Aryl-bipyridine amine derivatives as phosphatidylinositol phosphate kinase inhibitors

This application is a U.S. National Phase Application, filed under 35 U.S.C. 371, of International Application No. PCT/US2018/067267, filed on Dec. 21, 2018, which claims the benefit of priority of U.S. Provisional Application No. 62/609,604, filed Dec. 22, 2017, which the entire disclosure of each are incorporated herein by reference in their entirety.

The present invention is directed to inhibitors of phosphatidylinositol-5-phosphate-4-kinase (PI5P4K) useful in the treatment of diseases or disorders associated with PI5P4K enzymes. In particular, the invention is concerned with compounds and compositions inhibiting PI5P4K, methods of treating diseases or disorders associated with PI5P4K, and methods of synthesis of these compounds.

A minor but ubiquitous component of cells, phosphoinositol lipids are pivotal players in many intracellular signal transduction pathways. Phosphoinositol lipids are formed when phosphatidylinositol (PtdIns) is converted, by the catalytic action of lipid kinases, to polyphosphoinositides. As a prototypic example, the membrane associated phospholipid, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), is formed by two successive phosphorylations of PtdIns by the phosphatidylinositol phosphate kinases (PIP kinases).

PtdIns(4,5)P2 is a substrate for phospholipase C (PLC) and is converted into the second messengers inositol-1,4,5-trisphosphate and diacylglycerol (DAG). Phosphoinositides are involved in regulating a broad spectrum of activities from cytoskeletal assembly and motility to vesicle trafficking and exocytosis to transduction of intracellular signals including stimulating the release of intracellular calcium stores (Hinchliffe et al., Biochem. Soc. Trans., 1999, 27, 657-661).

PIP kinases comprise a unique and promiscuous family of enzymes that catalyze the production of poly-phosphorylated inositol lipids from mono-phosphorylated phosphoinositides. Isolation and purification of several different PIP kinase enzymes able to catalyze phosphorylation of phosphatidylinositol 4-phosphate and produce PtdIns(4,5)P2 led to the further categorization of these enzymes, dubbed the phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks), into two types having different activities. The PIP kinases have no homology to other lipid or protein kinases at the primary sequence level, and are distinguished from each other by their lack of immuno-cross reactivity and by the fact that type I PIP5Ks are stimulated in vitro by phosphatidic acid, whereas the type II PIP5Ks are not. Furthermore, the recent discovery that the type II PTP5Ks are able to phosphorylate multiple lipid substrates in vitro suggests that this family of kinases is potentially able to generate several distinct, often subcellularly compartmentalized, phosphoinositol products for regulation of a variety of physiologically important processes (Hinchliffe et al., Biochem. Soc. Trans., 1999, 27, 657-661).

One particular species of PI, phosphatidylinositol 5-phosphate (PI5P), has been implicated in the regulation of the tumor suppressor ING2 and the oncogene AKT. The phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) family (α, β, γ isoforms) catalyzes the conversion of PI5P to P14, 5 P2. These enzymes therefore represent one means by which cells can regulate endogenous PI5P levels. Mice deficient for PI5P4Kβ (PI5P4Kβ−/−) have been shown to exhibit enhanced insulin sensitivity and activation of AKT in skeletal muscle.

The pharmacological modulation of PIP5KII-beta activity and/or expression is therefore believed to be an appropriate point of therapeutic intervention in pathological conditions in which cell differentiation, proliferation, and/or motility are compromised, such as cancer or inflammation, and in metabolic disorders.

Currently, there are no known therapeutic agents which effectively inhibit the synthesis of PIP5KII-beta. Inhibition of PI5P4K with small molecule inhibitors, therefore, has the potential to be a treatment for cancers and other disorders. For this reason, there remains a considerable need for novel and potent small molecule inhibitors and agents capable of effectively inhibiting PIP5KII-beta function.

A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, isomers, or tautomers, thereof,

wherein:

X, Y, and Z are independently CH, C(C 1-6 alkyl) or N, wherein at least one of X, Y, and Z is CH;

Ring A is aryl, heteroaryl, or heterocyclyl;

R 1 is —N(R 6 )C(O)R 7 , —C(O)N(R 6 )(R 7 ), —(CH 2 ) t C(O)N(R 6 )(R 7 ), pyrrolidinyl, isoxazolyl, indolinyl, triazolyl, pyridinyl, pyridazinyl, imidazolyl, tetrazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 2,8-diazaspiro[4.5]decanyl, or isothiazolidine 1,1-dioxidyl; wherein pyrrolidinyl, isoxazolyl, indolinyl, triazolyl, pyridinyl, pyridazinyl, imidazolyl, tetrazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 2,8-diazaspiro[4.5]decanyl, or isothiazolidine 1,1-dioxidyl is optionally substituted with one or more R 8 ;

R 2 is —H, —NH 2 , or C 1-6 alkyl;

Q 1 is a bond;

each R 3 is independently, at each occurrence, —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —C(O)OR 6 , —S(O) 2 R 6 , —S(O) 2 N(R 6 )(R 7 ), wherein the alkyl, heterocyclyl, or cycloalkyl is optionally substituted with one or more R 8 ; or

two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, wherein the heterocyclyl, spirocycloalkyl, spiroheterocycloalkyl, or cycloalkyl is optionally substituted with one or more R 8 ;

R 4 is —H, C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , —C(O)N(R 10 )— R 9 , —C(O)—R 9 , —N(R 10 )—(C 0 -C 6 alkylene)-R 9 , —(C 0 -C 6 alkylene)-N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 , —N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 —N(R 10 )C(O)—(C 0 -C 6 alkylene)-, —N(R 10 )C(O)—R 9 , —(CH 2 ) q —R 9 , —(CH 2 ) r —N(R 10 )C(O)—(CH 2 ) s —R 9 , wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 9 ;

R 5 is —H, halogen, —OH, C 1-6 alkyl, C 1-6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with R 10 ;

R 6 is independently, at each occurrence, —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ;

R 7 is independently, at each occurrence, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 8 ; or

R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle, wherein the cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle is optionally substituted with one or more R 8 ;

R 8 is —CN, halogen, —OH, —NH 2 , —NO 2 , —C(O)NH 2 , —C(O)OH, oxo, C 1-6 alkyl, C 1-6 alkoxy, aryl, C 3-6 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, aryl, heterocyclyl, or heteroaryl is optionally substituted with one or more R 9 ;

R 9 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 11 , —C(O)O(R 11 ), —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 2 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, or —N(R 11 )C(O)—Ar, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 2 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 2 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar;

Ar is aryl optionally substituted with —NR 11 R 12 , —C(O)-Q 2 -N(R 11 )—F or —N(R 11 )C(O)-Q 2 -N(R 12 )—F;

Q 2 is —CH═CH(CH 2 ) m , —(CH 2 ) m , or —(CH 2 CH 2 O) o —CH 2 CH 2 —;

V is —CH═CH(CH 2 ) m , —(CH 2 ) m , or —(CH 2 CH 2 O) o —CH 2 CH 2 —;

F is —H, C 1-6 alkyl, or —C(O)-Q 2 -N(R 11 )(R 12 );

R 10 is independently —H, halogen, —CN, —OH, —NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl;

R 11 and R 12 are independently —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more —H, halogen, —CN, —OH, —NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 ;

R 13 and R 14 are independently, at each occurrence, —H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more H, halogen, —CN, —OH, —NH 2 , —NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl;

each m is independently 1-4;

o is 1-3;

n is 1, 2, or 3;

q is 1-4;

r is 0-4;

s is 0-4; and

t is 1-6

provided that:

(1) A is not oxadiazolyl, 1,3a-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-only, or piperidinyl;

(2) when A is phenyl, R 3 is not —S(O) 2 R 6 ;

(3) when R 1 is pyrimidinyl and A is pyridinyl both R 3 and R 4 are not simultaneously H;

(4) when R 1 is —N(R 6 )C(O)R 7 , R 6 is H, and R 7 is not methyl;

(5) when R 1 is —C(O)N(R 6 )(R 7 ), R 6 is H, and R 7 is alkyl, R 8 can not independently be both —OH and aryl;

(6) when R 1 is —C(O)N(R 6 )(R 7 ), R 6 is H, and R 7 is alkyl, R 8 is not —OH;

(7) when R 1 is —C(O)N(R 6 )(R 7 ) and R 6 is H, R 7 is not isopropyl;

(8) when R 1 is tetrazolyl, R 1 is substituted with R 8 ;

(9) when R 1 is imidazolyl and R 1 is substituted with R 8 , R 8 is not aryl;

(10) when A is tetrahydropyranyl, thiophenyl, or 1,3,4-oxadiazolyl, both R 3 and R 4 are not simultaneously H; and

(11) when R 3 is —N(R 6 )(R 7 ) and R 6 is H, R 7 is not methyl.

Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of PI5P4K. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of PI5P4K an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibiting PI5P4K. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a neurodegenerative disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a viral infection or disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating an inflammatory disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of inducing cell cycle arrest, apoptosis in tumor cells and/or enhanced tumor-specific T-cell immunity. The method comprises contacting the cells with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Another aspect of the present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting PI5P4K.

Another aspect of the present invention relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a disease associated with inhibiting PI5P4K.

The present invention further provides methods of treating a disease or disorder associated with modulation of PI5P4K including, cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The present invention provides inhibitors of PI5P4K that are therapeutic agents in the treatment of diseases such as cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases.

The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known PI5P4K inhibitors. The present disclosure also provides agents with novel mechanisms of action toward PI5P4K enzymes in the treatment of various types of diseases including cancer and metastasis, neurodegenerative diseases, immunological disorders, diabetes, bone and joint diseases, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, viral infectivity and/or latency, and bacterial infections and diseases. Ultimately the present invention provides the medical community with a novel pharmacological strategy for the treatment of diseases and disorders associated with PI5P4K enzymes.

The present invention relates to compounds and compositions that are capable of inhibiting the activity PI5P4K. The invention features methods of treating, preventing or ameliorating a disease or disorder in which PI5P4K plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present invention can be used in the treatment of a variety of PI5P4K dependent diseases and disorders by inhibiting the activity of PI5P4K enzymes. Inhibition of PI5P4K provides a novel approach to the treatment, prevention, or amelioration of diseases including, but not limited to, cancer and metastasis, neurodegenerative diseases, immunological disorders, osteoporosis, arthritis inflammatory disorders, cardiovascular diseases, ischemic diseases, viral infections and diseases, and bacterial infections and diseases.

In a first aspect of the invention, the compounds of Formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein A, X, Y, Z, Q 1 , R 1 , R 2 , R 3 , R 4 , R 5 , and n are described herein above.

The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH 2 CN, —O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 )haloalkoxy, —O—(C 2 -C 6 )alkenyl, —O—(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —OH, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —NH 2 , —NH((C 1 -C 6 )alkyl), —N((C 1 -C 6 )alkyl) 2 , —NHC(O)(C 1 -C 6 )alkyl, —C(O)NH(C 1 -C 6 )alkyl, —S(O) 2 (C 1 -C 6 )alkyl, —S(O)NH(C 1 -C 6 )alkyl, and S(O)N((C 1 -C 6 )alkyl) 2 . The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified group bears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. The term “aryl” also encompasses polycyclic ring systems in which at least one ring is aromatic and is fused with 1 to 2 saturated or partially unsaturated cycloalkyl or heterocyclyl containing one or more heteroatoms selected from N, O, S, P, or B, and the cycloalkyl or heterocyclyl is optionally substituted with one or more oxo. For example, the term “aryl” may include polycyclic groups such as indanyl, Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, —H, halogen, —O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, —O—(C 2 -C 6 )alkenyl, —O—(C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, —OH, —OP(O)(OH) 2 , —OC(O)(C 1 -C 6 )alkyl, —C(O)(C 1 -C 6 )alkyl, —OC(O)O(C 1 -C 6 )alkyl, —NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , —S(O) 2 —(C 1 -C 6 )alkyl, —S(O)NH(C 1 -C 6 )alkyl, and —S(O)N((C 1 -C 6 )alkyl) 2 . The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2 -pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with a fully unsaturated ring, e.g., a 5-membered heteroaromatic ring containing 1-3 heteroatoms selected from N, S, or O, or a 6-membered heteroaromatic ring containing 1-3 nitrogens, wherein the saturated or partially unsaturated ring includes 0-4 heteroatoms selected from N, O, S, P, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine, pyrazolo[1,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl. Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C 1 -C 6 )alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, i.e., —O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a C 1 -C 6 alkylene. An alkylene may further be a C 1 -C 4 alkylene. Typical alkylene groups include, but are not limited to, —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )—, —CH 2 C(CH 3 ) 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, and the like.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norbornenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing 3-24 carbon atoms further substituted with (C 1 -C 6 )alkyl groups. In general cycloalkylalkyl groups herein described display the following formula

where m is an integer from 1 to 6 and n is an integer from 1 to 16. The cycloalkyl ring or carbocycle may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norbornenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl, decahydronaphthalenyl, octahydro-1H-indenyl, cyclopentenyl, cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl, 1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl, 3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl, bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl, 2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings containing carbon and heteroatoms taken from containing one or more ring heteroatoms selected from N, O, S, P, or B and wherein there is not delocalized 7 electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

The term “hydroxyalkyl” means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalkyl groups include HO—CH 2 —, HO—CH 2 —CH 2 — and CH 3 —CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, i.e., C≡N.

The term “amine” as used herein refers to primary (R—NH 2 , R≠H), secondary (R 2 —NH, R 2 ≠H) and tertiary (R 3 —N, R≠H) amines. A substituted amine is intended to mean an amine where at least one of the hydrogen atoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at least one nitrogen atom. Specifically, —NH 2 , —NH(alkyl) or alkylamino, —N(alkyl) 2 or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “amino”.

The term “dialkylamino” as used herein refers to an amino or —NH 2 group where both of the hydrogens have been replaced with alkyl groups, as defined herein above, i.e., —N(alkyl) 2 . The alkyl groups on the amino group can be the same or different alkyl groups. Example of alkylamino groups include, but are not limited to, dimethylamino (i.e., —N(CH 3 ) 2 ), diethylamino, dipropylamino, diisopropylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C 3 -C 12 ) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

The term “solvate” refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

The term “isomer” refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

The present invention also contemplates isotopically-labelled compounds of Formula I (e.g., those labeled with 2 H and 14 C). Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative “pharmaceutically acceptable salts” include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

The term “carrier”, as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

The term “administer”, “administering”, or “administration” as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

The present invention relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting PI5P4K, which are useful for the treatment of diseases and disorders associated with modulation of a PI5P4K enzyme. The invention further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for inhibiting PI5P4K.

In one embodiment, the compounds of Formula (I) have the structure of Formula (Ia):

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ib):

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ic):

In another embodiment, the compounds of Formula (I) have the structure of Formula (Id):

wherein U and Q 3 are O, S, NH, or CH, provided that at least one of U or Q 3 is NH, S, or O; T, V, and W is CH or N, provided that only one of W or T is N;

is a circle or curve which represents an optional double bond conferring aromaticity to the rings.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ie):

wherein

U and Q 3 are independently N or CH, provided that at least one of U or Q 3 is NH;

T and W are independently CH or N.

In another embodiment, the compounds of Formula (I) have the structure of Formula (If):

wherein

T and W are independently CH or N;

represents an optional double bond which confers aromaticity or partial or full saturation to the ring.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig):

wherein

T and W are independently CH or N;

is a circle or curve which represents an optional double bond conferring aromaticity to the rings;

p is an integer from 0 to 3.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ih):

wherein

T and W are independently CH or N;

is a circle or curve which represents an optional double bond conferring aromaticity to the rings;

p is an integer from 0 to 3.

In another embodiment, the compounds of Formula (I) have the structure of Formula (Ii):

In some embodiments of the compounds of Formula I, R 1 is —N(R 6 )C(O)R 7 , —C(O)N(R 6 )(R 7 ), —(CH) 1-6 C(O)N(R 6 )(R 7 ), heterocyclyl, or heteroaryl. In another embodiment, R 1 is —N(R 6 )C(O)R 7 . In another embodiment, R 1 is —C(O)N(R 6 )(R 7 ). In another embodiment, R 1 is —(CH) 1-6 C(O)N(R 6 )(R 7 ). In another embodiment, R 1 is heterocyclyl. In another embodiment, R 1 is heteroaryl.

In some embodiments of the compounds of Formula I, R 1 is —N(R 6 )C(O)R 7 , —C(O)N(R 6 )(R 7 ), —(CH 2 ) t C(O)N(R 6 )(R 7 ), pyrrolidinyl, isoxazolyl, indolinyl, triazolyl, pyridinyl, pyridazinyl, imidazolyl, tetrazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 2,8-diazaspiro[4.5]decanyl, or isothiazolidine 1,1-dioxidyl. In another embodiment, R 1 is pyrrolidinyl. In another embodiment, R 1 is isoxazolyl. In another embodiment, R 1 is indolinyl. In another embodiment, R 1 is triazolyl. In another embodiment, R 1 is pyridinyl. In another embodiment, R 1 is pyridazinyl. In another embodiment, R 1 is imidazolyl. In another embodiment, R 1 is tetrazolyl. In another embodiment, R 1 is 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl. In another embodiment, R 1 is 2,8-diazaspiro[4.5]decanyl. In another embodiment, R 1 is isothiazolidine 1,1-dioxidyl.

In some embodiments of the compounds of Formula I, R 1 is —N(R 6 )C(O)R 7 , —C(O)N(R 6 )(R 7 ), (CH) 1-6 C(O)N(R 6 )(R 7 ), pyrrolidinyl, isoxazolyl, indolinyl, triazolyl, pyridinyl, pyridazinyl, imidazolyl, tetrazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 2,8-diazaspiro[4.5]decanyl, or isothiazolidine 1,1-dioxidyl; wherein pyrrolidinyl, isoxazolyl, indolinyl, triazolyl, pyridinyl, pyridazinyl, imidazolyl, tetrazolyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 2,8-diazaspiro[4.5]decanyl, or isothiazolidine 1,1-dioxidyl is optionally substituted with one or more R 8 . In another embodiment, R 1 is pyrrolidinyl optionally substituted with one or more R 8 . In another embodiment, R 1 is isoxazolyl optionally substituted with one or more R 8 . In another embodiment, R 1 is indolinyl optionally substituted with one or more R 8 . In another embodiment, R 1 is triazolyl optionally substituted with one or more R 8 . In another embodiment, R 1 is pyridinyl optionally substituted with one or more R 8 . In another embodiment, R 1 is pyridazinyl optionally substituted with one or more R 8 . In another embodiment, R 1 is imidazolyl optionally substituted with one or more R 8 . In another embodiment, R 1 is tetrazolyl optionally substituted with one or more R 8 . In another embodiment, R 1 is 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl optionally substituted with one or more R 8 . In another embodiment, R 1 is 2,8-diazaspiro[4.5]decanyl optionally substituted with one or more R 8 . In another embodiment, R 1 is isothiazolidine 1,1-dioxidyl optionally substituted with one or more R 8 .

In some embodiments of the compounds of Formula I, X is CH or N. In another embodiment, X is CH. In another embodiment, X is N.

In some embodiments of the compounds of Formula I, Y is CH or N. In another embodiment, Y is CH. In another embodiment, Y is N.

In some embodiments of the compounds of Formula I, Z is CH or N. In another embodiment, Z is CH. In another embodiment, Z is N.

In some embodiments of the compounds of Formula I, at least one of X, Y, and Z is CH. In another embodiment, at least two of X, Y, and Z are CH. In another embodiment, X, Y, and Z are CH.

In some embodiments of the compounds of Formula I, Ring A is aryl, heteroaryl, or heterocyclyl. In another embodiment, Ring A is aryl or heteroaryl. In another embodiment, Ring A is aryl. In another embodiment, Ring A is heteroaryl. In another embodiment, Ring A is heterocyclyl.

In some embodiments of the compounds of Formula I, R 2 is —H, —NH 2 , or C 1-6 alkyl. In one embodiment, R 2 is —H. In one embodiment, R 2 is —NH 2 . In one embodiment, R 2 is C 1-6 alkyl.

In some embodiments of the compounds of Formula I, Q 1 is a bond.

n some embodiments of the compounds of Formula I, X 2 is C(R 5 ) or N. In one embodiment, X 2 is C(R 5 ). In one embodiment, X 2 is N.

In some embodiments of the compounds of Formula I, R 3 is independently, at each occurrence, —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —C(O)OR 6 , —S(O) 2 R 6 , or —S(O) 2 N(R 6 )(R 7 ). In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , —C(O)OR 6 , or —S(O) 2 R 6 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, —C(O)NR 6 R 7 , —N(R 6 )C(O)R 7 , or —C(O)OR 6 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, —C(O)NR 6 R 7 , or —N(R 6 )C(O)R 7 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , —CN, or —C(O)NR 6 R 7 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —NR 6 R 7 , or —CN. In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , or —NR 6 R 7 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, heterocyclyl, or —OR 6 . In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, or heterocyclyl. In another embodiment, R 3 is —H, halogen, oxo, C 1-6 alkyl, or C 3-6 cycloalkyl. In another embodiment, R 3 is —H, halogen, oxo, or C 1-6 alkyl. In another embodiment, R 3 is —H, halogen, or oxo. In another embodiment, R 3 is —H or halogen. In another embodiment, R 3 is —H. In another embodiment, R 3 is halogen. In another embodiment, R 3 is oxo. In another embodiment, R 3 is C 1-6 alkyl. In another embodiment, R 3 is C 3-6 cycloalkyl. In another embodiment, R 3 is heterocyclyl. In another embodiment, R 3 is —OR 6 . In another embodiment, R 3 is —NR 6 R 7 . In another embodiment, R 3 is CN. In another embodiment, R 3 is —C(O)NR 6 R 7 . In another embodiment, R 3 is —N(R 6 )C(O)R 7 . In another embodiment, R 3 is —C(O)OR 6 . In another embodiment, R 3 is —S(O) 2 R 6 . In another embodiment, R 3 is —S(O) 2 N(R 6 )(R 7 ). In another embodiment, R 3 is C 1-6 alkyl optionally substituted with one or more R 8 . In another embodiment, R 3 is C 3-6 cycloalkyl optionally substituted with one or more R 8 . In another embodiment, R 3 is heterocyclyl optionally substituted with one or more R 8 .

In some embodiments of the compounds of Formula I, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, or spiroheterocycloalkyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl or C 5 -C 8 spirocycloalkyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 5 -C 8 spirocycloalkyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a spiroheterocycloalkyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a heterocyclyl. In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 4-8 cycloalkyl optionally substituted with one or more R 8 . In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a C 5 -C 8 spirocycloalkyl optionally substituted with one or more R 8 . In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a spiroheterocycloalkyl optionally substituted with one or more R 8 . In another embodiment, two R 3 , when on adjacent atoms, with the atoms they are attached, form a heterocyclyl optionally substituted with one or more R 8 .

In other embodiments of the compounds of Formula I, R 4 is H, C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, aryl, heterocyclyl, heteroaryl, —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , —C(O)N(R 10 )— R 9 , —C(O)—R 9 , —N(R 10 )—(C 0 -C 6 alkylene)-R 9 , —(C 0 -C 6 alkylene)-N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 , —N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 —N(R 10 )C(O)—(C 0 -C 6 alkylene)-, —N(R 10 )C(O)—R 9 , or —(CH 2 ) q —R 9 , —(CH 2 )—N(R 10 )C(O)—(CH 2 ) s —R 9 . In another embodiment, R 4 is H. In another embodiment, R 4 is C 3 —C cycloalkyl. In another embodiment, R 4 is C 5 -C 8 spirocycloalkyl. In another embodiment, R 4 is spiroheterocycloalkyl. In another embodiment, R 4 is aryl. In another embodiment, R 4 is heterocyclyl. In another embodiment, R 4 is heteroaryl. In another embodiment, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 . In another embodiment, R 4 is, —C(O)N(R 10 )— R 9 . In another embodiment, R 4 is —N(R 10 )—(C 0 -C 6 alkylene)-R 9 . In another embodiment, R 4 is —(C 0 -C 6 alkylene)-N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 . In another embodiment, R 4 is —N(R 10 )C(O)—(C 0 -C 6 alkylene)-R 9 —N(R 10 )C(O)—(C 0 -C 6 alkylene)-. In another embodiment, R 4 is —N(R 10 )C(O)—R 9 . In another embodiment, R 4 is —(CH 2 ) q R 9 , —(CH 2 ) r —N(R 10 )C(O)—(CH 2 ) s —R 9 . In another embodiment, R 4 is C 3 -C 8 cycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 4 is C 5 -C 8 spirocycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 4 is spiroheterocycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 4 is aryl optionally substituted with one or more R 9 . In another embodiment, R 4 is heterocyclyl optionally substituted with one or more R 9 .

In other embodiments of the compounds of Formula I, R 5 is H, halogen, OH, C 1-6 alkyl, or C 1-6 alkoxy. In another embodiment, R 5 is H, halogen, OH, or C 1-6 alkyl. In another embodiment, R 5 is H, halogen, or OH. In another embodiment, R 5 is H or halogen. In another embodiment, R 5 is H. In another embodiment, R 5 is halogen. In another embodiment, R 5 is OH. In another embodiment, R 5 is C 1-6 alkyl. In another embodiment, R 5 is C 1-6 alkoxy. In another embodiment, R 5 is C 1-6 alkyl optionally substituted with R 10 . In another embodiment, R 5 is C 1-6 alkoxy optionally substituted with R 10 .

In other embodiments of the compounds of Formula I, R 6 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In another embodiment, R 6 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, or aryl. In another embodiment, R 6 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, or heterocyclyl. In another embodiment, R 6 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-8 cycloalkyl. In another embodiment, R 6 is —H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl. In another embodiment, R 6 is —H, C 1-6 alkyl, or C 2-6 alkenyl. In another embodiment, R 6 is —H or C 1-6 alkyl. In another embodiment, R 6 is H. In another embodiment, R 6 is C 1-6 alkyl. In another embodiment, R 6 is C 2-6 alkenyl. In another embodiment, R 6 is C 2-6 alkynyl. In another embodiment, R 6 is C 3-8 cycloalkyl. In another embodiment, R 6 is heterocyclyl. In another embodiment, R 6 is aryl. In another embodiment, R 6 is heteroaryl. In another embodiment, R 6 is C 1-6 alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is C 2-6 alkenyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is C 2-6 alkynyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is C 3 — cycloalkyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is heterocyclyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is aryl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is heteroaryl alkyl optionally substituted with one or more R 8 .

In other embodiments of the compounds of Formula I, R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl. In another embodiment, R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, or aryl. In another embodiment, R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, or heterocyclyl. In another embodiment, R 7 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or C 3-8 cycloalkyl. In another embodiment, R 7 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl. In another embodiment, R 7 is C 1-6 alkyl, or C 2-6 alkenyl. In another embodiment, R 7 is or C 1-6 alkyl. In another embodiment, R 7 is C 1-6 alkyl. In another embodiment, R 7 is C 2-6 alkenyl. In another embodiment, R 7 is C 2-6 alkynyl. In another embodiment, R 7 is C 3-8 cycloalkyl. In another embodiment, R 7 is heterocyclyl. In another embodiment, R 7 is aryl. In another embodiment, R 7 is heteroaryl. In another embodiment, R 7 is C 1-6 alkyl optionally substituted with one or more R 8 . In another embodiment, R 7 is C 2-6 alkenyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 7 is C 2-6 alkynyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 7 is C 3-8 cycloalkyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 7 is heterocyclyl alkyl optionally substituted with one or more R 8 . In another embodiment, R 6 is aryl alkyl optionally substituted with one or more R 8 . In another embodiment, R 7 is heteroaryl alkyl optionally substituted with one or more R 8 .

In some embodiments of the compounds of Formula I, R 6 and R 7 when taken together with the atom to which they are each attached form a C 4-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 4-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, or spiroheterocycloalkyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 4-8 cycloalkyl or C 5 -C 8 spirocycloalkyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 4-8 cycloalkyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 5 -C 8 spirocycloalkyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a spiroheterocycloalkyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a heterocyclyl. In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 4-8 cycloalkyl optionally substituted with one or more R 8 . In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a C 5 -C 8 spirocycloalkyl optionally substituted with one or more R 8 . In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a spiroheterocycloalkyl optionally substituted with one or more R 8 . In another embodiment, R 6 and R 7 when taken together with the atom to which they are each attached form a heterocyclyl optionally substituted with one or more R 8 .

In other embodiments of the compounds of Formula I, R 8 is —CN, halogen, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, aryl, C 3-8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, or heteroaryl. In another embodiment, R 8 is —CN. In another embodiment, R 8 is halogen. In another embodiment, R 8 is OH. In another embodiment, R 8 is NH 2 . In another embodiment, R 8 is NO 2 . In another embodiment, R 8 is oxo. In another embodiment, R 8 is C 1-6 alkyl. In another embodiment, R 8 is C 1-6 alkoxy. In another embodiment, R 8 is aryl. In another embodiment, R 8 is C 3-8 cycloalkyl. In another embodiment, R 8 is C 5 -C 8 spirocycloalkyl. In another embodiment, R 8 is spiroheterocycloalkyl. In another embodiment, R 8 is heterocyclyl. In another embodiment, R 8 is heteroaryl. In another embodiment, R 8 is C 1-6 alkyl optionally substituted with one or more R 9 . In another embodiment, R 8 is C 1-6 alkoxy optionally substituted with one or more R 9 . In another embodiment, R 8 is aryl optionally substituted with one or more R 9 . In another embodiment, R 8 is C 3-8 cycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 8 is C 5 -C 8 spirocycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 8 is spiroheterocycloalkyl optionally substituted with one or more R 9 . In another embodiment, R 8 is heterocyclyl optionally substituted with one or more R 9 . In another embodiment, R 8 is heteroaryl optionally substituted with one or more R 9 .

In some embodiments of the compounds of Formula I, R 9 is —H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR 11 , —C(O)O(R 11 ), —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is —H. In another embodiment, R 9 is halogen. In another embodiment, R 9 is C 1-6 alkyl. In another embodiment, R 9 is C 2-6 alkenyl. In another embodiment, R 9 is C 2-6 alkynyl. In another embodiment, R 9 is C 3-8 cycloalkyl. In another embodiment, R 9 is heterocyclyl. In another embodiment, R 9 is aryl. In another embodiment, R 9 is heteroaryl. In another embodiment, R 9 is —OR 11 . In another embodiment, R 9 is —C(O)O(R 11 ). In another embodiment, R 9 is —C(O)N(R 11 )(R 12 ). In another embodiment, R 9 is —N(R 11 )(R 12 ). In another embodiment, R 9 is —CN. In another embodiment, R 9 is —N(R 11 )C(O)OR 12 . In another embodiment, R 9 is —N(R 11 )C(O)R 2 . In another embodiment, R 9 is —C(O)—V—N(R 11 )—F. In another embodiment, R 9 is —N(R 11 )C(O)—V—N(R 2 )—F. In another embodiment, R 9 is —C(O)—Ar. In another embodiment, R 9 is —N(R 11 )C(O)—Ar. In another embodiment, R 9 is C 1-6 alkyl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 12 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is C 2-6 alkenyl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 12 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is C 2-6 alkynyl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 2 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 12 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 2 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is C 3-8 cycloalkyl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 2 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 2 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 2 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is heterocyclyl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 2 ), —O-Q 2 —N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is aryl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 12 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar. In another embodiment, R 9 is heteroaryl optionally substituted with one or more —OR 11 , —C(O)N(R 11 )(R 12 ), —N(R 11 )(R 12 ), —CN, —N(R 11 )C(O)OR 12 , —N(R 11 )C(O)R 12 , —C(O)—V—N(R 11 )—F, —N(R 11 )C(O)—V—N(R 12 )—F, —C(O)—Ar, —N(R 11 )C(O)—V—O(R 2 ), —O-Q 2 -N(R 11 )C(O)—V—O(R 12 ), or —N(R 11 )C(O)—Ar.

In some embodiments of the compounds of Formula I, R 10 is independently H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 10 is —H. In another embodiment, R 10 is halogen. In another embodiment, R 10 is CN. In another embodiment, R 10 is OH. In another embodiment, R 10 is NO 2 . In another embodiment, R 10 is oxo. In another embodiment, R 10 is C 1-6 alkyl. In another embodiment, R 10 is C 2-6 alkenyl. In another embodiment, R 10 is C 2-6 alkynyl. In another embodiment, R 10 is C 3-8 cycloalkyl. In another embodiment, R 10 is heterocyclyl. In another embodiment, R 10 is aryl. In another embodiment, R 10 is heteroaryl.

In some embodiments of the compounds of Formula I, R 11 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl. In another embodiment, R 11 is —H. In another embodiment, R 11 is C 1-6 alkyl. In another embodiment, R 11 is C 2-6 alkenyl. In another embodiment, R 11 is C 2-6 alkynyl. In another embodiment, R 11 is C 3-8 cycloalkyl. In another embodiment, R 11 is heterocyclyl. In another embodiment, R 11 is aryl. In another embodiment, R 11 is heteroaryl. In another embodiment, R 11 is C 1-6 alkyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is C 2-6 alkenyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is C 2-6 alkynyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is C 3-8 cycloalkyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is heterocyclyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is aryl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 11 is heteroaryl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 .

In some embodiments of the compounds of Formula I, R 12 is —H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl. In another embodiment, R 12 is —H. In another embodiment, R 12 is C 1-6 alkyl. In another embodiment, R 12 is C 2-6 alkenyl. In another embodiment, R 12 is C 2-6 alkynyl. In another embodiment, R 12 is C 3-8 cycloalkyl. In another embodiment, R 12 is heterocyclyl. In another embodiment, R 12 is aryl. In another embodiment, R 12 is heteroaryl. In another embodiment, R 12 is C 1-6 alkyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is C 2-6 alkenyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is C 2-6 alkynyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is C 3-8 cycloalkyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is heterocyclyl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 3 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is aryl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 . In another embodiment, R 12 is heteroaryl optionally substituted with one or more H, halogen, CN, OH, NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, aryl, —N(R 13 )(R 14 ), —C(O)R 13 , —N(R 13 )C(O)R 14 , —C(O)N(R 13 )(R 14 ), —C(O)OR 13 .

In some embodiments of the compounds of Formula I, Ar is aryl. In another embodiment, Ar is aryl optionally substituted with one or more substituted with —NR 11 R 12 , —C(O)—V—N(R 11 )—F or —N(R 11 )C(O)—V—N(R 12 )—F.

In other embodiments of the compounds of Formula I, V is —CH═CH(CH 2 ) m —, —(CH 2 ) m —, —(CH 2 ) m —Ar—, or —(CH 2 CH 2 O) o —CH 2 CH 2 —. In another embodiment, V is —CH═CH(CH 2 ) m —. In another embodiment, V is —(CH 2 ) m —. In another embodiment, V is —(CH 2 ) m —Ar—. In another embodiment, V is —(CH 2 CH 2 O) o —CH 2 CH 2 —.

In other embodiments of the compounds of Formula I, Q 2 is —CH═CH(CH 2 ) m —, —(CH 2 ) m —, or —(CH 2 CH 2 O) o —CH 2 CH 2 —. In another embodiment, Q 2 is —CH═CH(CH 2 ) m —. In another embodiment, Q 2 is —(CH 2 ) m —. In another embodiment, Q 2 is —(CH 2 CH 2 O) o —CH 2 CH 2 —.

In other embodiments of the compounds of Formula I, F is H, C 1-6 alkyl, or —C(O)—V—N(R 11 )(R 12 ). In another embodiment, F is H. In another embodiment, F is C 1-6 alkyl. In another embodiment, F is —C(O)-Q-N(R 23 )(R 23 ).

In some embodiments of the compounds of Formula I, R 13 is —H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl. In another embodiment, R 13 is —H. In another embodiment, R 13 is C 1-6 alkyl. In another embodiment, R 13 is C 1-6 alkoxy. In another embodiment, R 13 is C 2-6 alkenyl. In another embodiment, R 13 is C 2-6 alkynyl. In another embodiment, R 13 is C 3-8 cycloalkyl. In another embodiment, R 13 is heterocyclyl. In another embodiment, R 13 is aryl. In another embodiment, R 13 is heteroaryl. In another embodiment, R 13 is C 1-6 alkyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is C 1-6 alkoxy optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is C 2-6 alkenyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is C 2-6 alkynyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is C 3-8 cycloalkyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is heterocyclyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is aryl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 13 is heteroaryl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl.

In some embodiments of the compounds of Formula I, R 14 is —H, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl. In another embodiment, R 13 is —H. In another embodiment, R 14 is C 1-6 alkyl. In another embodiment, R 13 is C 1-6 alkoxy. In another embodiment, R 14 is C 2-6 alkenyl. In another embodiment, R 14 is C 2-6 alkynyl. In another embodiment, R 14 is C 3-8 cycloalkyl. In another embodiment, R 14 is heterocyclyl. In another embodiment, R 14 is aryl. In another embodiment, R 14 is heteroaryl. In another embodiment, R 14 is C 1-6 alkyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is C 1-6 alkoxy optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is C 2-6 alkenyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is C 2-6 alkynyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is C 3-8 cycloalkyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is heterocyclyl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is aryl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment, R 14 is heteroaryl optionally substituted with one or more H, halogen, CN, OH, NH 2 , NO 2 , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl.

In one embodiment, r is 0, 1, 2, 3, or 4. In another embodiment r is 0, 1, 2, or 3. In another embodiment r is 0, 1 or 2. In another embodiment r is 0 or 1. In another embodiment r is 0. In another embodiment r is 1. In another embodiment r is 2. In another embodiment r is 3. In another embodiment r is 4.

In one embodiment, s is 0, 1, 2, 3, or 4. In another embodiment s is 0, 1, 2, or 3. In another embodiment s is 0, 1 or 2. In another embodiment s is 0 or 1. In another embodiment s is 0. In another embodiment s is 1. In another embodiment s is 2. In another embodiment s is 3. In another embodiment s is 4.

In one embodiment, m is 1, 2, 3, or 4. In another embodiment m is 1, 2, or 3. In another embodiment m is 1 or 2. In another embodiment m is 1. In another embodiment m is 2. In another embodiment m is 3. In another embodiment m is 4.

In one embodiment, q is 1, 2, 3, or 4. In another embodiment q is 1, 2, or 3. In another embodiment q is 1 or 2. In another embodiment q is 1. In another embodiment q is 2. In another embodiment q is 3. In another embodiment q is 4.

In one embodiment, n is 1, 2, or 3. In another embodiment n is 1 or 2. In another embodiment n is 1. In another embodiment n is 2. In another embodiment n is 3.

In one embodiment, o is 1, 2, or 3. In another embodiment o is 1 or 2. In another embodiment o is 1. In another embodiment o is 2. In another embodiment o is 3.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is aryl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, and R 2 is NH 2 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is alkyl, Ring A is heterocyclyl, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heterocyclyl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is H, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is C 1-6 alkyl, R 3 is H, R 4 is —C(O)N(R 10 )—(C 0 -C 6 alkylene)-R 9 , and R 6 and R 7 when taken together with the atom to which they are each attached form a C 3 -C 8 cycloalkyl, C 5 -C 8 spirocycloalkyl, spiroheterocycloalkyl, or heterocycle.

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is heteroaryl, Ring A is heteroaryl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is C 1-6 alkyl, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heteroaryl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is NH 2 , R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —C(O)N(R 6 )(R 7 ), Ring A is heterocyclyl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is N, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is H, R 3 is H, —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CR 1a , R 1a and R 5 are taken together to form heterocyclyl, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, R 2 is H, n is 1-3, each R 3 is independently H, C 1-6 alkyl optionally substituted with R 5 , —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CR 1a , R 1a and R 5 are taken together to form heterocyclyl, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, R 2 is H, n is 1-3, each R 3 is independently H, C 1-6 alkyl optionally substituted with R 8 , —C(O)NR 6 R 7 , or —C(O)OR 6 , R 6 and R 7 are independently, at each occurrence, —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is H, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , R 5 is H, R 2 is H, Ring A is heteroaryl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 1 is —N(R 6 )C(O)R 7 , R 5 is H, and R 2 is H, Ring A is heterocyclyl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 8 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CR 1a , R 1a is C 1-6 alkyl, R 5 is H, R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CR 1a , R 1a is C 1-6 alkyl, R 1 is —N(R 6 )C(O)R 7 , R 5 is H, R 2 is H, Ring A is heteroaryl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CR 1a , R 1a is C 1-6 alkyl, R 1 is —N(R 6 )C(O)R 7 , R 5 is H, R 2 is H, Ring A is heterocyclyl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is C 1-6 alkyl, and R 2 is H.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is C 1-6 alkyl, R 2 is H, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is C 1-6 alkyl, R 2 is H, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is H, and R 2 is C 1-6 alkyl.

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is H, R 2 is C 1-6 alkyl, R 1 is —N(R 6 )C(O)R 7 , Ring A is heteroaryl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

In one embodiment of the compounds of Formula I, X is CH, Y is CH, Z is CH, R 5 is H, and R 2 is C 1-6 alkyl, R 1 is —N(R 6 )C(O)R 7 , Ring A is heterocyclyl, and R 6 and R 7 are independently —H, C 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with one or more R 5 , or R 6 and R 7 are taken together to form heterocyclyl optionally substituted with one or more R 8 .

Non-limiting illustrative compounds of the present disclosure include:

2′-amino-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(quinolin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 4-(5-(4-(dimethylcarbamoyl)phenyl)pyridin-3-yl)-N,1-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-(2-hydroxypropan-2-yl)-[3,4′-bipyridin]-5-yl)-N,N-dimethylbenzamide, 4-([3,4′-bipyridin]-5-yl)-N,N-dimethylbenzamide, 4-(5-(1,6-naphthyridin-4-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 4-(6-amino-[3,4′-bipyridin]-5-yl)-N,N-dimethylbenzamide, 4-(6-amino-6′-oxo-1′,6′-dihydro-[3,3′-bipyridin]-5-yl)-N,N-dimethylbenzamide, 4-(2-amino-5-(3,6-dihydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 2′-amino-2″-(2-cyanopropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-2″-(1-cyanocyclopropyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-2″-(tert-butyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-2″-cyano-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-[2,3′:5′,3″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(2H-pyrazolo[3,4-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(6-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1,6-naphthyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 2′-amino-N,N-dimethyl-5′-(pyridazin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(furo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-2″-(2-hydroxypropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-5′-(7-(dimethylamino)quinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, N,N-dimethyl-4-(5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)benzamide, N,N-dimethyl-4-(5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)benzamide, 4-(5′-(1H-pyrrolo[2,3-b]pyridin-4-yl)-[3,3′-bipyridin]-5-yl)-N,N-dimethylbenzamide, 4-(5-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 2′-amino-5′-(7-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1,8-naphthyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(5-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, 2′-amino-5′-(1H-imidazo[4,5-b]pyridin-7-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, tert-butyl (3-(3-(((2′-amino-5-(dimethylcarbamoyl)-[2,3′:5′,4″-terpyridin]-2″-yl)methyl)amino)-3-oxopropyl)phenyl)carbamate, 2′-amino-2″-((3-(3-aminophenyl)propanamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, (E)-2′-amino-2″-((3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(2H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide 2′,2″-diamino-N,N-dimethyl-[2,3′:5′,3″-terpyridine]-5-carboxamide, tert-butyl (3-(((2′-amino-5-(dimethylcarbamoyl)-[2,3′:5′,4″-terpyridin]-2″-yl)methyl)carbamoyl)phenyl)carbamate, 2′-amino-2″-((3-aminobenzamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, (E)-2′-amino-2″-((3-(4-(dimethylamino)but-2-enamido)benzamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, tert-butyl (4-(((2′-amino-5-(dimethylcarbamoyl)-[2,3′:5′,4″-terpyridin]-2″-yl)methyl)carbamoyl)phenyl)carbamate, 2′-amino-2″-((4-aminobenzamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, (E)-2′-amino-2″-((4-(4-(dimethylamino)but-2-enamido)benzamido)methyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide, 1-(2′-amino-5′-(imidazo[1,2-a]pyridin-5-yl)-[2,3′-bipyridin]-5-yl)pyrrolidin-2-one, 1-(2′-amino-5′-(benzo[d]thiazol-7-yl)-[2,3′-bipyridin]-5-yl)pyrrolidin-2-one, 1-(2′-amino-5′-(thieno[2,3-b]pyridin-3-yl)-[2,3′-bipyridin]-5-yl)pyrrolidin-2-one, 4-(5-(4-(dimethylcarbamoyl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(2′-amino-5′-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2,3′-bipyridin]-5-yl)pyrrolidin-2-one, 5-(4-(dimethylcarbamoyl)phenyl)-N,N-dimethyl-[3,4′-bipyridine]-2′-carboxamide, 1-(4-(5-(2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-N,N-dimethylbenzamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N,N-dimethyl-H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2′-amino-5′-(6-((3-aminophenyl)amino)pyrimidin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(6-aminopyrimidin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(5-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-N,N-dimethylbenzamide, N,N-dimethyl-4-(5-(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)benzamide, 2′-amino-5′-(2-(3-hydroxyazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(2-(3-carbamoylazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(6-((3-(3-aminobenzamido)phenyl)amino)pyrimidin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 1-(4-(5-(2H-pyrazolo[4,3-b]pyridin-7-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, N,N-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, 1′-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)-[3,4′-bipyridin]-2′(1′H)-one, 1-(4-(5-(5-methoxy-TH-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-methyl-TH-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 5′-(4-(2-oxopyrrolidin-1-yl)phenyl)-[3,3′-bipyridin]-6(1H)-one, 1-methyl-5′-(4-(2-oxopyrrolidin-1-yl)phenyl)-[3,3′-bipyridin]-6(1H)-one, 7-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 2′-amino-N,N-dimethyl-5′-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(benzylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-((2,2,2-trifluoroethyl)carbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-isobutyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2′-amino-N,N-dimethyl-5′-(2-(piperazine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2′-amino-N,N-dimethyl-5′-(2-(pyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(2-(1,1-dioxidothiomorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(6-((4-aminopyridin-2-yl)amino)pyrimidin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile, 1-(4-(5-(2H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one 1-(4-([3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-chloro-2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-methyl-2H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-methyl-N-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)-[3,4′-bipyridin]-2′-yl)acetamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 1-(4-(5-(1-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 6-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, N-(2-amino-2-oxoethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, (4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycine, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-((3R,4S)-4-aminotetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 5′-(2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-2H-pyrazolo[3,4-b]pyridine-5-carboxamide, N-(2-methoxyethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-5-carboxamide, N-benzyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-isobutyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(2-(pyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-phenethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(pyridin-3-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N,N-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-cyclopropyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1,6-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one, N-(2-(1H-imidazol-2-yl)ethyl)-4-(5-(4-(pyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-(benzo[d]oxazol-2-ylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2-isopropyl-N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 2-isopropyl-N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(pyridin-2-yl)ethyl)-H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(pyridin-4-yl)ethyl)-H-pyrrolo[2,3-b]pyridine-2-carboxamide, methyl 4-(5-(2-oxopyrrolidin-1-yl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, N,N,1,2-tetramethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, N,N,2-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, N-(2-(2H-tetrazol-5-yl)ethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2-cyclopropyl-N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 1-(4-(5-(1H-pyrrolo[3,2-b]pyridin-1-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N,N-dimethyl-1-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[3,2-b]pyridine-6-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(pyrazin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(thiazol-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(6-amino-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one, N-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-7-(cyclopropylmethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, 1-(1-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-2-one, 1-(4-(2-amino-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-methoxyethyl)furo[2,3-b]pyridine-2-carboxamide, 6-isobutyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 1-(4-(5-(6-methoxy-2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(cyclopropylmethyl)furo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, N-(2-methoxyethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, 1-(4-(2-amino-5-(1-methyl-5-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(2-amino-5-(7-methoxy-2H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, N,1,6-trimethyl-7-oxo-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxamide, N,N,1,6-tetramethyl-7-oxo-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxamide, N-(2-(1H-pyrrol-2-yl)ethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 2-cyclopropyl-N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 1,6-dimethyl-7-oxo-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-phenylcyclopropyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide, 1-(4-(5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1,6-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, N-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate, 1-(4-(5-(6-cyclopropyl-2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(4-(methoxymethyl)-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N,1-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, 1-(4-(5-(5-(piperidin-3-yloxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-ethoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 6-benzyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 1-(4-(5-(7-methoxy-2H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, methyl 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 1-(4-(4-methyl-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one, 1-(4-(2-amino-5-(5-(1-hydroxyethyl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(oxetan-3-yl)furo[2,3-b]pyridine-2-carboxamide, 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-isobutyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 1-(4-([3,4′-bipyridin]-5-yl)-3-methylphenyl)pyrrolidin-2-one, 1-(4-(5-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(6-methyl-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one, 1-[4-[5-(7-Methylpyrrolo[2,3-d]pyrimidin-5-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 2-Methyl-8-[5-(4-pyridyl)-3-pyridyl]-2,8-diazaspiro[4.5]decan-1-one, trans-N-[(4-aminocyclohexyl)methyl]-N-methyl-4-[5-(4-pyridyl)-3-pyridyl]benzamide, 1-[4-[5-(3-Bromo-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-[4-[5-[3-(1-Hydroxyethyl)-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl]-3-pyridyl]phenyl]pyrrolidin-2-one, 1-[4-[5-(7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizin-5-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-(4-(5-(imidazo[1,2-a]pyrimidin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 5-ethyl-6-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, 1-(4-(5-(5-(2-oxopyrrolidin-1-yl)furo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-(1-hydroxyethyl)furo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 5-isopropyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-5-carboxamide, N-(3-(1H-1,2,3-triazol-1-yl)phenyl)-4-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)-N-methylbenzamide, 7-methyl-4-(5-(4-(2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(5-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 6-(2-hydroxyethyl)-2,5-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, (S)-7-methyl-4-(5-(4-(4-methyl-2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, (R)-7-methyl-4-(5-(4-(4-methyl-2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(5-(methoxymethyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-(4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)pyrimidin-2-yl)cyclobutanecarboxamide, 6-ethyl-5-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, N-(4-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)-2-(2-azabicyclo[2.2.1]heptan-2-yl)-2-oxoacetamide, 7-methyl-4-(5-(4-(6-oxo-5-azaspiro[2.4]heptan-5-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(6-ethyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-ethyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-methyl-4-(5-(4-(4-methyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(8-cyclobutyl-7H-purin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-7-(pyridin-2-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, N-(4-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)-5-cyclobutylisoxazole-3-carboxamide, N-(4-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-2-oxoacetamide, 4-(5-(4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, methyl 5-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, (S)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one, (R)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one, 1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one, 1-(4-(5-(2-cyclopropyl-5-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, (S)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one, (R)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(thieno[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, (R)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, (S)-1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide, methyl 5-chloro-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-((1r,3r)-3-phenylcyclobutyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-(oxetan-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, N,N-dimethyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one, N,N-dimethyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one, methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-(thiazol-5-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1-methyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-([3,4′-bipyridin]-5-yl)-N-methyl-N-(piperidin-4-ylmethyl)benzamide, methyl 4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 2-(1-methyl-7-oxo-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetonitrile, methyl 4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 4-([3,4′-bipyridin]-5-yl)-N-(((1r,4r)-4-aminocyclohexyl)methyl)-N-methylbenzamide, isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate, 1-(4-(5-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-([3,4′-bipyridin]-5-yl)-N-methyl-N-(piperidin-3-ylmethyl)benzamide, 1-(4-(5-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-methyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, ethyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 2-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, 1-(4-(5-(1-methyl-3-(2-methylpyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(5-methyl-2-(piperidin-1-yl)thiazolo[4,5-d]pyrimidin-7-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1H-pyrazolo[4,3-b]pyridin-7-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-methyl-TH-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-[4-[5-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-[4-[5-(4-Pyridyl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-(4-(5-(2-methyl-2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-chloro-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(7-methoxy-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(6-methoxy-TH-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-[5-[4-(2-Oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-5,6-dihydropyrrolo[3,4-b]pyridin-7-one, 1-(4-(2-amino-5-(7-methoxy-TH-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide, 2′-amino-5′-(3H-imidazo[4,5-b]pyridin-7-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide, 2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide, 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-[4-[5-(7-methoxy-2-methyl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 8-([3,4′-bipyridin]-5-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one, 1-[4-[5-(7,8-Dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, 1-[4-[5-(4-Methyl-2,4,5-triazatricyclo[7.3.0.03,7]dodeca-1,3(7),5,8-tetraen-8-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, (R)-7-methyl-4-(5-(4-(2-methyl-5-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(3-methylisoxazolo[5,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 7-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(2-amino-5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-3-yl)-H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-phenyl-H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N,3-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(6-amino-5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-((4-methyl-1H-benzo[d]imidazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(3-methyl-2H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-(benzo[d]thiazol-2-ylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((6-methyl-1H-benzo[d]imidazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((1H-benzo[d]imidazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, N-ethyl-N-methyl-4-(5-(7-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-4-yl)pyridin-3-yl)benzamide, 1-(4-(5-(2-(6-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(5,5-dimethyl-2-oxopiperidin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-methyl-4-(5-(4-(morpholine-4-carbonyl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-phenyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-(oxazol-2-ylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 7-(1,5-dimethyl-1H-pyrazol-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(2-(1-oxa-7-azaspiro[4.5]decane-7-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(7-cyclopropyl-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(3-(2-aminopyrimidin-5-yl)imidazo[1,2-a]pyrimidin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(4,4-dimethylpiperidine-1-carbonyl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(7-methyl-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(3-(6-aminopyridin-3-yl)imidazo[1,2-a]pyrimidin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(2-cyclopropyl-5-(2-hydroxypropan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(2-(7-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-([1,2,4]triazolo[4,3-a]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(3-(pyrimidin-5-yl)imidazo[1,2-a]pyrimidin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(4,4-dimethyl-2-oxopiperidin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, N-(5-(1-methyl-5-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-yl)acetamide, 1-(4-(5-(3-(pyridin-3-yl)imidazo[1,2-a]pyrimidin-6-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 7-methyl-4-(5-(4-(2-oxoazepan-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-methyl-4-(5-(4-(2-oxopiperidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(3-(6-aminopyridin-3-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-methyl-4-(5-(4-(pyrrolidine-1-carbonyl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, N-(5-(1-methyl-5-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-2-yl)acetamide, 1-(4-(5-(3-(1-hydroxyethyl)-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(7,8-dihydro-6H-pyrimido[5,4-b]pyrrolizin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(3-bromo-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 7-methyl-4-(5-(4-(piperidine-1-carbonyl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 1-(4-(5-(3-(2-aminopyrimidin-5-yl)-1-methyl-TH-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 4-(5-(4-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-5-methyl-7-(pyridin-2-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(5-isopropyl-TH-1,2,3-triazol-1-yl)phenyl)pyridin-3-yl)-7-(pyridin-2-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-ethyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(1-isopropyl-1H-imidazol-5-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, (S)-4-(5-(4-(4-(sec-butyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, (R)-4-(5-(4-(4-(sec-butyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(6-amino-5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(4-isopropylisoxazol-5-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(1-isopropyl-1H-imidazol-2-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-cyclobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(6-amino-5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-(pyridin-2-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(5-isopropyl-TH-1,2,3-triazol-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-(2-cyclopropylethyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 7-methyl-4-(5-(4-(4-methylpyridazin-3-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-benzyl-4-(5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-benzyl-4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(6-amino-5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-(cyclopropylmethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isopropylisoxazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-(cyclopropylmethyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-(tert-butyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-7-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(5-isopropylpyridin-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(3,3-dimethylazetidine-1-carbonyl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(7-azabicyclo[2.2.1]heptane-7-carbonyl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-(pyridin-4-ylmethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(5-(4-(1-isopropyl-1H-tetrazol-5-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)-4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, N-((4,5-dimethyloxazol-2-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(6-amino-5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-(cyclopropylmethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, 4-(6-amino-5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-(cyclopropylmethyl)furo[2,3-b]pyridine-2-carboxamide, N-(1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(4-(3,3-difluorocyclobutyl)-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, N-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)octyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-N-(2-(pyridin-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 1-(4-(5-(2-((2S,4R)-2-(2-hydroxypropan-2-yl)-4-methylpyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, 1-(4-(5-(2-(3-cyclopropyl-3-hydroxypiperidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one, methyl 4-(5-(4-(4-isopropyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, N-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)methyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, 4-(5-(4-(5-azaspiro[2.4]heptane-5-carbonyl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one, and 4-(5-(4-(1,1-dioxidoisothiazolidin-2-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one.

It should be understood that all isomeric forms are included within the present invention, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a di-substituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

The compounds of the invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of the invention incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within the scope of this invention. Reference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

The present invention relates to compounds which are modulators of PI5P4K. In one embodiment, the compounds of the present invention are inhibitors of PI5P4K.

The invention is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Scheme 1 which comprise different sequences of assembling intermediates or compounds (II) Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.

A compound of formula (I) may be obtained (Scheme 1) by starting from, for example, a compound of formula (II), wherein T represents a coupling metal including, but not limited to, boronic acid (B(OH) 2 ) or a boronic ester (B(OR) 2 ) or a potassium trifluoroborate (BF 3 K) or a MIDA boronate or a stannane and reacting said compound (II) with a compound of formula LG-A, wherein LG represents a leaving group including, but not limited to, halogen (such as chlorine, bromine or iodine), or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate), under the influence of a transition metal catalyst as described in for example Metal - Catalyzed Cross - Coupling Reactions, 2 nd , Completely Revised and Enlarged Edition by A. de Meijere and F. Diederich, Wiley VCH, 2004. The compound of formula (II) may be generated from the corresponding LG-(II), wherein LG represents a leaving group such as, but not limited to, halogen (such as chlorine, bromine or iodine), or an alkyl-, aryl- or haloalkyl-sulfonate (such as triflate), by known methods as described in for example Advanced Organic Chemistry, Part A and B by F. A. Carey and R. J. Sundberg, 5 th edition, Springer Science, 2007.

The reaction may be carried out by coupling of a compound of formula LG-A, with an appropriate aryl or heteroaryl boronic acid or boronic ester or stannane of formula (II). The reaction may also be carried out using a suitable metal catalyst including, but not limited to, palladium catalyst (e.g., bis (di-tert-butylphosphino)ferrocene palladium (II) dichloride, tetrakis(triphenylphosphine)palladium (0), palladium (diphenylphosphino)ferrocene dichloride, palladium(II) acetate or bis(dibenzylideneacetone) palladium (0)). Optionally a suitable ligand, for example, triphenylphosphine, tri-tert-butylphosphine or 2-(dicyclohexylphosphino)biphenyl or 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenylis employed. Suitable bases, including an alkyl amine base, (e.g., triethylamine), an alkali metal or alkaline earth metal carbonate or hydroxide, or phosphate base, (e.g., potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, or potassium phosphate), may be used in the reaction. Said reaction may be performed at a temperature range between +20° C. and +160° C., in suitable solvents, including, without limitation, toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, water, ethanol, N,N-dimethylacetamide or N,N-dimethylformamide, or mixtures thereof. If enantiomerically pure or enriched compound (II) is used in this reaction, an enantiomerically pure or enantiomerically enriched compound (I) is obtained.

Compounds of formula (II) and LG-A are commercially available compounds, or are known in the literature, or they are prepared by standard processes known in the art. A compound of formula (I), (II) or LG-A may be separated into its enantiomers by standard processes known in the art by for example chromatography on a chiral stationary phase.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating a disease or disorder associated with modulation of PI5P4K. The method comprises administering to a patient in need of a treatment for diseases or disorders associated with modulation of PI5P4K an effective amount the compositions and compounds of Formula (I).

In another aspect, the present invention is directed to a method of inhibiting PI5P4K. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treating, preventing, inhibiting or eliminating a disease or disorder in a patient associated with the inhibition of PI5P4K, the method comprising administering to a patient in need thereof an effective amount of a compound of Formula (I). In one embodiment, the disease may be, but not limited to, cancer or cell proliferative disorder, a metabolic disorder, neurodegenerative disease, and an inflammatory disease.

The present invention also relates to the use of an inhibitor of PI5P4K for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of a disease or condition mediated by PI5P4K, wherein the medicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for the manufacture of a medicament for treating, preventing, inhibiting, or eliminating a disease or condition mediated by PI5P4K, wherein the medicament comprises a compound of Formula (I).

Another aspect of the present invention relates to a compound of Formula (I) for use in the manufacture of a medicament for treating a disease associated with inhibiting PI5P4K.

In another aspect, the present invention relates to the use of a compound of Formula (I) in the treatment of a disease associated with inhibiting PI5P4K.

Another aspect of the invention relates to a method of treating cancer. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In another aspect of the invention, the method relates to treating a cell proliferative disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In yet another aspect, the present invention relates to a method of treating a neurodegenerative disease. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

In another aspect, the present invention relates to a method of treating an inflammatory disease or condition. The method comprises administering to a patient in need thereof an effective amount of a compound of Formula (I).

Another aspect of the invention relates to a method of inducing cell cycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific T cell immunity. The method comprises contacting the cells with an effective amount of a compound of Formula (I).

In one embodiment, the present invention relates to the use of an inhibitor of PI5P4K for the preparation of a medicament used in treatment, prevention, inhibition or elimination of a disease or disorder associated with cancer or cell proliferative disorder, a metabolic disorder, neurodegenerative disease, and an inflammatory disease.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of cancers or cell proliferative disorders including, but not limited to, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of neurodegenerative diseases including, but not limited to, brain trauma, spinal cord trauma, trauma to the peripheral nervous system, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffman disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru and fatal familial insomnia, age-related dementia, vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica or frontal lobe dementia, neurodegenerative disorders resulting from cerebral ischemia or infaction including embolic occlusion and thrombotic occlusion as well as intracranial hemorrhage of any type, intracranial and intravertebral lesions, hereditary cerebral angiopathy, normeuropathic hereditary amyloid, Down's syndrome, macroglobulinemia, secondary familial Mediterranean fever, Muckle-Wells syndrome, multiple myeloma, pancreatic- and cardiac-related amyloidosis, chronic hemodialysis arthropathy, and Finnish and Iowa amyloidosis.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of inflammatory disease. In some embodiments, the inflammatory disease is associated with a metabolic disorder. In some embodiments the treated inflammation is associated with, but not limited to, Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, and macular edema.

In yet another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of a metabolic disease including, but not limited, Type II diabetes, insulin resistance cardiovascular disease, arrhythmia, atherosclerosis, coronary artery disease, hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, and macular edema.

In another embodiment, the present invention relates to a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier used for the treatment of inflammatory disease associated with inflammatory disease. In some embodiments the treated inflammation is associated with, but not limited to, ileitis, ulcerative colitis, Barrett's syndrome, or Crohn's disease.

In some embodiments, the patient is selected for treatment based on gene amplification and/or elevated tumor expression of PI5P4K. In other embodiments, the patient is selected for treatment based on gene amplification and/or elevated tumor expression of PI5P4Ku gene, PI5P4KP gene, or PI5P4Ky gene. In other embodiments, the patient is selected for the treatment based on tumor expression of p53 mutations.

In some embodiments, administration of a compound of Formula (I) or a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier induces a change in the cell cycle or cell viability.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease or disorder associated with modulation of PI5P4K including, cancer or cell proliferative disorder, a metabolic disorder, neurodegenerative disease, and an inflammatory disease, comprising administering to a patient suffering from at least one of said diseases or disorder a compound of Formula (I).

One therapeutic use of the compounds or compositions of the present invention which inhibit PI5P4K is to provide treatment to patients or subjects suffering from c cancer or cell proliferative disorder, a metabolic disorder, neurodegenerative disease, and an inflammatorydisease.

The disclosed compounds of the invention can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.

Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a Compound of the Invention and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also; c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion, etc. For example, the disclosed compound is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension. Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in U.S. Pat. No. 5,262,564 which is hereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonal antibodies as individual carriers to which the disclosed compounds are coupled. The disclosed compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, poly(hydroxypropyl)methacrylamide-phenol, poly(hydroxyethyl)-aspanamide phenol, or poly(ethyleneoxide)-polylysine substituted with palmitoyl residues. Furthermore, the Disclosed compounds can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. In one embodiment, disclosed compounds are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.

Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular disclosed compound employed. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.

The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. All solvents used were of analytical grade and commercially available anhydrous solvents were routinely used for reactions. Starting materials were available from commercial sources, or prepared according to literature procedures. Room temperature refers to +20-25° C. Solvent mixture compositions are given as volume percentages or volume ratios.

Microwave heating was performed in a Biotage Initiator microwave cavity producing continuous irradiation at 2.45 GHz. It is understood that microwaves may be used for the heating of reaction mixtures.

Straight phase chromatography was manually performed on Merck Silica gel 60 (0.040-0.063 mm), or automatically using an ISCO Combiflash® Companion™ system using SiliaSep™ normal-phase flash columns using the solvent system indicated.

NMR spectra were recorded on a 400 MHz (or higher field) NMR spectrometer fitted with a probe of suitable configuration. Spectra were recorded at ambient temperature unless otherwise stated. Chemical shifts are given in ppm down- and upfield from TMS (0.00 ppm). The following reference signals were used: the residual solvent signal of DMSO-d6 δ 2.5, CDCl3 δ 7.26 or Methanol-d4 δ 3.31. Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet and broad, respectively.

High pressure liquid chromatography (HPLC) was performed on a reverse phase column. A linear gradient was applied using for example mobile phase A (aqueous 0.1% NH 3 or aqueous 0.1% acetic acid or aqueous 0.1% formic acid) and B (acetonitrile or methanol). Mass spectrometer (MS) analyses were performed in positive ion mode using electrospray ionization (ES+).

Preparative chromatography was run on a Gilson-PREP GX271 or GX281 with Trilution 1c as software on a reverse phase column. A linear gradient was applied using for example mobile phase A (aqueous 0.1% NH 3 or aqueous 0.1% acetic acid or aqueous 0.1% formic acid) and B (acetonitrile or methanol).

Preparative chiral chromatography for separation of enantiomers was run on a Thar SFC using supercritical fluid chromatography on a chiral stationary phase. A linear gradient was applied using mobile phase A (carbon dioxide) and B (acetonitrile or methanol or ethanol or 2-propanol or any mixtures thereof). Additives (such as diethyl amine or isopropyl amine or ammonia or formic acid or TFA) may be used.

Abbreviations used in the following examples and elsewhere herein are:

AcOH acetic acid AlMe 3 trimethylaluminum Amphos bis(4-(N,N-Dimethylamino)phenyl)di-tert-butyl phosphine anh. anhydrous atm atmosphere aq. aqueous br broad B 2 Pin 2 bis(pinacolato)diboron BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene Boc tert-butyloxycarbonyl BrettPhos 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl BrettPhos Pd G3 [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate brine saturated aqueous sodium chloride n-BuLi n-butyllithium n-BuOH n-butanol Calc'd calculated cataCXium A-Pd-G2 chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) CDCl 3 deuterated chloroform CDI carbonyldiimidazole Chloroform-d deuterated chloroform d doublet dd doublet of doublets dt doublet of triplets DCE dichloroethane DCM dichloromethane DIAD diisopropyl azodicarboxylate DIPEA N,N-diisopropylethylamine DMAc N,N-dimethyl acetamide DMAP N,N-dimethylpyridin-4-amine DME 1,2-dimethoxyethane DMEDA N,N′-dimethylethylenediamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d 6 deuterated dimethyl sulfoxide Dowtherm® A eutectic mixture of 26.5% diphenyl and 73.5% diphenyl oxide EDA ethylenediamine EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et 2 O diethyl ether EtOAc ethyl acetate EtOH ethanol ESI electrosprayionization g gram h hour(s) H hydrogen 1 H NMR nuclear magnetic resonance (proton nucleus) HATU [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBTU 3-[bis(dimethylamino)methylene]-3H-benzotriazol-1-oxide hexafluorophosphate Hoveyda Grubbs dichloro[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene](2-cat. 2 nd gen. isopropoxyphenylmethylene)ruthenium(II) HOBt hydroxybenzotriazole HPLC high pressure (or performance) liquid chromatography Hz hertz J coupling constant KHMDS potassium hexamethyldisilazide KOAc potassium acetate LCMS liquid chromatography mass spectrometry LHMDS lihtium hexamethyldisilazide [#] M molar concentration m multiplet [M+H] + molecular ion plus hydrogen [M-tBu+H] + molecular ion minus tert-butyl plus hydrogen mCPBA meta-chloroperoxybenzoic acid Me 2 NH dimethylamine Me 4 NBr tetramethylammonium bromide MeCN acetonitrile Meldrum's acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeNH 2 methylamine MeOH methanol Methanol-d4 deuterated methanol 2-MeTHF 2-methyl tetrahydrofuran mg milligram MHz megahertz min min mmol millimole mL milliliter MS mass spectrometry MS ES mass spectrometry electrospray Ms 2 O methanesulfonic anhydride MTBE methyl tert-butyl ether MW microwave m/z mass-to-charge ratio μL microliter N 2 nitrogen NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance PEPPSI-iPr [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride PdCl 2 (Amphos) bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(O) Pd(OAc) 2 palladium(II) acetate PdCl 2 (dppf) [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PdCl 2 (MeCN) 2 bis(acetonitrile)dichloropalladium(II) PdCl 2 (PPh 3 ) 2 bis(triphenylphosphinepalladium(II) dichloride Pd(P(Cy) 3 ) 2 Cl 2 dichlorobis(tricyclohexylphosphine)palladium(II) Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium(O) Pd(t-Bu 3 P) 2 bis(tri-tert-butylphosphine)palladium(O) pH potential of hydrogen PMB 4-methoxybenzyl PMBCl 4-methoxybenzyl chloride ppm parts per million prep preparative py pyridine q quartet qd quartet of doublets quant. quantitative quin. quintuplet quind quintuplet of doublets Rt retention time rt room temperature s singlet sat. saturated sat. aq. saturated aqueous SEMCl 2-(trimethylsilyl)ethoxymethyl chloride t triplet t-BuLi tert-butyllithium td triplet of doublets TMS trimethylsilyl TMSCl trimethylsilyl chloride tt triplet of triplets T3P polyphosphonic anhydride TBAB tetrabutylammonium bromide TEA triethylamine TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer chromatography TPPO triphenylphosphine oxide XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

A mixture of 4-iodo-N,N-dimethyl-benzamide (1.04 g, 3.78 mmol), (5-bromo-3-pyridyl)boronic acid (763 mg, 3.78 mmol), Pd(PPh 3 ) 4 (218 mg, 0.19 mmol) and K 2 CO 3 (1.3 g, 9.41 mmol) in n-BuOH (12 ml) and H 2 O (3 ml) was stirred at 90° C. for 2.5 h. The reaction mixture was filtered through celite and rinsed with EtOAc. The organic phase was washed with brine, dried over MgSO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (900 mg, 78%). MS ES+m/z 305 [M+H] + .

Step 2: Intermediate 2—N,N-dimethyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]benzamide

4-(5-Bromo-3-pyridyl)-N,N-dimethyl-benzamide (490 mg, 1.61 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (570 mg, 2.24 mmol), PdCl 2 (dppf) (60 mg, 0.08 mmol) and KOAc (280 mg, 2.85 mmol) were taken up in 1,4-dioxane (10 ml) and the resulting mixture was stirred at 90° C. for 4 h. When cooled to rt the mixture was filtered through celite and the filter cake rinsed with EtOAc. The filtrate was concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (184 mg, 33%). MS ES+m/z 353 [M+H] + .

N,N-dimethyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]benzamide (70 mg, 0.2 mmol), 4-chloro-1,6-naphthyridine (36 mg, 0.22 mmol), Pd(PPh 3 ) 4 (12 mg, 0.01 mmol) and K 2 CO 3 (69 mg, 0.5 mmol) were taken up in 1,4-dioxane (1 ml) and water (0.25 ml) and the resulting mixture was stirred at 90° C. for 1 h. When cooled to rt the mixture was filtered through celite and the filter cake rinsed with EtOAc. The filtrate was concentrated and purified by preparative HPLC to give the product as a solid (18 mg, 26%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 3.08 (s, 3H), 3.16 (s, 3H), 7.63 (m, J=8.20 Hz, 2H), 7.81 (d, J=4.41 Hz, 1H), 7.92 (m, J=8.20 Hz, 2H), 8.10 (d, J=5.99 Hz, 1H), 8.45 (t, J=1.89 Hz, 1H), 8.82 (d, J=6.12 Hz, 1H), 8.85 (s, 1H), 9.11 (d, J=2.21 Hz, 1H), 9.24 (d, J=4.73 Hz, 1H), 9.33 (s, 1H). MS ES+m/z 355 [M+H] + .

K 2 CO 3 (105 mg, 0.76 mmol) and iodomethane (60 μl, 0.96 mmol) were added to a solution of methyl 4-chloro-H-pyrrolo[2,3-b]pyridine-2-carboxylate(160 mg, 0.76 mmol) in THF (5 ml) and the resulting mixture was stirred at 50° C. for 2 h. More iodomethane (60 μl, 0.96 mmol) and TEA (250 μl, 1.8 mmol) were added and stirring continued at 50° C. overnight. LiOH H 2 O (159 mg, 3.8 mmol), MeOH (2 ml) and water (2 ml) were added and stirring continued at 50° C. for 4 h. The mixture was concentrated and the resulting residue was taken up in water (5 ml) and EtOAc (5 ml). The aqueous layer was separated and the organic layer extracted with 1M aq. NaOH (5 ml). The pH of the combined aqueous layer was adjusted to ˜3 using conc. HCl and the milky suspension was kept in refrigerator for 1 h. The formed precipitate was filtered off and dried to give the product as a solid (110 mg, 69%). MS ES+m/z 211 [M+H] + .

4-Chloro-1-methyl-pyrrolo[2,3-b]pyridine-2-carboxylic acid (110 mg, 0.52 mmol), DIPEA (130 μl, 0.75 mmol) and methylamine (33% in EtOH, 90 μl, 0.72 mmol) were taken up in EtOAc (2 ml). DMF (1 ml) was added to give a clear solution. Propylphosphonic anhydride (50% in EtOAc, 350 μl, 0.59 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was concentrated and the product was purified on a silica gel column eluted with 0-50% EtOAc in Heptane to give the product as a solid (60 mg, 51%). MS ES+m/z 224 [M+H] + .

Step 3: 4-(5-(4-(dimethylcarbamoyl)phenyl)pyridin-3-yl)-N,1-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described for Example 7, replacing 4-chloro-1,6-naphthyridine for 4-chloro-N,1-dimethyl-pyrrolo[2,3-b]pyridine-2-carboxamide and using PdCl 2 (PPh 3 ) 2 instead of Pd(PPh 3 ) 4 , in n-BuOH, to give the product as a solid (26 mg, 23%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.77-2.82 (m, 3H), 3.00 (br d, J=18.60 Hz, 6H), 4.11 (s, 3H), 7.37-7.41 (m, 1H), 7.53 (d, J=4.73 Hz, 1H), 7.58 (d, J=8.20 Hz, 2H), 7.95 (d, J=8.20 Hz, 2H), 8.45 (t, J=2.05 Hz, 1H), 8.51-8.57 (m, 1H), 8.58-8.65 (m, 1H), 9.03 (d, J=2.21 Hz, 1H), 9.07 (d, J=1.89 Hz, 1H). MS ES+m/z 414 [M+H] + .

Example 14: 4-(5-(4-(dimethylcarbamoyl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide

Step 1: Intermediate 5—Methyl 5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]furan-2-carboxylate

Ethyl 5-aminofuran-2-carboxylate (2 g, 12.9 mmol) was added to a mixture of triethyl orthoformate (10 ml, 60.1 mmol) and 2-propanol (10 ml) at rt. Meldrum's acid (2.25 g, 15.6 mmol) was added and the resulting mixture was stirred at 100° C. for 1.5 h. When cooled to rt the precipitate was filtered off, washed sequentially with 2-propanol (2×3 ml), Pentane (4 ml) and dried to give the product as a solid (2.8 g, 67%). 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.77 (s, 6H), 3.91 (s, 3H), 6.08 (d, J=3.78 Hz, 1H), 7.22 (d, J=3.47 Hz, 1H), 8.64 (d, J=13.56 Hz, 1H), 11.51 (br d, J=12.61 Hz, 1H). MS ES+m/z 238 [M+H]+(NH 3 mobile phase).

Methyl 5-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylamino]furan-2-carboxylate (2.8 g, 9.48 mmol) was taken up in Dowtherm® A (20 ml) and the resulting mixture was stirred at 200° C. for 1 h, followed by 220° C. for 15 min. When cooled to rt Et 2 O (10 ml) was added and the precipitate was filtered off, washed with Et 2 O (2×5 ml) and dried to give the product as a solid (1.53 g, 84%). MS ES+m/z 194 [M+H] + .

Methyl 4-hydroxyfuro[2,3-b]pyridine-2-carboxylate (250 mg, 1.29 mmol) and LiOH H 2 O (163 mg, 3.88 mmol) were taken up in THF (5 ml), MeOH (1 ml) and water (0.5 ml) and the resulting mixture was stirred at 50° C. overnight. The mixture was concentrated and the residue was taken up in SOCl 2 (5 ml, 68.5 mmol) and 2-MeTHF (5 ml). DMF (3 drops) was added and the mixture refluxed for 1 h. When cooled to rt the mixture was concentrated and the resulting residue was suspended in THF (5 ml) and added slowly to a solution of 40% aq. methylamine (1 ml, 11.6 mmol) in THF (5 ml) at 0° C. The resulting mixture was stirred at 0° C. for 30 min. Sat. aq. NH 4 Cl (5 ml) and EtOAc (5 ml) were added and the organic layer separated. The aqueous layer was diluted with water to give a clear solution and extracted with EtOAc (2×5 ml). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was triturated with Et 2 O to give the product as a solid (225 mg, 83%). MS ES+m/z 211 [M+H] + .

The title compound was prepared as described for Example 7, replacing 4-chloro-1,6-naphthyridine for 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide and using PdCl 2 (dppf) instead of Pd(PPh 3 ) 4 , in n-BuOH, to give the product as a solid (3 mg, 2%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.82-2.86 (m, 3H), 2.98-3.03 (m, 6H), 7.56-7.63 (m, 2H), 7.83-7.85 (m, 2H), 7.96-8.00 (m, 2H), 8.51 (t, J=2.05 Hz, 1H), 8.60 (d, J=5.36 Hz, 1H), 8.87 (q, J=4.41 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H), 9.11 (d, J=1.89 Hz, 1H). MS ES+m/z 401 [M+H] + .

Example 15:4-(5-(5-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-N,N-dimethylbenzamide

N-bromosuccinimide (863 mg, 4.85 mmol) was added to a solution of 1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (518 mg, 3.23 mmol) in DCM (3 mL) at 0° C. and the resulting mixture was stirred for 40 min. Sat. aq. Na 2 S 2 O 3 was added and the mixture extracted with EtOAc. The combined organics were dried over MgSO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (697 mg, 90%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 2.66-2.80 (m, 3H), 7.61 (s, 1H), 8.51 (d, J=1.89 Hz, 1H), 8.92-8.96 (m, 1H). MS ES+m/z 239 [M+H] + .

NaBH 4 (130 mg, 3.44 mmol) was added portion wise to a solution of 1-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (411 mg, 1.72 mmol) in methanol (5 ml) at 0° C. and the resulting mixture was stirred at rt for 1 h. The mixture was concentrated and the resulting residue was dissolved in DCM and water. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organics were dried over MgSO 4 , filtered and concentrated to give the product as a solid (361 mg, 87%). MS ES+m/z 241 [M+H] + .

The title compound was prepared as described for Example 7, replacing 4-chloro-1,6-naphthyridine for 1-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol and using PdCl 2 (Amphos) instead of Pd(PPh 3 ) 4 , to give the product as a solid (8 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.44 (d, J=6.62 Hz, 3H), 3.00 (br d, J=17.02 Hz, 6H), 4.92-4.97 (m, 1H), 5.23 (d, J=4.41 Hz, 1H), 7.54-7.60 (m, 2H), 7.89-7.93 (m, 2H), 8.14 (s, 1H), 8.29-8.32 (m, 2H), 8.35 (t, J=2.05 Hz, 1H), 8.80 (d, J=2.21 Hz, 1H), 9.00 (d, J=1.89 Hz, 1H), 12.02 (br s, 1H). MS ES+m/z 387 [M+H] + .

5-(4-Pyridyl)pyridin-2-amine (780 mg, 4.56 mmol) and NBS (811 mg, 4.56 mmol) were taken up in DMF (5 ml) and the resulting mixture was stirred at rt overnight. Water (30 ml) and DCM (25 ml) were added and the mixture filtered. The organic layer was separated and the aqueous layer extracted with DCM (2×20 ml). The mixture was filtered every time before separation of the layers. The combined organics were washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was taken up in DCM (3 ml) and stirred at rt for 10 min. The precipitate was filtered off, washed with DCM and dried to give the product as a solid (130 mg, 11%). MS ES+m/z 250 [M+H] + .

3-Bromo-5-(4-pyridyl)pyridin-2-amine (50 mg, 0.2 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (42 mg, 0.22 mmol), PdCl 2 (Amphos) (7 mg, 0.01 mmol) and K 2 CO 3 (69 mg, 0.5 mmol) were taken up in DMF (1.5 ml) and water (0.5 ml). The resulting mixture was heated in a microwave reactor at 150° C. for 1 h. When cooled to rt the mixture was poured into water (10 ml) and extracted with EtOAc (3×5 ml). The combined organics were washed with water, brine, dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ=8.54 (d, J=5.7 Hz, 2H), 8.50 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.9 Hz, 1H), 7.72 (d, J=5.7 Hz, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 6.14 (s, 2H), 3.00 (br s, 6H). MS ES+m/z 319 [M+H] + .

The title compound was prepared as described in Example 16, starting from 5-bromo-3-iodo-pyridin-2-amine and [4-(dimethylcarbamoyl)phenyl]boronic acid, in 1,4-dioxane, water, EtOH (6:3:1) and heating in a microwave reactor at 130° C. for 1 h, to give the product as a solid (412 mg, 77%). MS ES+m/z 320 [M+H] + .

4-(2-Amino-5-bromo-3-pyridyl)-N,N-dimethyl-benzamide (260 mg, 0.81 mmol), (6-methoxy-3-pyridyl)boronic acid (149 mg, 0.97 mmol), PdCl 2 (Amphos) (29 mg, 0.04 mmol) and K 2 CO 3 (337 mg, 2.44 mmol) were taken up in 1,4-dioxane:H 2 O:EtOH (6:3:1, 2 ml) and the resulting mixture was heated in a microwave reactor at 130° C. for 1 h. When cooled to rt the mixture was diluted with EtOAc (20 ml) and water (10 ml). The organic layer was separated and the aqueous layer extracted with EtOAc (2×20 ml). The combined organics were washed with water and brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was dissolved in DCM (4 ml), BBr 3 (1.25 ml, 12.96 mmol) was added and the mixture stirred at rt overnight. Aq. 2M HCl (5 mL) was added and the mixture heated in a microwave reactor at 100° C. for 30 min. Water (20 ml) and DCM (20 ml) were added and the pH of the aqueous phase was adjusted to 8 with aq. 6M KOH. The organic layer was separated and the aqueous layer extracted with DCM (3×15 ml), the combined organics were washed with brine, dried over MgSO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (0.8 mg, 0.3%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 3.06-3.13 (m, 3H), 3.16 (s, 3H), 6.63 (d, J=9.46 Hz, 1H), 7.56-7.61 (m, 2H), 7.61-7.66 (m, 3H), 7.75 (d, J=2.52 Hz, 1H), 7.88 (dd, J=9.30, 2.68 Hz, 1H), 8.16 (d, J=2.52 Hz, 1H). MS ES+m/z 335 [M+H] + .

The title compound was prepared as described in Example 16, starting from 4-(2-amino-5-bromo-3-pyridyl)-N,N-dimethyl-benzamide and 3,6-dihydro-2H-pyran-4-ylboronic acid, in 1,4-dioxane, water, EtOH (6:3:1) and heating in a microwave reactor at 130° C. for 1 h, to give the product as a solid (9 mg, 13%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 2.00 (s, 1H), 2.51 (br dd, J=4.41, 2.52 Hz, 2H), 3.06-3.12 (m, 3H), 3.12-3.24 (m, 3H), 3.93 (t, J=5.52 Hz, 2H), 4.30 (q, J=2.73 Hz, 2H), 6.13 (br s, 1H), 7.51-7.62 (m, 5H), 8.05 (br s, 1H). MS ES+m/z 324 [M+H] + .

6-Bromo-N,N-dimethyl-pyridine-3-carboxamde (394 mg, 1.72 mmol), (2-amino-3-pyridyl)boronic acid (220 mg, 1 mmol), PdCl 2 (Amphos) (122 mg, 0.17 mmol) and K 2 CO 3 (536 mg, 3.88 mmol) was taken up inn-BuOH (3 ml) and water (0.75 ml) and the resulting mixture was stirred at 90° C. for 5 h. When cooled to rt EtOAc (20 ml) and water (15 ml) were added and the organic layer separated. The aqueous layer was extracted with EtOAc (2×15 ml) and the combined organics were concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as an oil (135 mg, 560%). MS ES+m/z 243 [M+H] + .

A solution of Br 2 (58 μl, 1.14 mmol) in AcOH (0.58 ml) was added dropwise to a solution of 6-(2-amino-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamde (250 mg, 1.0 mmol) in AcOH (3 ml) at rt and the resulting mixture was stirred for 4 h. Sat. aq. Na 2 S 2 O 3 (5 ml) was added followed by water (10 ml) and EtOAc (20 ml). The aqueous layer was separated, the pH adjusted to ˜9 using aq. 2 M NaOH followed by extraction with EtOAc (2×30 ml). The combined organics were washed with brine, dried over MgSO 4 , filtered and concentrated to give the product as a solid (228 mg, 69%). MS ES+m/z 321 [M+H] + .

The title compound was prepared as described in Example 16, starting from 6-(2-amino-5-bromo-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamide and 4-pyridylboronic acid, in 1,4-dioxane, water, EtOH (6:3:1) and heating in a microwave reactor at 130° C. for 1 h, to give the product as a solid (8 mg, 18%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 3.03 (br d, J=11.98 Hz, 6H), 7.76-7.92 (m, 4H), 8.01 (dd, J=8.20, 1.58 Hz, 1H), 8.29 (d, J=8.51 Hz, 1H), 8.46-8.54 (m, 1H), 8.55-8.64 (m, 3H), 8.74 (s, 1H). MS ES+m/z 320 [M+H] + .

The title compound was prepared as described in Example 16, starting from 6-(2-amino-5-bromo-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamide and quinoline-4-boronic acid, in DME and water, and heating in a microwave reactor at 130° C. for 1.5 h, to give the product as a solid (8 mg, 7%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 3.09 (s, 3H), 3.14 (s, 3H), 7.54 (d, J=4.41 Hz, 1H), 7.63 (m, J=7.60, 7.60 Hz, 1H), 7.81 (m, J=7.70, 7.70 Hz, 1H), 7.93-7.98 (m, 1H), 8.00-8.12 (m, 3H), 8.24-8.25 (m, 1H), 8.27-8.28 (m, 1H), 8.76 (d, J=1.58 Hz, 1H), 8.88 (d, J=4.41 Hz, 1H). MS ES+m/z 370 [M+H] + .

Step 1: Intermediate 14—2′-amino-N,N-dimethyl-5′-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

The title compound was prepared as described in Intermediate 12, starting from 6-(2-amino-5-bromo-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamide and 1-(benzenesulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, to give the product as an oil (40 mg, 32%). MS ES+m/z 499 [M+H] + .

A mixture of 6-[2-amino-5-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-pyridyl]-N,N-dimethyl-pyridine-3-carboxamide (40 mg, 0.08 mmol) and 5.6 M dimethyl amine EtOH (2 ml) was heated in a microwave reactor at 120° C. for 15 min. Water (1 ml) and LiOH monohydrate (10 mg, 0.24 mmol) was added and the mixture was stirred at 50° C. for 1 h. EtOAc (10 ml) and water (10 ml) were added and the organic layer separated. The aqueous layer was extracted with EtOAc (10 ml) and the combined organics were washed with brine, dried over MgSO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (5 mg, 17%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 3.10 (s, 3H), 3.15 (s, 3H), 6.71 (d, J=3.47 Hz, 1H), 7.26 (d, J=5.04 Hz, 1H), 7.46 (d, J=3.47 Hz, 1H), 7.99 (dd, J=8.20, 2.21 Hz, 1H), 8.07 (d, J=8.20 Hz, 1H), 8.24 (d, J=5.04 Hz, 1H), 8.45 (d, J=1.89 Hz, 1H), 8.50 (d, J=2.21 Hz, 1H), 8.76 (d, J=1.58 Hz, 1H). MS ES+m/z 359 [M+H] + .

1-(6-Chloro-3-pyridyl)pyrrolidin-2-one (2.47 g, 12.5 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (3.87 g, 17.6 mmol), K 2 CO 3 (3.47 g, 25.1 mmol) and Pd(dppf)Cl 2 (918 mg, 1.25 mmol) were taken up in n-BuOH (36 ml) and water (12 ml) and the mixture was stirred at 90° C. overnight. When cooled to rt the mixture was filtered through celite and washed with DCM. The filtrate was concentrated and the resulting residue was dissolved in DCM, washed with brine, dried over MgSO 4 , filtered and concentrated. The resulting residue was dissolved in DCM (200 ml), cooled to 0° C. and a solution of Br 2 (645 uL, 12.5 mmol) was added slowly. The reaction mixture was stirred for 1 h and then basified to pH 9 using aq. 1M NaOH. Sat. aq. NaHCO 3 (10 mL) and sat. aq. Na 2 S 2 O 3 (1 mL) were added and the organic layer separated, washed with brine, dried over MgSO 4 , filtered concentrated and crystallized from DCM:pentane to give the product as a solid (1.29 g). The mother liquor was concentrated and purified on a silica gel column to give additional product (670 mg). The crops were combined to give the product as a solid (1.96 g, 47%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.13 (quin, J=7.57 Hz, 2H), 2.53-2.57 (m, 2H), 3.93 (t, J=7.09 Hz, 2H), 7.59 (br s, 2H), 8.04-8.08 (m, 2H), 8.17 (d, J=2.21 Hz, 1H), 8.27 (dd, J=8.83, 2.84 Hz, 1H), 8.94 (d, J=2.52 Hz, 1H). MS ES+m/z 333 [M+H] + .

Step 1: Intermediate 15—1-[6-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-3-pyridyl]pyrrolidin-2-one

The title compound was prepared as described in Intermediate 2, starting from 1-[6-(2-amino-5-bromo-3-pyridyl)-3-pyridyl]pyrrolidin-2-one, replacing 1,4-dioxane for toluene and stirring the mixture at 110° C. overnight. Crystallization from 2-propanol/heptane gave the product as a solid (744 mg, 55%). MS ES+m/z 381 [M+H] + .

1-[6-[2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]-3-pyridyl]pyrrolidin-2-one (146 mg, 0.38 mmol), 3-bromothieno[2,3-b]pyridine (82 mg, 0.38 mmol), K 2 CO 3 (106 mg, 0.77 mmol) and PdCl 2 (dppf) (28 mg, 0.04 mmol) were taken up in n-BuOH (2 ml) and water (0.5 ml) and stirred at 90° C. for 1 h. When cooled to rt the mixture was filtered through celite and washed with DCM. The filtrate was evaporated and purified by preparative HPLC to give the product as a solid (9 mg, 6%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.10-2.16 (m, 2H), 2.53-2.56 (m, 2H), 3.92 (q, J=7.25 Hz, 2H), 7.45-7.55 (m, 1H), 7.59 (br s, 2H), 7.98 (s, 1H), 8.12 (d, J=8.83 Hz, 1H), 8.21-8.24 (m, 1H), 8.24-8.28 (m, 1H), 8.28-8.37 (m, 2H), 8.63 (dd, J=4.57, 1.42 Hz, 1H), 8.95-8.96 (m, 1H). MS ES+m/z 388 [M+H] + .

A mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (9.4 g, 32.7 mmol), 3,5-dibromopyridine (7.04 g, 29.7 mmol) and K 2 CO 3 (10.7 g, 77.2 mmol) in n-BuOH (20 mL) and water (5 mL) was degassed with nitrogen for 5 min. PdCl 2 (PPh 3 ) 2 (555 mg, 0.76 mmol) was added and the resulting mixture was stirred at 70° C. for 1 h. When cooled to rt the precipitate was filtered off and washed sequentially with water, 2-propanol and pentane and dried to give the product as a solid (9.96 g, quant.). MS ES+m/z 317 [M+H] + .

Step 2: Intermediate 17—1-[4-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one

A mixture of 1-[4-(5-bromo-3-pyridyl)phenyl]pyrrolidin-2-one (9.42 g, 29.7 mmol), bis(pinacolato)diboron (9.05 g, 35.6 mmol) and KOAc (8.74 g, 89.1 mmol) were taken up in toluene (200 ml) and degassed with nitrogen for 10 min. PdCl 2 (dppf) (1.09 g, 1.48 mmol) was added and the resulting mixture was stirred at 90° C. for 1 h. When cooled to rt EtOAc (25 ml) and celite (3 spoons) were added and the mixture filtered through celite. The celite was rinsed with EtOAc (2×10 ml) and the filtrate was washed with water (25 mL), sat. aq. NaHCO 3 (25 mL), brine, stirred with MgSO 4 and active charcoal (2 g), filtered through celite and concentrated. The residue was suspended in Et 2 O (15 ml) and pentane (10 ml) was added. The resulting mixture was stirred at rt for 2 h and the precipitate was filtered off, washed sequentially with Et 2 O/Pentane (1:1, 20 ml), pentane (10 ml) and dried to give the product as a solid (5.77 g, 53% yield). MS ES+m/z 365 [M+H] + .

The title compound was prepared as described in Example 23, replacing 3-bromothieno[2,3-b]pyridine for 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine, to give the product as a solid (2 mg, 2%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.15 (m, 2H), 2.52-2.57 (m, 2H), 3.92 (t, J=7.09 Hz, 2H), 7.81-7.86 (m, 2H), 7.86-7.93 (m, 2H), 8.25 (s, 1H), 8.28-8.36 (m, 2H), 8.46 (d, J=2.21 Hz, 1H), 8.80 (d, J=2.21 Hz, 1H), 8.94 (d, J=1.89 Hz, 1H), 12.40 (br s, 1H). MS ES+m/z 389 [M+H] + .

4-Chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.26 mmol), 2-bromoethan-1-ol (462 μl, 6.51 mmol) and K 2 CO 3 (1.35 g, 9.77 mmol) were taken up in DMF (5 ml) and the resulting mixture was stirred at 80° C. for 2 h. When cooled to rt water (20 ml) and EtOAc (5 ml) were added and the organic layer separated. The aqueous layer was extracted with EtOAc (2×5 ml) and the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (540 mg, 84%). MS ES+m/z 198 [M+H] + .

Step 2: 1-(4-(5-(1-(2-hydroxyethyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 2-(4-chloropyrazolo[3,4-b]pyridin-1-yl)ethanol, to give the product as a solid (49 mg, 45%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.87-3.93 (m, 4H), 4.58 (t, J=5.99 Hz, 2H), 4.89 (br s, 1H), 7.60 (d, J=4.73 Hz, 1H), 7.80-7.86 (m, 2H), 7.90-7.94 (m, 2H), 8.43-8.46 (m, 1H), 8.46-8.47 (m, 1H), 8.67 (d, J=4.73 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H), 9.06 (d, J=2.21 Hz, 1H). MS ES+m/z 400 [M+H] + .

Example 45: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

Step 1: Intermediate 19—Methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-chloro-pyrrolo[2,3-b]pyridine-2-carboxylate

Methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2 g, 9.50 mmol) was taken up in DMF (30 ml), cooled to 0° C. and KOtBu (1.1 g, 9.80 mmol) was added. After 30 min tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate (2.3 g, 10.3 mmol) was added, the cooling bath removed, and the mixture stirred at rt for 1.5 h. Aq. 10% citric acid (50 ml) and EtOAc (30 ml) were added and the organic layer separated. The aqueous layer was extracted with EtOAc (3×15 ml) and the combined organics were washed with water (3×20 ml), brine (20 ml), dried over Na 2 SO 4 , filtered and concentrated to give the product as a gum, which solidified upon standing (2.9 g, 86%). MS ES+m/z 354 [M+H] + .

TFA (6 ml, 80.8 mmol) was added to a solution of methyl 1-[2-(tert-butoxycarbonylamino)ethyl]-4-chloro-pyrrolo[2,3-b]pyridine-2-carboxylate (2.9 g, 8.20 mmol) in DCM (20 ml) at rt and the mixture was stirred at rt overnight. The mixture was concentrated and the resulting residue was taken up in MeOH (20 ml). K 2 CO 3 (4.5 g, 32.6 mmol) was added portion wise and the mixture was stirred at rt for 3 h. Water (20 ml) and EtOAc (30 ml) were added and the organic layer separated. The aqueous layer was extracted with EtOAc (2×10 ml) and the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. Recrystallization from 2-propanol (10 ml) and water (5 ml) gave the product as a solid (1.05 g, 58%). MS ES+m/z 222 [M+H] + .

Step 3: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-8,9-dihydro-7H-pyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one, to give the product as a solid (19 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.13 (m, 2H), 2.51-2.58 (m, 2H), 3.66-3.73 (m, 2H), 3.87-3.93 (m, 2H), 4.39-4.45 (m, 2H), 7.16 (s, 1H), 7.53 (d, J=4.73 Hz, 1H), 7.81-7.86 (m, 2H), 7.86-7.91 (m, 2H), 8.33 (br s, 1H), 8.39 (t, J=2.05 Hz, 1H), 8.56 (d, J=4.73 Hz, 1H), 8.94 (d, J=1.89 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H). MS ES+m/z 424 [M+H] + .

Example 46: 7-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

60% NaH in mineral oil (69 mg, 1.8 mmol) was added to a solution of 4-chloro-8,9-dihydro-7H-pyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one (100 mg, 0.45 mmol) in THF (2 ml) at rt. After 10 min, iodomethane (31 μl, 0.5 mmol) was added and the resulting mixture was stirred at rt overnight. Sat. aq. NH 4 Cl was added and the mixture extracted with EtOAc. The combined organics were dried over MgSO 4 , filtered and concentrated to give the product as a solid (108 mg, quant.). MS ES+m/z 236 [M+H] + .

Step 2: 7-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-7-methyl-8,9-dihydropyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one, to give the product as a solid (52 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.07-3.11 (m, 3H), 3.83-3.93 (m, 4H), 4.42-4.51 (m, 2H), 7.14 (s, 1H), 7.52 (d, J=4.73 Hz, 1H), 7.78-7.86 (m, 2H), 7.86-7.93 (m, 2H), 8.36-8.40 (m, 1H), 8.55 (d, J=5.04 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H), 8.95-9.11 (m, 1H). MS ES+m/z 438 [M+H] + .

Example 47: 7-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

Step 1: Intermediate 22—4-Chloro-7-(cyclopropylmethyl)-8,9-dihydropyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one

The title compound was prepared as described for Intermediate 21, replacing iodomethane for bromomethyl cyclopropane, using 4 eq. of NaH and refluxing the mixture over weekend, to give the product (138 mg, quant.). MS ES+m/z 276 [M+H] + .

Step 2: 7-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-7-(cyclopropylmethyl)-8,9-dihydropyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one, to give the product as a solid (18 mg, 14%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.30-0.36 (m, 2H), 0.47-0.54 (m, 2H), 1.05-1.16 (m, 1H), 2.07-2.13 (m, 2H), 2.51-2.58 (m, 2H), 3.44 (d, J=6.94 Hz, 2H), 3.90 (t, J=7.09 Hz, 2H), 3.93-3.98 (m, 2H), 4.46-4.54 (m, 2H), 7.16 (s, 1H), 7.54 (d, J=4.73 Hz, 1H), 7.82-7.87 (m, 2H), 7.87-7.92 (m, 2H), 8.40 (t, J=2.21 Hz, 1H), 8.56 (d, J=4.73 Hz, 1H), 8.95 (d, J=2.21 Hz, 1H), 9.04 (d, J=2.21 Hz, 1H). MS ES+m/z 478 [M+H] + .

Example 48: 1-(4-(5-(5-(1-hydroxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanol, to give the product as a solid (9 mg, 6%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.44 (d, J=6.31 Hz, 3H), 2.06-2.14 (m, 2H), 2.52-2.58 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.91-4.97 (m, 1H), 5.22 (d, J=4.41 Hz, 1H), 7.81-7.84 (m, 2H), 7.84-7.88 (m, 2H), 8.12 (s, 1H), 8.27-8.30 (m, 2H), 8.30-8.32 (m, 1H), 8.77 (d, J=2.21 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H), 12.01 (br s, 1H). MS ES+m/z 399 [M+H] + .

Example 49: N-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (4 mg, 5%). 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.23 (t, J=7.57 Hz, 2H), 2.64-2.69 (m, 2H), 3.08 (d, J=5.04 Hz, 3H), 3.94 (t, J=7.09 Hz, 2H), 6.71-6.83 (m, 1H), 7.48 (d, J=5.04 Hz, 1H), 7.65-7.68 (m, 3H), 7.80-7.83 (m, 2H), 8.12 (t, J=2.21 Hz, 1H), 8.55 (d, J=5.04 Hz, 1H), 8.89 (d, J=2.21 Hz, 1H), 8.96 (d, J=2.21 Hz, 1H). MS ES+m/z 413 [M+H] + .

Example 50: N,N-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Intermediate 7, replacing methylamine for dimethylamine HCl and TEA, to give the product as a solid (200 mg, 64%). MS ES+m/z 225 [M+H] + .

Step 2: N,N-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-N,N-dimethyl-furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (68 mg, 36%). 1 H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.23 (t, J=7.57 Hz, 2H), 2.67 (t, J=8.04 Hz, 2H), 3.18 (br s, 3H), 3.44 (br s, 3H), 3.95 (t, J=7.09 Hz, 2H), 7.48 (d, J=5.04 Hz, 1H), 7.60 (s, 1H), 7.65-7.69 (m, 2H), 7.79-7.83 (m, 2H), 8.14 (t, J=2.21 Hz, 1H), 8.55 (d, J=5.04 Hz, 1H), 8.90 (d, J=2.21 Hz, 1H), 8.96 (d, J=2.21 Hz, 1H). MS ES+m/z 427 [M+H] + .

Example 51: 3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile

A mixture of 1H-pyrrolo[2,3-b]pyridine-2-carbonitrile (653 mg, 4.56 mmol) and NBS (1.22 g, 6.84 mmol) in DCM (20 ml) was stirred at 0° C. for 40 min. The mixture was concentrated onto silica gel and purified on a silica gel column, eluted with 0-20% MeOH in DCM to give the product as a solid (195 mg, 19%). MS ES+m/z 222 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 3-bromo-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile, to give the product as a solid (9 mg, 9%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.13 (m, 2H), 2.52-2.56 (m, 2H), 3.90 (t, J=7.09 Hz, 2H), 7.16 (dd, J=8.04, 4.57 Hz, 1H), 7.81-7.86 (m, 4H), 8.26 (d, J=8.20 Hz, 1H), 8.30 (t, J=2.21 Hz, 1H), 8.45 (d, J=4.41 Hz, 1H), 8.86 (d, J=1.89 Hz, 1H), 8.88 (d, J=1.89 Hz, 1H). MS ES+m/z 380 [M+H] + .

Benzenesulfonyl chloride (873 μl, 6.81 mmol) was added to a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (877 mg, 5.67 mmol) and TEA (791 μl, 5.67 mmol) in NMP (5 ml) and the resulting mixture was stirred at rt over weekend. EtOAc and water were added, and the organic layer was separated, washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in isohexane to give the product as a solid (544 mg, 33%). MS ES+m/z 295 [M+H] + .

Step 2: Intermediate 26—1-[4-[5-[1-(Benzenesulfonyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3-pyridyl]phenyl]pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-(benzenesulfonyl)-4-chloro-pyrazolo[3,4-d]pyrimidine, to give the product as a solid (27 mg, 8%). MS ES+m/z 497 [M+H] + .

1-[4-[5-[1-(Benzenesulfonyl)pyrazolo[3,4-d]pyrimidin-4-yl]-3-pyridyl]phenyl]pyrrolidin-2-one (27 mg, 0.05 mmol) and pyrrolidine (5 μl, 0.07 mmol) was dissolved in 2-propanol (0.5 ml) and the resulting mixture was heated in a microwave reactor at 100° C. for 1.5 h. The mixture was purified by preparative HPLC to give the product as a solid (1.4 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.58 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 7.82-7.88 (m, 2H), 7.89-7.94 (m, 2H), 8.77-8.81 (m, 2H), 9.08 (s, 1H), 9.14 (d, J=2.21 Hz, 1H), 9.39 (d, J=2.21 Hz, 1H). MS ES+m/z 357 [M+H] + .

4-Iodo-1H-pyrazolo[3,4-b]pyridine (1 g, 4.08 mmol) was dissolved in NMP (5 ml) at rt and then cooled to 0° C. mCPBA (1.2 g, 5.22 mmol) was added portion wise and the resulting mixture was stirred at rt overnight. More mCPBA (200 mg, 0.87 mmol) was added and the mixture stirred at rt for 1 h. MTBE (10 ml) was added and the mixture stirred vigorously for 30 min. The formed precipitate was filtered off, washed with pentane and dried to give the product as a solid (820 mg, 77%). MS ES+m/z 262 [M+H] + .

POCl 3 (1 ml, 10.7 mmol) was added slowly to a suspension of 4-iodo-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium (600 mg, 2.3 mmol) in MeCN (5 ml) and the resulting mixture was stirred at rt for 2 h. 20% aq. NaOH (5 ml) was added slowly, followed by sat. aq. NaHCO 3 until pH 7. The formed precipitate was filtered off, washed with water and dried to give the product as a solid (1.1 g, quant.). MS ES+m/z 280 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 6-chloro-4-iodo-1H-pyrazolo[3,4-b]pyridine, to give the product as a solid (73 mg, 34%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07-2.14 (m, 2H), 2.52-2.58 (m, 2H), 3.91 (t, J=6.94 Hz, 2H), 7.72 (s, 1H), 7.81-7.86 (m, 2H), 7.91-7.98 (m, 2H), 8.47 (d, J=1.26 Hz, 1H), 8.51 (t, J=2.21 Hz, 1H), 9.05 (d, J=2.21 Hz, 1H), 9.09 (d, J=2.21 Hz, 1H), 14.05 (s, 1H). MS ES+m/z 390 [M+H] + .

Example 54: 6-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

5-Bromo-1,4-dimethyl-3-nitro-pyridin-2-one (1.67 g, 6.76 mmol), Fe (1.89 g, 33.8 mmol) and ammonium chloride (723 mg, 13.5 mmol) were taken up in EtOH (25 ml), THF (25 ml), water (8 ml) and the resulting mixture was refluxed for 1.5 h. When slightly cooled the mixture was filtered through celite, rinsed with MeOH and the filtrate was concentrated. The resulting residue was dissolved in EtOAc, washed with sat. aq. NaHCO 3 , brine, dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (1.19 g, 81%). MS ES+m/z 217 [M+H] + .

3-Amino-5-bromo-1,4-dimethyl-pyridin-2-one (1.19 g, 5.48 mmol) was dissolved in toluene (30 ml). Acetic anhydride (1.55 ml, 16.4 mmol) was added followed by KOAc (646 mg, 6.58 mmol) and the reaction mixture was stirred at 50° C. for 4 h. Isoamyl nitrite (1.1 ml, 8.22 mmol) was added and the reaction mixture was stirred at 80° C. for 48 h. Additional isoamyl nitrite (1.1 ml, 8.22 mmol) was added and the mixture was stirred at 90° C. for 8 h. When cooled to rt the mixture was washed with water, brine, dried over MgSO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in isohexane to give the product as a solid (323 mg, 26%). MS ES+m/z 228 [M+H] + .

Step 3: 6-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-6-methyl-TH-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (5 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.52-2.57 (m, 2H), 3.64 (s, 3H), 3.91 (t, J=6.94 Hz, 2H), 7.83-7.89 (m, 3H), 7.93-7.98 (m, 2H), 8.27-8.34 (m, 1H), 8.56-8.61 (m, 1H), 8.96 (d, J=1.89 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H). MS ES+m/z 386 [M+H] + .

Example 55: 1,6-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

1M LHMDS (526 μl, 0.53 mmol) was added to a solution of 4-bromo-6-methyl-1H-pyrazolo[3,4-c]pyridin-7-one (100 mg, 0.44 mmol) in THF (1 mL) at rt. After 5 min iodomethane (33 μl, 0.53 mmol) was added and the resulting mixture was stirred at rt overnight. EtOAc and water were added, the organic layer was separated, dried over MgSO 4 , filtered and concentrated to give the product as a solid (96 mg, 90%). MS ES+m/z 242 [M+H] + .

Step 2: 1,6-dimethyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-1,6-dimethyl-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (12 mg, 9%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07-2.15 (m, 2H),2.52-2.58 (m, 2H), 3.52-3.59 (m, 3H), 3.86-3.94 (m, 2H), 4.09-4.15 (m, 3H), 7.61-7.67 (m, 1H), 7.77-7.85 (m, 2H), 7.85-7.91 (m, 2H), 8.16-8.24 (m, 1H), 8.49-8.53 (m, 1H), 8.77-8.82 (m, 1H), 8.84-8.90 (m, 1H). MS ES+m/z 400 [M+H] + .

Example 56: 1-(4-(5-(1-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 5-chloro-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.2 mmol), tert-butyl piperazine-1-carboxylate (313 mg, 1.68 mmol), KOtBu (337 mg, 3 mmol) and PEPPSI-IPr (82 mg, 0.12 mmol) in 1,4-dioxane (1.5 ml) was heated in a microwave reactor at 150° C. for 3 h. The mixture was filtered through celite and rinsed with EtOAc and MeOH. The filtrate was concentrated, and the resulting residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried over MgSO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-20% MeOH in DCM to give the product as a solid (113 mg, 30%). MS ES+m/z 317 [M+H] + .

Step 2: Intermediate 33—tert-Butyl 4-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate

tert-Butyl 4-(1-methylpyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate (113 mg, 0.36 mmol) was dissolved in DCM (1.5 ml) and cooled down to 0° C. before NBS (76 mg, 0.43 mmol) was added. The reaction mixture was stirred at 0° C. for 15 min. DCM (3 ml) was added and the mixture washed with sat. aq. Na 2 S 2 O 3 , sat. aq. NaHCO 3 , dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (142 mg, quant.). MS ES+m/z 395 [M+H] + .

Step 3: Intermediate 34—tert-Butyl 4-[1-methyl-3-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]pyrrolo[2,3-b]pyridin-5-yl]piperazine-1-carboxylate

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for tert-butyl 4-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)piperazine-1-carboxylate, to give the product as a solid (43 mg, 22%). MS ES+m/z 553 [M+H] + .

Step 4: 1-(4-(5-(1-methyl-5-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

TFA (12 μl, 0.16 mmol) was added to a solution of tert-butyl 4-[1-methyl-3-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]pyrrolo[2,3-b]pyridin-5-yl]piperazine-1-carboxylate (43 mg, 0.08 mmol) in DCM (0.5 ml) at 0° C. The resulting mixture was stirred at rt overnight. Sat. aq. NaHCO 3 was added and the organic layer separated. The aqueous layer was extracted with DCM and the combined organics were dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (32 mg, 91%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.51-2.57 (m, 2H), 2.86-2.92 (m, 4H), 3.03-3.11 (m, 4H), 3.82-3.87 (m, 3H), 3.88-3.93 (m, 2H), 7.73-7.77 (m, 1H), 7.79-7.89 (m, 4H), 8.08 (s, 1H), 8.20 (d, J=2.52 Hz, 1H), 8.24 (s, 1H), 8.76 (d, J=2.21 Hz, 1H), 8.86-8.91 (m, 1H). MS ES+m/z 453 [M+H] + .

NaH (43 mg, 1.88 mmol) was added to a solution of N-(4-bromo-2-pyridyl)acetamide (337 mg, 1.57 mmol) in THF (3 mL) at 0° C. Iodomethane (98 μl, 1.57 mmol) was added and the resulting mixture was stirred at rt overnight. EtOAc was added and the mixture was washed with water, dried over MgSO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (208 mg, 58%). MS ES+m/z 229 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for N-(4-bromo-2-pyridyl)-N-methyl-acetamide, to give the product as a solid (28 mg, 26%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07 (s, 3H), 2.09-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.32 (s, 3H), 3.90 (t, J=6.94 Hz, 2H), 7.79-7.86 (m, 3H), 7.88-7.94 (m, 2H), 8.02 (d, J=0.95 Hz, 1H), 8.48 (t, J=2.21 Hz, 1H), 8.60 (dd, J=5.36, 0.63 Hz, 1H), 8.99-9.02 (m, 2H). MS ES+m/z 387 [M+H] + .

Step 1: Intermediate 36—1-[4-[5-[1-(Benzenesulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-pyridyl]phenyl]pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-(benzenesulfonyl)-4-chloro-pyrrolo[2,3-b]pyridine, to give the product as a solid (32 mg, 16%). MS ES+m/z 495 [M+H] + .

A mixture of 1-[4-[5-[1-(benzenesulfonyl)pyrrolo[2,3-b]pyridin-4-yl]-3-pyridyl]phenyl]pyrrolidin-2-one (32 mg, 0.06 mmol), pyrrolidine (30 μl, 0.36 mmol) and KOH (4 mg, 0.06 mmol) in 2-propanol (0.5 ml), MeCN (0.5 ml) and NMP (1 ml) was heated in a microwave reactor at 140° C. for 30 min. EtOAc and water were added and the organic layer separated. The aqueous layer was extracted with EtOAc and the combined organics were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was dissolved in a minimal amount of DCM and MeOH was added. The formed precipitate was filtered off and dried to give the product as a solid (5 mg, 23%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.10 (t, J=7.57 Hz, 2H), 2.51-2.57 (m, 2H), 3.86-3.93 (m, 2H), 6.64-6.70 (m, 1H), 7.33-7.40 (m, 1H), 7.58-7.63 (m, 1H), 7.79-7.85 (m, 2H), 7.86-7.91 (m, 2H), 8.33-8.37 (m, 2H), 8.94 (d, J=1.89 Hz, 1H), 8.99 (d, J=2.21 Hz, 1H), 11.83-11.95 (m, 1H). MS ES+m/z 355 [M+H] + .

A mixture of 4-chloro-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-ol (300 mg, 0.92 mmol), K 2 CO 3 (319 mg, 2.31 mmol) and ethyl iodide (89 μl, 1.11 mmol) in MeCN (5 ml) was stirred at rt until all starting material was consumed. EtOAc and water were added, the organic layer separated, dried over Na 2 SO 4 , filtered and concentrated to give the product (292 mg, 90%). MS ES+m/z 353 [M+H] + .

Step 2: Intermediate 38—1-[4-[5-(5-Ethoxy-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for (4-chloro-5-ethoxy-pyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane, to give the product as a solid (93 mg, 23%). MS ES+m/z 555 [M+H] + .

TBAF in THF (1M, 168 μl, 0.17 mmol) was added to a solution of 1-[4-[5-(5-ethoxy-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (93 mg, 0.17 mmol) THF (1 ml) and the resulting mixture was stirred at rt for 2 h. 1,2-Dichloroethane and sat. aq. NaHCO 3 solution were added and the organic layer separated. The aqueous layer was extracted with 1,2-dichloroethane and the combined organics were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (16 mg, 24%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.19-1.25 (m, 3H),2.07-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.86-3.92 (m, 2H), 4.04-4.12 (m, 2H), 6.29-6.37 (m, 1H), 7.50-7.55 (m, 1H), 7.78-7.85 (m, 4H), 8.21-8.25 (m, 1H), 8.25-8.28 (m, 1H), 8.71-8.79 (m, 1H), 8.87-8.98 (m, 1H), 11.62-11.73 (m, 1H). MS ES+m/z 399 [M+H] + .

Example 60: N,1-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

A mixture of methyl 3-bromo-H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.2 g 8.63 mmol) and Cs 2 CO 3 (5.62 g, 17.3 mmol) in DMF (25 ml) was stirred at rt for 1 h. Iodomethane (0.67 ml, 10.8 mmol) was added and the mixture stirred at rt overnight. Water (150 ml) was added and the mixture extracted with EtOAc. The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (2.2 g, 95%). MS ES+m/z 269 [M+H] + .

A mixture of methyl 3-bromo-1-methyl-pyrrolo[2,3-b]pyridine-5-carboxylate (2.4 g, 8.92 mmol) and LiOH (235 mg, 9.81 mmol) in MeOH (20 ml), THF (20 ml) and water (5 ml) was stirred at rt over weekend. Water (30 ml) was added and the organic solvents were removed in vacuo. The aqueous residue was acidified with 2M aq. HCl to pH 5 and the mixture was kept at rt overnight. The formed precipitate was filtered off and washed with pentane to give the product as a solid (2.17 g, 87%). MS ES+m/z 255 [M+H] + .

Oxalyl chloride (1.09 ml, 12.9 mmol) was added to a mixture of 3-bromo-1-methyl-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.1 g, 4.31 mmol) and DMF (5 drops) in DCM (50 ml) at 0° C. The resulting mixture was stirred at rt for 3 h. The mixture was concentrated and the resulting residue was suspended in THF (20 ml) and added to 40% aq. methylamine (19 ml, 216 mmol) at 0° C. After 1 h at rt the volatiles were removed in vacuo. The resulting aqueous residue was kept at rt for 2 h and the formed precipitate was filtered off, washed with water and dried. The solid was suspended in Et 2 O and EtOAc, stirred at rt for 1 h, filtered and dried to give the product as a solid (0.75 g, 59%). MS ES+m/z 268 [M+H] + .

Step 4: N,1-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 3-bromo-N,1-dimethyl-pyrrolo[2,3-b]pyridine-5-carboxamide, to give the product as a solid (55 mg, 39%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.52-2.56 (m, 2H), 2.82-2.86 (m, 3H), 3.89-3.93 (m, 2H), 3.93-3.95 (m, 3H), 7.81-7.86 (m, 2H), 7.86-7.90 (m, 2H), 8.27-8.30 (m, 1H), 8.31-8.34 (m, 1H), 8.64-8.70 (m, 1H), 8.80-8.82 (m, 1H), 8.82-8.83 (m, 1H), 8.86 (d, J=1.89 Hz, 1H), 9.01 (d, J=2.21 Hz, 1H). MS ES+m/z 426 [M+H] + .

Example 61: N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Intermediate 41, replacing methylamine for dimethylamine (1M in THF). Purification on a silica gel column eluted with 0-20% MeOH in DCM gave the product as a solid (1.02 g, 84%). MS ES+m/z 282 [M+H] + .

Step 2: N,N,1-trimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 3-bromo-N,N,1-trimethyl-pyrrolo[2,3-b]pyridine-5-carboxamide, to give the product as a solid (46 mg, 23%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.52-2.56 (m, 2H), 2.99-3.07 (m, 6H), 3.88-3.93 (m, 2H), 3.93-3.95 (m, 3H), 7.81-7.84 (m, 2H), 7.85-7.88 (m, 2H), 8.27-8.29 (m, 1H), 8.29-8.30 (m, 1H), 8.40-8.42 (m, 1H), 8.42-8.43 (m, 1H), 8.79-8.81 (m, 1H), 8.90-8.93 (m, 1H). MS ES+m/z 440 [M+H] + .

Example 62: 1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (400 mg, 2.5 mmol) and NBS (668 mg, 3.25 mmol) in DCM (2.5 ml) was stirred at 0° C. for 40 min. Sat. aq. Na 2 S 2 O 3 was added and the reaction mixture was extracted DCM (4×). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in Heptane to give the product as a solid (650 mg, quant.). MS ES+m/z 239 [M+H] + .

The title compound was prepared as described in Intermediate 39, replacing methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate for 1-(3-bromo-1H-pyrrolo[2,3-b]pyridin-5-yl)ethenone, to give the product as a solid (380 mg, 56%). MS ES+m/z 253 [M+H] + .

NaBH 4 (114 mg, 3 mmol) was added to a solution of 1-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)ethanone (380 mg, 1.5 mmol) in MeOH (5 ml) and THF (2 ml) at 0° C. and the resulting mixture was stirred at 0° C. for 1 h. Aq. 50% AcOH was added, the mixture concentrated and purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (260 mg, 68%). MS ES+m/z 255 [M+H] + .

Step 4: 1-(4-(5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)ethanol, to give the product as a solid (59 mg, 43%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.44 (d, J=6.31 Hz, 2H), 2.10 (quin, J=7.57 Hz, 2H), 2.52-2.58 (m, 2H), 3.89-3.95 (m, 5H), 4.93-5.11 (m, 1H), 5.26 (d, J=4.73 Hz, 1H), 7.77-7.91 (m, 4H), 8.18 (s, 1H), 8.27 (t, J=2.21 Hz, 1H), 8.30 (d, J=1.89 Hz, 1H), 8.36 (d, J=1.89 Hz, 1H), 8.78 (d, J=2.21 Hz, 1H), 8.92 (d, J=1.89 Hz, 1H). MS ES+m/z 413 [M+H] + .

Example 63: 1-(4-(5-(6-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

6-Chloro-1H-pyrazolo[3,4-b]pyridine (1.05 g, 6.82 mmol) was dissolved in MeCN (25 ml) at rt. 4-Methoxybenzylchloride (1.69 ml, 11.6 mmol) was added followed by K 2 CO 3 (2.83 g, 20.5 mmol) and the resulting mixture was stirred at 60° C. for 1 h. Sat. aq. NaHCO 3 (30 ml) was added and the mixture extracted with DCM (3×30 ml). The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in Heptane to give the product as a solid (1.9 g, quant.). MS ES+m/z 274 [M+H] + .

6-Chloro-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (1 g, 3.65 mmol), cyclopropyl boronic acid (628 mg, 7.31 mmol), K 2 CO 3 (1.01 g, 7.31 mmol) and PdCl 2 (PPh 3 ) 2 (133 mg, 0.18 mmol) were taken up in 1,4-dioxane (3 ml) and water (0.7 ml) and the mixture was heated in a microwave reactor at 130° C. for 1 h. The mixture was dried over Na 2 SO 4 , filtered through celite, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in Heptane to give the product as a solid (874 mg, 86%). MS ES+m/z 280 [M+H] + .

6-Cyclopropyl-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyridine (874 mg, 3.13 mmol) was dissolved in TFA (5 ml, 21.5 mmol) and stirred at 75° C. for 2 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (330 mg, 66%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.98-1.04 (m, 4H), 2.22 (tt, J=7.88, 4.89 Hz, 1H), 7.12 (d, J=8.20 Hz, 1H), 8.01 (s, 1H), 8.05 (d, J=8.20 Hz, 1H). MS ES+m/z 160 [M+H] + .

m-CPBA (954 mg, 4.15 mmol) was added portion wise to a solution of 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine (330 mg, 3.36 mmol) in DME (5 ml) at rt and the resulting mixture was stirred at rt for 3 h. The reaction mixture was washed with sat. aq. NaHCO 3 , dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (374 mg, quant.). MS ES+m/z 176 [M+H] + .

Oxalyl chloride (351 μL, 4.14 mmol) was added dropwise to a suspension of 6-cyclopropyl-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium (363 mg, 2.07 mmol) in DMF (2 ml) at 0° C. and the resulting mixture was stirred at rt overnight. Water was added and the mixture extracted with DCM. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-20% MeOH in DCM to give the product as a solid (80 mg, 20%). MS ES+m/z 194 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine, to give the product as a solid (6 mg, 4%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.03-1.14 (m, 4H), 2.10 (quin, J=7.57 Hz, 2H), 2.31-2.39 (m, 1H), 2.52-2.58 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 7.52 (s, 1H), 7.82-7.85 (m, 2H), 7.91-7.95 (m, 2H), 8.28 (s, 1H), 8.46 (t, J=2.05 Hz, 1H), 9.02 (d, J=2.21 Hz, 1H), 9.03-9.06 (m, 1H), 13.43-13.68 (m, 1H). MS ES+m/z 396 [M+H] + .

Example 64: 1-(4-(5-(6-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

Methanesulfonyl chloride (479 μl, 6.18 mmol) was added dropwise to a solution of DIPEA (2.69 ml, 15.5 mmol) and 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine×2 HCl (995 mg, 5.15 mmol) in DCM (10 ml) at −10° C. and the resulting mixture was stirred at rt overnight. Additional DCM was added and the mixture washed with sat. aq. NaHCO 3 , dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (1.02 g, quant.). MS ES+m/z 199 [M+H] + .

The title compound was prepared as described in Intermediate 49, replacing 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine for 6-methylsulfonyl-5,7-dihydropyrrolo[3,4-b]pyridine. Et 2 O was added to the reaction mixture and the formed precipitate was filtered off and dried to give the product as a solid (751 mg, 68%). MS ES+m/z 215 [M+H] + .

The title compound was prepared as described in Intermediate 50, replacing 6-cyclopropyl-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium for 6-methylsulfonyl-1-oxido-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium, to give the product as a solid (80 mg, 10%). MS ES+m/z 233 [M+H] + .

Step 4: 1-(4-(5-(6-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-6-methylsulfonyl-5,7-dihydropyrrolo[3,4-b]pyridine, to give the product as a solid (53 mg, 38%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.08-2.14 (m, 2H), 2.53-2.58 (m, 2H), 3.06-3.12 (m, 3H), 3.89-3.95 (m, 2H), 4.71-4.77 (m, 2H), 4.92-4.98 (m, 2H), 7.64-7.67 (m, 1H), 7.82-7.87 (m, 2H), 7.87-7.92 (m, 2H), 8.30-8.34 (m, 1H), 8.63-8.68 (m, 1H), 8.81-8.85 (m, 1H), 9.02-9.06 (m, 1H). MS ES+m/z 435 [M+H] + .

Example 65: methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

The title compound was prepared as described in Intermediate 51, replacing methanesulfonyl chloride for methyl chloroformate, to give the product as a solid (1.3 g, 97%). MS ES+m/z 179 [M+H] + .

The title compound was prepared as described in Intermediate 49, replacing 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine for methyl 5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate, to give the product as a solid (950 mg, 67%). MS ES+m/z 195 [M+H] + .

The title compound was prepared as described in Intermediate 50, replacing 6-cyclopropyl-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium for methyl 1-oxido-5,7-dihydropyrrolo[3,4-b]pyridin-1-ium-6-carboxylate, to give the product as a solid (115 mg, 23%). MS ES+m/z 213 [M+H] + .

Step 4: methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for methyl 4-chloro-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate, to give the product as a solid (59 mg, 43%). 1 H NMR (500 MHz, DMSO-d 6 ) 2.11 (quin, J=7.49 Hz, 2H), 2.53-2.57 (m, 2H), 3.64-3.74 (m, 3H), 3.91 (t, J=7.09 Hz, 2H), 4.72 (br d, J=15.13 Hz, 2H), 4.92 (br d, J=12.30 Hz, 2H), 7.61 (t, J=5.36 Hz, 1H), 7.80-7.90 (m, 4H), 8.31 (br s, 1H), 8.63 (d, J=5.04 Hz, 1H), 8.79 (br d, J=9.46 Hz, 1H), 9.03 (br s, 1H). MS ES+m/z 415 [M+H] + .

Example 66: 1-(4-(5-(5-(piperidin-3-yloxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Intermediate 57—tert-Butyl 3-(4-chloro-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-yl)oxypiperidine-1-carboxylate

DIAD (197 μl, 1 mmol) was added dropwise to a solution of 4-chloro-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-ol (250 mg, 0.77 mmol), tert-butyl 3-hydroxypiperidine-1-carboxylate (201 mg, 1 mmol) and PPh 3 (262 mg, 1 mmol) in toluene (2.5 ml) at rt and the resulting mixture was stirred at rt overnight. EtOAc and water were added and the organic layer was separated, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (283 mg, 72%). MS ES+m/z 508 [M+H] + .

Step 2: Intermediate 58—tert-Butyl 3-[4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-yl]oxypiperidine-1-carboxylate

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for tert-butyl 3-(4-chloro-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-yl)oxypiperidine-1-carboxylate. Extraction of the reaction mixture, using 1,2-dichloroethane and concentration of the organic layer gave a solid (252 mg), which was used in the next step. MS ES+m/z 710 [M+H] + .

Step 3: 1-(4-(5-(5-(piperidin-3-yloxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

tert-Butyl 3-[4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-5-yl]oxypiperidine-1-carboxylate (crude from previous step, 252 mg) was dissolved in MeOH (2 mL) at rt, a few drops of conc. HCl was added and the mixture was stirred at rt for 2 h. 1,2-dichloroethane and sat. aq. NaHCO 3 were added and the organic layer separated. The aqueous layer was extracted with 1,2-dichloroethane and the combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was dissolved in DCM, a few drops of TFA was added and the mixture was stirred at rt until all Boc-groups had been deprotected. Sat. aq. NaHCO 3 was added and the mixture extracted with DCM. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (8 mg, 5%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 1.55-1.72 (m, 2H), 1.73-1.82 (m, 1H), 1.86-1.92 (m, 1H), 2.15-2.27 (m, 2H), 2.63 (t, J=8.04 Hz, 2H), 2.95-3.22 (m, 4H), 3.92-4.05 (m, 2H), 4.10-4.23 (m, 1H), 6.43 (d, J=3.47 Hz, 1H), 7.44-7.56 (m, 1H), 7.74-7.84 (m, 4H), 8.19-8.29 (m, 1H), 8.33-8.41 (m, 1H), 8.77-8.85 (m, 1H), 8.92 (d, J=2.21 Hz, 1H). MS ES+m/z 454 [M+H] + .

Example 67: 6-benzyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

NaH (60% in mineral oil, 395 mg, 10.3 mmol) was added to a solution of 5-bromo-4-methyl-3-nitro-1H-pyridin-2-one (2 g, 8.58 mmol) in DMF (30 ml). After 15 min benzyl bromide (1.02 ml, 8.58 mmol) was added and the resulting mixture was stirred at rt overnight. The mixture was poured into ice/water and stirred for 15 min. The formed precipitate was filtered off washed with water and dried to give the product as a solid (2.57 g, 93%). MS ES+m/z 323 [M+H] + .

The title compound was prepared as described in Intermediate 29, replacing 5-bromo-1,4-dimethyl-3-nitro-pyridin-2-one for 1-benzyl-5-bromo-4-methyl-3-nitro-pyridin-2-one, to give the product as solid (2.3 g, quant). MS ES+m/z 293 [M+H] + .

Acetic anhydride (4.3 ml, 45.5 mmol) and KOAc (937 mg, 9.55 mmol) were added to a solution of 3-amino-1-benzyl-5-bromo-4-methyl-pyridin-2-one (2.3 g, 7.95 mmol) in toluene (30 ml) and the resulting mixture was stirred at 50° C. overnight. EtOAc and brine were added and the organic layer was separated, dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give the product as a solid (1.22 g, 46%). MS ES+m/z 335 [M+H] + .

N-(1-benzyl-5-bromo-4-methyl-2-oxo-3-pyridyl)acetamide (803 mg, 2.4 mmol) was dissolved in toluene (15 mL) and KOAc (282 mg, 2.87 mmol) was added followed by isoamyl nitrite (641 μl, 4.79 mmol) and acetic anhydride (450 μl, 4.79 mmol). The resulting mixture was stirred at 110° C. for 2 h. Water was added and the mixture extracted with EtOAc. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (131 mg, 18%). MS ES+m/z 304 [M+H] + .

Step 5: 6-benzyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 6-benzyl-4-bromo-1H-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (8 mg, 4%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.04-2.13 (m, 2H), 2.51-2.57 (m, 2H), 3.86-3.92 (m, 2H), 5.24-5.35 (m, 2H), 7.24-7.41 (m, 6H), 7.79-7.91 (m, 4H), 8.16-8.26 (m, 2H), 8.75-8.94 (m, 2H), 14.20-14.43 (m, 1H). MS ES+m/z 462 [M+H] + .

Example 68: 6-isobutyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Intermediate 61, replacing benzyl bromide for 1-iodo-2-methyl-propane, to give the product as solid (790 mg, 42%). MS ES+m/z 289 [M+H] + .

The title compound was prepared as described in Intermediate 29, replacing 5-bromo-1,4-dimethyl-3-nitro-pyridin-2-one for 5-bromo-1-isobutyl-4-methyl-3-nitro-pyridin-2-one, to give the product as solid (640 mg, 92%). MS ES+m/z 259 [M+H] + .

The title compound was prepared as described in Intermediate 63, to give the product as solid (970 mg, 77%). MS ES+m/z 301 [M+H] + .

The title compound was prepared as described in Intermediate 64, to give the product as solid (238 mg, 59%). MS ES+m/z 270 [M+H] + .

Step 5: 6-isobutyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-6-isobutyl-1H-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (10 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.93 (d, J=6.62 Hz, 6H), 2.07-2.25 (m, 3H), 2.53-2.59 (m, 2H), 3.87-3.99 (m, 4H), 7.65-7.73 (m, 1H), 7.77-7.96 (m, 4H), 8.21-8.29 (m, 2H), 8.85 (s, 1H), 8.89 (s, 1H), 14.29 (br s, 1H). MS ES+m/z 428 [M+H] + .

Example 69: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Intermediate 61, replacing benzyl bromide for 4-bromomethyl tetrahydropyran, to give the product as solid (2 g, 49%). MS ES+m/z 331 [M+H] + .

The title compound was prepared as described in Intermediate 29, replacing 5-bromo-1,4-dimethyl-3-nitro-pyridin-2-one for 5-bromo-4-methyl-3-nitro-1-(tetrahydropyran-4-ylmethyl)pyridin-2-one, to give the product as solid (1.6 g, 88%). MS ES+m/z 301 [M+H] + .

The title compound was prepared as described in Intermediate 63, to give the product as solid (1.39 g, 76%). MS ES+m/z 343 [M+H] + .

The title compound was prepared as described in Intermediate 64, to give the product as solid (970 mg, 78%). MS ES+m/z 312 [M+H] + .

Step 5: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-6-(tetrahydropyran-4-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (30 mg, 19%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.35 (qd, J=12.09, 4.41 Hz, 2H), 1.50 (br d, J=11.35 Hz, 2H), 2.06-2.19 (m, 3H), 2.53-2.59 (m, 2H), 3.22-3.30 (m, 2H), 3.75-3.96 (m, 4H), 3.98-4.08 (m, 2H), 7.72 (s, 1H), 7.76-7.91 (m, 4H), 8.19-8.27 (m, 2H), 8.83-8.92 (m, 2H), 14.25-14.34 (m, 1H). MS ES+m/z 470 [M+H] + .

Example 70: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

1M LHMDS in THF (1.92 ml, 1.92 mmol) was added to a solution of 4-bromo-6-(tetrahydropyran-4-ylmethyl)-1H-pyrazolo[3,4-c]pyridin-7-one (500 mg, 1.6 mmol) in THF (4.5 ml) at rt. After 15 min iodomethane (0.12 ml, 1.92 mmol) was added and the resulting mixture was stirred at rt overnight. Water was added and the mixture extracted with EtOAc. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-12% MeOH in DCM to give the product as a solid (280 mg, 45%). MS ES+m/z 326 [M+H] + .

Step 2: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-1-methyl-6-(tetrahydropyran-4-ylmethyl)pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (50 mg, 34%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm, 1.33 (qd, J=12.14, 4.26 Hz, 2H), 1.49 (br d, J=12.30 Hz, 2H), 2.11 (quin, J=7.57 Hz, 3H), 2.53-2.58 (m, 2H), 3.21-3.30 (m, 2H), 3.85 (br d, J=8.83 Hz, 2H), 3.88-3.97 (m, 4H), 4.13 (s, 3H), 7.62 (s, 1H), 7.81-7.91 (m, 4H), 8.21 (t, J=2.05 Hz, 1H), 8.52 (s, 1H), 8.81 (d, J=1.89 Hz, 1H), 8.87 (d, J=1.89 Hz, 1H). MS ES+m/z 484 [M+H] + .

Example 71: N-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Intermediate 41, replacing 3-bromo-1-methyl-pyrrolo[2,3-b]pyridine-5-carboxylic acid for 3-bromo-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid, to give the product as a solid (1.02 g, 81%). MS ES+m/z 254 [M+H] + .

Step 2: N-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 3-bromo-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, to give the product as a solid (8 mg, 6%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.57 (m, 2H), 2.85 (d, J=4.41 Hz, 3H), 3.92 (t, J=7.09 Hz, 2H), 7.83-7.91 (m, 4H), 8.25 (s, 1H), 8.37 (t, J=2.05 Hz, 1H), 8.62-8.68 (m, 1H), 8.79-8.84 (m, 3H), 9.03 (d, J=2.21 Hz, 1H), 12.36 (br s, 1H). MS ES+m/z 412 [M+H] + .

Example 72: N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Intermediate 41, replacing methylamine for dimethylamine (aq. 40%), to give the product as a solid (840 mg, 63%). MS ES+m/z 268 [M+H] + .

Step 2: N,N-dimethyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 3-bromo-N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, to give the product as a solid (18 mg, 13%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.57 (m, 2H), 3.04 (s, 6H), 3.92 (t, J=7.09 Hz, 2H), 7.81-7.90 (m, 4H), 8.23 (s, 1H), 8.33 (t, J=2.21 Hz, 1H), 8.39 (d, J=7.75 Hz, 2H), 8.80 (d, J=2.21 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H), 12.33 (br s, 1H). MS ES+m/z 426 [M+H] + .

The title compound was prepared as described in Intermediate 30, replacing 3-amino-5-bromo-1,4-dimethyl-pyridin-2-one for 5-bromo-2-methoxy-4-methyl-pyridin-3-amine, to give the product as a solid (430 mg, 82%). MS ES+m/z 228 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine, to give the product as a solid (75 mg, 50%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.51-2.56 (m, 2H), 3.90 (t, J=7.09 Hz, 2H), 4.14 (s, 3H), 7.80-7.85 (m, 2H), 7.88-7.93 (m, 2H), 8.05 (s, 1H), 8.30-8.35 (m, 1H), 8.38 (d, J=1.58 Hz, 1H), 8.90 (d, J=2.21 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H), 14.01-14.20 (m, 1H). MS ES+m/z 386 [M+H] + .

Example 74: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

NaI (19 mg, 0.13 mmol) and TMSCl (17 μl, 0.14 mmol) were added to a solution of 1-(4-(5-(7-methoxy-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg, 0.13 mmol) in MeCN (3 ml) and the resulting mixture was stirred at 60° C. overnight. The formed precipitate was filtered off, washed sequentially with EtOAc, DCM, MeOH, 2-propanol and dried to give the product as a solid (19 mg, 39%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07-2.13 (m, 2H), 2.52-2.56 (m, 2H), 3.88-3.92 (m, 2H), 7.33-7.39 (m, 1H), 7.79-7.83 (m, 2H), 7.86-7.90 (m, 2H), 8.12-8.27 (m, 2H), 8.77-8.91 (m, 2H), 11.60-11.79 (m, 1H), 14.16-14.33 (m, 1H). MS ES+m/z 372 [M+H] + .

The title compound was prepared as described in Intermediate 49, replacing 6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine for 6-methoxy-1H-pyrazolo[3,4-b]pyridine, to give the product as a solid (286 mg, quant.). MS ES+m/z 166 [M+H] + .

The title compound was prepared as described in Intermediate 50, replacing 6-cyclopropyl-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium for 6-methoxy-7-oxido-1H-pyrazolo[3,4-b]pyridin-7-ium, to give the product as a solid (23 mg, 10%). MS ES+m/z 184 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-6-methoxy-1H-pyrazolo[3,4-b]pyridine, to give the product as a solid (2 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (quin, J=7.57 Hz, 2H), 2.51-2.55 (m, 2H), 3.87-3.93 (m, 2H), 3.98 (s, 3H), 7.77-7.84 (m, 4H), 8.05 (s, 1H), 8.20 (t, J=2.21 Hz, 1H), 8.30 (s, 1H), 8.71 (d, J=2.21 Hz, 1H), 8.87 (d, J=2.21 Hz, 1H), 13.49 (s, 1H). MS ES+m/z 386 [M+H] + .

Example 76: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

Pyridinium perbromide (7.08 g, 22.1 mmol) was added portion wise over 30 min to a solution of 4-chloro-1-methyl-pyrrolo[2,3-b]pyridine (1.23 g, 7.38 mmol) in t-BuOH (60 ml) at rt and the resulting mixture was stirred at rt for 1.5 h. EtOAc (150 ml) was added and the mixture was washed with water, brine, dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (2.4 g, 96%). MS ES+m/z 339 [M+H] + .

Zinc (4.61 g, 70.5 mmol) was added in portions over 10 min to a solution of 3,3-dibromo-4-chloro-1-methyl-pyrrolo[2,3-b]pyridin-2-one (2.4 g, 7.05 mmol) in MeCN (30 ml) and AcOH (20 ml) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The mixture was filtered through celite and the filtrate concentrated. The resulting residue was dissolved in EtOAc and washed with sat. aq. NaHCO 3 (3×), dried over Na 2 SO 4 , filtered and concentrated. Recrystallization from Et 2 O gave the product as a solid (815 mg, 63%). MS ES+m/z 183 [M+H] + .

Step 3: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-1-methyl-3H-pyrrolo[2,3-b]pyridin-2-one, to give the product as a solid (68 mg, 52%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.57 (m, 2H), 3.17-3.22 (m, 3H), 3.91 (t, J=6.94 Hz, 2H), 3.97 (s, 2H), 7.36 (d, J=5.36 Hz, 1H), 7.81-7.90 (m, 4H), 8.31 (d, J=5.55 Hz, 1H), 8.34 (s, 1H), 8.87 (d, J=2.21 Hz, 1H), 9.01 (d, J=2.21 Hz, 1H). MS ES+m/z 385 [M+H] + .

Example 77: 1-(1-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-2-one

The title compound was prepared as described in Intermediate 29, replacing 5-bromo-1,4-dimethyl-3-nitro-pyridin-2-one for 3-iodo-1-methyl-5-nitro-2,3-dihydropyrrolo[2,3-b]pyridine, to give the product as solid (1.29 g, 95%). MS ES+m/z 274 [M+H] + .

4-Chlorobutyryl chloride (0.78 ml, 6.98 mmol) was added drop wise to a solution of 3-iodo-1-methyl-pyrrolo[2,3-b]pyridin-5-amine (1.29 g, 5.59 mmol) and TEA (1.17 ml, 8.38 mmol) in DCM (25 ml) at 0° C. and the resulting mixture was stirred for 1 h. EtOAc and brine were added, the organic layer was separated and washed with sat. aq. NaHCO 3 , dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (2 g, 95%). MS ES+m/z 378 [M+H] + .

KOtBu (743 mg, 6.62 mmol) was added to a solution of 4-chloro-N-(3-iodo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)butanamide (2 g, 5.30 mmol) in THF (25 ml) at 0° C. and the resulting mixture was stirred for 1 h. Water was added, the mixture neutralized using aq. 5% citric acid and extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. Recrystallization from EtOAc gave the product as a solid (720 mg, 40%). MS ES+m/z 342 [M+H] + .

Step 4: 1-(1-methyl-3-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-(3-iodo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-2-one, to give the product as a solid (59 mg, 38%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.12 (dquin, J=12.00, 7.56, 7.56, 7.56, 7.56 Hz, 4H), 2.52-2.57 (m, 4H), 3.89-4.06 (m, 7H), 7.80-7.90 (m, 4H), 8.22 (s, 1H), 8.28 (t, J=2.21 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H), 8.60 (d, J=2.21 Hz, 1H), 8.80 (d, J=2.21 Hz, 1H), 8.90 (d, J=2.21 Hz, 1H). MS ES+m/z 452 [M+H] + .

Aq. 25% NH 3 (0.5 ml) was added to a solution of methyl 3-(bromomethyl)-4-chloro-2,3-dihydropyridine-2-carboxylate (660 mg, 2.47 mmol) in THF (5 ml) and the resulting mixture was stirred at 70° C. for 2 h. Additional aq. 25% NH 3 (2 ml) was added and the reaction was stirred for 2 h at 70° C. The mixture was concentrated and the resulting residue was purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (370 mg, 89%). MS ES+m/z 169 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-5,6-dihydropyrrolo[3,4-b]pyridin-7-one, to give the product as a solid (60 mg, 47%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.53-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.72 (s, 2H), 7.81-7.87 (m, 2H), 7.87-7.93 (m, 3H), 8.41 (t, J=2.05 Hz, 1H), 8.87 (d, J=5.52 Hz, 1H), 8.91 (s, 1H), 9.05 (d, J=1.89 Hz, 1H), 9.14 (s, 1H). MS ES+m/z 371 [M+H] + .

Example 79: N-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Intermediate 7, replacing methylamine for aminomethyl cyclopropane, to give the product as a solid (102 mg, quant.). MS ES+m/z 251 [M+H] + .

Step 2: N-(cyclopropylmethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-N-(cyclopropylmethyl)furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (32 mg, 39%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.24-0.28 (m, 2H), 0.43-0.47 (m, 2H), 1.02-1.10 (m, 1H), 2.10 (dt, J=14.90, 7.53 Hz, 2H), 2.51-2.58 (m, 2H), 3.17 (t, J=6.31 Hz, 2H), 3.91 (t, J=7.09 Hz, 2H), 7.81-7.84 (m, 2H), 7.84-7.86 (m, 2H), 7.91-7.94 (m, 2H), 8.46 (t, J=2.21 Hz, 1H), 8.59 (d, J=5.04 Hz, 1H), 8.96-9.01 (m, 2H), 9.08 (d, J=2.21 Hz, 1H). MS ES+m/z 453 [M+H] + .

Example 80: N-(2-methoxyethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Intermediate 7, replacing methylamine for 2-methoxyethylamine, to give the product as a solid (103 mg, quant.). MS ES+m/z 255 [M+H] + .

Step 2: N-(2-methoxyethyl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 4-chloro-N-(2-methoxyethyl)furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (20 mg, 25%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.14 (m, 2H), 2.54 (t, J=8.04 Hz, 2H), 3.27-3.29 (s, 3H), 3.44-3.50 (m, 4H), 3.90 (t, J=7.09 Hz, 2H), 7.80-7.83 (m, 2H), 7.83-7.85 (m, 1H), 7.87 (s, 1H), 7.89-7.93 (m, 2H), 8.44 (t, J=2.05 Hz, 1H), 8.58 (d, J=5.04 Hz, 1H), 8.92 (t, J=5.36 Hz, 1H), 8.97 (d, J=2.21 Hz, 1H), 9.07 (d, J=1.89 Hz, 1H). MS ES+m/z 457 [M+H] + .

Step 1: Intermediate 86—1-[3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one

1-(4-Bromo-3-methyl-phenyl)pyrrolidin-2-one (1.36 g, 5.35 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.49 g, 5.89 mmol) and KOAc (1.57 g, 16 mmol) were taken up in toluene (15 ml) and degassed with nitrogen for 5 min. PdCl 2 (dppf) (116 mg, 0.16 mmol) was added and the resulting mixture was stirred at 110° C. for 2 h. When cooled to rt 1,2-dichloroethane and water were added, the organic layer separated and the aqueous layer extracted with 1,2-dichloroethane. The combined organics were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was dissolved in a small amount of 1,2-dichloroethane and filtered through celite. To the filtrate was added Et 2 O and the formed precipitate was filtered off and dried to give the product as a solid (330 mg, 21%). MS ES+m/z 302 [M+H] + .

1-[3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (150 mg, 0.5 mmol) and 3,5-dibromopyridine (121 mg, 0.51 mmol) were dissolved in 1,4-dioxane (1 ml) and water (0.1 ml) and degassed with nitrogen. PdCl 2 (PPh 3 ) 2 (18 mg, 0.02 mmol) and K 2 CO 3 (138 mg, 1 mmol) were added and the mixture was stirred at 100° C. for 2 h. When cooled to rt 1,2-dichloroethane and water were added, the organic layer separated and the aqueous layer extracted with 1,2-dichloroethane. The combined organics were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was taken up in 1,4-dioxane (1 ml) and water (0.1 ml). 4-Pyridylboronic acid (61 mg, 0.5 mmol) was added followed by PdCl 2 (Amphos) (18 mg, 0.02 mmol) and K 2 CO 3 (138 mg, 1 mmol) and the resulting mixture was stirred at 100° C. for 2 h. When cooled to rt 1,2-dichloroethane and water were added, the organic layer separated and the aqueous layer extracted with 1,2-dichloroethane. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (14 mg, 9%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 2.16-2.23 (m, 2H), 2.31-2.35 (m, 3H), 2.59-2.65 (m, 2H), 3.93-3.99 (m, 2H), 7.28-7.34 (m, 1H), 7.55-7.60 (m, 1H), 7.61-7.65 (m, 1H), 7.80-7.86 (m, 2H), 8.17 (t, J=2.21 Hz, 1H), 8.60 (d, J=2.21 Hz, 1H), 8.63-8.69 (m, 2H), 8.92 (d, J=2.21 Hz, 1H). MS ES+m/z 330 [M+H] + .

The title compound was prepared as described in Example 81, replacing 1-[3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one for 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one and 3,5-dibromopyridine for 3,5-dibromo-4-methyl-pyridine, to give the product as a solid (82 mg, 20%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.04-2.13 (m, 2H), 2.14-2.18 (m, 3H), 2.51-2.56 (m, 2H), 3.84-3.94 (m, 2H), 7.42-7.49 (m, 2H), 7.50-7.54 (m, 2H), 7.76-7.83 (m, 2H), 8.41 (s, 1H), 8.42-8.47 (m, 1H), 8.66-8.74 (m, 2H). MS ES+m/z 330 [M+H] + .

NaBH 4 (86 mg, 2.27 mmol) was added to a solution of 3-bromo-5-chloro-pyridine-4-carbaldehyde (250 mg, 1.13 mmol) in MeOH (10 mL) at 0° C. and the resulting mixture was stirred for 2 h. The mixture was concentrated and the resulting residue was dissolved in EtOAc, washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was dissolved in THF (3 ml) and NaH (60% in mineral oil, 87 mg, 2.27 mmol) was added at rt. After 10 min iodomethane (141 μl, 2.27 mmol) was added and the reaction mixture was stirred at rt overnight. Water was added, the organic layer separated, dried over Na 2 SO 4 , filtered and concentrated to give the product (213 mg, 79%). MS ES+m/z 236 [M+H] + .

1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (128 mg, 0.45 mmol) and 3-bromo-5-chloro-4-(methoxymethyl)pyridine (158 mg, 0.67 mmol) were dissolved in 1,4-dioxane (6 ml) and water (1.6 ml) and degassed with nitrogen. PdCl 2 (PPh 3 ) 2 (16 mg, 0.02 mmol) and K 2 CO 3 (62 mg, 0.45 mmol) were added and the mixture was stirred at 50° C. for 2 h. DCM and brine were added, the organic layer separated and the aqueous layer extracted with DCM. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (73 mg, 52%). MS ES+m/z 317 [M+H] + .

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for 1-[4-[5-chloro-4-(methoxymethyl)-3-pyridyl]phenyl]pyrrolidin-2-one and 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, to give the product as a solid (12 mg, 17%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 2.16-2.26 (m, 2H), 2.59-2.66 (m, 2H), 3.15-3.20 (m, 3H), 3.95-3.97 (m, 1H), 3.97-4.01 (m, 1H), 4.05-4.09 (m, 2H), 7.53-7.59 (m, 2H), 7.63-7.67 (m, 2H), 7.77-7.81 (m, 2H), 8.49-8.54 (m, 1H), 8.55-8.60 (m, 1H), 8.64-8.70 (m, 2H). MS ES+m/z 360 [M+H] + .

The title compound was prepared as described in Example 81, replacing 1-[3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one for 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one and 3,5-dibromopyridine for 5-bromo-3-iodo-pyridin-2-amine, to give the product as a solid (9 mg, 2%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.84-3.91 (m, 2H), 5.99-6.03 (m, 8.49 (m, 1H), 8.51-8.56 (m, 2H). MS ES+m/z 331 [M+H] + .

Example 85: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide

1-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one (456 mg, 1.59 mmol) and 5-bromo-3-iodo-pyridin-2-amine (500 mg, 1.67 mmol) were dissolved in n-BuOH (8 ml) and water (1 ml). The solution was degassed with nitrogen, PdCl 2 (PPh 3 ) 2 (59 mg, 0.08 mol) and K 2 CO 3 (277 mg, 2 mmol) were added and the resulting mixture was stirred at 100° C. for 5 h. When cooled to rt the mixture was diluted with DCM and water. The organic layer was separated and the aqueous layer extracted with DCM. The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-10% MeOH in DCM to give the product as a solid (420 mg, 76%). MS ES+m/z 332 [M+H] + .

Step 2: Intermediate 90—1-[4-[2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one

A mixture of 1-[4-(2-amino-5-bromo-3-pyridyl)phenyl]pyrrolidin-2-one (1.5 g, 4.52 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.72 g, 6.77 mmol), KOAc (1.33 g, 13.5 mmol) and PdCl 2 (dppf) (330 mg, 0.45 mmol) in DMSO (21 ml) was stirred at 100° C. for 2 h. When cooled to rt water and 1,2-dichloroethane were added, the organic layer was separated and the aqueous layer extracted with 1,2-dichloroethane. The combined organics were dried over Na 2 SO 4 , filtered through celite and concentrated. The resulting residue was triturated with cold Et 2 O to give the product as a solid (680 mg, 40%). MS ES+m/z 380 [M+H] + .

Step 3: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-methylfuro[2,3-b]pyridine-2-carboxamide

1-[4-[2-Amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (100 mg, 0.26 mmol), 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (58 mg, 0.28 mmol), K 2 CO 3 (73 mg, 0.53 mmol) and PdCl 2 (Amphos) (10 mg, 0.014 mmol) were taken up in 1,4-dioxane (1 ml) and distilled water (0.3 ml) and the mixture was stirred at 90° C. for 30 min. When cooled to rt the mixture was filtered, concentrated and purified by preparative HPLC to give the product as a solid (49 mg, 43%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.10 (t, J=7.57 Hz, 2H), 2.52-2.55 (m, 2H), 2.81 (d, J=4.41 Hz, 3H), 3.89 (t, J=7.09 Hz, 2H), 6.17 (s, 2H), 7.57-7.60 (m, 2H), 7.61 (d, J=5.36 Hz, 1H), 7.72 (s, 1H), 7.75 (d, J=2.52 Hz, 1H), 7.78-7.81 (m, 2H), 8.42 (d, J=5.36 Hz, 1H), 8.46 (d, J=2.21 Hz, 1H), 8.80 (d, J=4.73 Hz, 1H). MS ES+m/z 428 [M+H] + .

Example 86: 1-(4-(2-amino-5-(7-methoxy-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine, to give the product as a solid (2 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.14 (m, 2H), 2.51-2.55 (m, 2H), 3.86-3.91 (m, 2H), 4.06-4.11 (m, 3H), 5.75-5.82 (m, 2H), 7.57-7.61 (m, 2H), 7.62-7.64 (m, 1H), 7.75-7.80 (m, 2H), 7.81 (s, 1H), 8.29 (s, 1H), 8.30-8.33 (m, 1H), 13.57-14.26 (bs, 1H). MS ES+m/z 401 [M+H] + .

Example 87: 1-(4-(2-amino-5-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 3-bromo-1-methyl-pyrrolo[2,3-b]pyridine and 1,4-dioxane for DMSO, to give the product as a solid (7 mg, 14%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.13 (m, 2H), 2.51-2.57 (m, 2H), 3.83-3.86 (m, 3H), 3.86-3.90 (m, 2H), 5.59 (s, 2H), 7.12-7.18 (m, 1H), 7.54-7.59 (m, 2H), 7.59-7.62 (m, 1H), 7.75-7.80 (m, 2H), 7.82-7.88 (m, 1H), 8.19-8.23 (m, 1H), 8.31 (br d, J=2.52 Hz, 2H). MS ES+m/z 384 [M+H] + .

Example 88: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-7-(cyclopropylmethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-chloro-7-(cyclopropylmethyl)-8,9-dihydropyrido[3,4]pyrrolo[3,5-b]pyrazin-6-one, to give the product as a solid (18 mg, 23%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.20-0.32 (m, J=4.73 Hz, 2H), 0.48-0.52 (m, J=4.73 Hz, 2H), 1.06-1.09 (m, 1H), 2.10 (m, 2H), 2.52-2.57 (m, 2H), 3.43 (d, J=6.94 Hz, 2H), 3.89 (t, J=6.94 Hz, 2H), 3.92-3.94 (m, 2H), 4.43-4.45 (m, 2H), 6.06 (s, 2H), 7.12 (s, 1H), 7.35 (d, J=5.04 Hz, 1H), 7.57 (d, J=8.83 Hz, 2H), 7.73 (d, J=2.52 Hz, 1H), 7.80 (d, J=8.83 Hz, 2H), 8.42 (d, J=5.04 Hz, 1H), 8.44 (d, J=2.52 Hz, 1H). MS ES+m/z 493 [M+H] + .

Example 89: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(cyclopropylmethyl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-chloro-N-(cyclopropylmethyl)furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (21 mg, 25%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.25 (dd, J=4.73, 1.58 Hz, 2H), 0.45 (dd, J=8.04, 1.73 Hz, 2H), 1.01-1.08 (m, 1H), 2.10 (t, J=7.72 Hz, 2H), 2.52-2.56 (m, 2H), 3.16 (t, J=6.31 Hz, 2H), 3.89 (t, J=6.94 Hz, 2H), 6.16 (s, 2H), 7.54-7.60 (m, 2H), 7.61 (d, J=5.36 Hz, 1H), 7.76 (d, J=2.52 Hz, 1H), 7.77 (s, 1H), 7.78-7.81 (m, 2H), 8.42 (d, J=5.36 Hz, 1H), 8.47 (d, J=2.21 Hz, 1H), 8.94 (s, 1H). MS ES+m/z 468 [M+H] + .

Example 90: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(2-methoxyethyl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-chloro-N-(2-methoxyethyl)furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (30 mg, 36%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (d, J=7.57 Hz, 2H), 2.52-2.55 (m, 2H), 3.27 (s, 3H), 3.41-3.50 (m, 4H), 3.89 (t, J=6.94 Hz, 2H), 6.17 (s, 2H), 7.58 (d, J=8.83 Hz, 2H), 7.61 (d, J=5.04 Hz, 1H), 7.75 (d, J=2.21 Hz, 1H), 7.77-7.82 (m, 3H), 8.42 (d, J=5.36 Hz, 1H), 8.47 (d, J=2.52 Hz, 1H), 8.85-8.88 (m, 1H). MS ES+m/z 472 [M+H] + .

Example 91: 1-(4-(2-amino-5-(1-methyl-5-(2-oxopyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 1-(3-iodo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)pyrrolidin-2-one, to give the product as a solid (40 mg, 33%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quind, J=7.49, 7.49, 7.49, 7.49, 4.10 Hz, 4H), 2.48-2.49 (m, 1H), 2.52-2.56 (m, 3H), 3.84-3.96 (m, 7H), 5.60 (s, 2H), 7.54-7.60 (m, 3H), 7.79 (d, J=7.80 Hz, 2H), 7.87 (s, 1H), 8.29 (d, J=2.21 Hz, 1H), 8.43 (d, J=2.21 Hz, 1H), 8.50 (d, J=2.21 Hz, 1H). MS ES+m/z 467 [M+H] + .

Example 92: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1-methyl-6-((tetrahydro-2H-pyran-4-yl)methyl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-bromo-1-methyl-6-(tetrahydropyran-4-ylmethyl)pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (30 mg, 30%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.23-1.37 (m, 2H), 1.46 (br d, J=11.03 Hz, 2H), 2.04-2.15 (m, 3H), 2.52-2.56 (m, 2H), 3.17-3.29 (m, 2H), 3.81-3.93 (m, 6H), 4.10 (s, 3H), 5.72 (s, 2H), 7.30 (s, 1H), 7.53-7.59 (m, 3H), 7.78 (d, J=7.75 Hz, 2H), 8.21 (d, J=2.52 Hz, 1H), 8.36 (s, 1H). MS ES+m/z 499 [M+H] + .

Example 93: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-N-(oxetan-3-yl)furo[2,3-b]pyridine-2-carboxamide

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-chloro-N-(oxetan-3-yl)furo[2,3-b]pyridine-2-carboxamide, to give the product as a solid (1 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.10 (t, J=7.57 Hz, 2H), 2.51-2.55 (m, 2H), 3.89 (t, J=7.09 Hz, 2H), 4.64 (t, J=6.46 Hz, 2H), 4.77 (dd, J=7.25, 6.62 Hz, 2H), 5.04 (m, 1H), 6.18 (s, 2H), 7.57-7.61 (m, 2H), 7.62 (d, J=5.36 Hz, 1H), 7.76 (d, J=2.52 Hz, 1H), 7.80 (d, J=8.83 Hz, 2H), 7.85 (s, 1H), 8.44 (d, J=5.36 Hz, 1H), 8.47 (d, J=2.52 Hz, 1H), 9.52 (d, J=6.62 Hz, 1H). MS ES+m/z 470 [M+H] + .

Example 94: methyl 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, to give the product as a solid (3 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.10 (quin, J=7.49 Hz, 2H), 2.51-2.56 (m, 2H), 3.87 (s, 3H), 3.87-3.92 (m, 2H), 6.04 (s, 2H), 7.24 (s, 1H), 7.30 (d, J=5.04 Hz, 1H), 7.53-7.61 (m, 2H), 7.71 (d, J=2.21 Hz, 1H), 7.77-7.82 (m, 2H), 8.41 (d, J=4.73 Hz, 1H), 8.43 (d, J=2.52 Hz, 1H). MS ES+m/z 428 [M+H] + .

Example 95: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-chloro-5,6-dihydropyrrolo[3,4-b]pyridin-7-one, to give the product as a solid (2 mg, 2%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.13 (m, 2H), 2.52-2.57 (m, 2H), 3.84-3.92 (m, 2H), 4.62-4.68 (m, 2H), 6.08-6.13 (m, 2H), 7.51-7.58 (m, 2H), 7.68-7.72 (m, 1H), 7.72-7.76 (m, 1H), 7.76-7.81 (m, 2H), 8.36-8.39 (m, 1H), 8.66-8.71 (m, 1H), 9.00-9.04 (m, 1H). MS ES+m/z 386 [M+H] + .

Example 96: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dimethyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-bromo-1,6-dimethyl-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (29 mg, 13%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.13 (m, 2H), 2.51-2.55 (m, 2H), 3.49-3.51 (m, 3H), 3.86-3.91 (m, 2H), 4.08-4.11 (m, 3H), 5.69-5.73 (m, 2H), 7.31-7.33 ((m, 1H), 7.52-7.54 (m, 1H), 7.54-7.58 (m, 2H), 7.74-7.80 (m, 2H), 8.18-8.22 (m, 1H), 8.35 (s, 1H). MS ES+m/z 415 [M+H] + .

Example 97: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-6-isobutyl-1-methyl-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 4-bromo-6-isobutyl-1-methyl-pyrazolo[3,4-c]pyridin-7-one, to give the product as a solid (14 mg, 12%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.89 (d, J=6.62 Hz, 6H), 2.05-2.18 (m, 3H), 2.52-2.56 (m, 2H), 3.80 (d, J=7.25 Hz, 2H), 3.89 (t, J=7.09 Hz, 2H), 4.10 (s, 3H), 5.72 (s, 2H), 7.28 (s, 1H), 7.53-7.60 (m, 3H), 7.78 (d, J=7.86 Hz, 2H), 8.21 (d, J=2.52 Hz, 1H), 8.36 (s, 1H). MS ES+m/z 457 [M+H] + .

Example 98: 1-(4-(2-amino-5-(5-(1-hydroxyethyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for 1-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)ethanol, to give the product as a solid (12 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.42 (d, J=6.31 Hz, 3H), 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.56 (m, 2H), 3.84 (s, 3H), 3.90 (t, J=7.09 Hz, 2H), 4.92 (br dd, J=6.31, 3.47 Hz, 1H), 5.21 (d, J=3.78 Hz, 1H), 5.58 (s, 2H), 7.54-7.61 (m, 3H), 7.78-7.83 (m, 3H), 8.13 (d, J=1.89 Hz, 1H), 8.31 (dd, J=9.30, 2.05 Hz, 2H). MS ES+m/z 428 [M+H] + .

Example 99: 4-(6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

A mixture of 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (95 mg, 0.25 mmol) and 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine (57 mg, 0.25 mmol) in 1,4-dioxane (1 ml) and water (0.1 ml) was degassed with nitrogen. PdCl 2 (Amphos) (9 mg, 0.013 mmol) and K 2 CO 3 (69 mg, 0.5 mmol) were added and the resulting mixture was stirred at 100° C. for 2 h. When cooled to rt water and 1,2-dichloroethane were added, the organic layer was separated and the aqueous layer extracted with 1,2-dichloroethane. The combined organics were dried over Na 2 SO 4 , filtered and concentrated. The resulting residue was dissolved in MeCN (3 ml), NaI (38 mg, 0.25 mmol) and TMSCl (33 μl, 0.26 mmol) were added and the mixture was stirred at 60° C. for 1 h. When cooled to rt water and 1,2-dichloroethane were added, the aqueous layer was separated, concentrated and purified by preparative HPLC to give the product as a solid (3 mg, 3%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.14 (m, 2H), 2.51-2.55 (m, 2H), 3.86-3.90 (m, 2H), 5.64-5.74 (m, 2H), 7.00-7.08 (m, 1H), 7.49-7.54 (m, 1H), 7.54-7.60 (m, 2H), 7.73-7.80 (m, 2H), 8.02-8.13 (m, 1H), 8.18-8.24 (m, 1H), 11.29-11.51 (m, 1H), 13.30-14.75 (m, 1H). MS ES+m/z 387 [M+H] + .

A mixture of 3-bromopyridin-2-amine (14.0 g, 80.9 mmol), B 2 Pin 2 (41.1 g, 162 mmol), KOAc (23.8 g, 243 mmol) and Pd(dppf)Cl 2 (2.37 g, 3.24 mmol, 4 mol %) in dioxane (200 mL) was stirred at 110° C. for 3 hour under N 2 atmosphere. The red suspension turned to black. Crude LCMS showed the purity of product is 11% (Rt=0.775 min; MS Calc'd: 220.1; MS Found: 221.1 [M+H] + ). The reaction mixture was diluted with EtOAc (80 mL), filtered and concentrated to give crude compound 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (60.0 g) as black oil and directly used to next step.

To a mixture of methyl 6-bromopyridine-3-carboxylate (15.0 g, 69.4 mmol) in THF (75 mL) and H 2 O (15 mL) was added NaOH (11.1 g, 278 mmol) in one portion at 25° C. Then the mixture was stirred for 16 h. TLC showed the reaction was completed. The mixture was poured into water (100 mL) and washed with EtOAc (150 mL×2). The aqueous phase was acidified with HCl aq. (1N) to pH=3 and extracted with EtOAc (150 mL×3). The combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum to afford 6-bromonicotinic acid (13.0 g, yield: 93%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.80 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=8.4, 2.4 Hz), 8.48 (1H, d, J=2.4 Hz).

A mixture of 6-bromonicotinic acid (13.0 g, 64.3 mmol) in SOCl 2 (150 mL) was heated at 80° C. for 2 h under N 2 atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure. Then to the mixture was added DCM (240 mL), Me 2 NH (7.00 g, 85.8 mmol) and TEA (60 mL), the mixture was stirred at 25° C. for 16 h under N 2 . TLC showed the reaction was completed. The residue was poured into water (100 mL) and extracted with DCM (100 mL×3). The combined organic layer was washed with water (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 6-bromo-N,N-dimethylnicotinamide (12.2 g, yield: 83%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.92 (3H, s), 2.99 (3H, s), 7.59 (1H, dd, J=8.4, 0.8 Hz), 7.92 (1H, dd, J=8.4, 2.4 Hz), 8.47 (1H, dd, J=2.4, 0.8 Hz).

A mixture of 6-bromo-N,N-dimethylnicotinamide (11.0 g, 48.0 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (17.8 g, 80.9 mmol), Na 2 CO 3 (2 M in water, 120 mL) and Pd(dppf)Cl 2 (2.11 g, 2.88 mmol, 6 mol %) in DME (240 mL) was stirred at 110° C. for 16 h under N 2 atmosphere. Crude LCMS showed the purity of product is 38% (Rt=0.286 min; MS Calc'd: 242.1; MS Found: 242.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (300 mL), washed with water (80 mL×3), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (85% EtOAc in pentane) to afford 2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (11.3 g, yield: 97%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 6.69 (1H, dd, J=7.6, 4.8 Hz), 7.44 (2H, s), 7.95 (1H, dd, J=8.4, 2.4 Hz), 8.01 (1H, dd, J=8.4, 0.8 Hz), 8.06 (1H, s), 8.08 (1H, dd, J=4.4, 1.6 Hz), 8.70 (1H, dd, J=2.4, 1.2 Hz).

To a mixture of 2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (11.3 g, 46.6 mmol) in MeCN (120 mL) was added NBS (8.50 g, 48.0 mmol) in one portion at 0° C. The mixture was stirred at 25° C. for 16 hour. The color of the mixture was form light to deep yellow. TLC showed the reaction was completed. The residue was quenched with sat. aq. Na 2 S 2 O 3 (100 mL) and NaHCO 3 (100 mL) and stirred for 30 min. The reaction mixture was extracted with EtOAc (100 mL×3). The combined organic layer was washed with sat. NaHCO 3 (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (14.3 g, yield: 95%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.99 (3H, s), 3.02 (3H, s), 7.62 (2H, br s), 7.95 (1H, dd, J=8.4, 2.4 Hz), 8.08 (1H, dd, J=8.4, 0.8 Hz), 8.12 (1H, d, J=2.0 Hz), 8.23 (1H, d, J=2.4 Hz), 8.70 (1H, dd, J=2.0, 0.8 Hz).

Step 6: Preparation of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (250 mg, 0.778 mmol), B 2 Pin 2 (237 mg, 0.934 mmol), Pd(dppf)Cl 2 (57 mg, 0.078 mmol, 10 mol %) and KOAc (229 mg, 2.34 mmol) in dioxane (3 mL) was stirred at 100° C. for 5 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 5% (Rt=0.559 min; MS Calc'd: 368.2; MS Found: 368.8 [M+H] + ). The mixture was filtered and concentrated in vacuum to afford 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (300 mg, crude) as a red solid and immediately used to next step.

Step 7: Preparation of 2′-amino-5′-(6-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (292 mg, 0.795 mmol, crude), 4-chloroquinoline-6-carbonitrile (100 mg, 0.530 mmol), Cs 2 CO 3 (1 M in water, 1.1 mL) and CataCXium A-Pd-G2 (35 mg, 0.053 mmol, 10 mol %) in dioxane (5 mL) was stirred at 100° C. for 17 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 15% (Rt=0.631 min; MS Calc'd: 394.2; MS Found: 395.1 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (90% EtOAc in pentane), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as additive) and lyophilized to afford 2′-amino-5′-(6-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (17.4 mg, yield: 8%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 99.88%, Rt=1.050 min; MS Calc'd.: 394.2; MS Found: 395.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 7.15 (2H, br s), 7.50 (1H, d, J=4.4 Hz), 7.78 (1H, d, J=8.8 Hz), 7.89 (1H, dd, J=4.0, 1.6 Hz), 7.91 (1H, dd, J=3.6, 2.4 Hz), 8.01 (1H, d, J=2.0 Hz), 8.27 (1H, d, J=8.8 Hz), 8.30 (1H, d, J=2.4 Hz), 8.41 (1H, d, J=1.2 Hz), 8.78 (1H, dd, J=2.4, 0.8 Hz), 9.08 (1H, d, J=4.0 Hz).

To a solution of Methyl 4-bromopyridine-2-carboxylate 9a (300 mg, 1.39 mmol) in THF (10 mL) was added MeMgBr (3 M in THF, 2.3 mL) at 0° C. The reaction was warmed to 25° C. and stirred for 0.5 h. The colourless reaction mixture turned to yellow. TLC showed the reaction was completed. After quenching with saturated NaHCO 3 (5 mL), diluting with DCM (40 mL), the resulting mixture was stirred vigorously for 30 min to break up the resulting solid. The organic layer was washed with NaHCO 3 (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. This residue were purified by Combi Flash (7% EtOAc in PE) to give compound 9 (170 mg, yield: 57%) as yellow oil. 1H NMR (400 MHz, CDCl 3 ) δ 1.54 (3H, s), 1.56 (3H, s), 4.50 (1H, s), 7.37 (1H, dd, J=5.6, 2.0 Hz), 7.58 (1H, s), 8.34 (1H, d, J=5.2 Hz)

Step 2: Preparation of 2′-amino-2″-(2-hydroxypropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (300 mg, crude), 2-(4-bromo-2-pyridyl)propan-2-ol (100 mg, 0.463 mmol), Cs 2 CO 3 (452 mg, 1.39 mmol) and Pd(t-Bu 3 P) 2 (24 mg, 0.046 mmol, 10 mol %) in dioxane (1 mL) and H 2 O (0.1 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 37% (Rt=0.540 min; MS Calc'd: 377.2; MS Found: 378.0 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (10% MeOH in EtOH) to give an impure product which was purified by re-crystallization from MeCN (1 mL) to give the pure 2′-amino-2″-(2-hydroxypropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide (16 mg, yield: 9%) as a yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 99.29%, Rt=2.260 min; MS Calc'd.: 377.2, MS Found: 378.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 1.61 (6H, s), 3.10 (3H, s), 3.17 (3H, m), 4.90 (1H, s), 7.03 (2H, br s), 7.35-7.45 (1H, m), 7.55 (1H, s), 7.87 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=2.4 Hz), 8.13 (1H, d, J=2.8 Hz), 8.47 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=4.8 Hz), 8.75 (1H, d, J=2.0 Hz).

To a mixture of 4-bromo-2-fluoropyridine (500 mg, 2.84 mmol) and isobutyronitrile (216 mg, 3.12 mmol) in toluene (10 mL) was added LHMDS (1 M in hexane, 4.3 mL) at −5° C. and the mixture was stirred at 25° C. for 16 hour. TLC showed the reaction was completed. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (5% EtOAc in pentane) to 2-(4-bromopyridin-2-yl)-2-methylpropanenitrile (590 mg, yield: 92%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.71 (6H, s), 7.69 (1H, dd, J=5.6, 2.0 Hz), 7.84 (1H, s), 8.50 (1H, d, J=5.2 Hz).

Step 2: Preparation of 2′-amino-2″-(2-cyanopropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (150 mg, 0.407 mmol, crude), 2-(4-bromopyridin-2-yl)-2-methylpropanenitrile (46 mg, 0.204 mmol), Na 2 CO 3 (2 M in water, 0.51 mL) and Pd(dppf)Cl 2 (15 mg, 0.020 mmol, 10 mol %) in DME (2 mL) was stirred at 110° C. for 16 hour under N 2 atmosphere. Crude LCMS showed the purity of product is 31% (Rt=0.865 min; MS Calc'd: 386.2; MS Found: 387.2 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (90% EtOAc in pentanepentane), then the impure product was purified by prep-HPLC (0.1% TFA as additive) and lyophilized to afford 2′-amino-2″-(2-cyanopropan-2-yl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide (39.0 mg, yield: 49%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 99.79%, Rt=2.590 min; MS Calc'd.: 386.2, MS Found: 387.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.77 (6H, s) 2.98 (3H, s), 3.02 (3H, s), 7.82 (1H, dd, J=5.2, 1.6 Hz), 7.91 (1H, d, J=1.2 Hz), 8.06 (1H, dd, J=8.4, 2.0 Hz), 8.31 (1H, d, J=7.8 Hz), 8.63 (1H, d, J=2.4 Hz), 8.64 (1H, s), 8.71 (1H, d, J=2.4 Hz), 8.73 (1H, dd, J=2.4, 0.8 Hz).

To a mixture of 4-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol) and cyclopropanecarbonitrile (572 mg, 8.52 mmol) in toluene (10 mL) was added LHMDS (1 M in hexane, 10.0 mL) at −5° C. and the mixture was stirred at 25° C. for 16 h. TLC showed the reaction was completed. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (5% EtOAc in pentane) to afford 1-(4-bromopyridin-2-yl)cyclopropane-1-carbonitrile (300 mg, yield: 47%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.64-1.77 (2H, m), 1.77-1.94 (2H, m), 7.53-7.70 (1H, m), 7.67 (1H, s), 8.40 (1H, d, J=5.2 Hz).

Step 2: Preparation of 2′-amino-2″-(1-cyanocyclopropyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (196 mg, 0.534 mmol, crude), 1-(4-bromopyridin-2-yl)cyclopropane-1-carbonitrile (80 mg, 0.36 mmol), Na 2 CO 3 (2 M in water, 0.9 mL) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol) in DME (4 mL) was stirred at 100° C. for 16 hour under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 38% (Rt=0.538 min; MS Calc'd: 384.2; MS Found: 384.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (85% EtOAc in pentane), then the impure product was washed with MTBE (3 mL×3) to afford 2′-amino-2″-(1-cyanocyclopropyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide as an off-white solid. At last, the product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as additive) and lyophilized to afford 2′-amino-2″-(1-cyanocyclopropyl)-N,N-dimethyl-[2,3′:5′,4″-terpyridine]-5-carboxamide (27.8 mg yield: 20%) as a light yellow solid.

LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 99.83%, Rt=2.586 min; MS Calc'd.: 384.2, MS Found: 385.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 1.75 (2H, q, J=3.6 Hz), 1.89 (2H, q, J=4.0 Hz), 3.10 (3H, s), 3.17 (3H, s), 7.06 (2H, br s), 7.36 (1H, dd, J=5.2, 2.0 Hz), 7.90-7.85 (2H, m), 7.92 (1H, dd, J=8.4, 2.0 Hz), 8.16 (1H, d, J=3.2 Hz), 8.47 (1H, dd, J=5.6, 0.8 Hz), 8.49 (1H, d, J=2.4 Hz), 8.75 (1H, dd, J=2.4, 0.4 Hz).

A mixture of furo[2,3-b]pyridine 7-oxide (170 mg, 1.26 mmol) in CHCl 3 (10 mL) was added POBr 3 (361 mg, 1.26 mmol) and the mixture was stirred at 70° C. for 18 h. The colourless solution produced yellow precipitate. TLC showed the reaction was completed. The mixture was poured into ice-water (20 mL) and stirred at 25° C. for 30 min. The aqueous phase was extracted with DCM (20 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (5% EtOAc in pentane) to give 4-bromofuro[2,3-b]pyridine (90 mg, yield: 36%) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 6.83 (1H, d, J=2.4 Hz), 7.42 (1H, d, J=5.2 Hz), 7.76 (1H, d, J=2.4 Hz), 8.16 (1H, d, J=5.2 Hz).

Step 2: Preparation of 2′-amino-5′-(furo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

A mixture of 4-bromofuro[2,3-b]pyridine (80 mg, 0.40 mmol), 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (229 mg, 0.622 mmol), Pd(t-Bu 3 P) 2 (21 mg, 0.040 mmol, 10 mol %) and Cs 2 CO 3 (1 M in water, 1 mL) in dioxane (4 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 36%. (Rt=0.610 min; MS Calc'd: 359.1; MS Found: 360.0 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (85% EtOAc in pentane) then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as additive) and lyophilized to give 2′-amino-5′-(furo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (5.6 mg, yield: 4%) as a yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 98.36%, Rt=2.359 min; MS Calc'd.: 359.1, MS Found: 360.1 [M+H] + .

1 H NMR (400 MHz, CDCl 3 ) δ 3.11 (3H, s), 3.17 (3H, s), 6.99 (1H, d, J=2.4 Hz), 7.08 (2H, br s), 7.33 (1H, d, J=5.2 Hz), 7.78 (1H, d, J=2.4 Hz), 7.85 (1H, dd, J=8.4, 0.4 Hz), 7.93 (1H, dd, J=4.4, 2.4 Hz), 8.20 (1H, d, J=2.0 Hz), 8.39 (1H, d, J=4.8 Hz), 8.53 (1H, d, J=2.0 Hz), 8.76 (1H, dd, J=2.0, 0.8 Hz).

Example 105: 2′-amino-N,N-dimethyl-5′-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.02 mmol) in DMF (3 mL) was added NaH (49 mg, 2.0 mmol, 60% in mineral oil) at 0° C. Then to the mixture was stirred at 0° C. for 30 min. And then MeI (290 mg, 2.04 mmol) was added to the above mixture at 0° C., then the mixture was stirred at 25° C. for 15.5 h. TLC showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was poured into water (50 mL) and stirred at 0° C. for 30 min. The aqueous phase was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (10% EtOAc in pentane) to give 4-bromo-1-methyl-H-pyrrolo[2,3-b]pyridine (180 mg, yield: 84%) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 3.89 (3H, s), 6.49 (1H, d, J=3.6 Hz), 7.20-7.25 (1H, m), 7.26 (1H, d, J=2.4 Hz), 8.13 (1H, d, J=5.2 Hz).

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (360 mg, crude),4-bromo-1-methyl-pyrrolo[2,3-b]pyridine (103 mg, 0.489 mmol), Na 2 CO 3 (2 M in water, 1 mL) and Pd(dppf)Cl 2 (36 mg, 0.049 mmol, 10 mol %) in DME (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 13% (Rt=0.513 min; MS Calc'd: 372.1; MS Found: 372.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (90% EtOAc in pentane), then the impure product was purified by prep-HPLC (0.1% TFA as additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide (15.8 mg, yield: 9%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 97.33%, Rt=2.472 min; MS Calc'd.: 372.1, MS Found: 373.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.11 (3H, s, overlapped with H 2 O signal), 3.19 (3H, s, overlapped with H 2 O signal), 4.05 (3H, s), 6.72 (1H, d, J=3.6 Hz), 7.29 (1H, d, J=5.2 Hz), 7.40 (1H, d, J=3.6 Hz), 7.98 (1H, d, J=8.4 Hz), 8.04 (1H, dd, J=8.0, 1.6 Hz), 8.37 (1H, s), 8.60 (1H, d, J=6.4 Hz), 8.61 (1H, s), 8.80 (1H, d, J=1.6 Hz). 10.27 (2H, br s).

To a mixture of 4-bromopyridine-2,3-diamine (1.00 g, 5.32 mmol) in THF (30 mL) was added CDI (1.73 g, 10.6 mmol). The mixture was stirred at 80° C. for 8 h under N 2 . A deep yellow solution was formed. TLC showed the starting material was consumed completely. The reaction mixture was filtered and concentrated. The residue was washed with DCM (30 mL) to give 7-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.01 g, yield: 89%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.15 (1H, d, J=5.6 Hz), 7.72 (1H, d, J=5.6 Hz), 11.48 (2H, br s).

Step 2: Preparation of 7-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a solution of 7-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.01 g, 4.72 mmol) was added NaH (472 mg, 11.8 mmol, 60% purity in mineral oil) in DMF (15 mL). The reaction mixture was cooled to 0° C. for 0.5 h, and then added SEMCl (2.1 mL, 11.80 mmol) dropwise. The reaction mixture was warmed to 20° C., stirred at 20° C. for 16 h under N 2 atmosphere. The yellow solution turned to dark red gradually. LCMS showed the purity of the desired product (Rt=0.963 min; MS Calc'd: 473.1; MS Found: 476.1 [M+H] + ). The reaction mixture was quenched with MeOH (2 mL), then DMF was removed under reduced pressure. The residue was purified by Combi Flash (2% EA in pentane) to afford 7-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.65 g, yield: 74%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 0.01 (18H, s), 0.92-0.99 (4H, m), 3.60-3.72 (4H, m), 5.42 (2H, s), 5.58 (2H, s), 7.18 (1H, d, J=5.6 Hz), 7.89 (1H, d, J=5.2 Hz).

Step 3: Preparation of 2′-amino-N,N-dimethyl-5′-(2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (170 mg, crude), 7-bromo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (169 mg, 0.355 mmol), Cs 2 CO 3 (1 M in water, 0.1 mL) and Pd(t-Bu 3 P) 2 (18 mg, 0.036 mmol) in dioxane (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 55% (Rt=0.732 min; MS Calc'd: 635.3; MS Found: 636.3 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by prep-HPLC to afford 2′-amino-N,N-dimethyl-5′-(2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide (35.0 mg, yield: 16%) as yellow oil.

Step 4: Preparation of 2′-amino-N,N-dimethyl-5′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 2′-amino-N,N-dimethyl-5′-(2-oxo-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide (35 mg, 0.55 mmol) in DCM (1 mL) was added TFA (1 mL) at 20° C., and it was stirred at 20° C. for 1 hour. Then the mixture was concentrated under reduced pressure and the residue was diluted with MeOH (1 mL) and then EDA (0.1 mL) was added at 20° C. The residue was stirred at 20° C. for 16 h under N 2 atmosphere. Crude LCMS showed the purity of product (Rt=0.459 min, MS Calc'd.: 375.1; MS Found: 376.0 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% TFA as an additive) and lyophilized to give 2′-amino-N,N-dimethyl-5′-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide (6.0 mg, yield: 29%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 99.37%, Rt=1.284 min; MS Calc'd.: 375.1; MS Found: 376.0 [M+H] + .

1 H NMR (400 MHz, DMSO) δ 3.00 (3H, s), 3.03 (3H, s), 7.14 (1H, d, J=4.8 Hz), 7.77 (2H, br s), 7.91 (1H, d, J=5.6 Hz), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.26-8.18 (2H, m), 8.35 (1H, d, J=2.4 Hz), 8.35 (1H, d, J=1.2 Hz), 11.16 (H, br s), 11.39 (H, br s).

Example 114: methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (404 mg, crude), methyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (200 mg, 0.784 mmol), Cs 2 CO 3 (1 M in water, 0.8 mL) and Pd(t-Bu 3 P) 2 (40 mg, 0.078 mmol) in dioxane (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 14% (Rt=0.593 min; MS Calc'd: 416.2; MS Found: 417.3 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (3.5 mg, yield: 1%) as a yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 95.10%, Rt=1.451 min; MS Calc'd.: 416.2; MS Found: 417.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.08 (3H, s), 3.17 (3H, s), 3.55 (3H, s), 7.20 (1H, d, J=4.8 Hz), 7.80 (1H, d, J=8.4 Hz), 7.88 (1H, dd, J=8.4, 2.4 Hz), 8.01 (1H, d, J=1.6 Hz), 8.14 (1H, s), 8.25 (1H, d, J=1.6 Hz), 8.42 (1H, d, J=4.8 Hz), 8.73 (1H, d, J=2.0 Hz), 9.78 (1H, br s).

Example 115:2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (279 mg, crude),4-bromo-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.505 mmol), Na 2 CO 3 (161 mg, 1.52 mmol) in water (1 ml) and Pd(dppf)Cl 2 (37 mg, 0.051 mmol) in DME (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 11% (Rt=0.480 min; MS Calc'd: 359.2; MS Found: 359.8 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (EtOAc), then the impure product was purified by prep-HPLC (0.1% TFA as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide (21.0 mg, yield: 12%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA]to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 98.02%, Rt=1.333 min; MS Calc'd.: 359.2; MS Found: 360.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.11 (3H, s), 3.19 (3H, s), 7.31 (1H, d, J=4.8 Hz), 7.98 (1H, d, J=8.4 Hz), 8.05 (1H, dd, J=8.4, 2.4 Hz), 8.28 (1H, s), 8.39 (1H, d, J=2.0 Hz), 8.66-8.61 (2H, m), 8.81 (1H, d, J=1.6 Hz), 10.32 (2H, br s).

Example 116: 2′-amino-5′-(3H-imidazo[4,5-b]pyridin-7-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of 7-bromo-3H-imidazo[4,5-b]pyridine (100 mg, 0.505 mmol) in anhydrous DMF (2.5 mL) was added NaH (31 mg, 1.27 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h under N 2 atmosphere. To the mixture was added SEM-C 1 (126 mg, 0.758 mmol) at 0° C., and stirred for another 16 h at 25° C. The light solution turned to deep yellow. Crude LCMS indicated that the purity of product is 37% (Rt=0.736 min; MS Calc'd.: 327.0; MS Found: 327.6 [M+H] + with bromine isotope). The mixture was quenched with H 2 O (15 mL) and then extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (25 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by Combi Flash (20-25% EtOAc in pentane) to give 7-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (93.0 mg, yield: 56%) as yellow oil.

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (156 mg, crude), 7-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridine (93 mg, 0.28 mmol), Cs 2 CO 3 (1 M in water, 0.3 mL) and Pd(t-Bu 3 P) 2 (15 mg, 0.028 mmol) in dioxane (3 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 33% (Rt=0.642 min; MS Calc'd: 489.2; MS Found: 490.0 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc) to afford 2′-amino-N,N-dimethyl-5′-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide (70 mg, crude) as black oil.

Step 3: Preparation of 2′-amino-5′-(3H-imidazo[4,5-b]pyridin-7-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of 2′-amino-N,N-dimethyl-5′-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-7-yl)-[2,3′-bipyridine]-5-carboxamide (30 mg, crude) in DCM (1.5 mL) was added TFA (1.5 mL) at 25° C., and it was stirred at 25° C. for 1 hour. Then the mixture was concentrated under reduced pressure and the residue was diluted with MeOH (1.5 mL) and then EDA (1.5 mL) was added at 25° C. The residue was stirred at 25° C. for 16 h under N 2 atmosphere. Crude LCMS showed the purity of product was 42% (Rt=0.565 min, MS Calc'd.: 359.2; MS Found: 360.2 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.1% TFA as an additive) and lyophilized to give 2′-amino-5′-(3H-imidazo[4,5-b]pyridin-7-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (7.6 mg, two steps yield: 8%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 98.42%, Rt=1.378 min; MS Calc'd.: 359.2; MS Found: 360.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.05 (3H, s), 7.80 (1H, d, J=5.2 Hz), 8.10 (1H, dd, J=8.4, 2.0 Hz), 8.28 (1H, d, J=8.4 Hz), 8.44 (1H, d, J=5.2 Hz), 8.61 (1H, d, J=0.8 Hz), 8.77 (1H, d, J=2.0 Hz), 9.23-9.16 (2H, m). 1 H NMR (400 MHz, DMSO-d 6 +-D 20 ) δ 2.98 (3H, s), 3.02 (3H, s), 7.74 (1H, d, J=5.6 Hz), 8.06 (1H, dd, J=8.0, 1.6 Hz), 8.24 (1H, d, J=8.0 Hz), 8.45 (1H, d, J=5.2 Hz), 8.56 (1H, s), 8.74 (1H, d, J=2.4 Hz), 9.05 (1H, s), 9.12 (1H, s).

Example 117:2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 3-bromo-H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.502 mmol) in anhydrous DMF (4 mL) was added NaH (18 mg, 0.75 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 0.5 h under N 2 atmosphere. The mixture was added SEM-C 1 (168 mg, 1.00 mmol) at 0° C., and stirred for another 16 h at 25° C. The light solution turned to deep yellow. TLC showed the starting material was consumed. The mixture was quenched with H 2 O (15 mL) and then extracted with EtOAc (20 mL×2). The combined organic layer was washed with brine (25 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by Combi Flash (20-25% EtOAc in pentane) to give 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, yield: 60%) as yellow oil.

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (168 mg, crude), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.30 mmol), Cs 2 CO 3 (1 M in water, 0.3 mL) and Pd(t-Bu 3 P) 2 (16 mg, 0.030 mmol) in dioxane (4 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 31% (Rt=0.636 min; MS Calc'd: 490.2; MS Found: 490.9 [M+H] + ). The reaction mixture was diluted with EtOAc (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc) to afford 2′-amino-N,N-dimethyl-5′-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide (100 mg, crude) as black oil.

Step 3: Preparation of 2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 2′-amino-N,N-dimethyl-5′-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide (100 mg, crude) in DCM (5 mL) was added TFA (7 mL) and stirred at 20° C. for 1 hour. Then the mixture was concentrated under reduced pressure and the residue was diluted with MeOH (5 mL) and then EDA (1 mL) was added at 20° C. The residue was stirred at 20° C. for 16 h under N 2 atmosphere. Crude LCMS showed the purity of product (Rt=0.465 min, MS Calc'd.: 360.1; MS Found: 360.7 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (10% MeOH in DCM) to give 2′-amino-N,N-dimethyl-5′-(1H-pyrazolo[3,4-d]pyrimidin-3-yl)-[2,3′-bipyridine]-5-carboxamide (3.6 mg, two steps yield: 4%) as a yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 95.22%, Rt=1.443 min; MS Calc'd.: 360.1; MS Found: 361.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.02 (3H, s), 3.04 (3H, s), 7.95 (2H, br s), 8.02 (1H, dd, J=8.0, 1.6 Hz), 8.24 (1H, dd, J=8.0, 0.4 Hz), 8.67 (1H, s), 8.75 (1H, d, J=1.6 Hz), 8.80 (1H, d, J=2.0 Hz), 9.03 (1H, s), 9.73 (1H, s), 14.16 (1H, s).

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (284 mg, crude), 4-bromoquinoline-5-carbonitrile (120 mg, 0.515 mmol), Cs 2 CO 3 (1 M in water, 1 mL) and Pd(t-Bu 3 P) 2 (26 mg, 0.051 mmol) in dioxane (6 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. The color of the mixture was black still. TLC showed the reaction was completed. The reaction mixture was diluted with EtOAc (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (EtOAc), then the impure product (70 mg) was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-5′-(5-cyanoquinolin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (4.8 mg, yield: 2%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 99.80%, Rt=2.317 min; MS Calc'd.: 394.2, MS Found: 395.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.07 (3H, s), 3.14 (3H, s), 7.11 (2H, br s), 7.47 (1H, d, J=4.4 Hz), 7.78-7.83 (2H, m), 7.85 (1H, dd, J=8.4, 2.4 Hz), 7.94 (1H, d, J=2.0 Hz), 8.03 (1H, dd, J=8.4, 1.6 Hz), 8.20 (1H, d, J=2.0 Hz), 8.44 (1H, dd, J=8.8, 1.2 Hz), 8.72 (1H, dd, J=2.4, 1.2 Hz), 9.03 (1H, d, J=4.0 Hz).

A mixture of 3-bromopyridin-2-amine (470 mg, 2.72 mmol), B 2 Pin 2 (1.38 g, 5.44 mmol), KOAc (800 mg, 8.16 mmol) and Pd(dppf)Cl 2 (199 mg, 0.272 mmol) in dioxane (7 mL) was stirred at 110° C. for 3 h under N 2 atmosphere. The red mixture turned to black. Crude LCMS showed the purity of product is 10%. (Rt=0.782 min; MS Calc'd: 220.1; MS Found: 221.1 [M+H] + ). The mixture was diluted with EtOAc (20 mL), filtered and concentrated under reduced pressure to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (crude) as a black solid and directly used to next step.

A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (883 mg, 4.02 mmol), 6-bromo-N,N-dimethylnicotinamide (460 mg, 2.01 mmol), Na 2 CO 3 (2 M in water, 5 mL) and Pd(dppf)Cl 2 (147 mg, 0.201 mmol, 10 mol %) in DME (13 mL) was stirred at 110° C. for 16 h under N 2 atmosphere. The colour of the mixture was black still. Crude LCMS showed the purity of product is 54%. (Rt=0.791 min; MS Calc'd: 242.1; MS Found: 243.1 [M+H] + ). The reaction mixture was diluted with EtOAc (50 mL), washed with water (15 mL×3), dried over Na 2 SO 4 , filtered and concentrated. The reaction mixture was purified by Combi Flash (75% EtOAc in pentane), then the crude product was purified by prep-TLC (DCM:MeOH=10:1) to give 2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (12.0 mg, yield: 2%) as a white solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 —H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 97.69%, Rt=1.875 min; MS Calc'd.: 242.1, MS Found: 243.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.09 (3H, s), 3.15 (3H, s), 6.73 (1H, dd, J=7.6, 4.8 Hz), 6.77 (2H, br s), 7.75 (1H, dd, J=8.4, 0.8 Hz), 7.86 (1H, dd, J=4.4, 2.4 Hz), 7.88 (1H, dd, J=4.0, 1.6 Hz), 8.14 (1H, dd, J=4.8, 1.6 Hz), 8.70 (1H, dd, J=2.0, 0.4 Hz).

To a mixture of 2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (11.3 g, 46.6 mmol) in MeCN (120 mL) was added NBS (8.50 g, 48.0 mmol) in one portion at 0° C. The mixture was stirred at 25° C. for 16 h. The color of the mixture was form light to deep yellow. TLC showed the reaction was completed. The residue was quenched with sat.Na 2 S 2 O 3 (100 mL) and NaHCO 3 (100 mL). The mixture was stirred for 30 min, extracted with EtOAc (100 mL×3). The combined organic layer was washed with sat.NaHCO 3 (100 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (14.3 g, yield: 95%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.99 (3H, s), 3.02 (3H, s), 7.62 (2H, br s), 7.95 (1H, dd, J=8.4, 2.4 Hz), 8.08 (1H, dd, J=8.4, 0.8 Hz), 8.12 (1H, d, J=2.0 Hz), 8.23 (1H, d, J=2.4 Hz), 8.70 (1H, dd, J=2.0, 0.8 Hz).

A mixture of 3-bromopyridine (150 mg, 0.949 mmol), B 2 Pin 2 (362 mg, 1.42 mmol), KOAc (280 mg, 2.85 mmol) and Pd(dppf)Cl 2 (70 mg, 0.095 mmol) in dioxane (5 mL) was stirred at 110° C. for 3 h under N 2 atmosphere. The red suspension turned to black. TLC showed the reaction was completed. The reaction mixture was diluted with EtOAc (10 mL), filtered and concentrated to give crude 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (crude) as black oil and directly used to next step.

A mixture of 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (188 mg, 0.585 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (180 mg, crude), Na 2 CO 3 (2 M in water, 1 mL) and Pd(dppf)Cl 2 (43 mg, 0.059 mmol) in DME (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 11% (Rt=0.306 min; MS Calc'd: 319.1; MS Found: 319.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford reparation of 2′-amino-N,N-dimethyl-[2,3′:5′,3″-terpyridine]-5-carboxamide (107 mg, yield: 57%) as alight yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 97.98%, Rt=2.079 min; MS Calc'd.: 319.1, MS Found: 320.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 6.95 (2H, br s), 7.36-7.42 (1H, m), 7.86 (1H, d, J=4.0 Hz), 7.88 (1H, d, J=6.4 Hz), 7.93 (1H, dd, J=8.4, 2.4 Hz), 8.09 (1H, d, J=2.0 Hz), 8.40 (1H, d, J=2.4 Hz), 8.60 (1H, dd, J=4.8, 1.6 Hz), 8.75 (1H, d, J=1.2 Hz), 8.84 (1H, d, J=2.0 Hz).

A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (250 mg, crude), 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (244 mg, 0.760 mmol), Na 2 CO 3 (2 M in water, 1 mL) and Pd(t-Bu 3 P) 2 (56 mg, 0.076 mmol, 10 mol %) in DME (4 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 7% (Rt=0.262 min; MS Calc'd: 334.1; MS Found: 335.2 [M+H] + ). The reaction mixture was diluted with EtOAc (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′,2″-diamino-N,N-dimethyl-[2,3′:5′,3″-terpyridine]-5-carboxamide (14.2 mg, two steps yield: 6%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 99.23%, Rt=1.294 min; MS Calc'd.: 334.1; MS Found: 334.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.08 (3H, s), 3.16 (3H, s), 4.55 (2H, br s), 6.77 (1H, dd, J=7.2, 4.8 Hz), 6.93 (2H, br s), 7.38 (1H, dd, J=7.2, 1.6 Hz), 7.78 (1H, d, J=8.0 Hz), 7.88 (1H, dd, J=8.0, 2.0 Hz), 8.01 (1H, d, J=2.4 Hz), 8.09 (1H, dd, J=5.2, 2.0 Hz), 8.21 (1H, d, J=2.0 Hz), 8.73 (1H, dd, J=2.4, 0.8 Hz).

Example 121: 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine (3.00 g, 19.7 mmol) in anhydrous DMF (40 mL) was added NaH (1.18 g, 29.5 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h under N 2 atmosphere. To the mixture was added MeI (6.02 g, 42.4 mmol) at 0° C., and stirred for another 5 h at 20° C. The solution turned to light yellow. TLC showed the reaction was completed. The mixture was quenched with MeOH (30 mL) concentrated under reduced pressure. The residue was purified by Combi Flash (pentane) to give 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (3.14 g, yield: 96%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.87 (3H, s), 6.40 (1H, d, J=3.2 Hz), 7.21 (1H, d, J=3.6 Hz), 7.86 (1H, d, J=2.0 Hz), 8.26 (1H, d, J=2.0 Hz).

To a mixture of 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (3.14 g, 18.9 mmol) in DCM (60 mL) was added NBS (3.52 g, 19.8 mmol) in one portion at 0° C. Then the mixture was stirred at 20° C. for 16 h. Crude LCMS showed the purity of product is 81% (Rt=0.754 min; MS Calc'd: 245.9; MS Found: 246.5 [M+H] + ). The reaction was quenched with sat.Na 2 S 2 O 3 (30 ml) and NaHCO 3 (30 ml) and stirred for 30 min. The mixture was extracted with EtOAc (15 mL×3). The combined organic phase was washed with NaHCO 3 (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (5% EtOAc in pentane) to afford 3-bromo-5-chloro-1-methyl-H-pyrrolo[2,3-b]pyridine (4.40 g, yield: 95%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.86 (3H, s), 7.24 (1H, s), 7.83 (1H, d, J=2.0 Hz), 8.29 (1H, d, J=2.4 Hz).

A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.51 g, 7.34 mmol), 3-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (900 mg, 3.67 mmol), Cs 2 CO 3 (1 M in water, 7 mL) and Pd(t-Bu 3 P) 2 (188 mg, 0.367 mmol) in dioxane (15 mL) was stirred at 100° C. for 15 h under N 2 atmosphere. The color of the mixture was black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 73% (Rt=0.502 min; MS Calc'd: 243.1; MS Found: 243.6 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (35% EtOAc in pentane) to afford 5-chloro-1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (850 mg, yield: 95%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.95 (3H, s), 7.35-7.40 (1H, m), 7.47 (1H, s), 7.85-7.89 (1H, m), 8.13 (1H, d, J=2.0 Hz), 8.34 (1H, d, J=2.0 Hz), 8.54 (1H, dd, J=4.8, 1.6 Hz), 8.85 (1H, s).

Step 4: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (260 mg, crude), 5-chloro-1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine (101 mg, 0.415 mmol), K 3 PO 4 (1 M in water, 0.1 mL) and Pd(t-Bu 3 P) 2 (21 mg, 0.042 mmol) in dioxane (4 mL) was stirred at 100° C. for 14 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 30% (Rt=0.501 min; MS Calc'd: 449.2; MS Found: 449.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide (30.5 mg, yield: 16%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 96.57%, Rt=1.349 min; MS Calc'd.: 449.2; MS Found: 450.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 4.01 (3H, s), 7.06 (2H, br s), 7.40 (1H, dd, J=8.0, 4.8 Hz), 7.50 (1H, s), 7.85-7.96 (3H, m), 8.13 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=2.0 Hz), 8.40 (1H, d, J=2.4 Hz), 8.55 (1H, dd, J=4.8, 1.2 Hz), 8.60 (1H, d, J=2.4 Hz), 8.75 (1H, d, J=1.6 Hz), 8.96 (1H, d, J=1.6 Hz).

Example 122:2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of pyrimidin-5-ylboronic acid (909 mg, 7.33 mmol), 3-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 2.44 mmol), Cs 2 CO 3 (1 M in water, 5 mL) and Pd(t-Bu 3 P) 2 (125 mg, 0.367 mmol) in dioxane (10 mL) was stirred at 100° C. for 15 h under N 2 atmosphere. The color of the mixture was black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 64% (Rt=0.768 min; MS Calc'd: 244.0; MS Found: 244.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (40% EtOAc in pentane) to afford 5-chloro-1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (400 mg, yield: 67%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.97 (3H, s), 7.54 (1H, s), 8.11 (1H, d, J=1.6 Hz), 8.37 (1H, d, J=2.4 Hz), 8.97 (2H, s), 9.15 (1H, s).

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (260 mg, crude),5-chloro-1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine (102 mg, 0.415 mmol), K 3 PO 4 (1 M in water, 0.1 mL) and Pd(t-Bu 3 P) 2 (21 mg, 0.042 mmol) in dioxane (4 mL) was stirred at 100° C. for 14 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 26% (Rt=0.502 min; MS Calc'd: 450.2; MS Found: 450.8 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide (27.4 mg, yield: 15%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 95.07%, Rt=1.467 min; MS Calc'd.: 450.2; MS Found: 451.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 4.03 (3H, s), 6.90 (2H, br s), 7.57 (1H, s), 7.87 (1H, dd, J=8.4, 0.4 Hz), 7.92 (1H, dd, J=8.4, 2.0 Hz), 8.09 (1H, d, J=2.4 Hz), 8.25 (1H, d, J=2.0 Hz), 8.42 (1H, d, J=2.4 Hz), 8.64 (1H, d, J=2.0 Hz), 8.75 (1H, dd, J=2.4, 0.8 Hz), 9.06 (2H, s), 9.15 (1H, s).

Example 123: 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 5-chloro-2-fluoronicotinaldehyde (3.00 g, 18.8 mmol) in EtOH (10 mL) was added NH 2 NH 2 H 2 O (2.82 g, 56.4 mmol) at 15° C. The mixture stirred 16 h at 80° C. The solution turned to light yellow. TLC showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (20% EtOAc in pentane) to give 5-chloro-1H-pyrazolo[3,4-b]pyridine (2.80 g, yield: 97%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (1H, s), 8.09 (1H, d, J=2.0 Hz), 8.52 (1H, d, J=2.4 Hz).

To a solution of 5-chloro-H-pyrazolo[3,4-b]pyridine (2.50 g, 16.3 mmol) in anhydrous DMF (25 mL) was added NaH (977 mg, 24.4 mmol, 60% in mineral oil) at 0° C. The mixture was stirred at 0° C. for 1 h under N 2 atmosphere. To the mixture was added Me (4.62 g, 32.6 mmol) at 0° C., and stirred for another 4 h at 20° C. The solution turned to light yellow. TLC showed the reaction was completed. The mixture was quenched with MeOH (30 mL) concentrated under reduced pressure. The residue was purified by Combi Flash (pentane) to give 5-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.90 g, yield: 70%) as a white solid. 1H NMR (400 MHz, CDCl 3 ) δ 4.14 (3H, s), 7.95 (1H, s), 8.01 (1H, d, J=2.4 Hz), 8.47 (1H, d, J=2.0 Hz).

To a mixture of 5-chloro-1-methyl-H-pyrazolo[3,4-b]pyridine (1.50 g, 8.95 mmol) in CHCl 3 (18 mL) was added Br 2 (2.86 g, 17.9 mmol) in one portion at 0° C. Then the mixture was stirred at 18° C. for 16 h. The solution turned to red. TLC showed the reaction was almost completed. The mixture was quenched with sat.Na 2 S 2 O 3 (30 ml) and NaHCO 3 (30 ml) and stirred for 30 min. The reaction mixture was extracted with DCM (20 mL×3). The combined organic phase was washed with NaHCO 3 (50 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by Combi Flash (10% EtOAc in pentane) to afford 3-bromo-5-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.40 g, yield: 63%) as an off-white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.12 (3H, s), 7.93 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.0 Hz).

A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (599 mg, 2.92 mmol), 3-bromo-5-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (400 mg, 1.62 mmol), Cs 2 CO 3 (1 M in water, 3 mL) and Pd(t-Bu 3 P) 2 (83 mg, 0.162 mmol) in dioxane (15 mL) was stirred at 100° C. for 15 h under N 2 atmosphere. The red solution turned to black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 70% (Rt=0.530 min; MS Calc'd: 244.0; MS Found: 244.9 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (15% EtOAc in pentane) to afford 5-chloro-1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine 490 mg, yield: 99%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.21 (3H, s), 7.45 (1H, dd, J=8.0, 4.8 Hz), 8.22 (1H, d, J=8.0 Hz), 8.29 (1H, d, J=0.8 Hz), 8.53 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=3.6 Hz), 9.16 (1H, s).

Step 5: Preparation of 1-methyl-3-(pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine

A mixture of 5-chloro-1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine (190 mg, 0.777 mmol), B 2 Pin 2 (296 mg, 0.116 mmol), Pd(dppf)Cl 2 (57 mg, 0.078 mmol) and KOAc (229 mg, 2.34 mmol) in dioxane (5 mL) was stirred at 100° C. for 5 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 8% (Rt=0.610 min; MS Calc'd: 336.1; MS Found: 337.0 [M+H] + ). The mixture was filtered and concentrated in vacuum to afford 1-methyl-3-(pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (400 mg, crude) as a black gum and immediately used to next step.

Step 6: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (207 mg, 0.644 mmol),1-methyl-3-(pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (260 mg, crude), K 3 PO 4 (1 M in water, 0.2 mL) and Pd(t-Bu 3 P) 2 (33 mg, 0.064 mmol) in dioxane (5 mL) was stirred at 100° C. for 16 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 49% (Rt=0.526 min; MS Calc'd: 450.2; MS Found: 451.3 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide (23.0 mg, yield: 8%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 96.22%, Rt=2.592 min; MS Calc'd.: 450.2, MS Found: 451.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 4.27 (3H, s), 7.00 (2H, br s), 7.47 (1H, dd, J=7.6, 4.8 Hz), 7.90 (1H, d, J=8.4 Hz), 7.94 (1H, dd, J=8.0, 2.0 Hz), 8.12 (1H, d, J=2.0 Hz), 8.28-8.33 (1H, m), 8.40-8.44 (2H, m), 8.67 (1H, d, J=4.0 Hz), 8.76 (1H, d, J=1.2 Hz), 8.81 (1H, d, J=2.0 Hz), 9.27 (1H, s).

Example 124:2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of pyrimidin-5-ylboronic acid (502 mg, 4.06 mmol), 3-bromo-5-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 2.03 mmol), Cs 2 CO 3 (1 M in water, 4 mL) and Pd(t-Bu 3 P) 2 (104 mg, 0.203 mmol) in dioxane (15 mL) was stirred at 100° C. for 15 h under N 2 atmosphere. The red solution turned to black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 70% (Rt=0.591 min; MS Calc'd: 245.0; MS Found: 246.0 [M+H] + ). The reaction mixture was diluted with ethyl acetate (10 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (EtOAc) to afford 5-chloro-1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridine (490 mg, yield: 98%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 4.24 (3H, s), 8.27 (1H, s), 8.57 (1H, d, J=2.0 Hz), 9.26 (1H, s), 9.28 (2H, s).

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (250 mg, 0.778 mmol), B 2 Pin 2 (297 mg, 0.117 mmol), Pd(dppf)Cl 2 (57 mg, 0.078 mmol) and KOAc (229 mg, 2.34 mmol) in dioxane (5 mL) was stirred at 100° C. for 5 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 47% (Rt=0.496 min; MS Calc'd: 286.1; MS Found: 286.9 [M+H] + ). The mixture was filtered and concentrated in vacuum to afford 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (300 mg, crude) as a black gum and immediately used to next step.

Step 3: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (170 mg, crude), 5-chloro-1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridine (95 mg, 0.385 mmol), K 3 PO 4 (1 M in water, 0.1 mL) and Pd(t-Bu 3 P) 2 (20 mg, 0.038 mmol) in dioxane (4 mL) was stirred at 100° C. for 14 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 32% (Rt=0.534 min; MS Calc'd: 451.2; MS Found: 452.1 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (10% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide (31.6 mg, yield: 18%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: from 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] to 5% [water+0.05% NH 3 ·H 2 O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finally changed to 100% [water+0.05% NH 3 ·H 2 O] and 0% [MeCN] and under this condition for 0.09 min.) purity is 100.00%, Rt=2.445 min; MS Calc'd.: 451.2, MS Found: 452.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.17 (3H, s), 4.29 (3H, s), 6.95 (2H, br s), 7.89 (1H, d, J=8.8 Hz), 7.94 (1H, dd, J=8.8, 2.4 Hz), 8.10 (1H, d, J=2.0 Hz), 8.37 (1H, d, J=2.0 Hz), 8.43 (1H, d, J=2.4 Hz), 8.76 (1H, dd, J=2.0, 0.8 Hz), 8.84 (1H, d, J=2.0 Hz), 9.26 (1H, s), 9.38 (2H, s).

Example 125:2′-amino-N,N-dimethyl-5′-(1-methyl-3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (604 mg, 3.03 mmol), 3-bromo-5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine (372 mg, 1.52 mmol), Cs 2 CO 3 (0.8 M in water, 6 mL) and Pd(t-Bu 3 P) 2 (77 mg, 0.152 mmol) in dioxane (8 mL) was stirred at 100° C. for 15 h under N 2 atmosphere. The color of the mixture was black. Crude LCMS showed the starting material was consumed completely and the purity of the desired product is 10% (Rt=0.695 min; MS Calc'd: 249.0; MS Found: 249.9 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (50% EtOAc in pentane) to afford 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (35.0 mg, yield: 9%) as a yellow solid. 1H NMR (400 MHz, CDCl 3 ) δ 3.94 (3H, s), 7.24 (1H, d, J=3.2 Hz), 7.81-7.84 (2H, m), 8.34 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz).

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (77 mg, crude), 5-(5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazole (35 mg, 0.14 mmol), K 3 PO 4 (1 M in water, 0.4 mL) and Pd(t-Bu 3 P) 2 (7 mg, 0.014 mmol) in dioxane (4 mL) was stirred at 100° C. for 14 h under N 2 atmosphere. A black suspension was formed. Crude LCMS showed the purity of product is 19% (Rt=0.573 min; MS Calc'd: 455.2; MS Found: 456.1 [M+H] + ). The reaction mixture was diluted with ethyl acetate (20 mL), dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by Combi Flash (5% MeOH in EtOAc), then the impure product was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to afford 2′-amino-N,N-dimethyl-5′-(1-methyl-3-(thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-[2,3′-bipyridine]-5-carboxamide (4.0 mg, yield: 6%) as a light yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is 96.12%, Rt=1.543 min; MS Calc'd.: 455.2; MS Found: 456.0 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 3.10 (3H, s), 3.16 (3H, s), 3.99 (3H, s), 6.89 (2H, br s), 7.24 (1H, d, J=3.6 Hz), 7.84 (1H, d, J=3.2 Hz), 7.85 (1H, s), 7.90 (1H, s), 7.91 (1H, d, J=2.0 Hz), 8.16 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.0 Hz), 8.60 (1H, d, J=2.0 Hz), 8.69 (1H, d, J=2.0 Hz), 8.75 (1H, s).

Example 126: methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

To a mixture of 1H-pyrrolo[2,3-b]pyridine (20.0 g, 169 mmol) in anhydrous THF (100 mL) was added drop wise n-BuLi (2.0 M, 93.1 mL) in hexane at −70° C. for 30 min. After stirring for 30 min at −70° C., the mixture was bubbled with CO 2 for 30 min. The mixture is then allowed to return to 25° C., and concentrated under reduced pressure. A white solid was obtained, which was dissolved in THF (400 mL). This solution was cooled to −70° C. and t-BuLi (1.3 M, 143.25 mL) in hexane was then added drop wise for 30 min. After stirring for 30 min at −70° C., the mixture was bubbled with CO 2 for 30 min. A yellow suspension was formed. TLC showed the starting material was consumed completely. The mixture was then allowed to return to 25° C., and this reaction mixture was then poured into 200 mL of distilled water cooled to 0° C. The THF was evaporated off under reduced pressure. The residual aqueous solution was diluted with 500 mL of distilled water, washed twice with DCM (500 mL), acidified to pH=1 by adding aqueous 5 N hydrochloric acid solution, and then concentrated under reduced pressure. 20 g of a pasty solid are obtained, which is recrystallized from MeOH (50 mL) to give 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (15.0 g, impure) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.19 (1H, dd, J=8.0, 4.8 Hz), 7.30-7.40 (1H, m), 8.17 (1H, dd, J=8.0, 1.6 Hz), 8.36-8.46 (1H, m), 8.46-8.59 (1H, br s), 12.48 (1H, br s).

To a solution of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (20.0 g, 92.5 mmol) in MeOH (100 mL) are added SOCl 2 (49.2 g, 414 mmol) at 25° C. The reaction mixture is then stirred for 40 h at 25° C. A yellow suspension was formed. LCMS showed the purity of product is 25% (Rt=0.631 min; MS Calc'd: 176.1; MS Found: 176.9 [M+H] + ) and TLC showed most of the starting material was consumed. The mixture was concentrated under reduced pressure and purified by Combi Flash (DCM) to give methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (8.00 g, yield for 2 steps: 20%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.88 (3H, s), 7.10-7.21 (2H, m), 8.11 (1H, d, J=7.2 Hz), 8.41 (1H, dd, J=4.8, 1.6 Hz), 12.51 (1H, br s).

To a solution of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (5.00 g, 28.4 mmol) in DCM (50 mL) was added m-CPBA (10.5 g, 42.6 mmol, 70% purity). And the mixture was stirred 25° C. for 16 h. TLC showed the reaction was completed. LCMS showed the purity of product is 87% (Rt=0.763 min; MS Calc'd: 192.1; MS Found: 192.8 [M+H] + ). A white suspension was formed. The resulting mixture was concentrated under reduced pressure and purified by Combi Flash (10% MeOH in DCM) to give 2-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (5.00 g, crude) as a yellow solid.

To a stirred solution of 2-(methoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (5.00 g, 26.0 mmol) and Me 4 NBr (6.01 g, 39.0 mmol) in CHCl 3 (50 mL) at 0° C. was added portion wise over 5 min Ms 2 O (9.06 g, 52.0 mmol). The reaction was allowed to warm to 25° C. and stirred for 16 h. A white suspension was formed. LCMS showed the purity of product is 86% (Rt=0.796 min; MS Calc'd: 254.0; MS Found: 254.8 [M+H] + ). The reaction was evaporated to dryness under vacuum, neutralized with cold 0.5 N aq NaHCO 3 (100 mL), filtered, rinsed with cold water, and concentrated under vacuum to give methyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (5.00 g, yield for 2 steps: 69%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.90 (3H, s), 7.06 (1H, d, J=2.4 Hz), 7.47 (1H, d, J=5.2 Hz), 8.28 (1H, d, J=4.8 Hz), 12.98 (1H, br s).

Step 5: Preparation of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

A mixture of 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (7.22 g, crude), methyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (2.50 g, 9.80 mmol), Cs 2 CO 3 (9.58 g, 29.4 mmol) and Pd(t-Bu 3 P) 2 (5.01 g, 9.80 mmol) in dioxane (150 mL) and H 2 O (15 mL) was stirred at 90-100° C. for 16 h under N 2 atmosphere. The color of the mixture was black still. LCMS showed the purity of product is 40% (Rt=0.642 min; MS Calc'd: 416.2; MS Found: 416.9 [M+H] + ) and TLC showed the starting material was consumed completely. The mixture was concentrated under reduced pressure. The residue was purified by Combi Flash (5% MeOH in DCM) to give methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.20 g, yield: 29%) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.12 (3H, s), 3.18 (3H, s), 4.01 (3H, s), 7.12 (2H, br s), 7.25 (1H, s), 7.42 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.94 (1H, d, J=8.4 Hz), 8.28 (1H, d, J=2.0 Hz), 8.56-8.65 (2H, m), 8.78 (1H, d, J=1.6 Hz), 11.09 (1H, br s).

Example 127: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Step 1: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

A mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.00 g, 2.40 mmol) and KOH (269 mg, 4.80 mmol) in acetone (2 mL) and H 2 O (20 mL) was stirred at 25° C. for 16 h. A yellow solution was formed. LCMS showed the purity of product is 98% (Rt=0.643 min; MS Calc'd: 402.1; MS Found: 403.0 [M+H] + ). The reaction mixture was concentrated under reduced pressure. Then the residue was lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.10 g, crude) as a yellow solid.

Step 2: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a solution of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50 mg, 0.12 mmol) and Me 2 NH·HCl (11 mg, 0.25 mmol) in pyridine (1 mL) was added EDC⋅HCl (48 mg, 0.25 mmol) under N 2 atmosphere. The mixture was stirred at 18-20° C. for 16 h under N 2 atmosphere. A red solution was formed. LCMS showed the purity of product is 75% (Rt=0.609 min; MS Calc'd: 429.2; MS Found: 430.0 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N,N-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (14.8 mg, yield: 28%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.02 (3H, s), 3.04 (3H, s), 3.10-3.30 (6H, m, overlapped with H 2 O signal), 6.98 (1H, d, J=0.8 Hz), 7.34 (1H, d, J=5.2 Hz), 7.78 (2H, br s), 7.99 (1H, d, J=6.4 Hz), 8.18 (1H, d, J=8.4 Hz), 8.36 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.75 (1H, d, J=2.0 Hz), 12.19 (1H, br s).

Example 128:2′-amino-N,N-dimethyl-5′-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

Step 1: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

A mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.00 g, 2.40 mmol) and KOH (269 mg, 4.80 mmol) in acetone (2 mL) and H 2 O (20 mL) was stirred at 25° C. for 16 hours. A yellow solution was formed. LCMS showed the purity of product is 98% (Rt=0.643 min; MS Calcd: 402.1; MS Found: 403.0 [M+H] + ). The reaction mixture was concentrated under reduced pressure. Then the residue was lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.10 g, crude) as a yellow solid

Step 2: Preparation of 2′-amino-N,N-dimethyl-5′-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50 mg, 0.12 mmol) and morpholine hydrochloride (31 mg, 0.25 mmol) in pyridine (1 mL) was added EDC·HCl (48 mg, 0.25 mmol) under N 2 atmosphere. The mixture was stirred at 18-20° C. for 16 hours under N 2 atmosphere. A red solution was formed. LCMS showed the purity of product is 75% (Rt=0.609 min; MS Calcd: 429.2; MS Found: 430.0 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was further purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 2′-amino-N,N-dimethyl-5′-(2-(morpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide (13.6 mg, purity: 100%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.98-3.07 (4H, m), 3.60-3.88 (10H, m), 6.94 (1H, s), 7.35 (1H, d, J=4.8 Hz), 7.78 (2H, br s), 7.99 (1H, dd, J=8.4, 2.0 Hz), 8.19 (1H, dd, J=8.4, 3.6 Hz), 8.36 (1H, d, J=4.8 Hz), 8.41 (1H, d, J=2.0 Hz), 8.55 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz), 12.26 (1H, br s).

Example 129: 2′-amino-5′-(2-(3-hydroxyazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of azetidin-3-ol (33 mg, 0.30 mmol, HCl salt) and 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (100 mg, 0.249 mmol) in pyridine (1 mL) was added EDC⋅HCl (95 mg, 0.50 mmol) under N 2 atmosphere. The mixture was stirred at 25° C. for 16 h under N 2 atmosphere. A red solution was formed. LCMS showed the purity of product is 68% (Rt=0.605 min; MS Calc'd: 457.2; MS Found: 458.0 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.05% HCl as an additive), prep-HPLC (0.05% NH 3 H 2 O as an additive) and lyophilized to give 2′-amino-5′-(2-(3-hydroxyazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (7.9 mg, yield: 7%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 3.75-4.00 (1H, m, overlapped with H 2 O signal), 4.20-4.40 (2H, m), 4.50-4.63 (1H, m), 4.67-4.79 (1H, m), 5.84 (1H, d, J=6.0 Hz), 6.95 (1H, s), 7.35 (1H, d, J=4.8 Hz), 7.78 (2H, br s), 7.98 (1H, dd, J=8.4, 1.6 Hz), 8.18 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=4.8 Hz), 8.42 (1H, s), 8.56 (1H, s), 8.74 (1H, s), 12.22 (1H, br s).

Example 130: 2′-amino-5′-(2-(3-carbamoylazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of azetidine-3-carboxamide (50 mg, 0.36 mmol, HCl salt) and 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (100 mg, 0.249 mmol) in pyridine (1 mL) was added EDC⋅HCl (95 mg, 0.50 mmol) under N 2 atmosphere. The mixture was stirred at 25° C. for 16 h under N 2 atmosphere. A red solution was formed. LCMS showed the purity of product (Rt=0.595 min; MS Calc'd: 484.2; MS Found: 485.1 [M+H] + ). The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (0.05% HCl as an additive), prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 2′-amino-5′-(2-(3-carbamoylazetidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (4.1 mg, yield: 3%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 4.00-4.25 (2H, m, overlapped with H 2 O signal), 4.49-4.59 (2H, m), 4.64-4.75 (1H, m), 6.97 (1H, s), 7.11 (1H, s), 7.35 (1H, d, J=4.8 Hz), 7.54 (1H, s), 7.77 (2H, br s), 7.99 (1H, d, J=2.0 Hz), 8.18 (1H, d, J=8.4 Hz), 8.38 (1H, d, J=5.2 Hz), 8.42 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz), 12.24 (1H, br s).

Example 131: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-isobutyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 2-methylpropan-1-amine (28 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS the purity of product is 14% (Rt=0.650 min; MS Calc'd: 457.2; MS Found: 480.1 [M+Na]+). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (10 mL) and then filtered. The filter cake was washed with EtOAc (5 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-isobutyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (20.3 mg, purity: 99.37%, yield: 46%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.90 (6H, d, J=6.8 Hz), 1.74-1.90 (1H, m), 3.02 (3H, s), 3.03 (3H, s), 3.11 (2H, t, J=6.4 Hz), 7.35 (1H, d, J=5.2 Hz), 7.47 (1H, d, J=1.6 Hz), 7.79 (2H, br s), 7.99 (1H, dd, J=8.4, 2.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.35 (1H, d, J=4.8 Hz), 8.41 (1H, d, J=2.0 Hz), 8.54 (1H, br s), 8.58 (1H, d, J=2.4 Hz), 8.75 (1H, d, J=1.6 Hz), 12.16 (1H, br s).

Example 132: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 2-methoxyethanamine (29 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product is 35% (Rt=0.610 min; MS Calc'd: 459.2; MS Found: 460.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (10 mL) and then filtered. The filter cake was washed with EtOAc (5 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-methoxyethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (6.1 mg, purity: 100%, yield: 14%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50-2.55 (2H, m), 3.02 (3H, s), 3.03 (3H, s), 3.27 (3H, s), 3.43-3.50 (2H, m), 7.35 (1H, d, J=4.8 Hz), 7.48 (1H, s), 7.79 (2H, br s), 8.00 (1H, dd, J=8.0, 2.0 Hz), 8.20 (1H, d, J=8.0 Hz), 8.36 (1H, d, J=5.2 Hz), 8.41 (1H, d, J=2.0 Hz), 8.57 (1H, d, J=2.0 Hz), 8.65 (1H, br s), 8.75 (1H, d, J=2.0 Hz), 12.18 (1H, br s).

Example 133: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (80 mg, 0.19 mmol), tert-butyl N-(2-aminoethyl)carbamate (123 mg, 0.768 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.38 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 1.5 h to give a yellow suspension. LCMS showed the purity of product is 71% (Rt=0.660 min; MS Calc'd: 544.3; MS Found: 545.3 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (20 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (30 mL×2). The combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give an intermediate (0.1 g, crude) as a yellow solid.

To a mixture of the intermediate (100 mg, 0.184 mmol) in DCM (5 mL) was added TFA (1 mL), the reaction mixture was stirred at 25° C. for 2 h to give a yellow solution. TLC (DCM:MeOH=10:1) showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (5 mL), then adjust to pH=7-8 with NaHCO 3 solid. DCM (20 mL) was added into it and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give an impure product (25 mg). The impure product was further purified by prep-HPLC (0.225% FA as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-aminoethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (24.3 mg, purity: 98.21%, yield: 27%, FA salt) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.95-3.10 (8H, m), 3.52 (2H, q, J=5.6 Hz), 7.38-7.44 (2H, m), 7.81 (3H, br s), 8.03 (1H, dd, J=8.0, 2.0 Hz), 8.23 (1H, d, J=8.4 Hz), 8.40 (1H, d, J=4.8 Hz), 8.51 (1H, d, J=2.0 Hz), 8.57 (1H, d, J=2.4 Hz), 8.72 (1H, br s), 8.76 (1H, d, J=2.0 Hz), 12.31 (1H, br s).

Example 134: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (20 mg, 0.048 mmol), benzylamine (10 mg, 0.096 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.048 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 h, then stirred at 60° C. for 2 h to give a yellow solution. LCMS showed the purity of the desired product is 36% (Rt=0.668 min; MS Calc'd: 491.2; MS Found: 492.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue (20 mg, crude) as a yellow solid.

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (20 mg, 0.048 mmol) in MeOH (5 mL) was added benzylamine (20 mg, 0.19 mmol), the reaction mixture was stirred at 65° C. for 4 h to give a yellow suspension. TLC (DCM:MeOH=10:1) showed no reaction. The mixture was concentrated under reduced pressure to give a residue. The residue in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.096 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 65° C. and stirred for another 2.5 h to give a yellow solution. TLC (DCM:MeOH=10:1) and LCMS showed the reaction was completed. A byproduct (4-(2′-amino-5-(benzylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide, amide was hydrolyzed to acid) was found by LCMS. The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue and the first batch were combined and purified by washing with MeCN (12 mL) to give an impure product (38 mg). The impure product was further purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (9.2 mg, purity: 99.93%, average yield: 19%) as a yellow solid and 4-(2′-amino-5-(benzylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-benzyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (4.2 mg, purity: 98.31%, average yield: 8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 4.51 (2H, d, J=6.0 Hz), 7.20-7.28 (1H, m), 7.30-7.39 (5H, m), 7.53 (1H, s), 7.79 (2H, br s), 7.99 (1H, dd, J=8.4, 2.4 Hz), 8.20 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=2.0 Hz), 8.57 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=1.2 Hz), 9.12 (1H, br s), 12.24 (1H, br s). 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.48-4.56 (4H, m), 7.20-7.28 (2H, m), 7.31-7.39 (9H, m), 7.53 (1H, s), 7.85 (2H, br s), 8.27 (1H, d, J=8.4 Hz), 8.35-8.40 (2H, m), 8.45 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.0 Hz), 9.12 (1H, br s), 9.16 (1H, d, J=2.0 Hz), 9.31 (1H, br s), 12.24 (1H, br s).

Example 135: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 4-pyridylmethanamine (42 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. TLC (DCM:MeOH=10:1) showed the reaction was completed. The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (10 mL) and then filtered. The filter cake was washed with EtOAc (5 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (9.0 mg, purity: 100%, yield: 19%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 4.53 (2H, d, J=6.0 Hz), 7.33 (2H, d, J=6.0 Hz), 7.37 (1H, d, J=5.2 Hz), 7.56 (1H, s), 7.80 (2H, br s), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.38 (1H, d, J=4.8 Hz), 8.43 (1H, d, J=2.0 Hz), 8.51 (2H, d, J=6.0 Hz), 8.59 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz), 9.22 (1H, br s), 12.29 (1H, br s).

Example 136: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 3-pyridylmethanamine (42 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product is 86% (Rt=0.587 min; MS Calc'd: 492.2; MS Found: 493.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (10 mL) and then filtered. The filter cake was washed with EtOAc (5 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(pyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (11.8 mg, purity: 96.48%, yield: 24%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.03 (3H, s), 4.53 (2H, d, J=6.0 Hz), 7.33-7.39 (2H, m), 7.51 (1H, s), 7.70-7.85 (3H, m), 7.99 (1H, dd, J=8.4, 2.4 Hz), 8.20 (1H, d, J=8.0 Hz), 8.37 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=2.0 Hz), 8.47 (1H, dd, J=4.4, 1.6 Hz), 8.55-8.61 (2H, m), 8.74 (1H, d, J=1.6 Hz), 9.17 (1H, br s), 12.27 (1H, br s).

Example 137: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), tetrahydropyran-4-amine (39 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product is 88% (Rt=0.620 min; MS Calc'd: 485.2; MS Found: 486.2 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (6.4 mg, purity: 99.32%, yield: 14%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51-1.60 (2H, m), 1.72-1.88 (2H, m), 3.02 (3H, s), 3.03 (3H, s), 3.45-3.50 (2H, m), 3.83-3.95 (2H, m), 3.96-4.10 (1H, m), 7.35 (1H, d, J=4.4 Hz), 7.48 (1H, s), 7.78 (2H, br s), 8.00 (1H, dd, J=8.8, 2.4 Hz), 8.21 (1H, d, J=8.0 Hz), 8.32-8.44 (3H, m), 8.59 (1H, d, J=2.0 Hz), 8.75 (1H, br s), 12.17 (1H, br s).

Example 138: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 2,2,2-trifluoroethanamine (38 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 h, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product is 47% (Rt=0.652 min; MS Calc'd: 483.2; MS Found: 484.2 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (20 mL×2). The combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (5.5 mg, purity 99.12%, yield: 12%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.02 (3H, s), 3.03 (3H, s), 4.10-4.21 (2H, m), 7.38 (1H, d, J=5.2 Hz), 7.62 (1H, d, J=2.0 Hz), 7.81 (2H, br s), 8.00 (1H, dd, J=8.8, 2.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.39 (1H, d, J=4.8 Hz), 8.43 (1H, d, J=2.4 Hz), 8.58 (1H, d, J=2.0 Hz), 8.75 (1H, d, J=1.6 Hz), 9.16 (1H, br s), 12.35 (1H, br s).

Example 139: 4-(2′-amino-5-((2,2,2-trifluoroethyl)carbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 4-(2′-amino-5-carboxy-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50 mg, 0.12 mmol) in DMF (5 mL) was added EDC⋅HCl (71 mg, 0.37 mmol) and hydroxybenzotriazole (HOBt) (50 mg, 0.37 mmol), TEA (38 mg, 0.37 mmol), the reaction mixture was stirred at 25° C. for 0.5 hour to give a yellow suspension. 2,2,2-trifluoroethanamine (49 mg, 0.50 mmol) was added into the resulting mixture and stirred at 25° C. for another 15.5 h to give a yellow suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-((2,2,2-trifluoroethyl)carbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2,2,2-trifluoroethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (6.0 mg, yield: 9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 4.05-4.23 (4H, m), 7.39 (1H, d, J=4.8 Hz), 7.62 (1H, s), 7.87 (2H, br s), 8.31 (1H, d, J=8.4 Hz), 8.35-8.43 (2H, m), 8.47 (1H, d, J=2.0 Hz), 8.61 (1H, d, J=2.4 Hz), 9.10-9.16 (2H, m), 9.38 (1H, br s), 12.35 (1H, br s).

Example 140: 2′-amino-N,N-dimethyl-5′-(2-(piperazine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), piperazine (66 mg, 0.77 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product is 64% (Rt=0.561 min; MS Calc'd: 470.2; MS Found: 471.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with DCM (10 mL×2). The filtrate was extracted with DCM/MeOH (20 mL/2 mL×2). The combined extracts was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 2′-amino-N,N-dimethyl-5′-(2-(piperazine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide (20.0 mg, purity: 99.66%, yield: 44%) as a yellow solid.

1 H NMR (400 MHz, DMSO-d 6 ) δ 2.69-2.78 (4H, m), 3.02 (3H, s), 3.03 (3H, s), 3.54-3.68 (4H, m), 6.88 (1H, s), 7.34 (1H, d, J=4.8 Hz), 7.77 (2H, br s), 7.99 (1H, dd, J=8.0, 2.0 Hz), 8.17 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=2.0 Hz), 8.55 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=1.6 Hz), 12.21 (1H, br s).

Example 141: 2′-amino-N,N-dimethyl-5′-(2-(pyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), pyrrolidine (27 mg, 0.38 mmol) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 hour, then heated to 50° C. and stirred for another 2.5 h to give a yellow suspension. LCMS showed the purity of product (Rt=0.623 min; MS Calc'd: 455.2; MS Found: 456.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (15 mL) and then filtered. The filter cake was washed with DCM (10 mL×2). The filtrate was extracted with DCM/MeOH (20 mL/2 mL×2). The combined extracts was washed with brine (20 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 2′-amino-N,N-dimethyl-5′-(2-(pyrrolidine-1-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-[2,3′-bipyridine]-5-carboxamide (8.2 mg, purity: 100%, yield: 19%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.75-2.04 (4H, m), 3.02 (3H, s), 3.03 (3H, s), 3.55 (2H, t, J=6.8 Hz), 3.83 (2H, t, J=6.8 Hz), 7.08 (1H, s), 7.34 (1H, d, J=4.8 Hz), 7.77 (2H, br s), 7.98 (1H, dd, J=8.4, 2.4 Hz), 8.18 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=5.2 Hz), 8.42 (1H, d, J=2.0 Hz), 8.57 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz), 12.16 (1H, br s).

Example 142: 2′-amino-5′-(2-(1,1-dioxidothiomorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a mixture of methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (40 mg, 0.096 mmol), 1,4-thiazinane 1,1-dioxide (66 mg, 0.38 mmol, HCl salt) in toluene (5 mL) was added AlMe 3 (2 M in toluene, 0.19 mL) at 0° C., then warmed to 25° C. and stirred for 0.5 h, then heated to 50° C. and stirred for another 7.5 h to give a yellow suspension. LCMS showed the purity of product (Rt=0.594 min; MS Calc'd: 519.2; MS Found: 520.1 [M+H] + ). The mixture was quenched with a saturated aqueous solution of sodium potassium tartrate (10 mL) and then filtered. The filter cake was washed with EtOAc (10 mL×2). The filtrate was extracted with EtOAc (20 mL/2 mL×2). The combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 2′-amino-5′-(2-(1,1-dioxidothiomorpholine-4-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (15.8 mg, purity: 99.60%, yield: 32%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.92-3.10 (8H, m), 3.25-3.30 (2H, m), 4.03-4.12 (4H, m), 7.08 (1H, s), 7.38 (1H, d, J=5.2 Hz), 7.78 (2H, br s), 8.00 (1H, dd, J=8.4, 2.0 Hz), 8.19 (1H, d, J=8.8 Hz), 8.37 (1H, d, J=4.8 Hz), 8.45 (1H, d, J=2.4 Hz), 8.58 (1H, d, J=2.0 Hz), 8.74 (1H, d, J=2.0 Hz), 12.26 (1H, br s).

Example 143: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Step 1: Preparation of 2′-(bis(4-methoxybenzyl)amino)-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of 2′-amino-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (2.00 g, 6.23 mmol) in DMF (10 mL) was added NaH (0.997 g, 24.9 mmol, 60% in mineral oil) at 0° C. PMBCl (3.90 g, 24.9 mmol) was added dropwise at 0° C. The mixture was warmed to 25° C. and stirred for another 1 hour. The red suspension turned to yellow. TLC (pentane/EtOAc=1:1, by UV) showed that starting material was consumed and a less polar spot was formed. The reaction was added sat.NH 4 Cl (50 mL), extracted with EtOAc (50 mL×3), the combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by Combi Flash (EA in PE from 0 to 50%) to give 2′-(bis(4-methoxybenzyl)amino)-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (4.00 g, 92% yield) as a yellow gum. 1 H NMR (400 MHz, CDCl 3 ) δ 3.03 (3H, s), 3.16 (3H, s), 3.80 (6H, s), 4.15 (4H, s), 6.81 (4H, d, J=8.8 Hz), 7.00 (4H, d, J=8.8 Hz), 7.79-7.80 (2H, m), 8.00 (1H, d, J=2.4 Hz), 8.33 (1H, d, J=2.4 Hz), 8.75 (1H, t, J=1.6 Hz).

Step 2: Preparation of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide

To a solution of 2′-(bis(4-methoxybenzyl)amino)-5′-bromo-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (4.00 g, 7.12 mmol) in dioxane (20 mL) was added B 2 Pin 2 (2.71 g, 10.7 mmol), KOAc (2.10 g, 21.4 mmol,) and Pd(dppf)Cl 2 (0.521 g, 0.712 mmol). The reaction mixture was stirred at 90° C. under N 2 atmosphere for 4 h to give a brown suspension. LCMS showed starting material was consumed and the purity of boronic acid (Rt=0.704 min; MS Calc'd: 526.1; MS Found: 527.1 [M+H] + ) The mixture was filtered to give 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide in dioxane as black solution, which was used to next step directly.

Step 3: Preparation of methyl 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (310 mg, 0.510 mmol, crude solution) in dioxane (5 mL) and H 2 O (0.5 mL) was added methyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (100 mg, 0.392 mmol), Na 2 CO 3 (125 mg, 1.18 mmol) and Pd(dppf)Cl 2 (29 mg, 0.039 mmol), the resulting mixture was stirred at 90° C. for 12 h to give a brown suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (EtOAc:MeOH=100:0 to 95:5 to 10:1) (TLC:DCM:MeOH=10:1) to give methyl 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (180 mg, yield: 70%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.92 (3H, s), 3.02 (3H, s), 3.72 (6H, s), 3.89 (3H, s), 4.25 (4H, s), 6.85 (4H, d, J=8.4 Hz), 7.09 (4H, d, J=8.4 Hz), 7.29 (1H, d, J=2.0 Hz), 7.39 (1H, d, J=4.8 Hz), 7.87 (1H, d, J=8.0 Hz), 7.94 (1H, dd, J=8.0, 2.4 Hz), 8.16 (1H, d, J=2.8 Hz), 8.46 (1H, d, J=5.2 Hz), 8.70 (1H, d, J=2.4 Hz), 8.75 (1H, d, J=1.2 Hz), 12.73 (1H, br s).

Step 4: Preparation of 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of methyl 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (90 mg, 0.137 mmol) in MeOH (1 mL) was added NH 3 (liquid, 10 mL), the reaction mixture was stirred at 120° C. for 16 h in a sealed tube to give a white suspension. LCMS showed the purity of the desired product (Rt=1.84 min; MS Calc'd: 641.3; MS Found: 642.1 [M+H] + ). The mixture was concentrated under reduced pressure to give 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (60 mg, yield: 68%) as a white solid.

Step 5: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (60 mg, 0.093 mmol) in DCM (1 mL) was added TFA (3 mL), the reaction mixture was stirred at 50° C. for 4 h to give a brown solution. LCMS showed the purity of the desired product (Rt=0.578 min; MS Calc'd: 401.2; MS Found: 402.2 [M+H] + ). The mixture and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.1% TFA as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (15.6 mg, purity: 100%, yield: 42%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.01 (3H, s), 3.04 (3H, s), 7.38-7.47 (2H, m), 7.53 (1H, br s), 8.04 (1H, br s), 8.08 (1H, dd, J=8.8, 2.4 Hz), 8.32 (1H, d, J=8.8 Hz), 8.43 (1H, d, J=4.8 Hz), 8.58 (1H, d, J=2.0 Hz), 8.73 (1H, d, J=2.0 Hz), 8.78 (1H, d, J=1.2 Hz), 12.33 (1H, br s).

Example 144: N-(2-amino-2-oxoethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3.5 g, 18.4 mmol) in DCM (50 mL) was added m-CPBA (5.95 g, 27.6 mmol, 80% purity), the reaction mixture was stirred at 25° C. for 16 h to give a brown suspension. TLC (pentane:EtOAc=2:1) showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue. The residue was washed with MTBE (50 mL×2) and filtered. The filter cake was concentrated under reduced pressure to give an impure product. The impure product was further washed with MTBE (30 mL) and then filtered. The filter cake was concentrated under reduced pressure to give 2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (3.5 g, yield: 92%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.34 (3H, t, J=7.2 Hz), 4.33 (2H, q, J=7.2 Hz), 7.17 (1H, dd, J=8.0, 6.4 Hz), 7.29 (1H, s), 7.76 (1H, d, J=8.0 Hz), 8.32 (1H, d, J=6.0 Hz).

To a stirred solution of 2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (500 mg, 2.42 mmol) and Me 4 NBr (560 mg, 3.64 mmol) in CHCl 3 (15 mL) at 0° C. was added Ms 2 O (845 mg, 4.85 mmol) in portions. The reaction mixture was allowed to warm to 25° C. and stir for 16 h. A pale yellow suspension was formed. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue of ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.8 g, crude) as an off-white solid.

To a stirred solution of 2-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (3.50 g, 17.0 mmol) and Me 4 NBr (3.92 g, 25.5 mmol) in CHCl 3 (40 mL) at 0° C. was added Ms 2 O (5.91 g, 34.0 mmol) in portions. The reaction mixture was allowed to warm to 25° C. and stir for 16 h. A pale yellow suspension was formed. LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure to give a residue. The residue and the above batch were combined and neutralized with cold 0.5 N aq NaHCO 3 (80 mL) and stirred for 0.5 hour and then filtered. The filter cake was further purified by washing with EtOAc/pentane (15 mL/30 mL) to give ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (3.2 g, average yield: 61%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.36 (3H, t, J=7.2 Hz), 4.37 (2H, q, J=7.2 Hz), 7.06 (1H, s), 7.48 (1H, d, J=5.2 Hz), 8.29 (1H, d, J=4.8 Hz), 12.96 (1H, br s).

A mixture of ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.50 g, 5.57 mmol) in MeOH (20 mL) was added NaOH (446 mg, 11.2 mmol) in H 2 O (2 mL), the reaction mixture was stirred at 50° C. for 6 h to give a yellow suspension. LCMS showed the reaction was completed. The mixture was filtered. The filter cake was washed with MeCN (10 mL×2) to give 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.2 g, yield: 89%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.51 (1H, s), 7.27 (1H, d, J=5.2 Hz), 8.06 (1H, d, J=5.2 Hz).

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (250 mg, 1.04 mmol) in DMF (15 mL) was added hydroxybenzotriazole (HOBt) (280 mg, 2.07 mmol), EDC⋅HCl (398 mg, 2.07 mmol), TEA (315 mg, 3.11 mmol), the reaction mixture was stirred at 50° C. for 0.5 hour and then added 2-aminoacetamide (230 mg, 3.11 mmol). The mixture was stirred for another 5.5 h to give a pale yellow suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL). Some white solid was precipitate out. The white suspension was filtered. The filter cake was washed with MeCN (10 mL) to give N-(2-amino-2-oxoethyl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (250 mg, yield: 81%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.86 (2H, d, J=6.0 Hz), 7.10 (1H, br s), 7.22 (1H, s), 7.36-7.48 (2H, m), 8.20 (1H, d, 5.2 Hz), 8.92 (1H, br s), 12.51 (1H, br s).

Step 7: Preparation of N-(2-amino-2-oxoethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (246 mg, 0.404 mmol, crude) in dioxane (5 mL) and H 2 O (0.5 mL) was added N-(2-amino-2-oxoethyl)-4-bromo-H-pyrrolo[2,3-b]pyridine-2-carboxamide (100 mg, 0.337 mmol), Na 2 CO 3 (107 mg, 1.01 mmol) and Pd(dppf)Cl 2 (25 mg, 0.034 mmol), the resulting mixture was stirred at 90° C. for 12 h to give a brown suspension. LCMS showed the purity of desired product (Rt=0.757 min; MS Calc'd: 698.3; MS Found: 699.3 [M+H] + ). The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (EtOAc:MeOH=100:0 to 95:5 to 10:1) (TLC:DCM:MeOH=10:1) to give N-(2-amino-2-oxoethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (190 mg, yield: 81%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.92 (3H, s), 3.02 (3H, s), 3.72 (6H, s), 3.86 (2H, d, J=6.0 Hz), 4.26 (4H, s), 6.85 (4H, d, J=8.8 Hz), 7.01-7.11 (5H, m), 7.35 (1H, d, J=6.0 Hz), 7.44 (1H, br s), 7.51 (1H, d, J=2.4 Hz), 7.88 (1H, dd, J=8.0, 0.8 Hz), 7.94 (1H, dd, J=8.0, 2.0 Hz), 8.17 (1H, d, J=2.4 Hz), 8.38 (1H, d, J=6.0 Hz), 8.72-8.79 (2H, m), 8.88 (1H, br s), 12.29 (1H, br s).

Step 8: Preparation of N-(2-amino-2-oxoethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of N-(2-amino-2-oxoethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (100 mg, 0.143 mmol) in DCM (1 mL) was added TFA (2 mL), the reaction mixture was stirred at 50° C. for 3 h to give a brown solution. LCMS showed the purity of the desired product (Rt=0.568 min; MS Calc'd: 458.2; MS Found: 459.2 [M+H] + ). The mixture and concentrated under reduced pressure, then dissolved in MeOH (15 mL). The mixture was adjust to pH=8 with NaHCO 3 solid. DCM (20 mL) was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give N-(2-amino-2-oxoethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (4.3 mg, purity: 99.60%, yield: 7%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.02 (3H, s), 3.03 (3H, s), 3.85 (2H, d, J=6.0 Hz), 7.07 (1H, br s), 7.36 (1H, d, 6.0 Hz), 7.42 (1H, br s), 7.51 (1H, s), 7.79 (2H, br s), 8.01 (1H, dd, J=8.0, 2.4 Hz), 8.20 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=1.6 Hz), 8.58 (1H, d, J=1.6 Hz), 8.75 (1H, d, J=2.0 Hz), 8.82 (1H, br s), 12.22 (1H, br s).

Example 145: (4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycine

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (300 mg, 1.24 mmol) in DMF (15 mL) was added hydroxybenzotriazole (HOBt) (335 mg, 2.48 mmol), EDC·HCl (475 mg, 2.48 mmol) and TEA (376 mg, 3.72 mmol), the reaction mixture was stirred at 50° C. for 0.5 hour, then added tert-butyl 2-aminoacetate (325 mg, 2.48 mmol) and stirred for another 5.5 h to give a pale yellow suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL). Some white solid was precipitated out. The white suspension was filtered. The filter cake was washed with MeCN (10 mL) to give tert-butyl (4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycinate (300 mg, yield: 68%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.44 (9H, s), 3.95 (2H, d, J=6.0 Hz), 7.22 (1H, s), 7.43 (1H, d, J=5.2 Hz), 8.21 (1H, d, J=5.2 Hz), 9.09 (1H, br s), 12.62 (1H, br s).

Step 2: Preparation of tert-butyl (4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycinate

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (200 mg, 0.329 mmol, crude) in dioxane (5 mL) and H 2 O (0.5 mL) was added tert-butyl (4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycinate (97 mg, 0.274 mmol), Na 2 CO 3 (87 mg, 0.82 mmol) and Pd(dppf)Cl 2 (20 mg, 0.027 mmol), the resulting mixture was stirred at 90° C. under N 2 atmosphere for 12 h to give a brown suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (EtOAc:MeOH=100:0 to 95:5 to 10:1) (TLC:DCM:MeOH=10:1) to give tert-butyl (4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycinate (160 mg, yield: 77%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.44 (9H, s), 2.92 (3H, s), 3.02 (3H, s), 3.72 (6H, s), 3.94 (2H, d, J=6.0 Hz), 4.26 (4H, s), 6.86 (4H, d, J=8.4 Hz), 7.10 (4H, d, J=8.8 Hz), 7.35 (1H, d, J=5.2 Hz), 7.51 (1H, d, J=2.0 Hz), 7.88 (1H, d, J=8.8 Hz), 7.94 (1H, dd, J=8.0, 2.4 Hz), 8.17 (1H, d, J=2.8 Hz), 8.39 (1H, d, J=6.0 Hz), 8.75 (2H, d, J=2.4 Hz), 9.03 (1H, br s), 12.34 (1H, br s).

Step 3: Preparation of (4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycine

A mixture of tert-butyl (4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycinate 80 mg, 0.11 mmol) in DCM (2 mL) as added TFA (2 mL), the reaction mixture was stirred at 50° C. for 6 h to give a brown solution. The reaction was repeated once. LCMS (first batch) showed the purity of the desired product is 81% (Rt=0.587 min; MS Calc'd: 459.2; MS Found: 460.3 [M+H] + ). LCMS (second batch) showed the purity of the desired product is 83% (Rt=0.582 min; MS Calc'd: 459.2; MS Found: 460.2 [M+H] + ). The two batches were combined and concentrated under reduced pressure, then dissolved with MeOH (15 mL). The mixture was adjust to pH=8 with NaHCO 3 solid. DCM (20 mL) was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give (4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)glycine (19.1 mg, purity: 100%, yield: 20%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.02 (6H, s), 3.90 (2H, d, J=6.0 Hz), 7.36 (1H, d, J=4.8 Hz), 7.49 (1H, s), 7.79 (2H, br s), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.20 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=2.4 Hz), 8.58 (1H, d, J=2.0 Hz), 8.75 (1H, d, J=1.6 Hz), 8.84 (1H, br s), 12.27 (1H, br s).

Example 146: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Step 1: Preparation of ethyl 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

A solution of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (3.00 g, 4.93 mmol) in dioxane (15 mL) and H 2 O (5 mL) was added ethyl 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (1.00 g, 3.72 mmol), Pd(dppf)Cl 2 (0.271 g, 0.371 mmol) and Na 2 CO 3 (1.18 g, 11.2 mmol). The mixture was stirred at 90° C. under N 2 atmosphere for 16 h. A black suspension was formed. LCMS showed the purity of desired product (Rt=0.709 min; MS Calc'd: 670.8; MS Found: 671.3 [M+H] + ). The mixture was added sat.NH 4 Cl (40 mL), extracted with EtOAc (40 mL×3). The combined layer was washed with brine (30 mL), dried over Na 2 SO 4 and concentrate. The residue was purified by Combi Flash (EtOAc in PE from 0 to 100%) to give ethyl 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.9 g, yield: 36.1%) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.44 (3H, t, J=7.2 Hz), 3.03 (3H, s), 3.15 (3H, s), 3.80 (6H, s), 4.15 (4H, s), 4.46 (2H, q, J=7.2 Hz), 6.83 (4H, d, J=8.4 Hz), 7.06 (4H, d, J=8.4 Hz), 7.28 (1H, d, J=4.8 Hz), 7.47 (1H, s), 7.75-7.81 (2H, m), 8.21 (1H, d, J=2.4 Hz), 8.55 (1H, d, J=4.8 Hz), 8.75-8.78 (2H, m), 10.13 (1H, br s).

Step 2: Preparation of ethyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

To a solution of ethyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.900 g, 1.34 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at 50° C. for 5 h. LCMS showed the purity of desired product (Rt=0.651 min; MS Calc'd: 430.5; MS Found: 431.2 [M+H] + ). The mixture was added sat.Na 2 CO 3 (20 mL), extracted with EtOAc (30 mL×3) and DCM (20 mL×2), dried over Na 2 SO 4 and concentrated. The residue was purified by Combi Flash (MeOH in DCM from 0 to 8%) to give ethyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.7 g, crude) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 1.45 (3H, t, J=7.2 Hz), 3.15 (3H, s), 3.17 (3H, s), 4.46 (2H, q, J=6.8 Hz), 7.26 (1H, d, J=5.2 Hz), 7.42 (1H, s), 7.89 (1H, d, J=8.4 Hz), 7.95 (1H, dd, J=8.4, 2.4 Hz), 8.29 (1H, s), 8.60-8.61 (2H, m), 8.79 (1H, dd, J=2.0, 0.8 Hz), 12.44 (1H, br s).

Step 3: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylicacid

To a mixture of ethyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.650 g, 1.51 mmol) in THF (10 mL) was added KOH (169 mg, 3.02 mmol) in H 2 O (10 mL). The mixture was stirred at 50° C. for 2 h. LCMS showed the purity of desired product (Rt=0.590 min; MS Calc'd: 402.4; MS Found: 403.1 [M+H] + ). The yellow suspension turned to brown solution. The mixture was added HCl (2 M) to adjust pH=3. A yellow solid was formed. Solvent was removed in high vacuum to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (0.600 g, crude) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ 3.03 (3H, s), 3.04 (3H, s), 7.28 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=4.8 Hz), 8.03 (1H, dd, J=8.8, 2.0 Hz), 8.22 (1H, d, J=8.0 Hz), 8.45 (1H, d, J=5.2 Hz), 8.51 (1H, s), 8.57 (1H, d, J=2.0 Hz), 8.76 (1H, d, J=2.0 Hz), 9.50 (1H, br s), 12.50 (1H, s).

Step 4: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a solution of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50.0 mg, 0.124 mmol) and oxetan-3-amine (27.3 mg, 373 umol) in DMF (1 mL) was added hydroxybenzotriazole (HOBt) (33.6 mg, 0.248 mmol), EDC⋅HCl (47.6 mg, 0.248 mmol) and TEA (37.7 mg, 0.37 mmol). The mixture was stirred at 25° C. for 16 h. A yellow solution was formed. LCMS showed the purity of desired product (Rt=0.607 min; MS Calc'd: 457.5; MS Found: 458.1 [M+H] + ). The mixture was added H 2 O (10 mL), extracted with EtOAc (10 mL×3). The combined organic layer was dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(oxetan-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (12.0 mg, yield: 21%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.03 (3H, s), 3.05 (3H, s), 4.60 (2H, dd, J=6.4 Hz), 4.82 (2H, dd, J=6.8 Hz), 5.04-5.11 (1H, m), 7.38 (1H, d, J=2.0 Hz), 7.57 (1H, d, J=2.0 Hz), 7.82 (2H, br s), 8.02 (1H, dd, J=8.4, 2.4 Hz), 8.23 (1H, d, J=8.8 Hz), 8.38 (1H, d, J=6.4 Hz), 8.43 (1H, d, J=2.0 Hz), 8.61 (1H, d, J=2.8 Hz), 8.76 (1H, d, J=2.0 Hz), 9.20 (1H, d, J=7.2 Hz), 12.45 (1H, s).

Example 147: 5′-(2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide

To a solution of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (50.0 mg, 0.124 mmol) and 2-oxa-6-azaspiro[3.3]heptane (37.0 mg, 0.373 mmol) in DMF (1 mL) was added hydroxybenzotriazole (HOBt) (33.6 mg, 0.248 mmol), EDC·HCl (47.6 mg, 0.249 mmol,) and TEA (37.7 mg, 0.373 mmol). The mixture was stirred at 25° C. for 16 h. A yellow solution was formed. LCMS showed the purity of desired product (Rt=0.614 min; MS Calc'd: 483; MS Found: 484.1 [M+H] + ). The mixture was filtered purified by preparative HPLC and triturated with MeCN (2 mL) to give 5′-(2-(2-oxa-6-azaspiro[3.3]heptane-6-carbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2′-amino-N,N-dimethyl-[2,3′-bipyridine]-5-carboxamide (10.0 mg, yield: 16.6%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.12 (3H, s), 3.18 (3H, s), 4.44 (2H, s), 4.68 (2H, s), 4.85 (4H, s), 6.85 (1H, d, J=1.6 Hz), 7.11 (2H, br s), 7.20 (1H, d, J=5.2 Hz), 7.87 (1H, d, J=8.8 Hz), 7.93 (1H, dd, J=8.8, 2.4 Hz), 8.20 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=5.2 Hz), 8.60 (1H, d, J=2.0 Hz), 8.78 (1H, d, J=2.0 Hz), 10.30 (1H, s).

Example 148: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Step 1: Preparation of N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

First Batch:

To a mixture of 4-bromo-H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (100 mg, 0.415 mmol) in DMF (10 mL) was added cis-tetrahydrofuran-3,4-diamine (145 mg, 0.830 mmol, 2 HCl salt), TEA (210 mg, 2.07 mmol, 0.29 mL), EDC·HCl (159 mg, 0.83 mmol) and hydroxybenzotriazole (HOBt) (112 mg, 0.830 mmol), the reaction mixture was stirred at 50° C. for 4 h to give an off-white suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give N-(-4-aminotetrahydrofuran-3-yl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (130 mg, crude) as a white solid.

Second Batch:

To a mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (260 mg, 1.08 mmol) in DMF (20 mL) was added (3R,4S)-tetrahydrofuran-3,4-diamine (378 mg, 2.16 mmol, 2 HCl salt), TEA (655 mg, 6.47 mmol, 0.90 mL), EDC·HCl (414 mg, 2.16 mmol) and hydroxybenzotriazole (HOBt) (292 mg, 2.16 mmol), the reaction mixture was stirred at 50° C. for 4 h to give an off-white suspension. LCMS showed the reaction was completed. The mixture was diluted with water (15 mL), then extracted with DCM (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue and the above batch were combined and purified by Combi Flash (DCM:MeOH=100:1 to 10:1) (TLC:DCM:MeOH=10:1) to give N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (120 mg, purity: 83%, average yield: 21%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.42-3.46 (1H, m), 3.51-3.54 (1H, m), 3.63-3.68 (1H, m), 3.90-3.98 (1H, m), 3.98-4.06 (1H, m), 4.36-4.44 (1H, m), 7.78 (1H, s), 7.43 (1H, d, J=5.2 Hz), 8.21 (1H, d, J=5.2 Hz).

Step 2: Preparation of N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (271 mg, 0.446 mmol, crude) in dioxane (5 mL) was added N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (120 mg, 0.371 mmol), Na 2 CO 3 (118 mg, 1.11 mmol) in H 2 O (0.5 mL) and Pd(dppf)Cl 2 (27 mg, 0.037 mmol), the resulting mixture was stirred at 90° C. for 12 h to give a brown suspension. LCMS showed the purity of desired product (Rt=0.749 min; MS Calc'd: 726.3; MS Found: 727.2 [M+H] + ). The mixture was diluted with water (20 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (EtOAc:MeOH=100:0 to 95:5 to 10:1 to 8:1) (TLC:DCM:MeOH=10:1) to give N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (40 mg, purity: 81%, yield: 12%) as a brown gum.

Step 3: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (40 mg, 0.055 mmol) in DCM (1 mL) was added TFA (2 mL), the reaction mixture was stirred at 50° C. for 6 h to give a brown solution. LCMS showed the purity of the desired product (Rt=0.572 min; MS Calc'd: 486.2; MS Found: 487.1 [M+H] + ). The mixture was concentrated under reduced pressure and then dissolved with MeOH (10 mL). The mixture was adjust to pH=8 with NaHCO 3 solid. DCM (15 mL) was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-((3S,4R)-4-aminotetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (2.41 mg, purity: 100%, yield: 9%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.98-3.02 (6H, m), 3.50-3.52 (1H, m), 3.52-5.56 (1H, m), 3.56-3.67 (1H, m), 3.86-4.02 (2H, m), 4.41-4.52 (1H, m), 7.36 (1H, d, J=4.4 Hz), 7.53 (1H, s), 7.78 (2H, br s), 7.99 (1H, dd, J=8.0, 2.0 Hz), 8.20 (1H, d, J=8.0 Hz), 8.37 (1H, d, J=5.6 Hz), 8.41 (1H, d, J=1.6 Hz), 8.60 (1H, d, J=2.0 Hz), 8.75 (1H, d, J=2.0 Hz), 12.23 (1H, br s).

Example 149: 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 4-bromo-H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (200 mg, 0.830 mmol) in DMF (10 mL) was added 3-aminopyrrolidin-2-one (208 mg, 2.07 mmol), TEA (252 mg, 2.49 mmol), EDC⋅HCl (318 mg, 1.66 mmol) and hydroxybenzotriazole (HOBt) (224 mg, 1.66 mmol), the reaction mixture was stirred at 50° C. for 4 h to give an off-white suspension. LCMS showed the reaction was completed. The mixture was diluted with water (20 mL). Some white solid was precipitate out. The white suspension was filtered. The filter cake was washed with MeCN (10 mL) to give 4-bromo-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (140 mg, yield: 52%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.91-2.04 (1H, m), 2.41-2.50 (1H, m), 3.21-3.38 (2H, m), 4.50-4.64 (1H, m), 7.24 (1H, s), 7.43 (1H, d, J=5.2 Hz), 7.93 (1H, br s), 8.21 (1H, d, J=5.2 Hz), 8.93 (1H, br s), 12.60 (1H, br s).

Step 2: Preparation of 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (271 mg, 0.446 mmol, crude) in dioxane (5 mL) and H 2 O (0.5 mL) was added 4-bromo-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (120 mg, 0.371 mmol), Na 2 CO 3 (118 mg, 1.11 mmol) and Pd(dppf)Cl 2 (27 mg, 0.037 mmol), the resulting mixture was stirred at 90° C. for 12 h to give a brown suspension. LCMS showed the purity of desired product (Rt=0.768 min; MS Calc'd: 724.3; MS Found: 725.4 [M+H] + ). The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (EtOAc:MeOH=100:0 to 95:5 to 10:1) (TLC:DCM:MeOH=10:1) to give 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (180 mg, yield: 67%) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45-2.47 (1H, m), 2.50-2.52 (1H, m), 2.93 (3H, s), 3.02 (3H, s), 3.35-3.38 (2H, m), 3.72 (6H, s), 4.26 (4H, s), 4.50-4.54 (1H, m), 6.86 (4H, d, J=8.8 Hz), 7.10 (4H, d, J=8.8 Hz), 7.35 (1H, d, J=5.2 Hz), 7.52 (1H, d, J=2.0 Hz), 7.85-7.89 (1H, m), 7.90-7.96 (2H, m), 8.17 (1H, d, J=2.4 Hz), 8.38 (1H, d, J=5.2 Hz), 8.72-8.77 (2H, m), 8.88 (1H, br s), 12.30 (1H, br s).

Step 3: Preparation of 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of 4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (100 mg, 0.138 mmol) in DCM (1 mL) was added TFA (2 mL), the reaction mixture was stirred at 50° C. for 3 h to give a brown solution. LCMS showed the purity of the desired product (Rt=0.591 min; MS Calc'd: 484.2; MS Found: 485.3 [M+H] + ). The mixture was concentrated under reduced pressure and then dissolved with MeOH (15 mL). The mixture was adjust to pH=8 with NaHCO 3 solid. DCM (20 mL) was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-N-(2-oxopyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (21.8 mg, purity: 98.59%, yield: 32%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.90-2.14 (1H, m), 2.31-2.43 (1H, m), 2.96-3.08 (6H, m), 3.19-3.27 (2H, m), 4.53-4.64 (1H, m), 7.36 (1H, d, J=5.2 Hz), 7.51 (1H, s), 7.79 (2H, br s), 7.90 (1H, br s), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.21 (1H, d, J=8.4 Hz), 8.37 (1H, d, J=4.8 Hz), 8.42 (1H, d, J=1.6 Hz), 8.58 (1H, d, J=2.0 Hz), 8.75 (1H, d, J=2.0 Hz), 8.80 (1H, br s), 12.24 (1H, br s).

Example 150: N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (200 mg, 0.830 mmol) in DMF (15 mL) was added hydroxybenzotriazole (HOBt) (224 mg, 1.66 mmol), EDC⋅HCl (318 mg, 1.66 mmol), TEA (420 mg, 4.15 mmol, 0.58 m), the reaction mixture was stirred at 50° C. for 0.5 hour, then added 2-(1H-imidazol-2-yl) ethanamine (305 mg, 1.66 mmol, 2 HCl salt) into it and continued stirred for another 2.5 h to give a pale yellow suspension. LCMS showed the purity of the desired product (Rt=0.600 min; MS Calc'd: 333.0; MS Found: 333.9 [M+H] + ). The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (25 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give N-(2-(1H-imidazol-2-yl)ethyl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (250 mg, purity: 92%, yield: 83%) as an off-white solid

1 H NMR (400 MHz, DMSO-d 6 ) δ 2.86-2.95 (2H, m), 3.52-3.65 (2H, m), 6.85-6.98 (2H, m), 7.15 (1H, s), 7.42 (1H, d, J=5.2 Hz), 8.19 (1H, d, J=4.8 Hz), 8.83 (1H, br s), 11.82 (1H, br s), 12.56 (1H, br s).

Step 2: Preparation of N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

To a mixture of 2′-(bis(4-methoxybenzyl)amino)-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide (262 mg, 0.431 mmol, crude) dioxane (5 mL) and in H 2 O (0.5 mL) was added N-(2-(1H-imidazol-2-yl)ethyl)-4-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (120 mg, 0.359 mmol), Na 2 CO 3 (114 mg, 1.08 mmol) and Pd(dppf)Cl 2 (26 mg, 0.036 mmol), the resulting mixture was stirred at 90° C. for 12 h to give a brown suspension. LCMS showed the purity of desired product (Rt=0.637 min; MS Calc'd: 735.3; MS Found: 736.4 [M+H] + ). The mixture was diluted with water (15 mL), then extracted with EtOAc (20 mL×2), the combined extracts was washed with brine (30 mL×2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by Combi Flash (EtOAc:MeOH=100:1 to 95:5 to 10:1) (TLC:DCM:MeOH=10:1) to give N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (80 mg, purity: 49%, yield: 15%) as a brown solid.

Step 3: Preparation of N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

A mixture of N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-(bis(4-methoxybenzyl)amino)-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (80 mg, 0.11 mmol) in DCM (1 mL) was added TFA (2 mL), the reaction mixture was stirred at 50° C. for 6 h to give a brown solution. LCMS showed the purity of the desired product (Rt=0.568 min; MS Calc'd: 495.2; MS Found: 496.1 [M+H] + ). The mixture was concentrated under reduced pressure and then dissolved with MeOH (10 mL). The mixture was adjust to pH=8 with NaHCO 3 solid. DCM (20 mL) was added. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (0.05% NH 3 ·H 2 O as an additive) and lyophilized to give N-(2-(1H-imidazol-2-yl)ethyl)-4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (24.8 mg, purity: 100%, yield: 46%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.89 (2H, t, J=6.0 Hz), 3.01 (3H, s), 3.03 (3H, s), 3.59 (2H, dt, J=6.0 Hz), 6.70-7.08 (2H, m), 7.35 (1H, dd, J=4.8, 2.0 Hz), 7.43 (1H, s), 7.78 (2H, br s), 7.96-8.04 (1H, m), 8.19 (1H, d, J=8.4 Hz), 8.36 (1H, dd, J=6.0, 2.0 Hz), 8.41 (1H, s), 8.56 (1H, d, J=2.0 Hz), 8.66-8.79 (2H, m), 11.79 (1H, br s), 12.19 (1H, br s).

Example 151: 4-(5-(4-(6-ethyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6 (7H)-one

A mixture of 6-bromoindolin-2-one (1.50 g, 7.07 mmol), ethylboronic acid (1.50 g, 20.3 mmol), Pd(dppf)Cl 2 (1.04 g, 1.41 mmol), and K 3 PO 4 (4.50 g, 21.2 mmol) in H 2 O (10 mL) and dioxane (25 mL) was stirred at 90° C. for 24 hours under N 2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 27% (Rt=0.796 min; MS Calcd: 161.2; MS Found: 161.9 [M+H] + ). The reaction mixture was diluted with EtOAc (50 mL) and H 2 O (30 mL) then separated. The aqueous was extracted with EtOAc (40 mL×2). The combined organic phase was dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by Combi Flash (20% EtOAc in PE) to give 6-ethylindolin-2-one (300 mg, yield: 26% yield) as a white solid.

1 H NMR (400 MHz, CDCl 3 ) δ 1.23 (3H, t, J=7.6 Hz), 2.63 (2H, q, J=7.6 Hz), 3.50 (2H, s), 6.73 (1H, s), 6.86 (1H, d, J=7.2 Hz), 7.13 (1H, d, J=7.6 Hz), 7.80 (1H, brs).

A mixture of 6-ethylindolin-2-one (400 mg, 2.48 mmol), 1-bromo-4-iodobenzene (850 mg, 3.00 mmol), CuI (400 mg, 2.10 mmol), L-PROLINE (240 mg, 2.08 mmol) and CsF (750 mg, 4.94 mmol) in EtOAc (20 mL) was stirred at 50° C. for 36 hours under N 2 atmosphere. A black suspension was formed. TLC (PE/EtOAc=5/1, Rf=0.45) showed the starting material was consumed nearly. The reaction mixture was diluted with EtOAc/H 2 O (100 mL, 2/1) then separated. The aqueous was extracted with EtOAc (80 mL×3). The combined organic phase was concentrated. The residue was purified by Combi Flash (10% EtOAc in PE) to give 1-(4-bromophenyl)-6-ethylindolin-2-one (600 mg, yield: 76%) as an off-white solid.

1 H NMR (400 MHz, CDCl 3 ) δ 1.19 (3H, t, J=7.6 Hz), 2.60 (2H, q, J=7.6 Hz), 3.67 (2H, s), 6.62 (1H, d, J=2.8 Hz), 6.93 (1H, d, J=8.0 Hz), 7.18 (1H, m), 7.22 (1H, d, J=7.6 Hz), 7.31 (1H, d, J=8.4 Hz), 7.67 (1H, d, J=8.8 Hz), 7.86 (1H, d, J=8.8 Hz).

Step 3. Preparation of 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indolin-2-one

A mixture of 1-(4-bromophenyl)-6-ethylindolin-2-one (600 mg, 1.90 mmol), Bispin (580 mg, 2.28 mmol), Pd(dppf)Cl 2 (140 mg, 0.191 mmol) and KOAc (560 mg, 5.71 mmol) in dioxane (20 mL) was stirred at 100° C. for 16 hours under N 2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 54% (Rt=1.058 min; MS Calcd: 363.2; MS Found: 364.0 [M+H] + ). The reaction mixture was filtered and the filtrate was concentrated to give 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indolin-2-one (700 mg, crude) as black brown oil, which was used for the next step without further purification.

A mixture of 6-ethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indolin-2-one (689 mg, 1.90 mmol), 3,5-dibromopyridine (730 mg, 3.08 mmol), Na 2 CO 3 (600 mg, 5.66 mmol) and Pd(dppf)Cl 2 (150 mg, 0.205 mol) in dioxane (20 mL) and H 2 O (5 mL) was stirred at 100° C. for 1 hours under N 2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 50% (Rt=0.997 min; MS Calcd: 393.2; MS Found: 393.8 [M+H] + ). The reaction mixture was diluted with EtOAc/H 2 O (40 mL, 1/1) then extracted with EtOAc (30 mL×4). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated. The residue was purified by Combi Flash (25% EtOAc in PE) to give 1-(4-(6-bromopyridin-3-yl)phenyl)-6-ethylindolin-2-one (190 mg, yield: 25% for two steps) as an off-white solid.

1 H NMR (400 MHz, CDCl 3 ) δ 1.21 (3H, t, J=7.2 Hz), 2.62 (2H, q, J=7.6 Hz), 3.61 (2H, s), 6.70 (1H, s), 6.95 (1H, d, J=7.6 Hz), 7.23 (1H, s), 7.57 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 8.07 (1H, t, J=2.0 Hz), 8.70 (1H, d, J=2.0 Hz), 8.81 (1H, d, J=2.0 Hz).

Step 5. Preparation of 6-ethyl-1-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)indolin-2-one

A mixture of 1-(4-(6-bromopyridin-3-yl)phenyl)-6-ethylindolin-2-one (90 mg, 0.23 mmol), Bispin (70 mg, 0.28 mmol), Pd(dppf)Cl 2 (20 mg, 0.027 mmol) and KOAc (70 mg, 0.71 mmol) in dioxane (3 mL) was stirred at 100° C. for 1.5 hours under N 2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 37% (Rt=0.809 min; MS Calcd: 358.1; MS Found: 358.9 [M+H] + ). The reaction mixture was filtered and the filtrate was concentrated to 6-ethyl-1-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)indolin-2-one (100 mg, crude) as black brown oil, which was used for the next step without further purification.

Step 6 Preparation of 4-(5-(4-(6-ethyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one

A mixture of 6-ethyl-1-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)indolin-2-one (100 mg, 0.227 mmol), 4-chloro-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (67 mg, 0.28 mmol), Cs 2 CO 3 (223 mg, 0.685 mmol) and Pd(t-Bu 3 P) 2 (20 mg, 0.034 mmol) in dioxane (4 mL) and H 2 O (2 mL) was stirred at 100° C. for 1 hour under N 2 atmosphere. A black suspension was formed. LCMS showed the purity of the desired product is 23% (Rt=0.883 min; MS Calcd: 513.2; MS Found: 536.1 [M+Na]+). The reaction mixture was diluted with brine (10 mL) and DCM (20 mL) then extracted with DCM (20 mL×4). The resulting mixture was dried over anhydrous Na 2 SO 4 and concentrated. The residue was prep-HPLC (0.04% NH 3 H 2 O+10 mM NH 4 HCO 3 as additives) and lyophilized to 4-(5-(4-(6-ethyl-2-oxoindolin-1-yl)phenyl)pyridin-3-yl)-7-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (2.21 mg, yield: 2% for two steps) as a white solid.

1 H NMR (400 MHz, DMSO-d 6 ) δ 1.13 (3H, t, J=7.6 Hz), 2.56-2.58 (2H, overlapped with DMSO signal), 3.710 (3H, s), 3.72 (2H, s), 3.87 (2H, t, J=5.6 Hz), 4.50 (2H, t, J=5.2 Hz), 6.68 (1H, s), 6.94 (1H, d, J=7.6 Hz), 7.20 (1H, s), 7.27 (1H, d, J=7.6 Hz), 7.57 (1H, d, J=4.8 Hz), 7.60 (2H, d, J=8.4 Hz), 8.07 (2H, d, J=7.6 Hz), 8.49 (1H, t, J=2.0 Hz), 8.57 (1H, d, J=4.8 Hz), 9.02 (1H, d, J=2.0 Hz), 9.11 (1H, d, J=2.4 Hz).

Example 152: 1-(4-(5-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Intermediate 59—(4-Chloro-5-tetrahydropyran-4-yloxy-pyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane

The title compound was prepared as described in Intermediate 57, replacing tert-butyl 3-hydroxypiperidine-1-carboxylate for tetrahydropyran-4-ol, to give the product as an oil (260 mg, 83%). MS ES+m/z 409 [M+H] + .

Step 2: Intermediate 60—1-[4-[5-(5-Tetrahydropyran-4-yloxy-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one

The title compound was prepared as described in Example 30, replacing 5-bromo-7H-pyrrolo[2,3-d]pyrimidine for (4-chloro-5-tetrahydropyran-4-yloxy-pyrrolo[2,3-b]pyridin-1-yl)-triisopropyl-silane. Extraction of the reaction mixture, using 1,2-dichloroethane and concentration of the organic layer gave a solid (117 mg), which was used in the next step. MS ES+m/z 611 [M+H] + .

Step 3: 1-(4-(5-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-[5-(5-Tetrahydropyran-4-yloxy-1-triisopropylsilyl-pyrrolo[2,3-b]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (117 mg, 0.19 mmol) was dissolved in MeOH (2 mL) at rt, a few drops of conc. HCl was added and the mixture was stirred at rt for 2 h. Sat. aq. NaHCO 3 was added and the mixture was extracted with DCM. The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give the product as a solid (14 mg, 16%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 1.50-1.59 (m, 2H), 1.80-1.88 (m, 2H), 2.13-2.23 (m, 2H), 2.57-2.64 (m, 2H), 3.35-3.40 (m, 2H), 3.63-3.72 (m, 2H), 3.90-3.96 (m, 2H), 4.24-4.36 (m, 1H), 6.36-6.43 (m, 1H), 7.41-7.48 (m, 1H), 7.69-7.75 (m, 2H), 7.75-7.81 (m, 2H), 8.16-8.21 (m, 1H), 8.29-8.35 (m, 1H), 8.74-8.82 (m, 1H), 8.82-8.90 (m, 1H). MS ES+m/z 455 [M+H] + .

Intermediate 98 was prepared in a similar manner as Intermediate 39 in Example 60, replacing methyl 3-bromo-1H-pyrrolo[2,3-b]pyridine-5-carboxylate for 5-bromo-7H-pyrrolo[2,3-d]pyrimidine, to give Intermediate 98 as a solid (120 mg, 28%). MS ES+m/z 212 [M+H] + .

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. 1-(4-(5-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 98, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, to give the 1-(4-(5-(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one as a solid (8 mg, 5%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.15 (m, 2H), 2.52-2.57 (m, 2H), 3.86-3.93 (m, 5H), 7.81-7.84 (m, 2H), 7.87-7.91 (m, 2H), 8.30 (s, 1H), 8.37 (t, J=2.21 Hz, 1H), 8.82 (d, J=2.21 Hz, 1H), 8.90 (s, 1H), 8.98 (d, J=2.21 Hz, 1H), 9.46 (s, 1H). MS ES+m/z 370 [M+H] + .

Example 154: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

To a solution of 1-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)ethanone (178 mg, 0.7 mmol) in THF (3 mL) was added 3M MeMgCl in THF (0.47 ml, 1.41 mmol) dropwise. The resulting mixture was stirred at rt for 2 h. To the mixture was added sat. aq. NH 4 Cl and the mixture was concentrated. The resulting aqueous residue was extracted with EtOAc and the combined organics were dried over Na 2 SO 4 , filtered, and concentrated to give Intermediate 99 as an oil (180 mg, 95%). MS ES+m/z 269 [M+H] + .

Step 2: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 99, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, to give 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one as a solid (51 mg, 36%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.55 (s, 6H), 2.06-2.13 (m, 2H), 2.51-2.56 (m, 2H), 3.87-3.92 (m, 5H), 5.16-5.38 (m, 1H), 7.81-7.87 (m, 4H), 8.16 (s, 1H), 8.27 (t, J=2.21 Hz, 1H), 8.40 (d, J=1.89 Hz, 1H), 8.49 (d, J=1.89 Hz, 1H), 8.78 (d, J=2.21 Hz, 1H), 8.93 (d, J=1.89 Hz, 1H). MS ES+m/z 427 [M+H] + .

Example 155: 1-(4-(5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

To a solution of NaH (60% dispersion in mineral oil, 33 mg, 0.87 mmol) in DMF (1 ml) at 0° C. was added a solution of 2-(3-bromo-1-methyl-pyrrolo[2,3-b]pyridin-5-yl)propan-2-ol (90 mg, 0.33 mmol) in DMF (1 ml). The resulting mixture was stirred at rt for 1 h, cooled to 0° C., and iodomethane (25 μl, 0.4 mmol) was added. The resulting mixture was stirred at rt overnight. Water was added and the mixture was extracted with EtOAc. The combined organics were dried over Na 2 SO 4 , filtered and concentrated to give the product as a solid (93 mg, 98%). MS ES+m/z 283 [M+H] + .

Step 2: 1-(4-(5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. 1-(4-(5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 100, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, to give 1-(4-(5-(5-(2-methoxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one as a solid (46 mg, 32%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.59 (s, 6H), 2.10 (quin, J=7.49 Hz, 2H), 2.52-2.56 (m, 2H), 3.02 (s, 3H), 3.88-3.94 (m, 5H), 7.82-7.88 (m, 4H), 8.18 (s, 1H), 8.23 (d, J=2.21 Hz, 1H), 8.28 (t, J=2.21 Hz, 1H), 8.43 (d, J=2.21 Hz, 1H), 8.78-8.80 (m, 1H), 8.90-8.94 (m, 1H). MS ES+m/z 441 [M+H] + .

Example 156: 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine (1.1 g, 4.82 mmol) and Cs 2 CO 3 (3.14 g, 9.65 mmol) in DMF (25 ml) was stirred at rt for 30 min. Iodomethane (0.38 ml, 6.03 mmol) was added and the mixture was stirred at rt overnight. Aqueous 5% citric acid was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified on a silica gel column eluted with 0-100% EtOAc in heptane to give Intermediate 101 as a solid (770 mg, 66%), MS ES+m/z 242 [M+H] + .

Step 2: 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 101, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one. Purification on a silica gel column, eluted with 0-10% MeOH in DCM gave 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one as a solid (360 mg, 90%). A portion (50 mg) of the isolated 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was further purified by preparative HPLC to yield 18 mg of solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.08-4.22 (m, 3H), 4.28-4.36 (m, 3H), 7.79-7.87 (m, 2H), 7.88-7.92 (m, 2H), 8.03 (s, 1H), 8.31 (s, 1H), 8.32 (s, 1H), 8.88 (d, J=2.21 Hz, 1H), 8.96 (d, J=2.21 Hz, 1H). MS ES+m/z 400 [M+H] + .

Example 157: 1-[4-[5-(7-methoxy-2-methyl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one

A mixture of 4-bromo-7-methoxy-1H-pyrazolo[3,4-c]pyridine (1.1 g, 4.82 mmol) and Cs 2 CO 3 (3.14 g, 9.65 mmol) in DMF (25 ml) was stirred at rt for 30 min. Iodomethane (0.38 ml, 6.03 mmol) was added and the mixture was stirred at rt overnight. Aqueous 5% citric acid was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated. The resulting residue was purified on a silica gel column eluted with 0-100% EtOAc in heptane to give Intermediate 102 as a solid (360 mg, 31%), MS ES+m/z 242 [M+H] + .

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. 1-[4-[5-(7-methoxy-2-methyl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 102, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one. Purification on a silica gel column, eluted with 0-10% MeOH in DCM gave 1-[4-[5-(7-methoxy-2-methyl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one as a solid (160 mg, 99%). A portion (40 mg) of the isolated 1-[4-[5-(7-methoxy-2-methyl-pyrazolo[3,4-c]pyridin-4-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was further purified by preparative HPLC to yield 12 mg of solid. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07-2.15 (m, 2H), 2.52-2.57 (m, 2H), 3.88-3.94 (m, 2H), 4.09 (s, 3H), 4.24 (s, 3H), 7.81-7.95 (m, 5H), 8.30 (t, J=2.21 Hz, 1H), 8.75 (s, 1H), 8.88 (d, J=1.89 Hz, 1H), 8.93 (d, J=2.21 Hz, 1H). MS ES+m/z 400 [M+H] + .

Example 158: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 156.

1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one was prepared in a similar manner as described in Example 74, replacing 1-(4-(5-(7-methoxy-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one with 1-(4-(5-(7-methoxy-1-methyl-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one. Purification on a silica gel column, eluted with 0-10% MeOH in DCM, gave 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as a solid (250 mg, 84%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.52-2.56 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.33 (s, 3H), 7.36 (s, 1H), 7.80-7.90 (m, 4H), 8.09 (s, 1H), 8.20 (t, J=2.21 Hz, 1H), 8.79 (d, J=2.21 Hz, 1H), 8.87 (d, J=2.21 Hz, 1H), 11.68 (br s, 1H). MS ES+m/z 386 [M+H] + .

Example 159: 2-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

1-(4-(5-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 157.

2-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one was prepared in a similar manner as described in Example 74, replacing 1-(4-(5-(7-methoxy-1H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one with 1-(4-(5-(7-methoxy-2-methyl-2H-pyrazolo[3,4-c]pyridin-4-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one. Purification on a silica gel column, eluted with 0-10% MeOH in DCM, gave 2-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-2,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one as a solid (35 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.07-2.14 (m, 2H), 2.52-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.13 (s, 3H), 7.26 (s, 1H), 7.81-7.90 (m, 4H), 8.20 (t, J=2.21 Hz, 1H), 8.48 (s, 1H), 8.78 (d, J=2.21 Hz, 1H), 8.86 (d, J=2.21 Hz, 1H), 11.25 (br s, 1H). MS ES+m/z 386 [M+H] + .

Example 160: 2-(1-methyl-7-oxo-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetonitrile

Step 1: 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one

1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one was prepared according to Example 158.

Step 2: 2-(1-methyl-7-oxo-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,7-dihydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetonitrile

A mixture of 1-methyl-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one (300 mg, 0.78 mmol) and Cs 2 CO 3 (507 mg, 1.56 mmol) in DMF (10 ml) was stirred at rt for 30 min. 2-Bromoacetonitrile (68 μl, 0.97 mmol) was added and the mixture was stirred at rt for 1 h. Water was added and the mixture was extracted with DCM (4×). The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-6% MeOH in DCM to give the product as a solid (170 mg, 52%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.52-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.33-4.37 (m, 3H), 5.17 (s, 2H), 7.81-7.90 (m, 5H), 8.19 (s, 1H), 8.25 (t, J=2.05 Hz, 1H), 8.82 (d, J=1.89 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H). MS ES+m/z 425 [M+H] + .

Example 161: isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Step 1: methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared in a similar manner as compound methyl 4-(2′-amino-5-(dimethylcarbamoyl)-[2,3′-bipyridin]-5′-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate in Example 126, replacing 2′-amino-N,N-dimethyl-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[2,3′-bipyridine]-5-carboxamide for 1-[4-[5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one.

Step 2: isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

To a solution of methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (42 mg, 0.1 mmol) in 2-propanol (1 ml) was added NaH (60% in mineral oil, 5 mg, 0.12 mmol). The mixture was stirred at rt over the weekend. The reaction mixture was quenched by dropwise addition of water. The mixture filtered and purified by preparative HPLC to give isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as a solid (14 mg, 31%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.33 (d, J=6.31 Hz, 6H), 2.06-2.13 (m, 2H), 2.52-2.56 (m, 2H), 3.91 (t, J=6.94 Hz, 2H), 5.12-5.19 (m, 1H), 7.19 (s, 1H), 7.40 (br d, J=4.41 Hz, 1H), 7.82-7.87 (m, 2H), 7.87-7.91 (m, 2H), 8.38 (t, J=2.21 Hz, 1H), 8.50 (d, J=4.73 Hz, 1H), 8.93 (d, J=2.21 Hz, 1H), 9.02 (d, J=2.21 Hz, 1H). MS ES+m/z 441 [M+H] + .

Example 162: ethyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Step 1: methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (not shown)

methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to Example 161.

Step 2: ethyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

ethyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to Example 161, replacing 2-propanol for ethanol to give ethyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as a solid (4 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.33 (t, J=7.09 Hz, 3H), 2.10 (t, J=7.57 Hz, 2H), 2.54 (t, J=8.04 Hz, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.34 (d, J=6.94 Hz, 2H), 7.24 (s, 1H), 7.40-7.50 (m, 1H), 7.82-7.85 (m, 2H), 7.86-7.94 (m, 2H), 8.38 (t, J=2.21 Hz, 1H), 8.47-8.58 (m, 1H), 8.94 (d, J=2.21 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H). MS ES+m/z 427 [M+H] + .

Example 163: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

Step 1: methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (not shown)

methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to Example 161.

Step 2: 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

To a solution of methyl 4-[5-[4-(2-oxopyrrolidin-1-yl)phenyl]-3-pyridyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (204 mg, 0.5 mmol) in MeOH:THF (1:1, 5 ml) was added a solution of LiOH H 2 O (25 mg, 0.59 mmol) in H 2 O (2 ml). The resulting mixture was refluxed for 3 h, cooled to rt, and concentrated. The crude product was purified by preparative HPLC to give 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid as a solid (51 mg, 26%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.14 (m, 2H), 2.52-2.55 (m, 2H), 3.90 (t, J=7.09 Hz, 2H), 7.05 (s, 1H), 7.42 (d, J=4.73 Hz, 1H), 7.82-7.86 (m, 2H), 7.86-7.91 (m, 2H), 8.38 (t, J=2.21 Hz, 1H), 8.45 (d, J=4.73 Hz, 1H), 8.93 (d, J=1.89 Hz, 1H), 9.01 (d, J=2.21 Hz, 1H). MS ES+m/z 399 [M+H] + .

Intermediate 93 was prepared according to Example 81, replacing 1-(4-bromo-3-methyl-phenyl)pyrrolidin-2-one with 1-(4-bromophenyl)pyrrolidin-2-one.

1-(4-(5-bromo-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 81, replacing 1-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one with 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one, and replacing 3,5-dibromopyridine with 5-bromo-3-chloro-2-methyl-pyridine.

1-(4-(6-methyl-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one was prepared according to Example 81, replacing 1-(4-(5-bromopyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one for 1-(4-(5-bromo-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one, to give 1-(4-(6-methyl-[3,4′-bipyridin]-5-yl)phenyl)pyrrolidin-2-one as a solid (10 mg, 2%). 1 H NMR (500 MHz, METHANOL-d 4 ) δ ppm 2.16-2.23 (m, 2H), 2.31-2.35 (m, 3H), 2.59-2.65 (m, 2H), 3.93-3.99 (m, 2H), 7.28-7.34 (m, 1H), 7.55-7.60 (m, 1H), 7.61-7.65 (m, 1H), 7.80-7.86 (m, 2H), 8.17 (t, J=2.21 Hz, 1H), 8.60 (d, J=2.21 Hz, 1H), 8.63-8.69 (m, 2H), 8.92 (d, J=2.21 Hz, 1H). MS ES+m/z 330 [M+H] + .

Example 165: methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate

To a suspension of methyl 4-hydroxyfuro[2,3-b]pyridine-2-carboxylate (Intermediate 6; Example 14) (193 mg, 1 mmol) in CHCl 3 (10 ml) was added oxalyl chloride (0.42 ml, 5 mmol) and a few drops of DMF. The resulting mixture was stirred at 60° C. for 2 h. When cooled to rt the mixture was concentrated and chased with toluene. The resulting residue was dissolved in DCM, passed through a short plug of silica and concentrated to give Intermediate 103 as a solid (185 mg, 87%). MS ES+m/z 212 [M+H] + .

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate was prepared according to Example 85, replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, and replacing K 2 CO 3 for TEA, to give methyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate as a solid (12 mg, 17%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.53-2.57 (m, 2H), 3.90-3.95 (m, 5H), 7.82-7.88 (m, 3H), 7.92 (d, J=7.69 Hz, 2H), 8.02 (s, 1H), 8.45 (t, J=2.21 Hz, 1H), 8.67 (d, J=5.04 Hz, 1H), 8.98 (d, J=1.89 Hz, 1H), 9.08 (d, J=2.21 Hz, 1H). MS ES+m/z 414 [M+H] + .

Example 166: N-(oxetan-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

Intermediate 104 was prepared according to Example 14, replacing methylamine for oxetan-3-amine to give Intermediate 104 as a solid (27 mg, 66%). MS ES+m/z 253 [M+H] + .

Step 2: N-(oxetan-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. N-(oxetan-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide was prepared according to Example 85, replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, and replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (Intermediate 7) with Intermediate 104, to give N-(oxetan-3-yl)-4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide as a solid (16 mg, 35%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.17 (m, 2H), 2.52-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 4.64 (t, J=6.62 Hz, 2H), 4.78 (dd, J=7.57, 6.62 Hz, 2H), 5.01-5.09 (m, 1H), 7.82-7.84 (m, 2H), 7.85 (s, 1H), 7.92 (d, J=0.95 Hz, 2H), 7.93 (s, 1H), 8.46 (s, 1H), 8.60 (d, J=5.04 Hz, 1H), 8.97 (d, J=2.21 Hz, 1H), 9.08 (d, J=2.21 Hz, 1H), 9.56 (br s, 1H). MS ES+m/z 455 [M+H] + .

Example 167: isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate

To a mixture of methyl 4-hydroxyfuro[2,3-b]pyridine-2-carboxylate (2 g, 10.4 mmol) in MeOH (40 ml) and THF (40 ml) was added a solution of LiOH H 2 O (0.891 g, 21.2 mmol) in water (40 ml) and the resulting mixture was stirred at 60° C. overnight. The mixture was cooled to rt, concentrated, and the resulting aqueous residue was neutralized using 2M aq. HCl. The precipitate was filtered, washed with water, washed with pentane, and dried to give 4-hydroxyfuro[2,3-b]pyridine-2-carboxylic acid (Intermediate 105; not shown) as a solid (1.76 g, 95%). MS ES+m/z 180 [M+H] + .

To a solution of 4-hydroxyfuro[2,3-b]pyridine-2-carboxylic acid (Intermediate 105; not shown) (179 mg, 1 mmol) in CHCl 3 (10 ml) was added oxalyl chloride (0.846 ml, 10 mmol) and a few drops of DMF. The reaction was stirred at rt over the weekend, and then concentrated, and redissolved in DCM. The resulting solution was slowly added to a cooled solution of 2-propanol (10 ml) and TEA (2.5 ml). The ice bath was removed and the mixture was stirred at rt for 1 h. The reaction was quenched with sat. aq. NaHCO 3 and the resulting mixture was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, concentrated and purified on a silica gel column eluted with 0-50% EtOAc in heptane to give Intermediate 106 as a solid (125 mg, 52%). MS ES+m/z 240 [M+H] + .

Step 2: isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine. isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate was prepared according to Example 85, replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, and replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (Intermediate 7) with Intermediate 106, to give isopropyl 4-(5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxylate as a solid (58 mg, 53%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.37 (d, J=6.31 Hz, 6H), 2.11 (quin, J=7.57 Hz, 2H), 2.53-2.57 (m, 2H), 3.91 (t, J=7.09 Hz, 2H), 5.22 (spt, J=6.25 Hz, 1H), 7.83-7.87 (m, 3H), 7.90-7.96 (m, 3H), 8.45 (t, J=2.21 Hz, 1H), 8.66 (d, J=5.04 Hz, 1H), 8.97 (d, J=2.21 Hz, 1H), 9.08 (d, J=2.21 Hz, 1H). MS ES+m/z 442 [M+H] + .

Example 168: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one

Step 1a: Intermediate 108—1-(3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-(5-bromo-3-pyridyl)-3-methyl-phenyl]pyrrolidin-2-one (Intermediate 107; not shown) was prepared according to Example 85, replacing (4-(2-oxopyrrolidin-1-yl)phenyl)boronic acid with (2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)boronic acid, replacing 5-bromo-3-iodo-pyridin-2-amine with 3,5-dibromopyridine, and replacing n-BuOH for 1,4-dioxane. Intermediate 107 was obtained as a solid (662 mg, 38%). MS ES+m/z 331 [M+H] + .

Step 1b: Intermediate 108—1-(3-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

Intermediate 108 was prepared according to Example 85, replacing 1-[4-(2-amino-5-bromo-3-pyridyl)phenyl]pyrrolidin-2-one with 1-[4-(5-bromo-3-pyridyl)-3-methyl-phenyl]pyrrolidin-2-one (Intermediate 107; not shown), and replacing DMSO for toluene. Intermediate 108 was obtained as a solid (297 mg, 39%). MS ES+m/z 379 [M+H] + .

Intermediate 99 was prepared in Example 156.

Step 3: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one

1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one was prepared according to Example 85, replacing 1-[3-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one and 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide for Intermediate 99, and replacing 1-[4-[2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one (Intermediate 90) with Intermediate 108. 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one was obtained as a solid (5 mg, 13%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.54 (s, 6H), 2.06-2.13 (m, 2H), 2.36 (s, 3H), 2.52-2.54 (m, 2H), 3.88 (s, 3H), 3.88-3.90 (m, 2H), 5.21 (s, 1H), 7.34-7.39 (m, 1H), 7.63-7.66 (m, 2H), 8.02 (t, J=2.21 Hz, 1H), 8.11 (s, 1H), 8.36 (d, J=2.21 Hz, 1H), 8.44 (d, J=2.21 Hz, 1H), 8.48 (d, J=1.89 Hz, 1H), 8.94 (d, J=2.21 Hz, 1H). MS ES+m/z 441 [M+H] + .

Example 169: N,N-dimethyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Intermediate 107 was prepared according to Example 13, replacing methylamine with dimethylamine, and replacing methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate with methyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate.

Step 2: N,N-dimethyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

N,N-dimethyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide was prepared according to Example 85, replacing Intermediate 90 with Intermediate 108, and replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (Intermediate 7) with Intermediate 106. N,N-dimethyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide was obtained as a solid (21 mg, 26%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (quin, J=7.57 Hz, 2H), 2.37 (s, 3H), 2.51-2.54 (m, 2H), 3.05-3.20 (m, 6H), 3.88 (t, J=7.09 Hz, 2H), 6.93 (s, 1H), 7.37 (d, J=4.73 Hz, 1H), 7.41 (d, J=8.51 Hz, 1H), 7.60-7.67 (m, 2H), 8.14 (t, J=2.21 Hz, 1H), 8.43 (d, J=4.73 Hz, 1H), 8.68 (d, J=1.89 Hz, 1H), 8.97 (d, J=2.21 Hz, 1H). MS ES+m/z 440 [M+H] + .

Example 170: N-methyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

Intermediate 7 was prepared in Example 14.

Step 2: N-methyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

N-methyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide was prepared according to Example 85, replacing Intermediate 90 with Intermediate 108. N-methyl-4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide was obtained as a solid (6 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (quin, J=7.57 Hz, 2H), 2.35 (s, 3H), 2.51-2.54 (m, 2H), 2.82 (d, J=4.41 Hz, 3H), 3.89 (t, J=7.09 Hz, 2H), 7.42 (d, J=7.88 Hz, 1H), 7.64-7.67 (m, 2H), 7.75 (s, 1H), 7.77 (d, J=5.04 Hz, 1H), 8.19 (t, J=2.21 Hz, 1H), 8.56 (d, J=5.04 Hz, 1H), 8.74 (d, J=2.21 Hz, 1H), 8.86 (br d, J=4.41 Hz, 1H), 9.00 (d, J=2.21 Hz, 1H). MS ES+m/z 427 [M+H] + .

Example 171: methyl 4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Intermediate 5 was prepared in Example 128.

Step 2: methyl 4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

methyl 4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to Example 85, replacing Intermediate 90 with Intermediate 108. methyl 4-(5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was obtained as a solid (51 mg, 45%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (d, J=7.88 Hz, 2H), 2.36 (s, 3H), 2.52-2.55 (m, 2H), 3.85-3.92 (m, 5H), 7.27 (s, 1H), 7.40 (d, J=9.14 Hz, 1H), 7.45 (d, J=4.73 Hz, 1H), 7.65 (s, 2H), 8.13 (t, J=2.05 Hz, 1H), 8.54 (d, J=4.73 Hz, 1H), 8.71 (d, J=2.21 Hz, 1H), 8.97 (d, J=2.21 Hz, 1H), 12.68-12.91 (m, 1H). MS ES+m/z 427 [M+H] + .

Example 172: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

Intermediate 99 was prepared in Example 156.

Step 2: Intermediate 110—1-(4-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

Intermediate 110 was prepared according to Example 85. (4-(2-oxopyrrolidin-1-yl)phenyl)boronic acid was replaced with 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrrolidin-2-one to afford 1-[4-(5-Bromo-4-methyl-3-pyridyl)phenyl]pyrrolidin-2-one (Intermediate 109; not shown) as a solid (789 mg, quant.). MS ES+m/z 331 [M+H] + . Further, 5-bromo-3-iodo-pyridin-2-amine was replaced with 3,5-dibromo-4-methyl-pyridine. Intermediate 110 was obtained as a solid (741 mg, 86%). MS ES+m/z 379 [M+H] + .

Step 3: 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing Intermediate 90 for Intermediate 110, and replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (Intermediate 7) with Intermediate 99. 1-(4-(5-(5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one was obtained as a solid (2 mg, 6%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.51 (s, 6H), 2.05-2.14 (m, 2H), 2.22 (s, 3H), 2.53 (d, J=8.20 Hz, 2H), 3.89 (s, 3H), 3.90 (s, 2H), 5.11-5.16 (m, 1H), 7.50 (d, J=8.51 Hz, 2H), 7.73 (s, 1H), 7.80 (d, J=8.83 Hz, 2H), 7.95 (d, J=1.89 Hz, 1H), 8.35 (s, 1H), 8.48 (d, J=2.21 Hz, 1H), 8.51 (s, 1H). MS ES+m/z 441 [M+H] + .

Example 173: N,N-dimethyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

Intermediate 107 was prepared in Example 171.

Intermediate 110 was prepared in Example 174.

Step 3: N,N-dimethyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide

N,N-dimethyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide was prepared according to Example 85, replacing Intermediate 90 for Intermediate 110, and replacing 4-chloro-N-methyl-furo[2,3-b]pyridine-2-carboxamide (Intermediate 7) with Intermediate 107. N,N-dimethyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide was obtained as a solid (5 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.09 (s, 5H), 2.52-2.55 (m, 2H), 2.94-3.11 (br s, 3H), 3.11-3.24 (br s, 3H), 3.87-3.93 (m, 2H), 6.61 (s, 1H), 7.15 (d, J=5.04 Hz, 1H), 7.52-7.56 (m, 2H), 7.79-7.84 (m, 2H), 8.43 (d, J=5.04 Hz, 1H), 8.48 (d, J=1.58 Hz, 2H), 12.19-12.39 (m, 1H). MS ES+m/z 440 [M+H] + .

Example 174: N-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

Intermediate 7 was prepared in Example 14.

Intermediate 110 was prepared in Example 172.

Step 3: N-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide

N-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide was prepared according to Example 85, replacing Intermediate 90 for Intermediate 110. N-methyl-4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)furo[2,3-b]pyridine-2-carboxamide was obtained as a solid (11 mg, 16%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.06-2.15 (m, 5H), 2.53 (t, J=8.04 Hz, 2H), 2.81 (d, J=4.73 Hz, 3H), 3.91 (t, J=7.09 Hz, 2H), 7.46 (s, 1H), 7.53 (d, J=5.04 Hz, 1H), 7.54 (d, J=8.51 Hz, 2H), 7.79-7.83 (m, 2H), 8.50 (s, 1H), 8.52 (s, 1H), 8.57 (d, J=5.04 Hz, 1H), 8.81 (q, J=4.62 Hz, 1H). MS ES+m/z 427 [M+H] + .

Example 175: methyl 4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

Intermediate 5 was prepared in Example 128.

Intermediate 110 was prepared in Example 174.

Step 3: methyl 4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

methyl 4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to Example 85, replacing Intermediate 90 for Intermediate 110, and replacing Intermediate 7 for Intermediate 5. methyl 4-(4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was obtained as a solid (64 mg, 37%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.08 (s, 3H), 2.08-2.13 (m, 2H), 2.51-2.55 (m, 2H), 3.86 (s, 3H), 3.88-3.92 (m, 2H), 6.95 (s, 1H), 7.22 (d, J=4.73 Hz, 1H), 7.54 (d, J=8.83 Hz, 2H), 7.80 (d, J=8.83 Hz, 2H), 8.46 (s, 1H), 8.47-8.50 (m, 1H), 8.50-8.56 (m, 1H), 12.75 (br s, 1H). MS ES+m/z 427 [M+H] + .

Example 176: 1-(4-(5-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

To a solution of 3-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (463 mg, 2 mmol) in DMF (10 ml) was added Cs 2 CO 3 (1.3 g, 4 mmol) and the suspension was stirred at rt for 1 h. Iodomethane (0.156 ml, 2.5 mmol) was added and the mixture was stirred at rt overnight. The reaction was added to water and extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na 2 SO 4 , filtered, and concentrated to give 3-bromo-5-chloro-1-methyl-pyrrolo[2,3-b]pyridine as a solid (480 mg, 98%). MS ES+m/z 245 [M+H] + .

Intermediate 111 (246 mg, 1 mmol), pyrimidine-5-boronic acid (124 mg, 1 mmol), K 2 CO 3 (276 mg, 2 mmol), PdCl 2 (PPh 3 ) 2 (37 mg, 0.05 mmol) were taken up in 1,4-dioxane (4 ml) and water (1 ml) and the resulting mixture was stirred at 80° C. for 3 h. The mixture was cooled to rt, brine was added, and the mixture extracted with DCM (3×). The combined organics were washed with brine, dried over Na 2 SO 4 , filtered, concentrated, and purified on a silica gel column eluted with 0-6% MeOH in DCM to give Intermediate 112 as a solid (190 mg, 54%). MS ES+m/z 245 [M+H] + .

1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one was prepared according to Example 85, replacing 5-bromo-3-iodo-pyrin-2-amine with 3,5-dibromopyridine.

Step 3: 1-(4-(5-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(5-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing Intermediate 90 for 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, and replacing Intermediate 7 for Intermediate 112. 1-(4-(5-(1-methyl-3-(pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was obtained as a solid (12 mg, 7%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.11 (quin, J=7.57 Hz, 2H), 2.53-2.57 (m, 2H), 3.89-3.94 (m, 2H), 3.97 (s, 3H), 7.82-7.86 (m, 2H), 7.90-7.94 (m, 2H), 8.31 (s, 1H), 8.50 (t, J=2.21 Hz, 1H), 8.83 (dd, J=8.99, 2.05 Hz, 2H), 8.92 (d, J=2.21 Hz, 1H), 9.03 (d, J=2.21 Hz, 1H), 9.10 (s, 1H), 9.32 (s, 2H). MS ES+m/z 447 [M+H] + .

5-Bromopyridin-3-amine (500 mg, 2.89 mmol) was dissolved in 2-MeTHF (5 ml) and cooled to −10° C. LHMDS (1.06 M, 6.82 ml, 7.22 mol) was added and the mixture was stirred for 10 min. To the cooled mixture was added 1-fluoro-2-nitro-benzene (0.321 ml, 3.03 mmol) and the resulting mixture was allowed to stir for 10 min at −10° C. and then allowed to stir at rt for 3 h. The reaction was quenched with sat. aq. NH 4 Cl. Water and EtOAc were added and the organic layer was separated, filtered, concentrated, and purified on a silica gel column eluted with 0-100% EtOAc in heptane to give Intermediate 113 as a solid (486 mg, 57%). MS ES+m/z 294 [M+H] + .

The nitro group in Intermediate 113 reduced under the conditions outlined in Example 54, step 1, to give Intermediate 114 as a solid (564 mg, quant.). MS ES+m/z 264 [M+H] + .

A mixture of diethoxymethoxyethane (0.549 ml, 3.30 mmol), Ni-(5-bromo-3-pyridyl)benzene-1,2-diamine (Intermediate 114) (436 mg, 1.65 mmol) and 4-methylbenzenesulfonic acid hydrate (63 mg, 0.33 mmol) in 1,4-dioxane (5 ml) was stirred at 100° C. for 1 h. Water and EtOAc were added, the organic layer was separated, dried over Na 2 SO 4 , filtered and concentrated to give Intermediate 115 as a solid (383 mg, 85%). MS ES+m/z 274 [M+H] + .

1-(4-(5-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was prepared according to Example 85, replacing Intermediate 90 for 1-[4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]phenyl]pyrrolidin-2-one, and replacing Intermediate 7 for Intermediate 115. 1-(4-(5-(1H-benzo[d]imidazol-1-yl)pyridin-3-yl)phenyl)pyrrolidin-2-one was obtained as a solid (28 mg, 11%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 2.05-2.14 (m, 2H), 2.52-2.57 (m, 2H), 3.87-3.93 (m, 2H), 7.32-7.41 (m, 2H), 7.71-7.76 (m, 1H), 7.80-7.86 (m, 3H), 7.90-7.96 (m, 2H), 8.39-8.44 (m, 1H), 8.70-8.74 (m, 1H), 8.89-8.93 (m, 1H), 9.02-9.07 (m, 1H). MS ES+m/z 355 [M+H] + .

A mixture of 3-bromo-5-(4-pyridyl)pyridine (118 mg, 0.5 mmol) and 2-methyl-2,8-diazaspiro[4.5]decan-1-one⋅hydrochloride (102 mg, 0.5 mmol) in 1,4-dioxane (4 ml) was degassed with argon for 5 min. Cs 2 CO 3 (489 mg, 1.5 mmol), XantPhos (28 mg, 0.05 mmol) and Pd(OAc) 2 (11 mg, 0.05 mmol) were added and the resulting mixture was stirred at 90° C. for 6 h. When cooled to rt water was added and the mixture extracted with DCM (3×10 ml). The combined organics were dried over Na 2 SO 4 , filtered, concentrated and purified by preparative HPLC to give 8-([3,4′-bipyridin]-5-yl)-2-methyl-2,8-diazaspiro[4.5]decan-1-one as a solid (20 mg, 12%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 1.46 (br d, J=13.24 Hz, 2H), 1.75-1.86 (m, 2H), 1.99 (t, J=6.94 Hz, 2H), 2.75 (s, 3H), 2.99 (td, J=12.37, 2.68 Hz, 2H), 3 3.29-3.35 (m, 2H), 3.86 (dt, J=13.08, 3.55 Hz, 2H), 7.65 (s, 1H), 7.78-7.81 (m, 2H), 8.38 (d, J=1.89 Hz, 1H), 8.41 (d, J=2.84 Hz, 1H), 8.64-8.69 (m, 2H). MS ES+m/z 323 [M+H] + .

Step 1: Intermediate 116—(4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)(methyl)carbamoyl)phenyl)boronic acid

To a solution of 4-boronobenzoic acid (100 mg, 0.6 mmol) in MeCN (1 ml) was added N-methylmorpholine (0.13 ml, 1.2 mmol), followed by T3P (50% in EtOAc, 0.54 ml, 0.9 mmol) and tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate (0.15 ml, 0.66 mmol). The resulting mixture was heated and stirred at 90° C. for 2 h. The reaction was cooled to rt, water and EtOAc were added, and the organic layer separated. The aqueous layer was extracted with EtOAc and the combined organics were dried over MgSO 4 , filtered, and concentrated to give Intermediate 116 as a solid (200 mg, 88%). MS ES+m/z 321 [M-tBu+H] + .

A mixture of 3-bromo-5-(4-pyridyl)pyridine (79 mg, 0.34 mmol) and [4-[(1-tert-butoxycarbonyl-4-piperidyl)methyl-methyl-carbamoyl]phenyl]boronic acid (Intermediate 116) (91 mg, 0.24 mmol) in 1,4-dioxane (5 ml) and water (0.3 ml) was degassed with nitrogen for 5 min. PdCl 2 (Amphos) (9 mg, 0.01 mmol) and K 2 CO 3 (67 mg, 0.48 mmol) were added and the resulting mixture was stirred at 100° C. for 2 h. When cooled to rt 1,2-dichloroethane and water were added. The organic layer was separated, concentrated and purified by preparative HPLC. The resulting material was dissolved in EtOH (2 ml) and a few drops of conc. HCl was added. The reaction was stirred at rt until all Boc protection group had been removed. The mixture was concentrated and the resulting residue was redissolved in aq. 0.5 M HCl (1 ml) and extracted with EtOAc. The aqueous layer was made alkaline using aq. 2M KOH and then extracted with EtOAc (2×). The combined organics were dried over dried over MgSO 4 , filtered and concentrated to give 4-([3,4′-bipyridin]-5-yl)-N-methyl-N-(piperidin-4-ylmethyl)benzamide as a solid (17 mg, 18%). 1 H NMR (500 MHz, MeOD) δ ppm 0.82-0.95 (m, 1H), 1.29-1.38 (m, 1H), 1.55-1.63 (m, 1H), 1.75-1.82 (m, 1H), 1.83-2.08 (m, 1H), 2.49-2.60 (m, 1H), 2.61-2.71 (m, 1H), 2.92-2.99 (m, 1H), 3.01-3.16 (m, 5H), 3.48-3.54 (m, 1H), 7.54-7.62 (m, 2H), 7.86-7.91 (m, 4H), 8.45-8.51 (m, 1H), 8.66-8.72 (m, 2H), 8.92-9.00 (m, 2H). MS ES+m/z 387 [M+H] + .

Intermediate 117 was prepared according to Example 182, replacing tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate for tert-butyl 3-(methylaminomethyl)piperidine-1-carboxylate, to give Intermediate 117 as a solid (200 mg, 61%). MS ES+m/z 377 [M+H] + .

4-([3,4′-bipyridin]-5-yl)-N-methyl-N-(piperidin-3-ylmethyl)benzamide was prepared according to Example 181, replacing Intermediate 116 for Intermediate 117. Purification by preparative HPLC gave 4-([3,4′-bipyridin]-5-yl)-N-methyl-N-(piperidin-3-ylmethyl)benzamide as a solid (di-acetic acid salt, 2 mg, 1%). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 0.68 (s, 1H), 1.20-1.47 (m, 2H), 1.53-1.64 (m, 1H), 1.72-1.81 (m, 7H), 1.82-1.93 (m, 1H),