.99- 3.10 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.55 (s, 5 H), 1.55- 1.77 (m, 4 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-((3,5-dicyano-4-ethyl-6-(2-
	(pyrrolidin-1-
	ylmethyl)morpholino)pyridin-2-
	yl)thio)-2-phenylacetamide
561
437.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.01-8.17 (m, 4 H), 7.52- 7.58 (m, 2 H), 7.34-7.47 (m, 4 H), 5.56 (s, 1 H), 4 56 (d, J = 13.2 Hz, 1 H), 4.43 (d, J = 11.9 Hz, 1 H), 4.04 (d, J = 10.9 Hz, 1 H), 3.73-3.81 (m, 1 H), 3.51-3.59 (m, 1 H), 3.38- 3.44 (m, 1 H), 3.15 (br. s., 1 H), 3.09 (dd, J = 13.4, 10.4 Hz, 1 H), 2.91 (br. s., 1 H), 2.79 (q, J = 7.4 Hz, 2 H), 1.23 (t, J = 7.6 Hz, 3 H)
	(R)-2-((6-((R)-2-
	(aminomethyl)morpholino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide,
	Hydrochloride
562
437.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.93-8.08 (m, 1 H), 7.48- 7.56 (m, 2 H), 7.30-7.44 (m, 4 H), 5.48-5.56 (m, 1 H), 4.50- 4.66 (m, 1 H), 4.39-4.49 (m, 1 H), 3.89-4.01 (m, 1 H), 3.45- 3.59 (m, 1 H), 3.36-3.43 (m, 1 H), 3.22-3.33 (m, 1 H), 2.95- 3.07 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.61-2.71 (m, 2 H), 1.46-1.68 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H)
	2-((6-(2-
	(aminomethyl)morpholino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
563
451.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90-8.06 (m, 1 H), 7.48- 7.56 (m, 2 H), 7.31-7.44 (m, 4 H), 5.46-5.56 (m, 1 H), 4.40- 4.64 (m, 2 H), 3.90-3.98 (m, 1 H), 3.44-3.61 (m, 2 H), 3.23- 3.32 (m, 1 H), 3.14-3.20 (m, 1 H), 3.00-3.12 (m, 1 H), 2.77 (q, J = 7.7 Hz, 2 H), 2.57-2.62 (m, 2 H), 2.27-2.32 (m, 3 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-((3,5-dicyano-4-ethyl-6-(2-
	((methylamino)methyl)
	morpholino)pyridin-2-yl)thio)-2-
	phenylacetamide
564
437.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91-8.09 (m, 1 H), 7.52 (d, J = 5.3 Hz, 2 H), 7.31-7.46 (m, 4 H), 5.47-5.58 (m, 1 H), 4.51-4.67 (m, 1 H), 4.39-4.49 (m, 1 H), 3.87-4.03 (m, 1 H), 3.45-3.61 (m, 1 H), 3.37-3.44 (m, 1 H), 3.21-3.29 (m, 1 H), 2.95-3.07 (m, 1 H), 2.72-2.83 (m, 2 H), 2.60-2.72 (m, 2 H), 1.74 (br. s., 2 H), 1.21 (t, J = 7.4 Hz, 3 H)
	2-((6-((R)-2-
	(aminomethyl)morpholino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
565
463.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86-8.04 (m, 1 H), 7.48- 7.56 (m, 2 H), 7.30-7.42 (m, 4 H), 5.50-5.56 (m, 1 H), 4.29- 4.55 (m, 2 H), 3.15-3.26 (m, 1 H), 2 94-3.12 (m, 1 H), 2.76 (q, J = 7.6 Hz, 2 H), 1.97-2.20 (m, 8 H), 1.72-1.89 (m, 3 H), 1.41-1.62 (m, 1 H), 1.23-1.30 (m, 1 H), 1.20 (t, J = 7.5 Hz, 3 H)
	2-((3,5-dicyano-6-(3-
	((dimethylamino)methyl)
	piperidin-1-yl)-4-ethylpyridin-2-yl)thio)-
	2-phenylacetamide
566
449.4 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90-8.33 (m, 1H), 7.49- 7.57 (m, 2 H), 7.30-7.42 (m, 4 H), 5.49-5.59 (m, 1 H), 4.38- 4.76 (m, 2 H), 3.16-3.27 (m, 1 H), 2.83-3.04 (m, 1 H), 2.76 (q, J = 7.4 Hz, 2 H), 2.31-2.46 (m, 2 H), 2.23-2.30 (m, 3 H), 1.69-1.88 (m, 3 H), 1.40-1.62 (m, 1 H), 1.25-1.34 (m, 1 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-((3,5-dicyano-4-ethyl-6-(3-
	((methylamino)methyl)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
567
507.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91 (s, 1 H), 7.48-7.55 (m, 2 H), 7.31-7.43 (m, 4 H), 5.48-5.55 (m, 1 H), 4.43-4.62 (m, 2 H), 3.90-4.01 (m, 1 H), 3.44-3.61 (m, 2 H), 3.20-3.30 (m, 1 H), 3.05-3.16 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.66 (br. s., 2 H), 2.29 (br. s., 2 H), 1.45 (br. s., 1 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.83-0.89 (m, 9 H)
	2-((3,5-dicyano-4-ethyl-6-((S)-
	2-
	((neopentylamino)methyl)
	morpholino)pyridin-2-yl)thio)-2-
	phenylacetamide
568
505.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90-8.00 (m, 1H), 7.48- 7.56 (m, 2 H), 7.30-7.42 (m, 4 H), 5.48-5.56 (m, 1 H), 4.37- 4.59 (m, 2 H), 3.02-3.23 (m, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 2.39-2.47 (m, 2 H), 2.15-2.29 (m, 2 H), 1.81-1.92 (m, 1 H), 1.67-1.81 (m, 2 H), 1.25-1.61 (m, 3 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.84 (s, 9 H)
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-
	((neopentylamino)methyl)
	piperidin-1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
569
555.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.48 (m, 2 H), 7.34- 7.40 (m, 2 H), 4.51 (s, 2 H), 4.29-4.41 (m, 2 H), 3.29-3.38 (m, 2 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.58-2.71 (m, 1 H), 2.29 (s, 2 H), 1.86-1.97 (m, 2 H), 1.27- 1 43 (m, 3 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.86 (s, 9 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-(neopentylamino)piperidin-1-
	yl)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
570
513.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41-7.46 (m, 2 H), 7.34- 7.40 (m, 2 H), 4.54 (s, 2 H), 3.86 (t, J = 6.8 Hz, 2 H), 3.38 (s, 3 H), 3.22 (s, 3 H), 2.93 (s, 3H), 2.78 (q, J = 7.6 Hz, 2 H), 2.67 (t, J = 6.8 Hz, 2 H), 2.38-2.46 (m, 4 H), 1.57-1.66 (m, 4 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(methyl(2-(pyrrolidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
571
529.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.49 (m, 2 H), 7.33- 7.41 (m, 2 H), 4.55-4.63 (m, 1 H), 4.52 (s, 2 H), 4.33-4.43 (m, 1 H), 3.88-3.98 (m, 1 H), 3.59-3.70 (m, 1 H), 3.48-3.58 (m, 1 H), 3.24-3.33 (m, 1 H), 3.22 (s, 3 H), 2.97-3.06 (m, 1 H), 2.93 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.28-2.39 (m, 2 H), 2.16 (s, 6 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-6-(2-
	((dimethylamino)methyl)
	morpholino)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
572
570.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.69-7.78 (m, 1 H), 7.42- 7.49 (m, 2 H), 7.34-7.40 (m, 2 H), 4.51 (s, 2 H), 4.40-4.48 (m, 2 H), 3.76-3.95 (m, 1 H), 3.27-3.33 (m, 2 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 1.79-1.93 (m, 4 H), 1.45-1.60 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H), 1.17 (s, 6 H)
	2-amino-N-(1-(3,5-dicyano-4-
	ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)piperidin-4-
	yl)-2-methylpropanamide
573
525.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.48 (m, 2 H), 7.33- 7.40 (m, 2 H), 4.51 (s, 2 H), 4.28-4.41 (m, 2 H), 3.29-3.40 (m, 2 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.70-2.87 (m, 3 H), 2.24 (br. s., 1 H), 2.04-2.13 (m, 1 H), 1.86-2.00 (m, 2 H), 1.27- 1.40 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.34-0.42 (m, 2 H), 0.17- 0.25 (m. 2 H)
	N-(4-(((3,5-dicyano-6-(4-
	(cyclopropylamino)piperidin-1-
	yl)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
574
555.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.48 (m, 2 H), 7.33- 7.40 (m, 2 H), 4.61-4.74 (m, 1 H), 4.51 (s, 2 H), 4.33-4.43 (m, 1 H), 3.87-3.98 (m, 1 H), 3.61-3.71 (m, 1 H), 3.48-3.59 (m, 1 H), 3.26-3.33 (m, 1 H), 3.22 (s, 3 H), 2.97-3.06 (m, 1 H), 2.93 (s, 3 H), 2.78 (q, J = 7.4 Hz, 2 H), 2.55-2.69 (m, 1 H), 2.33-2.50 (m, 5 H), 1.50-1.70 (m, 4 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(2-(pyrrolidin-1-
	ylmethyl)morpholino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
575
522.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.08-8.20 (m, 1 H), 7.88- 8.04 (m, 1 H), 7.49-7.59 (m, 2 H), 7.29-7.47 (m, 4 H), 5.50- 5.57 (m, 1 H), 4.34-4.53 (m, 2 H), 3.91-4.03 (m, 1 H), 3.47- 3.63 (m, 2 H), 3.13-3.31 (m, 3 H), 2.96-3.09 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 1.95 (br. s., 2 H), 1.14-1.25 (m, 9H)
	2-amino-N-(((2S)-4-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)morpholin-2-
	yl)methyl)-2-methylpropanamide
576
435.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.11-8.39 (m, 1H), 7.49- 7.63 (m, 2 H), 7.29-7.43 (m, 4 H), 5.53-5.62 (m, 1 H), 4.40- 4.80 (m, 2 H), 3.14-3.26 (m, 2 H), 2.80-3.00 (m, 1 H), 2.76 (q, J = 7.5 Hz, 2 H), 2.52-2.60 (m, 1 H), 2.35-2.47 (m, 1 H), 1.88-2.22 (m, 1 H), 1.73-1.87 (m, 2 H), 1.39-1.66 (m, 2 H), 1.16-1.31 (m, 4 H)
	2-((6-((S)-3-
	(aminomethyl)piperidin-1-yl)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
577
527.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.40-7.45 (m, 2H), 7.33- 7.39 (m, 2H), 4.53 (s, 2H), 3.84 (t, J = 6.6 Hz, 2H), 3.34 (s, 3H), 3.21 (s, 3H), 2.92 (s, 3H), 2.77 (q, J = 7.6 Hz, 2H), 2.45-2.49 (m, 2H), 2.22-2.36 (m, 4H), 1.26- 1 41 (m, 6H), 1.21 (t, J = 7.6 Hz, 3H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(methyl(2-(piperidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
578
493.4 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.83-7.95 (m, 1H), 7.48- 7.55 (m, 2 H), 7.31-7.44 (m, 4 H), 5.47-5.56 (m, 1 H), 4.47- 4.59 (m, 2 H), 3.87-3.98 (m, 1 H), 3.41-3.63 (m, 2 H), 3.14- 3.26 (m, 1 H), 3.02-3.14 (m, 1 H), 2.77 (q, J = 7.4 Hz, 2 H), 2.39-2.59 (m, 6 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.90-0.98 (m, 6 H)
	2-((3,5-dicyano-6-((R)-2-
	((diethylamino)methyl)morpholino)-
	4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
579
515.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41-7.47 (m,2H), 7.31- 7.40 (m, 2 H), 4.53 (s, 2 H), 3.84 (t, J = 6.5 Hz, 2 H), 3.36 (s, 3 H), 3.22 (s, 3 H), 2.93 (s, 3 H), 2.78 (q, J = 7.5 Hz, 2 H), 2.59 (t, J = 6.5 Hz, 2 H), 2.42 (q, J = 7.1 Hz, 4 H), 1.22 (t, J = 7.6 Hz, 3 H), 0.86 (t, J = 7.1 Hz, 6 H)
	N-(4-(((3,5-dicyano-6-((2-
	(diethylamino)ethyl)(methyl)
	amino)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
580
557.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41-7.47 (m, 2 H), 7.34- 7.40 (m, 2 H), 4.63-4.73 (m, 1 H), 4.52 (s, 2 H), 4.37-4.45 (m, 1 H), 3.88-3.98 (m, 1 H), 3.47-3.65 (m, 2 H), 3.25-3.33 (m, 1 H), 3.22 (s, 3 H), 3.02 (dd, J = 10.4, 13.4 Hz, 1H), 2.93 (s, 3 H), 2.78 (q, J = 7.4 Hz, 2H), 2.36- 2.49 (m, 6 H), 1.22 (t, J = 7.6 Hz, 3 H), 0.90 (t, J = 7.1 Hz, 6 H)
	N-(4-(((3,5-dicyano-6-(2-
	((diethylamino)methyl)
	morpholino)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
581
522.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.08-8.21 (m, 1 H), 7.91- 8.04 (m, 1 H), 7.50-7.57 (m, 2 H), 7.30-7.46 (m, 4 H), 5.49- 5.57 (m, 1 H), 4.35-4.51 (m, 2 H), 3.91-4.02 (m, 1 H), 3.46- 3.63 (m, 2 H), 3.12-3.33 (m, 3 H), 2.95-3.09 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 1.94 (s, 2H), 1.13-1.24 (m, 9 H)
	2-amino-N-(((2R)-4-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)morpholin-2-
	yl)methyl)-2-
	methylpropanamide
582
539.2 [M + H] +	1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39- 7.44 (m, 2 H), 7.33-7.38 (m, 2 H), 4.49-4.60 (m, 2 H), 4.42 (s, 2 H), 3.32-3.35 (m, 3 H), 3.20-3.31 (m, 2 H), 2.92 (q, J = 7.4 Hz, 2 H), 2.85-2.88 (m, 3 H), 2.53-2.72 (m, 4 H), 2.24- 2 46 (m, 1 H), 2.05 (d, J = 12.9 Hz, 2 H), 1.76-1.94 (m, 4 H), 1.61-1.75 (m, 2 H, 1.34 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-(pyrrolidin-1-yl)piperidin-1-
	yl)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
583
440.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.39-8.45 (m, 1 H), 7.77- 7.84 (m, 1 H), 7.74 (s, 1 H), 7.46-7.53 (m, 2 H), 5.98 (s, 1 H), 4.29-4.40 (m, 2 H), 3.24- 3.32 (m, 2 H), 2.85-2.96 (m, 1 H), 2.78 (q, J = 7.6 Hz, 2H), 1.67- 1.86 (m, 4 H), 1.18-1.35 (m, 5 H)
	2-((6-(4-aminopiperidin-1-yl)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-(3-fluoropyridin-2-
	yl)acetamide
584
556.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.76 (d, J = 7.9 Hz, 1 H), 7.41-7.48 (m, 2 H), 7.32-7.41 (m, 2 H), 4.51 (s, 2 H), 4.36- 4.46 (m, 2 H), 3.82-3.97 (m, 1 H), 3.40-3.28 (m, 2 H), 3.17- 3.25 (m, 4 H), 2.93 (s, 3 H), 2.77 (q, J = 7.6 Hz, 2 H), 1.71- 1.91 (m, 4 H), 1.41-1.57 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H)
	(R)-2-amino-N-(1-(3,5-dicyano-
	4-ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)piperidin-4-
	yl)propanamide
585
556.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.76 (d, J = 8.1 Hz, 1 H), 7.42-7.48 (m, 2 H), 7.33-7.41 (m, 2 H), 4 51 (s, 2 H), 4.34- 4.47 (m, 2 H), 3.80-3.97 (m, 1 H), 3.41-3.27 (m, 2 H), 3.14- 3.26 (m, 4 H), 2.93 (s, 3 H), 2.77 (q, J = 7.6 Hz, 2 H), 1.70- 1 90 (m, 4 H), 1 41-1.56 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H)
	(S)-2-amino-N-(1-(3,5-dicyano-
	4-ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)piperidin-4-
	yl)propanamide
586
437.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89-8.09 (m, 1 H), 7.49- 7.56 (m, 2 H), 7.31-7.44 (m, 4 H), 5.49-5.55 (m, 1 H), 4.51- 4.66 (m, 1 H), 4.38-4.49 (m, 1 H), 3.90-4.01 (m, 1 H), 3.45- 3.60 (m, 1 H), 3.39-3.44 (m, 1 H), 3.18-3.29 (m, 1 H), 2.97- 3.06 (m, 1 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.60-2.72 (m, 2 H), 1.49-1.90 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-((6-((S)-2-
	(aminomethyl)morpholino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
587
485.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.49 (m, 2 H), 7.32- 7.40 (m, 2 H), 4.51 (s, 2 H), 4.32-4.43 (m, 2 H), 3.25-3.32 (m, 2 H), 3.22 (s, 3 H), 2.84- 2.96 (m, 4 H), 2.76 (q, J = 7.4 Hz, 2 H), 1.72-1.96 (m, 4 H), 1.16-1.35 (m, 5H)
	N-(4-(((6-(4-aminopiperidin-1-
	yl)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
588
520.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90-8.10 (m, 2 H), 7.50- 7.57 (m, 2 H), 7.31-7.49 (m, 4 H), 5.48-5.58 (m, 1 H), 4.32- 4.47 (m, 2 H), 3.04-3.19 (m, 2 H), 2.87-3.04 (m, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 1.88-2.06 (m, 2 H), 1.72-1.86 (m, 3 H), 1.25-1.61 (m, 2 H), 1.14-1.23 (m, 9 H)
	2-amino-N-(((3S)-1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)piperidin-3-
	yl)methyl)-2-
	methylpropanamide
589
492.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91-8.08 (m, 2 H), 7.49- 7.57 (m, 2 H), 7.28-7.46 (m, 4 H), 5.49-5.58 (m, 1 H), 4.35- 4.53 (m, 2 H), 3.08-3.19 (m, 4 H), 2.89-3.08 (m, 2 H), 2.75 (q, J = 7.4 Hz, 2 H), 2.19-2.40 (m, 2 H), 1.71-1.88 (m, 3 H), 1.25-1.64 (m, 2 H), 1.20 (t, J = 7.5 Hz, 3 H)
	2-amino-N-(((3S)-1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)piperidin-3-
	yl)methyl)acetamide
590
542.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.70-7.87 (m, 1H), 7.42- 7.49 (m, 2 H), 7.33-7.42 (m, 2 H), 4.51 (s, 2 H), 4.36-4.47 (m, 2 H), 3.86-4.03 (m. 1 H), 3.28-3.39 (m, 2 H), 3.22 (s, 3 H), 3.06 (br. s., 2 H), 2.93 (s, 3 H), 2.77 (q, J = 7.6 Hz, 2 H), 1.66- 1.92 (m, 4 H), 1.41-1.56 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H)
	2-amino-N-(1-(3,5-dicyano-4-
	ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)piperidin-4-
	yl)acetamide
591
501.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.49 (m, 2 H), 7.34- 7.41 (m, 2 H), 4.47-4.61 (m, 3 H), 4.35-4.44 (m, 1 H), 3.89- 4.00 (m, 1 H), 3.45-3.57 (m, 1 H), 3.26-3.43 (m, 2 H), 3.22 (s, 3 H), 2.98-3.08 (m, 1 H), 2.93 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.54-2.69 (m, 2 H), 1.39- 1.76 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((6-(2-
	(aminomethyl)morpholino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
592
494.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.03-8.12 (m, 1 H), 7.92- 8.02 (m, 1 H), 7.50-7.57 (m, 2 H), 7.31-7.45 (m, 4 H), 5.50- 5.57 (m, 1 H), 4.47-4.56 (m, 1 H), 4.34-4.47 (m, 1 H), 3.93- 4.03 (m, 1 H), 3.47-3.64 (m, 2 H), 3.17-3.42 (m, 3 H), 3.11 (s, 2 H), 2.95-3.08 (m, 1 H), 2.77 (q, J = 7.4 Hz, 2 H), 1.88 (br. s., 2H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-amino-N-(((2R)-4-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)morpholin-2-
	yl)methyl)acetamide
593
453.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.09-8.36 (m, 1H), 7.55- 7.64 (m, 2 H), 7.35-7.47 (m, 1 H), 7.23 (t, J = 8.7 Hz, 2 H), 5.55-5.61 (m, 1 H), 4.38-4.73 (m, 2 H), 3.03-3.25 (m, 3 H), 2.83-3.00 (m, 1 H), 2.76 (q, J = 7.6 Hz, 2 H), 2.44-2.62 (m, 2 H), 1.75-1.90 (m, 2 H), 1.72- 1.59 (m, 1 H), 1.41-1.57 (m, 1 H), 1.24-1.34 (m, 1 H), 1.21 (t, J = 7.5 Hz, 3 H)
	2-((6-((R)-3-
	(aminomethyl)piperidin-1-yl)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-(4-
	fluorophenyl)acetamide
594
523.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.98 (br. s., 1 H), 7.53- 7.61 (m, 2 H), 7.40 (br. s., 1 H), 7.22 (t, J = 8.9 Hz, 2 H), 5.53- 5.58 (m, 1 H), 4.36-4.57 (m, 2 H), 3.02-3.23 (m, 2 H), 2.75 (q, J = 7.6 Hz, 2 H), 2.39-2.47 (m, 2 H), 2.14-2.30 (m, 2 H), 1.81- 1.93 (m, 1 H), 1.68-1.81 (m, 2 H), 1.25-1.64 (m, 3 H), 1.20 (t, J = 7.6 Hz, 3 H), 0.80-0.86 (m, 9 H)
	2-((3,5-dicyano-4-ethyl-6-((R)-
	3-
	((neopentylamino)methyl)
	piperidin-1-yl)pyridin-2-yl)thio)-2-(4-
	fluorophenyl)acetamide
595
517.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41-7.48 (m, 2 H), 7.33- 7.40 (m, 2 H), 5.63 (d, J = 45.9 Hz, 2 H), 4.52 (s, 2 H), 3.80- 3.94 (m, 4 H), 3.30 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.59- 2.70 (m, 2 H), 2.45-2.49 (m, 2 H), 2.23 (s, 3 H), 1.83-1.96 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-methyl-1,4-diazepan-1-
	yl)pyridin-2-
	yl)thio)methyl)phenyl)-1-fluoro-
	N-methylmethanesulfonamide
596
515.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42-7.49 (m, 2 H), 7.35- 7.41 (m, 2 H), 4.48-4.57 (m, 3 H), 4.35-4.44 (m, 1 H), 3.90- 4.00 (m, 1 H), 3.54-3.64 (m, 1 H), 3.47-3.54 (m, 1 H), 3.25- 3.32 (m, 2 H), 3.19-3.24 (m, 3 H), 3.02-3.12 (m, 1 H), 2.90- 2.96 (m, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.55-2.69 (m, 2 H), 2.17-2.35 (m, 3 H), 1.19-1.25 (m, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(2-
	((methylamino)methyl)
	morpholino)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
597
527.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.43-7.49 (m, 2 H), 7.33- 7.40 (m, 2 H), 4.49-4.60 (m, 3 H), 4.28-4.39 (m, 1 H), 3.23- 3.32 (m, 1 H), 3.22 (s, 3 H), 2.98-3.07 (m, 1 H), 2.93 (s, 3 H), 2.77 (q, J = 7.6 Hz, 2 H), 2.05- 2.16 (m, 7 H), 1.97-2.04 (m, 1 H), 1.68-1.89 (m, 3 H), 1.44- 1.59 (m, 1 H), 1.16-1.29 (m, 4 H)
	N-(4-(((3,5-dicyano-6-(3-
	((dimethylamino)methyl)
	piperidin-1-yl)-4-ethylpyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
598
494.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.03-8.12 (m, 1 H), 7.91- 8.02 (m, 1 H), 7.50-7.57 (m, 2 H), 7.31-7.45 (m, 4 H), 5.51- 5.57 (m, 1 H), 4.47-4.57 (m, 1 H), 4.36-4.47 (m, 1 H), 3.92- 4.03 (m, 1 H), 3.47-3.62 (m, 2 H), 3.36-3.43 (m, 1 H), 3.18- 3.31 (m, 2 H), 3.11 (s, 2 H), 2.95-3.07 (m, 1 H), 2.77 (q, J = 7.4 Hz, 2 H), 1.85 (br. s., 2 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-amino-N-(((2S)-4-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-yl)morpholin-2-
	yl)methyl)acetamide
599
495.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.96 (s, 1 H), 7.87 (t, J = 5.8 Hz, 1 H), 7.50-7.55 (m, 2 H), 7.32-7.44 (m, 4 H), 5.54 (s, 1 H), 4.46-4.56 (m, 1 H), 4.39 (d, J = 11.7 Hz, 1 H), 3.97 (d, J = 11.7 Hz, 1 H), 3.84 (s, 2 H), 3.46-3.62 (m, 4 H), 3.21- 3.36 (m, 2 H), 3.01 (dd, J = 13.4, 10.4 Hz, 1 H), 2.72-2.82 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3 H)
	N-(((R)-4-(6-(((R)-2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)morpholin-2-yl)methyl)-2-
	hydroxyacetamide
600
497.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.37-7.44 (m, 2 H), 7.13- 7.20 (m, 2 H), 4.47 (s, 2 H), 4.35-4.44 (m, 2 H), 3.72 (t, J = 6.5 Hz, 2 H), 3.51 (t, J = 7.5 Hz, 2 H), 3.27-3.33 (m, 2 H), 2.84-2.95 (m, 1 H), 2.76 (q, J = 7.6 Hz, 2 H), 2.40 (quin, J = 7.0 Hz, 2 H), 1.79-1.90 (m, 2 H), 1.64 (br. s., 2 H), 1.25- 1.36 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3 H)
	2-(4-aminopiperidin-1-yl)-6-((4-
	(1,1-dioxidoisothiazolidin-2-
	yl)benzyl)thio)-4-ethylpyridine-
	3,5-dicarbonitrile
601
511.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.38-7.46 (m, 2 H), 7.23- 7.33 (m, 2 H), 4.50 (s, 2 H), 4.30-4.43 (m, 2 H), 3.60-3.67 (m, 2 H), 3.25-3.31 (m, 4 H), 2.84-2.94 (m, 1 H), 2.76 (q, J = 7.4 Hz, 2 H), 2.07-2.20 (m, 2 H), 1.75-1.89 (m, 4 H), 1.60 (br. s., 2 H), 1.16-1.33 (m, 5H)
	2-(4-aminopiperidin-1-yl)-6-((4-
	(1,1-dioxido-1,2-thiazinan-2-
	yl)benzyl)thio)-4-ethylpyridine-
	3,5-dicarbonitrile
602
535.0 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.44-7.50 (m, 2 H), 7.36- 7.42 (m, 2 H), 7.26 (t, J = 52.5 Hz, 1 H), 4.53 (s, 2 H), 3.80- 3.93 (m, 4 H), 3.36 (s, 3 H), 2.78 (q, J = 7.6 Hz, 2 H), 2.60- 2.67 (m, 2 H), 2.44-2.48 (m, 2 H), 2.23 (s, 3 H), 1.83-1.95 (m, 2 H), 1.22 (t, J = 7.6 Hz, 3 H)
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-methyl-1,4-diazepan-1-
	yl)pyridin-2-
	yl)thio)methyl)phenyl)-1,1-
	difluoro-N-
	methylmethanesulfonamide
603
567.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.41 (d, J = 8.6 Hz, 2 H), 7.16 (d, J = 8.6 Hz, 2 H), 4.47 (s, 2 H), 4.39 (d, J = 13.4 Hz, 2 H), 3.72 (t, J = 6.5 Hz, 2 H), 3.51 (t, J = 7.4 Hz, 2 H), 3.27-3.40 (m, 2 H), 2.76 (q, J = 7.6 Hz, 2 H), 2.62-2.71 (m, 1 H), 2.40 (quin, J = 6.9 Hz, 2 H), 2.30 (br. s., 2 H), 1.86-1.99 (m, 2 H), 1.28- 1.42 (m, 3 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.86 (s, 9 H)
	2-((4-(1,1-dioxidoisothiazolidin-
	2-yl)benzyl)thio)-4-ethyl-6-(4-
	(neopentylamino)piperidin-1-
	yl)pyridine-3,5-dicarbonitrile
604
581.3 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.42 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 4.50 (s, 2 H), 4.37 (d, J = 13.4 Hz, 2 H), 3.59-3.66 (m, 2 H), 3.22-3.40 (m, 4 H), 2.76 (q, J = 7.6 Hz, 2 H), 2.59-2.71 (m, 1 H), 2.29 (br. s., 2 H), 2.09-2.19 (m, 2 H), 1.86-1.97 (m, 2 H), 1.74- 1.84 (m, 2 H), 1.26-1.42 (m, 3 H), 1.21 (t, J = 7.6 Hz, 3 H), 0.86 (s, 9 H)
	2-((4-(1,1-dioxido-1,2-
	thiazinan-2-yl)benzyl)thio)-4-
	ethyl-6-(4-
	(neopentylamino)piperidin-1-
	yl)pyridine-3,5-dicarbonitrile
605
421.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.07 (br. s., 3H), 7.98 (s, 1H), 7.56-7.48 (m, 2H), 7.44- 7.30 (m, 4H), 5.55 (s, 1H), 4.59 (d, J = 13.9 Hz, 2H), 3.46-3.33 (m, 1H), 3.31-3.17 (m, 2H), 2.77 (q, J = 7.6 Hz, 2H), 2.12- 2.00 (m, 2H), 1.66-1.49 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H)
	(S)-2-((6-(4-aminopiperidin-1-
	yl)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide,
	Hydrochloride
606
467.11 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.52-7.25 (m, 7 H), 5.51 (br s, 1 H), 4.61-4.93 (m, 3 H), 3.58 (br s, 2 H), 3.39 (br s, 2 H), 3.31 (s, 3 H), 2.90 (br s, 3 H), 2.78 (q, J = 7.53 Hz, 2 H), 1.22 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(2-
	hydroxyethyl)-N-
	methylacetamide
607
435.19 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.94 (s, 1 H), 7.53 (dd, J = 7.23, 1.53 Hz, 2 H), 7.41- 7.30 (m, 4 H), 5.56 (d, J = 4.17 Hz, 1 H), 4.46-4.38 (m, 1 H), 4.28-4.18 (m, 1 H), 3.42- 3.31 (m, 2 H), 2.82-2.67 (m, 3 H), 2.37 (d, J = 7.02 Hz, 3 H), 2.02-1.95 (m, 1 H), 1.87-1.78 (m, 1 H), 1.38-1.58 (m, 2 H), 1.21 (t, J = 7.56 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-(methylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
608
435.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1 H), 7.54-7.49 (m, 2 H), 7.39-7.30 (m, 4 H), 5.53 (s, 1 H), 4.12-4.05 (m, 2 H), 3.76-3.68 (m, 2 H), 2.75 (q, J = 7.67 Hz, 2 H), 1.66-1.47 (m, 6 H), 1.20 (t, J = 7.56 Hz, 3 H), 1.11 (s, 3H).
	2-((6-(4-amino-4-
	methylpiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
609
507.16 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.85 (br d, J = 10.96 Hz, 1 H), 7.48 (t, J = 7.02 Hz, 2 H), 7.41-7.31 (m, 4 H), 5.49 (d, J = 12.50 Hz, 1 H), 5.07-4.87 (m, 2 H), 4.68 (br d, J = 18.20 Hz, 0.5 H), 4.35 (t, J = 5.92 Hz, 0.5 H), 3.41-3.33 (m, 2 H), 3.29-3.15 (m, 5 H), 3.05-2.85 (m, 3 H), 2.76 (q, J = 7.31 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H), 0.49-0.36 (m, 4 H)
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-((1-
	(hydroxymethyl)cyclopropyl)
	methyl)-N-methylacetamide
610
462.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.55 (br s, 1 H), 7.83 (s, 1 H), 7.52-7.47 (m, 2 H), 7.40- 7.31 (m, 3 H), 7.23 (s, 1 H), 5.54 (s, 1 H), 4.66 (br s, 3 H), 4.31 (br s, 2 H), 3.13 (s, 2 H), 2.12-2.04 (m, 1 H), 1.83 (br s, 2 H), 1.17-1.09 (m, 2 H), 0.98- 0.92 (m, 2 H).
	2-amino-N-(1-(6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-cyclopropylpyridin-2-
	yl)azetidin-3-yl)acetamide
611
492.04 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.57 (br s, 1 H), 7.85 (s, 1 H), 7.52-7.46 (m, 2 H), 7.39- 7.31 (m, 3 H), 7 22 (s, 1 H), 5.54 (s, 1 H), 4.78-4.61 (m, 4 H), 4.32 (br s, 2H), 3.55-3.43 (m, 2 H), 3.22 (t, J = 5.48 Hz, 1 H), 2.11-2.03 (m, 1 H), 1.86 (br s, 2 H), 1.14-1.08 (m, 2 H), 0.98-0.92 (m, 2 H)
	(2S)-2-amino-N-(1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)azetidin-3-yl)-3-
	hydroxypropanamide
612
421.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90 (s, 1 H) 7.50-7.56 (m, 2 H) 7.30-7.42 (m, 4 H) 5.51 (s, 1 H) 4.25-4.44 (m, 2 H) 3.18-3.27 (m, 1 H) 2.98 (dd, J = 12.72, 9.21 Hz, 1 H) 2.75 (q, J = 7.45 Hz, 3 H) 1.94-2.09 (br, 2 H) 1.76-1.93 (m, 2 H) 1.42- 1.54 (m, 1 H) 1.27-1.37 (m, 1 H) 1.21 (t, J = 7.67 Hz, 3 H).
	2-((6-((S)-3-aminopiperidin-1-
	yl)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
613
479.27 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88-7.77 (m, 1 H) 7.61- 7.44 (m, 2 H) 7.42-7.14 (m, 4 H) 5.51-5.43 (m, 1 H) 5.13- 4.94 (m, 1 H) 4.84-4.51 (m, 2 H) 4.38-4.25 (m, 1 H) 3.79- 3.30 (m, 7 H) 2.81-2.65 (m, 2 H) 2.00-1.73 (m, 2 H) 1.20 (t, J = 7.56 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((R)-3-hydroxypyrrolidin-1-yl)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
614
492.04 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.58 (br s, 1 H), 7.85 (s, 1 H), 7.50 (d, J = 6.80 Hz 2 H), 7.42-7.28 (m, 3 H), 7.23 (s, 1 H), 5.54 (s, 1 H), 4.80-4.57 (m, 4 H), 4.32 (br s, 2 H), 3.57- 3.43 (m, 2 H), 3.21 (t, J = 5.37 Hz, 1 H), 2.11-2.04 (m, 1 H), 1.90-1.70 (m, 2 H), 1.18-1.07 (m, 2 H), 0.98-0.91 (m, 2 H)
	(2R)-2-amino-N-(1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)azetidin-3-yl)-3-
	hydroxypropanamide
615
509.11 [M + H] +	1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.37 (m, 5 H), 6.72 (br s, 1 H), 5.55 (br s, 1 H), 5.24 (s, 1 H), 4.78 (d, J = 17.10 Hz, 1 H), 4.51 (d, J = 17.32 Hz, 1 H), 4.20 (m, 1 H), 3.47 (s, 3 H), 3.34 (s, 1 H), 3.22-3.04 (m, 6H), 2.94 (q, J = 7.53 Hz, 2 H), 1.34 (t, J = 7.56 Hz, 3 H), 0.95 (s, 3 H), 0.90 (s, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(3-
	hydroxy-2,2-dimethylpropyl)-N-
	methylacetamide
616
479.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89-7.77 (m, 1H), 7.54- 7.42 (m, 2H), 7.42-7.27 (m, 4H), 5.51-5.46 (m, 1H), 5.09 (d, J = 3.73 Hz, 1H), 4.86-4.42 (m, 2H), 4.39-4.23 (m, 1H), 3.33 (d, J = 2.41 Hz, 7H), 2.78 (q, J = 7.23 Hz, 2H), 2.08-1.66 (m, 2H), 1.20 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((S)-3-hydroxypyrrolidin-1-yl)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
617
435.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1H), 7.51 (d, J = 7.02 Hz, 2H), 7.45-7.17 (m, 4H), 5.53 (s, 1H), 4.09 ( d, J = 13.81 Hz, 2H), 3.79-3.61 (m, 2H), 2.78 (q, J = 7.23 Hz, 2H), 1.64-1.41 (m, 6H), 1.20 (t, J = 7.67 Hz, 3H), 1.10 (s, 3H).
	2-((6-(4-amino-4-
	methylpiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
618
453.33 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.19-7.92 (m, 4H), 7.54 (d, J = 7.23 Hz, 2H), 7.43-7.28 (m, 4H), 5.58 (s, 1H), 4.44 (d, J = 14.25 Hz, 2H), 3.47-3.33 (m, 2H), 3.19-3.09 (m, 2H) 2.78 (q, J = 7.23 Hz, 2H), 2 08-1.73 (m, 4H), 1.24-1.12 (m, 3H).
	2-((6-(4-(aminomethyl)-4-
	fluoropiperidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	hydrochloride
619
464.09 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.39 (t, J = 5.92 Hz, 1H), 7.98 (s, 1H), 7.91 (s, 3H), 7.54- 7.48 (m, 2H), 7.42-7.31 (m, 4H), 5.57 (s, 1H), 4.56-4.40 (m, 2H), 3.37 (s, 2H), 3.35 (s, 3H), 2.89 (t, J = 6.03 Hz, 2H), 2.15-2 06 (m, 1H), 1.17-1.11 (m, 2H), 0.98-0.92 (m, 2H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)(methyl)amino)-N-(2-
	aminoethyl)acetamide
	hydrochloride
620
463.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1H), 7.54-7.43 (m, 2H), 7.43-7.27 (m, 4H), 5.49 (s, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 3.50-3.42 (m, 4H), 3.42-3.25 (s, 3H), 2.76 (q, J = 7.45 Hz, 2H), 1.89 (m, 2H), 1 77 (m, 2H), 1 20 (t, J = 7.67 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-oxo-2-(pyrrolidin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
621
493.18 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.85 (s, 1H), 7.52-7.46 (m, 2H), 7.42-7.30 (m, 4H), 5.51 (s, 1H), 4.90-4.85 (m, 1H), 4.74-4.64 (m, 2H), 3.89- 3.82 (m, 1H), 3.75-3.66 (m, 1H), 3.63-3.56 (m, 1H), 3.28 (s, 3H), 3.20-3.05 (m, 2H), 2.75 (q, J = 7.67 Hz, 2H), 1.82- 1.66 (m, 2H), 1.52-1.42 (m, 1H), 1.36-1.25 (m, 1H), 1.19 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	(4-hydroxypiperidin-1-yl)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
622
478.06 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.85 (s, 1H), 7.52-7.46 (m, 2H), 7.42-7.29 (m, 4H), 5.51 (s, 1H), 4.87 (m, 1H), 4.66 (m, 1H), 3.38 (d, J = 4.60 Hz, 4H), 3.29 (s, 3H), 2.79-2.69 (m, 4H), 2.66-2.62 (m, 2H), 1.19 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-oxo-2-(piperazin-1-
	yl)ethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
623
479.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1H), 7.51-7.47 (m, 2H), 7.42-7.31 (m, 4H), 5.49 (s, 1H),4.89 (m, 1H), 4.69 (m, 1H), 3.65-3.54 (m, 4H), 3.44 (m, 4H), 3.31 (s, 3H), 2.76 (q, J = 7.60 Hz, 2H), 1.20 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(2-morpholino-2-
	oxoethyl)amino)pyridin-2-
	yl)thio)-2-phenylacetamide
624
437.19 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.15 (s, 4H), 7.57 (d, J = 7.02 Hz, 2H), 7.41-7.29 (m, 3H), 7.22 (s, 1H), 5.72 (d, J = 8.33 Hz, 2H), 4.08-3.91 (m, 3H), 3.87 (s, 1H), 3.12-3.07 (m, 2H), 2.75 (q, J = 7.45 Hz, 2H), 2.06 (d, J = 5.70 Hz, 2H), 1.21 (t, J = 7.45 Hz, 3H).
	(R)-2-((6-((S)-3-(amino methyl)-
	3-hydroxypyrrolidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
625
465.09 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1H), 7.62-7.45 (m, 2H), 7.42-7.31 (m, 3H), 7.30-7.24 (s, 1H), 5.61 (d, J = 4.38 Hz, 1H), 5.06 (s, 2H), 4.41 (d, J = 8.33 Hz, 3H), 4.09- 3.70 (m, 4H), 2.76 (q, J = 7.47 Hz, 2H), 2.18 (m, 1H), 2.03- 1.91 (m, 1H), 1.20 (t, J = 7.45 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-(guanidinooxy)pyrrolidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
626
471.7 [M + H] +	1 H NMR (400 MHz, DMSO) δ 8.03 (s, 3H), 7.54 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.53 (d, J = 19.8 Hz, 4H), 3.39 (s, 4H), 3.26 (t, J = 12.6 Hz, 2H), 2.79 (q, J = 7.4 Hz, 2H), 2.05 (d, J = 11.4 Hz, 2H), 1.58 (d, J = 11.7 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).
	4-(((6-(4-aminopiperidin-1-yl)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)methyl)phenyl
	methanesulfonate 2,2,2-
	trifluoroacetate
627
480.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.17 (s, 1H), 7.99 (s, 1H), 7.54-7.50 (m, 2H), 7.40- 7.30 (m, 4H), 4.82-4.76 (m, 1H), 3.99-3.92 (m, 1H), 3.81- 3.72 (m, 1H), 3.43-3.34 (m, 5H), 2.75 (q, J = 7.53 Hz, 2H), 2.53-2.47 (m, 2H), 1.20 (t, J = 7.45 Hz, 3H), 1.14-1.06 (m, 6H).
	2-amino-N-(2-((6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)(methyl)amino)ethyl)-2-
	methylpropanamide
628
439.15 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.35 (s, 1H), 7.95 (s, 1H), 7.52-7.48 (m, 2H), 7.41- 7.32 (m, 4H), 5.52 (s, 1H), 4.00- 3.96 (m, 2H), 3.64 (t, J 5.04 Hz, 2H), 3.48 (t, J = 5.37 Hz, 2H), 3.40 (s, 3H), 2.82 (s, 2H), 2.74 (q, J = 7.50 Hz, 2H), 1.21 (t, J = 7.56 Hz, 3H).
	2-((6-((2-(2-
	aminoethoxy)ethyl)(methyl)
	amino)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
629
506.32 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.41 (s, 1H), 8.00 (d, J = 7.45 Hz, 1H), 7.95 (s, 1H), 7.54- 7.48 (m, 2H), 7.42-7.26 (m, 4H), 5.54 (s, 1H), 4.41 (m, 2H), 3.94-3.90 (m, 1H), 3.30-3.41 (m, 2H), 2.80-2.66 (m, 4H), 2.17 (t, J = 7.34 Hz, 2H), 1.89 (m, 2H), 1.73 (m, 2H), 1.52- 1.37 (m, 2H), 1.21 (t, J = 7.56 Hz, 3H).
	4-amino-N-(1-(6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)piperidin-4-yl)butanamide
	formate
630
452.19 [M + H] +	1H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.40-8.37 (t, J = 5.59 Hz, 1H), 8.04-7.80 (m, 4H), 7.52-7.51 (d, J = 6.80 Hz, 2 H), 7.45-7.26 (m, 4H), 5.59 (s, 1H), 4.58-4.38 (m, 2H), 3.45-3.32 (m, 5H), 2.89 (s, 2H), 2.78-2.74 (q, J = 7.53 Hz, 2H), 1.23-1.19 (t, J = 7.56 Hz, 3H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(2-
	aminoethyl)acetamide
	hydrochloride
631
449.10 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1H), 7.52-7.47 (m, 2H), 7.41-7.30 (m, 4H), 5.53 (s, 1H), 4.59 (m, 1H), 4.40 (m, 1H), 4.22-4.07 (m, 2H), 3.96-3.86 (m, 2H), 3.31 (s, 3H), 2.77 (q, J = 7.53 Hz, 2H), 2.24 (m, 2H), 1.20 (t, J = 7.67 Hz, 3H).
	2-((6-((2-(azetidin-1-yl)-2-
	oxoethyl)(methyl)amino)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
632
439.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (s, 1H), 7.60-7.53 (m, 2H), 7.45-7.19 (m, 4H), 5.60 (s, 1H), 4.23-3.79 (m, 4H), 3.05-2.86 (d, J = 5.7 Hz, 2H), 2.75 (q, J = 7.7 Hz, 2H), 2.31- 1.97 (m, 2H), 1.73 (s, 1H), 1.20 (t, J = 7.5 Hz, 3H).
	2-((6-((R)-3-(aminomethyl)-3-
	fluoropyrrolidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
633
465.09 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.85 (d, J = 8.55 Hz, 1H), 7.54-7.46 (m, 2H), 7.42-7.32 (m, 4H), 5.75 (d, J = 5.70 Hz, 1H), 5.51 (d, J = 8.11 Hz, 1H), 4.68-4.56 (m, 1H), 4.53-4.45 (m, 1H), 4.44-4.34 (m, 1H), 4.29 (t, J = 7.45 Hz, 1H), 4.16- 4.07 (m, 1H), 3.99-3.86 (m, 1H), 3.69-3.57 (m, 1H), 3.31 (d, J = 2.41 Hz, 3H), 2.77 (q, J = 7.23 Hz, 2H), 1.20 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	(3-hydroxyazetidin-1-yl)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
634
479.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90 (s, 1H), 7.55-7.47 (m, 2H), 7.42-7.27 (m, 4H), 5.53 (s, 1H), 5.07 (s, 2H), 4.34 (s, 2H), 4.14-3.96 (m, 2H), 3.92-3.84 (m, 1H), 3.83-3.74 (m, 2H), 2.75 (q, J = 7.60 Hz, 2H), 1.93-1.80 (m, 2H), 1.78- 1.66 (m, 2H), 1.20 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	(guanidinooxy)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
635
393.24 [M + H] +	1 H NMR (400 MHz, TFA-d) δ ppm 7.48 (s, 5H), 5.69 (s, 1H), 5.09-4.97 (m, 2H), 4.94-4.88 (m, 2H), 4.64 (s, 1H), 3.01 (d, J = 7.23 Hz, 2H), 1.42 (t, J = 7.45 Hz, 3H).
	2-((6-(3-aminoazetidin-1-yl)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	(single stereoisomer)
636
435.19 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.09 (s, 2H), 7.62-7.54 (m, 2H), 7.42-7.29 (m, 4H), 5.70 (d, J = 10.30 Hz, 1H), 4.54- 4.69 (m, 1H), 4.28-4.13 (m, 1H), 3.55-3.34 (m, 2H), 3.07 (s, 1H), 2.78 (q, J = 7.60 Hz, 2H), 2.53 (d, J = 2.19 Hz, 3H), 2.15-2.05 (m, 1H), 1.94-1.82 (m, 1H), 168-1.54 (m, 2H), 1.21 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((R)-
	3-(methylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
637
509.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.90-7.74 (m, 1H), 7.60- 7.42 (m, 2H), 7.42-7.00 (m, 4H), 5.50-5.40 (m, 1H), 5.05- 4.90 (m, 1H), 4.76-4.38 (m, 3H), 4.32-4.16 (m, 1H), 3.70- 3.30 (m, 8H), 3.18-3.05 (m, 1H), 2.76 (q, J = 7.38 Hz, 2H), 2.34-2.13 (m, 1H), 1.20 (t, J = 7.67 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((3R,4S)-3-hydroxy-4-
	(hydroxymethyl)pyrrolidin-1-yl)-
	2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
638
439.17 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.47 (s, 3H), 8.16 (s, 1H), 7.58 (d, J = 7.02 Hz, 2H), 7.43-7.32 (m, 3H), 7.27 (s, 1H), 5.76 (s, 1H), 4.40-3.90 (m, 4H), 3.57-3.33 (m, 2H), 2.77 (q, J = 7.38 Hz, 2H), 2.45- 2.16 (m, 2H), 1.21 (t, J = 7.56 Hz, 3H).
	(R)-2-((6-((S)-3-(aminomethyl)-
	3-fluoropyrrolidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
639
495.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.83-7.73 (m, 2H), 7.55- 7.45 (m, 2H), 7.42-7.27 (m, 4H), 5.52-5.45 (m, 1H), 4.67- 4.63 (m, 2H), 4.54-4.45 (m, 1H), 4.42-4.31 (m, 1H), 3.89- 3.73 (m, 1H), 3.51-3.39 (m, 4H), 3.33 (s, 3H), 2.05-2.16 (m, 1H), 1.18-1.08 (m, 2H), 1.00-0.90 (m, 2H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)(methyl)amino)-N-(1,3-
	dihydroxypropan-2-yl)acetamide
640
477.16 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1H), 7.51 (d, J = 7.02 Hz, 2H), 7.40-7.28 (m, 4H), 5.52 (d, J = 5.04 Hz, 1H), 4.66-4.57 (m, 2H), 4.43-4.32 (m, 1H), 4.32-4.20 (m, 3H), 4.04-3.95 (m, 1H), 3.16-3.08 (m, 1H), 3.06-2.95 (m, 1H), 2.76 (q, J = 7.60 Hz, 2H), 2.62- 2.51 (m, 2H), 1.93-1.76 (m, 2H), 1.53-1.30 (m, 2H), 1.21 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-(oxetan-3-ylamino)piperidin-
	1-yl)pyridin-2-yl)thio)-2-
	phenylacetamide
641
509.17 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.79 (s, 1H), 7.50-7.45 (m, 2H), 7.40-7.29 (m, 4H), 5.43 (s, 1H), 5.03 (t, J = 5.26 Hz, 1H), 4.91-4.84 (m, 1H), 4.77-4.68 (m, 2H), 3.60 (q, J = 5.33 Hz, 2H), 3.53 (q, J = 5.92 Hz, 2H), 3.45-3.33 (m, 4H), 3.26 (s, 3H), 2.14-2.05 (m, 1H), 1.16-1.07 (m, 2H), 0.97- 0.91 (m, 2H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)(methyl)amino)-N,N-bis(2-
	hydroxyethyl)acetamide
642
490.03 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.27 (s, 1H), 7.96 (d, J = 7.67 Hz, 1H), 7.89 (s, 1H), 7.52- 7.45 (m, 2H), 7.41-7.27 (m, 4H), 5.52 (s, 1H), 4.43-4.32 (m, 2H), 3.93 (s, 1 H), 3.39- 3.27 (m, 2H), 3.21 (s, 2H), 2.19- 2.04 (m, 1H), 1.93-1.82 (m, 2H), 1.58-1.40 (m, 2H), 1.21- 1.11 (m, 2H), 1.00-0.88 (m, 2H).
	2-amino-N-(1-(6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-cyclopropylpyridin-2-
	yl)piperidin-4-yl)acetamide
	formate
643
479.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1H), 7.54-7.48 (m, 2H), 7.40-7.30 (m, 4H), 5.53 (s, 1H), 4.46 (s, 1H), 4.08- 3.99 (m, 2H), 3.77-3.67 (m, 2H), 3.47 (s, 2H), 2.75 (q, J = 7.45 Hz, 2H), 2.55 (t, J = 5.81 Hz, 2H), 1.67-1.61 (m, 3H), 1.53-1.43 (m, 2H), 1.20 (t, J = 7.56 Hz, 3H), 1.08 (s, 3H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-hydroxyethyl)amino)-4-
	methylpiperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
644
453.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91 (s, 1H), 7.53-7.47 (m, 2H), 7.40-7.27 (m, 4H), 5.58 (s, 1H), 5.00 (s, 2H), 4.33 (s, 2H), 4.13-3.89 (m, 2H), 3.87-3.82 (m, 2H), 3.38 (s, 3H), 2.74 (q, J = 7.50 Hz, 2H), 1.20 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	(guanidinooxy)ethyl)(methyl)
	amino)pyridin-2-yl)thio)-2-
	phenylacetamide
645
464.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.69 (s, 2H), 8.32 (s, 3H), 7.98 (s, 1H), 7.55-7.51 (m, 2H), 7.43-7.32 (m, 4H), 5.58 (s, 1H), 4.63 (s, 2H), 3.49 (s, 1H), 3.27-3.18 (m, 6H), 2.77 (q, J = 7.31 Hz, 2H), 2.27-2.18 (m, 2H), 1.75-1.62 (m, 2H) 1.22 (t, J = 7.67 Hz, 3H).
	2-((6-(4-((2-
	aminoethyl)amino)piperidin-1-
	yl)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
	dihydrochloride
646
507.16 [M − H] −	1 H NMR (400 MHz, 90° C., DMSO-d 6 ) δ ppm 7.48 (d, J = 7.23 Hz, 2H), 7.40-6.98 (m, 5H), 5.52 (s, 1H), 4.90-4.60 (m, 2H), 4.42 (s, 1H), 4.04- 3.68 (m, 3H), 3.64-3.35 (m, 5H), 3.32 (s, 3H), 3.02-3.00 (m, 1H), 2.79 (q, J = 7.67 Hz, 2H), 1.22 (t, J = 7.56 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((S)-2-
	(hydroxymethyl)morpholino)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
647
495.26 [M + H] +	1 H NMR (400 MHz, 90° C., DMSO-d 6 ) δ ppm 7.50-7.44 (m, 2H), 7.42-7.26 (m, 5H), 5.49 (d, J = 7.23 Hz, 1H), 4.70- 4.49 (m, 4H), 4.18-3.99 (m, 2H), 3.72-3.61 (m, 1H), 3.48 (s, 1H), 3.33 (s, 5H), 2.79 (q, J = 7.60 Hz, 2H), 1.22 (t, J = 7.78 Hz, 3H).
	2-((3,5-dicyano-6-((2-((cis)-3,4-
	dihydroxypyrrolidin-1-yl)-2-
	oxoethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
648
493.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1H), 7.48 (d,J = 7.89 Hz, 2H), 7.42-7.23 (m, 4H), 5.52-5.42 (m, 1H), 4.82- 4.47 (m, 3H), 3.64-3.31 (m, 8H), 3.25-3.08 (m, 1H), 2.75 (q, J = 7.45 Hz, 2H), 2.42-2.21 (m, 1H), 1.99-1.55 (m, 2H), 1.19 (t, J = 7.67 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((S)-3-
	(hydroxymethyl)pyrrolidin-1-yl)-
	2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
649
509.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.84 (d, J = 11.84 Hz, 1H), 7.52-7.44 (m, 2H), 7.43- 7.27 (m, 4H), 5.52-5.43 (m, 1H,), 5.19-5.04 (m, 1H), 4.77- 4.49 (m, 3H), 4.16-3.99 (m, 1H), 3.75-3.59 (m, 1H), 3.55- 3.31 (m, 6H), 3.28-3.17 (m, 2H), 2.75 (q, J = 7.45 Hz, 2H), 2.25-2.06 (m, 1H), 1.20 (t, J = 7.56 Hz, 3H).
	((3S,4S)-3-hydroxy-4-
	(hydroxymethyl)pyrrolidin-1-yl)-
	2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
650
542.18 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.00 (t, J = 5.92 Hz, 1H), 7.47-7.42 (m, 2H), 7.39-7.33 (m, 2H), 4.52 (s, 2H), 3.95- 3.74 (m, 3H), 3.55 (s, 1H), 3.24- 3.14 (m, 5H), 3.08 (s, 2H), 2.93 (s, 3H), 2.75 (q, J = 7.45 Hz, 2H), 2.47-2.42 (m, 1H), 2.07-1.98 (m, 1H), 1.90-1.67 (m, 3H), 1.21 (t, J = 7.56 Hz, 3H).
	(R)-2-amino-N-((1-(3,5-
	dicyano-4-ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)pyrrolidin-3-
	yl)methyl)acetamide
651
491.23 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (s, 1H), 7.72-7.48 (m, 2H), 7.45-7.20 (m, 4H), 5.53 (s, 1H), 4.56-4.04 (m, 2H), 3.34-3.29 (m, 1H), 3.28-3.20 (m, 1H), 2.75 (q, J = 7.5 Hz, 2H), 2.60 (s, 1H), 2.41-2.28 (m, 2H), 1.99-1.90 (m, 1H), 1.87-1.77 (m, 1H) 1.60-1.27 (m, 3H), 1.27-1.10 (t, J = 7.6 Hz, 3H), 0.85 (s, 9H).
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-(neopentylamino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
652
491.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.86 (s, 1H), 7.48 (d, J = 7.0 Hz, 2H), 7.44-7.18 (m, 4H), 5.59-5.43 (m, 1H), 4.82-4.35 (m, 3H), 3.64-3.32 (m, 5H), 3.29 (s, 3H), 3.15 (m, 1H), 2.76 (q, J = 7.7 Hz, 2H), 2.42-2.19 (m, 1H), 2.02-1.81 (m, 1H), 1.77-1.53 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((R)-3-
	(hydroxymethyl)pyrrolidin-1-yl)-
	2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
653
495.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.76 (s, 1H), 7.54-7.43 (m, 2H), 7.41-7.32 (m, 4H), 7.28 (s, 1H), 5.41 (d, J = 10.3 Hz, 1H), 5.27 (m, 1H), 5.19 (m, 1H), 4.81-4.78 (m, 1H), 4.76-4.73 (m, 1H), 4.06-3.91 (m, 2H), 3.79-3.64 (m, 1H), 3.34 (s, 3H), 3.49-3.30 (m, 2H), 2.77 (q, J = 7.7 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	2-((3,5-dicyano-6-((2-((3R,4R)-
	3,4-dihydroxypyrrolidin-1-yl)-2-
	oxoethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
654
438.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91-7.84 (brs, 1H), 7.51 (dt, J = 6.2, 1.5 Hz, 2H), 7.44-7.32 (m, 3H), 7.26 (brs, 1H), 5.59 (s, 1H), 4.95 (s, 2H), 3.92 (brs, 3H), 3.68 (brs, 1H), 3.55-3.39 (m, 2H), 2.74 (q, J = 7.5 Hz, 2H), 2.04 (m, 1H), 1.78 (brs, 1H), 1.20 (t, J = 7.5 Hz, 3H).
	(R)-2-((3,5-dicyano-4-ethyl-6-
	((S)-3-hydroxy-3-
	(hydroxymethyl)pyrrolidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
655
504.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1 H), 7.74 (br d, J = 7.89 Hz, 1 H), 7.49-7.53 (m, 2 H), 7.27-7.39 (m, 4 H), 5.52 (s, 1 H), 4.39 (br t, J = 12.83 Hz, 2 H), 3.89 (m, 1 H), 3.33 (br s, 2 H), 3.19-3.24 (m, 1 H), 2.08- 2.14 (m, 1 H), 1.87 (m, 2 H), 1.75 (br s, 2 H), 1.43-1.51 (m, 2 H), 1.09-1.14 (m, 5 H), 0.95- 1.00 (m, 2 H).
	(2S)-2-amino-N-(1-(6-((2-
	amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-cyclopropylpyridin-2-
	yl)piperidin-4-yl)propanamide
656
477.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (s, 1 H), 7.54-7 48 (m, 2 H), 7.41-7.23 (m, 4 H), 5.52 (s, 1 H), 4.12-4.00 (m, 2 H), 3.67-3.50 (m, 4 H), 3.43 (t, J = 5.70 Hz, 3 H), 2.69 (t, J = 5.81 Hz, 2 H), 2.15-2.05 (m, 1 H), 1.98-1.85 (m, 2 H), 1.63-1.48 (m, 2 H), 1.17-1.08 (m, 2 H), 1.00-0.92 (m, 2 H).
	2-((6-(4-(2-
	aminoethoxy)piperidin-1-yl)-
	3,5-dicyano-4-
	cyclopropylpyridin-2-yl)thio)-2-
	phenylacetamide
657
477.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1 H), 7.58-7.43 (m, 2 H), 7.23-7.40 (m, 4 H), 5.52 (s, 1 H), 4.48-4.42 (m 1 H), 4.37-4.24 (m, 2 H), 3.48-3.43 (m, 2 H), 3.25-3.38 (m, 2 H), 2.79-2.72 (m, 1 H), 2.63 (t, J = 5.81 Hz, 2H), 2.15-2.00 (m, 1 H), 1.95-1.86 (m, 2 H), 1.75 (s, 1 H), 1.38-1.23 (m, 2 H), 1.18-1.07 (m, 2 H), 0.98-0.87 (m, 2 H).
	2-((3,5-dicyano-4-cyclopropyl-
	6-(4-((2-
	hydroxyethyl)amino)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
658
481.15 [M − H] −	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.85-7.76 (m, 2H), 7.54- 7.47 (m, 2 H), 7.43-7.27 (m, 4 H), 5.51 (s, 1 H), 4.65 (td, J = 5.48, 1.97 Hz, 2 H), 4.55- 4.48 (m, 1 H), 4.41-4.34 (m, 1 H), 3.84-3.74 (m, 1 H), 3.49- 3.42 (m, 3 H), 3.35 (s, 3 H), 2.77 (q, J = 7.67 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(1,3-
	dihydroxypropan-2-yl)acetamide
659
507.09 [M − H] −	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1 H), 7.49-7.26 (m, 2 H), 7.41-7.29 (m, 4 H), 5.52 (d, J = 5.04 Hz, 1 H), 5.09- 4.95 (m, 2 H), 4.91-4.81 (m, 1 H), 4.75-4.63 (m, 1 H), 4.37- 4.23 (m, 1 H), 3.71-3.56 (m, 2 H), 3.46-3.36 (m, 1 H), 3.27 (d, J = 5.70 Hz, 3 H), 2.80-2.62 (m, 3 H), 2.36-2.25 (m, 1 H), 2.23- 2.10 (m, 1 H), 1.30-1.14 (m, 4 H).
	2-((3,5-dicyano-6-((2-((3R,5S)-
	3,5-dihydroxypiperidin-1-yl)-2-
	oxoethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
660
495.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.76 (br s, 1H), 7.51- 7.44 (m, 2H), 7.41-7.32 (m, 3H), 7.31-7.27 (m, 1H), 5.41 (d, J = 10.1 Hz, 1H), 5.27 (dd, J = 1.9, 3.4 Hz, 1H), 5.19 (dd, J = 3.3, 7.9 Hz, 1H), 4.77 (br dd, J = 3.4, 17.4 Hz, 1H), 4.56 (br d, J = 17.3 Hz, 1H), 4.05-3.87 (m, 2H), 3.79-3.60 (m, 1H), 3.53- 3.32 (m, 6H), 2.77 (q, J = 7.4 Hz, 2H), 1.27-1.15 (m, 3H).
	2-((3,5-dicyano-6-((2-((3S,4S)-
	3,4-dihydroxypyrrolidin-1-yl)-2-
	oxoethyl)(methyl)amino)-4-
	ethylpyridin-2-yl)thio)-2-
	phenylacetamide
661
495.18 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89 (br s, 1 H), 7.51 (br d, J = 7.02 Hz, 2 H), 7.41-7.29 (m, 4 H), 5.53 (s, 1 H), 4.54 (br s, 1 H), 4.46 (br t, J = 4.82 Hz, 1 H), 4.18 (br d, J = 12.93 Hz, 2 H), 3.65-3.55 (m, 2 H), 3.46 (q, J = 4.97 Hz, 2 H), 3.27 (br d, J = 4.38 Hz, 2 H), 2.75 (q, J = 7.53 Hz, 2 H), 2.60-2.51 (m, 2 H), 1.65-1.50 (m, 5 H), 1.26- 1.18 (m, 3 H).
	2-((3,5-dicyano-4-ethyl-6-(4-
	((2-hydroxyethyl)amino)-4-
	(hydroxymethyl)piperidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
662
509.17 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 , 90° C.) δ ppm: 7.48 (d, J = 7.02 Hz, 2 H), 7.39-7.26 (m, 4 H), 7.26-7.11 (m, 1 H), 5.52 (s, 1 H), 4.81 (br s, 1 H), 4.69 (br s, 1 H), 4.43 (br s, 1 H), 4.24- 4.06 (m, 1 H), 3.84 (br d, J = 11.62 Hz, 2 H), 3.55-3.28 (m, 8 H), 2.99-2.97 (m, 1 H), 2.79 (q, J = 7.31 Hz, 2 H), 1.22 (t, J = 7.45 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((R)-2-
	(hydroxymethyl)morpholino)-2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
663
439.09 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.34 (s, 1 H), 7.79 (s, 1 H), 7.50 (d, J = 7.02 Hz, 2 H), 7.41-7.31 (m, 4 H), 5.56 (s, 1 H), 4.49 (br d, J = 17.32 Hz, 1 H), 4.30 (br d, J = 16.88 Hz, 1 H), 3.78-3.60 (m, 3 H), 3.39- 3.32 (m, 3 H), 2.78 (q, J = 7.45 Hz, 2 H), 1.21 (br t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-
	methoxyacetamide
664
509.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.84 (br d, J = 12.28 Hz, 1 H), 7.48 (td, J = 4.38, 2.41 Hz, 2 H), 7.27-7.43 (m, 4 H), 5.43- 5.53 (m, 1 H), 5.04-5.20 (m, 1 H), 4.45-4.81 (m, 3 H), 3.99- 4.16 (m, 1 H), 3.31-3.76 (m, 7 H), 3.15-3.28 (m, 2 H), 2.76 (q, J = 7.31 Hz, 2 H), 2.06-2.26 (m, 1 H), 1.20 (t, J = 7.56 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-((2-
	((3R,4R)-3-hydroxy-4-
	(hydroxymethyl)pyrrolidin-1-yl)-
	2-
	oxoethyl)(methyl)amino)pyridin-
	2-yl)thio)-2-phenylacetamide
665
481.09 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (s, 1H), 7.44-7.55 (m, 2H), 7.27-7.54 (m, 4H), 5.54-5.49 (m, 1H), 4.79-4.97 (m, 1H), 4.59-4.75 (m, 1H), 4.38 (t, J = 5.2 Hz, 1H), 3.31- 3.49 (m, 4H), 3.29 (s, 3H), 2.97 (s, 2H), 2.83 (s, 1H), 2.75 (q, J = 7.60 Hz, 2H), 1.58-1.79 (m, 2H), 1.19 (t, J = 7.56 Hz, 3H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(3-
	hydroxypropyl)-N-
	methylacetamide
666
483.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.02 (br t, J = 5.81 Hz, 1 H), 7.82 (s, 1 H), 7.49 (br d, J = 7.23 Hz, 2 H), 7.29-7.41 (m, 4 H), 5.53 (s, 1 H), 4.74 (dd, J = 5.04, 2.63 Hz, 1H), 4.47- 4.58 (m, 2 H), 4.36 (br d, J = 17.10 Hz, 1 H), 3.54 (dt, J = 10.36, 5.23 Hz, 1 H), 3.33- 3.39 (m, 3 H), 3.34-3.22 (m, 3 H), 3.00-3.10 (m, 1 H), 2.77 (q, J = 7.53 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-((R)-2,3-
	dihydroxypropyl)acetamide
667
490.15 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 7.88 (s, 1 H), 7.55-7.48 (m, 2 H), 7.41-7.18 (m, 5 H), 7.03 (s, 1 H), 5.52 (s, 1 H), 4.32 (d, J = 13.15 Hz, 2 H), 3.26-3.21 (m, 2 H), 3.10 (s, 2 H), 2.75- 2.64 (m, 1 H), 2.22 (s, 1 H), 2.15-2.04 (m, 1 H), 1.94- 1.83 (m, 2 H), 1.41-1.27 (m, 2 H), 1.16-1.08 (m, 2 H), 1.00- 0.93 (m, 2 H).
	2-((6-(4-((2-amino-2-
	oxoethyl)amino)piperidin-1-yl)-
	3,5-dicyano-4-
	cyclopropylpyridin-2-yl)thio)-2-
	phenylacetamide
668
497.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.81 (s, 1 H), 7.51-7 47 (m, 2 H), 7.40-7.32 (m, 4 H), 5.45 (s, 1 H), 5.03 (t, J = 5.15 Hz, 1 H), 4.93-4.86 (m, 1 H), 4.80-4.71 (m, 2 H), 3.61 (q, J = 5.33 Hz, 2 H), 3.56-3.50 (m, 2 H), 3.45-3.36 (m, 4 H), 3.28 (s, 3 H), 2.76 (q, J = 7.67 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N,N-bis(2-
	hydroxyethyl)acetamide
669
453.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.06 (t, J = 5.26 Hz, 1 H), 7.81 (s, 1 H), 7.52-7.45 (m, 2 H), 7.40-7.30 (m, 4 H), 5.54 (s, 1 H), 4.69 (t, J = 5.48 Hz, 1 H), 4.57-4.46 (m, 1 H), 4.39- 4.28 (m, 1 H), 3.43 (q, J = 5.99 Hz, 2 H), 3.36 (s, 3 H), 3.19 (q, J = 5.70 Hz, 2 H), 2.77 (q, J = 7.38 Hz, 2 H), 1.20 (t, J = 7.67 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(2-
	hydroxyethyl)acetamide
670
409.19 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.05 (s, 1 H), 7.93 (br s, 2 H), 7.51-7.57 (m, 2 H), 7.34- 7.42 (m, 4 H), 5.53 (s, 1 H), 3.71-3.87 (m, 2 H), 3.36 (s, 3 H), 2.74-2.89 (m, 4 H), 1.90- 1.98 (m, 2 H), 1.17-1.28 (m, 4 H).
	2-((6-((3-
	aminopropyl)(methyl)amino)-
	3,5-dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
	hydrochloride
671
407.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.82 (s, 1 H), 7.54-7.46 (m, 2 H), 7.40-7.30 (m, 3 H), 7.25 (s, 1 H), 5.55 (s, 1 H), 4.44 (s, 2 H), 4.14 (s, 2 H), 2.80- 2.78 (q, J = 7.60 Hz, 2 H), 2.72- 2.65 (m, 3 H), 2.0 (s, 2 H), 1.18 (t, J = 7.56 Hz, 3H).
	2-((6-(3-(aminomethyl)azetidin-
	1-yl)-3,5-dicyano-4-
	ethylpyridin-2-
	yl)thio)-2-phenylacetamide
672
542.05 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.01 (t, J = 5.70 Hz, 1 H), 7.48-7.43 (m, 2 H), 7.38-7.32 (m, 2 H), 4.53 (s, 2 H), 4.01- 3.67 (m, 3 H), 3.58-3.51 ( m, 1 H), 3.26-3.14 (m, 5 H), 3.09 (s, 2 H), 2.93 (s, 3 H), 2.80-2.69 (m, 2 H), 2.49-2.41 (m, 1 H), 2.10-1.93 (m, 2 H), 1.73 (dd, J = 12.39, 7.13 Hz, 1 H), 1.25- 1.18 (m, 4 H).
	(S)-2-amino-N-((1-(3,5-
	dicyano-4-ethyl-6-((4-(N-
	methylmethylsulfonamido)
	benzyl)thio)pyridin-2-yl)pyrrolidin-3-
	yl)methyl)acetamide
673
493.11 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.03 (t, J = 5.70 Hz, 1 H), 7.81 (s, 1 H), 7.49 (d, J = 6.80 Hz, 2 H), 7.41-7.29 (m, 4 H), 5.55 (s, 1 H), 4.57 (d, J = 17.10 Hz, 1 H), 4.46 (t, J = 5.70 Hz, 1 H), 4.37 (d, J = 17.10 Hz, 1 H), 3.35 (s, 3H), 3.26 (dd, J = 5.70, 1.97 Hz, 2H), 3.16 (d, J = 5.70 Hz, 2 H), 2.77 (q, J = 7.38 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H), 0.41-0.22 (m, 4 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-((1-
	(hydroxymethyl)cyclopropyl)
	methyl)acetamide
674
444.08 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1H), 7.56 (td, J = 8.7, 6.4 Hz, 1H), 7.42 (s, 1H), 7.31 (ddd, J = 10.5, 9.2, 2.7 Hz, 1H), 7.13 (td, J = 8.5, 2.6 Hz, 1H), 5.83 (s, 1H), 5.12 (d, J = 3.6 Hz, 1H), 4.40 (s, 1H), 3.79- 3.53 (m, 4H), 2.76 (q, J = 7.5 Hz, 2H), 2.10-1.81 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	(R)-2-((3,5-dicyano-4-ethyl-6-
	((S)-3-hydroxypyrrolidin-1-
	yl)pyridin-2-yl)thio)-2-(2,4-
	difluorophenyl)acetamide
675
495.10 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.55 (s, 1 H), 7.81 (s, 1 H), 7.49-7.54 (m, 2 H), 7.31- 7.43 (m, 4 H), 5.54 (s, 1 H), 5.11 (t, J = 5.92 Hz, 1 H), 4.44- 4.57 (m, 5 H), 4.36 (d, J = 17.32 Hz, 1 H), 3.67 (d, J = 5.92 Hz, 2 H), 3.35 (s, 3 H), 2.77 (q, J = 7.45 Hz, 2H), 1.21 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(3-
	(hydroxymethyl)oxetan-3-
	yl)acetamide
676
451.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1 H), 7.54-7.48 (m, 2 H), 7.41-7.29 (m, 3 H), 7.25 (s, 1 H), 5.57 (s, 1 H), 5.24 (s, 2 H), 4.69-4.22 (m, 7H), 2.69 (q, J = 7.38 Hz, 2 H), 1.18 (t, J = 7.67 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-(3-
	(guanidinooxy)azetidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
677
467.11 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.03 (br t, J = 5.59 Hz, 1 H), 7.81 (s, 1 H), 7.45-7.52 (m, 2 H), 7.29-7.42 (m, 4 H), 5.55 (s, 1 H), 4.52 (d, J = 17.10 Hz, 1 H), 4.39 (t, J = 5.26 Hz, 1 H), 4.31 (d, J = 17.10 Hz, 1 H), 3.38- 3.44 (m, 2 H), 3.36 (s, 3 H), 3.12-3.20 (m, 2 H), 2.77 (q, J = 7.67 Hz, 2 H), 1.57 (quin, J = 6.63 Hz, 2 H), 1.20 (t, J = 7.67 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(3-
	hydroxypropyl)acetamide
678
495.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.20 (s, 1 H), 7.89 (s, 1 H), 7.54-7.42 (m, 2 H), 7.40- 7.10 (m, 4 H), 5.51 (s, 1 H), 3.97-3.80 (m, 4 H), 3.62-3.55 (m, 2 H), 3.34-3.27 (m, 2 H), 2.89-2.68 (m, 4 H), 2.68-2.61 (m, 2 H), 2.57-2.52 (m, 1 H), 2.39-2.32 (m, 1 H), 1.90 (m, 2 H), 1.21 (t, J = 7.56 Hz, 3 H).
	2-((3,5-dicyano-6-(4-(2,3-
	dihydroxypropyl)-1,4-diazepan-
	1-yl)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
679
425 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 , 90° C.) δ ppm 10.26 (br s, 1 H), 8.76 (br s, 2 H), 7.51 (br d, J = 6.80 Hz, 2 H), 7.42-7.20 (m, 3 H), 7.15 (br s, 1 H), 5.58 (s, 1 H), 4.59-4.25 (m, 2 H), 3.38 (s, 3 H), 2.80 (q, J = 7.23 Hz, 2 H), 1.23 (t, J = 7.56 Hz, 3 H).
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-
	hydroxyacetamide
680
504.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.73 (s, 1 H), 7.83 (s, 1 H), 7.53-7.44 (m, 2 H), 7.42- 7.24 (m, 3 H), 7.23 (s, 1 H), 5.54 (s, 1 H), 4.88-4.60 (m, 5 H), 4.39 (d, J = 6.14 Hz, 5 H), 2.08 (t, J = 8.69, 5.67 Hz, 1 H), 1.19-1.06 (m, 2 H), 1.01-0.90 (m, 2 H).
	3-amino-N-(1-(6-((2-amino-2-
	oxo-1-phenylethyl)thio)-3,5-
	dicyano-4-cyclopropylpyridin-2-
	yl)azetidin-3-yl)oxetane-3-
	carboxamide
681
499.18 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.15 (s, 3H), 7.56-7.48 (m, 2H), 7.43-7.36 (m, 2H), 5.15 (q, J = 7.0 Hz, 1H), 4.51 (d, J = 13.7 Hz, 2H), 3.39 (s, 1H), 3.23 (s, 5H), 2.95 (s, 3H), 2.77 (q, J = 7.5 Hz, 2H), 2.15- 2.04 (m, 2H), 1.73 (d, J = 7.1 Hz, 3H), 1.68-1.58 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	ISOMER 2
	N-(4-(1-((6-(4-aminopiperidin-1-
	yl)-3,5-dicyano-4-ethylpyrid in-
	2-yl)thio)ethyl)phenyl)-N-
	methylmethanesulfonamide
682
426.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (br s, 1 H), 7.52 (br t, J = 7.56 Hz, 1 H), 7.36-7.45 (m, 2 H), 7.19-7.30 (m, 2 H), 5.86 (s, 1 H), 5.12 (br s, 1 H), 4.40 (br s, 1 H), 3.68-3.98 (m, 4 H), 2.76 (q, J = 7.53 Hz, 2 H), 1.87-2.05 (m, 2 H), 1.21 (brt, J = 7.45 Hz, 3 H).
	2-((3,5-dicyano-4-ethyl-6-((S)-
	3-hydroxypyrrolidin-1-yl)pyridin-
	2-yl)thio)-2-(2-
	fluorophenyl)acetamide
683
487.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.13 (br s, 3 H), 7.47- 7.42 (m, 2 H), 7.41-7.35 (m, 2 H), 4.51 (s, 3 H), 4.46 (br s, 1 H), 4.27 (s, 3 H), 3.41-3.34 (m, 1H), 3.26 (s, 2H), 3.22 (s, 3H), 2.93 (s, 3 H), 2.10-2.02 (m, 2 H), 1.65-1.54 (m, 2 H).
	N-(4-(((6-(4-aminopiperidin-1-
	yl)-3,5-dicyano-4-
	methoxypyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
	hydrochloride
684
461.19 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1H), 7.53-7.49 (m, 2H), 7.40-7.29 (m, 4H), 5.53 (d, J = 4.6 Hz, 1H), 4.52- 4.44 (m, 1H), 4.36-4.28 (m, 1H), 3.27-3.02 (m, 2H), 2.78- 2.74 (m, 3H), 2.12-2.08 (m, 1H), 2.02-1.98 (m, 1H), 1.81- 1.77 (m, 1H), 1.47-1.43 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.40-0.35 (m, 2H), 0.22-0.14 (m, 2H).
	2-((3,5-dicyano-6-((S)-3-
	(cyclopropylamino)piperidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
685
495.13 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.97 (t, J = 6.03 Hz, 1 H), 7.83 (s, 1 H), 7.54-7.44 (m, 2 H), 7.42-7.28 (m, 4 H), 5.56 (s, 1 H), 4.63-4.48 (m, 1 H), 4.54-4.41 (m, 1 H), 4.43-4.38 (m, 1 H), 3.34 (s, 3 H), 3.10 (d, J = 5.92 Hz, 2 H), 3.00 (d, J = 6.14 Hz, 2 H), 2.65-2.83 (m, 2 H), 1.20 (t, J = 7.67 Hz, 3 H), 0.77 (s, 6 H)
	2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)-N-(3-
	hydroxy-2,2-
	dimethylpropyl)acetamide
686
504.07 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.47 (s, 2 H), 8.23 (br t, J = 5.70 Hz, 1 H), 7.86 (s, 1 H), 7.44-7.54 (m, 2 H), 7.28-7.42 (m, 4 H), 5.54 (s, 1 H), 4.49 (d, J = 17.32 Hz, 1 H), 4.33-4.43 (m, 1 H), 4.12 (t, J = 5.70 Hz, 2 H), 3.40-3.49 (m, 2 H), 3.29 (s, 3 H), 2.77 (q, J = 7.60 Hz, 2 H), 1.20 (t, J = 7.56 Hz, 3 H).
	N-(2-(4H-1,2,4-triazol-4-
	yl)ethyl)-2-((6-((2-amino-2-oxo-
	1-phenylethyl)thio)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)(methyl)amino)acetamide
687
466.11 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.88 (br t, J = 5.92 Hz, 1 H), 8.01 (br s, 1 H), 7.89-7.74 (m, 2 H), 7.63 (br s, 1 H), 7.53 (br d, J = 7.23 Hz, 2 H), 7.46- 7.23 (m, 4 H), 5.56 (s, 1 H), 4.05-3.94 (m, 1 H), 3.85-3.75 (m, 1 H), 3.48 (br dd, J = 13.26, 6.47 Hz, 1 H), 3.39 (s, 4 H), 2.76 (q, J = 7.38 Hz, 2 H), 1.21 (brt, J = 7.45 Hz, 3 H).
	N1-(2-((6-((2-amino-2-oxo-1-
	phenylethyl)thio)-3,5-dicyano-
	4-ethylpyridin-2-
	yl)(methyl)amino)ethyl)
	oxalamide
688
425.12 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.82 (s, 1 H), 7.54-7.49 (m, 2 H), 7.42-7.33 (m, 3 H), 7.27 (s, 1 H), 5.56 (s, 1 H), 4.66- 4.53 (m, 2 H), 4.49-4.37 (m, 2 H), 3.03-2.95 (m, 2 H), 2.71 (q, J = 7.45 Hz, 2 H), 1.81 (br s, 2 H), 1.24-1.17 (m, 3 H).
	2-((6-(3-(aminomethyl)-3-
	fluoroazetidin-1-yl)-3,5-
	dicyano-4-ethylpyridin-2-
	yl)thio)-2-phenylacetamide
689
438.14 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1 H), 7.52 (d, J = 7.02 Hz, 2 H), 7.40-7.29 (m, 3 H), 7.26 (br s, 1 H), 5.61 (s, 1 H), 5.02-4.90 (m, 2 H), 4.10- 3.67 (m, 4 H), 3.53-3.42 (m, 2 H), 2.82-2.69 (m, 2 H), 2.13- 1.93 (m, 1 H), 1.78 (s, 1 H), 1.20 (t, J = 7.45 Hz, 3 H).
	(R)-2-((3,5-dicyano-4-ethyl-6-
	((R)-3-hydroxy-3-
	(hydroxymethyl)pyrrolidin-1-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
690
485.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1 H), 7.51 (d, J = 7.45 Hz, 2 H), 7.43-7.30 (m, 4 H), 6.09-5.89 (m, 1 H), 5.58- 5.52 (m, 1 H), 4.47-4.31 (m, 2 H), 3.22-2.94 (m, 4 H), 2.80- 2.65 (m, 3 H), 2.11-1.91 (m, 2 H), 1.83-1.76 (m, 1 H), 1.58- 1.37 (m, 2 H), 1.21 (t, J = 7.67 Hz, 3 H).
	2-((3,5-dicyano-6-((S)-3-((2,2-
	difluoroethyl)amino)piperidin-1-
	yl)-4-ethylpyridin-2-yl)thio)-2-
	phenylacetamide
691
421.2 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.91 (br s, 1 H), 7.52 (br d, J = 7.02 Hz, 2 H), 7.28-7.44 (m, 4 H), 5.52 (s, 1 H), 4.24- 4.44 (m, 2 H), 3.18-3.25 (m, 2 H), 3.01 (br dd, J = 13.15, 9.65 Hz, 1H), 2.71-2.84 (m, 4 H), 1.75-1.95 (m, 2 H), 1.43-1.60 (m, 1 H), 1.30-1.41 (m, 1 H), 1.21 (br t, J = 7.56 Hz, 3 H).
	2-((6-((R)-3-aminopiperidin-1-
	yl)-3,5-dicyano-4-ethylpyridin-
	2-yl)thio)-2-phenylacetamide
692
528.8 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.18 (s, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 4.52 (s, 2H), 4.44-4.40 (m, 2H), 3.52-3.50 (m, 2H), 3.31-3.26 (m, 3H), 3.22 (s, 3H), 2.94 (s, 3H), 2.93-2.91 (m, 1H), 2.82-2.70 (m, 4H), 1.97 (m, 2H), 1.41 (m, 2H), 1.22 (t, J = 7.5 Hz, 3H).
	N-(4-(((3,5-dicyano-4-ethyl-6-
	(4-((2-
	hydroxyethyl)amino)piperidin-1-
	yl)pyridin-2-
	yl)thio)methyl)phenyl)-N-
	methylmethanesulfonamide
693
422.8 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.15-8.00 (br, 3H), 7.98- 7.92 (br, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.42-7.32 (m, 4H), 5.54 (s, 1H), 4.55 (m, 2H), 4.27 (s, 3H), 3.46-3.35 (m, 1H), 3.29-3.19 (m, 2H), 2.09-2.01 (m, 2H), 1.62-1.49 (m, 2H).
	2-((6-(4-aminopiperidin-1-yl)-
	3,5-dicyano-4-methoxypyridin-
	2-yl)thio)-2-phenylacetamide
	2,2,2-trifluoroacetate
694
409.8 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.94 (s, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.41-7.35 (m, 4H), 5.64 (br, 1H), 5.57 (s, 1H), 4.73 (br, 1H), 4.15-4.03 (m, 3H), 4.00 (d, J = 11.9 Hz, 1H), 2.80-2.76 (m, 2H), 1.22-1.18 (m, 3H).
	ISOMER 2
	2-((3,5-dicyano-4-ethyl-6-((S)-
	4-hydroxyisoxazolidin-2-
	yl)pyridin-2-yl)thio)-2-
	phenylacetamide
695
409.8 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.88 (s, 1H), 7.51 (d, J = 7.1 Hz, 2H), 7.43-7.30 (m, 4H), 5.61 (s, 1H), 4.77 (br, 1H), 3.92 (dt, J = 14.6, 7.2 Hz, 1H), 3.76 (dt, J = 14.3, 7.2 Hz, 1H), 3.49 (m, 2H), 3.34 (s, 3H), 2.76 (q, J = 7.5 Hz, 2H), 1.81 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H).
	(R)-2-((3,5-dicyano-4-ethyl-6-
	((3-
	hydroxypropyl)(methyl)amino)
	pyridin-2-yl)thio)-2-phenylacetamide
696
409.8 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.92 (s, 1H), 7.54-7.48 (m, 2H), 7.41-7.30 (m, 4H), 5.60 (s, 1H), 5.23-5.07 (br, 1H), 4.44-4.37 (m, 1H), 4.23 (s, 3H), 3.93-3.64 (m, 4H), 2.02- 1.87 (m, 2H).
	2-((3,5-dicyano-6-((S)-3-
	hydroxypyrrolidin-1-yl)-4-
	methoxypyridin-2-yl)thio)-2-
	phenylacetamide
697
491.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.92 (s, 1H), 7.54-7.48 (m, 2H), 7.41-7.30 (m, 4H), 5.52 (s, 1H), 4.23-4.15 (m, 2H), 3.99-3.92 (m, 1H), 3.53-3.44 (m, 4H), 3.17 (s, 3H), 2.83-2.71 (m, 4H), 2.37-2.29 (m, 1H), 1.78- 1.66 (m, 2H), 1.34-1.22 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(3-methoxyazetidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-phenylacetamide
698
509.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ 7.94 (s, 1H), 7.59-7.51 (m, 2H), 7.38 (s, 1H), 7.27- 7.18 (m, 2H), 5.54 (s, 1H), 4.24-4.10 (m, 2H), 3.99- 3.91 (m, 1H), 3.53-3.44 (m, 4H), 3.17 (s, 3H), 2.82-2.71 (m, 4H), 2.37-2.30 (m, 1H), 1.78-1.69 (m, 2H), 1.33- 1.23 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-(4-
	(3-methoxyazetidin-1-
	yl)piperidin-1-yl)pyridin-2-
	yl)thio)-2-(4-
	fluorophenyl)acetamide
699
435.1 [M + H] +	1 H NMR (400 MHz, DMSO-d 6 ) δ = 8.36-8.27 (m, 1H), 8.06-7.92 (m, 1H), 7.53- 7.48 (m, 2H), 7.43-7.30 (m, 4H), 5.56-5.45 (m, 1H), 3.65-3.38 (m, 2H), 2.74- 2.61 (m, 3H), 2.48-2.28 (m, 4H), 2.27-2.24 (m, 3H), 1.98-1.85 (m, 1H), 1.55- 1.41 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H)
	2-((3,5-dicyano-4-ethyl-6-
	(methyl(1-methylpyrrolidin-3-
	yl)amino)pyridin-2-yl)thio)-2-
	phenylacetamide

TABLE 2

INGREDIENTS	AMOUNTS
2-((3,5-dicyano-4-cyclopropyl-6-(1,4-diazepan-1-yl)pyridin-	7 mg
2-yl)thio)-2-phenylacetamide (Compound of Example 4)
Lactose	53 mg
Talc	16 mg
Magnesium Stearate	4 mg

TABLE 3

INGREDIENTS	AMOUNTS
N-(4-((3,5-Dicyano-4-ethyl-6-(4-(pyrrolidin-1-yl)piperidin-	12 mg
1-yl)pyridin-2-ylthio)methyl)benzyl)acetamide
trifluoroacetate (Compound of Example 66)
calcium sulfate dehydrate	30 mg
Sucrose	4 mg
Starch	2 mg
Talc	1 mg
stearic acid	0.5 mg

description truncated at 500,000 characters. 1 of 62 part labels are ours — the grant heads the rest

Stored text is truncated at the source; the tail of the description is not held.

Claims as granted

21 claims

Classifications

9 codes

IPC · International Patent Classification

Section A — Human necessities

A61P35/00
A61P37/00

Section C — Chemistry; metallurgy

C07D213/73
C07D401/14
C07D413/14
C07D401/04
C07D213/74
C07D417/12
C07D401/12

Claim changes

Soon

Coming soonHow the claims changed between publication and grant

See which claims were amended, added or cancelled during examination, with every added and removed word marked.

AmendedAddedCancelledUnchanged

The published claims of this application are not paired with the granted ones in what we hold.

File wrapper

⤢ drag to zoom

USPTOApplicanthover for detail · click to open

Pendency

3.8 y

1,400 days filing → grant

Office actions

none on record

Responses

1 RCE

Examiner

Timothy R Rozof

art unit 1625 · TC 1600

Law firm

Law firm · Log in to unlock

Citations: 72 back · 0 forward

See the full prosecution history — every USPTO and applicant action on this file, in order.

Documents

Log in to open the documents of this file: the application as filed, every office action and response, the notice of allowance.

Chain of title

⤢ drag to zoom

Titlehover for detail · click to open

See the full assignment history — every owner this patent has passed through, with recordation dates and reel/frame numbers.