The present disclosure relates to compounds of formula (I) and pharmaceutical compositions thereof and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with SHP2 deregulation with the compounds and compositions of the disclosure. [structure]

Description

83 parts

›CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S. provisional application Ser. No. 62/511,583, filed May 26, 2017; 62/646,091, filed Mar. 21, 2018; and 62/661,882, filed Apr. 24, 2018; the contents of each of which are hereby incorporated by reference in their entirety.

›BACKGROUND

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two Src homology 2 (SH2) NH 2 -terminal domains and a C-terminal protein-tyrosine phosphatase domain. It is ubiquitously expressed in various tissues and cell types. SHP2 plays an important role in diverse signaling pathways to regulate cellular biological processes and is involved in the signaling pathways of a variety of growth factors and cytokines. Within a single signaling pathway, SHP2 can play both positive (signal enhancing) and negative (signal diminishing) roles in intracellular signaling processes. SHP2 is believed to function by dephosphorylating its associated signaling molecules, thereby attenuating the local signaling flow. However, the main effect of SHP2 action in most signaling pathways (e.g., growth factor, cytokine, and extracellular matrix receptors) is to enhance signal transduction. For example, SHP2 is a positive regulator of the ERK/MAPK signaling pathway, playing a key role in regulating cellular proliferation and survival. (For a review of SHP2 phosphatase, see, e.g, K. S. Grossman et al., Adv. Cancer Res. 2010, 106, 53-89; and references cited therein.)

In the basal state, SHP2 is normally auto-inhibited due to intramolecular interactions between its N-terminal SH2 (N-SH2) domain and its catalytic (PTP) domain, which blocks access to the catalytic site. Activating proteins that interact with the SH2 domains induce a conformational change that reverses this inhibition and allows substrate access to the catalytic site. Mutations in the PTPN11 gene that affect the N-SH2 or PTP domain residues involved in basal inhibition of SHP2 result in more readily activatable forms of SHP2 protein, which can lead to unregulated or increased SHP2 activity. Such activated mutants of SHP2 have been associated with developmental disorders such as Noonan syndrome, where nearly all mutated forms of SHP2 demonstrate increased PTP activity. Thus, there is a need for SHP2 phosphatase inhibitor compounds and methods for treating cancer and other disorders with these compounds.

›SUMMARY · 1 of 2

In an embodiment, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula I is represented by:

wherein:

R X together with R 1 and the nitrogen to which they are attached form a nitrogen-containing monocyclic, bicyclic or tricyclic ring system selected from the group consisting of a 8-14 membered bicyclic heteroaryl, a 11-15 membered tricyclic heteroaryl, a 5-7 membered monocyclic heteroaryl, and a 4-7 membered heterocyclyl, wherein the nitrogen-containing monocyclic, bicyclic or tricyclic ring system may optionally be substituted with one, two or more substituents each independently selected from the group consisting of R 10 , —OR 10 , —S(O) w R 10 (wherein w is 0, 1 or 2), —C 1-6 alkyl-S(O) w —C 1-3 alkyl, —N(R 10 ) 2 , —N(CO)R 10 , —N—S(O) w —R 10 (where w is 0, 1 or 2), —OS(O) w —R 10 (wherein w is 0, 1, or 2), —S(O) w —N(R 10 ) 2 (wherein w is 0, 1 or 2), —S(O)(NH)R 10 , —N(H)—SO 2 —C 1-3 alkyl, —N(SO 2 —C 1-3 alkyl) 2 , P(O)(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , oxo, halogen, hydroxyl, cyano, nitro, —C(═N—OR a )—C 1-3 alkyl, —C(═N—OR a )—H, —S(O)(NR a )C 1-3 alkyl,

phenyl (optionally substituted with one, two or three halogen, —O-phenyl, C 1-3 alkyl or C 1-3 haloalkyl), C 1-3 alkyl, C 2-6 -alkynyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl (optionally substituted with one, two or three halogen, oxo, C 1-3 alkyl or C 1-3 haloalkyl), and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl, C 1-3 alkyl-OH, or C 1-3 haloalkyl);

R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and P(O)(R 20 ) 2 ; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 -alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, and heteroaryl may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, —NR a C(O)—R 20 , —C(O)—R 20 , —C(NR a )R b , —NR a R b , C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;

R 20 is selected from the group consisting of hydrogen, hydroxyl, halogen, —NR a R b , C 1-6 alkyl and C 1-6 alkoxy;

R 4 and R 5 are each independently, selected from the group consisting of H, —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , halogen, —(C 1 -C 6 )alkyl-N(R 6 ) 2 , or cyano, wherein said —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , or —(C 1 -C 6 )alkyl-N(R 6 ) 2 is optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , oxo, and halogen,

or R 4 and R 5 , taken together with the atoms to which they are attached, form a 3-7 membered carbocyclic or heterocyclic saturated or partially unsaturated ring, which ring is optionally substituted with one or more substituents selected from the group consisting of —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , halogen, oxo, or cyano;

or R 4 and R 8 , taken together with the atoms to which they are attached, form a 4-7 membered carbocyclic or heterocyclic ring, which ring is optionally substituted with —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , halogen, oxo, or cyano;

or R 4 is absent, and R 4 and R 8 , taken together with the atoms to which they are attached, form a 3-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , halogen, oxo, or cyano;

R 6 is independently for each occurrence selected from the group consisting of H, —(C 1 -C 6 )alkyl, —C(O)OC 1-4 alkyl, and phenyl;

R 11 and R 12 are, each independently selected from the group consisting of, H, —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , aryl, arylalkylene, heteroaryl, heteroarylalkylene, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , halogen, —(C 1 -C 6 )alkyl-N(R 6 ) 2 , —CO 2 H, or cyano, wherein said —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , aryl, arylalkylene, heteroaryl, heteroarylalkylene, or —(C 1 -C 6 )alkyl-N(R 6 ) 2 is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(H) 2 , and halogen;

or R 11 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered heterocyclic ring;

or R 4 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

or R 8 and R 11 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

R 8 and R 9 are each independently selected from the group consisting of H, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 6 ) 2 , —OR 6 , —(C 1 -C 6 )alkyl-O—R 6 , —C(O)NH 2 , —N(R 6 ) 2 , halogen, or cyano;

R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-6 alkyl; wherein C 1-6 alkyl may optionally be substituted by one or more substituents selected from halogen, cyano, oxo and hydroxyl;

or R a and R b , together with the nitrogen to which they are attached, may form a 4-6 membered monocyclic heterocyclic ring, which may have an additional heteroatom selected from the group consisting of O, S, and N; wherein the 4-6 membered heterocyclic ring may optionally be substituted by one or more substituents selected from the group consisting of halogen, cyano, oxo or hydroxyl;

and each of m and n is, independently, 0, 1, 2, or 3, with m+n being at least 2 and no more than 4.

The disclosure also provides pharmaceutical compositions containing the compounds described herein. Further, the disclosure provides a method of inhibiting SHP2 phosphatase activity in a subject by administering a therapeutically effective amount of a compound or composition described herein, to a subject, e.g., a human, in need. The method may include additionally administering a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.

›SUMMARY · 2 of 2

The disclosure further provides a method of treating a disorder in a subject by administering a therapeutically effective amount of a compound or composition described herein, to a subject in need thereof. Examples of disorders include Noonan syndrome, neutropenia, diabetes, neuroblastoma, melanoma, acute myeloid leukemia, juvenile leukemia, juvenile myelomonocytic leukemia, breast cancer, lung cancer, and colorectal cancer. In addition to the compound or composition described herein, such method may include administration of a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor.

The present disclosure is based, in part, on certain discoveries which are described more fully in the Examples section of the present application. For example, the present disclosure is based, in part, on the discovery of compounds disclosed herein, e.g., of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), Formula (XIII), or Formula (XIV) and the SHP2 phosphatase inhibition exhibited by such compounds.

These and other embodiments of the disclosure are further described in the following sections of the application, including the Detailed Description, Examples, and Claims. Still other objects and advantages of the disclosure will become apparent by those of skill in the art from the disclosure herein, which are simply illustrative and not restrictive. Thus, other embodiments will be recognized by the ordinarily skilled artisan without departing from the spirit and scope of the disclosure.

›DETAILED DESCRIPTION · 1 of 13

Activating SHP2 mutations have been detected in juvenile myelomonocytic leukemia (e.g., Q506P), chronic myelomonocytic leukemia (e.g., Y63C), neuroblastoma (e.g., T507K), melanoma (e.g., R138Q), acute myeloid leukemia (e.g., G503V), breast cancer, lung cancer (e.g., E76V), colorectal cancer (e.g., E76G). (M. Bentires-Alj et al., in Cancer Res. 2004, 64, 8816-8820; and references cited therein. SHP2 phosphatase inhibitors are disclosed, e.g., in WO 2015/107493; WO 2015/107494; WO 2015/107495; and J. G. Fortanet et al., in J. Med. Chem. 2016, DOI: 10.1021/acs.jmedchem.6b00680; and references cited therein. The effects of SHP2 phsophatase inhibition are described, e.g., Y.-N. P. Chen et al., in Nature, 2016, doi:10.1038/nature18621; J. Wang et al., in J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein.

The compounds and/or compositions of the disclosure, alone or in combination with other treatments, may be effective in treating, reducing, and/or suppressing disorders related to SHP2 phosphatase activity such as, e.g., Noonan syndrome, Leopard Syndrome, diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia, acute myeloid leukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer (including adenocarcinoma of the lung), colorectal cancer, esophageal cancer, gastric cancer, squamous-cell carcinoma of the head and neck (SCCHN), neutropenia (Kostmann's syndrome), and systemic lupus erythematosus. See, e.g, N. Aceto et al. Nature Medicine, 2012, 28, 529-538; C. M. Furcht et al. Oncogene, 2013, 32, 2346-2355; V. E. Schneeberger et al. Oncotarget, 2015, 6, 6191-6202; P. Cai et al., Biomedicine & Pharmacotherapy 2014, 68, 285-290; and references cited therein.

Abbreviations and Definitions

The term “isomer” as used herein refers to a compound having the identical chemical formula but different structural or optical configurations. The term “stereoisomer” as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in positioning of atoms and/or functional groups in the space. All stereoisomers of the present compounds (e.g., those which may exist due to asymmetric carbons on various substituents), including enantiomeric forms and diastereomeric forms, are contemplated within the scope of this disclosure.

The term “tautomer” as used herein refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions by reorganization of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.

The term “isotopic substitution” as used herein refers to the substitution of an atom with its isotope. The term “isotope” as used herein refers to an atom having the same atomic number as that of atoms dominant in nature but having a mass number (neutron number) different from the mass number of the atoms dominant in nature. It is understood that a compound with an isotopic substitution refers to a compound in which at least one atom contained therein is substituted with its isotope. Atoms that can be substituted with its isotope include, but are not limited to, hydrogen, carbon, and oxygen. Examples of the isotope of a hydrogen atom include 2 H (also represented as D) and 3 H. Examples of the isotope of a carbon atom include 13 C and 14 C. Examples of the isotope of an oxygen atom include 18 O.

The term “alkyl”, as used herein, unless otherwise indicated, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C 1 -C 10 alkyl” denotes alkyl having 1 to 10 carbon atoms, and straight or branched hydrocarbons of 1-6, 1-4, or 1-3 carbon atoms, referred to herein as C 1-6 alkyl, C 1-4 alkyl, and C 1-3 alkyl, respectively. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, 2-methylbutyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl.

The term “cycloalkyl,” as used herein, refers to saturated cyclic alkyl moieties having 3 or more carbon atoms, for example, 3-10, 3-6, or 4-6 carbons, referred to herein as C 3-10 cycloalkyl, C 3-6 cycloalkyl or C 4-6 cycloalkyl, respectively for example. Unless otherwise stated, such saturated cyclic alkyl moieties can contain up to 18 carbon atoms and include monocycloalkyl, polycycloalkyl, and benzocycloalkyl structures. Monocycloalkyl refers to groups having a single ring group. Polycycloalkyl denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common; i.e., a spiro, fused, or bridged structure. Benzocycloalkyl signifies a monocyclic alkyl group fused to a benzene ring, referred to herein as C 8-12 benzocycloalkyl, for example. Examples of monocycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, cycloheptadecyl, and cyclooctadecyl. Examples of polycycloalkyl groups include, but are not limited to, decahydronaphthalene, spiro[4.5]decyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, pinanyl, norbornyl, adamantyl, and bicyclo[2.2.2]octyl. Examples of benzocycloalkyl groups include, but are not limited to, tetrahydronaphthyl, indanyl, and 1.2-benzocycloheptanyl.

The terms “heteroaryl” or “heteroaromatic group” as used herein refers to a monocyclic aromatic 5-7 membered ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur, or a 8-14 (e.g. 8-12) membered bicyclic or 11-15 membered tricyclic unsaturated or partially unsaturated ring system containing one or more heteroatoms, for example one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, said heteroaryl ring may be linked to the adjacent radical though carbon or nitrogen. Examples of heteroaryl rings include but are not limited to furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine or pyrimidine, tetrahydroquinoline, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinoxalin-1-yl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-1-yl, 1H-benzo[d]imidazol-1-yl, indolin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl, isoindolin-2-yl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-4-yl, 2-(3,4-dihydroisoquinolin-1(2H)-one), 2-(3,4-dihydroisoquinolin-1(2H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, piperidin-1-yl, 1-(1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one), 1,2,3,4-tetrahydro-1,8-naphthyridin-1-yl, 1-(3,4-dihydro-1,5-naphthyridin-2(1H)-one), 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 1-(2,3-dihydroquinolin-4(1H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, 1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-4-yl, 3,4-dihydroquinoxalin-1-yl-2(1H)-one, 2,3,4,6-tetrahydro-1,6-naphthyridin-1-yl-5(1H)-one, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl, 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl, 3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl 11-dioxide, 1,2,3,4-tetrahydropyrazino[2,3-d]pyridazin-1-yl, 1,4-dihydropyrido[3,4-b]pyrazin-1-yl-3(2H)-one, 5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-1-yl, 5,8-dihydropteridin-5-yl-7(6H)-one, 4,5,6,7-tetrahydrothieno[3,2-b]pyridin-4-yl, 5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-5-yl, and 1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,4-f]quinolin-3-only, etc.

›DETAILED DESCRIPTION · 2 of 13

The terms “heterocyclyl”, “heterocyclylalkyl” or “heterocyclic group” are art-recognized and refer to saturated 4-10 (e.g., 4-7) membered monocyclic and bicyclic ring structures, including bridged or fused rings, and whose ring structures include one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Where possible, heterocyclyl rings may be linked to the adjacent radical through carbon or nitrogen.

The term “pharmaceutically acceptable salt” is intended to include salts derived from inorganic or organic acids including, e.g., hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2 sulfonic and other acids; and salts derived from inorganic or organic bases including, e.g., sodium, potassium, calcium, magnesium, zinc, ammonia, lysine, arginine, histidine, polyhydroxylated amines or tetrafluoroborate. Exemplary pharmaceutically acceptable salts are found, e.g., in Berge, et al. ( J. Pharm. Sci. 1977, 66(1), 1; and Gould, P. L., Int. J. Pharmaceutics 1986, 33, 201-217, each hereby incorporated by reference in its entirety. Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts are those salts derived from acids comprising two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid and citric acid. Other exemplary hemi-salts are those salts derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

As used herein the term “about” is used herein to mean approximately, roughly, around, or in the region of. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20 percent up or down (higher or lower).

An “effective amount”, “sufficient amount” or “therapeutically effective amount” as used herein is an amount of a compound that is sufficient to effect beneficial or desired results, including clinical results. As such, the effective amount may be sufficient, e.g., to reduce or ameliorate the severity and/or duration of afflictions related to SHP2 phosphatase, or one or more symptoms thereof, prevent the advancement of conditions or symptoms related to afflictions related to SHP2 phosphatase, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes the amount of the compound that avoids or substantially attenuates undesirable side effects.

As used herein and as well understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminution of extent of disease or affliction, a stabilized (i.e., not worsening) state of disease or affliction, preventing spread of disease or affliction, delay or slowing of disease or affliction progression, amelioration or palliation of the disease or affliction state and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

The phrase “in need thereof” refers to the need for symptomatic or asymptomatic relief from conditions related to SHP2 phosphatase activity or that may otherwise be relieved by the compounds and/or compositions of the disclosure.

The present disclosure provides, for example, a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula I is represented by:

wherein:

phenyl (optionally substituted with one, two or three halogen, —O-phenyl, C 1-3 alkyl or C 1-3 haloalkyl), C 1-3 alkyl, C 2-6 alkynyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl (optionally substituted with one, two or three halogen, oxo, C 1-3 alkyl or C 1-3 haloalkyl), and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl, C 1-3 alkyl-OH, or C 1-3 haloalkyl);

R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and P(O)(R 20 ) 2 ; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, and heteroaryl may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, —NR a C(O)—R 20 , —C(O)—R 20 , —C(NR a )—R b , —NR a R b , C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;

›DETAILED DESCRIPTION · 3 of 13

R 20 is selected from the group consisting of hydrogen, hydroxyl, halogen, —NR a R b , C 1-6 alkyl and C 1-6 alkoxy;

or R 4 is absent, and R 4 and Re, taken together with the atoms to which they are attached, form a 3-membered carbocyclic or heterocyclic ring, which ring is optionally substituted with —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , halogen, oxo, or cyano;

R 6 is independently for each occurrence selected from the group consisting of H, —(C 1 -C 6 )alkyl, —C(O)OC 1-4 alkyl, and phenyl;

R 11 and R 12 are, each independently selected from the group consisting of, H, —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , aryl, arylalkylene, heteroaryl, heteroarylalkylene, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , halogen, —(C 1 -C 6 )alkyl-N(R 6 )2, —CO 2 H, or cyano, wherein said —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , aryl, arylalkylene, heteroaryl, heteroarylalkylene, or —(C 1 -C 6 )alkyl-N(R 6 ) 2 is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(H) 2 , and halogen;

or R 11 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered heterocyclic ring;

or R 4 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

or R 8 and R 11 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

and each of m and n is, independently, 0, 1, 2, or 3, with m+n being at least 2 and no more than 4.

In some embodiments, R X together with R 1 and the nitrogen to which they are attached form a ring moiety selected from the group consisting of 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinoxalin-1-yl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-1-yl, 1H-benzo[d]imidazol-1-yl, indolin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl, isoindolin-2-yl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-4-yl, 2-(3,4-dihydroisoquinolin-1(2H)-one), 2-(3,4-dihydroisoquinolin-1(2H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, piperidin-1-yl, 1-(1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one), 1,2,3,4-tetrahydro-1,8-naphthyridin-1-yl, 1-(3,4-dihydro-1,5-naphthyridin-2(1H)-one), 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 1-(2,3-dihydroquinolin-4(1H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, 1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-4-yl, 3,4-dihydroquinoxalin-1-yl-2(1H)-one, 2,3,4,6-tetrahydro-1,6-naphthyridin-1-yl-5(1H)-one, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl, 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl, 3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl 11-dioxide, 1,2,3,4-tetrahydropyrazino[2,3-d]pyridazin-1-yl, 1,4-dihydropyrido[3,4-b]pyrazin-1-yl-3(2H)-one, 5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-1-yl, 5,8-dihydropteridin-5-yl-7(6H)-one, 4,5,6,7-tetrahydrothieno[3,2-b]pyridin-4-yl, 5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-5-yl, and 1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,4-f]quinolin-3-onyl; wherein the nitrogen ring moiety may be optionally substituted with one or two substituents each independently selected from the group consisting of Cl, F, —CN, C 1-4 alkyl, —OC 1-4 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, —C(H)═N—OCH 3 , —C(H)═N—OH, —C(CH 3 )═N—OH, —(CH 2 ) 0-1 C(O)NH 2 , —(CH 2 ) 0-1 C(O)NHC 1-4 alkyl, —(CH 2 ) 0-1 C(O)N(C 1-4 alkyl) 2 , —(CH 2 ) 0-1 C(O)OC 1-4 alkyl, —(CH 2 ) 0-1 C(O)OH, —S(O) 2 C 1-4 alkyl, —(CH 2 ) 0-1 NH 2 , —(CH 2 ) 0-1 NHC 1-4 alkyl, —(CH 2 ) 0-1 (C 1-4 alkyl) 2 , —(CH 2 ) 0-1 NH(CO)C 1-4 alkyl, phenyl, optionally substituted heteroaryl and optionally substituted heterocyclyl, wherein C 1-4 alkyl or C 3-6 cycloalkyl may be optionally substituted with cyano, one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups.

In some embodiments, heteroaryl is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,4-triazol-3-yl, thiazol-2-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, oxazol-2-yl, oxazol-5-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl, 1,3,4-thiadiazol-2-yl, and 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-triazol-2-yl, and 1,3,4-triazol-2-yl; wherein heteroaryl may be optionally substituted with C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two 2 hydroxyl groups, or one or two —OC 1-2 alkyl groups).

›DETAILED DESCRIPTION · 4 of 13

In some embodiments, heterocyclyl is selected from the group consisting of tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, pyrrolidine-1-yl, piperazin-1-yl, piperidin-4-yl, piperidin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl, 2,5-dihydrofuran-3-yl, piperazin-1-yl-3-one, morpholino, tetrahydropyran-2-yl, 1,2,4-oxadiazo-3-yl-5-one, and pyrrolidin-2-one-4-yl; wherein heterocyclyl may be optionally substituted with hydroxyl or C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two 2 hydroxyl groups, or one or two —OC 1-2 alkyl groups).

In some embodiments, R X together with R 1 and the nitrogen to which they are attached form a 1,2,3,4-tetrahydroquinoline moiety optionally substituted with one, two or three halo, —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R 10 ) 2 C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl, C 1-3 alkyl-OH, or C 1-3 haloalkyl).

In some embodiments, R X together with R 1 and the nitrogen to which they are attached form a 1,2,3,4-tetrahydro-1,5,napthyridine moiety optionally substituted with one, two or three halo, —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 1-3 haloalkyl, and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R 10 ) 2 C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl, C 1-3 alkyl-OH, or C 1-3 haloalkyl).

In some embodiments, m is an integer selected from 1 or 2; and n is 1.

In some embodiments, R 4 and R 5 are independently selected from the group consisting of H, —OH, —(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkyl-COOH, —O(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkyl-O—R 6 , —C(O)NH 2 , —N(R 6 ) 2 , halogen, —(C 1 -C 3 )alkyl-N(R 6 ) 2 , and cyano, wherein said —(C 1 -C 3 )alkyl, —O(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkyl-O—R 6 , or —(C 1 -C 3 )alkyl-N(R 6 ) 2 , is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R 6 ) 2 , and halogen;

or R 4 and R 5 , taken together with the atoms to which they are attached, form a 3-7 membered carbocyclic or heterocyclic ring; which ring is optionally substituted with one or more substituents selected from the group consisting of —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , halogen, oxo, or cyano;

or R 4 and R 8 , taken together with the atoms to which they are attached, form a 4-7 membered carbocyclic or heterocyclic ring;

or R 4 is a bond, and R 4 and R 8 , taken together with the atoms to which they are attached, form a 3-membered carbocyclic or heterocyclic ring; and

each R 6 is independently H or —(C 1 -C 3 )alkyl.

In some embodiments, the moiety

of Formula I is selected from the group consisting of:

In some embodiments, the moiety

of Formula i is represented by:

wherein q is 0 or 1.

In some embodiments, the moiety

of Formula I is represented by:

In some embodiments, the moiety

of Formula I is selected from the group consisting of:

In some embodiments, the moiety

of Formula I is selected from the group consisting of:

The present disclosure also provides, for example, a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula II is represented by:

wherein:

R X together with R 1 and the nitrogen to which they are attached form a nitrogen-containing monocyclic, bicyclic or tricyclic ring system selected from the group consisting of a 8-14 membered bicyclic heteroaryl, a 8-14 membered tricyclic heteroaryl, a 5-7 membered monocyclic heteroaryl, and a 4-7 membered heterocyclyl, wherein the nitrogen-containing monocyclic, bicyclic or tricyclic ring system may optionally be substituted with one, two or more substituents each independently selected from the group consisting of R 10 , —OR 10 , —S(O) w R 10 (wherein w is 0, 1 or 2), —C 1-6 alkyl-S(O) w —C 1-3 alkyl, —N(R 10 ) 2 , —N(CO)R 10 , —N—S(O) w —R 10 (where w is 0, 1 or 2), —OS(O) w —R 10 (wherein w is 0, 1, or 2), —S(O) w —N(R 10 ) 2 (wherein w is 0, 1 or 2), —S(O)(NH)R 10 , —N(H)—SO 2 —C 1-3 alkyl, —N(SO 2 —C 1-3 alkyl) 2 , P(O)(R 10 ) 2 , —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , oxo, halogen, hydroxyl, cyano, nitro, —C(═N—OR a )—C 1-3 alkyl, —C(═N—OR a )—H, —S(O)(NR a )—C 1-3 alkyl, phenyl (optionally substituted with one, two or three halogen, —O-phenyl, C 1-3 alkyl or C 1-3 haloalkyl), C 1-3 alkyl, C 2-6 alkynyl, C 1-3 haloalkyl, C 1-6 cycloalkyl, heterocyclyl (optionally substituted with one, two or three halogen, oxo, C 1-3 alkyl or C 1-3 haloalkyl), and heteroaryl (optionally substituted with one, two or three halogen, —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 1-3 alkyl-O—C 1-3 alkyl, C 1-3 alkyl-OH, or C 1-3 haloalkyl);

R 10 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, heteroaryl, and P(O)(R 20 ) 2 ; wherein C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, C 2-6 heteroalkyl, heterocycloalkyl, aryl, and heteroaryl may optionally be substituted by one, two, three or more substituents each independently selected from the group consisting of halogen, hydroxyl, cyano, —NR a C(O)—R 20 , —C(O)—R 20 , —C(NR a )R b , —NR a R b , C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;

R 20 is selected from the group consisting of hydrogen, hydroxyl, halogen, —NR a R b , C 1-6 alkyl and C 1-6 alkoxy;

R 4 and R 5 are each independently, selected from the group consisting of H, —OH, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , —C(O)N(R 6 ) 2 , —N(R) 2 , halogen, —(C 1 -C 6 )alkyl-N(R 6 ) 2 , or cyano, wherein said —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-O—R 6 , or —(C 1 -C 6 )alkyl-N(R 6 ) 2 is optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , oxo, and halogen,

›DETAILED DESCRIPTION · 5 of 13

R 6 is independently for each occurrence selected from the group consisting of H, —(C 1 -C 6 )alkyl, —C(O)OC 1-4 alkyl, and phenyl;

or R 11 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered heterocyclic ring;

or R 4 and R 12 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

or R 8 and R 11 , taken together with the atoms to which they are attached, form a 5-7 membered carbocyclic or heterocyclic ring;

q is 0 or 1.

In some embodiments, R X together with R 1 and the nitrogen to which they are attached form a ring moiety selected from the group consisting of 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydro-1,5-naphthyridin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, 1,2,3,4-tetrahydroquinoxalin-1-yl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-1-yl, 1H-benzo[d]imidazol-1-yl, indolin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl, 2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl, isoindolin-2-yl, 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-4-yl, 2-(3,4-dihydroisoquinolin-1(2H)-one), 2-(3,4-dihydroisoquinolin-1(2H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, piperidin-1-yl, 1-(1,2,3,4-tetrahydro-6H-pyrido[1,2-a]pyrimidin-6-one), 1,2,3,4-tetrahydro-1,8-naphthyridin-1-yl, 1-(3,4-dihydro-1,5-naphthyridin-2(1H)-one), 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 1-(2,3-dihydroquinolin-4(1H)-one), 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl, 1,2,3,4-tetrahydro-1,6-naphthyridin-1-yl, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,3]diazepin-4-yl, 3,4-dihydroquinoxalin-1-yl-2(1H)-one, 2,3,4,6-tetrahydro-1,6-naphthyridin-1-yl-5(1H)-one, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl, 1,2,3,4-tetrahydro-2,6-naphthyridin-2-yl, 3,4-dihydro-2H-benzo[b][1,4]thiazin-4-yl 11-dioxide, 1,2,3,4-tetrahydropyrazino[2,3-d]pyridazin-1-yl, 1,4-dihydropyrido[3,4-b]pyrazin-1-yl-3(2H)-one, 5,6,7,8-tetrahydro-1,6-naphthyridin-6-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 1,2,3,4-tetrahydropyrido[3,4-b]pyrazin-1-yl, 5,8-dihydropteridin-5-yl-7(6H)-one, 4,5,6,7-tetrahydrothieno[3,2-b]pyridin-4-yl, 5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-5-yl, and 1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,4-f]quinolin-3-only; wherein the nitrogen ring moiety may be optionally substituted with one or two substituents each independently selected from the group consisting of Cl, F, —CN, C 1-4 alkyl, —OC 1-4 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, —C(H)═N—OCH 3 , —C(H)═N—OH, —C(CH 3 )═N—OH, —(CH 2 ) 0-1 C(O)NH 2 , —(CH 2 ) 0-1 C(O)NHC 1-4 alkyl, —(CH 2 ) 0-1 C(O)N(C 1-4 alkyl) 2 , —(CH 2 ) 0-1 C(O)OC 1-4 alkyl, —(CH 2 ) 0-1 C(O)OH, —S(O) 2 C 1-4 alkyl, —(CH 2 ) 0-1 NH 2 , —(CH 2 ) 0-1 NHC 1-4 alkyl, —(CH 2 ) 0-1 (C 1-4 alkyl) 2 , —(CH 2 ) 0-1 NH(CO)C 1-4 alkyl, phenyl, optionally substituted heteroaryl and optionally substituted heterocyclyl, wherein C 1-4 alkyl or C 3-6 cycloalkyl may be optionally substituted with cyano, one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups.

In some embodiments, heteroaryl is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,4-triazol-3-yl, thiazol-2-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, oxazol-2-yl, oxazol-5-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl, 1,3,4-thiadiazol-2-yl, and 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-triazol-2-yl, and 1,3,4-triazol-2-yl; wherein heteroaryl may be optionally substituted with C 1-2 alkyl (optionally substituted with one to three fluorine atoms, up to 2 hydroxyl groups, or up to two —OC 1-2 alkyl groups).

In some embodiments, heterocyclyl heterocyclyl is selected from the group consisting of tetrahydrofuran-3-yl, tetrahydrofuran-2-yl, pyrrolidine-1-yl, piperazin-1-yl, piperidin-4-yl, piperidin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl, 2,5-dihydrofuran-3-yl, piperazin-1-yl-3-one, morpholino, tetrahydropyran-2-yl, 1,2,4-oxadiazo-3-yl-5-one, and pyrrolidin-2-one-4-yl; wherein heterocyclyl may be optionally substituted with hydroxyl or C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two 2 hydroxyl groups, or one or two —OC 1-2 alkyl groups).

›DETAILED DESCRIPTION · 6 of 13

In some embodiments, R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, —(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkoxy, and —N(R) 2 , wherein said —(C 1 -C 3 )alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R 6 ) 2 , and halogen.

In some embodiments, R 4 and R 5 are independently selected from the group consisting of fluorine, —NH 2 , —CH 3 , —OCH 3 , —CH 2 OH, —CH 2 NH 2 and —CH(NH) 2 CH 3 .

In some embodiments, R 4 and R 5 taken together, are selected from the group consisting of:

In some embodiments, q is 1.

Also disclosed herein, for example, is a compound of Formula III, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula III is represented by:

wherein:

Z 2 is selected from the group consisting of CR 22 and N;

Z 1 is selected from the group consisting of: NR 61 , C(R 23 ) 2 ; C(O), and O;

R 21 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, N(R 6 ) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, —C(O)N(R 6 ) 2 , heterocycloalkyl, phenyl, and heteroaryl, wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, heterocycloalkyl, phenyl, and heteroaryl may each be substituted by one, two or three or more substituents each selected from the group consisting of halo, —C(O)—OR 26 , —C(O)R 26 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , C 1-3 alkyl (optionally substituted by hydroxyl or methoxy), C 1 -C 3 alkyoxy, and C 1-3 haloalkyl;

R 22 is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, N(R 6 ) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, —C(O)N(R 6 ) 2 , heterocycloalkyl, phenyl, and heteroaryl, wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, heterocycloalkyl, phenyl, and heteroaryl may each be substituted by one, two or three or more substituents each selected from the group consisting of halo, oxo, hydroxyl, cyano, —C(O)—OR 26 , —C(O)R 26 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , C 1-3 alkyl (optionally substituted by hydroxyl or methoxy), C 1 -C 3 alkyoxy, and C 1-3 haloalkyl;

R 29 is selected from the group consisting of hydrogen, halogen, N(R 6 ) 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, —C(O)N(R 6 ) 2 , heterocycloalkyl, phenyl, and heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyoxy, heterocycloalkyl, phenyl, and heteroaryl may each be substituted by one, two or three or more substituents each selected from the group consisting of halo, —C(O)R 26 , —C(O)—OR 26 , —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , C 1-3 alkyl (optionally substituted by hydroxyl or methoxy) and C 1-3 haloalkyl;

q is 0 or 1;

R 23 independently, for each occurrence, is selected from the group consisting of H, halogen, and C 1 -C 6 alkyl;

R 24 is selected from the group consisting of H, halogen, and C 1 -C 6 alkyl;

R 26 is selected from the group consisting of hydrogen and C 1-3 alkyl;

R 4 and R 5 are each independently selected from the group consisting of hydrogen, C 1 -C 6 )alkyl, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , halogen, and cyano, wherein said —(C 1 -C 6 )alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R 6 ) 2 , oxo, and halogen,

or R 4 and R 5 , taken together with the carbon to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring, which ring is optionally substituted with one or two substituents each independently selected from the group consisting of (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , —C(O)N(R) 2 , halogen, oxo, and cyano;

R 6 is independently for each occurrence selected from the group consisting of H, —(C 1 -C 6 )alkyl, —C(O)OC 1-4 alkyl, and phenyl; and

R 61 is selected from the group consisting of hydrogen, —(C 1 -C 6 )alkyl (optionally substituted with one or two halogens), —C(O)—(C 1 -C 6 )alkyl, C 3-6 cycloalkyl (optionally substituted with one or two hydroxyl or C 1-2 alkyl) and phenyl.

In some embodiments, Z 2 is N. In some embodiments, Z 2 is CH. In some embodiments, Z 1 is C(R 23 ) 2 .

In some embodiments, R 23 for each occurrence is hydrogen. In some embodiments, R 23 for each occurrence is methyl.

In some embodiments, R 22 and R 24 , for each occurrence, is hydrogen.

In some embodiments, R 21 is selected from the group consisting of H, halogen, cyano, CF 3 , N(R 6 ) 2 , C(O)N(R 6 ) 2 , heteroaryl, and phenyl. In some embodiments, R 21 is C(O)NHCH 3 .

In some embodiments, R 21 is heteroaryl. In some embodiments, R 21 is selected from the group consisting of selected from the group consisting of:

In some embodiments, R 21 is hydrogen.

In some embodiments, R 4 and R 5 are independently selected from the group consisting of fluorine, —NH 2 , —CH 3 , —OCH 3 , —CH 2 OH, —CH 2 NH 2 and —CH(NH) 2 CH 3 .

In some embodiments, R 4 and R 5 taken together, are selected from the group consisting of:

›DETAILED DESCRIPTION · 7 of 13

In some embodiments, q is 1.

Also disclosed herein, for example, is a compound of Formula IV, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula IV is represented by:

wherein:

A is selected from the group consisting of:

wherein:

R 17 is selected from the group consisting of H, Cl, F, CHF 2 , CF 3 , —CN, C 1-4 alkyl, C 3-6 cycloalkyl, C 5-6 cycloalkenyl, —OC 1-4 alkyl, —O-heteroaryl, C 2-4 alkenyl, C 2-4 alkynyl, —C═N—OC 1-4 alkyl, —C═N—OH, —C(C 1-4 alkyl)=N—OH, —(CH 2 ) 0-1 C(O)NH 2 , —(CH 2 ) 0-1 C(O)NHC 1-4 alkyl, —(CH 2 ) 0-1 C(O)NHC 1-4 alkyl-heteroaryl, —(CH 2 ) 0-1 C(O)N(C 1-4 alkyl) 2 , —(CH 2 ) 0-1 C(O)OC 1-4 alkyl, —(CH 2 ) 0-1 C(O)OH, —(CH 2 ) 0-1 S(O) 2 C 1-4 alkyl, —(CH 2 ) 0-1 NH 2 , —(CH 2 ) 0-1 NHC 1-4 alkyl, —(CH 2 ) 0-1 (C 1-4 alkyl) 2 , —(CH 2 ) 0-1 NH(CO)C 1-4 alkyl, phenyl, heteroaryl, and heterocyclyl,

wherein heteroaryl and O-heteroaryl may optionally be substituted with one or more C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups); and wherein heterocyclyl may optionally be substituted with one or more hydroxyl or C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups);

R 18 is selected from the group consisting of H, Cl, F, —CN, NO 2 , C 1-4 alkyl, C 3-4 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, —OC 1-4 alkyl, —(CH 2 ) 0-1 C(O)NH 2 , —(CH 2 ) 0-1 C(O)NHC 1-4 alkyl, —(CH 2 ) 0-1 C(O)N(C 1-4 alkyl) 2 , —(CH 2 ) 0-1 C(O)OC 1-4 alkyl, —(CH 2 ) 0-1 C(O)OH, NH 2 , —NHC(O)C 1-4 alkyl, —NHS(O) 2 C 1-4 alkyl, —N(S(O) 2 C 1-4 alkyl) 2 , —N(C 1-4 alkyl)S(O) 2 C 1-4 alkyl, —N═S(O)(C 1-4 alkyl) 2 , —(CH 2 ) 0-1 SC 1-4 alkyl, —(CH 2 ) 0-1 S(O)C 1-4 alkyl, —(CH 2 ) 0-1 S(O) 2 C 1-4 alkyl, —S(O) 2 C 3-4 cycloalkyl, —S(O) 2 heteroaryl, —S(O)(═NH)C 1-4 alkyl, —S(O)(═NC 1-4 alkyl)C 1-4 alkyl, phenyl, heteroaryl, and heterocyclyl;

wherein phenyl, heteroaryl and heterocyclyl may optionally be substituted with one or more groups independently selected from the group consisting of F, C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups), cyclopropyl, —C(O)NH 2 , —C(O)NHC 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —C(O)OC 1-4 alkyl, and —C(O)OH;

each of R 19 and R 20 is independently selected from the group consisting of H and —C 1-4 alkyl; or

R 19 and R 20 together with the carbon atom to which they are attached form a C 2-4 alkenyl moiety which may optionally be substituted with one or two fluorine atoms;

R 21 is selected from the group consisting of H, C 1-4 alkyl, —C 3-4 cycloalkyl, —(CH 2 ) 0-4 C(O)C 1-4 alkyl, —(CH 2 ) 0-4 C(O)OC 1-4 alkyl, —(CH 2 ) 0-4 C(O)NH 2 , —(CH 2 ) 0-4 C(O)NHC 1-4 alkyl, —(CH 2 ) 0-4 C(O)N(C 1-4 alkyl) 2 , —(CH 2 ) 0-4 S(O) 2 C 1-4 alkyl, and heterocyclyl;

wherein each C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-4 cycloalkyl, C 3-6 cycloalkyl, or C 5-6 cycloalkenyl of R 7 , R 18 , R 19 , R 20 , or R 21 may optionally be substituted with one, two or three fluorine atoms, one or two cyano groups, one or two hydroxyl groups, one or two —C 1-2 alkyl groups, or one or two —OC 1-2 alkyl groups;

R 6 is independently for each occurrence selected from the group consisting of H, —(C 1 -C 6 )alkyl, —C(O)OC 1-4 alkyl, and phenyl.

In some embodiments, R 17 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 1,2,4-triazol-3-yl, thiazol-2-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-2-yl, oxazol-2-yl, oxazol-5-yl, isoxazol-5-yl, thiazol-2-yl, thiazol-5-yl, 1,3,4-thiadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, 1,2,4-triazol-2-yl, and 1,3,4-triazol-2-yl; wherein R 7 may optionally be substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups.

In some embodiments, R 17 is selected from the group consisting of tetrahydrofuran-3-yl, pyrrolidine-1-yl, piperazin-1-yl, piperidin-4-yl, piperidin-1-yl, 1,2,3,6-tetrahydropyridin-4-yl, 2,5-dihydrofuran-3-yl, piperazin-1-yl-3-one, morpholino, tetrahydropyran-2-yl, and 1,2,4-oxadiazo-3-yl-5-one; wherein R 7 may optionally be substituted with one or more hydroxyl or C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups).

In some embodiments, R 18 is selected from the group consisting of phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazol-3-yl, pyrazol-4-yl, thiazol-2-yl, 1,2,4-oxadiazol-3-yl, and 1,3,4-oxadiazol-2-yl; wherein R 18 may optionally be substituted with one or more groups independently selected from the group consisting of F, C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups), cyclopropyl, —C(O)NH 2 , —C(O)NHC 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —C(O)OC 1-4 alkyl, and —C(O)OH.

In some embodiments, R 18 is selected from the group consisting of —(CH 2 ) 0-1 -morpholino, tetrahydropyranyl, tetrahydrofuranyl, oxiranyl, isothiazolidin-2-yl-1,1-dioxide, pyrrolidin-2-one-4-yl, and —(CH 2 ) 0-1 -oxazolidin-3-yl-2-one; wherein R 18 may optionally be substituted with one or more groups independently selected from the group consisting of F, C 1-2 alkyl (optionally substituted with one, two or three fluorine atoms, one or two hydroxyl groups, or one or two —OC 1-2 alkyl groups), cyclopropyl, —C(O)NH 2 , —C(O)NHC 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —C(O)OC 1-4 alkyl, and —C(O)OH.

›DETAILED DESCRIPTION · 8 of 13

In some embodiments, R 19 is —CH 3 or —CHF 2 , R 20 is H, and the carbon to which R 19 and R 20 are attached has an (R)-configuration. In some embodiments, R 19 is H, R 20 is —CH 3 or —CHF 2 , and the carbon to which R 19 and R 20 are attached has an (S)-configuration.

In some embodiments, R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, —(C 1 -C 3 )alkyl, —(C 1 -C 3 )alkoxy, and —N(R 6 ) 2 , wherein said —(C 1 -C 3 )alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R 6 ) 2 , and halogen. In some embodiments, R 4 and R 5 are independently selected from the group consisting of fluorine, —NH 2 , —CH 3 , —OCH 3 , —CH 2 OH, —CH 2 NH 2 and —CH(NH) 2 CH 3 .

In some embodiments, R 4 and R 5 taken together, are selected from the group consisting of:

In some embodiments, q is 1.

In some embodiments, a disclosed compound is represented by any one of Formulas:

R 6 is H and each of q, R 17 , R 18 , R 19 , R 20 , and R 21 is as defined herein.

Examples of compounds of the present disclosure include those listed in Table 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

In some embodiments, the moiety

is selected from the group consisting of

In some embodiments, the moiety

is selected from the group consisting of

In some embodiments, the moiety shown below is referred to as R 2 .

In some embodiments, R 2 is

In some embodiments R 2 is

In some embodiments, R 2 is

In some embodiments, R 2

In some embodiments, R 2 is

In some embodiments, R2 is

In some embodiments, R 2 is

In another embodiment, SHP2 phosphatase inhibitors described herein encompass compounds of Formula XIII, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula XIII is represented by:

wherein:

X is selected from the group consisting of —NR X1 CH 2 — and —S—CH 2 —;

q is 0 or 1;

A is selected from the group consisting of phenyl and pyridyl, wherein A is optionally substituted with one, two or more substituents each independently selected from the group consisting of —R 10 , —N(R) 2 , —C(O)N(R) 2 , oxo, halogen, and cyano;

or A is —C 1-6 alkyl-NR a R b ;

R 10 is independently selected for each occurrence from the group consisting of —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, (C 3 -C 6 )cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein R 10 may be substituted one, two or three or more substituents each selected from the group consisting of halo, C(O)R 20 , C 1-6 alkyl and C 1-6 haloalkyl;

R 20 is selected from the group consisting of —OH, halo, or —(C 1 -C 6 )alkyl;

R X1 is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 3 is selected from the group consisting of hydrogen and C 1-6 alkyl;

R 4 and R 5 are each independently, selected from the group consisting of H, C 1 -C 6 )alkyl, —C(O)N(R 6 ) 2 , —N(R 6 ) 2 , halogen, and cyano; wherein —(C 1 -C 6 )alkyl is optionally substituted with one or more substituents selected from the group consisting of —OH, —N(R 6 ) 2 , oxo, and halogen;

or R 4 and R 5 , taken together with the carbon to which they are attached, form a 3-7 membered carbocyclic or heterocyclic ring, which ring is optionally substituted with one or two substituents each independently selected from the group consisting of (C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —N(R 6 ) 2 , —C(O)N(R 6 ) 2 , halogen, oxo, and cyano; and R a and R b are independently selected, for each occurrence, from the group consisting of hydrogen and C 1-6 alkyl.

For example, the A moiety of Formula (XIII) may be phenyl; wherein phenyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of —OR 10 , halogen, and cyano; or A may be pyridyl; wherein pyridyl may optionally be substituted by one, two, or three substituents each independently selected from the group consisting of —OR 10 , halogen, and cyano. In some embodiments, A may be selected from the group consisting of —CH 2 —NH 2 , —CH 2 —N(H)CH— and —CH 2 —N(CH 3 ) 2 . In some embodiments, R 3 may be hydrogen.

In some embodiments, R 4 and R 5 of Formula (XIII) may be, for example, independently selected from the group consisting of —(C 1 -C 3 )alkyl and —N(R 6 ) 2 , wherein —(C 1 -C 3 )alkyl is optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyl, —N(R 6 ) 2 , and halogen. For example, R 4 and R 5 may be independently selected from the group consisting of —NH 2 , —CH 3 , and —CH 2 NH 2 . In some embodiments, q is 1.

Additional SHP2 phosphatase inhibitors described herein encompass compounds of Formula (XIV), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Formula (XIV) is represented by:

wherein:

X is selected from the group consisting of —NH—, —NCH 3 —, —O— and —S—;

A is selected from the group consisting of phenyl, pyridyl, pyridonyl, piperidinyl, quinazolinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridyl, indolyl, isoquinolinyl, and pyrrolo[2,3-b]pyridyl;

›DETAILED DESCRIPTION · 9 of 13

wherein A may optionally be substituted on one or more available carbons by a substituent each independently selected from R f ; and wherein pyridonyl, piperidinyl, indolyl, and pyrrolo[2,3-b]pyridyl may optionally be substituted on an available nitrogen by a substituent selected from R g ;

R f is independently selected for each occurrence from the group consisting of hydrogen, chloro, fluoro, —CH 3 , —CF 3 , —OCH 3 , —NH 2 , —N(H)CH 3 , —C(O)—NH 2 , —COOH, —C(NH)—O—C(O)—CF 3 , —C 1-2 alkyl-C(O)—O—C 1-2 alkyl, and a 5-membered heteroaryl;

R g is selected from the group consisting of hydrogen, —CH 3 , and —C(O)CH 3 ;

Y is represented by:

R4 is selected from the group consisting of fluoro and —CH 3 ;

R 5 is selected from the group consisting of —NH 2 and —CH 2 —NH 2 ; or R 4 and R 5 , taken together with the carbon to which they are attached, form a tetrahydrofuranyl or cyclopentyl ring; wherein tetrahydrofuranyl or cyclopentyl may optionally be substituted by one or two substituents each independently selected from the group consisting of —NH 2 and —CH 3 ; and is 0 or 1 e.g., q may be 0.

For example, Y may be:

or for example, Y may be selected from the group consisting of

Compounds or compositions of the disclosure can be useful in applications that benefit from inhibition of SHP2 phosphatase enzymes. For example, inhibition of SHP2 phosphatase may offer a therapeutic approach for the treatment of cancer. (See, e.g., Y.-N. P. Chen et al., in Nature, 2016, doi:10.1038/nature18621; and references cited therein; each of which hereby incorporated by reference in its entirety.) Inhibition of SHP2 phosphatase also has been found to ameliorate the pathogensis of systemic lupus erythematosus. (See, e.g., J. Wang et al., in. J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein; each of which hereby incorporated by reference in its entirety.)

In some embodiments, compounds or compositions of the disclosure can be useful in suppressing tumor cell growth. In some embodiments, compounds or compositions of the disclosure can be useful in ameliorating the pathogenesis of systemic lupus erythematosus. In some embodiments, compounds or compositions of the disclosure can be useful in the treatment of various other disorders, including Noonan syndrome (NS), diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia, acute myeloid leukemia, HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer (including adenocarcinoma of the lung), colorectal cancer (SW480, SW620, CACO2, HCT116, HT29 colon cancer cell lines), esophageal cancer, gastric cancer, squamous-cell carcinoma of the head and neck (SCCHN), and neutropenia (Kostmann's syndrome).

In some embodiments, compounds or compositions of the disclosure can be used in combination with other treatments and/or cancer therapies. For example, compounds or compositions of the disclosure can be used in combination with, but are not limited to, antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. The compounds or compositions of the disclosure can also be used in combination with other treatments and/or cancer therapies as disclosed in WO 2015/107495; and references cited therein; each of which is hereby incorporated by reference in its entirety. For example, the compounds disclosed herein (or pharmaceutical compositions containing them) can be used in the treatment of one or more of the diseases mentioned herein, alone or in combination with another therapeutic agent. For example, a compound disclosed herein can be used in combination with the following agents: BCR-ABL inhibitors: imatinib mesylate; inilotinib hydrochloride; nilotinib; dasatinib; bosutinib; ponatinib; bafetinib; danusertib; saracatinib; N-[2-[(1S,4R)-6-[[4-(Cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide. ALK inhibitors: crizotinib; 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine, ceritinib, alectinib, brigatinib, entrecinib. BRAF inhibitors: vemurafenib and dabrafenib. FGFR inhibitors: infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547, FLT3 inhibitors: sunitinib malate; midostaurin; tanutinib; sorafenib, lestaurtinib, quizartinib and crenolanib. MEK Inhibitors: trametinib, combimetinib, binimetinib, selumetinib. VEGF receptor inhibitors: bevacizumab, axitinib, aflibercept, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, brivanib alaninate ((S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide, pasireotide, sorafenib. Tyrosine kinase inhibitors: erlotinib hydrochloride, linifanib, sunitinib malate, pazopanib. Epidermal growth factor receptor (EGFR) inhibitors: gefitnib, osimertinib, cetuximab, panitumumab. HER2 receptor inhibitors: trastuzumab, neratinib, lapatinib or lapatinib ditosylate. MET inhibitors: crizotinib, cabozantinib. CD20 antibodies: rituximab, tositumomab, ofatumumab. DNA Synthesis inhibitors: capecitabine, gemcitabine hydrochloride, nelarabine, hydroxycarbamide. Antineoplastic agents: oxaliplatin. HER dimerization inhibitors: pertuzumab. Human Granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim. Immunomodulators: Afutuzumab, lenalidomide, thalidomide. CD40 inhibitors: Dacetuzumab. Pro-apoptotic receptor agonists (PARAs): Dulanermin. Heat Shock Protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin). Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide. Proteasome inhibitors: Bortezomib. PI3K inhibitors: 4-[2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]mocholine, 2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile, buparlisib, taselisib, idelalisib, duvelisib, TGR 1202. Phospholipase A2 inhibitors: Anagrelide. BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl] amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide. Mitogen-activated protein kinase kinase (MEK) inhibitors: XL-518. Aromatase inhibitors: Exemestane, letrozole, anastrozole, faslodex, tamoxifen. Topoisomerase I inhibitors: Irinotecan, topotecan hydrochloride. Topoisomerase II inhibitors: etoposide, teniposide. mTOR inhibitors: Temsirolimus, ridaforolimus, everolimus. Osteoclastic bone resorption inhibitors: 1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate. CD33 Antibody Drug Conjugates: Gemtuzumab ozogamicin. CD22 Antibody Drug Conjugates: Inotuzumab ozogamicin. CD20 Antibody Drug Conjugates: Ibritumomab tiuxetan. Somatostain analogs: octreotide. Synthetic Interleukin-11 (IL-11): oprelvekin. Synthetic erythropoietin: Darbepoetin alfa. Receptor Activator for Nuclear Factor κ B (RANK) inhibitors: Denosumab. Thrombopoietin mimetic peptides: Romiplostim. Cell growth stimulators: Palifermin. Anti-Insulin-like Growth Factor-1 receptor (IGF-1R) antibodies: Figitumumab. Anti-CS1 antibodies: Elotuzumab. CD52 antibodies: Alemtuzumab. CTLA-4 inhibitors: Tremelimumab, ipilimumab. PD1 inhibitors: Nivolumab; pembrolizumab; an immunoadhesin; Pidilizumab; and AMP-224. PDL1 inhibitors: MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105. LAG-3 inhibitors: BMS-986016. GITR agonists: GITR fusion proteins and anti-GITR antibodies. Histone deacetylase inhibitors (HDI): Voninostat. Anti-CTLA4 antibodies: Tremelimumab; and Ipilimumab. Alkylating agents: Temozolomide, dactinomycin, melphalan, altretamine carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, mustine and mechloroethamine hydrochloride, streptozocin, thiotepa. Biologic response modifiers: bacillus calmette-guerin, denileukin diftitox. Anti-tumor antibiotics: doxorubicin, bleomycin, daunorubicin, daunorubicin liposomal, mitoxantrone, epirubicin, idarubicin, mitomycin C. Anti-microtubule agents: Estramustine. Cathepsin K inhibitors: Odanacatib. Epothilone B analogs: Ixabepilone. TpoR agonists: Eltrombopag. Anti-mitotic agents: Docetaxel. Adrenal steroid inhibitors: aminoglutethimide. Anti-androgens: Nilutamide, Androgen Receptor inhibitors: enzalutamide, abiraterone acetate, orteronel, galeterone, and seviteronel, bicalutamide, flutamide. Androgens: Fluoxymesterone. CDK1 inhibitors: Alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib. Gonadotropin-releasing hormone (GnRH) receptor agonists: Leuprolide or leuprolide acetate. Taxane anti-neoplastic agents: Cabazitaxel (1-hydroxy-10-dimethoxy-9-oxo-5,20-epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-yl benzoate). 5HT1a receptor agonists: Xaliproden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine. HPC vaccines: Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; Iron Chelating agents: Deferasinox. Anti-metabolites: Claribine (2-chlorodeoxyadenosine), 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin. Bisphosphonates: Pamidronate. Demethylating agents: 5-azacitidine, decitabine. Plant Alkaloids: Paclitaxel protein-bound; vinblastine, vincristine, vinorelbine, paclitaxel. Retinoids: Alitretinoin (sold under the tradename Panretin®), tretinoin (all-trans retinoic acid, also known as ATRA, sold under the tradename Vesanoid®), Isotretinoin (13-cis-retinoic acid, sold under the tradenames Accutane®, Amnesteem®, Claravis®, Claras®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), bexarotene (sold under the tradename Targretin®). Glucocorticosteroids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate® and Lanacort®), dexamethazone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxy acetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-3-one), prednisolone (sold under the tradenames Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-Methylprednisolone, Methylprednisolone Acetate, Methylprednisolone Sodium Succinate, sold under the tradenames Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®). Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the tradename Proleukin®), interleukin-11 (also known as oprevelkin, sold under the tradename Neumega®), alpha interferon alfa (also known as IFN-alpha, sold under the tradenames Intron® A, and Roferon-A®). Estrogen receptor downregulators: Fulvestrant (sold under the tradename Faslodex®). Anti-estrogens: tamoxifen (sold under the tradename Novaldex®). Toremifene (sold under the tradename Fareston®). Selective estrogen receptor modulators (SERMs): Raloxifene (sold under the tradename Evista®). Leutinizing hormone releasing hormone (LHRH) agonists: Goserelin (sold under the tradename Zoladex®); Progesterones: megestrol (also known as megestrol acetate, sold under the tradename Megace®); Miscellaneous cytotoxic agents: Arsenic trioxide (sold under the tradename Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the tradenames Elspar® and Kidrolase®). Anti-nausea drugs: NK-1 receptor antagonists: Casopitant (sold under the tradenames Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the tradename Ethyol®), leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid). Immune checkpoint inhibitors: The term “immune checkpoints” refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40, and LAG3. Immunotherapeutic agents which can act as immune checkpoint inhibitors useful in the methods of the present disclosure, include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGFR beta.

›DETAILED DESCRIPTION · 10 of 13

The compounds described herein can function as allosteric inhibitors and block the activation of SHP2 by targeting the auto-inhibited conformation of SHP2.

The compounds described herein can also inhibit SHP2 function through incorporation into agents that catalyze the destruction of SHP2. For example, the compounds can be incorporated into proteolysis targeting chimeras (PROTACs). A PROTAC is a bifunctional molecule, with one portion capable of engaging an E3 ubiquitin ligase, and the other portion having the ability to bind to a target protein meant for degradation by the cellular protein quality control machinery. Recruitment of the target protein to the specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that engages the E3 ligase is connected to the portion of the PROTAC that engages the target protein via a linker which consists of a variable chain of atoms. Recruitment of SHP2 to the E3 ligase will thus result in the destruction of the SHP2 protein. The variable chain of atoms can include, for example, rings, heteroatoms, and/or repeating polymeric units. It can be rigid or flexible. It can be attached to the two portions described above using standard techniques.

The compounds described herein can be linked to one end of a variable chain, while the other end of the variable chain can be bound to the E3 ligase. Recruitment of SHP2 to the ligase will thus result in the destruction of the SHP2 protein.

In some embodiments, compounds or compositions of the disclosure can be used in combination with an antibody. In some embodiments, compounds or compositions of the disclosure can be used in combination with an antibody-drug conjugate. In some embodiments, compounds or compositions of the disclosure can be used in combination with a kinase inhibitor. In some embodiments, compounds or compositions of the disclosure can be used in combination with an immunomodulator. In some embodiments, compounds or compositions of the disclosure can be used in combination with a histone deacetylase inhibitor.

In some embodiments, a compound disclosed herein can be administered to a subject in need of treatment at dosages ranging from about 0.0001 mg to about 100 mg/kg body weight of the subject to be treated per day, such as from about 1.0 to 10 mg/kg. However, additional variations are within the scope of the disclosure.

In some embodiments, a compound disclosed herein can be administered alone or in combination with pharmaceutically acceptable carriers, such as diluents, fillers, aqueous solution, and even organic solvents. The compound and/or compositions of the disclosure can be administered as a tablet, powder, lozenge, syrup, injectable solution, and the like. Additional ingredients, such as flavoring, binder, excipients, and the like are within the scope of the disclosure.

In some embodiments, pharmaceutically acceptable compositions can contain a compound disclosed herein and/or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 2.0 wt %, such as 0.01 to about 1 wt % or about 0.05 to about 0.5 wt/o. The composition can be formulated as a solution, suspension, ointment, or a capsule, and the like. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-modifying ingredients and the like.

In some embodiments, the present disclosure provides for the use of pharmaceutical compositions and/or medicaments comprised of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in a method of treating a disease state, and/or condition caused by or related to SHP2 phosphatase.

In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein or a pharmaceutically acceptable salt thereof; and (iii) administering said disclosed compound in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.

In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof; and (iii) administering said composition in a therapeutically effective amount to treat, suppress and/or prevent the disease state or condition in a subject in need of such treatment.

In some embodiments, the subject is an animal. Animals include all members of the animal kingdom, but are not limited to humans, mice, rats, cats, monkeys, dogs, horses, and swine. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, a rat, a cat, a monkey, a dog, a horse, or a pig.

In some embodiments, the compound or composition is administered orally. In some embodiments, the compound or composition is administered intravenously.

In some embodiments, the methods comprise administering to the subject an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well-known to those skilled in the art, and include, e.g., adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. Often, the pharmaceutically acceptable carrier is chemically inert toward the active compounds and is non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers may include, e.g., water or saline solution, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids, or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers may also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Other examples of suitable pharmaceutical carriers are described in e.g., Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)) (each of which hereby incorporated by reference in its entirety).

›DETAILED DESCRIPTION · 11 of 13

In some embodiments, the method of treatment, prevention and/or suppression of a condition related to SHP2 phosphatase comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein or a pharmaceutically acceptable salt thereof; or a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (iii) administering said compound or composition in a therapeutically effective amount to treat, prevent and/or suppress the disease state or condition related to SHP2 phosphatase in a subject in need of such treatment.

In some embodiments, the compounds of the disclosure are formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. According to another aspect, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein in admixture with a pharmaceutically acceptable diluent and/or carrier. The pharmaceutically-acceptable carrier is “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. The pharmaceutically-acceptable carriers employed herein may be selected from various organic or inorganic materials that are used as materials for pharmaceutical formulations and which are incorporated as analgesic agents, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and viscosity-increasing agents. Pharmaceutical additives, such as antioxidants, aromatics, colorants, flavor-improving agents, preservatives, and sweeteners, may also be added. Examples of acceptable pharmaceutical carriers include carboxymethyl cellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methyl cellulose, powders, saline, sodium alginate, sucrose, starch, talc and water, among others. In some embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

Surfactants such as, e.g., detergents, are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others, anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil, cationic surfactants, such as water-soluble quaternary ammonium salts of formula N + R′R″R′″R″″T, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals and Y is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used, amine salts of formula N + R′R′R′″, in which the R radicals are identical or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

When administered to a subject, a compound disclosed herein and pharmaceutically acceptable carriers can be sterile. Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The present compositions, if desired, may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The pharmaceutical formulations of the present disclosure are prepared by methods well-known in the pharmaceutical arts. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surface active agents, and the like) also are added. The choice of carrier is determined by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.

Additionally, the compounds and/or compositions of the present disclosure are administered to a human or animal subject by known procedures including oral administration, sublingual or buccal administration. In some embodiments, the compound and/or composition is administered orally.

For oral administration, a formulation of the compounds of the disclosure may be presented in dosage forms such as capsules, tablets, powders, granules, or as a suspension or solution. Capsule formulations may be gelatin, soft-gel or solid. Tablets and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which are known in the art. Examples of such include carbohydrates such as lactose or sucrose, dibasic calcium phosphate anhydrous, corn starch, mannitol, xylitol, cellulose or derivatives thereof, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffering agents, disintegrants, and colorants. Orally administered compositions may contain one or more optional agents such as, e.g., sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservative agents, to provide a pharmaceutically palatable preparation.

›DETAILED DESCRIPTION · 12 of 13

In some embodiments, the composition is in unit dose form such as a tablet, capsule or single-dose vial. Suitable unit doses, i.e., therapeutically effective amounts, may be determined during clinical trials designed appropriately for each of the conditions for which administration of a chosen compound is indicated and will, of course, vary depending on the desired clinical endpoint.

In accordance with the methods of the present disclosure, the compounds of the disclosure are administered to the subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms related to SHP2 phosphatase activity in the subject. This amount is readily determined by the skilled artisan, based upon known procedures, including analysis of titration curves established in vivo and methods and assays disclosed herein.

In some embodiments, the methods comprise administration of a therapeutically effective dosage of the compounds of the disclosure. In some embodiments, the therapeutically effective dosage is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, at least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg/kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, at least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg/kg body weight, about 0.1 mg to about 6 mg/kg body weight, about 0.1 mg to about 4 mg/kg body weight, or about 0.1 mg to about 2 mg/kg body weight.

In some embodiments the therapeutically effective dosage is in the range of about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg or about 40 to 80 mg.

In some embodiments, the methods comprise a single dosage or administration (e.g., as a single injection or deposition). Alternatively, the methods comprise administration once daily, twice daily, three times daily or four times daily to a subject in need thereof for a period of from about 2 to about 28 days, or from about 7 to about 10 days, or from about 7 to about 15 days, or longer. In some embodiments, the methods comprise chronic administration. In yet other embodiments, the methods comprise administration over the course of several weeks, months, years or decades. In still other embodiments, the methods comprise administration over the course of several weeks. In still other embodiments, the methods comprise administration over the course of several months. In still other embodiments, the methods comprise administration over the course of several years. In still other embodiments, the methods comprise administration over the course of several decades.

The dosage administered can vary depending upon known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; time of administration of active ingredient; age, sex, health and weight of the recipient; nature and extent of symptoms; kind of concurrent treatment, frequency of treatment and the effect desired; and rate of excretion. These are all readily determined and may be used by the skilled artisan to adjust or titrate dosages and/or dosing regimens.

The precise dose to be employed in the compositions will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each subject's circumstances. In specific embodiments of the disclosure, suitable dose ranges for oral administration of the compounds of the disclosure are generally about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 800 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 500 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 250 mg/day. In some embodiments, the oral dose is about 1 mg/day to about 100 mg/day. In some embodiments, the oral dose is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dose is about 5 mg/day. In some embodiments, the oral dose is about 10 mg/day. In some embodiments, the oral dose is about 20 mg/day. In some embodiments, the oral dose is about 30 mg/day. In some embodiments, the oral dose is about 40 mg/day. In some embodiments, the oral dose is about 50 mg/day. In some embodiments, the oral dose is about 60 mg/day. In some embodiments, the oral dose is about 70 mg/day. In some embodiments, the oral dose is about 100 mg/day. It will be recognized that any of the dosages listed herein may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit.

›DETAILED DESCRIPTION · 13 of 13

Any of the compounds and/or compositions of the disclosure may be provided in a kit comprising the compounds and/or compositions. Thus, in some embodiments, the compound and/or composition of the disclosure is provided in a kit.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described herein. Such equivalents are intended to be within the scope of the present disclosure.

The disclosure is further described by the following non-limiting Examples.

›EXAMPLES · 1 of 2

The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.

At least some of the compounds identified as “Intermediates” herein are contemplated as compounds of the disclosure.

Examples are provided herein to facilitate a more complete understanding of the disclosure. The following examples serve to illustrate the exemplary modes of making and practicing the disclosure. However, the scope of the disclosure is not to be construed as limited to specific embodiments disclosed in these Examples, which are illustrative only. The compounds of Formula (I), for example, can generally be prepared according to exemplary Scheme 1:

where NR X , R 1 , R 4 , R 5 , R 6 , R 8 , R 9 , R 11 , and R 12 are as defined as elsewhere herein, Q is independently a halogen, such as Cl, Br, i, and the like, or any other leaving group, such as OSO 2 Me, OMs, OTs, OTf, and the like. LG is a leaving group, such as Cl, Br, I, OTs, OTf, and the like, and P is a protecting group, such as 4-methoxybenzyl and the like. Alternative protecting groups that can be used are described, e.g., in Greene el al., Protective Groups in Organic Synthesis (4 th ed. 2006).

As shown in Scheme 1, an aryl compound such as a compound of Formula 1001 undergoes a cross-coupling reaction with a metalated or otherwise activated moiety to provide a compound of Formula 1002. The compound of Formula 1002 then undergoes a substitution reaction with an amine such as Compound 1005, followed by removal of the protecting group to provide a compound of Formula (I). In some embodiments, LG is I. In some embodiments, LG is Cl. In some embodiments, LG is OTf or OTs. Alternatively, a protected heteroaryl ether, such as a compound of Formula 1003, undergoes a cross-coupling reaction to provide a compound of Formula 1004. The ether protecting group is subsequently removed and the resulting hydroxyl group activated to form a Q group, such as OSO 2 Me, OMs, OTs, OTf, and the like, to form a compound of Formula 1002, which can then be carried forward to prepare compounds having the Formula (I).

Alternatively, compounds of the invention can generally be prepared according to exemplary Scheme 2:

wherein NR X , R 1 , R 4 , R 5 , R 6 , R 8 , R 9 , R 11 , and R 12 are as defined as elsewhere herein, Q is independently a halogen, such as Cl, Br, I, and the like, or any other leaving group, such as OSO 2 Me, OMs, OTs, OTf, and the like. LG is a leaving group, such as Cl, Br, I, OTs, OTf, and the like, and P is a protecting group, such as 4-methoxybenzyl and the like. Alternative protecting groups that can be used are described, e.g., in Greene et al., Protective Groups in Organic Synthesis (4 th ed. 2006).

As shown in Scheme 2, an aryl compound such as a compound of Formula 1001 undergoes a undergoes a substitution reaction with an amine such as 1005 to provide a compound of Formula 1006. The compound of Formula 1006 then undergoes a cross-coupling reaction with a metalated or otherwise activated moiety to provide a compound of Formula 1007. In some embodiments, the compound of Formula 1007 can be deprotected to produce a compound of Formula (I). In other embodiments, the compound of Formula 1007 can be left protected and functional groups on the R 1 moiety refunctionalized by methods known to those of ordinary skill in the art.

In some embodiments, the cross-coupling reaction is a Buchwald-Hartwig reaction. In some embodiments, the cross-coupling reaction is a Chan-Lam coupling reaction. In some embodiments, the cross-coupling reaction is an Ullmann reaction. In some embodiments, the cross-coupling reaction is a Suzuki reaction. In some embodiments, the cross-coupling reaction is a Stille reaction. In some embodiments, the cross-coupling reaction is a Negishi reaction. In some embodiments, the cross-coupling reaction is a Hiyama reaction. Other cross-coupling reactions may be employed as would be apparent to one of ordinary skill in the art.

In some embodiments, the protecting group is removed under acidic conditions, such as HBr in AcOH, Conditions for removal of the protecting group will depend on the nature of the protecting group. Conditions for the removal of various protecting groups can be found, e.g., in Greene et al., Protective Groups in Organic Synthesis (4 th ed 2006)

Reactions were monitored and final products were characterized using one of the following methods. LCMS standard conditions were: Waters HPLC system equipped with an Alliance 2695 main module, Waters 996 diode array detector and ZQ micromass ESI-MS detector. Mobile phase A: H 2 O (10.0 mM NH 4 HCO 2 ), mobile phase B: CH 3 CN. HPLC conditions were: XBridge C18 column, 4.6×30 mm, 3.5 μm, 0.0-0.2 min. isocratic (5% B), 0.2-2.0 min. gradient (5-100% B), 3.0-3.0 min. isocratic (100% B); flow rate: 3.0 mL/min; UV channel: 254 nm.

Purification of some racemic products was performed using semi preparative HPLC A, semi preparative HPLC B, or semi preparative SFC. Semi preparative HPLC A: Gilson 215 system equipped with a Waters 996 diode array detector and a Waters 2525 pump. Semi preparative HPLC B: Waters 2767 system equipped with a Waters 996 diode array detector, 2×Waters 515 pumps, a Waters 2525 pump and a ZQ micromass ESI-MS detector. Semi preparative SFC: Mettler Toledo Minigram SFC equipped with a Knauer K-2501 UV detector and an Alcott Model 1719 Autosampler.

›EXAMPLES · 2 of 2

Product homogeneity and enantiomeric excess determination were performed using Analytical HPLC A: Agilent 1100 HPLC system equipped with an Agilent G1315A diode array detector.

Nuclear Magnetic resonance: NMR spectra were recorded on Bruker Avance II Ultra shield spectrometer.

›ABBREVIATIONS · 1 of 63

Ac: acetyl

AcOH: acetic acid

ACN: acetonitrile

Ad: adamantyl

AIBN: 2,2′-azo bisisobutyronitrile

Anhyd: anhydrous

Aq: aqueous

B 2 Pin 2 : bis(pinacolato)diboron-4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)

BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

BH 3 : Borane

Bn: benzyl

Boc: tert-butoxycarbonyl

Boc 2 O: di-tert-butyl dicarbonate

BPO: benzoyl peroxide

n BuOH: n-butanol

CDI: carbonyldiimidazole

COD: cyclooctadiene

d: days

DABCO: 1,4-diazobicyclo[2.2.2]octane

DAST: diethylaminosulfur trifluoride

dba: dibenzylideneacetone

DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEA: diethylamine

DHP: dihydropyran

DIBAL-H: diisobutylaluminum hydride

DIPA: diisopropylamine

DIPEA or DIEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DME: 1,2-dimethoxyethane

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMP: Dess-Martin periodinane

DMSO-dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

dppf: 1,1′-bis(diphenylphosphino)ferrocene

EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

ee: enantiomeric excess

ESI: electrospray ionization

EA: ethyl acetate

EtOAc: ethyl acetate

EtOH: ethanol

FA: formic acid

h or hrs: hours

HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

HCl: hydrochloric acid

HPLC: high performance liquid chromatography

HOAc: acetic acid

IBX: 2-iodoxybenzoic acid

IPA: isopropyl alcohol

KHMDS: potassium hexamethyldisilazide

K 2 CO 3 : potassium carbonate

LAH: lithium aluminum hydride

LDA: lithium diisopropylamide

m-CPBA: meta-chloroperbenzoic acid

M: molar

MeCN: acetonitrile

MeOH: methanol

Me 2 S: dimethyl sulfide

MeONa: sodium methylate

MeI: iodomethane

min: minutes

mL: milliliters

mM: millimolar

mmol: millimoles

MPa: mega pascal

MOMCL: methyl chloromethyl ether

MsCl: methanesulfonyl chloride

MTBE: methyl tert-butyl ether

nBuLi: n-butyllithium

NaNO 2 : sodium nitrite

NaOH: sodium hydroxide

Na 2 SO 4 : sodium sulfate

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

NFSI: N-Fluorobenzenesulfonimide

NMO: N-methylmorpholine N-oxide

NMP: N-methylpyrrolidine

NMR: Nuclear Magnetic Resonance

° C.: degrees Celsius

Pd/C: Palladium on Carbon

Pd(OAc) 2 : Palladium Acetate

PBS: phosphate buffered saline

PE: petroleum ether

POCl 3 : phosphorus oxychloride

PPh 3 : triphenylphosphine

PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

Rel: relative

R.T, or rt: room temperature

RuPhos: 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

sat: saturated

SEMCl: chloromethyl-2-trimethylsilylethyl ether

SFC: supercritical fluid chromatography

SOCl 2 : sulfur dichloride

tBuOK: potassium tert-butoxide

TBAB: tetrabutylammonium bromide

TBAI: tetrabutylammonium iodide

TEA: triethylamine

Tf: trifluoromethanesulfonate

TfAA, TFMSA or Tf 2 O: trifluoromethanesulfonic anhydride

TFA: trifluoracetic acid

TIPS: triisopropylsilyl

THF: tetrahydrofuran

THP: tetrahydropyran

TLC: thin layer chromatography

TMEDA: tetramethylethylenediamine

pTSA: para-toluenesulfonic acid

wt: weight

Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

Syntheses of Intermediates

Synthesis of tert-butyl ((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl-3-methylpyrrolidin-3-yl)methyl)carbamate, Used in the Preparation of Compound 26

Step 1: A mixture of tert-butyl ((3-methylpyrrolidin-3-yl)methyl)carbamate (1.0 g, 4.7 mmol, CAS #125290-87-1), 3,5-dichloropyrazine-2-carbonitrile (810.0 mg, 4.7 mmol, CAS #313339-92-) and DIPEA (3.0 g, 23.3 mmol) in DMF (25.0 mL) was stirred at 70° C. for 2 hours. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (Petroleum ether: Ethyl acetate=6:1˜4:1) to afford tert-butyl ((1-(6-chloro-5-cyanopyrazin-2-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (1.4 g, 79.7% yield) as a yellow oil.

Step 2: To a mixture of (4-methoxybenzyl)hydrazine dihydrochloride (1.1 g, 4.8 mmol) and triethylamine (2.0 g, 19.9 mmol) in EtOH (30.0 mL) was added tert-butyl ((1-(6-chloro-5-cyanopyrazin-2-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (1.4 g, 4.0 mmol). The reaction mixture was stirred at 90° C. for 18 hours. On completion, the reaction mixture was concentrated in vacuo to give a residue, which was purified by column chromatography (Petroleum ether: Ethyl acetate=7:1 to 3:1) to afford the product of tert-butyl ((1-(3-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (1.4 g, 73.1% yield) as a yellow solid. LCMS m/z: 468.2 (M+H) +

Step 3: To a mixture of tert-butyl ((1-(3-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (1.3 g, 2.8 mmol) and NaNO 2 (229.0 mg, 3.3 mmol) in MeCN (30.0 mL) at 0° C. was added HBr (4.8 g, 27.7 mmol, 47%), then the mixture was stirred at 0° C. for 1 hour. Next, CuBr (39.8 mg, 278.0 umol) was added at 0° C., and the reaction mixture was stirred for another 1 hour. The reaction was quenched with sat Na 2 SO 3 (5.0 mL) and the reaction mixture was concentrated in vacuo to give a residue. The residue was dissolved in water (20.0 mL) and adjusted to pH=10 at 0° C. with NH 3 .H 2 O, which was then extracted with ethyl acetate (25.0 mL×2). The combined organic layers were washed with water (20.0 mL) and brine (20.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate=4:1˜1:1) to afford the product of tert-butyl ((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (830.0 mg, 54.7% yield) as a yellow solid. LCMS m/z: 531.1/533.1 (M+H) + .

Synthesis of tert-butyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate, Used in the Preparation of Compound 33

To a solution of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (CAS 2215028-64-9) (5 g, 13.7 mmol) and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (3.42 g, 15.0 mmol, CAS #1158759-03-5) in DMF (50 mL) was added N-ethyl-N-isopropylpropan-2-amine (7.12 mL, 41.0 mmol). The reaction mixture was stirred at room temperature for 12 h. On completion, EtOAc and water were added and the layers separated. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel chromatography with 30% EtOAc in heptanes. Tert-butyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (7.49 g, 13.4 mmol) was obtained as a light yellow powder. LCMS m/z: 557.3 (M+H) + .

›ABBREVIATIONS · 2 of 63

Preparation of 5-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline, Used in the Synthesis of Compound 59

5-(Pyridin-2-yl)-1,2,3,4-tetrahydroquinoline was prepared from 2-bromopyridine in similar manner as described for (5-(4-methylpyridin-3-yl)-1,2,3,4-tetrahydroquinoline). LCMS: [M+H] + =211.

Preparation of 2-(1,2,3,4-tetrahydroquinolin-5-yl)thiazole, Used in the Synthesis of Compound 64

2-(1,2,3,4-Tetrahydroquinolin-5-yl)thiazole was prepared from 2-bromothiazole in similar manner as (5-(4-methylpyridin-3-yl)-1,2,3,4-tetrahydroquinoline). LCMS: [M+H] + =217.

Synthesis of 5-phenyl-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 65

A mixture of 5-bromo-1,2,3,4-tetrahydroquinoline (300 mg, 1.4 mmol, 1.0 eq), phenylboronic acid (188 mg, 1.5 mmol, 1.1 eq), cesium carbonate (1.37 g, 4.2 mmol, 3.0 eq), and Pd(dppf)Cl 2 (103 mg, 141 μmol, 0.1 eq) in dioxane (10 mL) and water (1 mL) was evacuated and refilled with nitrogen three times. The the mixture was stirred at 100° C. for 15 h before being concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate) to afford 5-phenyl-1,2,3,4-tetrahydroquinoline (270 mg, 91.5% yield) as a yellow oil.

Synthesis of 4-methyl-1-(3-(5-(pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine, Used in the Preparation of Compound

Step a: A solution of pyridin-3-ylboronic acid (115 mg, 0.943 mmol), 5-bromo-1,2,3,4-tetrahydroquinoline (100 mg, 0.4715 mmol), tetrakis(triphenylphosphine)palladium (54.4 mg, 0.04715 mmol), and potassium carbonate (259 mg, 1.88 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 95° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by normal phase using 0-65% ethyl acetate in heptanes. The product 5-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (82.0 mg, 0.3899 mmol, 83% yield) was obtained as an off-white solid. LCMS: [M+H] + =211.

Synthesis of 5-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline, used in the preparation of Compound 66

A solution of pyridin-3-ylboronic acid (115 mg, 0.943 mmol), 5-bromo-1,2,3,4-tetrahydroquinoline (100 mg, 0.4715 mmol), tetrakis(triphenylphosphine)palladium (54.4 mg, 0.04715 mmol), and potassium carbonate (259 mg, 1.88 mmol) in dioxane (4 mL) and water (1 mL) was stirred at 95° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography using 0-65% ethyl acetate in heptanes. The product 5-(pyridin-3-yl)-1,2,3,4-tetrahydroquinoline (82.0 mg, 0.3899 mmol, 83% yield) was obtained as an off-white solid.

Preparation of (5-(4-methylpyridin-3-yl)-1,2,3,4-tetrahydroquinoline), Used in the Synthesis of Compound 67

A mixture of 3-bromo-4-methyl pyridine (40 mg, 0.232 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (90.6 mg, 0.301 mmol), potassium carbonate (96.1 mg, 0.696 mmol), and tetrakis(triphenylphosphine)palladium (26.8 mg, 0.023 mmol), in a sealed tube in 5 mL of a 4:1 mix of dioxane:water was degassed with nitrogen, capped, and stirred 3 hours at 95° C. The mixture was then cooled to room temperature, concentrated down to near dryness, and loaded as a silica gel slurry onto a 12 gram silica gel column, which was eluted with a heptane to EA gradient over 30 minutes to yield 5-(4-methylpyridin-3-yl)-1,2,3,4-tetrahydroquinoline (47.0 mg, 90% yield) as a yellow oil which solidified upon standing. LCMS: [M+H] + =225.

Synthesis of 4-(3-pyridyl)-2,3-dihydro-1H-quinoxaline, Used in the Preparation of Compound 68

A round bottomed flask was charged with 1,2,3,4-tetrahydroquinoxaline (500.0 mg, 3.7 mmol, 1.0 eq), 3-iodopyridine (840.3 mg, 4.1 mmol, 1.1 eq), RuPhos (173.9 mg, 372.6 umol, 0.1 eq), RuPhos-Pd-G4 (313.8 mg, 372.6 umol, 0.1 eq), and tBuONa (1.1 g, 11.2 mmol, 3.0 eq). Dioxane (8 mL) was added, and the reaction mixture was evacuated and refilled 3 times with nitrogen before being stirred at 80° C. for 12 h The reaction mixture was concentrated in vacuo and purified by flash silica gel chromatography (eluting with dichloromethane and methanol) to afford 4-(3-pyridyl)-2,3-dihydro-1H-quinoxaline (0.5 g, 63.5% yield) as a black brown solid.

Synthesis of 5-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 69

5-Bromo-1,2,3,4-tetrahydroquinoline (300.0 mg, 1.4 mmol, CAS #114744-50-2), (4-fluorophenyl)boronic acid (216.0 mg, 1.6 mmol), Pd(dppf)Cl 2 (103.0 mg, 141 μmol) and Cs 2 CO 3 (919.0 mg, 2.8 mmol) were added in the mixture of dioxane (20.0 mL) and H 2 O (2.0 mL). The reaction mixture was evacuated and refilled 3 times with N 2 and stirred at 100° C. for 12 hours. On completion, the reaction mixture was concentrated under reduced pressure to give a residue and purified by flash silica gel chromatography (Petroleum ether:EtOAc=100:0 to 100:10) to afford the product of 5-(4-fluorophenyl)-1,2,3,4-tetrahydroquinoline (300.0 mg, 93.7% yield) as a yellow solid.

Synthesis of 5-(3,4-difluorophenyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 70

The mixture of 5-bromo-1,2,3,4-tetrahydroquinoline (300 mg, 1.4 mmol, 1.0 eq), (3,4-difluorophenyl)boronic acid (244 mg, 1.5 mmol, 1.1 eq), Cs 2 CO 3 (1.37 g, 4.2 mmol, 3.0 eq) and Pd(dppf)Cl 2 (103 mg, 141 μmol, 0.1 eq) in dioxane (10 mL) and H 2 O (1 mL) was evacuated and refilled for 3 times using N 2 . Then the mixture was stirred at 100° C. for 15 hours under N 2 atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0-100:20) to afford the desired product of 5-(3,4-difluorophenyl)-1,2,3,4-tetrahydroquinoline (340 mg, 98.5% yield) as a colorless oil. LCMS m/z: 245.8 (M) + .

Preparation of ethyl 2-(1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylate, Used for the Preparation of Compound 71

Ethyl 2-(1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylate was prepared from ethyl 2-bromothiazole-4-carboxylate in similar manner as (5-(4-methylpyridin-3-yl)-1,2,3,4-tetrahydroquinoline). LCMS: [M+H] + =289.

›ABBREVIATIONS · 3 of 63

Synthesis of 5-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 72

5-Bromo-1,2,3,4-tetrahydroquinoline (300.0 mg, 1.4 mmol), (3,4,5-trifluorophenyl)boronic acid (248.0 mg, 1.4 mmol), Pd(dppf)Cl2 (103.0 mg, 141 μmol), and cesium carbonate (919.0 mg, 2.8 mmol) were added to a mixture of dioxane (20.0 mL) and water (2.0 mL). The reaction mixture was evacuated and refilled with nitrogen three times before being stirred at 100° C. for 12 h. The reaction mixture was concentrated in vacuo to give a residue that was purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate). Concentration in vacuo led to 5-(3,4,5-trifluorophenyl)-1,2,3,4-tetrahydroquinoline (200.0 mg, 53.9% yield) as a yellow solid.

Synthesis of 5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 73

Step 1: 5-bromo-1,2,3,4-tetrahydroquinoline (500 mg, 2.35 mmol), Bis(pinacolato)diboron (774 mg, 3.05 mmol) Pddppf-dichloromethane adduct (97.1 mg, 0.1175 mmol) and potassium acetate (922 mg, 9.40 mmol) were dissolved in dioxane (10 mL) and stirred at 100° C. 18 h. The mixture was cooled to room temperature, diluted with ethyl acetate, and filtered through a pad of celite. The residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in heptanes to give 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (413 mg, 1.59 mmol, 67.8% yield).

Step 2: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (100 mg, 0.3858 mmol), 8-bromo-3-methyl-[1,2,4]triazolo[4,3-a]pyridine (63 mg, 0.2967 mmol, CAS #54230-90-9), tetrakis(triphenylphosphine)palladium (34 mg, 0.02967 mmol), and potassium carbonate (82 mg, 0.5935 mmol) were dissolved in dioxane (4 mL) and water (1 mL) and stirred at 95° C. for 3 h. The mixture was cooled to room temperature and partitioned between water and ethyl acetate. Following separation of the layers, the organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in heptanes to give 5-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-yl)-1,2,3,4-tetrahydroquinoline (31.8 mg, 0.1203 mmol, 41% yield).

Synthesis of 5-(3-phenoxyphenyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 75

Step a: A solution of (3-phenoxyphenyl)boronic acid (500 mg, 2.34 mmol), 5-bromo-1,2,3,4-tetrahydroquinoline (250 mg, 1.17 mmol), tetrakis(triphenylphosphine)Palladium (135 mg, 0.117 mmol) and potassium carbonate (646 mg, 4.68 mmol) in dioxane/water (4:1, 5 mL) was stirred at 95 C for 1 h. Concentrated and purified on flash silica gel chromatography with 0-65% EtOAc in heptanes, followed by a second purification with 0-5% MeOH in DCM to give 5-(3-phenoxyphenyl)-1,2,3,4-tetrahydroquinoline (192 mg, 0.6380 mmol, 90% pure) as a light yellow oil. LCMS: [M+H]302.15.

Synthesis of 5-(difluoromethyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 78

Step a: To a solution of triethylamine trihydrofluoride (517 μL, 3.18 mmol) in DCM (3 ml) was added (diethylamino)difluorosulfonium tetrafluoroborate (545 mg, 2.38 mmol) and stirred until dissolved. Added quinoline-5-carbaldehyde (0.250 g, 1.59 mmol). Stirred at room temperature overnight. Quenched with 5% aq. sodium bicarb solution and stirred at rt. Extracted twice using DCM. Combined organic layers, dried over Na 2 SO 4 , filtered and concentrated. Purified by flash silica gel chromatography with 0-100% EtOAc in heptanes to give 5-(difluoromethyl)quinoline (100 mg, 0.5581 mmol).

Step b: Cycled a solution of 5-(difluoromethyl)quinoline (100 mg, 0.5581 mmol) in MeOH (10 mL) through H-Cube (10% Pd/C cartridge, 70 C, 70 bar, 1 mL/min). Reaction was complete after 10 min. Purified by flash silica gel chromatography using 0-5% MeOH in DCM w/1% NH4OH to give 5-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (35.0 mg, 0.1910 mmol). LCMS: [M+H] 184.06. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.55 (br s, 1H) 2.71-2.79 (m, 2H) 2.91-2.98 (m, 2H) 3.31 (s, 1H) 6.95 (s, 1H) 7.09 (s, 1H) 7.14-7.25 (m, 2H) 7.33 (d, J=7.57 Hz, 1H).

Synthesis of Methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate, Used in the Preparation of Compound 79

Step a: To a solution of 5-bromo-1,2,3,4-tetrahydroquinoline (1.0 g, 4.71 mmol) in THF (30.0 mL) was added NaHMDS (9.42 mL, 9.42 mmol, 1.0 M in THF) under N 2 . The reaction was stirred at 25° C. for 2 h. (Boc) 2 O (2.05 g, 9.42 mmol) was added thereto, and the reaction mixture was stirred at 25° C. for 12 h. To the mixture was added H 2 O (30.0 mL), then the solution was extracted with EtOAc (30.0 mL×2). The combined organic layers were washed with saturated NH 4 Cl (20.0 mL), dried anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product. The residue was purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether from 0% to 5%) to give tert-butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (1.5 g, 102% yield) as orange oil.

Step b: A solution of tert-butyl 5-bromo-3,4-dihydroquinoline-1(2H)-carboxylate (1.5 g, 4.8 mmol), Pd(dppf)Cl 2 (702.0 mg, 960.0 umol) and Et 3 N (1.44 g, 14.3 mmol) in MeOH (30.0 mL) was degassed and purged with CO for three times. The reaction mixture was stirred at 80° C. for 12 h under CO (50 psi). On completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether from 0% to 5%) to give 1-tert-butyl 5-methyl 3,4-dihydroquinoline-1,5(2H)-dicarboxylate (400.0 mg, 28.7% yield) as yellow oil.

Step c: A solution of 1-tert-butyl 5-methyl 3,4-dihydroquinoline-1,5(2H)-dicarboxylate (400.0 mg, 1.37 mmol) in HCl/MeOH (3.42 mL, 4.0 M) was stirred at 25° C. for 12 h. On completion, the reaction mixture was concentrated in vacuum to give methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate (350.0 mg, crude) as yellow solid. LCMS m/z 191.9(M) + .

›ABBREVIATIONS · 4 of 63

Synthesis of 4-propyl-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 83

Step a: To a solution of 4-bromoquinoline (500 mg, 2.40 mmol) and potassium carbonate (663 mg, 4.80 mmol) in Dioxane (5 mL) was added Pd(Ph3)4 (277 mg, 0.2399 mmol) and 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (403 mg, 2.40 mmol). Flushed with nitrogen. Heated to 100 C overnight. Partitioned between water and EtOAc. Separated layers, extracted aqueous layer with EtOAc (2×), combined organic layers, dried over Na 2 SO 4 , filtered and concentrated. Purified by flash silica gel chromatography using 0-10% MeOH in DCM to give 4-cyclopropylquinoline (124 mg, 0.7327 mmol).

Step b: Cycled solution of 4-cyclopropylquinoline (124 mg, 0.7327 mmol) in MeOH (10 mL) through H-cube (10% Pd/C, 70 C, 70 bar, 1 mL/min) for 30 min in a continuous loop. Concentrated to give crude 4-propyl-1,2,3,4-tetrahydroquinoline (114 mg), which was used in next step without purifying. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.08 Hz, 3H) 1.23-1.35 (m, 1H) 1.35-1.45 (m, 2H) 1.47-1.56 (m, 1H) 1.63-1.77 (m, 2H) 2.59-2.67 (m, 1H) 3.09-3.19 (m, 2H) 5.58-5.64 (m, 1H) 6.35-6.41 (m, 2H) 6.78-6.83 (m, 1H) 6.84 (d, J=7.57 Hz, 1H)

Synthesis of 4-ethyl-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound

Step a: In a microwave vial, combined 4-bromoquinoline (500 mg, 2.40 mmol), potassium phosphate (1.01 g, 4.80 mmol), tetrakis(triphenylphosphane) palladium (277 mg, 0.240 mmol), and ethylboronic acid (354 mg, 4.80 mmol) and dissolved in DME (20 mL). Heated in uW at 120 C for 2 h. Partitioned between EtOAc and water. Separated layers, dried over Na 2 SO 4 , concentrated and purified by flash silica gel chromatography to give 4-ethylquinoline (234 mg, 1.48 mmol) as a yellow oil.

Step b: Cycled solution of 4-ethylquinoline (200 mg, 1.27 mmol) in MeOH (20 mL) through H-cube (10% Pd/C, 70 C, 70 bar, 1 mL/min) for 3 h in a continuous loop. Concentrated to give crude 4-ethyl-1,2,3,4-tetrahydroquinoline (165 mg, 1.02 mmol) which was used in the next step without purifying. LCMS: [M+H] 162.06.

Synthesis of 4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine and 8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 90

Step a: To a solution of 4-bromo-1,5-naphthyridine dihydrobromide (250 mg, 0.6740 mmol) and potassium carbonate (185 mg, 1.34 mmol) in dioxane (2.5 mL) was added Pd(Ph3)4 (77.8 mg, 0.0674 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (375 μL, 2.69 mmol). Flushed with nitrogen. Stirred at rt for 2 h, then heated to 100 C overnight. Partitioned between water and EtOAc. Separated layers, extracted organic layer with EtOAc (2×). Combined organic layers, dried over Na 2 SO 4 , filtered and concentrated. Purified by flash silica gel chromatography using 0-10% MeOH in DCM to give 4-methyl-1,5-naphthyridine (50.0 mg, 0.3468 mmol).

Step b: Cycled a solution of 4-methyl-1,5-naphthyridine (141 mg, 0.9779 mmol) in MeOH (20 mL) through H-Cube (10% Pd/C, 70 C, 70 bar, 1 mL/min) for 90 min. Concentrated to give 142 mg crude material as a 5:1 mixture of Product A to Product B. Carried crude mixture onto next step without purifying further.

Synthesis of (2R,4R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol, Used in the Preparation of Compound 95

Step a: The compound of (2R,4R)-tert-butyl 4-hydroxy-2-methylpiperidine-1-carboxylate (400 mg, 1.8 mmol) was added in HCl/MeOH (10 mL, 2N). The reaction mixture was stirred at 25° C. for 12 hours. On completion, the mixture was adjusted to pH=7˜8 with NaHCO 3 solid and filtered. The filtrate was concentrated to give the product of (2R,4R)-2-methylpiperidin-4-ol (300 mg) as a white solid.

Step b: The compound of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (600 mg, 1.6 mmol), (2R,4R)-2-methylpiperidin-4-ol (207 mg, 1.80 mmol) and CsF (747 mg, 4.9 mmol) were placed into DMSO (10 mL). The reaction mixture was stirred at 70° C. for 20 hours. The reaction mixture was then diluted with EtOAc (100 mL) and H 2 O (30 mL), the partitioned layers were separated. The organic phase was washed with H 2 O (30 mL×3), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 70/100) to afford the product of (2R,4R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (530 mg, 73% yield) as a white solid. LCMS m/z 443.9 (M) + .

Synthesis of 4-phenyl-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 96

Step a: A solution of 4-bromoquinoline (200.0 mg, 961.0 μmol) and phenylboronic acid (140.0 mg, 1.2 mmol) in dioxane (10.0 mL) and H 2 O (1.0 mL) was added Pd(dppf)Cl 2 (70.3 mg, 96.1 μmol) and Cs 2 CO 3 (625.0 mg, 1.9 mmol). The reaction mixture was degassed and purged with N 2 gas 3 times and stirred at 100° C. for 12 hours under N 2 atmosphere. Then the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:50). The product of 4-phenylquinoline (180.0 mg, 91% yield) was obtained as a light yellow oil.

Step b: A solution of 4-phenylquinoline (180.0 mg, 876.0 μmol), diphenyl hydrogen phosphate (43.7 mg, 175.0 μmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (663.0 mg, 2.6 mmol) in toluene (5.0 mL) was stirred at 80° C. for 12 hours under N 2 gas. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:10). The product of 4-phenyl-1,2,3,4-tetrahydroquinoline (180.0 mg, 98% yield) was obtained as light yellow oil. LCMS m/z: 210.0 (M+H) + .

Synthesis of Methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate, Used in the Preparation of Compound 99

Step a: SOCl 2 (15.0 mL) was added drop-wise in MeOH (20.0 mL) at 0° C. Then quinoline-4-carboxylic acid (2.0 g, 11.5 mmol) in MeOH (10.0 mL) was added and stirred at 90° C. for 2 h. The solution was poured into H 2 O (100.0 mL) and then extracted with EtOAc (50.0 mL×2). The combined organic layers were washed with saturated NaCl (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as orange gum. The residue was purified by flash silica gel chromatography (20 g, Ethyl acetate in Petroleum ether from 0% to 25%) to give methyl quinoline-4-carboxylate (2.0 g, 93.0% yield) as yellow oil.

›ABBREVIATIONS · 5 of 63

Step b: A solution of methyl quinoline-4-carboxylate (1.90 g, 10.1 mmol), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (7.67 g, 30.3 mmol) and diphenyl phosphate (503.0 mg, 2.02 mmol) in toluene (50.0 mL) was stirred at 80° C. for 12 h under N 2 . The solution was poured into H 2 O (100.0 mL) and then extracted with EtOAc (50.0 mL×2). The combined organic layers were washed with saturated NaCl (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as brown gum. The residue was purified by flash silica gel chromatography (40 g, Ethyl acetate in Petroleum ether from 0% to 10%) to give methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate (1.1 g, 56.9% yield) as yellow oil.

Synthesis of 4-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 106

Step a: A solution of 4-(trifluoromethyl)quinoline (400 mg, 2.0 mmol), diphenyl hydrogen phosphate (101 mg, 0.4 mmol) and diethyl Hantzsch ester (1.5 g, 6.0 mmol) in PhMe (15 ml) was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (Petroleum ether:EtOAc=100:0 to 100:10) to afford the product of 4-(trifluoromethyl)-1,2,3,4-tetrahydroquinoline (300 mg, 74% yield) as a colorless oil. LCMS m/z: 201.9.

Synthesis of N-(1-(1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)4-methylpiperidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide, Used in the Preparation of Compound 110

Step a: To a mixture of tert-butyl 4-formyl-4-methylpiperidine-1-carboxylate (1.0 g, 4.4 mmol) in anhydrous THF (15 mL) was added 2-methylpropane-2-sulfinamide (637 mg, 5.3 mmol) followed by Ti(OEt) 4 (2.0 g, 8.8 mmol). The resulting mixture was stirred at 20° C. for 12 hours. The reaction mixture was quenched with sat NH 4 Cl and diluted with EtOAc (20 mL). The mixture was filtered and the filtrate was washed with H 2 O (20 mL×2). The organic phase was dried over Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (Petroleum ether:Ethyl acetate=6:1 to 4:1) to afford the product of (Z)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-4-methylpiperidine-1-carboxylate (1.4 g, 94.0% yield) as a colorless oil.

Step b: To a mixture of (Z)-tert-butyl 4-(((tert-butylsulfinyl)imino)methyl)-4-methylpiperidine-1-carboxylate (1.3 g, 3.9 mmol) in anhydrous THF (20 mL) at −70° C. under N 2 atmosphere was added CH 3 Li (1.6 M, 4.9 mL, 7.9 mmol), the resulting mixture was stirred at this temperature for 2 hours. The reaction mixture was quenched with sat.NH 4 Cl, diluted with EtOAc (30 mL) and washed with H 2 O (25 mL×2). The organic phase was separated, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=1:1 to 1:5) to afford the product of tert-butyl 4-(1-(1,1-dimethylethylsulfinamido)ethyl)-4-methylpiperidine-1-carboxylate (800 mg, 58.8% yield) as a yellow oil.

Step c: To a mixture of tert-butyl 4-(1-(1,1-dimethylethylsulfinamido)ethyl)-4-methylpiperidine-1-carboxylate (800 mg, 2.3 mmol) in DCM (15 mL) was added TFA (1.5 mL), and the resulting mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to afford the product of 2-methyl-N-(1-(4-methylpiperidin-4-yl)ethyl)propane-2-sulfinamide (600 mg, crude) as a yellow oil.

Step d: To a mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (500 mg, 1.4 mmol) and 2-methyl-N-(1-(4-methylpiperidin-4-yl)ethyl)propane-2-sulfinamide (505 mg, 2.1 mmol) in DMSO (15 mL) was added DIPEA (5 mL), and the resulting mixture was stirred at 70° C. for 12 hours. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (25 mL×2). The organic phase was combined, washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=1:0 to 0:1) to afford the product of N-(1-(1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (370 mg, 47% yield) as a yellow solid.

Synthesis of 1,2,3,4-tetrahydroquinoline-4-carbonitrile, Used in the Preparation of Compound 117

Step a: Quinoline-4-carbonitrile (300.0 mg, 1.9 mmol), diphenyl hydrogen phosphate (97.0 mg, 388.0 μmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g, 5.8 mmol) were added in toluene (10.0 mL), the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (EtOAc in Petroleum ether=0˜30%) to afford 1,2,3,4-tetrahydroquinoline-4-carbonitrile (200.0 mg, 65.3% yield) as a off-white oil.

Synthesis of 5-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate Used in the Preparation of Compound 120 and Compound 208

Step a: 5-methyl-1,2,3,4-tetrahydroquinoline (273 mg, 1.85 mmol) was dissolved in ACN (3.0 mL) in a round bottom flask and cooled to 0° C. before a solution of N-bromosuccinimide (493 mg, 2.78 mmol) in ACN (3.7 mL) was added. The reaction stirred at 0° C. for 5 min before adding sat. Na 2 S 2 O 3 at the same temperature. The reaction was warmed to ambient temperature and Et 2 O was added. The organic layer was extracted with Et 2 O (3×), and combined organic extracts were dried, concentrated and purified via silica gel chromatography (2-20% EtOAc in hexanes) to furnish 6-bromo-5-methyl-1,2,3,4-tetrahydroquinoline (208 mg, 0.920 mmol) in 50% yield, along with the dibrominated analog, which was not isolated. LCMS: [M+] 226.1 and 228.1.

Step b: A resealable vial was charged with 6-bromo-5-methyl-1,2,3,4-tetrahydroquinoline (208 mg, 0.920 mmol), [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (73.0 mg, 0.11 mmol), and zinc dicyanide (129 mg, 1.10 mmol) before being evacuated and backfilled with nitrogen (3×). A mixture of H 2 O (2.5 mL) and THF (0.5 mL) was then added and the reaction was heated to 40° C. for 16 h. After cooling, the reaction was partitioned between EtOAc and sat. sodium bicarbonate. The organic layer was extracted with EtOAc (3×), dried, concentrated and purified via silica gel chromatography (8-66% EtOAc in hexanes) to provide 5-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (110 mg, 0.639 mmol) as a white solid in 69% yield. LCMS: [M+H]+ 173.1.

›ABBREVIATIONS · 6 of 63

Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, Intermediate Used in the Preparation of Compound 121 and Compound 209

A reaction vial containing 5-bromo-1,2,3,4-tetrahydroquinoline (230 mg, 1.08 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (360 mg, 1.73 mmol), palladium tetrakis (124 mg, 0.110 mmol) and K 2 CO 3 (596 mg, 4.30 mmol) was charged with dioxane (2.90 mL) and H 2 O (0.70 mL). The reaction was degassed for 5 min, before being heated to 95° C. for 16 h. Following cooling to ambient temperature, the reaction was partitioned between dichloromethane and water and the organic layer was extracted (3×), concentrated and purified via silica gel chromatography (10-100% EtOAc in hexanes) to furnish 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (129 mg, 0.605 mmol) in 56% yield. LCMS: [M+H]+ 214.2

Step b: 5-cyclopropyl-1,2,3,4-tetrahydroquinoline (522 mg, 3.01 mmol) was dissolved in ACN (4.0 mL) in a round bottom flask and cooled to 0° C. before a solution of N-bromosuccinimide (533 mg, 3.0 mmol) in ACN (4.0 mL) was added. The reaction stirred at 0° C. for 5 min before adding sat. Na 2 S 2 O 3 at the same temperature. The reaction was warmed to ambient temperature and Et 2 O was added. The organic layer was extracted with Et 2 O (3×), and combined organic extracts were dried, concentrated and purified via silica gel chromatography (2-20% EtOAc in hexanes) to furnish 6-bromo-5-cyclopropyl-1,2,3,4-tetrahydroquinoline (300 mg, 1.19 mmol) in 40% yield, along with the dibrominated analog, which was not isolated. LCMS: [M+] 252.1 and 254.1.

Step c: A resealable vial was charged with 6-bromo-5-cyclopropyl-1,2,3,4-tetrahydroquinoline (300 mg, 1.19 mmol), [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (94.0 mg, 0.12 mmol), and zinc dicyanide (167 mg, 1.43 mmol) before being evacuated and backfilled with nitrogen (3×). A mixture of H 2 O (3.3 mL) and THF (0.66 mL) was then added and the reaction was heated to 40° C. for 16 h. After cooling, the reaction was partitioned between EtOAc and sat. sodium bicarbonate. The organic layer was extracted with EtOAc (3×), dried, concentrated and purified via silica gel chromatography (15-40% EtOAc in hexanes) to provide 5-cyclopropyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (102 mg, 0.514 mmol) as a white solid in 43% yield. LCMS: [M+H]+ 199.2.

Synthesis of 5-cyclopropyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate Used in the Preparation of Compounds 122 and 207

Step a: A reaction vial was charged with 5-bromo-1,2,3,4-tetrahydroquinoline (1000 mg, 4.70 mmol), cyclopropylboronic acid (2.60 g, 9.40 mmol), palladium tetrakis (530 mg, 0.460 mmol) and K 2 CO 3 (2.60 g, 18.8 mmol) and dissolved in dioxane (12.4 mL) and H 2 O (3.2 mL). The reaction was degassed for 5 min, before being heated to 100° C. for 16 h. Following cooling to ambient temperature, the reaction was partitioned between dichloromethane and water and the organic layer was extracted (3×), concentrated and purified via silica gel chromatography (0-10% EtOAc in hexanes) to provide 5-cyclopropyl-1,2,3,4-tetrahydroquinoline (522 mg, 3.01 mmol) in 64% yield.

Synthesis of 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile, Used in the Preparation of Compound 126

Step a: The mixture of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (300 mg, 1.77 mmol, 1.0 eq), Zn(CN) 2 (518 mg, 4.42 mmol, 2.5 eq), Zn (58 mg, 885 μmol, 0.5 eq), Pd 2 (dba) 3 (324 mg, 354 μmol, 0.2 eq) and dppf (98 mg, 177 μmol, 0.1 eq) in DMF (5 mL) was evacuated and refilled 3 times using N 2 , then stirred at 120° C. for 10 hours. The mixture was then concentrated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0˜1:1) to afford the desired product of 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (100 mg, 36% yield) as a yellow solid. LCMS m/z: 160.1 (M+H) + .

Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate for Compound 131

Step a: A round bottomed flask was charged with 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (460 mg, 2.16 mmol, 1 equiv.) and a stirbar. Acetonitrile (3 mL) and dioxane (1 mL) was added, and the solution was cooled to 0 C for the addition of N-bromosuccinimide (384 mg, 2.16 mmol, 1 equiv.) in acetonitrile (3 mL). After 5 min, the reaction was quenched with a saturated solution of sodium bisulfite. The product was extracted three times from the aqueous layer with diethyl ether. The combined organic fractions were concentrated in vacuo, and the residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield 6-bromo-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (228 mg).

Step b: A microwave vial was charged with 6-bromo-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (228 mg, 0.78 mmol, 1 equiv.), dicyanozinc (110 mg, 0.94 mmol, 1.2 equiv), tBuXPhos G3 (62 mg, 0.087 mmol, 0.1 equiv), and a stirbar before being sealed and evacuated/backfilled with nitrogen three times. 1:5 THF:water (0.3 volumes) was added, and the mixture was stirred at 40 C overnight. The reaction mixture was diluted with ethyl acetate and extract three times. The combined organic layers were dried with sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (65 mg).

Synthesis of 2-benzylpiperidin-4-yl)methanamine for Use in Compound 158 and Compound 159

Step a: To a solution of tert-butyl 2-benzyl-4-oxopiperidine-1-carboxylate (2.10 g, 7.26 mmol, 1.0 eq) in DME (30 mL) was added TosMIC (2.13 g, 10.89 mmol, 1.5 eq) in DME (30 mL) and t-BuOK (2.44 g, 21.77 mmol, 3.0 eq) at −10° C. under N2. Then the mixture was stirred at −10° C. for 30 min, the mixture was stirred at 25° C. for 16 hr. TLC (petroleum ether/ethyl acetate=5/1) showed that compound 1 (Rf=0.28) was consumed and a new spot (Rf=0.3) was formed. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (50 mL*3). Then combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=20/1-5/1, Rf=0.3) to give tert-butyl 2-benzyl-4-cyanopiperidine-1-carboxylate (1.3 g, crude) as a light yellow oil. 1H NMR (400 MHz CDCl3) δ: 7.34-7.16 (m, 5H), 4.56-4.45 (m, 1H), 4.21 (s, 1H), 3.30-2.71 (m, 4H), 1.98 (d, J=14.0 Hz, 1H), 1.83-1.73 (m, 3H), 1.41-1.30 (m, 9H).

›ABBREVIATIONS · 7 of 63

Step b: To a solution of tert-butyl 2-benzyl-4-cyanopiperidine-1-carboxylate (1.22 g, 4.05 mmol, 1.00 eq) in methyl alcohol (20 mL) was added Raney-Ni (0.50 g, 5.84 mmol, 1.44 eq). Then the mixture was stirred under H2 (50 psi) at 25° C. for 32 hr. LCMS (EW7754-10-P1A) showed that the desired MS (Rt=0.693 min) was detected. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 4-(aminomethyl)-2-benzylpiperidine-1-carboxylate (1.1 g, crude) as a colorless oil.

Step c: To a solution of tert-butyl 4-(aminomethyl)-2-benzylpiperidine-1-carboxylate (1.1 g, 3.61 mmol, 1.00 eq) in dichloromethane (10 mL) was added DIPEA (607.10 mg, 4.70 mmol, 818.20 uL, 1.30 eq) and CbzCl (678.05 mg, 3.97 mmol, 565.05 uL, 1.10 eq). Then the mixture was stirred at 25° C. for 2 hr. LCMS (EW7754-12-P1A) showed that desired MS (Rt=1.009 min) was detected. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL*3). Then combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=10/1-5/1, Rf=0.5) to provide tert-butyl 2-benzyl-4-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (1.4 g, 2.55 mmol, 70.5% yield, 79.8% purity) as a yellow oil.

Step d: To a solution of tert-butyl 2-benzyl-4-((((benzyloxy)carbonyl)amino)methyl)piperidine-1-carboxylate (0.9 g, 2.04 mmol, 1 eq) in HCl/ethyl acetate (10 mL) was stirred at 25° C. for 2 hr. TLC (petroleum ether/ethyl acetate=3/1) showed that compound 4 (Rf=0.5) was consumed and a new spot (Rf=0) was formed. The reaction mixture was concentrated to give benzyl ((2-benzylpiperidin-4-yl)methyl)carbamate hydrochloride (0.85933 g, crude, HCl) as a light yellow gum. 1H NMR (400 MHz DMSO-d6): δ 8.82-8.74 (m, 2H), 7.37-7.22 (m, 10H), 4.97 (dd, J=16.8 Hz, J=12.4 Hz, 2H), 3.57 (s, 1H), 3.26 (s, 1H), 3.08-2.87 (m, 5H), 2.52 (d, J=1.6 Hz, 2H), 1.98 (s, 5H), 1.75-1.23 (m, 4H).

Synthesis of 4-methyl-6-(4H-1,2,4-triazol-3-yl)-1,2,3,4-tetrahydroquinoline, Intermediate for Compound 165

Step a: To a round bottomed flask containing a solution of 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (1 g, 4.42 mmol) in THF (30 mL) was added sodium bis(trimethylsilyl)amide (8.84 mL, 8.84 mmol) under nitrogen. The reaction was stirred 2 h before the addition of di-tert-butyl dicarbonate (1.01 mL, 4.42 mmol). The suspension stirred at room temperature overnight before the addition of water. The product was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield tert-butyl 6-bromo-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (1.24 g, 3.80 mmol) as a yellow oil.

Step b: In a resealable vial, tert-butyl 6-bromo-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (1.24 g, 3.80 mmol), dicyanozinc (446 mg, 3.80 mmol) and 2-(2-aminophenyl)benzen-1-ide di-tert-butyl({2-[2,4,6-tris(propan-2-yl)phenyl]phenyl})phosphane dipalladiumylium methanesulfonate (171 mg, 0.19 mmol) were combined. The flask was evacuated and backfilled with nitrogen three times before the addition of THF (2 mL) and water (10 mL), and the reaction was stirred at 40 C. After completion, the mixture was partitioned between sat. NaHCO 3 and EtOAc and stirred for 2 h. The organic layer was separated, and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentration in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield tert-butyl 6-cyano-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (756 mg, 2.77 mmol) as an off-white solid.

Step c: In a round bottomed flask, tert-butyl 6-cyano-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (500 mg, 1.83 mmol) was dissolved in DMSO (10 mL) and cooled to 0 C. 50% aq. hydrogen peroxide (1 mL, 1.83 mmol) was added, followed by potassium carbonate (75.8 mg, 0.549 mmol), and the mixture was stirred at room temperature. After 30 min, the mixture was heated to 60 C, and ethanol (2 mL) was added. After 2 h, the mixture was partitioned between EtOAc and water. The water layer was washed EtOAc. The organic layers were combined and concentrated in vacuo to yield tert-butyl 6-carbamoyl-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (602 mg, 2.07 mmol) as a residue that was used in the next step without further purification.

Step d: In a round bottomed flask tert-butyl 6-carbamoyl-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (600 mg, 2.06 mmol) was dissolved in toluene (10 mL). 1,1-dimethoxy-N,N-dimethylmethanamine (818 μL, 6.18 mmol) was added, and the mixture was heated to 100 C 45 min before the solvent was removed in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield (E)-tert-butyl 6-(((dimethylamino)methylene)carbamoyl)-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (688 mg, 1.99 mmol).

Step e: (E)-tert-butyl 6-(((dimethylamino)methylene)carbamoyl)-4-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (300 mg, 0.8684 mmol) was dissolved in dioxane (3 mL) and added to a vial containing hydrazine hydrate (92.9 μL, 0.9552 mmol) and acetic acid (3 mL, 52.4 mmol). The solution was stirred at 90 C 30 min and overnight at room temperature. The mixture was concentrated in vacuo before being diluted with water and extracted twice with diethyl ether. The organic layers were dried over sodium sulfate and concentrated. The resulting residue was taken up in methanol (5 mL) for the addition of a few drops of conc. HCl. The solution was stirred at 60 C overnight before being concentrated in vacuo to yield 4-methyl-6-(1H-1,2,4-triazol-5-yl)-1,2,3,4-tetrahydroquinoline hydrochloride (169 mg, 0.6740 mmol).

Synthesis of rel-benzyl (((2S,4R)-2-phenylpiperidin-4-yl)methyl)carbamate hydrochloride and rel-benzyl (((2S,4S)-2-phenylpiperidin-4-yl)methyl)carbamate hydrochloride for Use in Compound 167 and Compound 168

›ABBREVIATIONS · 8 of 63

Step a: To a solution of tert-butyl 4-oxo-2-phenylpiperidine-1-carboxylate (2.3 g, 8.35 mmol, 1 eq) in DME (30 mL) was added TosMIC (2.45 g, 12.53 mmol, 1.5 eq) in DME (30 mL) and t-BuOK (2.81 g, 25.06 mmol, 3 eq) at −10° C. under N2. After stirring at −10° C. for 30 min, the mixture was stirred at 25° C. for 16 hr. TLC (petroleum ether/ethyl acetate=5/1) showed that compound 5 (Rf=0.28) was consumed and a new spot (Rf=0.25) was formed. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (50 mL*3). Then combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=20/1-5/1, Rf=0.25) to give tert-butyl 4-cyano-2-phenylpiperidine-1-carboxylate (1 g, crude) as a yellow oil. 1H NMR (400 MHz CDCl3): δ: 7.50-7.47 (m, 2H), 7.40-7.36 (m, 1H), 7.27-7.25 (d, J=8.0 Hz, 2H), 5.66 (s, 1H), 4.28-4.25 (m, 1H), 2.91-2.72 (m, 3H), 2.29-2.24 (m, 1H), 2.03-1.91 (m, 1H), 1.90-1.87 (m, 1H), 1.58 (s, 9H).

Step b: To a solution of tert-butyl 4-cyano-2-phenylpiperidine-1-carboxylate (1 g, 3.49 mmol, 1 eq) in methyl alcohol (20 mL) was added Raney-Ni (0.5 g, 5.84 mmol, 1.67 eq). Then the mixture was stirred under H2 (50 psi) at 25° C. for 32 hr. LCMS (EW7754-11-P1A) showed that the desired MS (Rt=0.658 min) was detected. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give tert-butyl 4-(aminomethyl)-2-phenylpiperidine-1-carboxylate (0.8 g, crude) as a colorless oil.

Step c: To a solution of tert-butyl 4-(aminomethyl)-2-phenylpiperidine-1-carboxylate (0.8 g, 2.75 mmol, 1 eq) in dichloromethane (10 mL) was added DIPEA (462.85 mg, 3.58 mmol, 623.79 uL, 1.3 eq) and CbzCl (516.95 mg, 3.03 mmol, 430.79 uL, 1.1 eq). Then the mixture was stirred at 25° C. for 2 hr. LCMS (EW7754-13-PIA) showed that the desired Ms (Rt=0.996 min) was detected. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (50 mL*2). Then combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=10/1-5/1, Rf=0.5) to give tert-butyl 4-((((benzyloxy)carbonyl)amino)methyl)-2-phenylpiperidine-1-carboxylate (1.1 g, 2.14 mmol, 77.5% yield, 82.4% purity) as a colorless oil.

Step d: To a solution of tert-butyl 4-((((benzyloxy)carbonyl)amino)methyl)-2-phenylpiperidine-1-carboxylate (0.74 g, 1.73 mmol, 1 eq) in HCl/ethyl acetate (10 mL) was stirred at 25° C. for 2 hr. The reaction mixture was concentrated to give rel-benzyl (((2S,4R)-2-phenylpiperidin-4-yl)methyl)carbamate hydrochloride and rel-benzyl (((2S,4S)-2-phenylpiperidin-4-yl)methyl)carbamate hydrochloride (678.94 mg, crude, HCl) as a white solid. 1HNMR (400 MHz DMSO-d6): δ 9.13 (s, 2H), 7.55-7.31 (m, 10H), 5.07-4.99 (m, 2H), 4.43 (d, J=10.0 Hz, 1H), 3.26-3.13 (m, 3H), 2.52 (d, J=1.6 Hz, 2H), 2.05-1.96 (m, 3H), 1.80-1.65 (m, 2H).

Synthesis of 4-(1,3-thiazol-2-yl)-2,3-dihydro-1H-indole, A-Ring for Compound 173 and Compound 221

Step a: The mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (4 g, 16.4 mmol, 1.0 eq), 2-bromo-1,3-thiazole (4.0 g, 24.5 mmol, 1.5 eq), Pd(dppf)Cl 2 (1.2 g, 1.6 mmol, 0.1 eq) and K 2 CO 3 (6.8 g, 49.1 mmol, 3.0 eq) in dioxane (50 mL) and H 2 O (5 mL) was evacuated and refilled for 3 times using N 2 and stirred at 90° C. for 6 hours. LCMS indicated that the starting material was remained and one main new peak with desired MS was detected. The mixture was diluted with H 2 O (50 mL), extracted with EtOAc (70 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=20:1˜8:1) to afford 4-(1,3-thiazol-2-yl)-1H-indole (1.7 g, 52% yield) as a yellow solid.

Step b: To a mixture of 4-(1,3-thiazol-2-yl)-1H-indole (2 g, 9.98 mmol, 1.0 eq) in AcOH (15 mL) was added NaBH 3 CN (1.88 g, 29.9 mmol, 1.0 eq). The mixture was stirred at 30° C. for 4 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (70 mL), adjusted with saturated NaHCO 3 to pH=8. The organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=20:1˜5:1) to afford the desired product of 4-(1,3-thiazol-2-yl)-2,3-dihydro-1H-indole (1.05 g, 52% yield) as a yellow oil.

Synthesis of 4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Synthesis of Compound 184

Step a: A resealable reaction vial was charged with 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (250 mg, 1.10 mmol), zincdicarbonitrile (258 mg, 2.20 mmol), palladium(1+) 2′-amino-1,1′-biphenyl-2-yl di-tert-butyl[2′,4′,6′-tris(propan-2-yl)-[1,1′-biphenyl]-2-yl]phosphane methanesulfonate (87.3 mg, 0.1100 mmol), dioxane (6 mL) and water (1 mL). The mixture was bubbled with nitrogen for 10 min. The vial was sealed, and the mixture was stirred at 90° C. for 2 hrs. The reaction mixture was concentrated and the residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=20:80 to 40:60) to afford 4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (67 mg) as a yellow solid. LCMS: [M+H] + 174.

Synthesis of 4-acetyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Intermediate Used in the Preparation of Compound 187 and Compound 302

Step a: A round bottom flask containing 1-(3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (192 mg, 1.09 mmol) (CAS: 6639-92-5) in ACN (1.5 mL) was cooled to 0° C. A solution of N-bromosuccinimide (192 mg, 1.09 mmol) in ACN (1.7 mL) was added and the reaction stirred at 0° C. for 5 min before adding sat. Na 2 S 2 O 3 at the same temperature. The reaction was warmed to ambient temperature and Et 2 O was added. The organic layer was extracted with Et 2 O (3×), and combined organic extracts were dried, concentrated and purified via silica gel chromatography (18-100% EtOAc in hexanes) to provide 1-(7-bromo-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (194 mg, 0.760 mmol) in 70% yield, along with the dibrominated analog, which was not isolated. LCMS: [M+] 255.1 and 257.1.

›ABBREVIATIONS · 9 of 63

Step b: A resealable vial was charged with 1-(7-bromo-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (122 mg, 0.0.480 mmol), [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(IT) methanesulfonate (38.0 mg, 0.048 mmol), and zinc dicyanide (67 mg, 0.57 mmol) before being evacuated and backfilled with nitrogen (3×). A mixture of H 2 O (1.3 mL) and THF (0.25 mL) was then added and the reaction was heated to 40° C. for 16 h. The reaction was cooled to ambient temperature and partitioned between EtOAc and sat. sodium bicarbonate. The organic layer was extracted with EtOAc (3×), dried, concentrated and purified via silica gel chromatography (25-100% EtOAc in hexanes) to provide 4-acetyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (48.0 mg, 0.239 mmol) in 50% yield. LCMS: [M+]201.2.

Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, Intermediate Used in the Preparation of Compound 188 and Compound 324

A resealable reaction vial was charged with 6-bromo-1H,2H,3H-pyrido[2,3-b][1,4]oxazine (555 mg, 2.58 mmol), (1-methyl-1H-pyrazol-4-yl)boronic acid (487 mg, 3.87 mmol), [2 (222 mg, 0.258 mmol), dipotassium carbonate (713 mg, 5.16 mmol), and a stirbar before being evacuated and purged with nitrogen three times. 10:1 dioxane:water(5.5 mL) was added, and the mixture was stirred at 90° C. 18 h. The mixture was diluted with ethyl acetate, filtered, and concentrated in vacuo with celite. The crude material was purified by silica gel chromatography (eluting with ethyl acetate, heptanes, and methanol). Product-containing fractions were concentrated in vacuo to yield 1-methyl-4-{1H,2H,3H-pyrido[2,3-b][1,4]oxazin-6-yl}-1H-pyrazole (540 mg, 2.49 mmol) as a orange oil. LCMS: [M+H]+ 217.

Synthesis of N-methyl-3,4-dibydroquinoxaline-1(2H)-carboxamide, Intermediate Used in the Preparation of Compound 342 and Compound 189

Step a: A round bottom flask was charged with tert-butyl 3,4-dihydroquinoxaline-1(2H)-carboxylate (150 mg, 0.640 mmol) (CAS: 887590-25-2) in DMF (6.40 mL) before the addition of N-methyl-1H-imidazole-1-carboxamide (800 mg, 6.40 mmol) and triethylamine (0.356 mL, 2.56 mmol) and the reaction was heated to 80° C. for 16 h. After cooling to ambient temperature, the residue was concentrated to dryness and purified via silica gel chromatography (10-100% EtOAc in hexanes) to furnish tert-butyl 4-(methylcarbamoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (73.0 mg, 0.25 mmol) in 40% yield. LCMS: [M+Na]+314.

Step b: To a round bottom flask containing tert-butyl 4-(methylcarbamoyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (73.0 mg, 0.25 mmol) in dichloromethane (4.0 mL) was added trifluoroacetic acid (0.50 mL) and the reaction was stirred at room temperature for 1 h. Solvent was evaporated and the residue was purified via silica gel chromatography (10-100% EtOAc in hexanes) to provide N-methyl-3,4-dihydroquinoxaline-1(2H)-carboxamide (47.8 mg, 0.25 mmol) in quantitative yield.

Synthesis of 5-methanesulfinyl-1,2,3,4-tetrahydroquinoline, A-Ring for Compound 192

Step a: A mixture of 5-bromoquinoline (2 g, 9.6 mmol), NaSCH 3 (1 g, 14.4 mmol) and DMF (25 mL) was placed into autoclave. The mixture was stirred at 130° C. for 1.5 h. The mixture was then cold to 15° C. The aq. NaClO (27.0 mL, 40 mmol, 10%) was added. The mixture was stirred at 15° C. for 5 min. The reaction was quenched by saturated Na 2 SO 3 (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate:Petroleum ether=50:100 to 100:100 then EtOAc:MeOH=100:10) to give the product of 5-methanesulfinylquinoline (700 mg, 38% yield in 2 steps) as a yellow solid.

Step b: A solution of 5-methanesulfinylquinoline (500 mg, 2.6 mmol), diphenoxyphosphinic acid (130 mg, 0.5 mmol) and 2-[5-(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyloxy]ethylium (1.64 g, 6.5 mmol) in PhMe (25 ml) was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (Petroleum ether:EtOAc=100:50 to 100:100, then MeOH:EtOAc=10:100) to afford the product of 5-methanesulfinyl-1,2,3,4-tetrahydroquinoline (400 mg, 78% yield) as a yellow solid.

Synthesis of 6-chloro-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine, Intermediate Used in the Preparation of Compound 195

A suspension of 6-chloro-4-methyl-1H,2H,3H,4H-pyrido[2,3-b]pyrazin-3-one (120 mg, 0.6072 mmol) in THF (1.2 mL) was added dropwise to lithium aluminum hydride (1.0M in THF, 3.03 mL, 3.03 mmol). Upon the cessation of gas evolution, the reaction vessel was sealed and heated to 65° C. for 16 h. The reaction was cooled and ice was added slowly until gas evolution was no longer observed. EtOAc was added to the reaction, and the organic layer was extracted with EtOAc (3×), concentrated and purified via silica gel chromatography (10-100% EtOAc in hexanes) to furnish 6-chloro-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (74.0 mg, 0.403 mmol) in 66% yield. LCMS: [M+H]+ 184.1.

Synthesis of tert-butyl ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate, Used in the Preparation of Compound 200

Step a: To a solution of tert-butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (40.0 g, 107 mmol, 1.00 eq) in MeOH (800 mL) was added HCl/MeOH (4 M, 267 mL, 10.0 eq). The mixture was stirred at 25° C. for 5 hrs, then the reaction mixture was concentrated. Next, methyl tert-butyl ether (500 mL) was added to the residue which was stirred for 15 min. Then the mixture was concentrated to give (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (29.3 g, crude, 2HCl) as a white solid. 1 H NMR: 400 MHz DMSO δ: 9.23-9.19 (m, 2H), 8.39 (s, 3H), 4.23-4.20 (m, 1H), 3.83-3.81 (d, J=9.2 Hz, 1H), 3.64-3.61 (d, J=8.8 Hz, 1H), 3.22 (m, 1H), 3.15 (m, 1H), 2.93-2.85 (m, 2H), 2.01-1.69 (m, 4H), 1.25-1.22 (d, J=11.2 Hz, 3H).

›ABBREVIATIONS · 10 of 63

Step b: To a mixture of (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (29.3 g, 120 mmol, 1.00 eq, 2HCl) in DMF (240 mL) was added DIPEA (62.3 g, 482 mmol, 84.0 mL, 4.00 eq) and 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (46.1 g, 127 mmol, 1.05 eq) at 25° C. The mixture was heated to 50° C., and stirred at 50° C. for 4 hrs. To the mixture was added Boc 2 O (31.6 g, 145 mmol, 33.2 mL, 1.20 eq) at 25° C. The mixture was stirred at 50° C. for 3 hrs. The mixture was diluted with methyl tert-butyl ether (1.50 L), washed with brine (500 mL*3), dried over Na 2 SO 4 and concentrated under vacuum. The residue was purified by column chromatography (SiO 2 , petroleum ether: ethyl acetate=1:0 to 0:1) to give tert-butyl ((3S,4S)-8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (50.5 g, 84.4 mmol) as a light yellow solid. LCMS m/z: 599.5 (M+1) + , 1 H NMR: 400 MHz CDCl 3 δ: 8.17 (s, 1H), 5.79-5.76 (d, J=12 Hz, 1H), 4.65-4.62 (d, J=10.4 Hz, 1H), 4.19-4.09 (m, 1H), 4.05-4.02 (m, 1H), 3.74-3.64 (m, 8H), 2.65-2.63 (m, 1H), 2.15-2.04 (m, 1H), 1.92-1.75 (m, 8H), 1.45 (s, 9H), 1.22-1.21 (m, J=6.4 Hz, 3H).

The building blocks for Compound 211 and Compound 213 were prepared according to reported procedures, starting from (S)-1-(4-methoxyphenyl)ethan-1-amine and 8-azaspiro[4.5]decan-1-one or 2-oxa-8-azaspiro[4.5]decan-4-one, and the resulting intermediates were used in a route analogous to that used for Compound 179.

Synthesis of Benzyl (8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-yl)carbamate, Used in the Preparation of Compound 211

Step a: A mixture tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate (1000 mg, 3.94 mmol, CAS #191805-29-5) and ammonium acetate (3037 mg, 39.4 mmol) in ethanol (10 mL) was stirred at room temperature for 5 min. Sodium cyanoborohydride (297 mg, 4.73 mmol) was added in three parts. The mixture was heated under microwave for 99 min at 110° C. The residue was dissolved in water and ethyl acetate and stirred vigorously. The ethyl acetate phase was separated, dried over MgSO 4 , filtered and concentrated to give crude product, which was taken to the next step without purification. MS (ES+) m/z 198.1 ((M-C4H9)+1) + .

Step b: Triethylamine (713 mL, 5.11 mmol) and benzyl chloroformate (810 mg, 4.72 mmol) were added to a solution of spiroamine (1000 mg, 3.93 mmol) in dichloromethane (25 mL) at 0° C. The resulting mixture was stirred at room temperature for 15 h, treated with saturated sodium bicarbonate and extracted two times with dichloromethane. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (hexane/Et 2 O, 5:1 to 1:1) to afford desired product tert-butyl 1-(((benzyloxy)carbonyl)amino)-8-azaspiro[4.5]decane-8-carboxylate (800 mg, 53% over two steps) as a clear oil. MS (ES+) m/z 333.1((M-C4H9)+1) + .

Step c: Tert-butyl 1-(((benzyloxy)carbonyl)amino)-8-azaspiro[4.5]decane-8-carboxylate (200 mg, 0.51 mmol) was dissolved in DCM (2 mL) and HCl in dioxane (4M, 2 mL, 8.0 mmol) was added. The mixture was stirred 15 min at room temperature and then concentrated under vacuum. The solid was dissolved in DCM and washed with a saturated solution of NaHCO 3 . The aqueous phase was extracted three further times with DCM. The organic phase was combined, dried over MgSO4, filtered and concentrated to give pure benzyl 8-azaspiro[4.5]decan-1-ylcarbamate (136 mg, 92%). 1 H NMR (500 MHz, CDCl3) δ 7.40-7.21 (m, 5H), 5.01 (dd, J=37.9, 12.2 Hz, 2H), 4.58 (s, 1H), 2.87 (s, 2H), 2.63 (dt, J=21.3, 10.7 Hz, 2H), 2.05-1.84 (m, 1H), 1.80-1.61 (m, 3H), 1.56 (dd, J=11.0, 8.2 Hz, 2H), 1.45-1.28 (m, 3H), 1.28-1.10 (m, 3H). MS (ES+) m/z 288.4 (M+H) + .

Step d: To a 10 mL seal tube, 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (300 mg, 0.82 mmol), benzyl 8-azaspiro[4.5]decan-1-ylcarbamate (400 mg, 1.23 mmol), cesium fluoride (250 mg, 1.65 mmol) and potassium phosphate (350 mg, 1.65 mmol) were suspended in dimethylacetamide (4 mL). The resulting heterogeneous mixture was then heated at 85° C. for 5 h. The reaction mixture was then cooled to room temperature, poured into water (20 mL) and ethyl acetate (20 mL) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were combined, washed with brine (300 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography using a gradient of ethyl acetate in hexanes (0 to 100%) to give benzyl (8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-yl)carbamate (370 mg, 73%) as a white solid after drying under high vacuum overnight. LCMS m/z 617.2 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ 8.42 (d, J=9.5 Hz, 1H), 7.34-7.16 (m, 5H), 5.68 (dt, J=19.2, 9.6 Hz, 1H), 5.03-4.90 (m, 2H), 4.31-4.17 (m, 3H), 3.91 (d, J=10.9 Hz, 1H), 3.68-3.59 (m, 2H), 3.23 (dd, J=13.1, 6.8 Hz, 2H), 2.45-2.33 (m, 2H), 1.99 (t, J=6.8 Hz, 1H), 1.86 (ddd, J=15.4, 10.4, 3.3 Hz, 2H), 1.60-1.43 (m, 6H), 1.43-1.30 (m, 4H).

Synthesis of 8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-methoxybenzyl)-2-oxa-8-azaspiro[4.5]decan-4-amine, Used in the Preparation of Compound 213

Step a: 2-oxa-8-azaspiro[4.5]decan-4-ol (500 mg, 3.18 mmol, CAS #777049-50-0) was suspended in DCM (30 mL). Di-tert-butyl dicarbonate (833 mg, 3.82 mmol) was added to the mixture and the reaction stirred at room temperature until TLC showed complete conversion to desired product. The mixture was then made slightly acidic with 1M hydrochloric acid (pH=5), and was extracted with ethyl acetate (2×). The combined organics were washed with brine and then dried over magnesium sulfate, filtered and concentrated in vacuo. Tert-butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was obtained as white solid (682 mg, 83% yield). 1 H NMR: (400 MHz, CDCl 3 ) δ 4.10 (dd, J=10.2, 4.7 Hz, 1H), 4.01 (dt, J=4.7, 1.6 Hz, 1H), 3.74 (d, J=8.6 Hz, 1H), 3.73 (dd, J=10.7, 2.0 Hz, 1H), 3.67 (d, J=8.6 Hz, 1H), 3.65-3.61 (m, 2H), 3.27 (dt, J=13.7, 6.7 Hz, 1H), 3.14 (ddd, J=12.9, 9.0, 3.5 Hz, 1H) 1.84-1.79 (m, 1H), 1.76 (ddd, J=13.3, 9.0, 3.9 Hz, 1H), 1.56 (ddd, J=13.3, 6.3, 3.5 Hz, 1H) 1.50-1.49 (m, 2H), 1.47 (s, 9H).

›ABBREVIATIONS · 11 of 63

Step b: tert-butyl 4-hydroxy-2-oxa-8-azaspro[4.5]decane-8-carboxylate (682 mg, 2.65 mmol) was dissolve in DCM (20 mL). Sodium bicarbonate (890 g, 10.60 mmol) and the Dess-Martin periodinane (2.25 g, 5.30 mmol) were added to the mixture. The reaction mixture was stirred at room temperature until TLC showed complete conversion to desired product. A 1:1:1 mixture of NaHCO 3 (sat.): Na 2 S 2 O 3 (sat.): DCM (10 mL in total) was added slowly (a few mL portions as gas was evolved). This mixture was stirred until two clear layer was observed (about h). The mixture was transferred to a separatory funnel and extracted with DCM (3×). The combined organics were washed with brine and then dried over magnesium sulfate, filtered and concentrated in vacuo. Ter-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate was obtained as white solid (609 mg g, 90% yield). LCMS m/z 256.2 [M+H + ].

Step c: tert-butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (609 mg, 2.39 mmol) was suspended in dichloroethane (15.0 mL). 4-methoxybenzylamine (0.34 mL, 2.62 mmol) and sodium cyanoborohydride (749 mg, 11.93 mmol) was added to the mixture and the reaction was stirred at room temperature overnight. The mixture was then quenched with sat. sodium bicarbonate solution and stirred for 1 h. The mixture was then extracted with ethyl acetate (3×), the combined organics were washed with brine and then dried over magnesium sulfate, filtered and concentrated in vacuo. The desired product was purified using flash chromatography with 10-100% EtOAc in hexanes. This gave tert-butyl 4-((4-methoxybenzyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (489 mg, 54% yield) as a clear oil. LCMS m/z 377.3 [M+H + ].

Step d: tert-butyl 4-((4-methoxybenzyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (489 mg, 1.29 mmol) was dissolved in a 4 M solution of HCl in dioxane (10 mL). The mixture was stirred for 1 hr at room temperature. The mixture was then concentrated in vacuo providing 4-((4-methoxybenzyl)ammonio)-2-oxa-8-azaspiro[4.5]decan-8-ium chloride (394 mg, 88% yield) as a white solid. LCMS m/z 277.2 [M+H + ].

Step e: 4-((4-methoxybenzyl)ammonio)-2-oxa-8-azaspiro[4.5]decan-8-ium chloride (394 mg, 1.13 mmol) was dissolved in NMP (5.0 mL). Potassium phosphate tribasic (426 mg, 2.0 mmol), cesium fluoride (305 mg, 2.00 mmol) and 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (365 mg, 1.00 mmol) was added to the mixture. The reaction was stirred at 85° C. until LCMS showed complete conversion to desired product. The mixture was cooled to room temperature and the desired product was purified using 20-100% MeCN in 10 mM ammonium bicarbonate buffer on reverse phase chromatography to give 8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-methoxybenzyl)-2-oxa-8-azaspiro[4.5]decan-4-amine (311 mg, 46% yield) after lyophilization. LCMS m/z 605.3 [M+H + ], 521.2 [M-THP + ]. 1 H NMR (400 MHz, CDCl 3 ) δ 8.17 (s, 1H), 7.25-7.20 (m, 2H), 6.88-6.82 (m, 2H), 5.77 (d, J=8.7 Hz, 1H), 4.08 (dd, J=24.7, 9.4 Hz, 3H), 3.82 (d, J=14.7 Hz, 1H), 3.78 (s, 3H), 3.77-3.59 (m, 4H), 3.37 (s, 1H), 3.00 (t, J=5.5 Hz, 1H), 2.70-2.56 (m, 1H), 2.14 (d, J=6.3 Hz, 1H), 1.92 (d, J=11.6 Hz, 1H), 1.76 (dd, J=19.8, 11.8 Hz, 2H), 1.64-1.49 (m, 8H).

Synthesis of 4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate Used in the Preparation of Compound 218

In a resealable vial, 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (1 g, 4.42 mmol) (CAS 946837-99-6) was combined with dicyanozinc (518 mg, 4.42 mmol) and tBuXPhos G4 (199 mg, 0.2210 mmol). The vessel was evacuated and backfilled with nitrogen three times. THF (2 mL) and water (10 mL) were added, and the solution stirred at 40 C 3 d. The mixture was partitioned between sat. NaHCO 3 and EtOAc. The organic layer was washed twice with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluting with ethyl acetate and heptanes) to yield 4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (407 mg, 2.36 mmol) as an off-white solid.

Synthesis of rel-(R)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline and rel-(S)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 219 and 220

Step a: To a solution of 4-methylquinoline (400 g, 2.79 mol, 370 mL, 1.00 eq) in toluene (2.00 L) was added Pd/C (40.0 g, 10.0% purity). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (3 MPa) at 120° C. for 32 h. TLC (Petroleum ether/Ethyl acetate=5/1) showed compound 1 (Rf=0.3) was consumed and the desired spot (Rf=0.7) was detected. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography eluted with Petroleum ether (Rf=0.7). 4-methyl-1,2,3,4-tetrahydroquinoline (900 g, 5.16 mol, 92.3% yield, 84.4% purity) was obtained as a light yellow oil. 1H NMR: 400 MHz CDCl3 7.11-7.09 (d, J=8.0 Hz, 1H), 7.02-6.98 (ddd, J=1.2, 7.4, 8.0 Hz, 1H), 6.69-6.65 (dt, J=1.2, 7.4 Hz, 1H), 6.52-6.50 (dd, J=1.2, 8.0 Hz, 1H), 3.88 (s, 1H), 3.39-3.30 (m, 2H), 2.98-2.93 (m, 1H), 2.05-2.01 (m, 1H), 1.76-1.66 (m, 1H), 1.34-1.33 (d, J=4.0 Hz, 3H).

Step b: To a solution of 4-methyl-1,2,3,4-tetrahydroquinoline (400 g, 1.00 eq, 84.4% purity) in DMF (1.20 L) was added NBS (428 g, 2.41 mol, 1.05 eq) in DMF (800 mL) drop-wise slowly at −20° C. The mixture was stirred at −20-0° C. for 0.5 h under a nitrogen atmosphere. TLC (Petroleum ether/Ethyl acetate=10/1) showed compound 2 (Rf=0.45) was consumed and the desired spot (Rf=0.4) was detected. The mixture was poured into water (6.00 L) then extracted with ethyl acetate (3.00 L*3). The combined organic layers were dried over Na2SO4, concentrated under vacuum. 946837-99-6 (570 g, crude) was obtained as brown oil. 946837-99-6 (700 g) was dissolved with ethyl acetate (1.50 L) and concentrated under vacuum. The residue was purified by silica gel chromatography (Petroleum ether-Petroleum ether/ethyl acetate=20/1, Rf=0.4). 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (230 g, 990 mmol, 97.4% purity) was obtained as an off-white solid. 1H NMR: 400 MHz CDCl3 7.15-7.14 (dd, J=0.8, 2.0 Hz, 1H), 7.05-7.02 (dd, J=2.0, 8.0 Hz, 1H), 6.36-6.34 (d, J=8.4 Hz, 1H), 3.87 (s, 1H), 3.35-3.25 (m, 2H), 2.93-2.85 (m, 1H), 1.97-1.93 (m, 1H), 1.68-1.64 (m, 1H), 1.29-1.27 (d, J=8.0 Hz, 3H).

›ABBREVIATIONS · 12 of 63

SFC: 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline was separated into its individual enantiomers by preparative SFC: Instrument: Thar 200 preparative SFC (SFC-20); Column: Chiral Cel OJ, 300×50 mm I.D., 10 μm; Mobile phase: A for C02 and B for ETOH; Gradient: B 20%; Flow rate: 240 mL/min; Back pressure: 100 bar; Column temperature: 38° C.; Wavelength: 220 nm; Cycle time: 3.7 min; Sample preparation: Compound was dissolved in ˜2300 mL; ETOH\DCM; Injection: 4 ml per injection; Ee values: faster eluting isomer: 99.7%; slower eluting isomer: 99.5%.

Synthesis of (R)-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate Used in the Preparation of Compound 219

A resealable reaction vial was charged with (4R)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (400 mg, 1.76 mmol), zinc dicarbonitrile (206 mg, 1.76 mmol), Pd/tBuXPhos G3 (69.9 mg, 0.08800 mmol), dioxane (6 mL) and water (0.5 mL). Nitrogen was bubbled through the mixture for 10 min before the vial was sealed and the mixture was stirred at 90° C. After 2.5 h, the reaction mixture was charged with further zinc dicarbonitrile (206 mg, 1.76 mmol) and Pd/tBuXPhos G3 (69.9 mg, 0.08800 mmol). After 18 h, the reaction was diluted with ethyl acetate, filtered, and concentrated in vacuo with silica gel. Purification by silica gel chromatography (eluting with ethyl acetate and heptanes) yielded (R)-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (250 mg) as a white fluffy solid. LCMS: [M+H]+ 173.

Synthesis of (4S)-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate for Compound 220

A solution of (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (1.9 g, 8.4 mmol), Zn(CN) 2 (2.0 g, 16.8 mmol), Pd2(dba)3 (614 mg, 0.67 mmol), dppf (743 mg, 1.3 mmol) and Zn (65 mg, 1.0 mmol) in DMF (100 mL) was stirred at 120° C. for 12 h under N2. The reaction mixture was concentrated and H2O (50 mL) was added, extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:20) to afford the product of (4S)-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (1.3 g, 90.2% yield) as a yellow solid. LCMS [M+H]+ 214.1.

Synthesis of 7-fluoro-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Intermediate for Compound 223

Step a: Adding ethanol (27.0 mL), 4-amino-2-fluorobenzonitrile (3.0 g, 22.0 mmol) and 2,3,5,6-tetrachloro-2,5-cyclohexadiene-1,4-dione (5.77 g, 23.5 mmol) to a 250 mL 3-neck-flask and stirred for 2-5 min under N 2 , then conc. HCl (5.5 mL, 66.0 mmol, 12 N) was added and stirred at 75° C. Diluted methyl vinyl ketone (2.31 g, 33.0 mmol) in EtOH (3.0 mL) was added slowly to reaction mixture over 30 min. The reaction mixture was stirred at 75° C. for 12 h. THF (33.0 mL) was added at 75° C., and stirred for 1 hour at 60° C. Cooled to room temperature and stirred for 1 additional hour. LCMS showed 40% desired product was detected. The reaction mixture was filtered, the filtered cake was washed with THF (100.0 mL) to give compound 3 (1.0 g) as a gray solid. Then the mixture was concentrated under reduced pressure. The residue was triturated by THF (50.0 mL). The filtered cake was wash with THF (50.0 mL) to give the compound 3a (2.0 g) as a gray solid.

Step b: A mixture of 7-fluoro-4-methylquinoline-6-carbonitrile (500.0 mg, 2.68 mmol), (R)-BINOL-phosphoric acid (46.6 mg, 134.0 μmol) and 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.62 g, 6.43 mmol) was stirred at 100° C. for 12 h. TLC (Petroleum ether/EtOAc=4:1) showed the starting material was consumed completely and one new spot with similar polarity was formed. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (EtOAc in Petroleum ether=0˜10%) to afford the racemic product of 7-fluoro-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (300 mg, 1.57 mmol) as a tan solid.

Synthesis of 3-(1,2,3,4-tetrahydro-1,6-naphthyridin-5-yl)oxazolidin-2-one, Used in the Preparation of Compound 225

Step a: A resealable reaction vial was charged with 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (200 mg, 1.18 mmol),THF (5 mL) and NaHMDS (258 mg, 1.41 mmol). After a few seconds, ppte crashed out. After 15 min, the reaction was charged with TsCl (268 mg, 1.41 mmol) and stirred at room temperature 18 h. The mixture was diluted with ethyl acetate and brine, and the organic layer was separated and concentrated in vacuo. 5-chloro-1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridine (165 mg) was isolated following purification by silica gel chromatography (eluting with ethyl acetate and heptanes). LCMS: [M+H]+ 323.

Step b: A resealable reaction vial was charged with 5-chloro-1-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydro-1,6-naphthyridine (165 mg, 0.5111 mmol), 1,3-oxazolidin-2-one (66.7 mg, 0.7666 mmol), Cs2CO3 (332 mg, 1.02 mmol), Pd/XantPhos G4 (49.1 mg, 0.05111 mmol) and dioxane (6 mL). The mixture was bubbled with nitrogen for 10 minutes, the vial was sealed and heated at 90° C. 18 h. The mixture was diluted with EA, filtered and pre-absorbed onto silica gel for purification by silica gel chromatography (eluting with 60-100% EA/hep). The main peak fractions were pooled and concentrated to yield 3-(1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-yl)oxazolidin-2-one (167 mg) as a light yellow foam. LCMS: [M+H]+ 374.

Step c: 3-[1-(4-methylbenzenesulfonyl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-yl]-1,3-oxazolidin-2-one (168 mg, 0.4498 mmol) was dissolved in H2SO4 (3 mL) and stirred at rt for 45 min. The reaction was slowly added to sat. bicarb then solid bicarb was added until gas evolution stopped. The aq. layer was extracted with ethyl acetate, dried over sodium sulfate, and concentrated in vacuo to yield the title compound, which was used without purification.

Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine, Intermediate Used in the Preparation of Compound 226

›ABBREVIATIONS · 13 of 63

Step a: A mixture of 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (110 mg, 0.6 mmol, CAS #98490-61-0), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (162 mg, 0.8 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (106 mg, 0.1 mmol) and K 2 CO 3 (224 mg, 1.6 mmol) in the solvent of dioxane (6 mL) and H 2 O (0.6 mL) was evacuated and refilled 3 times using N 2 . The mixture was stirred at 90° C. for 12 hours under N 2 . The reaction mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (DCM:MeOH=100:0 to 100:10) to give the product of 5-(1-methyl-1H-pyrazol-5-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine (100 mg, 71.9% yield) as a brown oil. LCMS m/z: 215.4 (M+H) + .

Synthesis of 1,2,3,4-tetrahydro-1,6-naphthyridine-5-carbonitrile, Intermediate Used in the Preparation of Compound 228

Step a: A round bottom flask was charged with 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (100 mg, 0.590 mmol) (CAS:98490-61-0) in THF (2.0 mL) and placed under an atmosphere of nitrogen before the addition of NaHMDS (1.0 M in THF, 1.18 mL, 1.18 mmol). The reaction stirred at ambient temperature for 15 min before the addition of tosyl chloride (225 mg, 1.18 mmol). After 5 min, the reaction was quenched by the addition of EtOAc and water. The organic layer was extracted with EtOAc (3×), concentrated and purified via silica gel chromatography (10-100% EtOAc in hexanes) to furnish 5-chloro-1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridine (100 mg, 0.310 mmol) in 53% yield. [M+H]+ 323.2.

Step b: A resealable vial was charged with furnish 5-chloro-1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridine (100 mg, 0.310 mmol), [(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)] palladium(II) methanesulfonate (25.0 mg, 0.031 mmol), and zinc dicyanide (44.0 mg, 0.372 mmol) before being evacuated and backfilled with nitrogen (3×). A mixture of H 2 O (0.8 mL) and THF (0.2 mL) was then added and the reaction was heated to 40° C. for 16 h. The reaction was cooled to ambient temperature and partitioned between EtOAc and sat. sodium bicarbonate. The organic layer was extracted with EtOAc (3×), dried, concentrated and purified via silica gel chromatography 85-66% EtOAc in hexanes) to provide 1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carbonitrile (61.0 mg, 0.195 mmol) in 63% yield. LCMS: [M+H]+ 314.2.

Step c: A round bottom flask containing 1-tosyl-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carbonitrile (61.0 mg, 0.195 mmol) was charged with sulfuric acid (1.15 mL). The reaction stirred at ambient temperature for 5 min before being slowly added to an Erlenmeyer flask containing sat. sodium bicarbonate till gas evolution ceased. The reaction was then partitioned between EtOAc and sat. sodium bicarbonate, and the organic layer was extracted with EtOAc (3×). Combined organic extracts were dried to yield 1,2,3,4-tetrahydro-1,6-naphthyridine-5-carbonitrile (25.0 mg, 0.157 mmol) which was used in subsequent steps without further purification. LCMS: [M+H]+ 160.2.

Synthesis of 4-(difluoromethylidene)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 231

Step a: A resealable reaction vial was charged with tert-butyl 4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 1.01 mmol), 2-difluoromethanesulfonylpyridine (162 mg, 0.8416 mmol) in DMF (10 mL). The solution was cooled to −50° C., and charged with (tert-butoxy)potassium (1.51 mL, 1.51 mmol) and stirred for 2 hrs at −40° C. The reaction was charged with sat. NH4Cl (2 mL) and 3N HCl (2 mL), warmed to rt and stirred for 0.5 hrs. The reaction was partitioned between ethyl acetate and brine. The org layer was dried, concentrated and the residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=0:100 to 15:85) to afford a colorless oil. The residue was dissolved in DCM (2 mL) and charged with TFA (1 mL) and stirred for 30 min. The solvent was removed to afford 4-(difluoromethylidene)-1,2,3,4-tetrahydroquinoline (45 mg) as a colorless oil. LCMS: [M+H] + 182.

Synthesis of 5-cyclopropyl-1,2,3,4-tetrahydro-1,6-naphthyridine, Intermediate Used in the Preparation of Compound 232

Step a: A round bottom flask containing 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (200 mg, 1.18 mmol) (CAS:98490-61-0) in THF (7.0 mL) was placed under an atmosphere of nitrogen before the addition of NaHMDS (1.0 M in THF, 2.40 mL, 2.40 mmol) at ambient temperature. Following the addition of di-tert-butyl dicarbonate (458 mg, 2.40 mmol) the reaction stirred at ambient temperature for 16 h. After the addition of EtOAc and water, the organic layer was extracted with EtOAc (3×), concentrated and purified via silica gel chromatography (isocratic, 25% EtOAc in hexanes) to furnish tert-butyl 5-chloro-3,4-dihydro-1,6-naphthyridine-1(2H)-carboxylate (277 mg, 1.03 mmol) as a white solid.

Step b: A reaction vial was charged with tert-butyl 5-chloro-3,4-dihydro-1,6-naphthyridine-1(2H)-carboxylate (138 mg, 0.510 mmol), cyclopropylboronic acid (88.0 mg, 1.02 mmol), palladium tetrakis (59.0 mg, 0.051 mmol) and K 2 CO 3 (281 mg, 2.04 mmol) and dissolved in dioxane (1.36 mL) and H 2 O (0.34 mL). The reaction was degassed for 5 min, before being heated to 100° C. for 16 h. Only partial conversion was observed, so the reaction was cooled and additional cyclopropylboronic acid (88.0 mg, 1.02 mmol) and palladium tetrakis (59.0 mg, 0.051 mmol) were added, the reaction was again sparged for 5 min before heating again to 100° C. for 4 h. Following cooling to ambient temperature, the reaction was partitioned between dichloromethane and water and the organic layer was extracted (3×), concentrated and purified via silica gel chromatography (5-50% EtOAc in hexanes) to provide tert-butyl 5-cyclopropyl-3,4-dihydro-1,6-naphthyridine-1(2H)-carboxylate (63.0 mg, 0.230 mmol) in 45% yield.

Step c: To a round bottom flask tert-butyl 5-cyclopropyl-3,4-dihydro-1,6-naphthyridine-1(2H)-carboxylate (63.0 mg, 0.230 mmol) in dichloromethane (2.3 mL) was added trifluoroacetic acid (0.175 mL) and the reaction was stirred at room temperature for 16 h. Solvent was evaporated and the residue was purified via silica gel chromatography (0-20% MeOH in dichloromethane with 0.1% NH 3 H 2 O) to 5-cyclopropyl-1,2,3,4-tetrahydro-1,6-naphthyridine (40 mg, 0.23 mmol) in quantitative yield. LCMS: [M+H]+ 175.2.

›ABBREVIATIONS · 14 of 63

Synthesis of 5-(difuoromethyl)-1,2,3,4-tetrahydro-1,6-naphthyridine, Used in the Preparation of Compound 236

Step a: SOCl2 (8.0 mL) was added in MeOH (20.0 mL) dropwise at 0° C. To the mixture was added 1,6-naphthyridine-5-carboxylic acid (1.0 g, 5.74 mmol) and stirred at 90° C. for 12 h. Orange solution was observed. Desired product was observed from LCMS. The mixture was concentrated in vacuum. The residue was added in saturated NaHCO 3 (10.0 mL) and then extracted with EtOAc (10.0 mL×2). The combined organic layers were concentrated in vacuum to give methyl 1,6-naphthyridine-5-carboxylate (1.0 g, crude) as a yellow solid.

Step b: To a solution of methyl 1,6-naphthyridine-5-carboxylate (300.0 mg, 1.59 mmol) in THF (10.0 mL) at −78° C. under N2 was added DIBAL-H (2.38 mL, 2.38 mmol). The mixture was stirred at −78° C. for 1 h. TLC (petroleum ether:EtOAc=1:1) showed starting material consumed and new spot was formed. To the mixture was added 10% AcOH (15.0 mL) and extracted with EtOAc (20.0 mL×2). The combined organic layers were washed NaHCO 3 (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give 1,6-naphthyridine-5-carbaldehyde (300.0 mg, crude) as a yellow solid. The solid was used in the next step without further purification.

Step c: To a solution of 1,6-naphthyridine-5-carbaldehyde (300.0 mg, 1.89 mmol) in DCM (10.0 mL) at 0° C. under N2 was added DAST (611.0 mg, 3.78 mmol). The mixture was stirred at 0° C. for 1 h. Orange solution was observed. To the mixture was added saturated NaHCO 3 (10.0 mL) and extracted with DCM (10.0 mL×2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give crude product as orange gum. The residue was purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether from 0% to 20%) to give 5-(difluoromethyl)-1,6-naphthyridine (120.0 mg, 35.2% yield) as an orange oil.

Step d: A solution of 5-(difluoromethyl)-1,6-naphthyridine (120.0 mg, 666 μmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (402.0 mg, 1.59 mmol) and diphenoxyphosphinic acid (33.2 mg, 133.0 umol) in dioxane (5.0 mL) was stirred at 90° C. for 12 h under N2. Yellow solution was observed. TLC (petroleum ether:EtOAc=2:1) showed new spots were observed. The solution was concentrated in vacuum to remove solvent. The residue was purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether from 0% to 30%) to give the product of 5-(difluoromethyl)-1,2,3,4-tetrahydro-1,6-naphthyridine (90.0 mg, 73.7% yield) as a yellow oil.

Synthesis of 6-(3,6-dihydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 237

Step a: A resealable reaction vial was charged with 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (250 mg, 1.17 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (367 mg, 1.75 mmol), tetrakis(triphenylphosphane) palladium (135 mg, 0.117 mmol), dipotassium carbonate (485 mg, 3.51 mmol), dioxane (9 mL) and water (1 mL). The mixture was bubbled with nitrogen for 5 min, the vial was sealed, and the mixture was stirred at 90° C. for 16 hrs. The reaction was poured in brine, extracted with ethyl acetate, dried and purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=20:80 to 80:20) to afford 6-(3,6-dihydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (250 mg) as a brown oil. LCMS: [M+H] + 217.

Synthesis of 6-(oxan-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 239

Step a: 6-(3,6-dihydro-2H-pyran-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (100 mg, 0.4623 mmol) was dissolved in MeOH and ethyl acetate (1/1, 10 mL). The solution was pumped through a 10% Pd/C cartridge at 1 mL/min under 5 bars of H 2 at RT for 60 min. The solvent was removed to afford 6-(oxan-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (95 mg) as a light yellow solid. LCMS: [M+H] + 219.

Synthesis of 6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one, Used in the Preparation of Compound 240

Step a: 1,6-naphthyridine (0.965 g, 7.41 mmol) was dissolved in MeOH (8.5 mL) and charged with iodomethane (921 μL, 14.8 mmol). The vial was sealed and heated to 65° C. and stirred for 16 hrs. The solvent was removed, the residue taken up in a small amount of MeOH (1-2 mL) and ethyla acetate was charged. The mixture was filtered, washed with EA and air dried to constant weight to afford 6-methyl-1,6-naphthyridin-6-ium iodide (1.56 g).

Step b: 6-methyl-1,6-naphthyridin-6-ium iodide (1.56 g, 5.73 mmol) was suspended in water (10 mL) and cooled to 0° C. The reaction was charged with NaOH (1.25 g, 31.5 mmol) in water (10 mL) and tripotassium hexakis(iminomethanide) iron (4.04 g, 12.3 mmol) in water (10 mL). The solution was stirred for 1 hr at 0° C. then overnight at rt. The mixture was extracted with CHCl 3 , dried and concentrated. The residue was purified by flash silica gel chromatography (eluting with MeOH:DCM=0:100 to 10:90) to afford 6-methyl-5,6-dihydro-1,6-naphthyridin-5-one (540 mg) as a light yellow solid. LCMS: [M+H] + 161.

Step c: 6-methyl-5,6-dihydro-1,6-naphthyridin-5-one (109 mg, 0.6805 mmol) was dissolved in MeOH (10 mL). The solution was pumped a 10% Pd/C cartridge at 1 mL/min under 70 bars of H 2 at 70° C. for 90 min. Solvent was removed to afford 6-methyl-1,2,3,4,5,6-hexahydro-1,6-naphthyridin-5-one (90 mg) as a white solid. LCMS: [M+H] + 165.

Synthesis of 4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine, Intermediate Used in the Preparation of Compound 245

Lithium aluminum hydride (1.0 M in THF, 2.46 mL, 2.46 mmol) was added to a microwave vial under an atmosphere of nitrogen before the slow addition of 4-methyl-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (200 mg, 1.23 mmol) (CAS: 1314974-86-1) in THF (2.0 mL). Following addition, the reaction was heated to 65° C. for 5 h until consumption of the starting material by TLC (EtOAc). Following slow addition of 1N NaOH, the reaction was filtered through celite, rinsing with dichloromethane to yield 4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (174 mg) which was used without further purification. LCMS: [M+H]+ 150.2.

›ABBREVIATIONS · 15 of 63

Synthesis 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile, Intermediate Used in the Preparation of Compound 248

5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile is commercially available (CAS: 1219022-67-9).

Synthesis of 4-methyl-1H,2H,3H,4H-pyrido[3,4-b]pyrazin-3-one, Used in the Synthesis of Compound 249

Step a: 1H,2H,3H,4H-pyrido[3,4-b]pyrazin-3-one (113 mg, 0.7576 mmol) was suspended in DMF (5 mL) and charged with sodium hydride (30.1 mg, 0.7576 mmol). The mixture was stirred for 30 min (came solution) and iodomethane (46.9 μL, 0.7576 mmol) was added and stirred at rt for 30 min. The reaction concentrated and the residue purified on Prep-HPLC (5-10% ACN/Water+0.1% NH 4 OH) to afford 4-methyl-1H,2H,3H,4H-pyrido[3,4-b]pyrazin-3-one (18 mg) as a white solid. LCMS: [M+H] + 164.

Synthesis of 4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline, Used in the Synthesis of Compound 250

Step a: Quinoline-4-carbaldehyde (1 g, 6.36 mmol) in DCM (20 mL) was cooled to 0° C., and charged with DAST (2.56 g, 15.9 mmol). The mixture was stirred for 1 hr at 0° C. then let warm to rt and stirred for 20 hrs. The reaction mixture was cooled to −10° C. carefully quenched with sat. bicarb and extracted with DCM. The organic layer was concentrated and purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=25:75 to 50:50) to afford 4-(difluoromethyl)quinoline (890 mg) as a colorless oil that crystallized to a white solid upon standing. LCMS: [M+H] + 180.

Step b: A resealable reaction vial was charged with 4-(difluoromethyl)quinoline (435 mg, 2.42 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.53 g, 6.05 mmol), diphenoxyphosphinic acid (30.2 mg, 0.121 mmol), toluene (6 mL). The vial was sealed the mixture was stirred at 50° C. for 20 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=0:100 to 30:100) to afford 4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline (375 mg) as a colorless oil. LCMS: [M+H] + 184.

Synthesis of 4-(oxan-4-yl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 251

Step a: A resealable reaction vial was charged with 4-bromoquinoline (250 mg, 1.20 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (504 mg, 2.40 mmol), tetrakis(triphenylphosphane) palladium (138 mg, 0.1199 mmol) and dipotassium carbonate (331 mg, 2.40 mmol). Evacuated and backfilled with N 2 (3×). Added dioxane (9 mL) and water (1 mL). Stirred at 90 C for 12 h. The reaction was poured in water/brine, extracted with EA, dried and purified by flash silica gel chromatography using 50-100% EtOAc in heptanes to give 4-(3,6-dihydro-2H-pyran-4-yl)quinoline (224 mg, 1.06 mmol) as a yellow oil.

Step b: Circulated a solution of 4-(3,6-dihydro-2H-pyran-4-yl)quinoline (224 mg, 1.06 mmol) in MeOH (10 mL) on H-Cube (10% Pd/C, 70 C, 70 bar, 1 mL/min) at 70 C/70 bar for 1 h. Concentrated and purified by flash silica gel chromatography w/0-100% EtOAc. Combined fractions and concentrated to give 4-(oxan-4-yl)-1,2,3,4-tetrahydroquinoline (155 mg, 0.7132 mmol) as a white solid.

Synthesis of Synthesis of 6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 252

Step a: To a solution of 2-chloro-4a,8a-dihydro-1,5-naphthyridine (300 mg, 1.80 mmol) in toluene (30 ml) was added 1H-pyrazole (183 mg, 2.70 mmol), CuI (34.2 mg, 180 μmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (128 mg, 900 umol) and K2CO3 (496 mg, 3.60 mmol), the mixture was stirred at 110° C. for 12 hours under N2. LCMS showed the product formed. The reaction was concentrated to dryness. The resulting crude material was purified by silica gel chromatography (eluent:Petroluem ether/Ethyl acetate=2:1) to give 2-(1H-pyrazol-1-yl)-4a,8a-dihydro-1,5-naphthyridine (310 mg, 1.56 mmol) as a white solid.

Step b: A solution of 2-(1H-pyrazol-1-yl)-1,5-naphthyridine (100 mg, 509 μmol), diphenoxyphosphinic acid (25.2 mg, 101 μmol) and 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (385 mg, 1.52 mmol) in toluene (10 mL) was stirred at 80° C. for 12 hours under N2. TLC (Petroleum ether:EtOAc=1:1) showed the reaction was complete. The mixture was concentrated and purified by flash silica gel chromatography (Petroleum ether:EtOAc=5:1 to 2:1) to afford the product of 6-(1H-pyrazol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (30.0 mg, 149 μmol, 29.7% yield) as a colorless oil.

Synthesis of Synthesis of 6-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Used in the Preparation of Compound 259

Step a: A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.6 mmol), DHP (280 mg, 3.3 mmol), TFA (58.6 mg, 514 μmol) in tolunene (15 mL) was stirred at 90° C. for 2 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed the reaction was consumed completely. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (40 mL) and sat. NaHCO 3 (20 mL) and separated, the aqueous layer was extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum: 15% to 30%) to afford the product of 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (490 mg, 68.6% yield) as a colorless oil.

Step b: A mixture of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (250 mg, 1.2 mmol), 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (486 mg, 1.8 mmol), Pd(dppf)Cl2.CH2Cl2 (142 mg, 175 μmol) and K2CO3 (402 mg, 2.9 mmol) in dioxane (15 mL)/H2O (3 mL) was stirred at 90° C. for 12 hours under N2 atmosphere. The reaction mixture was concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether: 75% to 85%) to afford the product of 6-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine (280 mg, 84.3% yield) as a yellow oil.

›ABBREVIATIONS · 16 of 63

Synthesis of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine, A-Ring for Compound 260

Step a: A solution of 2-chloro-1,5-naphthyridine (900 mg, 5.5 mmol), diphenoxyphosphinic acid (272 mg, 1.1 mmol) and 2-[5-(ethoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyloxy]ethylium (4.1 g, 16.3 mmol) in toluene (50 ml). The reaction mixture was evacuated and refilled for 3 times using N 2 . The mixture was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (Petroleum ether:EtOAc=100:0 to 100:20) to afford the product of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (780 mg, 84% yield) as an off-white solid.

Synthesis of (4S)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline and (4R)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 277 and Compound 278

Step a: A mixture of 5-bromo-2,3-dihydroquinolin-4(1H)-one, CAS 1391268-61-3 (950.0 mg, 4.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g, 5.9 mmol), Pd(dppf)Cl 2 (307.0 mg, 0.4 mmol) and K 2 CO 3 (1.2 g, 8.4 mmol) in dioxane (12.0 mL)/H 2 O (4.0 mL) was stirred at 90° C. for 12 hours under N 2 atmosphere. The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum: 100%) to afford the product of 5-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydroquinolin-4(1H)-one (935.0 mg, 98.0% yield) as a yellow solid.

Step b: To a mixture of Ph 3 PCH 3 Br (1.6 g, 4.6 mmol) in THF (10.0 mL) at 0° C. was added t-BuOK (5.5 mL, 5.5 mmol, 1.0 M in THF), the resulting mixture was stirred at this temperature for 0.5 hour. 5-(1-Methyl-1H-pyrazol-4-yl)-2,3-dihydroquinolin-4(1H)-one (420.0 mg, 1.8 mmol) in THF (5.0 mL) was added drop-wise at 0° C. The reaction mixture was warmed to 25° C., and stirred for 2.5 hours. The reaction mixture was diluted with H 2 O (25.0 mL), washed with ethyl acetate (30.0 mL×2). The organic phase was washed with brine (15.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum: 60% to 75%). to afford the product of 5-(1-methyl-1H-pyrazol-4-yl)-4-methylene-1,2,3,4-tetrahydroquinoline (600.0 mg, combined batches) as a white solid.

Step c: To a mixture of 5-(1-methyl-1H-pyrazol-4-yl)-4-methylidene-1,2,3,4-tetrahydroquinoline (530.0 mg, 2.4 mmol) in EtOH (15.0 mL) was added Pd/C (83.1 mg, 10 wt % wet), and the resulting mixture was stirred at 25° C. for 12 hours under H 2 (15 psi.). The reaction mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether: 60% to 80%) to afford the product of 4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (380.0 mg, 71.1% yield) as a white solid.

Step d: 4-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (95.0 mg, 417.0 μmol) was separated by chiral SFC (Column: ChiralPak AY-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO 2 B: Methanol (0.05% DEA) Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min Flow rate: 2.5 mL/min Column temperature: 40° C.) to afford the product of (4S)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (45.0 mg, 47.5% yield) as a white solid and (4R)-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (45.0 mg, 47.5% yield) as a white solid. The absolute configuration was arbitrarily assigned.

Synthesis of 6-(1H-1,2,4-triazol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 279

Step a: To the mixture of 4H-1,2,4-triazole (31.3 mg, 0.45 mmol) and 2-chloro-1,5-naphthyridine (50.0 mg, 0.3 mmol) in DMF (2.0 mL) was added Cs 2 CO 3 (0.42 g, 1.30 mmol) under N 2 . The mixture was stirred at 100° C. under N 2 for 12 hrs. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 1/1) to give the product of 2-(1H-1,2,4-triazol-1-yl)-1,5-naphthyridine (50.0 mg, 83.7% yield) as a white solid.

Step b: To the mixture of 2-(1H-1,2,4-triazol-1-yl)-1,5-naphthyridine (50 mg, 0.25 mmol) and BINOL-phosphoric acid (8.81 mg, 25.3 μmol) in toluene (4.0 mL) was added diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (160 mg, 0.63 mmol). The mixture was stirred at 100° C. under N 2 for 12 hrs. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 1/1) to give the product of 6-(1H-1,2,4-triazol-1-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (40.0 mg, 78.8% yield) as an off-white solid.

Synthesis of 6-(pyridazin-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 305

Step a: To a solution of pyridazine (1.10 g, 13.7 mmol) and tributyl(chloro)stannane (4.88 g, 15.0 mmol) in THF (10.0 mL) was added LDA (2.0 M in THF, 6.85 mL, 13.7 mmol) drop-wise at −70° C. under N 2 . Then the mixture was stirred at −70° C. for 1 hour. The reaction was quenched with saturated NH 4 Cl (50.0 mL) and extracted with EtOAc (50.0 mL×3). The organic layers were dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc in Petroleum ether=0˜30%) to afford 4-(tributylstannyl)pyridazine (2.60 g, 7.04 mmol, 51.0% yield) as a light yellow oil.

Step b: A mixture of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (100.0 mg, 593.0 μmol), 4-(tributylstannyl)pyridazine (262.0 mg, 711.0 μmol) and Pd(PPh 3 ) 4 (136.0 mg, 118.0 μmol) in toluene (5.0 mL) was stirred at 110° C. for 14 hours under N 2 . LCMS showed the starting material was consumed completely and 60% of desired product was found. The mixture was poured into water (50.0 mL) and extracted with EtOAc (50.0 mL×3), the organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc in Petroleum ether=0˜100%) to afford 6-(pyridazin-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (55.0 mg, crude) as a yellow solid. LCMS m/z: 213.4 (M+H) + .

›ABBREVIATIONS · 17 of 63

Synthesis of 5-(morpholin-4-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine, Used in the Preparation of Compound 307

Step a: 5-Chloro-1,6-naphthyridine (200.0 mg, 1.2 mmol, CAS #23616-32-2) and morpholine (315.0 mg, 3.6 mmol) were added in dioxane (3.0 mL), the reaction mixture was stirred at 130° C. for 2 hours under microwave. The reaction mixture was concentrated under reduced pressure to give a residue and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:70) to afford 5-(morpholin-4-yl)-1,6-naphthyridine (200.0 mg, 77% yield) as a yellow solid.

Step b: 5-(Morpholin-4-yl)-1,6-naphthyridine (200.0 mg, 929.0 μmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (516.0 mg, 2.0 mmol) and BINOL-phosphoric acid (64.4 mg, 185.0 μmol) were added in dioxane (10.0 mL). The reaction mixture was evacuated and refilled 3 times with N 2 and stirred at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 0:100) to afford the 5-(morpholin-4-yl)-1,2,3,4-tetrahydro-1,6-naphthyridine (120.0 mg, 96% purity, 56.6% yield) as a yellow solid. LCMS m/z: 220.0 (M+H) + .

Synthesis of 6-(4H-1,2,4-triazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 308

Step a: A solution of 2-chloro-1,5-naphthyridine (600.0 mg, 3.6 mmol), Cu(OAc) 2 (66.1 mg, 364.0 umol) and 28% aq. ammonia (4.53 g, 36.4 mmol) in NMP (2.0 mL) in sealed tube was heated to 150° C. for 12 hours. The reaction mixture was poured into water (30.0 mL). The precipitate was collected by filtration and dried in vacuo to give 1,5-naphthyridin-2-amine (420.0 mg, 79.5% yield) as a light blue solid.

Step b: A solution of (E)-N′—[(E)-N′—[(N,N-dimethylamino)methylidene]amino]-N,N-dimethylmethanimidamide dihydrochloride (589.0 mg, 2.7 mmol) and 1,5-naphthyridin-2-amine (200.0 mg, 1.4 mmol) in pyridine (10.0 mL) was stirred at 100° C. for 12 hours. The reaction mixture was evaporated in vacuo. The residue was purified by silica gel column (MeOH in EtOAc=0˜10%) to give 2-(4H-1,2,4-triazol-4-yl)-1,5-naphthyridine (220.0 mg, 81.4% yield) as a white solid.

Step c: A mixture of 2-(4H-1,2,4-triazol-4-yl)-1,5-naphthyridine (200.0 mg, 1.0 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (536.0 mg, 2.1 mmol) and BINOL-phosphoric acid (35.1 mg, 101.0 umol) in dioxane (50.0 mL) was stirred at 110° C. for 6 hours. The reaction mixture was evaporated in vacuo. The residue was purified by silica gel column (MeOH in EtOAc=0˜10%) to give 6-(4H-1,2,4-triazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (160.0 mg, 78.8% yield) as a yellow solid.

Synthesis of 5-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,6-naphthyridine, Used in the Preparation of Compound 289

Step a: A mixture of 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (100 mg, 593 μmol, CAS #98490-61-0), 1-(oxan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (197 mg, 711 μmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (96.3 mg, 118 μmol) and K 2 CO 3 (162 mg, 1.2 mmol) in dioxane (12 mL)/H 2 O (3 mL) was stirred at 90° C. for 12 hours under N 2 atmosphere. The reaction mixture was diluted with ethyl acetate (25 mL), and washed with H 2 O (20 mL×2). The organic phase was washed with brine (15 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (Methanol in Dichloromethane: 10% to 20%, 0.5% NH 3 .H 2 O) to afford the product of 5-[1-(oxan-2-yl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,6-naphthyridine (115 mg, 68.4% yield) as a brown oil. LCMS m/z: 285.4 (M+H) + .

Synthesis of 6-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 297

Step a: To a solution of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (1 g, 5.9 mmol) in THF (20 mL) at 0° C. under N 2 was added NaHMDS (11.8 mL, 11.8 mmol, 1M in THF). The mixture was stirred at 0° C. for 1 h. Then to the mixture was added Boc 2 O (1.9 g, 8.9 mmol). The mixture was stirred at 25° C. for 4 h. The reaction was quenched by addition of sat. NH 4 Cl (20 mL) and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 20/100) to give product of tert-butyl 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (500 mg, 31.4% yield) as a yellow solid.

Step b: A solution of tert-butyl 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (500 mg, 1.8 mmol), Pd(dppf)Cl 2 (340 mg, 0.5 mmol) and TEA (0.8 mL, 5.6 mmol) in MeOH (15 mL) was stirred at 80° C. for 48 h under CO (50 psi). The solution was concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 50/100) to give the product of 1-tert-butyl 6-methyl 1,2,3,4-tetrahydro-1,5-naphthyridine-1,6-dicarboxylate (340 mg, 62.6% yield) as an off-white solid.

Step c: To a solution of 1-tert-butyl 6-methyl 1,2,3,4-tetrahydro-1,5-naphthyridine-1,6-dicarboxylate (340 mg, 1.2 mmol) in THF (10 mL) was added DIBAL-H (1.7 mL, 1.7 mmol, 1M in toluene) at −78° C. under N 2 . The solution was stirred for 2 hours at −78° C. The reaction was quenched by a solution of 10% aqueous AcOH (20 mL) at −78° C. and the mixture was extracted with EtOAc (30 mL×3). The combined organic layers were adjusted pH to 8-9 with sat.NaHCO 3 and separated. The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 100/100) to give the product of tert-butyl 6-formyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (220 mg, 72.3% yield) as a white solid.

›ABBREVIATIONS · 18 of 63

Step d: The compound of tert-butyl 6-formyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (220 mg, 0.8 mmol) was placed in DCM (10 mL). DAST (0.3 mL, 2.1 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour. The mixture was concentrated to give the product tert-butyl 6-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (120 mg, crude product) as a yellow solid

Step e: The compound of tert-butyl 6-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (120 mg, 0.4 mmol) was dissolved in HCl/MeOH (10 mL, 2N). The mixture was stirred at 25° C. for 12 h. The mixture was concentrated to give a residue. The residue was diluted with MeOH (5 mL) and DCM (5 mL). The pH was adjusted to 8-9 by addition of NaHCO 3 (s). The mixture was filtered and concentrated to give the product of 6-(difluoromethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine (75.0 mg, crude product) as a yellow solid.

Synthesis of 6-(pyrimidin-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 304

Step a: A solution of of 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine CAS: 1196151-85-5 (150 mg, 0.9 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (218 mg, 1.1 mmol), Pd(dppf)Cl 2 ′CH 2 Cl 2 (144 mg, 0.2 mmol) and K 2 CO 3 (306 mg, 2.2 mmol) in dioxane (6.0 mL) and H 2 O (0.6 mL) was evacuated and refilled 3 times using N 2 . The mixture was stirred at 90° C. for 12 hours under N 2 . The reaction mixture was concentrated to give a residue which was diluted with EtOAc (20 mL) and H 2 O (20 mL) and the partitioned layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue which was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 80/100) to give 6-(pyrimidin-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (180 mg, 96% yield) as a brown solid. LCMS m/z: 213.4 (M+H) + .

Synthesis of Synthesis of (4R)-4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile and (4S)-4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 326 and Compound 327

Step a: The compound of 4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (100 mg, 0.5 mmol) was separated by chiral SFC (Column: ChiralCel OD-3 150×4.6 mm I.D., 3 um. Mobile phase: A: CO2 B: Methanol (0.05% DEA), Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL/min, Column temperature: 40° C.) to give the product of (4R)-4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (34.6 mg, 34.6% yield) as a white solid and (4S)-4-(difluoromethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (28.5 mg, 28.5% yield) as a white solid. The absolute configuration was assigned randomly.

Synthesis of 5,6,7,8-tetrahydropteridin-7-one, for Use in the Preparation of Compound 322

Step a: Pyrimidine-4,5-diamine (990 mg, 8.99 mmol) and sodium acetate (1.39 g, 17.0 mmol) was suspended in water (9 mL) and 5N aqueous AcOH (2.23 mL, 11.2 mmol). The mixture was charged with methyl 2-hydroxy-2-methoxyacetate (1.60 g, 13.4 mmol) and heated to 90° C. for 1 hr. The mixture was cooled, pH was adjusted to 2 with 5H H 2 SO 4 , filtered, washed with water and air dried to constant weight to afford 7,8-dihydropteridin-7-one (960 mg) a light orange solid. LCMS: [M+H] + 149.

Step b: 7,8-dihydropteridin-7-one (60 mg, 0.4050 mmol) was dissolved in MeOH (10 mL) then pumped through a Raney-Ni cartridge at 1 mL/min, under 5 bar of H 2 at 50° C. for 90 min. Solvent was removed, chased with toluene to afford 5,6,7,8-tetrahydropteridin-7-one (60 mg) as a light yellow solid. LCMS: [M+H] + 151.

Synthesis of 1-(7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one, Intermediate Used in the Preparation of Compound 323

Step a: To a round bottom flask containing 1-(3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (192 mg, 1.09 mmol) (CAS: 6639-92-5) was added ACN (1.5 mL) before it was cooled to 0° C. A solution of N-bromosuccinimide (192 mg, 1.09 mmol) in ACN (1.7 mL) was added and the reaction stirred at 0° C. for 5 min before adding sat. Na 2 S 2 O 3 at the same temperature. The reaction was warmed to ambient temperature and Et 2 O was added. The organic layer was extracted with Et 2 O (3×), and combined organic extracts were dried, concentrated and purified via silica gel chromatography (18-100% EtOAc in hexanes) to provide 1-(7-bromo-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (194 mg, 0.760 mmol) in 70% yield, along with the dibrominated analog, which was not isolated. LCMS: [M+] 255.1 and 257.1.

Step b: A reaction vial containing 1-(7-bromo-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (72 mg, 0.29 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (97.0 mg, 0.47 mmol), palladium tetrakis (33.5 mg, 0.0.29 mmol) and K 2 CO 3 (120 mg, 0.87 mmol) was charged with dioxane (0.80 mL) and H 2 O (0.20 mL). The reaction was degassed for 5 min, before being heated to 95° C. for 16 h. Following cooling to ambient temperature, the reaction was filtered through celite, rinsing with dichloromethane. The residue was concentrated and purified via silica gel chromatography (0-20% MeOH in dichloromethane with 0.1% NH 3 H 2 O) to furnish 1-(7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1(2H)-yl)ethan-1-one (28.0 mg, 0.110 mmol) in 38% yield. LCMS: [M+H]+ 257.2.

Synthesis of 5-methanesulfonyl-6-methyl-1,2,3,4-tetrahydroquinoline, for Use in the Preparation of Compound 345 and 5-methanesulfonyl-6-phenyl-1,2,3,4-tetrahydroquinoline, for Use in the Preparation of Compound 346

Step a: 5-methanesulfonyl-1,2,3,4-tetrahydroquinoline (505 mg, 2.39 mmol) in DMF (5 mL) was cooled to 0° C., and charged with 1-bromopyrrolidine-2,5-dione (425 mg, 2.39 mmol) in DMF (1 mL). The resulting solution was stirred at 0° C. for 1 h. The mixture was charged with water and extracted with ethyl acetate, dried and concentrated. The residue purified on C18 (20-50% ACN/water+0.1% FA) to afford 6-bromo-5-methanesulfonyl-1,2,3,4-tetrahydroquinoline (300 mg) as a yellow solid. LCMS: [M+H] + 290.

›ABBREVIATIONS · 19 of 63

Step b: A resealable reaction vial was charged with 6-bromo-5-methanesulfonyl-1,2,3,4-tetrahydroquinoline (125 mg, 0.4307 mmol), trimethyl-1,3,5,2,4,6-trioxatriborinane (81.0 mg, 0.6460 mmol), tetrakis(triphenylphosphane) palladium (49.7 mg, 0.04307 mmol), disodium carbonate (68.4 mg, 0.6460 mmol), and dioxane/water (5/1, 6 mL). The mixture was stirred at 90° C. for 16 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=20:80 to 50:50) to afford 2 product isolated separately: 5-methanesulfonyl-6-methyl-1,2,3,4-tetrahydroquinoline (25 mg) (LCMS: [M+H] + 226) and 5-methanesulfonyl-6-phenyl-1,2,3,4-tetrahydroquinoline (25 mg) (LCMS: [M+H] + 288) as colorless oils.

Synthesis of 1-(3,4-dihydroquinoxalin-1(2H)-yl)propan-1-one, Intermediate Used in the Preparation of Compound 360 and Compound 193

Step a: A reaction vial was charged with tert-butyl 1,2,3,4-tetrahydroquinoxaline-1-carboxylate (150 mg, 0.640 mmol) in DMF (6.4 mL) and TEA (0.356 mL) was added, followed by propanoyl chloride (0.070 mL, 0.768 mmol). The reaction was stirred at ambient temperature for 45 min before the addition of EtOAc and sat. sodium bicarbonate. The organic layer was extracted with EtOAc (3×), and the combined organic extracts were concentrated and purified via silica gel chromatography (10-100% EtOAc in hexanes) to yield tert-butyl 4-propionyl-3,4-dihydroquinoxaline-1(2H)-carboxylate, which was isolated contaminated with unreacted starting material, and was carried on to the subsequent step as this mixture.

Step b: To a vial containing tert-butyl 4-propionyl-3,4-dihydroquinoxaline-1(2H)-carboxylate in dichloromethane (4.0 mL) was added trifluoroacetic acid (0.5 mL). The reaction was stirred at ambient temperature for 45 min before being concentrated and purified via silica gel chromatography (10-100% EtOAc in hexanes) to yield 1-(3,4-dihydroquinoxalin-1(2H)-yl)propan-1-one (76.0 mg, 0.400 mmol) in 61% yield over two steps. LCMS: [M+H]+ 191.1.

Synthesis of 6-(4-methyl-1,3-thiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 361

Step a: 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (200 mg, 0.9386 mmol), XPhos G4 (161 mg, 0.1877 mmol) and Pd2(dba)3 (171 mg, 0.1877 mmol) were added to a reaction vial. Vial was evacuated and backfilled with N 2 (3×). Added dioxane (3 mL) followed by 4-methyl-2-(tributylstannyl)-1,3-thiazole (364 mg, 0.9386 mmol). Stirred at 100 C for 4 h. Partitioned between EtOAc and water. Separated layers, washed with EtOAc (2×). Combined organic layers, dried over Na 2 SO 4 , filtered and concentrated. Purified by flash silica gel chromatography using 0-100% EtOAc in heptanes to give 6-(4-methyl-1,3-thiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (89.0 mg, 0.3847 mmol) as a yellow powder. LCMS: [M+H] 232.28.

Synthesis of (R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine and (S)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 362

6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (24.00 g, 105.0 mmol) was separated by preparative SFC (column: DAICEL CHIRALPAK AD(250 mm×50 mm, 10 um), Mobile phase: 0.1% NH3.H2O, EtOH (Begin B: 25%, End B: 25%), Flow rate: 200 mL/min, Injections: 500) to afford the product of rel-(S)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (11.30 g, 49.7 mmol, Rt=3.08 min, the faster eluting isomer) as a yellow solid and rel-(R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (11.0 g, 48.4 mmol, Rt=3.77 min, the slower eluting isomer) as a yellow solid. Stereochemical assignments were made arbitrarily. Based on the data from analogs made with each compound, it was determined that the later-eluting compound led to more active analogs. LCMS: [M+H]+ 228.7.

1-cyclopropyl-8-methyl-1,2,3,4-tetrahydroquinoxaline, Intermediate Used in the Preparation of Compound 379

1-Cyclopropyl-8-methyl-1,2,3,4-tetrahydroquinoxaline is commercially available (CAS: 1553271-94-5).

Synthesis of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline, for Compound 381

Step a: To the mixture of 4-bromo-2-fluoro-1-nitrobenzene (25.0 g, 113.0 mmol) in MeOH (100.0 mL) and THF (50.0 mL) was added MeNH2 (67.5 mL, 135.0 mmol, 2 M in THF) dropwise. The mixture was stirred at 10° C. for 12 hours. TLC (petroleum ether/EtOAc=10/1) showed a new spot formed and major of 1 remained. MeNH2 (60.0 mL, 2 M in THF) was added to the mixture and the mixture was stirred at 45° C. for 12 hours. The mixture was concentrated in vacuum to give residue. Water (200.0 mL) added to the mixture and the mixture was extracted with EtOAc (200.0 mL×2). The organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum to give the product of 5-bromo-N-methyl-2-nitroaniline (25.5 g, 97.7% yield) as a yellow solid.

Step b: To the mixture of 5-bromo-N-methyl-2-nitroaniline (10.0 g, 43.2 mmol) in MeOH (150.0 mL) was added sodium dithionite (67.5 g, 388.0 mmol) in H2O (60.0 mL) dropwise. The mixture was stirred at 60° C. for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was extracted with EtOAc (200.0 mL×3), the organic layers were washed with H2O (100.0 mL) and brine (100.0 mL), dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated in vacuum to give the product of 5-bromo-N1-methylbenzene-1,2-diamine (8.60 g, crude) as a brown oil.

Step c: A mixture of 5-bromo-N1-methylbenzene-1,2-diamine (1.0 g, 4.97 mmol), 1,2-dibromoethane (2.13 mL, 24.8 mmol) and TBAB (4.80 g, 14.9 mmol) was stirred at 60° C. for 12 hours. The mixture was concentrated in vacuum and purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 2/1) to give the product of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (233.0 mg, 20.8% yield) as a brown solid.

Step d: To the mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (100.0 mg, 0.44 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137.0 mg, 0.66 mmol) in dioxane (5.0 mL) and H2O (1.0 mL) was added Pd(dppf)Cl2 (32.1 mg, 44 umol) and K3PO4 (205.0 mg, 0.97 mmol) under N2. The mixture was stirred at 100° C. under N2 for 12 hours. The mixture was concentrated in vacuum and purified by flash silica gel (petroleum ether/EtOAc=1/0 to 1/1) to give the product of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline (35.9 mg, 35.9% yield) as a yellow oil. LCMS 229.1 [M+H]+

›ABBREVIATIONS · 20 of 63

Synthesis of 6-(5-methyl-1,3-thiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 382

Step a: To a solution of 2-chloro-1,5-naphthyridine (1.0 g, 6.1 mmol, 1.0 eq) and Sn 2 Me 6 (3.0 g, 9.1 mmol, 1.5 eq) in toluene (15 mL) was added Pd(PPh 3 ) 4 (2.1 g, 1.8 mmol, 0.3 eq). The mixture was stirred at 60° C. for 10 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The reaction mixture will be used in the next step directly without further purification.

Step b: To a solution of 2-(trimethylstannyl)-1,5-naphthyridine (1.8 g, 6.0 mmol, 1.0 eq) and Pd(PPh 3 ) 4 (2.1 g, 1.8 mmol, 0.3 eq) in toluene (15 mL) was added 2-bromo-5-methyl-1,3-thiazole (1.1 g, 6.0 mmol, 1.0 eq). The mixture was stirred at 110° C. for 10 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The mixture was quenched with saturated KF (50 mL), extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0˜3:1) to afford 2-(5-methyl-1,3-thiazol-2-yl)-1,5-naphthyridine (530 mg, 38.6% yield) as a yellow solid.

Step c: The mixture of 2-(5-methyl-1,3-thiazol-2-yl)-1,5-naphthyridine (300 mg, 1.3 mmol, 1.0 eq) and PtO 2 (59.4 mg, 262 μmol, 0.2 eq) in MeOH (5 mL) was evacuated and refilled for 3 times using H 2 , stirred at 15° C. for 12 hours and 30° C. for 20 hours under H 2 atmosphere (15 psi). LCMS indicated a small amount of the starting material was remained and one main new peak with desired MS was detected. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0-1:1) to afford the desired product of 6-(5-methyl-1,3-thiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (90 mg, 60% purity, 17.8% yield) as a yellow solid.

Synthesis of 4-methyl-1H,2H,3H,4H-pyrido[2,3-b]pyrazine-6-carbonitrile, A-Ring for Compound 383

Step a: To a mixture of 2,6-dichloro-3-nitropyridine (10.0 g, 51.8 mmol) and Na 2 CO, (13.6 g, 129 mmol) in EtOH (100 mL) at 0° C. was added MeNH 2 /EtOH (30% wet., 8.5 g) dropwise. After addition, the reaction mixture was warmed to 15° C. slowly and stirred for 3 hours. The reaction mixture was concentrated in vacuum to give a residue, which was dissolved in ethyl acetate (80 mL), washed with H 2 O (70 mL×2). The organic phase was washed with brine (60 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was crystallized with ethanol to afford the product of 6-chloro-N-methyl-3-nitropyridin-2-amine (8.2 g, 84.4% yield) as a light yellow solid.

Step b: A mixture of 6-chloro-N-methyl-3-nitropyridin-2-amine (2.0 g, 10.6 mmol), Zn(CN) 2 (1.8 g, 15.9 mmol), Pd 2 (dba) 3 (961 mg, 1.1 mmol) and dppf (1.2 g, 2.1 mmol) in DMF (50 mL) was stirred at 120° C. for 12 hours under N 2 atmosphere. TLC (Petroleum ether: Ethyl acetate=5:1) showed the reaction was consumed completely. The reaction mixture was diluted with ethyl acetate (100 mL), washed with H 2 O (90 mL×2). The organic phase was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether: 20% to 35%) to afford the product of 6-(methylamino)-5-nitropyridine-2-carbonitrile (1.1 g, 58.5% yield) as a yellow solid.

Step c: A mixture of 6-(methylamino)-5-nitropyridine-2-carbonitrile (1.0 g, 5.6 mmol), NH 4 Cl (890 mg, 16.8 mmol) and Fe (1.6 g, 28.0 mmol) in EtOH (10 mL)/2N HCl (2 mL) was stirred at 50° C. for 3 hours. TLC (Petroleum ether: Ethyl acetate=4:1) showed the reaction was consumed completely. The reaction mixture was filtered and the filtrate was concentrated in vacuum to afford the product of 5-amino-6-(methylamino)picolinonitrile (830 mg, crude) as a black solid.

Step d: A mixture of 5-amino-6-(methylamino)pyridine-2-carbonitrile (830 mg, 5.6 mmol, crude) and 1,2-dibromoethane (5.3 g, 28 mmol) in TBAB (5.4 g, 16.7 mmol) was stirred at 60° C. for 12 hours. The reaction mixture was diluted with H 2 O (50 mL), extracted with ethyl acetate (60 mL×2). The organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether: 35% to 45%) to afford the product of 4-methyl-1H,2H,3H,4H-pyrido[2,3-h]pyrazine-6-carbonitrile (240 mg) as a brown solid.

Synthesis of 4-(propan-2-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazine, for Use in the Preparation of Compound 387

Step a: A resealable reaction vial was charged with 2-chloro-3-nitropyridine (500 mg, 3.15 mmol) in DMF (13 mL), ethylbis(propan-2-yl)amine (822 μL, 4.72 mmol), methyl 2-[(propan-2-yl)amino]acetate (432 mg, 3.30 mmol). The vial was sealed, and the mixture was stirred at 80° C. for 16 hrs. The cooled mixture was charged with water (10 mL) and extracted with ethyl acetate and concentrated. The residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=0:100 to 40:60) to afford methyl 2-[(3-nitropyridin-2-yl)(propan-2-yl)amino]acetate (630 mg) as a yellow solid.

Step b: Methyl 2-[(3-nitropyridin-2-yl)(propan-2-yl)amino]acetate (630 mg, 2.48 mmol) was dissolved in AcOH (6 mL) and charged with iron (415 mg, 7.44 mmol). The mixture was heated 90° C. for 1 hr. The reaction was diluted with MeOH, filtered on celite and concentrated. The residue was taken up in DCM and washed with sat. bicarb. The aq. layer was back-extracted with CHCl 3 /IPA (3/1). The org layers combined, dried, concentrated. The residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=0:100 to 50:50) to afford 4-(propan-2-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazin-2-one (260 mg) as a white crystalline solid. LCMS: [M+H] + 192.

›ABBREVIATIONS · 21 of 63

Step c: A resealable reaction vial was charged with 4-(propan-2-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazin-2-one (100 mg, 0.5229 mmol) and THF (6 mL). The reaction was charged with lithioalumane (1.04 mL, 1.04 mmol) and the mixture was stirred at 25° C. for 1 hr. The reaction was cooled to 0° C., and quenched with 1N NaOH until gas evolution stopped (4 drops). The reaction was diluted with THF and DCM, charged with celite, filtered and concentrated to 4-(propan-2-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazine (95 mg) as a colorless oil. LCMS: [M+H] + 178.

Synthesis of 5-methanesulfonyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile, for Use in the Preparation of Compound 388

Step a: A resealable reaction vial was charged with 6-bromo-5-methanesulfonyl-1,2,3,4-tetrahydroquinoline (166 mg, 0.5720 mmol) (preparation described in Compound 346), zincdicarbonitrile (133 mg, 1.14 mmol),palladium(1+) 2′-amino-1,1′-biphenyl-2-yl di-tert-butyl[2′,4′,6′-tris(propan-2-yl)-[1,1′-biphenyl]-2-yl]phosphane methanesulfonate (45.4 mg, 0.05719 mmol), dioxane (6 mL) and water (0.5 mL). The mixture was bubbled with nitrogen for 5 min. The vial was sealed, and the mixture was stirred at 90° C. for 8 hrs. The reaction mixture was concentrated and purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=20:80 to 100:0) to afford 5-methanesulfonyl-1,2,3,4-tetrahydroquinoline-6-carbonitrile (140 mg) as a tan solid. LCMS: [M+H] + 237.

Synthesis of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoline, A-Ring for Compound 389

Step a: The mixture of 1-tert-butyl 5-methyl 1,2,3,4-tetrahydroquinoline-1,5-dicarboxylate (250 mg, 858 μmol, 1.0 eq) and LiOH (62 mg, 2.6 mmol, 3.0 eq) in MeOH (5 mL) and H 2 O (0.5 mL) was stirred at 50° C. for 10 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The mixture was adjusted with 2N HCl to pH=7. The mixture was concentrated under reduced pressure to afford 1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (350 mg, crude) as a white solid.

Step b: The mixture of 1-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (237 mg, 854 μmol, 1.0 eq), NH 2 NHBoc (168 mg, 1.3 mmol, 1.5 eq), HATU (972 mg, 2.6 mmol, 3.0 eq) and TEA (353 μL, 2.6 mmol, 3.0 eq) in DMF (5 mL) was stirred at 50° C. for 12 hours. TLC (Petroleum ether/Ethyl acetate=2:1) indicated that the starting material was consumed completely and one main new spot with lower polarity formed. The mixture was diluted with H 2 O (20 mL), extracted with EtOAc (20 mL×3). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10:0-3:1) to afford the desired product of tert-butyl 5-{N-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-1,2,3,4-tetrahydroquinoline-1-carboxylate (460 mg, crude) as a white solid.

Step c: The mixture of tert-butyl 5-{N-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-1,2,3,4-tetrahydroquinoline-1-carboxylate (460 mg, 70% purity, 822 μmol, 1.0 eq) in HCl/MeOH (5 mL, 4M) was stirred at 15° C. for 1.5 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The mixture was concentrated under reduced pressure to afford the desired product of 1,2,3,4-tetrahydroquinoline-5-carbohydrazide dihydrochloride (217 mg, 100% yield) as a white solid.

Step d: The mixture of 1,2,3,4-tetrahydroquinoline-5-carbohydrazide dihydrochloride (217 mg, 821 μmol, 1.0 eq) and MeC(OEt) 3 (2.7 g, 16.4 mmol, 20 eq) in dioxane (5 mL) was stirred at 120° C. for 10 hours. LCMS indicated that the starting material was consumed completely and one main new peak with desired MS was detected. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0˜3:1) to afford the desired product of 5-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoline (123 mg, 69.8% yield) as a white solid.

Synthesis of 5-(methoxymethyl)-1,2,3,4-tetrahydroquinoline, Used in the Synthesis of Compound 390

Step a: A solution of 5-bromo-1,2,3,4-tetrahydroquinoline (2.0 g, 9.42 mmol) in THE (40.0 mL) was added NaHMDS (28.2 mL, 28.2 mmol, 1M) under N 2 at 20° C. The reaction was stirred for 2 h. Brown solution was observed. (Boc) 2 O (4.30 mL, 18.8 mmol) in THF (30.0 mL) was added, the reaction mixture was stirred at 20° C. for 10 h under N 2 . Yellow solution was observed. TLC (EtOAc/Petroleum ether=1/10) showed a small amount of starting material was remained and a new main spot with lower polarity was formed. The combined mixture was diluted with water (200.0 mL) and extracted with EtOAc (200.0 mL×3). The combined organic layers were washed with water (300.0 mL) and brine (300.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc in Petroleum ether=0˜2%) to afford tert-butyl 5-bromo-1,2,3,4-tetrahydroquinoline-1-carboxylate (4.9 g, crude) which was confirmed by HNMR

Step b: To a solution of tert-butyl 5-bromo-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.5 g, 4.8 mmol) in MeOH (20 mL) were added Pd(dppf)Cl 2 (351 mg, 480 μmol) and TEA (1.4 g, 14.3 mmol). The mixture was evacuated and refilled for 3 times using CO, then stirred at 80° C. for 12 hours under CO (50 psi). LCMS showed the desired product formed. The reaction mixture was concentrated and was purified by silica gel chromatography (elution: Petroleum ether:ethyl acetate=5:1) to afford the product of 1-tert-butyl 5-methyl 1,2,3,4-tetrahydroquinoline-1,5-dicarboxylate (1.3 g, 90.0% yield) as a yellow solid.

Step c: To a solution of 1-tert-butyl 5-methyl 1,2,3,4-tetrahydroquinoline-1,5-dicarboxylate (750 mg, 2.6 mmol) in THF (5 mL) was added LiBH 4 (107 mg, 5.1 mmol) at 0° C., the mixture was stirred at 25° C. for 12 hours under N 2 . LCMS showed the desired product formed. The reaction was quenched by sat.NH 4 Cl (40 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (eluent: Petroleum ether:Ethyl acetate=3:1) to give tert-butyl 5-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (680 mg, 100% yield) as a colorless oil.

›ABBREVIATIONS · 22 of 63

Step d: To a solution of tert-butyl 5-(hydroxymethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (250 mg, 949 μmol) in DMF (2 ml) was added NaH (75.5 mg, 1.9 mmol) at 0° C., the mixture was stirred at 25° C. for 1 hour. Then MeI (1.1 g, 7.6 mmol) was added at 0° C., the mixture was stirred at 25° C. for 6 hours, LCMS showed the desired product formed. The reaction mixture was quenched by brine (10 mL), extracted with EtOAc (20 mL×3), the combined organic layers dried over anhydrous Na 2 SO 4 , filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (eluent: Petroleum ether:Ethyl acetate=5:1) to give tert-butyl 5-(methoxymethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (240 mg, 91.2% yield) as a colorless oil.

Step e: To a solution of tert-butyl 5-(methoxymethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (180 mg, 648 μmol) in MeOH (1 mL) was added HCl/MeOH (3.2 mL, 4 M)) at 0° C., the mixture was stirred at 20° C. for 6 hours. LCMS showed the desired product formed. The reaction mixture was concentrated to dryness, MeOH (2 mL) and K 2 CO 3 (100 mg) were added. The mixture was filtered and the filtrate was concentrated to dryness, which was purified by silica gel chromatography (eluent: Petroleum ether:Ethyl acetate=5:1) to give 5-(methoxymethyl)-1,2,3,4-tetrahydroquinoline (110 mg, 96.4% yield) as a white solid.

Synthesis of 2-(1,2,3,4-tetrahydroquinolin-5-yl)-1λ 6 ,2-thiazolidine-1,1-dione, for Use in the Preparation of Compound 392

Step a: A resealable reaction vial was charged with 5-bromoquinoline (200 mg, 0.9612 mmol), 1λ 6 ,2-thiazolidine-1,1-dione (139 mg, 1.15 mmol), dipotassium carbonate (265 mg, 1.92 mmol), tBuXPhos/Pd G3 (76.2 mg, 0.09612 mmol), and 2-MeTHF (8 mL). The mixture was bubbled nitrogen for 5 min, the vial was sealed, and the mixture was stirred at 80° C. for 72 hrs. The reaction mixture and concentrated. The residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=20:80 to 100:0) to afford 2-(quinolin-5-yl)-1λ 6 ,2-thiazolidine-1,1-dione (50 mg) as a white solid. LCMS: [M+H] + 249.

Step b: 13.15 2-(quinolin-5-yl)-1λ 6 ,2-thiazolidine-1,1-dione (50 mg, 0.2053 mmol) was dissolved in MeOH (10 mL) and pumped through a 10% Pd/C at 2 mL/min under 30 bars of H 2 at 30° C. for 45 min. Solvent was removed to afford 2-(1,2,3,4-tetrahydroquinolin-5-yl)-1λ 6 ,2-thiazolidine-1,1-dione (50 mg) as a colorless oil. LCMS: [M+H] + 253.

Synthesis of 4-(oxan-4-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazine, for Use in the Preparation of Compound 393

4-(oxan-4-yl)-1H,2H,3H,4H-pyrido[2,3-b]pyrazine (240 mg) (LCMS: [M+H] + 220) was prepared using 2-fluoro-3-nitropyridine (400 mg, 2.81 mmol) and methyl 2-[(oxan-4-yl)amino]acetate (486 mg, 2.81 mmol) following the procedure used for the building block of Compound 387.

Synthesis of 4H,5H,6H,7H-thieno[3,2-b]pyridine, Used in the Preparation of Compound 394

Step a: A mixture of thieno[3,2-b]pyridine (150.0 mg, 1.10 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (612.0 mg, 2.42 mmol) and diphenoxyphosphinic acid (27.5 mg, 110.0 μmol) in dioxane (5.0 mL) was stirred at 100° C. for 12 hours under N 2 . LCMS showed the desired product formed. Concentrated in vacuum, the residue was purified by silica gel column (EtOAc in Petroleum ether=0˜20%) to give 4H,5H,6H,7H-thieno[3,2-b]pyridine (160.0 mg, 65% purity, 67.9% yield) as a red oil.

Synthesis of 1-methyl-7-(1,3-oxazol-2-yl)-1,2,3,4-tetrahydroquinoxaline, Used in the Preparation of Compound 395

Step a: A mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (200.0 mg, 0.88 mmol), 2-(tributylstannyl)-1,3-oxazole (315.0 mg, 0.88 mmol) and Pd(PPh 3 ) 4 (101.0 mg, 0.088 mmol) in toluene (15.0 mL) was stirred at 110° C. under N 2 for 12 hours. After concentration, the residue was purified by silica column (Ethyl acetate in Petroleum ether=0-100%) to give the desired 1-methyl-7-(1,3-oxazol-2-yl)-1,2,3,4-tetrahydroquinoxaline (75.0 mg, 39.6% yield) as a yellow oil.

Synthesis of tert-butyl N-[(3S,4S)-8-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate, A-Ring for Compound 398

Step a: A solution of 4-bromo-2-fluoro-1-nitrobenzene (500.0 mg, 2.27 mmol), oxetan-3-amine (198.0 mg, 2.72 mmol) and TEA (687.0 mg, 6.81 mmol) in EtOH (10.0 mL) was stirred at 50° C. for 12 h. Yellow solution was observed. TLC (petroleum ether:EtOAc=10:1) showed the starting material consumed and a new spot was observed. The mixture was concentrated in vacuum to remove solvent. The residue was purified by flash silica gel chromatography (20 g, Ethyl acetate in Petroleum ether from 0% to 20%) to give N-(5-bromo-2-nitrophenyl)oxetan-3-amine (600.0 mg, 96.9% yield) as a yellow solid.

Step b: A solution of N-(5-bromo-2-nitrophenyl)oxetan-3-amine (600.0 mg, 2.19 mmol), Zn(CN) 2 (385.0 mg, 3.28 mmol), Pd 2 (dba) 3 (500.0 mg, 547.0 umol) and dppf (72.7 mg, 131.0 umol) in DMF (50.0 mL) was stirred at 120° C. for 12 h under N 2 . Brown solution was observed. TLC (petroleum ether:EtOAc=5:1) showed a new spot was observed and starting material consumed. The solution was added into H 2 O (200.0 mL) and then extracted with EtOAc (200.0 mL×2). The combined organic layers were washed with brine (200.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product as a brown gum. The residue was purified by flash silica gel chromatography (12 g, Ethyl acetate in Petroleum ether from 0% to 35%) to give 4-nitro-3-[(oxetan-3-yl)amino]benzonitrile (480.0 mg, 100% yield) as an orange solid.

Step c: A solution of 4-nitro-3-[(oxetan-3-yl)amino]benzonitrile (300.0 mg, 1.36 mmol) and Pd/C (100.0 mg, 10%, wet) in THF (20.0 mL) was stirred at 20° C. for 2 h under H 2 (15 psi). Brown solution was observed. Desired mass ion was observed from LCMS. The mixture was filtered and filtrate was concentrated in vacuum to give 4-amino-3-[(oxetan-3-yl)amino]benzonitrile (240.0 mg, 93.3% yield) as a yellow gum. The gum was used in the next step without further purification.

›ABBREVIATIONS · 23 of 63

Step d: A mixture of 4-amino-3-[(oxetan-3-yl)amino]benzonitrile (240.0 mg, 1.26 mmol), 1,2-dibromoethane (1.18 g, 6.30 mmol), TBAB (2.03 g, 6.30 mmol) and TEA (636.0 mg, 6.30 mmol) was stirred at 60° C. for 12 h. Orange solution was observed. Desired mass ion was observed from LCMS. The mixture was concentrated in vacuum to remove solvent. The mixture was added into H 2 O (100.0 mL) and then extracted with EtOAc (100.0 mL×2). The combined organic layers were washed with brine (100.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product as an orange gum. The residue was purified by flash silica gel chromatography (4 g, Ethyl acetate in Petroleum ether from 0% to 35%) to give tert-butyl N-[(3S,4S)-8-[3-iodo-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate (220.0 mg, 81.8% yield) as an orange oil.

Synthesis of 5-[(3R)-oxolan-3-yl]-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 400

Step a: To a solution of 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (240.0 mg, 1.2 mmol) and 6-bromoquinoline (278.0 mg, 1.3 mmol) in dioxane (5.0 mL) and water (0.5 mL) was added Pd(dppf)Cl 2 (89.3 mg, 122 μmol) and K 2 CO 3 (337.0 mg, 2.4 mmol). The reaction mixture was purged with N 2 for 3 min, and the reaction was stirred at 100° C. for 12 hours. LCMS showed the starting material was consumed completely and 37% desired product formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:20). The product of 5-(2,5-dihydrofuran-3-yl)quinoline (220.0 mg, 1.1 mmol, 91.6% yield) was obtained as a yellow oil.

Step b: A solution of 5-(2,5-dihydrofuran-3-yl)quinoline (210.0 mg, 1.1 mmol) and PtO 2 (48.1 mg) in MeOH (3.0 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). TLC (Petroleum ether/Ethyl acetate=2:1) showed the starting material was disappeared and a new spot with lower polarity was formed. PtO 2 was filtered off and the filtrate was concentrated under reduced pressure to give the product 5-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoline (180.0 mg, 885.0 μmol, 83.7% yield) as a white solid.

SFC: The compound 4 (95.0 mg, 467.0 μmol) was separated by preparative SFC. Column: Phenomenex-Amylose-1 (250 mm×30 mm, 5 um). Condition: 0.1% NH 3 .H 2 O EtOH. Begin B 15%, end B 15%. Flow rate: 50 mL/min. The product of 5-[(3R)-oxolan-3-yl]-1,2,3,4-tetrahydroquinoline (4a, 45.0 mg, 221 μmol, 47.4% yield, the faster eluting isomer) was obtained as a white solid.

Synthesis of 5-[(3S)-oxolan-3-yl]-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 401

SFC: 5-(tetrahydrofuran-3-yl)-1,2,3,4-tetrahydroquinoline (95.0 mg, 467.0 μmol) was separated by preparative SFC. Column: Phenomenex-Amylose-1 (250 mm×30 mm, 5 um). Condition: 0.1% NH 3 .H 2 O EtOH. Begin B 15%, end B 15%. Flow rate: 50 mL/min. The product of 5-[(3S)-oxolan-3-yl]-1,2,3,4-tetrahydroquinoline (45.0 mg, 221 μmol, 47.4% yield, the faster eluting isomer) was obtained as a white solid.

Synthesis of rel-(4R)-4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 402

Step a: The mixture of 3-fluoro-4-nitrobenzonitrile (1.0 g, 6.0 mmol, 1.0 eq), oxolan-3-amine (629 mg, 7.2 mmol, 1.2 eq) and TEA (2.4 mL, 18.0 mmol, 3.0 eq) in EtOH (15 mL) was stirred at 60° C. for 3 hours. TLC (Petroleum ether/Ethyl acetate=5:1) showed that the starting material was consumed completely and one main new spot with higher polarity was formed. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10:0-5:1) to afford 4-nitro-3-[(oxolan-3-yl)amino]benzonitrile (1.3 g, 92.8% yield) as a red solid.

Step b: The mixture of 4-nitro-3-[(oxolan-3-yl)amino]benzonitrile (700 mg, 3.0 mmol, 1.0 eq) and 10% Pd/C (100 mg, wet) in MeOH (10 mL) was evacuated and refilled for 3 times using H 2 , stirred at 15° C. for 2 hours under H 2 (15 psi) atmosphere. TLC (Petroleum ether/Ethyl acetate=1:1) indicated that the starting material was consumed completely and one main new spot with higher polarity was formed. The mixture was filtered and the filtrate was concentrated under reduced pressure to afford the desired product of 4-amino-3-[(oxolan-3-yl)amino]benzonitrile (560 mg, 91.9% yield) as a white solid.

Step c: The mixture of 4-amino-3-[(oxolan-3-yl)amino]benzonitrile (300 mg, 1.5 mmol, 1.0 eq) and TBAB (4.7 g, 14.7 mmol, 10.0 eq) in 1,2-dibromoethane (2.8 g, 14.7 mmol, 10.0 eq) was stirred at 60° C. for 12 hours. LCMS indicated that the starting material was remained and one main new peak with desired MS was detected. TEA (609 uL, 4.4 mmol, 3.0 eq) was added into the mixture and the mixture was stirred at 60° C. for another 20 hours. LCMS indicated that a small amount of the starting material was remained and one main new peak with desired MS was detected. The mixture was diluted with H 2 O (30 mL), extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0-3:1) to afford the desired product of 4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (210 mg, 62.3% yield) as a yellow oil.

SFC: 4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (150 mg, 654 μmol, 1.0 eq) was separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um). Condition: Ethanol (0.1% NH 3 /H 2 O). Begin B 45%, end B 45%. Flow rate: 70 mL/min.) to afford rel-(4R)-4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (70.0 mg, 46.9% yield, a faster eluting isomer) as a white solid.

Synthesis of rel-(4S)-4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 403

SFC: 4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (150 mg, 654 μmol, 1.0 eq) was separated by SFC (Column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um). Condition: Ethanol (0.1% NH 3 /H 2 O). Begin B 45%, end B 45%. Flow rate: 70 mL/min.) to afford rel-(4S)-4-(oxolan-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (50.0 mg, 33.5% yield, a slower eluting isomer) was obtained as a white solid.

›ABBREVIATIONS · 24 of 63

Synthesis of 4-ethyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 405

Step a: 3-Fluoro-4-nitrobenzonitrile (500.0 mg, 3.0 mmol), Et 3 N (1.2 mL, 9.0 mmol) and EtNH 2 (271.0 mg, 6.0 mmol) were added in EtOH (15.0 mL), the reaction mixture was stirred at 50° C. for 12 hours. LCMS indicated 98% of desired product formed. The reaction mixture was concentrated under reduced pressure to afford the product of 3-(ethylamino)-4-nitrobenzonitrile (650.0 mg, crude) as a yellow solid.

Step b: 3-(Ethylamino)-4-nitrobenzonitrile (575.0 mg, crude) and 10% wet Pd/C (100.0 mg) were added in MeOH (16.0 mL), the reaction mixture was evacuated and refilled for 3 times with H 2 (15 psi) and stirred at 15° C. for 12 hours. LCMS indicated 83% of desired product formed. The reaction mixture was filtered and concentrated under reduced pressure to afford the product of 4-amino-3-(ethylamino) benzonitrile (550.0 mg, crude) as a yellow solid.

Step c: 4-Amino-3-(ethylamino) benzonitrile (300.0 mg, crude) and 1,2-dibromoethane (1.7 g, 9.3 mmol) were added in TBAB (286.0 mg, 1.9 mmol), the reaction mixture was stirred at 60° C. for 12 hours. LCMS indicated 33% of desired product formed. TLC (Petroleum ether:Ethyl acetate=2:1) indicated one main spot formed. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=2:1) to afford the product of 4-ethyl-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (120.0 mg) as a yellow solid.

Synthesis of 4-(2-methoxyethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 406

Step a: 3-Fluoro-4-nitrobenzonitrile (500.0 mg, 3.0 mmol), 2-methoxyethan-1-amine (226.0 mg, 3.0 mmol) and Et 3 N (1.3 mL, 9.0 mmol) were added in EtOH (10.0 mL), the reaction mixture was stirred at 50° C. for 12 hours. LCMS indicated 99% of desired product formed. The reaction mixture was concentrated under reduced pressure to give the product of 3-[(2-methoxyethyl)amino]-4-nitrobenzonitrile (700.0 mg, crude) as a yellow solid.

Step b: 3-[(2-Methoxyethyl)amino]-4-nitrobenzonitrile (600.0 mg, crude) and 10% wet Pd/C (100.0 mg) were added in MeOH (15.0 mL), the reaction mixture was stirred at 25° C. for 12 hours under H 2 (15 psi). LCMS indicated 69% of desired product formed. The reaction mixture was filtered and concentrated under reduced pressure to afford the product of 4-amino-3-[(2-methoxyethyl)amino]benzonitrile (600.0 mg, crude) as a yellow solid which was used in next step without further purification.

Step c: 4-Amino-3-[(2-methoxyethyl)amino]benzonitrile (300.0 mg, crude), 1,2-dibromoethane (1.5 g, 7.8 mmol) and TBAB (720.0 mg, 4.7 mmol) were added in the bottle, the reaction mixture was stirred at 60° C. for 12 hours. LCMS indicated 43% of desired product formed. TLC (Petroleum ether:Ethyl acetate=2:1) indicated one main spot formed. The reaction mixture was concentrated under reduced pressure, diluted with Ethyl acetate (30.0 mL), washed with H 2 O (20.0 mL×3) and brine (20.0 mL), the organic phase was dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure to give a residue and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:50) to afford the product of 4-(2-methoxyethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (150.0 mg) as a yellow solid.

Synthesis of 6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 407

Step a: To a solution of methyl 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxylate (500 mg, 2.60 mmol) in MeOH (5 mL) was added hydrazine (151 μL, 3.12 mmol). Heated to reflux for 48 h. Cooled to rt. Material precipitated. Filtered, washed with MeOH, Concentrated filtrate, redissolved in MeOH (5 mL). Transferred to a microwave vial and added an additional 2.4 equivalents of hydrazine (302 uL). Heated in microwave at 120 C for 60 min. Concentrated and combined with precipitate to give 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbohydrazide (400 mg, 2.08 mmol).

Step b: To a solution of 5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbohydrazide (100 mg, 0.5202 mmol) in DCM (2 mL) was added ethylbis(propan-2-yl)amine (275 μL, 1.56 mmol) followed by 0.5 eq. acetic anhydride (25 uL). Stirred at rt for 2 h. Concentrated, dried under high vac. Carried on to next step without quantifying or further purification.

Step c: To a solution of N′-acetyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-c (121 mg, 0.5165 mmol) in toluene (3 mL) was added Lawesson's Reagent (416 mg, 1.03 mmol). Stirred at 80 C for 1 h. Partitioned between EtOAc and water. Extracted with EtOAc (3×). Combined org layers, washed with brine. Dried org over Na 2 SO 4 , filtered and concentrated. Purified by flash silica gel chromatography using 0-5% MeOH in DCM, followed by a second purification using 0-100% EtOAc in heptanes to give 6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (47.0 mg, 0.2023 mmol). LCMS: [M+H] 233.24. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (br d, J=8.54 Hz, 1H) 7.51-7.65 (m, 1H) 6.85 (br d, J=8.30 Hz, 1H) 6.55-6.65 (m, 1H) 3.98-4.06 (m, 1H) 3.72-3.81 (m, 1H) 3.19-3.25 (m, 1H) 2.80 (br t, J=6.35 Hz, 1H) 2.62-2.71 (m, 2H) 2.26-2.36 (m, 1H) 1.98 (s, 1H) 1.83-1.92 (m, 2H) 1.11-1.21 (m, 2H).

Synthesis of 4-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 408

Step a: A mixture of 3-fluoro-4-nitrobenzonitrile (518.0 mg, 3.1 mmol), 2-methanesulfonylethan-1-amine hydrochloride (600.0 mg, 3.8 mmol) and TEA (1.3 mL, 9.4 mmol) in EtOH (10.0 mL) were stirred at 60° C. for 12 hours. An orange suspension was found. TLC (EtOAc) showed one main new peak formed. The mixture was concentrated under reduced pressure, diluted with H 2 O (100.0 mL) and extracted with EtOAc (100.0 mL×3). The combined organic layers were washed with H 2 O (100.0 mL) and brine (100.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the product of 3-[(2-methanesulfonylethyl)amino]-4-nitrobenzonitrile (530.0 mg, crude) as a yellow solid.

›ABBREVIATIONS · 25 of 63

Step b: A mixture of 3-[(2-methanesulfonylethyl)amino]-4-nitrobenzonitrile (530.0 mg, 1.9 mmol) and 10% wet Pd/C (200.0 mg) was stirred at 20° C. for 12 hours under H 2 (15 psi). LCMS showed one main peak with desired MS formed. The mixture was filtered and concentrated under reduced pressure to give the product of 4-amino-3-[(2-methanesulfonylethyl)amino]benzonitrile (185.0 mg, crude) as a white solid.

Step c: A mixture of 4-amino-3-[(2-methanesulfonylethyl)amino]benzonitrile (185.0 mg, 773.0 μmol), TBAB (936.0 mg, 3.8 mmol) and TEA (534.0 μL, 3.8 mmol) was stirred at 60° C. for 12 hours. LCMS showed one main peak with desired MS (254 nm) was found. The mixture was concentrated under reduced pressure to give a residue, the residue was diluted with H 2 O (50.0 mL), extracted with EtOAc (50.0 mL×3). The organic layers were washed with brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue and purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether=0%˜70%) to afford 4-(2-methanesulfonylethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (90.0 mg, crude) as an off-white solid.

Synthesis of 4-(propan-2-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 409

Step a: A mixture of 3-fluoro-4-nitrobenzonitrile (500.0 mg, 3.0 mmol), propan-2-amine (195.0 mg, 3.3 mmol) and TEA (1.3 mL, 9.0 mmol) in dioxane (10.0 mL) were stirred at 60° C. for 12 hours. A yellow solution was found. LCMS showed one main new peak formed. The reaction mixture was concentrated under reduced pressure to give 4-nitro-3-[(propan-2-yl)amino]benzonitrile (800.0 mg, crude) as a yellow solid which was used in next step without further purification.

Step b: To a solution of 4-nitro-3-[(propan-2-yl)amino]benzonitrile (700.0 mg, 3.4 mmol) in MeOH (10.0 mL) was added 10% wet Pd/C (100.0 mg), and the mixture was stirred at 15° C. for 12 hours under H 2 (15 psi). LCMS showed one main new peak with desired MS formed. The combined mixture was filtered and concentrated under reduced pressure to give the product of 4-amino-3-[(propan-2-yl)amino]benzonitrile (750.0 mg, crude) as a brown oil which was used in next step without further purification.

Step c: A mixture of 4-amino-3-[(propan-2-yl)amino]benzonitrile (300.0 mg, 1.7 mmol), tetrabutylammonium bromide (1.3 g, 5.2 mmol) and 1,2-dibromoethane (1.6 g, 8.6 mmol) was stirred at 60° C. for 12 hours. LCMS showed 32.9% of desired MS formed. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (50.0 mL), washed with H 2 O (50.0 mL×2) and brine (50.0 mL). The organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue and purified by column chromatography (EtOAc in Petroleum ether=0%˜20%) to afford the product of 4-(propan-2-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (60.0 mg, 298.0 μmol) as a brown solid and 90.0 mg of starting material was recovered.

Synthesis of 6-[2-(trimethylsilyl)ethynyl]-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 410

Step a: A resealable reaction vial was charged with 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (250 mg, 1.17 mmol), dicaesio carbonate (570 mg, 1.75 mmol), XPhos/Pd G4 (201 mg, 0.234 mmol) and ACN (6 mL). The mixture was bubbled with nitrogen and charged with ethynyltrimethylsilane (485 μL, 3.51 mmol). The mixture further bubbled for 10 min, the vial was sealed, and the mixture was stirred at 80° C. for 6 hrs. The reaction was concentrated and the residue was purified by flash silica gel chromatography (eluting with ethyl acetate:heptanes=0:100 to 70:30) to afford 6-[2-(trimethylsilyl)ethynyl]-1,2,3,4-tetrahydro-1,5-naphthyridine (105 mg) as a tan crystalline solid. LCMS: [M+H] + 231

Synthesis of 4-(3-[(tert-butyldimethylsilyl)oxy]cyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 411

Step a: To a solution of 3-fluoro-4-nitrobenzonitrile (1.0 g, 6.0 mmol) and 3-aminocyclobutan-1-ol (576.0 mg, 6.6 mmol) in dioxane (5.0 mL) was added TEA (1.7 mL, 12.0 mmol). The mixture was purged with N 2 for 3 min in a sealed tube, and the reaction was stirred at 60° C. for 12 hours. LCMS showed the staring material was consumed completely and 92% desired product was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:10 and DCM/MeOH=100:0 to 100:10). The product of 3-[(3-hydroxycyclobutyl)amino]-4-nitrobenzonitrile (1.3 g, 5.6 mmol, 92.8% yield) was obtained as an orange solid.

Step b: A solution of 3-[(3-hydroxycyclobutyl)amino]-4-nitrobenzonitrile (1.2 g, 5.1 mmol) and wet 10%/Pd/C (200.0 mg) in MeOH (10.0 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). LCMS showed the starting material was consumed completely and 100% desired product was formed. Pd/C was filtered and the filtrate was concentrated under reduced pressure. The residue (1.0 g, 96.1% yield) was used for the next step directly.

Step c: A mixture of 4-amino-3-[(3-hydroxycyclobutyl)amnion]benzonitrile (500.0 mg, 2.5 mmol), 1,2-dibromoethane (2.3 g, 12.3 mmol), TEA (744.0 mg, 7.4 mmol) and TBAB (1.6 g, 4.9 mmol) was stirred at 60° C. for 12 hours. LCMS showed 22% starting material was remained and 49% desired product was formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (50.0 mL) and extracted ethyl acetate (50.0 mL×2). The combined organic layers were washed with water (30.0 mL) and brine (30.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:80). The product of 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (480.0 mg, 2.1 mmol, 85.1% yield) was obtained as a light yellow solid.

SFC: The compound 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (95.0 mg, 414.0 umol) was separated by SFC. Column: DAICEL CHIRALPAK AD-H(250 mm×30 mm, 5 um). Condition: 0.1% NH 3 .H 2 O EtOH. Begin B 40%, end B 40%. Flow rate: 50 mL/min. The trans-isoform (45.0 mg, 196 μmol, 47.4% yield, a faster eluting isomer) was obtained as a light yellow solid and trans-form.

›ABBREVIATIONS · 26 of 63

Step d: To a solution of 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (40.0 mg, 174.0 μmol) in DCM (5.0 mL) was added TBSCl (52.4 mg, 348.0 μmol) and imidazole (23.6 mg, 348.0 μmol). The reaction mixture was stirred at 40° C. for 1 hour. LCMS showed the starting material was consumed completely and 97% desired product was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:30). The product 4-{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (55.0 mg, 160 μmol, 92.1% yield) was obtained as a light yellow solid.

Synthesis of 4-{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 412

The synthetic procedure for 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile was described in Compound 411.

SFC: The compound 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (95.0 mg, 414.0 umol) was separated by SFC. Column: DAICEL CHIRALPAK AD-H(250 mm×30 mm, 5 um). Condition: 0.1% NH 3 .H 2 O EtOH. Begin B 40%, end B 40%. Flow rate: 50 mL/min. The cis-isoform (45.0 mg, 196 μmol, 47.4% yield, a slower eluting isomer) was obtained as a light yellow solid and cis-form.

Step d: To a solution of 4-(3-hydroxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (40.0 mg, 174.0 μmol) in DCM (5.0 mL) was added TBSCl (52.4 mg, 348.0 μmol) and imidazole (23.6 mg, 348.0 μmol). The reaction mixture was stirred at 40° C. for 1 hour. LCMS showed the starting material was consumed completely and 96% desired product was formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:30). The product 4-{3-[(tert-butyldimethylsilyl)oxy]cyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (55.0 mg, 160.0 μmol, 92.1% yield) was obtained as a light yellow solid.

Synthesis of 8-methyl-5H,6H,7H,8H-pyridazino[3,4-b]pyrazine, Used in the Preparation of Compound 413

The synthetic procedure for 3,4-dichloro-8-methyl-5H,6H,7H,8H-pyridazino[3,4-b]pyrazine was described in preparation of the intermediate used for Compound 414.

Step e: The compound of 3,4-dichloro-8-methyl-5H,6H,7H,8H-pyridazino[3,4-b]pyrazine (2.2 g, 10.0 mmol) was dissolved in EtOH (30 mL) and THF (20 mL). 10% Pd/C (220 mg, wet) and TEA (4.1 mL, 30.0 mmol) was added. The reaction mixture was evacuated and refilled for 3 times using H 2 . The reaction mixture was stirred at 25° C. for 12 hours under H 2 (15 psi). The reaction mixture was filtered through a pad of celite and washed with MeOH (50 mL). The filtrate was concentrated to give a residue. The residue was dissolved in sat.NaHCO 3 (50 mL). The mixture was lyophilized to give a white solid which was triturated with MeOH (100 mL). The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (EtOAc:MeOH=100:0 to 100:40) to afford the product of 8-methyl-5H,6H,7H,8H-pyridazino[3,4-b]pyrazine (1.93 g, crude) as a white solid.

Synthesis of of 1-methyl-1H,2H,3H,4H-pyridazino[4,5-b]pyrazine, Used in the Preparation of Compound 414

Step a: The compound of dichloropyridazine-3,6-diol (5 g, 27.6 mmol) and DIEA (19.1 mL, 110 mmol) were added in the POCl 3 (50 mL). The mixture was stirred at 120° C. for 12 h. TLC (Petroleum ether/Ethyl acetate=2:1) showed compound 1 was consumed completely and a new spot formed. (Monitor reaction: diluted with EtOAc and quenched the reaction mixture with saturated NaHCO 3 (0° C.) before TLC check). The reaction mixture was concentrated to give a residue which was diluted with EtOAc (100 mL). The mixture was added slowly into ice cooled sat. NaHCO 3 (100 mL). The partitioned layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the product of tetrachloropyridazine (6.3 g, crude product) as a brown solid.

Step b: The compound of tetrachloropyridazine (5.5 g, 25.2 mmol), tert-butyl N-(2-aminoethyl)-N-methylcarbamate (4.8 g, 27.7 mmol) and TEA (13.8 mL, 100 mmol) were placed in DMF (80 mL). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated and H 2 O (100 mL) was added, extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na 2 SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:10 to 100:40) to afford the product of tert-butyl N-methyl-N-{2-[(3,5,6-trichloropyridazin-4-yl)amino]ethyl}carbamate (6.60 g, 73.6% yield) as an off-white solid.

Step c: The compound of tert-butyl N-methyl-N-{2-[(3,5,6-trichloropyridazin-4-yl)amino]ethyl}carbamate (6.6 g, 18.5 mmol) was added into HCl/MeOH (100 mL, 2M). The mixture was stirred at 25° C. for 12 h. The mixture was concentrated to give the product of 3,5,6-trichloro-N-[2-(methylamino)ethyl]pyridazin-4-amine hydrochloride (5.4 g, crude product) as a white solid which was used in next step without further purification.

Step d: The compound of 3,5,6-trichloro-N-[2-(methylamino)ethyl]pyridazin-4-amine hydrochloride (5.4 g, 18.4 mmol) and TEA (12.7 mL, 92.0 mmol) were placed in DMF (100 mL). The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated to give a residue. The residue was triturated with H 2 O (100 mL). A lot of precipitate formed, the solid was collected by filtration. The filter cake was dried to give the product of 3,4-dichloro-8-methyl-5H,6H,7H,8H-pyridazino[3,4-b]pyrazine (5) (2.5 g, 62% yield) as a white solid. The aqueous phase was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue which was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=50/100 to 80/100) to give the product of 5,8-dichloro-1-methyl-1H,2H,3H,4H-pyridazino[4,5-b]pyrazine (5a) (500 mg, 12.4% yield) as a white solid.

›ABBREVIATIONS · 27 of 63

Step e: The compound of 5,8-dichloro-1-methyl-1H,2H,3H,4H-pyridazino[4,5-b]pyrazine (400 mg, 1.8 mmol) was dissolved in EtOH (20 mL). 10% Pd/C (50 mg, wet) and TEA (0.7 mL, 5.5 mmol) was added. The reaction mixture was evacuated and refilled for 3 times using H 2 . The reaction mixture was stirred at 25° C. for 12 hours under H 2 (15 psi). The reaction mixture was filtered through a pad of celite and washed with MeOH (20 mL). The filtrate was concentrated in vacuum to give a residue. The residue was dissolved in sat.NaHCO 3 (20 mL). The mixture was lyophilized to give a residue. The residue was purified by flash silica gel chromatography (EtOAc:MeOH=100:0 to 100:40) to afford the product of 1-methyl-1H,2H,3H,4H-pyridazino[4,5-b]pyrazine (205 mg, 1.36 mmol) as a white solid.

Synthesis of 1-methyl-7-(1,3-thiazol-2-yl)-1,2,3,4-tetrahydroquinoxaline, Used in the Preparation of Compound 415

Step a: To the mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (0.2 g, 0.9 mmol) and 2-(tributylstannyl)-1,3-thiazole (0.3 mL, 1.0 mmol) in toluene (10.0 mL) was added Pd(PPh 3 ) 4 (0.1 g, 88.0 μmol) under N 2 . The mixture was stirred at 110° C. under N 2 for 12 hours. The mixture was concentrated in vacuum to give a residue and purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 0/1) to give the product 1-methyl-7-(1,3-thiazol-2-yl)-1,2,3,4-tetrahydroquinoxaline (43.9 mg, 21.6% yield) as an off-white solid.

Synthesis of 5-methanesulfonyl-1,2,3,4-tetrahydro-1,6-naphthyridine, Used in the Preparation of Compound 416

Step a: To the mixture of 5-chloro-1,6-naphthyridine (0.2 g, 1.2 mmol) in DMF (2.0 mL) was added NaSMe (500.0 mg, 7.1 mmol). The mixture was stirred at 80° C. for 12 hours. LCMS showed 2 mass was found. 10% aqueous NaClO (2.0 mL) was added to the mixture and the mixture was stirred at 10° C. for 12 hours. The mixture was poured into water (10.0 mL) and extracted with EtOAc (15.0 mL×2). The organic layers were washed with Sat. Na 2 S 2 O 3 solution and brine, dried over anhydrous Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuum to give the product 5-(methylsulfonyl)-1,6-naphthyridine 1-oxide (150.0 mg, 55.1% yield) as an off-white solid.

Step b: To the mixture of 5-(methylsulfonyl)-1,6-naphthyridine 1-oxide (115.0 mg, 0.5 mmol) in MeOH (5.0 mL) and THF (2.0 mL) was added PtO 2 (50.0 mg, 0.2 mmol). The mixture was stirred at 10° C. under H 2 (15 psi) for 12 hours. LCMS showed no 2 remained and 1 HNMR showed a incomplete reduced intermediate formed. The mixture was filtered and PtO 2 was added to the filtrate. The mixture was stirred at 10° C. under H 2 (15 psi) for another 12 hours. The mixture was filtered and filtrate was concentrated in vacuum to give the product 5-methanesulfonyl-1,2,3,4-tetrahydro-1,6-naphthyridine(80.0 mg, 74.0% yield) as a colorless oil.

Synthesis of 1-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoxaline, Used in the Preparation of Compound 417

Step a: To the mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (0.5 g, 2.2 mmol) in THF (15.0 mL) was added NaHMDS (6.60 mL, 6.60 mmol, 1M in THF) under N 2 at 0° C. The mixture was stirred at 0° C. for 30 min. Boc 2 O (1.0 mL, 4.4 mmol) was added to the mixture and the mixture was stirred at 10° C. for 2 hours. LCMS showed 87.8% product formed. Sat. NH 4 Cl (5.0 mL) was added to the mixture and the mixture was poured into water (20.0 mL). The mixture was extracted with EtOAc (30.0 mL×3). The organic layers were washed with water (20.0 mL×2) and brine (30.0 mL), dried over anhydrous Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuum to give the product of tert-butyl 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (0.57 g, 79.1% yield) as a colorless oil.

Step b: To the mixture of tert-butyl 6-bromo-4-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (0.5 g, 1.6 mmol) and TEA (6.5 mL, 4.7 mmol) in MeOH (20.0 mL) was added Pd(dppf)Cl 2 (115.0 mg, 158.0 μmol). The mixture was stirred at 70° C. under CO (40 psi) for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuum to give residue. The residue was purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 5/1 to 4/1) to give 2 (300.0 mg) and 1-tert-butyl 6-methyl 4-methyl-1,2,3,4-tetrahydroquinoxaline-1,6-dicarboxylate (221.0 mg, 45.6% yield) as an off-white solid.

Step c: To the mixture of 1-tert-butyl 6-methyl 4-methyl-1,2,3,4-tetrahydroquinoxaline-1,6-dicarboxylate (0.2 mg, 0.7 mmol) in MeOH (5.0 mL) and H 2 O (1.0 mL) was added NaOH (85.9 mg, 2.2 mmol). The mixture was stirred at 40° C. for 12 hours. The mixture was concentrated in vacuum to remove MeOH. A solution of HCl (2 N) was added to the mixture until pH=7 and a lot of white solid precipitated out. The mixture was filtered and the filter cake was dried in vacuum to give the product of 1-[(tert-butoxy)carbonyl]-4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (175.0 mg, 83.7% yield) as a white solid.

Step d: To the mixture of 1-[(tert-butoxy)carbonyl]-4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (150.0 mg, 0.5 mmol) and (tert-butoxy)carbohydrazide (0.1 g, 0.8 mmol) in DMF (5.0 mL) were added HATU (233.0 mg, 615.0 mol) and DIEA (252.0 μL, 1.5 mmol). The mixture was stirred at 10° C. for 2 hours. The mixture was poured into water (30.0 mL) and extracted with EtOAc (25.0 mL×3). The organic layers was washed with H 2 O (30.0 mL×2) and brine (30.0 mL), dried over anhydrous Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuum to give residue. The residue was purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 2/3) to give the product of tert-butyl 6-{N-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-4-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (210.0 mg, 100% yield) an off white solid.

Step e: A mixture of tert-butyl 6-{N-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-4-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (210.0 mg, 506.0 μmol) in 4 N HCl/MeOH (5.0 mL) was stirred at 40° C. for 2 hours. The mixture was concentrated in vacuum to give the product of 4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbohydrazide dihydrochloride (130.0 mg, 465.0 μmol, 92.8% yield) as a yellow solid.

›ABBREVIATIONS · 28 of 63

Step f: To the mixture of 4-methyl-1,2,3,4-tetrahydroquinoxaline-6-carbohydrazide dihydrochloride (130.0 mg, 465.0 μmol) in dioxane (5.0 mL) was added MeC(OEt) 3 (425.0 μL, 2.3 mmol). The mixture was stirred at 110° C. under N 2 for 12 hours. The mixture was concentrated in vacuum and purified by flash silica gel chromatography (petroleum ether/EtOAc=1/0 to 2/3) to give the product 1-methyl-7-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoxaline (73.5 mg, 68.6% yield) as an off-white solid.

Synthesis of dimethyl[(1,2,3,4-tetrahydroquinolin-5-yl)imino]-λ 6 -sulfanone, A-Ring for Compound 418

Step a: A mixture of tert-butyl 5-bromo-1,2,3,4-tetrahydroquinoline-1-carboxylate (300.0 mg, 960.0 μmol), iminodimethyl-λ 6 -sulfanone (107.0 mg, 1.15 mmol), Cs 2 CO 3 (622.0 mg, 1.91 mmol), and XantPhos-Pd-G4 (92.3 mg, 96.0 μmol) in toluene (20.0 mL) was stirred at 100° C. for 2 hours under N 2 . TLC (EtOAc/Petroleum ether=10/1) showed the starting material was consumed completely and one new spot with larger polarity was found. Concentrated in vacuum, the residue was purified by silica gel chromatography (EtOAc in Petroleum ether=0˜100%) to afford tert-butyl 5-{[dimethyl(oxo)-λ 6 -sulfanylidene]amino}-1,2,3,4-tetrahydroquinoline-1-carboxylate (250.0 mg, 80.3% yield) as a yellow solid.

Step b: A solution of tert-butyl 5-{[dimethyl(oxo)-λ 6 -sulfanylidene]amino}-1,2,3,4-tetrahydroquinoline-1-carboxylate (240.0 mg, 739.0 μmol) in 4 M HCl/MeOH (20.0 mL) was stirred at 20° C. for 4 hours. A lot of white precipitate formed. HNMR showed the desired product formed. Concentrated in vacuum, the residue was dissolved in DCM/MeOH (50.0 mL, 10:1) and basified with solid K 2 CO 3 . The mixture was filtered and the filtrate was evaporated to give dimethyl[(1,2,3,4-tetrahydroquinolin-5-yl)imino]-λ 6 -sulfanone (140.0 mg, 84.8% yield) as a light yellow solid.

Synthesis of methyl[(R)-methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine, Used in the Preparation of Compound 419

Step a: A mixture of imino(methyl)(quinolin-5-yl)-λ 6 ˜sulfanone (200.0 mg, 0.97 mmol), HCHO (4.0 mL, 54.2 mmol) in HCOOH (15.0 mL) was stirred at 100° C. for 12 hours. LCMS showed starting material was still remained and the desired product formed. After concentration, the residue was purified by silica column (Methanol in Dichloromethane=0˜40%) to give the desired product of methyl[methyl(oxo)(quinolin-5-yl)-λ 6 -sulfanylidene]amine (200.0 mg, 93.8% yield) as a yellow oil.

Step b: A mixture of methyl[methyl(oxo)(quinolin-5-yl)-λ 6 -sulfanylidene]amine (200.0 mg, 0.91 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (549.0 mg, 2.17 mmol) and (PhO) 2 P(O)OH (45.2 mg, 0.18 mmol) in toluene (15.0 mL) was stirred at 80° C. under N 2 for 12 hours. LCMS showed starting material was consumed completely and 11% of desired product formed. After concentration, the residue was purified by silica column (Methanol in Dichloromethane=0˜50%) to give the desired methyl [methyl (oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine (120.0 mg, 59.1% yield) as a yellow oil.

SFC-E, Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 μm Mobile phase: A: CO 2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL/min Column temp.: 35° C., Wavelength: 220 nm Rt=2.875 min, e.e=98.4%.

Synthesis of methyl[methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine, Used in the Preparation of Compound 420

The synthetic procedure for methyl [methyl (oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine is described in synthesis of the intermediate used for Compound 419.

SFC: The compound of methyl[methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine (120.0 mg, 534 μmol) was separated by preparative SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), Mobile phase: A: CO 2 , B: Ethanol (0.1% NH 3 .H 2 O), Gradient: from 20% to 20% of B, Flow rate: 50 mL/min, Column temp: 35° C.) to give the desired methyl[(S)-methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]amine (the faster eluting isomer, 3A: 50.0 mg, 42.0% yield). SFC-E, Column: Chiralcel OJ-3 150×4.6 mm I.D., 3 μm Mobile phase: A: CO 2 B: ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min, Flow rate: 2.5 mL/min Column temp.: 35° C., Wavelength: 220 nm, Rt=2.633 min, e.e=99.2%.

Synthesis of tert-butyl N—[(S)-methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-6-sulfanylidene]carbamate, Used in the Preparation of Compound 421

Step a: A mixture of 5-bromoquinoline (5.0 g, 24.0 mmol), MeSNa (1.97 g, 28.1 mmol) and DMF (40.0 mL) was stirred at 130° C. for 1.5 h under N 2 . TLC (Petroleum ether/Ethyl acetate=5:1) showed starting material was consumed completely and a new spot formed. LCMS showed starting material was consumed completely and the desired product formed. The mixture (4.2 g, crude) was used in next step without further workup.

Step b: To a mixture of 5-(methylsulfanyl) quinoline (4.20 g, crude) in DMF (40.0 mL) was added 10% aqueous NaClO (52.9 g, 71.6 mmol). After stirred for 10 min at 15° C., LCMS showed starting material was consumed completely and the desired product formed. The mixture was quenched with sat. Na 2 SO 3 (60.0 mL) and extracted with ethyl acetate (60.0 mL×3). The combined organic layers were concentrated in vacuum. The residue was purified by silica column (Ethyl acetate in Petroleum ether=0˜100%) to give the desired 5-methanesulfinylquinoline (3.60 g) as a yellow solid.

›ABBREVIATIONS · 29 of 63

Step c: To a mixture of 5-(methylsulfinyl) quinoline (1.00 g, 5.23 mmol) and NH 2 CO 2 NH 4 (1.63 g, 20.9 mmol) in MeOH (30.0 mL) was added PhT(OAc) 2 (5.02 g, 15.6 mmol). The mixture was stirred 0.5 hour at 20° C. LCMS showed starting material was still remained and the desired product formed. After concentration, the residue was purified by silica column (Methanol in Dichloromethane=0˜50%) to give the desired 5-(S-methylsulfonimidoyl) quinoline (0.79 g, 73.1% yield) as yellow oil.

Step d: To a solution of imino (methyl) (quinolin-5-yl)-λ 6 -sulfanone (200.0 mg, 0.97 mmol) in THF (5.0 mL) was added 1.0 M t-BuOK (1.16 mL, 1.16 mmol) at 0° C. After 10 min, Boc 2 O (420.0 mg, 1.93 mmol) was added. The mixture was stirred for 1 hour at 15° C. LCMS showed starting material was consumed completely and 88% the desired product formed. The mixture was diluted with H 2 O (20.0 mL) and extracted with ethyl acetate (20.0 mL×3). The combined organic layers were washed with brine (10.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum. The residue was purified by silica column (Methanol in Dichloromethane=0˜30%) to give tert-butyl N-[methyl (oxo) (quinolin-5-yl)-λ 6 -sulfanylidene] carbamate (210.0 mg, 70.9% yield) as a yellow solid.

Step e: A mixture of 2-methylpropan-1-ylium-2-yl N-[methyl(oxo)(quinolin-5-yl)-λ 6 -sulfanylidene]carbamate (210.0 mg, 0.69 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (415.0 mg, 1.64 mmol) and (PhO) 2 P(O)OH (34.2 mg, 0.14 mmol) in Tol (15.0 mL) was stirred at 80° C. under N 2 for 12 hours. LCMS showed starting material was consumed completely and the desired product formed. After concentration, the residue was purified by silica column (Ethyl acetate in petroleum ether=0˜100%) to give the desired tert-butyl N-[methyl (oxo) (1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate (170.0 mg, 80.1% yield) as a yellow oil.

SFC: The compound of tert-butyl N-[methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate (170.0 mg, 547.0 μmol) was separated by preparative SFC ((Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), Mobile phase: A: CO 2 , B: Ethanol (0.1% NH 3 .H 2 O), Gradient: from 40% to 40% of B, Flow rate: 70 mL/min, Column temp: 35° C.) to give the desired tert-butyl N—[(S)-methyl(oxo(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate (the faster eluting isomer, 74.0 mg, 43.7% yield) as a yellow solid.

SFC-E, Column: Chiralpak AD-3 150×4.6 mm I.D., 3 um Mobile phase: A: CO 2 B:ethanol (0.05% DEA) Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min Flow rate: 2.5 mL/min Column temp.: 35° C., Wavelength: 220 nm, R t =3.134 min, e.e.=99.8%.

Synthesis of tert-butyl N—[(R)-methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate, Used in the Preparation of Compound 422

The synthetic procedure for tert-butyl N-[methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate is described in synthesis of the intermediate for Compound 421.

SFC: The compound of tert-butyl N-[methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate (170.0 mg, 547.0 μmol) was separated by preparative SFC ((Column: DAICEL CHIRALCEL OJ-H (250 mm*30 mm, 5 μm), Mobile phase: A: CO 2 , B: Ethanol (0.1% NH 3 .H 2 O), Gradient: from 40% to 40% of B, Flow rate: 70 mL/min, Column temp: 35° C.) to give the desired tert-butyl N—[(R)-methyl(oxo)(1,2,3,4-tetrahydroquinolin-5-yl)-λ 6 -sulfanylidene]carbamate (the slower eluting isomer, 84.0 mg, 49.7% yield) as a yellow solid.

Synthesis of 2-(1,2,3,4-tetrahydro-1,6-naphthyridin-5-yl)thiazole, Used in the Preparation of Compound 424

Step a: A mixture of 5-chloro-1,6-naphthyridine (400.0 mg, 2.43 mmol), 2-(tributylstannyl)-1,3-thiazole (909.0 mg, 2.43 mmol) and Pd(PPh 3 ) 4 (280.0 mg, 0.024 mmol) in toluene (15.0 mL) was stirred at 110° C. under N 2 for 12 hours. After concentration, the residue was purified by silica column (Ethyl acetate in Petroleum ether=0-100%) to give the desired 5-(1,3-thiazol-2-yl)-1,6-naphthyridine (400.0 mg, 77.2%) as a yellow solid.

Step b: A mixture of 5-(1,3-thiazol-2-yl)-1,6-naphthyridine (360.0 mg, 1.68 mmol) and PtO 2 (38.1 mg, 0.17 mmol) in MeOH (15.0 mL) was stirred at 25° C. under H 2 (15 psi) for 12 hours. The mixture was filtered and the filtrate was concentrated in vacuum to give the desired 2-(1,2,3,4-tetrahydro-1,6-naphthyridin-5-yl)thiazole (280.0 mg, crude) as a yellow oil.

Synthesis of (4R)-4-methyl-6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in the Preparation of Compound 432

Step a: To a solution of (4R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (100 mg, 440 μmol) in dioxane (10 mL) and H 2 O (1 mL) were added Cs 2 CO 3 (286 mg, 880 μmol), 1-(oxan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (122 mg, 440 umol and Pd(dppf)Cl 2 (41.0 mg, 44.0 umol), the mixture was stirred at 100° C. for 12 hours under N 2 atmosphere. LCMS showed the desired product formed. The reaction mixture was concentrated in vacuum and purified by silica gel column (elution: Petroleum ether:Ethyl acetate=1:5 to 1:1) to give (4R)-4-methyl-6-[1-(oxan-2-yl)-1H-pyrazol-5-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine (88.0 mg, 67.1% yield) as a yellow solid.

Synthesis of methyl 2-(1,2,3,4-tetrahydroquinolin-5-yl)acetate, Used in the Preparation of Compound 435

Step a: A mixture of tert-butyl 5-bromo-1,2,3,4-tetrahydroquinoline-1-carboxylate (500.0 mg, 1.60 mmol), 4-(4,4,5,5-tetranethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (374.0 mg, 1.92 mmol), Pd(dppf)Cl 2 (117.0 mg, 160.0 μmol) and KF (464.0 mg, 8.00 mmol) in DMSO/H 2 O (10.0 mL/2.0 mL) was stirred at 130° C. for 12 hours under N 2 . TLC (Petroleum ether/EtOAc=10/1) showed the starting material was consumed completely and one new spot with larger polarity was found. The reaction mixture was poured into EtOAc (100.0 mL) and washed with (30.0 mL×3). The organic layer was concentrated and purified by (EtOAc in Petroleum ether=0˜30%) to give tert-butyl 5-(cyanomethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (270.0 mg, 62.0% yield) as a yellow solid.

›ABBREVIATIONS · 30 of 63

Step b: A solution of tert-butyl 5-(cyanomethyl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (270.0 mg, 991.0 μmol) in 4 M HCl/MeOH (2.0 mL) was stirred at 50° C. for 14 hours. LCMS showed the desired product formed. The reaction mixture was evaporated in vacuum. The residue was poured into saturated NaHCO 3 (30.0 mL) and extracted with EtOAc (30.0 mL×2). The organic layers were concentrated and purified by silica gel column (EtOAc in Petroleum ether=0˜20%) to give methyl 2-(1,2,3,4-tetrahydroquinolin-5-yl)acetate (110.0 mg, 54.1% yield) as a yellow oil.

Synthesis of 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 439

Step a: 3-Fluoro-4-nitrobenzonitrile (500.0 mg, 3.0 mmol), NH 2 CH 2 CH 2 OH (275.0 mg, 4.5 mmol) and Et 3 N (1.3 mL, 9.0 mmol) were added in EtOH (20.0 mL), the reaction mixture was stirred at 50° C. for 12 hours. LCMS indicated 100% of desired product formed. The reaction mixture was concentrated under reduced pressure to afford the product of 3-[(2-hydroxyethyl)amino]-4-nitrobenzonitrile (700.0 mg, crude) as a yellow solid.

Step b: 3-[(2-Hydroxyethyl)amino]-4-nitrobenzonitrile (623.0 mg, crude) and 10% wet Pd/C (200.0 mg) were added in MeOH (10.0 mL), the reaction mixture was stirred at 15° C. for 12 hours under H 2 (15 psi). LCMS indicated 99% of desired product formed. The reaction mixture was filtered and concentrated under reduced pressure to afford the product of 4-amino-3-[(2-hydroxyethyl)amino]benzonitrile (600.0 mg, crude) as a yellow solid which was used in next step without further purification.

Step c: Crude 4-Amino-3-[(2-hydroxyethyl)amino]benzonitrile (300.0 mg), 1,2-dibromoethane (1.6 g, 8.5 mmol) and TBAB (1.6 g, 5.1 mmol) were added in bottle, the reaction mixture was stirred at 60° C. for 12 hours. LCMS indicated 43% of desired product formed. TLC (Petroleum ether:Ethyl acetate=10:1) indicated one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:10) to afford the product of 4-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (130.0 mg) as a colorless oil.

Step d: 4-(2-hydroxyethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (100.0 mg, 492.0 μmol), TBSCl (148.0 mg, 983.0 μmol) and Imidazole (100.0 mg, 1.5 mmol) were added in DCM (5.0 mL), the reaction mixture was stirred at 40° C. for 1 hour. LCMS indicated 95% of desired product formed. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:10) to afford the product of 4-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (100.0 mg, 64.5% yield) as a colorless oil.

Synthesis of 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline, Used in the Preparation of Compound 440

Step a: A mixture of 8-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (300.0 mg, 1.32 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (301.0 mg, 1.45 mmol), Pd(dppf)Cl 2 (96.6 mg, 132.0 umol) and Cs 2 CO 3 (858.0 mg, 2.64 mmol) in dioxane (10.0 mL) and H 2 O (1.0 mL) was stirred at 100° C. for 16 hours under N 2 . Brown solution was observed. Desired mass ion was observed from LCMS. The solution was added into H 2 O (50.0 mL) and then extracted with EtOAc (50.0 mL×2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product as a brown gum. The residue was purified by flash silica gel chromatography (12.0 g, Ethyl acetate in Petroleum ether from 0% to 50%) to give 1-methyl-8-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline (130.0 mg, 43.1% yield) as an orange oil.

Synthesis of 2-(1,2,3,4-tetrahydroquinolin-5-yl)acetonitrile, Used in the Preparation of Compound 441

Step a: 5-Bromoquinoline (5.0 g, 24.0 mmol) was added in CH 3 COOH (50.0 mL), NaBH 3 CN (5.2 g, 84.0 mmol) was added in one portion, the reaction mixture was stirred at 5° C. for 2 hours. TLC (Petroleum ether:Ethyl acetate=10:1) indicated one main spot formed. The reaction mixture was diluted with EtOAc(500.0 mL), adjusted pH=8 by adding saturated NaHCO 3 , the organic phase was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:EtOAc=10:1) to afford the product of 5-bromo-1,2,3,4-tetrahydroquinoline (4.5 g, 88.4% yield) as a yellow oil.

Step b: 5-bromo-1,2,3,4-tetrahydroquinoline (4.5 g, 21.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (4.1 g, 21.2 mmol), Pd(dppf)Cl 2 (1.5 g, 2.1 mmol) and KF (4.9 g, 84.8 mmol) were added in the mixture of DMSO (100.0 mL) and H 2 O (20.0 mL), the reaction mixture was evacuated and refilled for 3 times with N 2 and stirred at 100° C. for 2 hours and stirred at 130° C. for 12 hours. TLC (Petroleum ether:Ethyl acetate=2:1) indicated one new spot formed. The reaction mixture was diluted with EtOAc (1000.0 mL), washed with H 2 O (500.0 mL×3) and brine, dried over anhydrous Na 2 SO 4 , the organic phase was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:EtOAc=2:1) to afford the product of 2-(1,2,3,4-tetrahydroquinolin-5-yl)acetonitrile (1.3 g, 35.6% yield) as a yellow solid.

Synthesis of (R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile and (S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile, Used in the Preparation of Compound 452

Step a: A solution of 6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (1 g, 4.40 mmol), zincdicarbonitrile (774 mg, 6.60 mmol), Pd2(dba)3 (80.5 mg, 88.0 umol), dppf (97.6 mg, 176 umol) and Zn (34.3 mg, 528 umol) in DMF (20 mL) was stirred at 120° C. for 12 h under N2. The solution was added into H2O (50 mL) and then extracted with EtOAc (50 mL×2). The combined organic layers were washed with saturated NaCl (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give crude product as brown gum. The residue was purified by flash silica gel chromatography (40 g, Ethyl acetate in Petroleum ether from 0% to 45%) to give product (760 mg, 99.7% yield) as orange gum. LCMS: [M+H]+ 174.

›ABBREVIATIONS · 31 of 63

SFC: 8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (120 mg, 692 μmol) was purified by SFC (Column: ChiralPak IC-3 150×4.6 mm I.D., 3 um, Mobile phase: A: CO2 B:IPA (0.05% DEA), Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL/min Column temperature: 40° C.). (8R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (60.0 mg, 346 μmol) and (8S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (60.0 mg, 346 μmol) were obtained as white solid.

Synthesis of 5-(isopropylsulfonyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 456

Step a: A solution of 5-bromoquinoline (1.00 g, 4.81 mmol, 1 eq), propane-2-thiol (549.50 mg, 7.22 mmol, 673.41 uL, 1.5 eq), Xantphos (556.63 mg, 962.00 umol, 0.2 eq), Pd2(dba)3 (440.46 mg, 481.00 umol, 0.1 eq) and DIEA (1.86 g, 14.43 mmol, 2.51 mL, 3 eq) in dioxane (10 mL) was stirred at 100° C. under N2 for 12 hrs at sealed tuble. TLC (Petroleum ether/Ethyl acetate=8/1) showed that compound 1 (Rf=0.35) was consumed and a major spot (Rf=0.3) was given. The reaction mixture was cooled to 25° C., and filtered through a pad of celite. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0˜10/1, Rf=0.3 to give 5-(isopropylthio)quinoline (860 mg, 4.12 mmol, 85.5% yield, 97.3% purity) as a yellow oil. LCMS: m/z=204.2 (M+H)+.

Step b: To a solution of 5-(isopropylthio)quinoline (200 mg, 957.19 umol, 1 eq) in DCM (2 mL) was added m-CPBA (412.95 mg, 1.91 mmol, 80% purity, 2 eq) 0° C. Then the mixture was stirred at 25° C. for 2 hrs. LCMS (EW10678-1-P1A1) showed that the desired Ms (Rt=0.663 min) was detected. The reaction mixture was poured into saturated Na2SO3 solution (20 mL) and extracted with DCM (20 mL*2). The organic layer was washed with saturated Na2CO3 solution (20 mL*1), dried over Na2SO4, filtered and concentrated to give 5-(isopropylsulfonyl)quinoline (200 mg, crude) as a yellow oil. LCMS: m/z=236.0 (M+1)+.

Step c: To a solution of 5-(isopropylsulfonyl)quinoline (200 mg, 849.97 umol, 1 eq) in MeOH (10 mL) was added PtO2 (0.1 g, 440.38 umol, 5.18e-1 eq) at 20° C. under N2. Then the mixture was stirred under H2 (50 psi) at 25° C. for 16 hrs. LCMS (EW10678-2-P1A2) showed that the desired Ms (Rt=0.721 min) was detected. The reaction mixture was filtered. The filtrate was concentrated. The residue was purified by column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-40%, 11 min. Then the residue was lyophilized to give 5-(isopropylsulfonyl)-1,2,3,4-tetrahydroquinoline (79.0 mg, 280.72 umol, 33.0% yield, 98.0% purity, HCl) as a yellow solid. LCMS: m/z=240.2 (M+1)+.

Synthesis of 5-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 457

Step a: A solution of quinoline-5-thiol (500 mg, 3.10 mmol, 1 eq), bromocyclopropane (750.36 mg, 6.20 mmol, 496.93 uL, 2 eq) and Cs2CO3 (2.02 g, 6.20 mmol, 2 eq) in DMF (5 mL) was stirred at 100° C. for 16 hrs. LCMS (EW10678-9-P1A1) showed that the desired Ms (Rt=0.715 min) was detected. The reaction mixture was cooled to 25° C., and poured into H2O (50 mL), extracted with ethyl acetate (50 mL*3). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography SiO 2 , Petroleum ether/Ethyl acetate=1/0-10/1, (Rf=0.45, Petroleum ether/Ethyl acetate=1/1) to give 5-(cyclopropylthio)quinoline (300 mg, 1.35 mmol, 43.4% yield, 90.4% purity) as a yellow oil. LCMS: m/z=201.9 (M+H)+.

Step b: To a solution of 5-(cyclopropylthio)quinoline (300 mg, 1.35 mmol, 1 eq) in DCM (6 mL) was added m-CPBA (581.26 mg, 2.69 mmol, 80% purity, 2 eq). Then the mixture was stirred at 25° C. for 16 hrs. LCMS (EW10678-11-P1A) showed that the desired Ms (Rt=0.297 min) was detected. The reaction mixture was poured into saturated Na2SO3 solution (40 mL) and extracted with DCM (40 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give 5-(cyclopropylsulfonyl)quinoline 1-oxide (300 mg, 1.20 mmol, 89.3% yield) as a yellow solid. LCMS: m/z=250.0 (M+H)+.

Step c: To a solution of 5-(cyclopropylsulfonyl)quinoline 1-oxide (0.3 g, 1.20 mmol, 1 eq) in MeOH (12 mL) was added PtO2 (0.15 g, 660.56 umol, 5.49e-1 eq) under N2. Then the mixture was stirred under H2 (50 psi) at 25° C. for 16 hrs. LCMS (EW10678-16-P1A2) showed that the desired Ms (Rt=0.503 min) was detected. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-50%, 10 min. Then the mixture was lyophilized to give 5-(cyclopropylsulfonyl)-1,2,3,4-tetrahydroquinoline (99.23 mg, 355.20 umol, 29.5% yield, 98.0% purity, HCl) as a yellow solid. LCMS: m/z=238.2 (M+1)+.

Synthesis of 5-((2-methoxyethyl)sulfonyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 460

Step a: A solution of quinoline-5-thiol (500 mg, 3.10 mmol, 1 eq), 2-methoxyethyl 4-methylbenzenesulfonate (857.00 mg, 3.72 mmol, 1.2 eq), Cs2CO3 (1.21 g, 3.72 mmol, 1.2 eq) in DMF (5 mL) was stirred at 85° C. for 12 h. TLC (Petroleum ether/Ethyl acetate=3/1) showed that the compound 3 (Rf=0) was consumed and a major spot (Rf=0.24) was given. The reaction mixture was filtered and the filtrate was poured into water (30 mL), extracted with ethyl acetate (20 mL*2). The organic layer was concentrated under vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=3/1, Rf=0.24) to give 5-((2-methoxyethyl)thio)quinoline (480 mg, 1.99 mmol, 64.01% yield, 90.7% purity) as a red oil. LCMS: m/z=220.0 (M+1)+.

Step b: To the solution of 5-((2-methoxyethyl)thio)quinoline (480 mg, 1.99 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (856.47 mg, 3.97 mmol, 80% purity, 2 eq). Then the reaction mixture was stirred at 20° C. for 30 min. LCMS (EW10591-15-P1A1) showed the desired Ms (Rt=0.569 min) was given. The reaction mixture was poured into 10% saturated Na2SO3 solution (30 mL) and stirred for 30 min. The mixture was extracted with DCM (10 mL*2). The combined organic layer was concentrated under vacuum to give 5-((2-methoxyethyl)sulfonyl)quinoline (500 mg, crude) as yellow oil. LCMS: m/z=252.1 (M+1)+.

›ABBREVIATIONS · 32 of 63

Step c: A suspension of 5-((2-methoxyethyl)sulfonyl)quinoline (0.5 g, 1.99 mmol, 1 eq), PtO2 (0.3 g, 1.32 mmol, 6.64e-1 eq) in MeOH (20 mL) was stirred at 25° C. under H2 (50 psi) for 3 h. LCMS (EW10591-18-P1B) showed that the desired Ms (Rt=0.671 min) was given. The mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum. The residue was purified by Pre-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 16%-36%, 11 min). The mixture was concentrated to remove MeCN and adjusted to pH=8 with saturated NaHCO 3 solution. The mixture was extracted with ethyl acetate (30 mL*2). The combined organic layer was concentrated under vacuum to give 5-((2-methoxyethyl)sulfonyl)-1,2,3,4-tetrahydroquinoline (126.6 mg, 486.90 umol, 24.47% yield, 98.2% purity) as a yellow oil. LCMS: m/z=256.2 (M+H)+.

Synthesis of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline, Used in the Synthesis of Compound 463

Step a: To 4-bromo-2-fluoro-1-nitrobenzene (25.0 g, 113 mmol) in MeOH (100 mL) and THF (50 mL) was added 2M MeNH 2 (67.5 mL, 135 mmol) dropwise. The mixture was stirred at 10° C. for 12 hours. When TLC analysis (10/6 EtOAc/petroleum ether) indicated that the reaction was incomplete, additional 2M MeNH 2 in THF (60 mL) was added to the mixture and stirring continued at 45° C. for another 12 hours. The mixture was concentrated under reduced pressure and water (200 mL) added to the concentrated, followed by extraction with EtOAc (200 mL×2). The combined organics were washed with brine, dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 5-bromo-N-methyl-2-nitroaniline (25.5 g, 97.7% yield) as a yellow solid.

Step b: To 5-bromo-N-methyl-2-nitroaniline (10.0 g, 43.2 mmol) in MeOH (150 mL) was added sodium dithionite (67.5 g, 388 mmol) in H 2 O (60 mL) dropwise. The mixture was stirred at 60° C. for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was extracted with EtOAc (200 mL×3) and the combined organics washed with H 2 O (100 mL), brine (100 mL), and dried over anhydrous Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-bromo-N 1 -methylbenzene-1,2-diamine (8.60 g, crude) as a brown oil.

Step c: A mixture of 5-bromo-N 1 -methylbenzene-1,2-diamine (1.0 g, 4.97 mmol), 1,2-dibromoethane (2.13 mL, 24.8 mmol), and TBAB (4.80 g, 14.9 mmol) was stirred at 60° C. for 12 hours. The mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (0-30% EtOAc/petroleum ether) to give 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (233 mg, 20.8% yield) as a brown solid.

Step d: To the mixture of 7-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (100 mg, 0.44 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (137 mg, 0.66 mmol) in dioxane (5 mL) and H 2 O (1 mL) was added Pd(dppf)Cl 2 (32.1 mg, 44 umol) and K 3 PO 4 (205 mg, 0.97 mmol) under N 2 . The mixture was stirred at 100° C. under N 2 for 12 hours, cooled, concentrated under reduced pressure, and purified by flash silica gel (0-50% EtOAc/petroleum ether) to give 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline (35.9 mg, 35.9% yield) as a yellow oil.

Synthesis of 5-(oxetan-3-ylsulfonyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 464

Step a: A suspension of quinoline-5-thiol (500 mg, 3.10 mmol, 1 eq), oxetan-3-yl 4-methylbenzenesulfonate (849.15 mg, 3.72 mmol, 1.2 eq) and Cs2CO3 (1.21 g, 3.72 mmol, 1.2 eq) in DMF (5 mL) was stirred at 80° C. for 12 h. LCMS (EW10591-12-P1A1) showed the desired Ms (Rt=0.719 min) was given. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL*2). The combined organic layer was concentrated under vacuum. The residue was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate=1/1, Rf=0.2) to give 5-(oxetan-3-ylthio)quinoline (580 mg, crude) as a yellow oil. LCMS: m/z=218.2 (M+H)+.

Step b: To the solution of 5-(oxetan-3-ylthio)quinoline (580 mg, 2.67 mmol, 1 eq) in DCM (5 mL) was added m-CPBA (1.15 g, 5.34 mmol, 80% purity, 2 eq). Then the mixture was stirred at 20° C. for 30 min. LCMS (EW10591-14-P1A1) showed that the desired Ms (Rt=0.558 min) was given. The reaction mixture was poured into 10% saturated Na2SO3 solution (30 mL) and stirred for 30 min. The mixture was extracted with DCM (10 mL*2). The combined organic layer was concentrated under vacuum to give 5-(oxetan-3-ylsulfonyl)quinoline (600 mg, 2.41 mmol, 90.17% yield) as yellow oil. LCMS: m/z=250.1 (M+H)+.

Step c: A suspension of 5-(oxetan-3-ylsulfonyl)quinoline (0.6 g, 2.41 mmol, 1 eq), PtO2 (546.55 mg, 2.41 mmol, 1 eq) in MeOH (20 mL) was stirred at 25° C. under H2 (50 psi) for 3 h. LCMS (EW10591-17-P1B) showed the desired MS (Rt=0.666 min) was given. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under vacuum. The residue was purified by Pre-HPLC (column: Phenomenex luna C18 150*25 10u; mobile phase: [water (0.1% TFA)-ACN]; B %: 30/6-48%, 10 min) to give 5-(oxetan-3-ylsulfonyl)-1,2,3,4-tetrahydroquinoline (41.05 mg, 152.81 umol, 6.35% yield, 94.3% purity) as a yellow solid. LCMS: m/z=254.2 (M+H)+.

Synthesis of 5-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline, Used in the Preparation of Compound 465

Step a: A solution of quinoline-5-thiol (800 mg, 4.96 mmol, 1 eq), 4-iodo-1-methyl-pyrazole (1.24 g, 5.95 mmol, 1.2 eq), CuI (94.50 mg, 496.21 umol, 0.1 eq), K2CO3 (1.03 g, 7.44 mmol, 1.5 eq) and 1,10-phenanthroline (178.84 mg, 992.41 umol, 0.2 eq) in DMF (8 mL) was stirred under N2 at 120° C. for 16 hrs. LCMS (EW10678-12-P1A) showed that the desired Ms (Rt=0.663 min) was detected. The reaction mixture was cooled to 20° C. and filtered. The filter cake was washed with ethyl acetate (30 mL*4). The filtrate was washed with brine (60 mL*1). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0-10/1-0/1, Rf=0.1) to give 5-((1-methyl-1H-pyrazol-4-yl)thio)quinoline (700 mg, 1.94 mmol, 39.1% yield, 66.9% purity) as a yellow solid. LCMS: m/z=242.0 (M+1)+.

›ABBREVIATIONS · 33 of 63

Step b: To a solution of 5-((1-methyl-1H-pyrazol-4-yl)thio)quinoline_1 (400 mg, 1.11 mmol, 1 eq) in DCM (8 mL) was added m-CPBA (478.41 mg, 2.22 mmol, 80% purity, 2 eq). Then the mixture was stirred at 25° C. for 30 min. LCMS (EW10678-14-P1A) showed that the desired Ms (Rt=0.603 min) was detected. The reaction mixture was poured into saturated Na2SO3 solution (100 mL) and extracted with DCM (100 mL*2). The organic layer was dried over Na2SO4, filtered and concentrated to give 5-((1-methyl-1H-pyrazol-4-yl)sulfonyl)quinoline (400 mg, crude) as yellow oil. LCMS: m/z=274.1 (M+1)+.

Step c: To a solution of 5-((1-methyl-1H-pyrazol-4-yl)sulfonyl)quinoline (400 mg, 1.46 mmol, 1 eq) in MeOH (16 mL) was added PtO2 (0.2 g, 880.76 umol, 6.02e-1 eq) under N2. Then the mixture was stirred under H2 (50 psi) at 25° C. for 16 hrs. LCMS (EW10678-15-P1A3) showed that the desired Ms (Rt=0.514 min) was detected. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated. The residue was purified by column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 20%-44%, 8 min. Then the residue was lyophilized to give 5-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydroquinoline (182.88 mg, 578.12 umol, 39.5% yield, 99.2% purity, HCl) as a light yellow solid. LCMS: m/z=278.2 (M+1)+.

Synthesis of cis-4-(3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 469

Step a: A mixture of cis-3-methoxycyclobutan-1-amine hydrochloride (1.00 g, 7.26 mmol), 3-fluoro-4-nitrobenzonitrile (1.20 g, 7.26 mmol) and Et 3 N (2.19 g, 21.7 mmol) in EtOH (50.0 mL) was stirred at 80° C. for 2 hours. TLC (Petroleum ether/EtOAc=2/1) showed the starting material was consumed completely. The reaction was concentrated, dissolved in EtOAc (100.0 mL), washed with water (50.0 mL×2), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column (EtOAc in Petroleum ether=0˜30%) to give cis-3-[(3-methoxycyclobutyl)amino]-4-nitrobenzonitrile (1.70 g, 94.9% yield) as a yellow solid.

Step b: A mixture of cis-3-[(3-methoxycyclobutyl)amino]-4-nitrobenzonitrile (1.70 g, 6.87 mmol) and Pd/C (0.2 g, 10% wet) in THF (20.0 mL) was stirred at 20° C. under H 2 (15 psi.) for 6 hours. LCMS showed the starting material was consumed completely. The reaction mixture was filtered and concentrated to give cis-4-amino-3-[(3-methoxycyclobutyl)amino]benzonitrile (1.30 g, 87.2% yield) as a light red solid.

Step c: A mixture of cis-4-amino-3-[(3-methoxycyclobutyl)amino]benzonitrile (1.30 g, 5.98 mmol), 1,2-dibromoethane (4.48 g, 23.9 mmol), TBAB (7.70 g, 23.9 mmol) and Et 3 N (3.29 ml, 23.9 mmol) was stirred at 60° C. under N 2 for 12 hours. LCMS showed 13% of the starting material remained and about 60% of desired product formed. TLC (Petroleum ether/EtOAc=1/1) showed a little amount of the starting material remained and one major new spot with lower polarity was found. The reaction mixture was poured into water (100.0 mL) and extracted with DCM (50.0 mL×3). The organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica gel column (EtOAc in Petroleum ether=0˜30%) to give cis-4-(3-methoxycyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (1.15 g, 79.3% yield) as a light red oil.

Synthesis of 4-[trans-3-methoxycyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 470

Step a: To the mixture of 3-fluoro-4-nitrobenzonitrile (1.2 g, 7.3 mmol) and trans-3-methoxycyclobutan-1-amine hydrochloride (1.0 g, 7.3 mmol) in EtOH (30.0 mL) was added TEA (4.0 mL, 29.0 mmol). The mixture was stirred at 60° C. for 12 hours. TLC (Petroleum ether/EtOAc=10/1) showed a new spot formed. The mixture was concentrated in vacuum and washed with Petroleum ether/EtOAc (5/2, 40.0 mL×3). The solid was dried in vacuum to give the product of 3-[(3-methoxycyclobutyl)amino]-4-nitrobenzonitrile (2.0 g, crude) as a yellow solid.

Step b: To the mixture of 3-[(3-methoxycyclobutyl)amino]-4-nitrobenzonitrile (2.0 g, 8.1 mmol) in THF (40.0 mL) was added 10% Pd/C (400 mg, wet). The mixture was stirred at 10° C. under H 2 (15 psi) for 2 hours. LCMS showed 100% desired product formed. The mixture was filtered and the filtrate was concentrated in vacuum to give the product of 4-amino-3-[(3-methoxycyclobutyl)amino]benzonitrile (1.8 g, crude) as a brown oil.

Step c: A mixture of 4-amino-3-[(3-methoxycyclobutyl)amino]benzonitrile (1.8 g, 8.3 mmol), TBAB (5.3 g, 16.5 mmol), TEA (4.6 mL, 33.1 mmol) and 1,2-dibromoethane (1.0 mL) was stirred at 60° C. for 12 hours. LCMS showed 47.3% start material left. 1,2-dibromoethane (3.0 mL) was added to the mixture and the mixture was stirred at 60° C. for another 4 hours. LCMS showed 77.1% desired product was formed and 16.0% start material left. The mixture was poured into water (50.0 mL) and extracted with DCM (50.0 mL×3). The organic layers washed with brine and dried over anhydrous Na 2 SO 4 . The mixture was filtered and the filtrate was concentrated in vacuum to give residue. The residue was purified by flash silica gel chromatography (Petroleum ether/EtOAc=1/0 to 1/1) to give the product of 4-[trans-3-methoxycyclobutyl]-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (440.0 mg, 21.8% yield) as an off-white solid. Another batch a mixture of start material and desired product (700.0 mg) was remained.

Synthesis of 4-(1-acetylazetidin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 471

Step a: To a solution of 3-fluoro-4-nitrobenzonitrile (1.9 g, 11.6 mmol) in EtOH (20 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (2.0 g, 11.6 mmol) and Et 3 N (2.3 g, 23.2 mmol). The mixture stirred at 40° C. for 12 hours. LCMS showed ˜90% the desired product formed. The reaction mixture was concentrated to dryness, which was purified by silica gel chromatography (eluent: Petroleum ether:Ethyl acetate=5:1) to give tert-butyl 3-[(5-cyano-2-nitrophenyl)amino]azetidine-1-carboxylate (2.2 g, 59.6% yield) as a yellow solid.

›ABBREVIATIONS · 34 of 63

Step b: To a solution of tert-butyl 3-[(5-cyano-2-nitrophenyl)amino]azetidine-1-carboxylate (2.0 g, 6.3 mmol) in DCM (50 mL) was added TFA (10 mL), the mixture stirred at 25° C. for 2 hours, LCMS showed the desired product formed. The reaction mixture was concentrated to dryness, MeOH (20 mL), DCM (200 mL) and K 2 CO 3 (1 g) were added. The mixture was filtered and the filtrate was concentrated to dryness to give the product 3-[(azetidin-3-yl)amino]-4-nitrobenzonitrile (2.1 g, crude product) as a yellow solid.

Step c: A mixture of 3-[(azetidin-3-yl)amino]-4-nitrobenzonitrile (2 g, 9.2 mmol) in DCM (20 mL) was added TEA (1.9 g, 18.3 mmol) and AcCl (1.1 g, 13.7 mmol) at 0° C. The mixture stirred at 25° C. for 12 hours. LCMS showed the desired product was formed. The mixture washed with brine (10 mL) and concentrated. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=1:0 to 1:1) to give 3-[(1-acetylazetidin-3-yl)amino]-4-nitrobenzonitrile (1.2 g, 50.4% yield) as a yellow solid.

Step d: A solution of 3-[(1-acetylazetidin-3-yl)amino]-4-nitrobenzonitrile (1.1 g, 4.2 mmol) and wet 10% Pd/C (100 mg) in THF(10 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). LCMS showed the reaction was consumed completely. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the product of 3-[(1-acetylazetidin-3-yl)amino]-4-aminobenzonitrile (780 mg, 71.5% yield), which was used in the next step without further purification.

Step e: TEA (1.1 g, 10.4 mmol), 1,2-dibromoethane (2.0 g, 10.4 mmol) and TBAB (837 mg, 2.6 mmol) was stirred at 60° C. for 12 hours. LCMS showed the reaction was consumed completely. The mixture was diluted with H 2 O (20 mL) and extracted DCM (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (DCM:MeOH=10:0 to 10:1) to afford the product of 4-(1-acetylazetidin-3-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (490 mg, 73.5% yield) as a light yellow solid.

Synthesis of tert-butyl (1-(3-mercapto-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate, Used in the Preparation of Compound 477

Step a: A microwave vial was charged with tert-butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (390 mg, 719 μmol), (69.1 mg, 71.9 μmol), dioxane (4 mL), N-ethyl-N-isopropylpropan-2-amine (373 μL, 2.15 mmol) and 2-ethylhexyl 3-mercaptopropanoate (242 μL, 1.07 mmol). The vial was sealed, and the mixture was stirred in the microwave at 110° C. for 1 hr. The reaction was partitioned between EA/water, the organic layer was separated, washed with brine, dried and pre-adsorbed on SiO 2 . The residue was purified on ISCO Si-12g (10-50% EA/heptanes) to give 2-ethylhexyl 3-((6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)propanoate. LCMS m/z: 633.4 (M+H) + .

Step b: A resealable reaction vial was charged with 2-ethylhexyl 3-((6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)propanoate (450 mg, 711 μmol) and THF (5 mL) then cooled to −78° C. 1M tBuOK in THF (239 mg, 2.13 mmol) was added which made the reaction mixture became a gel-like solid. The reaction was warmed up to 25° C., and diluted with THF (10 mL). After 2 hrs, the reaction mixture was partitioned between sat. NH 4 Cl and ethyl acetate. The organic layer was separated, dried and concentrated to yield tert-butyl (1-(3-mercapto-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate as an orange foam. LCMS m/z: 471.2 (M+Na)+.

Synthesis of (1-acetyl-3-piperidyl) 4-methylbenzenesulfonate, Used in the Preparation of Compound 488

Step a: To a mixture of piperidin-3-one hydrochloride (5.0 g, 36.9 mmol) and TEA (11.2 g, 110.6 mmol) in DCM (50.0 mL) was added (Boc) 2 O (12.1 g, 55.3 mmol). The reaction mixture was stirred at 10° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether:ethyl acetate=20:1 to 10:1) to afford the product of tert-butyl 3-oxopiperidine-1-carboxylate (4.2 g, 54% yield) as a yellow oil.

Step b: To a mixture of tert-butyl 3-oxopiperidine-1-carboxylate (4.1 g, 20.6 mmol) in anhydrous MeOH (40.0 mL) at 0° C. was added NaBH4 (1.6 g, 41.2 mmol). Then the reaction mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether:ethyl acetate=4:1 to 1:1) to afford the product of tert-butyl 3-hydroxypiperidine-1-carboxylate (2.1 g, 48% yield) as a colorless oil.

Step c: To a mixture of NaH (1.3 g, 31.3 mmol, 60% in mineral oil) in anhydrous THF (20.0 mL) at 0° C. was added tert-butyl 3-hydroxypiperidine-1-carboxylate (2.1 g, 10.4 mmol). After stirred for 30 min at this temperature, TsCl (3.0 g, 15.6 mmol) in THF (5.0 mL) was added. The reaction mixture was warmed to 20° C., and stirred for 1 hour. The reaction mixture was quenched by addition of sat NH 4 Cl (5.0 mL) at 0° C., and then diluted with H 2 O (20.0 mL), and extracted with ethyl acetate (25.0 mL×2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography (petroleum ether: ethyl acetate=10:1 to 6:1) to afford the product of tert-butyl 3-(p-tolylsulfonyloxy)piperidine-1-carboxylate (2.0 g, 52% yield) as a colorless oil.

Step d: A mixture of tert-butyl 3-(p-tolylsulfonyloxy)piperidine-1-carboxylate (1.0 g, 2.8 mmol) in 4 M HCl/MeOH (10.0 mL) was stirred at 15° C. for 1 hour. The reaction mixture was concentrated in vacuo to afford the product of piperidin-3-yl 4-methylbenzenesulfonate hydrochloride (810.0 mg, crude product) as colorless oil, which was used in the next step without further purification.

›ABBREVIATIONS · 35 of 63

Step e: To a mixture of piperidin-3-yl 4-methylbenzenesulfonate hydrochloride (800.0 mg, 2.7 mmol) and TEA (1.4 g, 13.7 mmol) in anhydrous DCM (15.0 mL) at 0° C. was added a solution of AcCl (537.7 mg, 6.9 mmol) in anhydrous DCM (5.0 mL) slowly. The reaction mixture was warmed to 20° C. stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (35.0 mL×2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the product of (1-acetyl-3-piperidyl) 4-methylbenzenesulfonate (690.0 mg, crude product) as a yellow oil.

Synthesis of tert-butyl (1-(3-mercapto-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate, Used in the Preparation of 489

Step a: A resealable reaction vial was charged with tert-butyl (1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (1.00 g, 1.88 mmol), 2-ethylhexyl 3-mercaptopropanoate (615 mg, 2.82 mmol), BrettPhos (100 mg, 188 μmol), BrettPhos-Pd G4 (173 mg, 188 μmol), DiEA (983 μL, 5.64 mmol) and a stirbar before being evacuated and purged with nitrogen three times. dioxane (25 mL) was added, and the mixture was stirred at 120° C. for 12 h. The reaction mixture was concentrated to give a residue, which was purified by by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 20/100) to afford the product 2-ethylhexyl 3-((6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)propanoate (1.00 g, 1.49 mmol) as a yellow oil. LCMS: [M+H]+ 669.3.

Step b: The compound 2-ethylhexyl 3-((6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)propanoate (700 mg, 1.04 mmol) was dissolved in THF (5 mL). The reaction mixture was cooled to −78° C., and t-BuOK (1 M, 3.12 mL, in THF) was added drop wise in 10 min under N2. The reaction mixture was stirred at −78° C. for 20 min, then diluted with DCM (30 mL) and acidified with HCl/MeOH (2 N) to pH=6 at −78° C. The mixture was washed with H2O (20 mL) and brine (20 ml). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give the product tert-butyl (1-(3-mercapto-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (500 mg, 1.03 mmol), which was carried on without further purification.

Synthesis of tert-butyl (1-(3-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate, Used in the Preparation of Compound 510

Step a: A resealable reaction vial was charged with methyl 3,5-dichloropyrazine-2-carboxylate (3.12 g, 15.0 mmol) and DMF (30 mL) then cooled to 0-5° C. The reaction was charged with tert-butyl (4-methylpiperidin-4-yl)carbamate (3.36 g, 15.7 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.87 g, 30.0 mmol), and the mixture was stirred at 0-5° C. for 1 h. The reaction was partitioned between ethyl acetate/brine/water, the organic layer was dried over sodium sulfate and pre-adsorbed on SiO 2 (11g) before being purified by silica gel chromatography (eluting with ethyl acetate and heptane). The product containing fractions were pooled and concentrated in vacuo to yield methyl 5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-3-chloropyrazine-2-carboxylate (5.14 g) as a light yellow foam. LCMS: [M+H]+ 407.3.

Step b: A round bottomed flask was charged with methyl 5-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-3-chloropyrazine-2-carboxylate (4.75 g, 12.3 mmol) (note: SM is foam/gum, was not thoroughly dried so amount is over-estimated), EtOH (45 mL), (4-methoxybenzyl)hydrazine hydrochloride (2.77 g, 14.7 mmol) and triethylamine (5.13 mL, 36.9 mmol). The solution was stirred at 75° C. 18 h. The mixture was cooled to rt, filtered, the cake washed with EtOH and air dried to constant weight to give tert-butyl (1-(3-hydroxy-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (2.76 g) as a white solid. LCMS: [M+H]+ 469.5.

Synthesis of (rel)-5-[(3S)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 519

Step a: A mixture of tert-butyl 4-bromo-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4.4 g, 16.5 mmol), (quinolin-5-yl)boronic acid (3.4 g, 19.8 mmol), Pd(dppf)Cl 2 (603 mg, 825 μmol) and K 2 CO 3 (4.6 g, 33.0 mmol) in dioxane (70 mL)/H 2 O (10 mL) was stirred at 100° C. for 3 hours under N 2 atmosphere. LCMS showed the reaction was consumed completely. The reaction mixture was concentrated in vacuum to give a residue, which was dissolved in ethyl acetate (100 mL), washed with H 2 O (80 mL×2). The organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether=80% to 95%) to afford the product of tert-butyl 2-oxo-4-(quinolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.4 g, 67.3% yield) as a yellow solid.

Step b: A mixture of tert-butyl 2-oxo-4-(quinolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.4 g, 10.9 mmol) in HCl/MeOH (4 M, 50 mL) was stirred at 15° C. for 12 hours. LCMS showed the reaction was consumed completely. The reaction mixture was concentrated in vacuum to afford the product of 4-(quinolin-5-yl)-1H-pyrrol-2(5H)-one (2.1 g, 91.7% yield) as a yellow solid.

Step c: A mixture of 4-(quinolin-5-yl)-2,5-dihydro-1H-pyrrol-2-one (2.0 g, 9.5 mmol) and PtO 2 (215 mg, 951 μmol) in MeOH (40 mL) was stirred at 25° C. for 12 hours under H 2 atmosphere (15 psi). LCMS showed the reaction was consumed completely. The reaction mixture was filtered and concentrated in vacuum to afford the product of 4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one (2.0 g, crude product) as a yellow solid.

Step d: A mixture of 4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one (1.9 g, 8.8 mmol) and (Boc) 2 O (1.9 g, 8.8 mmol) in dioxane (50 mL) was stirred at 80° C. for 12 hours. LCMS showed the reaction was consumed completely. The reaction mixture was concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Methanol in Dichloromethane=0% to 8%) to afford the product of tert-butyl 5-(5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.5 g, 54.1% yield) as a yellow oil.

›ABBREVIATIONS · 36 of 63

Step e: To a mixture of NaH (60% in mineral oil, 365 mg) in anhydrous THF (30 mL) at 0° C. was added the solution of tert-butyl 5-(5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.5 g, 4.6 mmol) in THF (10 mL), the resulting mixture was stirred for 30 min. MeI (3.3 g, 22.9 mmol) in THF (10 mL) was added, the reaction mixture was warmed to 20° C., and stirred for 11.5 hours. LCMS showed the reaction was consumed completely. The reaction mixture was quenched with sat.NH4Cl, diluted with H 2 O (50 mL) and extracted with ethyl acetate (55 mL×2). The organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product, which was purified by silica gel chromatography (Ethyl acetate as eluent) to afford the product of tert-butyl 5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.2 g, 82.7% yield) as a yellow oil.

Step f: To a mixture of tert-butyl 5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (650 mg, 2.0 mmol) in DMF (30 mL) at 0° C. was added NBS (380 mg, 2.2 mmol), the reaction mixture was warmed to 15° C., and stirred for 12 hours. LCMS showed the reaction was consumed completely. The reaction mixture was diluted with ethyl acetate (60 mL), extracted with H 2 O (50 mL×2). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Ethyl acetate as eluent) to afford the product of tert-butyl 6-bromo-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (580 mg, 72.3% yield) as a colorless oil.

Step g: A mixture of tert-butyl 6-bromo-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (540 mg, 1.3 mmol), [(t-Bu 3 P) 2 ]Pd (66.9 mg, 131 μmol) and Zn(CN) 2 (303 mg, 2.6 mmol) in DMF (25 mL) was stirred at 130° C. for 12 hours under N 2 atmosphere. LCMS showed the reaction was consumed completely. The reaction mixture was diluted with ethyl acetate (70 mL), washed with H 2 O (50 mL×2). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give a residue, which was purified by silica gel chromatography (Methanol in Dichloromethane=0% to 7%) to afford the product of tert-butyl 6-cyano-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (450 mg, 96.7% yield) as a colorless oil.

Step h: A mixture of tert-butyl 6-cyano-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (440 mg, 1.2 mmol) in HCl/MeOH (4M, 10 mL) was stirred at 25° C. for 2 hours. LCMS showed the reaction was consumed completely. The reaction mixture was diluted with MeOH (10 mL) and adjusted pH=8 with solid NaHCO 3 . The mixture was filtered and concentrated in vacuum to give a residue, which was purified by prep-HPLC (NH 3 .H 2 O) to afford the product of 5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (140 mg, 44.5% yield) as a white solid.

SFC: The compound is separable in developing SFC (Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um Gradient: 40% of EtOH (0.05% DEA) in CO 2 Flow rate: 2.5 mL/min Column temperature: 35° C.). The compound of rac-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (140 mg, 548 μmol) was separated by preparative Chiral-SFC (Column: Phenomenex-Amylose-1 (250 mm*30 mm, 5 um). condition: 0.1% NH 3 .H 2 O EtOH, begin B: 30%, end B: 30%, Flow Rate: 50 ml/min) to afford the desired product of (rel)-5-[(3S)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (57 mg, 41% yield) as a white solid, which was confirmed by HPLC, SFC (e.e.=99.8%, the faster eluting isomer) and (rel)-5-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (57 mg, 41% yield) as a white solid, which was confirmed by HPLC, SFC (R t =4.863 min, e.e.=98.7%, the slower eluting isomer). The faster eluting isomer (R t =4.607 min) is the peak 1 in developing SFC. The slower eluting isomer (R, =4.863 min) is the peak 2 in developing SFC.

Synthesis of 2-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-J]quinolin-3-one, Used in the Preparation of Compound 520

Step a: The mixture of 5-bromoquinoline (2.0 g, 9.61 mmol, 1.0 eq), Zn(CN) 2 (2.26 g, 19.23 mmol, 2.0 eq) and XantPhos-Pd-G4 (924.8 mg, 961.3 umol, 0.1 eq) in dioxane (20.0 mL) and H 2 O (2.0 mL) was stirred at 80° C. for 16 hours under N 2 . LCMS showed the starting material was consumed completely and the desired MS was detected. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=1:1) to afford the product of quinoline-5-carbonitrile (1.28 g, 84.6% yield) as a white solid.

Step b: To a solution of quinoline-5-carbonitrile (780.0 mg, 5.06 mmol, 1.0 eq) in MeOH (10.0 mL) were added Raney-Ni (300.0 mg, 5.11 mmol, 1.0 eq) and NH 3 .H 2 O (1.91 g, 2.10 mL, 28% purity). The reaction mixture was degassed and refilled with H 2 for three times. The reaction mixture was stirred at 15° C. for 16 hours under H 2 (15 psi). LCMS showed the starting material was consumed completely and the desired MS was detected. The reaction mixture was filtered through a pad of celite and washed with MeOH (5.0 mL×4). The filtrate was concentrated under reduced pressure to give a green residue. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to afford the product of 5-quinolylmethanamine (550.0 mg, crude) as a green oil.

Step c: To a solution of 5-quinolylmethanamine (550.0 mg, 3.48 mmol, 1.0 eq) in DCM (7.0 mL) were added isopropyl carbonochloridate (852.1 mg, 6.95 mmol, 965.0 uL, 2.0 eq) and TEA (1.06 g, 10.43 mmol, 1.45 mL, 3.0 eq). The reaction mixture was stirred at 15° C. for 16 hours under N 2 . LCMS showed the starting material was consumed completely and the desired MS was detected. The reaction mixture was concentrated under reduced pressure to give a yellow residue. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=0:1) to afford the product of isopropyl N-(5-quinolylmethyl)carbamate (670.0 mg, 78.5% yield) as a white solid.

›ABBREVIATIONS · 37 of 63

Step d: To a solution of isopropyl-N-(5-quinolylmethyl)carbamate (830.0 mg, 3.40 mmol, 1.0 eq) and Cs 2 CO 3 (3.32 g, 10.19 mmol, 3.0 eq) in DMF (10.0 mL) was added a solution of MeI (578.7 mg, 4.08 mmol, 253.8 uL, 1.2 eq) in DMF (2.0 mL). The reaction mixture was stirred at 15° C. for 16 hours under N 2 . LCMS showed 40% of the starting material was remained and 42% of the desired product formed. The reaction mixture was concentrated under reduced pressure. The residue was washed with water (70.0 mL) and extracted with EtOAc (50.0 mL×3). The combined organic layer was concentrated under reduced pressure to give a red residue. The residue was purified by silica gel column chromatography (DCM:MeOH=10:1) to afford the product of isopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (610.0 mg, crude) as a red oil. The crude product was purified again by silica gel column chromatography (Petroleum ether/Ethyl acetate=0:1) to afford the product of isopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (210.0 mg, 96.4% yield) as a yellow oil.

Step e: To a solution of isopropyl-N-methyl-N-(5-quinolylmethyl)carbamate (130.0 mg, 503.3 umol, 1.0 eq) in MeOH (3.0 mL) was added PtO 2 (20.0 mg, 88.08 umol, 1.75 eq). The reaction mixture was degassed and refilled with H 2 for three times. The reaction mixture was stirred at 30° C. for 16 hours under H 2 (15 psi). LCMS showed the starting material was consumed completely and the desired MS was detected. The reaction mixture was filtered through a pad of celite and washed with MeOH (5.0 mL×3). The filtrate was concentrated under reduced pressure to give the product of isopropyl N-methyl-N-(1,2,3,4-tetrahydroquinolin-5-ylmethyl)carbamate (115.0 mg, 87.1% yield, crude) as a green oil.

Step f: To a solution of isopropyl N-methyl-N-(1,2,3,4-tetrahydroquinolin-5-ylmethyl)carbamate (60.0 mg, 228.7 umol, 1.0 eq) in DCM (3.8 mL) was added P 2 O 5 (324.6 mg, 2.29 mmol, 10.0 eq). The reaction mixture was stirred at 40° C. for 16 hours under N 2 . LCMS showed 10% of the starting material was remained and 60% of the desired product formed. The reaction mixture was adjusted to pH=8 by adding saturated NaHCO 3 aqueous solution and extracted with DCM (30.0 mL×2). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a yellow residue. The crude product on page ES9196-29 was combined with ES9196-30 for further purification. The combined crude product was purified by prep-HPLC (NH 4 HCO 3 ) (column: Waters Xbridge 150×25 5 u; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B %: 15%-45%, 7 min) to afford the product of 2-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,4-]quinolin-3-one (20.0 mg, 43.2% yield) as a white solid.

Synthesis of 5-[(2S)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 522

Step a: A mixture of 5-bromoquinoline (3.9 g, 18.7 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.6 g, 18.7 mmol), Pd(dppf)Cl 2 (1.3 g, 1.8 mmol) and K 2 CO 3 (7.7 g, 56.1 mmol) in dioxane/H 2 O(40 mL/4 mL) was stirred at 90° C. under N 2 for 12 hours. After concentration, the residue was purified by silica column (Ethyl acetate in Petroleum ether 0-30%) to give the desired product of 5-(furan-2-yl) quinoline (3.6 g, 98.6% yield) as a yellow oil.

Step b: A mixture of 5-(furan-2-yl)quinoline (3.6 g, 18.4 mmol) and 10% Pd/C (0.4 g, wet) in MeOH (40 mL) was stirred at 30° C. for 1 day under H 2 (15 psi). LCMS showed 60% of starting material 2 was still remained. The mixture was filtered and the filtrate was concentrated to give a residue (3.7 g) which was dissolved in MeOH (40 mL). 10% Pd/C (0.8 g, wet) was added. The mixture was stirred at 30° C. for 1 day under H 2 (15 psi). LCMS showed 34.7% of starting material 2 was still remained. The mixture was filtered and the filtrate was concentrated in vacuum to give a residue (3.9 g) as a yellow oil. The residue was dissolved in MeOH (40 mL). 10% Pd/C (1 g, wet) was added. The mixture was stirred at 30° C. for 1 day under H 2 (15 psi). LCMS showed the no starting material 2 was remained and the 59% product formed. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by silica column (ethyl acetate in petroleum ether=0˜50%) to give the desired product of 5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline (1.6 g, crude) as a yellow oil.

Step c: To a solution of 5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline (1.54 g, 7.57 mmol) in DMF (15.0 mL) was added NBS (1.34 g, 7.57 mmol) at 15° C. under N 2 . The mixture was stirred at 15° C. for 0.5 h. The mixture was diluted with EtOAc (50 mL), washed with H 2 O (10 mL×3), brine (10 mL) and concentrated in vacuum. The residue was purified by silica column (ethyl acetate in petroleum ether=0˜30%) to give the desired product of 6-bromo-5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline (1.92 g, 90.1% yield) as a yellow oil.

Step d: A mixture of 6-bromo-5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline (500 mg, 1.77 mmol), Zn(CN) 2 (415 mg, 3.54 mmol), Pd(t-Bu 3 P) 2 (90.4 mg, 177 μmol) in DMF (2.0 mL) was stirred at 130° C. for 12 hours under N 2 . After concentration, the residue was purified by silica column (ethyl acetate in petroleum ether=0˜50%) to give the desired

SFC: The compound of rac-5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (150 mg, 657 μmol) was separated by preparative chiral SFC (Column: DAICEL CHIRALCEL OJ-H(250 mm*30 mm, 5 um). Mobile phase: 30% of ethanol (0.1% NH 3 —H 2 O) in CO 2 . Flow rate: 65 mL/min.) to afford the desired product of 5-[(2S)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (74.0 mg, 49.6% yield, R t =2.864 min, e.e.=100%, the faster eluting isomer) as a yellow solid and the enantiomer 5-[(2R)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (75.0 mg, 50.3% yield, R t =3.246 min, e.e.=100%, the slower eluting isomer) as a yellow solid.

Synthesis of (4S)-1-methyl-4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one, Used in the Preparation of Compound 521 and Compound 523

›ABBREVIATIONS · 38 of 63

The enantiomers of 1-methyl-4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one were separable in developing SFC: (Column: Chiralpak AS-3 150×4.6 mm I.D., 3 um. Mobile phase: A: CO2; B: ethanol (0.05% DEA). Gradient: from 5% to 40% of B in 5 min and hold 40% for 2.5 min, then 5% of B for 2.5 min. Flow rate: 2.5 mL/min. Column temp: 35° C. ABPR: 1500 psi). The compound of 1-methyl-4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one (230.0 mg, 998.68 umol, 1.0 eq) was separated by preparative SFC column: (DATCEL CHIR ALPAK A S-H (250 mm×30 mm, 5 um). Mobile phase: 0.1% NH 3 —H 2 O, EtOH. Begin B: 45%, End B: 45%. Flow rate: 50 mL/min) to afford the product of (4S)-1-methyl-4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one (the faster eluting isomer, 105.0 mg, 455.9 umol, 45.7% yield): e.e.=99.4%, R t =3.734 min, as a yellow oil and the enantiomer (4R)-1-methyl-4-(1,2,3,4-tetrahydroquinolin-5-yl)pyrrolidin-2-one (1b, the slower eluting isomer, 105.0 mg, 455.9 umol, 45.7% yield): e.e.=99.9%, R t =4.728 min, as a yellow oil.

Synthesis of 5-[(2R)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 524

SFC: The compound of rac-5-(oxolan-2-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (150 mg, 657 μmol) was separated by preparative chiral SFC (Column: DAICEL CHIRALCEL OJ-H(250 mm*30 mm, 5 um). Mobile phase: 30% of ethanol (0.1% NH 3 .H 2 O) in CO 2 . Flow rate: 65 ml/min.) to afford the desired product 5-[(2R)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (75.0 mg, 50.3% yield, R t =3.246 min, e.e.=100%, the slower eluting isomer) as a yellow solid and the enantiomer 5-[(2S)-oxolan-2-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (74.0 mg, 49.6% yield, R t =2.864 min, e.e.=100%, the faster eluting isomer) as a yellow solid.

Synthesis of (rel)-5-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 525

›ABBREVIATIONS · 39 of 63

Step e: To a mixture of NaH (60% in mineral oil, 365 mg) in anhydrous THF (30 mL) at 0° C. was added the solution of tert-butyl 5-(5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.5 g, 4.6 mmol) in THF (10 mL), the resulting mixture was stirred for 30 min. MeI (3.3 g, 22.9 mmol) in THF (10 mL) was added, the reaction mixture was warmed to 20° C., and stirred for 11.5 hours. LCMS showed the reaction was consumed completely. The reaction mixture was quenched with sat.NH 4 Cl, diluted with H 2 O (50 mL) and extracted with ethyl acetate (55 mL×2). The organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum to give the crude product, which was purified by silica gel chromatography (Ethyl acetate as eluent) to afford the product of tert-butyl 5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.2 g, 82.7% yield) as a yellow oil.

SFC: The compound is separable in developing SFC (Column: ChiralPak AD-3 150×4.6 mm I.D., 3 um Gradient: 40% of EtOH (0.05% DEA) in CO 2 Flow rate: 2.5 mL/min Column temperature: 35° C.). The compound of rac-5-(1-methyl-5-oxopyrrolidin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (140 mg, 548 μmol) was separated by preparative Chiral-SFC (Column: Phenomenex-Amylose-1 (250 mm*30 mm, 5 um). condition: 0.1% NH 3 .H 2 O EtOH, begin B: 30%, end B: 30%, Flow Rate: 50 ml/min) to afford the desired product of (rel)-5-[(3S)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (57 mg, 41% yield) as a white solid, which was confirmed by HPLC, SFC (R t =4.607 min, e.e.=99.8%, the faster eluting isomer) and (rel)-5-[(3R)-1-methyl-5-oxopyrrolidin-3-yl]-1,2,3,4-tetrahydroquinoline-6-carbonitrile (57 mg, 41% yield) as a white solid, which was confirmed by HPLC, SFC (R t =4.863 min, e.e.=98.7%, the slower eluting isomer). The faster eluting isomer (R t =4.607 min) is the peak 1 in developing SFC. The slower eluting isomer (R t =4.863 min) is the peak 2 in developing SFC.

Synthesis of cis-4-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 526

Step a: A solution of cis-3-amino-1-methylcyclobutan-1-ol hydrochloride (900.0 mg, 6.5 mmol) and TEA (1.8 mL, 13.0 mmol) in EtOH (10.0 mL) was stirred at 60° C. for 10 min. To a solution was added 3-fluoro-4-nitrobenzonitrile (1.20 g, 7.2 mmol). The reaction mixture was stirred at 60° C. for 1 hour. TLC (Petroleum ether:Ethyl acetate=2:1) showed starting material was remained and one new spot with larger polarity was found. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:10 and CH 2 Cl 2 :MeOH=100:0 to 100:10). The product of cis-3-[(3-hydroxy-3-methylcyclobutyl)amino]-4-nitrobenzonitrile (1.50 g, 6.1 mmol, 93.1% yield) was obtained as a yellow solid.

Step b: A solution of cis-3-[(3-hydroxy-3-methylcyclobutyl)amino]-4-nitrobenzonitrile (1.50 g, 6.1 mmol), imidazole (1.20 g, 18.1 mmol), TEA (839.0 uL, 6.1 mmol) and TBSCl (2.70 g, 18.1 mmol) in DCM (20.0 mL) was stirred at 40° C. for 12 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed starting material was disappeared and one new spot with lower polarity. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:30). The product of cis-3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)-4-nitrobenzonitrile (2.00 g, 5.5 mmol, 91.3% yield) was obtained as a yellow solid.

›ABBREVIATIONS · 40 of 63

Step c: A solution of cis-3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)-4-nitrobenzonitrile (2.00 g, 5.53 mmol) and wet Pd/C (500.0 mg, 10%) in MeOH (15.0 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). TLC (Petroleum ether:Ethyl acetate=1:1) showed the starting material was disappeared and one spot with polarity was formed. Pd/C was filtered off and the filtrate was concentrated under reduced pressure. The residue (1.80 g, 98.3% yield) was used in the next step directly.

Step d: A mixture of cis-4-amino-3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)benzonitrile (1.80 g, 5.42 mmol), TBAB (5.20 g, 16.2 mmol), TEA (2.2 mL, 16.2 mmol) and 1,2-dibromoethane (5.0 mL) was stirred at 60° C. for 12 hours. LCMS showed the starting material was consumed completely and 53% desired product formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100.0 mL) and extracted Ethyl acetate (100.0 mL×2). The combined organic layers were washed with water (100.0 mL) and brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:10). The product cis-4-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (1.10 g, 56.9% yield) was obtained as an off-white solid.

Synthesis of 4-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 527

Step a: A solution of trans-3-amino-1-methylcyclobutan-1-ol hydrochloride (1.0 g, 7.3 mmol) and TEA (2.0 mL, 14.4 mmol) in EtOH (10.0 mL) was stirred at 60° C. for 10 min. To the solution was added 3-fluoro-4-nitrobenzonitrile (1.3 g, 7.9 mmol). The reaction mixture was stirred at 60° C. for 3 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed a little amount of 1 was remained and one new spot with larger polarity found. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:10 and DCM/MeOH=100:0 to 100:10). The product 3-[(3-hydroxy-3-methylcyclobutyl)amino]-4-nitrobenzonitrile (1.7 g, 6.8 mmol, 95.5% yield) was obtained as a yellow solid.

Step b: A solution of 3-[(3-hydroxy-3-methylcyclobutyl)amino]-4-nitrobenzonitrile (1.7 g, 6.9 mmol), TBSCl (2.8 g, 18.5 mmol), TEA (0.95 mL, 6.9 mmol) and imidazole (1.4 g, 20.6 mmol) in DCM (20.0 mL) was stirred at 40° C. for 12 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed starting material was disappeared and one new spot with lower polarity. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:30). The product 3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)-4-nitrobenzonitrile (2.2 g, 6.08 mmol, 88.7% yield) was obtained as a yellow solid.

Step c: A solution of 3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)-4-nitrobenzonitrile (2.2 g, 6.1 mmol) and wet Pd/C (500.0 mg, 10%) in MeOH (15.0 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). TLC ((Petroleum ether: Ethyl acetate=1:1) showed the starting material was disappeared and one spot with larger polarity was formed. Pd/C was filtered off and the filtrate was concentrated under reduced pressure. The residue (2.0 g, 99.5% yield) was used for the next step directly.

Step d: A mixture of 4-amino-3-({3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}amino)benzonitrile (2.0 g, 6.03 mmol), TBAB (5.8 g, 18.0 mmol), TEA (1.8 g, 18.0 mmol) and 1,2-dibromoethane (5.0 mL) was stirred at 60° C. for 12 hours. LCMS showed the starting material was consumed completely and 52% desired product formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100.0 mL) and extracted ethyl acetate (100.0 mL×2). The combined organic layers were washed with water (100.0 mL) and brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:10). The product 4-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutyl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (1.08 g, 3.02 mmol, 50.2% yield) was obtained as an off-white solid.

Synthesis of 5-(cyanomethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile, Used in the Preparation of Compound 528

›ABBREVIATIONS · 41 of 63

Step c: 2-(1,2,3,4-Tetrahydroquinolin-5-yl)acetonitrile (450.0 mg, 2.6 mmol) was dissolved in DMF (10.0 mL), NBS (464.0 mg, 2.6 mmol) dissolved in DMF (10.0 mL) was added in the reaction mixture, the reaction mixture was stirred at 15° C. for 2 hours. LCMS indicated 91% of desired product formed. The reaction mixture was diluted with EtOAc (300.0 mL), washed with H 2 O (100.0 mL×3), brine, dried over anhydrous Na 2 SO 4 , concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:30) to afford the product of 2-(6-bromo-1,2,3,4-tetrahydroquinolin-5-yl)acetonitrile (600.0 mg, 91.6% yield) as a white solid.

Step d: 2-(6-Bromo-1,2,3,4-tetrahydroquinolin-5-yl)acetonitrile (600.0 mg, 2.4 mmol), Zn(CN) 2 (416.0 mg, 3.6 mmol) and Pd(t-Bu 3 P) 2 (243.0 mg, 476.0 μmol) were added in DMF (30.0 mL), the reaction mixture was evacuated and refilled for 3 times with N 2 and stirred at 100° C. for 12 hours. LCMS indicated 98% of desired product formed. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:20) to afford the product of 5-(cyanomethyl)-1,2,3,4-tetrahydroquinoline-6-carbonitrile (356.7 mg, 75.9% yield) as a white solid.

Synthesis of 4-(2-fluoroethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 529

Step a: A solution of 2-fluoroethan-1-amine hydrochloride (1.0 g, 10.0 mmol) and Et 3 N (4.2 mL, 30.0 mmol) in EtOH (10.0 mL) was stirred at 40° C. for 15 min. To a reaction mixture was added 3-fluoro-4-nitrobenzonitrile (1.7 g, 10.0 mmol). The reaction was stirred at 40° C. for 12 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed the starting material was disappeared and one spot with lower polarity was formed. The reaction mixture was concentrated under reduced pressure to give the residue (2.0 g, 9.56 mmol, 95.6% yield).

Step b: A solution of 3-[(2-fluoroethyl)amino]-4-nitrobenzonitrile (2.0 g, 9.56 mmol) and wet Pd/C (500 mg, 10%) in MeOH (20.0 mL) was stirred at 10° C. for 12 hours under H 2 (15 psi). TLC (Petroleum ether: Ethyl acetate=1:1) showed the starting material was disappeared and one main spot with larger polarity formed. Pd/C was filtered off and the filtrate was concentrated under reduced pressure. The residue (1.6 g, 93.5% yield) was used in the next step directly.

Step c: A mixture of 4-amino-3-[(2-fluoroethyl)amino]benzonitrile (1.4 g, 7.8 mmol), TBAB (7.5 g, 23.4 mmol), TEA (2.2 mL, 15.6 mmol) and 1,2-dibromoethane (5.0 mL) was stirred at 60° C. for 10 hours. TLC (Petroleum ether: Ethyl acetate=2:1) showed a little amount of starting material was remained and main spot with lower polarity was formed. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100.0 mL) and extracted ethyl acetate (100.0 mL×2). The combined organic layers were washed with water (50.0 mL) and brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:20). The product 4-(2-fluoroethyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (950.0 mg, 4.6 mmol, 59.3% yield) was obtained as a light yellow solid.

Synthesis of 4-(3,3-difluorocyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 530

Step a: A solution of 3,3-difluorocyclobutan-1-amine hydrochloride (950.0 mg, 6.6 mmol) and TEA (2.7 mL, 19.8 mmol) in EtOH (15.0 mL) was stirred at 60° C. for 10 min. To a mixture solution was added 3-fluoro-4-nitrobenzonitrile (1.1 g, 6.6 mmol). The reaction was stirred at 60° C. for 12 hours. LCMS showed a little amount of starting material was remained and 93% desired product formed. TLC (Petroleum ether: Ethyl acetate=4:1) showed the starting material and product overlapped completely. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:20). The product 3-[(3,3-difluorocyclobutyl)amino]-4-nitrobenzonitrile (1.6 g, 6.3 mmol, 95.8% yield) was obtained as a yellow solid.

Step b: A solution of 3-[(3,3-difluorocyclobutyl)amino]-4-nitrobenzonitrile (1.6 g, 6.3 mmol) and 10% Pd/C (200 mg, wet) in MeOH (15.0 mL) was purged with H2 for 3 min and stirred at 10° C. for 12 hours under H2 (15 psi). TLC (Petroleum ether:Ethyl acetate=2:1) showed the starting material was disappeared and a main spot with larger polarity was formed. Pd/C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:40). The product 4-amino-3-[(3,3-difluorocyclobutyl)amino]benzonitrile (850.0 mg, 3.8 mmol, 60.7% yield) was obtained as a light yellow solid.

Step c: A solution of 4-amino-3-[(3,3-difluorocyclobutyl)amino]benzonitrile (810.0 mg, 3.6 mmol), TBAB (3.5 g, 10.8 mmol), TEA (2.0 mL, 14.4 mmol) and 1,2-dibromoethane (5.0 mL) was stirred at 60° C. for 5 hours. LCMS showed 63% desired product formed at 254 nm. The reaction mixture was diluted with water (100.0 mL) and extracted ethyl acetate (100.0 mL×2). The combined organic layers were washed with water (80.0 mL) and brine (80.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:20). The residue was diluted with MeOH (10.0 mL). The residue was purified by prep-HPLC (HCl). The starting material (300 mg) was recovered. The product 4-(3,3-difluorocyclobutyl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile hydrochloride (430 mg, 1.5 mmol, 41.7% yield) was obtained as an off-white solid. LCMS: [M+H]+ 250.1.

Synthesis of 4,5,6,7-tetrahydrothiazolo[5,4-b]pyridine, Used in the Preparation of Compound 531

Step a: A mixture of 4-bromo-1,3-thiazole (1.00 g, 6.09 mmol), tert-butyl N-(prop-2-yn-1-yl)carbamate (1.13 g, 7.30 mmol), CuI (115.0 mg, 609.0 umol), Pd(PPh3)4 (703.0 mg, 609 umol) and Et3N (1.22 g, 12.10 mmol) in THF (20 mL) was stirred at 70° C. under N2 for 4 hours. LCMS showed the desired product formed. Concentrated under reduced pressure, the residue was purified by silica gel column (EtOAc in Petroleum ether=0˜50%) to give the product of tert-butyl N-[3-(1,3-thiazol-4-yl)prop-2-yn-1-yl]carbamate (600.0 mg, 41.3% yield) as a yellow solid.

›ABBREVIATIONS · 42 of 63

Step b: A mixture of tert-butyl N-[3-(1,3-thiazol-4-yl)prop-2-yn-1-yl]carbamate (600.0 mg, 2.5 mmol) and Raney Ni (0.2 g) in THF (2 mL) and MeOH (10 mL) was stirred at 20° C. under H2 (15 psi.) for 12 hours. LCMS showed the one main peak with desired MS formed. The reaction mixture was filtered and concentrated in vacuum to give the product of tert-butyl N-[3-(1,3-thiazol-4-yl)propyl]carbamate (600.0 mg, 98.6% yield) as a yellow oil.

Step c: A mixture of tert-butyl N-[3-(1,3-thiazol-4-yl)propyl]carbamate (500.0 mg, 2.1 mmol) and NBS (546.0 mg, 3.1 mmol) in DMF (10 mL) was stirred at 40° C. for 1 hour. TLC (Petroleum ether/EtOAc=3/1) showed the one new spot with lower polarity formed. The reaction mixture was poured into EtOAc (50 mL) and washed with water (20 mL×2). The organic layer was concentrated in vacuum and purified by silica gel column (Petroleum ether/EtOAc=3/1) to give the product of tert-butyl N-[3-(5-bromo-1,3-thiazol-4-yl)propyl]carbamate (600.0 mg, 90.7% yield) as a colorless oil.

Step d: A mixture of tert-butyl N-[3-(5-bromo-1,3-thiazol-4-yl)propyl]carbamate (600.0 mg, 1.86 mmol), Pd2(dba)3 (170.0 mg, 186.0 μmol), BINAP (115.0 mg, 186.0 μmol) and Cs2CO3 (1.21 g, 3.72 mmol) in PhMe (20 mL) was stirred at 100° C. under N2 for 12 hours. TLC (Petroleum ether/EtOAc=2/1) showed one new spot with a little higher polarity formed, and a small amount of the starting material remained. The reaction mixture was concentrated and purified by silica gel column (Petroleum ether/EtOAc=5/1) to give the product of tert-butyl 4H,5H,6H,7H-[1,3]thiazolo[5,4-b]pyridine-4-carboxylate (400.0 mg, crude) as a yellow oil.

Step e: A solution of tert-butyl 4H,5H,6H,7H-[1,3]thiazolo[5,4-b]pyridine-4-carboxylate (200.0 mg, 832.0 μmol) in 4 M HCl/MeOH (10 mL) was stirred at 20° C. under 2 hours. LCMS showed the desired product formed. This combined mixture was concentrated under reduced pressure. The residue was purified by silica gel column (MeOH in DCM=0˜10%, 0.5% NH3.H2O) to give 4H,5H,6H,7H-[1,3]thiazolo[5,4-b]pyridine (100.0 mg) as a red oil.

Synthesis of 4-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile, Used in the Preparation of Compound 532

Step a: A solution of 3-fluoro-4-nitrobenzonitrile (651.0 mg, 3.92 mmol) and 3-fluorobicyclo[1.1.1]pentan-1-amine hydrochloride (450.0 mg, 3.3 mmol) in TEA (1.0 mL) was stirred at 100° C. for 12 hours. TLC (Petroleum ether:Ethyl acetate=2:1) showed the starting material was remained and a new yellow spot with larger polarity formed. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:30) to give the crude product which was further purified by TLC (Petroleum ether: Ethyl acetate=4:1) to afford the product of 3-((3-fluorobicyclo[1.1.1]pentan-1-yl)amino)-4-nitrobenzonitrile (320.0 mg, 39.6% yield) as a yellow solid.

Step b: A mixture of 3-({3-fluorobicyclo[1.1.1]pentan-1-yl}amino)-4-nitrobenzonitrile (300.0 mg) and 10% Pd/C (100.0 mg, wet) in MeOH (2.0 mL) was purged with H2 for 3 min and stirred at 10° C. for 12 hours under H2 (15 psi). Pd/C was filtered off and the filtrate was added HCl/MeOH (5.0 mL, 4M) and concentrated under reduced pressure to give the crude product of 4-amino-3-({3-fluorobicyclo[1.1.1]pentan-1-yl}amino)benzonitrile (200.0 mg, 1HCl salt).

Step c: A mixture of 4-amino-3-({3-fluorobicyclo[1.1.1]pentan-1-yl}amino)benzonitrile hydrochloride (200.0 mg) 1,2-dibromoethane (3.0 mL, 788.0 μmol), TBAB (760.0 mg, 2.4 mmol) and TEA (435.0 μL, 3.2 mmol) was stirred at 60° C. for 24 hours under N2. TLC (Petroleum ether: Ethyl acetate=4:1) showed the starting material disappeared and a main spot with lower polarity found. The residue was diluted with water (50.0 mL) and extracted ethyl acetate (50.0 mL×2). The combined organic layers were washed with water (20.0 mL) and brine (20.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Petroleum ether: Ethyl acetate=100:0 to 100:30). The product of 4-{3-fluorobicyclo[1.1.1]pentan-1-yl}-1,2,3,4-tetrahydroquinoxaline-6-carbonitrile (200.0 mg) was obtained as a black solid. LCMS: [M+H]+ 243.9.

Synthesis of 1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine, Used in the Preparation of Compound 6

Step a: A round bottomed flask was charged with 3,5-dichloropyrazine-2-carbonitrile (0.3 g, 1.7 mmol, 1.0 eq, CAS #313339-92-3), tert-butyl N-(4-methyl-4-piperidyl)carbamate (0.37 g, 1.7 mmol, 1.0 eq, CAS #163271-08-7), and CsF (0.78 g, 5.2 mmol, 3.0 eq). Dimethylsulfoxide (5.7 mL) was added and the reaction mixture was stirred at 70° C. for 2.5 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO 3 (30 mL), H 2 O (30 mL×2), and brine (30 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a yellow solid. The residue was purified by column chromatography (25-50% EtOAc/petroleum ether) to afford the product of tert-butyl N-[1-(6-chloro-5-cyano-pyrazin-2-yl)-4-methyl-4-piperidyl]carbamate (0.5 g, 83% yield) as a yellow solid: LCMS [M-tBu] + =295.

Step b: tert-Butyl N-[1-(6-chloro-5-cyano-pyrazin-2-yl)-4-methyl-4-piperidyl]carbamate (4.0 g, 11.4 mmol, 1.0 eq), Et 3 N (5.7 g, 56.8 mmol, 7.9 mL, 5.0 eq) and (4-methoxyphenyl)methylhydrazine, 2HCl (3.1 g, 13.6 mmol, 1.2 eq) were taken up in EtOH (50 mL). The mixture was stirred at 90° C. for 16 hours. A parallel reaction was run with the same ratio of materials, starting from 1 g of tert-butyl N-[1-(6-chloro-5-cyano-pyrazin-2-yl)-4-methyl-4-piperidyl]carbamate. Both reaction mixtures were combined and concentrated under reduced pressure to give a residue, which was triturated with H 2 O (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organics were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (25-60% EtOAc/petroleum ether) to afford tert-butyl-N-[1-[3-amino-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-4-piperidyl]carbamate (4.8 g) as a yellow solid: LCMS [M+H] + =468.

›ABBREVIATIONS · 43 of 63

Step c: A round bottomed flask was charged with tert-butyl N-[1-[3-amino-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b] pyrazin-6-yl]-4-methyl-4-piperidyl]carbamate (8.2 g, 17.5 mmol, 1.0 eq) and NaNO 2 (1.4 g, 21.0 mmol, 1.2 eq). Acetonitrile (150 mL) was added, followed by HBr (30.0 mL, 47% solution) and the mixture stirred at 0° C. for 1 hr. CuBr (251 mg, 1.7 mmol, 0.10 eq) was added at 0° C., and the reaction mixture allowed to warm to 25° C. for 1 h. The pH was adjusted to 10 with ammonium hydroxide and extracted with ethyl acetate (150 mL×3). The combined organics were washed with H 2 O (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluting with methylene chloride and methanol) to afford 1-[3-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-piperidin-4-amine (6.6 g, 76.7% yield) as a red solid. LCMS: [M+H] + =431/433.

Synthesis of 6-(2,5-dihydrofuran-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 309 and Compound 336

Step a: A mixture of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (145 mg, 680 μmol), 2-(2,5-dihydrofuran-3-yl)- 4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (198 mg, 1.0 mmol), Pd(dppf)Cl 2 (99.5 mg, 136 μmol) and K 2 CO 3 (186 mg, 1.4 mmol) in dioxane (9 mL)/H 2 O (3 mL) was stirred at 90° C. for 12 hours under N 2 atmosphere. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with H 2 O (15 mL×2). The organic phase was washed with brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Ethyl acetate in Petroleum ether: 30% to 50%) to afford the product of 6-(2,5-dihydrofuran-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (55 mg, 40.1% yield) as a white solid. LCMS m/z: 203.4 (M+H)+.

Synthesis of 6-[(1-methyl-1H-pyrazol-4-yl) oxy]-1, 2, 3, 4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 314

Step a: To a solution of 1-methyl-1H-pyrazol-4-ol (183 mg, 1.87 mmol) and 2-chloro-1,5-naphthyridine (306 mg, 1.87 μmol) in DMF (10.0 mL) was added Cs 2 CO 3 (911 mg, 2.80 mmol)). The mixture was heated to 100° C. for 2 h. The mixture was diluted with H 2 O (20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by silica column (Ethyl acetate in Petroleum ether 0-100%) to give the desired product of 2-[(1-methyl-1H-pyrazol-4-yl) oxy]-1,5-naphthyridine (415 mg, 98.5% yield) as a white solid.

Step b: To a solution of 2-[(1-methyl-1H-pyrazol-4-yl)oxy]-1,5-naphthyridine (410 mg, 1.8 mmol) and 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.10 g, 4.35 mmol) in PhMe (10 mL) was added diphenoxyphosphinic acid (90.5 mg, 0.36 mmol). The solution was stirred at 80° C. for 12 h. The mixture was directly concentrated in vacuo. The residue was purified by silica column (Ethyl acetate in Petroleum ether 0-100%) to give the desired product of 6-[(1-methyl-1H-pyrazol-4-yl) oxy]-1, 2, 3, 4-tetrahydro-1,5-naphthyridine (300 mg, 71.9% yield) as a yellow oil. LCMS m/z: 231.1 (M+H) + .

Synthesis of 6-methoxy-1, 2, 3, 4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 315

Step a: To a solution of 2-chloro-1,5-naphthyridine (300 mg, 1.82 mmol) in MeOH (10 mL) was added MeONa (492 mg, 9.11 mmol) and the solution was stirred at 70° C. for 2 h. The solution was then concentrated in vacuo. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give the desired product of 2-methoxy-1,5-naphthyridine (320 mg, crude) as a yellow oil.

Step b: To a solution of 2-methoxy-1,5-naphthyridine (320 mg, 1.99 mmol) and 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.20 g, 4.77 mmol) in PhMe (10 mL) was added diphenoxyphosphinic acid (99.5 mg, 0.40 mmol). The solution was stirred at 80° C. for 12 h. After concentration, the residue was purified by silica column chromatography (Ethyl acetate in Petroleum ether 0-50%) to give impure product, which was re-purified by prep. HPLC (NH 3 ) to give the desired product of 6-methoxy-1, 2, 3, 4-tetrahydro-1,5-naphthyridine (130 mg, 39.8% yield) as a yellow oil. LCMS m/z: 165.1 (M+H) + .

Synthesis of 6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 317

Step a: 1-(Difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200.0 mg, 819.0 μmol, CAS #1206640-82-5), 6-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine (138.0 mg, 819.0 μmol), Pd(dppf)Cl 2 (119.0 mg, 163.0 μmol), and K 2 CO 3 (338.0 mg, 2.5 mmol) were added in the mixture of dioxane (10.0 mL) and H2O (1.0 mL). The reaction mixture was evacuated and refilled 3 times with N 2 and stirred at 100° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:30) to afford 6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-1,2,3,4-tetrahydro-1,5-naphthyridine (120.0 mg, 81% purity, 47.6% yield) as a yellow solid. LCMS m/z: 251.0 (M+H) + .

Synthesis of 6-(1,3-oxazol-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 318

Step a: To a solution of 2-chloro-1,5-naphthyridine (500.0 mg, 3.00 mmol) and 1,3-oxazole (418.0 mg, 6.10 mmol) in DMA (10.0 mL) was added di-1-adamantylphosphine (108.0 mg, 303.0 μmol), pivalic acid (123.0 mg, 1.20 mmol), K 2 CO 3 (1.30 g, 9.10 mmol) and Pd(OAc) 2 (68.0 mg, 303.0 μmol). The mixture was evacuated and refilled 3 times using N 2 , then the reaction mixture was stirred at 110° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:100) to obtain 2-(1,3-oxazol-5-yl)-1,5-naphthyridine (300.0 mg) as a light yellow solid.

›ABBREVIATIONS · 44 of 63

Step b: A solution of 2-(1,3-oxazol-5-yl)-1,5-naphthyridine (300.0 mg, 1.52 mmol), BINOL-phosphoric acid (105.0 mg, 304.0 μmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.20 g, 4.60 mmol) in dioxane (5.0 mL) was stirred at 80° C. for 12 hours under N 2 . The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:80). The impure product was re-purified by prep-TLC (Petroleum ether/Ethyl acetate=1:4) to obtain 6-(1,3-oxazol-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (160.0 mg, 795.0 μmol, 52.4% yield) as a light yellow solid. LCMS m/z: 201.9 (M)+.

Synthesis of 6-(4-methyl-1,3-oxazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 328

Step a: To the mixture of 2-chloro-1,5-naphthyridine (350 mg, 2.12 mmol) and 4-methyl-1,3-oxazole (264 mg, 3.18 mmol) in toluene (10.0 mL) were added Pd(OAc) 2 (96.0 mg, 424 μmol), t-BuOK (713 mg, 6.36 mmol) and RuPhos (296 mg, 636 μmol) under N 2 . The mixture was stirred at 110° C. under N 2 for 12 hrs. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (DCM/MeOH=1/0 to 9/1) to give 2-(4-methyl-1,3-oxazol-2-yl)-1,5-naphthyridine (130 mg) as a yellow solid.

Step b: To the mixture of 2-(4-methyl-1,3-oxazol-2-yl)-1,5-naphthyridine (160 mg, 615 μmol) and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (387 mg, 1.53 mmol) in toluene (10.0 mL) was added 4-hydroxydinaphtho[2,1-d:1′,2′-f][1,3,2]dioxaphosphepine 4-oxide (21.4 mg, 61.5 μmol) under N 2 . The mixture was stirred at 100° C. under N 2 for 12 hrs. The mixture was concentrated in vacuo and purified by flash silica gel chromatography (DCM/MeOH=1/0 to 10/1) followed by prep-TLC (DCM/MeOH=20/1) to give 6-(4-methyl-1,3-oxazol-2-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (56.6 mg, 42.8% yield) as a brown solid. LCMS m/z: 215.9 (M)+.

Synthesis of tert-butyl 7-(pyridazin-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate, Used in Preparation of Compound 332

Step a: A solution of tert-butyl 7-bromo-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (700 mg, 2.23 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (459 mg, 2.23 mmol), Pd(dppf)Cl 2 (1.63 g, 2.23 mmol) and K 2 CO 3 (615 mg, 4.46 mmol) in Dioxane/H 2 O=10:1 (50 mL) was stirred at 100° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (eluent: Petroleum ether/Ethyl acetate=5:1 to 1:1) to afford tert-butyl 7-(pyridazin-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (260 mg, 832 μmol, 37% yield) as a yellow oil.

Synthesis of 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine, Used in Preparation of Compound 333

A solution of 5-chloro-1,6-naphthyridine (4.00 g, 24.3 mmol, CAS #23616-32-2), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (14.70 g, 58.3 mmol) and diphenoxyphosphinic acid (1.21 g, 4.86 mmol) in toluene (200.0 mL) was stirred at 80° C. for 12 h under N 2 . The solution was concentrated in vacuum to remove solvent. The residue was purified by flash silica gel chromatography (40 g, Ethyl acetate in Petroleum ether from 0% to 30%) to give 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (1.9 g, 46% yield) as an orange solid.

Synthesis of 6-(pyridazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 348

Step a: To a mixture of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (100.0 mg, 469.0 μmol) and 3-(tributylstannyl)pyridazine (173.0 mg, 469.0 μmol) in toluene (10.0 mL) was added Pd(PPh 3 ) 4 (270.0 mg, 234.0 μmol), then the mixture was stirred at 110° C. for 24 h under N 2 . The mixture was diluted with water (50.0 mL) and extracted with EtOAc (50.0 mL×3). The organic layers were washed with brine (50.0 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (MeOH in EtOAc=0˜10%) to afford 6-(pyridazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (45 mg, 212 μmol, 45% yield) as a yellow solid. LCMS m/z 213.1 (M+H) + .

Synthesis of 6-(pyrazin-2-yl)-1, 2, 3, 4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 350

Step a: To a solution of HTMP (1.96 g, 13.9 mmol) in THE (20 mL) was added n-BuLi (5.56 mL, 13.9 mmol) at −50° C. under N 2 . The solution was warmed to 0° C., and stirred for 20 min. 2-chloropyrazine (500 mg, 4.36 mmol) and Bu 3 SnCl (1.41 g, 4.36 mmol) in THF (20 mL) was then added to the solution at −78° C. The solution was warmed to −40° C. for 3 h. The mixture was quenched with conc.HCl/EtOH/THF (1:4:5, 20 mL) at −40° C. and the mixture was warmed to 20° C. The mixture was neutralized with sat. NaHCO 3 and the volatiles were removed. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica column (Ethyl acetate in Petroleum ether 0-10%) to give the desired product of 2-chloro-6-(tributylstannyl) pyrazine (1.16 g, 66.2% yield) as a yellow oil.

Step b: A mixture of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (300 mg. 1.40 mmol), 2-chloro-6-(tributylstannyl)pyrazine (565 mg. 1.40 mmol) and Pd(PPh 3 ) 4 (323 mg, 280 μmol) in PhMe (15 mL) was stirred at 120° C. for 12 h under N 2 After concentration, the residue was purified by silica column (Ethyl acetate in Petroleum ether 0-40%) to give the desired product of 6-(6-chloropyrazin-2-yl)-1, 2, 3, 4-tetrahydro-1,5-naphthyridine (200 mg, 57.9%) as a yellow solid.

Step c: To a solution of 6-(6-chloropyrazin-2-yl)-1, 2, 3, 4-tetrahydro-1,5-naphthyridine (180 mg, 729 μmol) in MeOH (10 mL) was added K 2 CO 3 (300 mg, 2.18 mmol) and Pd/C (10 wt % wet, 180 mg). The mixture was stirred at 15° C. for 12 h under H2 (15 psi). The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by prep HPLC (NH 3 ) to give the desired product of 6-(pyrazin-2-yl)-1, 2, 3, 4-tetrahydro-1,5-naphthyridine (120 mg, 77% yield) as a yellow solid. LCMS m/z: 213.0 (M+H)+.

›ABBREVIATIONS · 45 of 63

Synthesis of 2-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)acetonitrile, Used in Preparation of Compound 352

Step a: A solution of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (300 mg, 1.40 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (273 mg, 1.40 mmol), Pd(dppf)Cl 2 (102 mg, 140 umol) and K 2 CO 3 (386 mg, 2.80 umol) in dioxane:H 2 O=10:1 (10 mL) was stirred at 110° C. for 12 hours. TLC (PE:EA=1:1) showed the desired product was formed. The mixture concentrated and the resulting crude material was purified by silica gel chromatography (eluent: Petroleum ether/Ethyl acetate=1:1) to give 2-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)acetonitrile (120 mg, 692 μmol, 49.5% yield) as a yellow oil.

Synthesis of (4S)-4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoline, Used in Preparation of Compound 353

Step a: To a solution of (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline (1.0 g, 4.4 mmol, 1.0 eq) in THF (20 mL) was added NaHMDS (8.8 mL, 8.8 mmol, 1M in THF, 2.0 eq) dropwise under N 2 atmosphere. The mixture was stirred at 15° C. for 30 min. Then Boc 2 O (1.3 g, 5.7 mmol, 1.3 eq) was added and the mixture was stirred at 15° C. for 10 hours. The mixture was quenched with saturated NH 4 Cl and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10:0-10:1) to afford the desired product of tert-butyl (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.3 g, 90.2% yield) as a yellow oil.

Step b: The mixture of tert-butyl (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (1.3 g, 4.0 mmol, 1.0 eq), Pd(dppf)Cl 2 (291 mg, 398 μmol, 0.1 eq) and TEA (1.2 g, 11.9 mmol, 3.0 eq) in MeOH (20 mL) was evacuated and refilled 3 times using CO. Then the reaction mixture was stirred at 80° C. for 72 hours under CO (50 psi) atmosphere. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (Petroleum ether/Ethyl acetate=1:0-10:1) to afford the desired product of 1-tert-butyl 6-methyl (4S)-4-methyl-1,2,3,4-tetrahydroquinoline-1,6-dicarboxylate (754 mg, 62.3% yield) as a yellow oil.

Step c: The mixture of 1-tert-butyl 6-methyl (4S)-4-methyl-1,2,3,4-tetrahydroquinoline-1,6-dicarboxylate (750 mg, 2.5 mmol, 1.0 eq) and LiOH (176 mg, 7.4 mmol, 3.0 eq) in MeOH (5 mL) and H 2 O (0.5 mL) was stirred at 50° C. for 10 hours. The mixture was adjusted with 2N HCl to pH=7. The mixture was concentrated under reduced pressure to afford the product of (4S)-1-[(tert-butoxy)carbonyl]-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (900 mg, crude) as a white solid.

Step d: The mixture of (4S)-1-[(tert-butoxy)carbonyl]-4-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (450 mg, 80% purity, 1.2 mmol, 1.0 eq), NH 2 NHBoc (242 mg, 1.8 mmol, 1.5 eq), HATU (1.4 g, 3.7 mmol, 3.0 eq) and TEA (371 mg, 3.7 mmol, 3.0 eq) in DMF (5 mL) was stirred at 50° C. for 12 hours. The mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL×3). The organic layer was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10:0˜4:1) to afford the desired product of tert-butyl (4S)-6-{N-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-4-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (377 mg, 75.7% yield) as a white solid.

Step e: The mixture of tert-butyl (4S)-6-{N′-[(tert-butoxy)carbonyl]hydrazinecarbonyl}-4-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (377 mg, 929 μmol, 1.0 eq) in HCl/MeOH (5 mL, 4M) was stirred at 15° C. for 2 hours. The mixture was concentrated under reduced pressure and the residue was used in the next step directly without further purification.

Step f: To a solution of (4S)-4-methyl-1,2,3,4-tetrahydroquinoline-6-carbohydrazide dihydrochloride (250 mg, 898 μmol, 1.0 eq) in dioxane (5 mL) was added MeC(OEt) 3 (2.9 g, 17.9 mmol, 20 eq). The mixture was stirred at 120° C. for 10 hours. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=10:0˜3:1) to afford the desired product of (4S)-4-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-1,2,3,4-tetrahydroquinoline (155 mg, 75.6% yield) as a yellow solid. LCMS m/z: 230.4 (M+H) + .

Synthesis of 6-(1,3-thiazol-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine, Used in Preparation of Compound 356

Step a: A solution of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (300.0 mg, 1.40 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (295.0 mg, 1.40 mmol, CAS #1086111-09-2), Pd(dppf)Cl 2 (204.0 mg, 280.0 umol) and K 3 PO 4 (888.0 mg, 4.19 mmol) in dioxane/H 2 O (10.0 mL/1.0 mL) was stirred at 100° C. for 12 hours. The solution was added into H 2 O (50.0 mL) and extracted with EtOAc (50.0 mL×2). The combined organic layers were washed with brine (50.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as a brown gum. The residue was purified by flash silica gel chromatography (12 g, Ethyl acetate in Petroleum ether from 0% to 60%) to give 6-(1,3-thiazol-5-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (55.0 mg, 18.0% yield) as an orange oil. LCMS m/z: 217.9 (M) + .

Synthesis of methyl (8S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxylate, Used in Preparation of Compound 362

Step a: A solution of (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (5.0 g, 22.0 mmol) in THF (50.0 mL) was added 1 M NaHMDS (66.0 mL, 66.0 mmol) under N 2 at 20° C. The reaction was stirred for 2 hours. Next, (Boc) 2 O (10.0 mL, 44.0 mmol) in THF(50.0 mL) was added, and the reaction mixture was stirred at 20° C. for 12 hours under N 2 . The mixture was diluted with H 2 O (500.0 mL), extracted with EtOAc (500.0 mL×2) and washed with brine (500.0 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure and purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether=0%˜2%) to afford tert-butyl (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate(6.65 g, 92.4% yield) as a light yellow solid.

›ABBREVIATIONS · 46 of 63

Step b: To a solution of tert-butyl (4S)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1-carboxylate (6.65 g, 20.3 mmol) in MeOH (100.0 mL) was added Pd(dppf)Cl 2 (1.5 g, 2.0 mmol) and TEA (8.4 mL, 60.9 mmol). The mixture was evacuated and refilled 3 times with CO and stirred at 80° C. for 24 hours under CO (2 Mpa). The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (250.0 mL) and the organic layer was separated. The organic layer was washed with H 2 O (250.0 mL×2) and brine (250.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (Ethyl acetate in Petroleum ether=0˜10%) to afford 1-tert-butyl 6-methyl (4S)-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1,6-dicarboxylate (4.55 g, 73.2% yield) as an off-white solid.

Step c: A mixture of 1-tert-butyl 6-methyl (4S)-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine-1,6-dicarboxylate (4.5 g, 14.6 mmol) in HCl/EtOAc (45.0 mL, 4N) was stirred at 20° C. for 4 hours. The mixture was diluted with H 2 O (150.0 mL), washed with EtOAc (100.0 mL×2). The aqueous phase was adjusted to pH=8 with saturated NaHCO 3 and a lot of precipitate formed. The solid was collected by filtration and lyophilized. The filtrate was extracted with EtOAc (100.0 mL×2). The organic phase was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the product of methyl (8S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxylate (2.4 g obtained in total, 81% yield) as a white solid. LCMS m/z: 207.1 (M+H)+.

Synthesis of methyl (8R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxylate, Used in Preparation of Compound 363

Methyl (8R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carboxylate was synthesized as described above for the S enantiomer starting from (4R)-6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine.

Synthesis of (8R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile and (8S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile, Used in Preparation of Compound 370

Step a: A solution of 6-bromo-4-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (1.00 g, 4.40 mmol), Zn(CN) 2 (774.0 mg, 6.60 mmol), Pd 2 (dba) 3 (805.0 mg, 880.0 μmol), dppf (97.6 mg, 176.0 μmol) and Zn (34.3 mg, 528.0 μmol) in DMF (20.0 mL) was stirred at 120° C. for 12 hours under N 2 . The solution was then poured into H 2 O (50.0 mL) and extracted with EtOAc (50.0 mL×2). The combined organic layers were washed with brine (20.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as a brown solid. The residue was purified by flash silica gel chromatography (40 g, EtOAc in petroleum ether from 0% to 45%) to give 8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (760.0 mg, 99.7% yield) as an orange solid.

Step b: 8-Methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (120.0 mg, 692.0 μmol) was purified by SFC (Column: ChiralPak IC-3 150×4.6 mm I.D., 3 um, Mobile phase: A: CO 2 B: IPA (0.05% DEA), Gradient: from 5% to 40% of B in 5.5 min and hold 40% for 3 min, then 5% of B for 1.5 min, Flow rate: 2.5 mL/min Column temperature: 40° C.). (8R)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (60.0 mg, 346.0 μmol) and (8S)-8-methyl-5,6,7,8-tetrahydro-1,5-naphthyridine-2-carbonitrile (60.0 mg, 346.0 μmol) were obtained as white solids. The absolute configuration was assigned randomly.

Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline, Used in Preparation of Compound 365

Step a: A mixture of 6-bromoquinoline (400.0 mg, 1.92 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (478.0 mg, 2.30 mmol) K 2 CO 3 (662.0 mg, 4.80 mmol), and Pd(dppf)Cl 2 (70.0 mg, 0.09 mmol) in dioxane (20.0 mL)/H 2 O (2.0 mL) was evacuated and refilled 3 times using N 2 . The reaction mixture was then stirred at 100° C. for 12 hours under N 2 atmosphere. The mixture was then concentrated to give a residue which was purified by flash silica gel chromatography (Petroleum ether/Ethyl acetate=100:0 to 50:100) to give the product of 6-(1-methyl-1H-pyrazol-4-yl)quinoline (380.0 mg, 94.7% yield) as a white solid.

Step b: A solution of 6-(1-methyl-1H-pyrazol-4-yl)quinoline (380.0 mg, 1.81 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.37 g, 5.43 mmol) and diphenoxyphosphinic acid (90.5 mg, 0.36 mmol) in PhMe (15.0 mL) was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (Ethyl acetate:MeOH=100:0 to 100:10) to afford the product of 6-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoline (250.0 mg, 64.7% yield) as a white solid. LCMS m/z: 214.1 (M+H)+.

Synthesis of 8-methanesulfonyl-1-methyl-1,2,3,4-tetrahydroquinoxaline, Used in Preparation of Compound 367

Step a: To a solution of 1-bromo-2-chloro-3-nitrobenzene (2.00 g, 8.45 mmol) in dioxane (5.0 mL) was added 40% aq. methanamine (1.96 g) and the reaction mixture was stirred at 100° C. under N 2 for 2 hours. The mixture was poured into EtOAc (100.0 mL) and washed with water (50.0 mL×2). The organic layer was dried over anhydrous Na 2 SO 4 , filtered and evaporated in vacuo to give 2-bromo-N-methyl-6-nitroaniline (1.94 g, 8.39 mmol, 99.4% yield) as red oil.

Step b: 2-Bromo-N-methyl-6-nitroaniline (600.0 mg, 2.59 mmol), sodium methanesulfinate (792.0 mg, 7.76 mmol) and CuI (1.96 g, 10.30 mmol) in NMP (10.0 mL) was degassed under N 2 and stirred at 140° C. for 2 hours. The reaction was quenched by the addition of EtOAc (100.0 mL), filtered through a pad of celite, eluting with EtOAc (50.0 mL). The organic solution was washed with water (50.0 mL×3), concentrated and purified by silica gel column (EtOAc in Petroleum ether=0˜30%) to give 2-methanesulfonyl-N-methyl-6-nitroaniline (420.0 mg, 1.82 mmol, 70.4% yield) as a yellow solid.

Step c: A mixture of 2-methanesulfonyl-N-methyl-6-nitroaniline (420.0 mg, 1.82 mmol) and Pd/C (0.2 g, 10 wt % wet) in 2 N HCl (5.0 mL) and MeOH (20.0 mL) was hydrogenated under H 2 (15 psi) at 50° C. for 12 hours. The Pd/C was filtered off, and the filtrate was concentrated in vacuo to give 6-methanesulfonyl-N 1 -methylbenzene-1,2-diamine dihydrochloride (450.0 mg, 1.64 mmol, 90.5% yield) as a red solid.

›ABBREVIATIONS · 47 of 63

Step d: To a mixture of 6-methanesulfonyl-N-methylbenzene-1,2-diamine dihydrochloride (450.0 mg, 1.64 mmol) and pyridine (639.0 mg, 8.20 mmol) in DCM (20.0 mL) at 0° C. was added (COCl) 2 (416.0 mg, 3.28 mmol) drop-wise. The reaction was allowed to stir at 0-20° C. for 12 hours. The reaction mixture was poured into 1 N HCl (50.0 mL) and extracted with DCM (50.0 mL×3). The organic layers were concentrated in vacuo to give 8-methanesulfonyl-1-methyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione (350.0 mg, crude) as a yellow solid.

Step e: To a solution of 8-methanesulfonyl-1-methyl-1,2,3,4-tetrahydroquinoxaline-2,3-dione (350.0 mg, 1.37 mmol) in THF (10.0 mL) was added 1.0 M BH 3 -THF (13.7 mL, 13.7 mmol) and the reaction was stirred at 60° C. for 12 hours. The reaction was quenched with MeOH (5.0 mL) and concentrated in vacuo. The residue was purified by silica column (EtOAc in Petroleum ether=20˜80%) to give 8-methanesulfonyl-1-methyl-1,2,3,4-tetrahydroquinoxaline (50.0 mg, 220.0 μmol, 16.1% yield) as a white solid. LCMS m/z: 227.0 (M+H)+.

Synthesis of 5-(ethanesulfonyl)-1, 2, 3, 4-tetrahydroquinoline, Used in Preparation of Compound 368

Step a: To a mixture of quinoline-5-thiol (CAS 3056-03-9) (600 mg, 3.72 mmol) and KOH (208 mg, 3.72 mmol) in EtOH (10 mL) was added EtI (580 mg, 3.72 mmol). The mixture was stirred for 12 h at 15° C. After concentration, the residue was diluted with ethyl acetate (50 mL), washed with H 2 O (10 mL×3) and brine (10 mL). The organic layer was then dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give 5-(ethylsulfanyl)quinoline (570 mg, 80.9% yield) as a yellow oil.

Step b: A mixture of 5-(ethylsulfanyl) quinoline (518 mg, 2.74 mmol) in DMF (1 mL) and NaClO (10% w/w, 10 mL) was stirred at 50° C. for 12 h. The reaction mixture was then diluted with H 2 O (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica column (Ethyl acetate in petroleum ether 0-50%) to give the desired product of 5-(ethanesulfonyl)quinoline (230 mg, 38% yield) as a yellow oil.

Step c: A mixture of 5-(ethanesulfonyl)quinoline (230 mg, 1.03 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (625 mg, 2.47 mmol) and diphenoxyphosphinic acid (51.5 mg, 206 μmol) in toluene (10 mL) was stirred at 80° C. for 12 h under N 2 . After concentration, the residue was purified by silica column (ethyl acetate in oetroleum ether 0-50%) to give the desired product of 5-(ethanesulfonyl)-1, 2, 3, 4-tetrahydroquinoline (200 mg, 86% yield) as a yellow oil. LCMS m/z: 226.1.

Synthesis of 5-(dimethylphosphoryl)-1,2,3,4-tetrahydroquinoline, Used in Preparation of Compound 369

Step a: To the compound of 5-bromoquinoline (500 mg, 2.40 mmol), Pd(OAc) 2 (107 mg, 0.48 mmol), XantPhos (277 mg, 0.48 mmol), K 3 PO 4 (560 mg, 2.64 mmol) and dimethylphosphinous acid (206 mg, 2.64 mmol) was added DMF (7.5 mL). The mixture was stirred at 130° C. for 12 h. To the mixture was then added H 2 O (10 mL) and the mixture was extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to give a residue which was purified by flash silica gel chromatography (Ethyl acetate:MeOH=100:0 to 100:10) to give 5-(dimethylphosphoryl)quinoline (380 mg, 77% yield) as a yellow oil.

Step b: A solution of 5-(dimethylphosphoryl)quinoline (380 mg, 1.85 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.40 g, 5.55 mmol) and diphenoxyphosphinic acid (92.5 mg, 0.37 mmol) in PhMe (15 mL) was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (EtOAc:MeOH=100:0 to 100:10) to afford the product of 5-(dimethylphosphoryl)-1,2,3,4-tetrahydroquinoline (540 mg) as a yellow oil.

Synthesis of 1-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethan-1-one, Used in Preparation of Compound 397

Step a: A mixture of 2-chloro-1,5-naphthyridine (2.00 g, 12.1 mmol), tributyl(1-ethoxyethenyl)stannane (5.23 g, 14.5 mmol), Pd 2 (dba) 3 (600.0 mg, 0.66 mmol) and PPh 3 (317.0 mg, 1.21 mmol) in PhMe (50.0 mL) was stirred at 100° C. for 12 hours under N 2 . Then to the reaction mixture was added 2 N HCl (50.0 mL) and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was then extracted with petroleum ether (50.0 mL×2). The aqueous was basified with saturated Na 2 CO 3 until the pH=9.0 and extracted with EtOAc (50.0 mL×2). The combined organic layers were concentrated in vacuo and purified by silica gel column (Petroleum ether/EtOAc=100:0 to 100:50) to give the product of 1-(1,5-naphthyridin-2-yl)ethan-1-one (1.30 g, 62.5% yield) as a light red solid.

Step b: A solution of 1-(1,5-naphthyridin-2-yl)ethan-1-one (600.0 mg, 3.48 mmol), 3,5-diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.63 g, 10.4 mmol) and diphenoxyphosphinic acid (174.0 mg, 0.70 mmol) in toluene (12.0 mL) was stirred at 80° C. for 12 hours under N 2 . The mixture was concentrated and purified by flash silica gel chromatography (petroleum ether:EtOAc=100:0 to 100:20) to afford 1-(5,6,7,8-tetrahydro-1,5-naphthyridin-2-yl)ethan-1-one (195.0 mg, 31.8% yield) as a yellow solid.

Synthesis of methyl 2-(7-cyano-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate, Used in Preparation of Compound 399

Step a: To a solution of methyl 2-aminoacetate hydrochloride (1.35 g, 10.8 mmol) and TEA (3.73 mL, 27.0 mmol) in MeOH (100.0 mL) was added 3-fluoro-4-nitrobenzonitrile (1.5 g, 9.03 mmol) at 50° C. The mixture was stirred at 50° C. for 0.5 h. The mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (40 g, Ethyl acetate in Petroleum ether from 0% to 13%) to give methyl 2-[(5-cyano-2-nitrophenyl)amino]acetate (1.0 g, 47.1% yield) as a yellow solid.

Step b: A solution of methyl 2-[(5-cyano-2-nitrophenyl)amino]acetate (1.0 g, 4.25 mmol) and wet Pd/C (200.0 mg, 10 wt %) in THF (50.0 mL) was stirred at 20° C. for 0.5 h under H 2 (15 psi). The mixture was filtered and filtrate was concentrated in vacuo to give methyl 2-[(2-amino-5-cyanophenyl)amino]acetate (800.0 mg, 91.7% yield) as a yellow solid.

›ABBREVIATIONS · 48 of 63

Step c: A mixture of methyl 2-[(2-amino-5-cyanophenyl)amino]acetate (500.0 mg, 2.43 mmol), 1,2-dibromoethane (1.82 g, 9.72 mmol), TBAB (3.13 g, 9.72 mmol) and TEA (1.34 mL. 9.72 mmol) was stirred at 60° C. for 12 h. The mixture was concentrated in vacuo to remove solvent. The mixture was then added into H 2 O (100.0 mL) and then extracted with EtOAc (100.0 mL×2). The combined organic layers were washed with brine (100.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as a brown gum. The residue was purified by flash silica gel chromatography (12 g, Ethyl acetate in Petroleum ether from 0% to 30%) to give methyl 2-(7-cyano-1,2,3,4-tetrahydroquinoxalin-1-yl)acetate (300.0 mg, 53.4% yield) as an orange oil. LCMS m/z: 232.0 (M+H) + .

Synthesis of Examples

Preparation of 1-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine, Compound 6

Step a: To a 5 mL vial were added 1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (50 mg, 0.12 mmol), Pd 2 dba 3 (5 mg, 5 mol %), XantPhos (7 mg, 10 mol %), 2-chloro-thiophenol (16 μL, 0.14 mmol), and N,N-diisopropylethylamine (41 μL, 0.23 mmol), followed by dioxane (0.2 mL). The resulting mixture was sealed, degassed with nitrogen, and heated under microwave irradiation at 130° C. for 1.5 h. After full conversion, the volatiles were evaporated under reduced pressure. The resulting residue was purified by reversed phase chromatography (eluting with acetonitrile and water with 0.1% ammonium formate) to give 1-(3-((2-chlorophenyl)thio)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (55 mg, 96%) as an off-white solid after lyophilization: LCMS [M+H]+=496.2.

Step b: In a 25-mL round bottomed flask, 1-(3-((2-chlorophenyl)thio)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (57 mg, 0.115 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL) at room temperature. The resulting yellow-orange mixture was placed in a preheated oil bath at 70° C. and stirred at this temperature for 45 min. After this time, the mixture cooled to room temperature and slowly dropped into diethyl ether (20 mL). The resulting yellow/orange precipitate was filtered through a piece of cotton. The gummy residue obtained was redissolved in water (3-4 mL) and neutralized with a solution of saturated sodium bicarbonate until the pH was neutral. The resulting aqueous solution was loaded onto a reversed phase chromatography column and purified using a gradient of acetonitrile in 0.1% formic acid in water (10 to 50%) to give 1-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (24.2 mg, 56%) as an off-white solid.

Preparation of (4-methyl-1-(3-(phenylthio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine, Compound 7

Step a: Benzyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (50 mg, 0.085 mmol) was dissolved in i-PrOH (0.9 mL) in a 5 mL vial. Copper iodide (16 mg, 0.085 mmol), potassium carbonate (24 mg, 0.170 mmol), ethylene glycol (10 μL, 0.17 mmol), and thiophenol (19 μL. 0.102 mmol) were successively added and the vial was flushed with N 2 , sealed, and placed in a preheated oil bath at 100° C. The resulting yellow heterogeneous mixture was stirred at this temperature for 5 hrs. After this time, additional copper iodide (16 mg) and thiophenol (19 μL) were added and the resulting mixture heated overnight at 100° C. After full conversion, the mixture was cooled to room temperature, filtered through a piece of cotton, and the vial and cotton rinsed with ethyl acetate. The filtrate was washed with aqueous ammonia (2×10 mL), brine (2×10 mL), and the organics dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of ethyl acetate in hexanes (0 to 70%), affording benzyl ((4-methyl-1-(3-(phenylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (45 mg, 93%) as a pale yellow oil: LCMS [M+H] + =573.1.

Step b: Benzyl ((4-methyl-1-(3-(phenylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (45 mg, 0.079 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL) at 0-4° C. The resulting yellow-orange mixture was stirred at this temperature for 5 min and allowed to progressively reach room temperature. The reaction mixture was stirred an additional 40 min at room temperature. The mixture was slowly dropped into diethyl ether (20 mL). A gummy yellow precipitate formed which was redissolved in water (10 mL). The layers were separated and the aqueous layer basified with sat. aq. Na 2 CO 3 solution (30 mL), followed by the addition of dichloromethane (20 mL). The layer was further extracted with dichloromethane (3×10 mL) and the combined organics were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to provide (4-methyl-1-(3-(phenylthio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (17.7 mg, 64%) as an off-white solid after lyophilization.

Preparation of 4-methyl-1-(3-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine, Compound 8

Step a: 1-(3-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (50 mg, 0.12 mmol), Pd 2 dba 3 (53 mg, 0.06 mmol), XantPhos (69 mg, 0.12 mmol), 2-(trifluoromethyl)pyridine-3-thiol (42 mg, 0.23 mmol, 1801693-48-0), and N,N-diisopropylethylamine (41 μL, 0.23 mmol) were successively added in a 5 mL vial, followed by the addition of dioxane (0.3 mL). The resulting mixture was sealed, degassed with N 2 , and heated under microwave irradiation at 130° C. for 1.5 hrs. The volatiles were removed under reduced pressure and the resulting residue purified by reversed phase chromatography (25 to 65% gradient of acetonitrile/10 mM aqueous ammonium formate) to give 1-(1-(4-methoxybenzyl)-3-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (32 mg, 52%) as an off-white solid after lyophilization: LCMS [M+H] + =530.5.

›ABBREVIATIONS · 49 of 63

Step b: 1-(1-(4-Methoxybenzyl)-3-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (32 mg, 0.06 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL) at room temperature. The resulting yellow-orange mixture was placed in a preheated oil bath at 70° C., and stirred at this temperature for 1 hr. After this time, the mixture was allowed to cool to room temperature, then slowly dropped into diethyl ether (20 mL). The resulting yellow/orange precipitate was filtered through a piece of cotton. The gummy residue was redissolved in water (3-4 mL), loaded on a reversed phase chromatography column, and purified using a gradient of acetonitrile/0.1% formic acid in water (0 to 50%) to give 4-methyl-1-(3-((2-(trifluoromethyl)pyridin-3-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine (16 mg, 65%) as an off-white solid.

Preparation of (1-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine, Compound 9

Step a: Benzyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (50 mg, 0.085 mmol) was dissolved in i-PrOH (0.9 mL) in a 5 mL vial. Copper iodide (32 mg, 0.17 mmol), potassium carbonate (24 mg, 0.170 mmol), ethylene glycol (10 μL, 0.17 mmol), and 2-chloro-thiophenol (20 μL, 0.17 mmol) were successively added and the vial flushed with N 2 , sealed, and placed in a preheated oil bath at 100° C. The resulting yellow heterogeneous mixture was stirred at this temperature for 5 hr. Additional copper iodide (16 mg) and 2-chloro-thiophenol (19 μL) were added and the resulting mixture heated overnight at 100° C. The mixture was cooled to room temperature, filtered through a piece of cotton, and the vial and cotton rinsed with ethyl acetate. The filtrate was washed with aqueous ammonia (2×10 mL), brine (2×10 mL), and the organic layer dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography using a gradient of ethyl acetate in hexanes (0 to 70%), affording benzyl ((1-(3-((2-chlorophenyl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (40 mg, 60% purity by LCMS): LCMS [M+H] + =607.4.

Step b: Benzyl ((1-(3-((2-chlorophenyl)thio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (20 mg, 0.033 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL) at 0-4° C. The resulting yellow-orange mixture was stirred at this temperature for 5 min and allowed to progressively reach room temperature. The reaction was stirred an additional 40 min at room temperature then slowly dropped into diethyl ether (20 mL). The gummy yellow precipitate formed was redissolved in water (10 mL) and the aqueous layer basified with sat. aq. Na 2 CO 3 solution (30 mL), followed by the addition of dichloromethane (20 mL). The layers were separated and the aqueous layer back-extracted with dichloromethane (3×10 mL). The combined organics were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The crude residue was purified by reversed phase chromatography (15 to 70% gradient of acetonitrile/10 mM aqueous ammonium formate) to give (1-(3-((2-chlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (4.1 mg, 32%) as a pale yellow solid after lyophilization.

Synthesis of 2-((6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)benzonitrile, Compound 10

Step a: To a flame-dried Biotage microwave vial equipped with a conic magnetic stirbar and a septum was added the 1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (43 mg, 0.100 mmol, 1.0 equiv). Anhydrous 1,4-Dioxane (0.500 mL, 0.20 M) and DIPEA (25.8 mg, 0.034 mL, 2.0 equiv) were added. The solution was degassed by passing a flow of nitrogen through the solution with a balloon of nitrogen for 5 minutes. Pd2(dba)3 (9.2 mg, 0.01 mmol, 0.10 equiv), XantPhos (11.6 mg, 0.0200 mmol, 0.2 equiv), and 2-cyanothiophenol (20.3 mg, 0.150 mmol, 1.5 equiv) were added to the solution. The septum was taken off the vial and a blue microwave cap was rapidly crimped on the vial. The solution was heated to 130° C. using an oil bath and heated for 16 hours. After 3 hours, additional of Pd2(dba)3 (36 mg, 0.04 mmol, 40 mol %), XantPhos (46.4 mg, 0.08 mmol, 80 mol %), and 2-cyanothiophenol (20.3 mg, 0.150 mmol, 1.5 equiv) were added to the vial which was crimped with a new seal cap. The reaction was further heated at 130° C. for overnight. The vial was opened to air and transferred to a 60 mL extraction funnel using DCM. The solution was quenched with a sat. aq. sol. NaHCO 3 (approx. 10 mL). The biphasic mixture was extracted and the layers were separated. The aqueous layer was further extracted with DCM (3×10 mL) and the organic layers were combined. The organic layers were then washed with brine (3×10 mL), dried over Na2SO4, filtered and evaporated to dryness. It resulted in a yellow film which was purified by silica gel chromatography (eluting with ethyl acetate, hexanes, and methanol). Concentration of the product-containing fractions in vacuo yielded 2-((6-(4-amino-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)benzonitrile (26 mg, 53% yield) as a yellow oil.

Step b: To a 20 mL scintillation vial equipped with a magnetic stirbar was added 2-((6-(4-amino-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)thio)benzonitrile (26 mg, 0.062 mmol, 1.00 equiv). Excess 33% HBr in AcOH (1.0 mL) was added, and the reaction was stirred at 80° C. 1 h. The reaction was cooled to room temperature and quenched by addition of water (10 mL), followed by ethyl acetate (10 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The aqueous layer was basified by the addition of Na2CO3 sat. aq, and diluted with more DCM (15 mL). The aqueous layer was back-extracted and layers were separated. The aqueous layer was extracted with more DCM (3×20 mL). Organic layer was then dried over Na2SO4, filtered, concentrated in vacuo, and lyophilized to yield the title compound (12 mg, 61%) as a yellow powder.

›ABBREVIATIONS · 50 of 63

Preparation of 6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-N-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-3-amine, Compound 11

Step a: Benzyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (70 mg, 0.119 mmol), SPhos Pd G1 (4.6 mg, 5 mol %), 2-chloroaniline (45 mg, 0.136 mmol), and potassium phosphate (50 mg, 0.237 mmol) were successively added to a 5 mL vial, followed by the addition of degassed dioxane (0.6 mL) and degassed water (0.2 mL). The resulting mixture was sealed, degassed with N 2 and heated at 100° C. overnight. After full conversion, the volatiles were evaporated under reduced pressure. The crude residue was purified by flash chromatography (0 to 100% gradient of ethyl acetate/hexanes) to give benzyl ((1-(3-((2-chlorophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (10 mg, 14%) as a yellow solid. MS m/z 590.2 [M+H] + .

Step b: Benzyl ((1-(3-((2-chlorophenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (10 mg, 0.0169 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL), at 0-4° C. The resulting yellow-orange mixture was stirred at this temperature for 5 min and allowed to progressively reach room temperature. The reaction was stirred an additional 70 min at room temperature, followed by the addition of diethyl ether (2.5 mL). The liquid was removed and the precipitate remaining triturated with diethyl ether (2 mL). The crude residue was purified by reversed phase chromatography (0 to 50% gradient of acetonitrile/10 mM aqueous ammonium formate) to provide 6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-N-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-3-amine (2.5 mg, 33%) as an off white solid after lyophilization.

Preparation of 6-(4-amino-4-methylpiperidin-1-yl)-N-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-3-amine, Compound 12

Step a: 1-(3-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (70 mg, 0.162 mmol), tBuXPhos Pd G1 (11.2 mg, 10 mol %), 2-chloropyridin-3-amine (63 mg, 0.487 mmol), and sodium tert-butoxide (31 mg, 0.3246 mmol) were successively added to a 5 mL vial, followed by the addition of degassed toluene (0.8 mL). The resulting mixture was sealed, degassed with N 2 , and heated at 100° C. overnight. The volatiles were evaporated under reduced pressure and the residue purified by flash chromatography (0 to 100% gradient of methanol/dichloromethane) to give 6-(4-amino-4-methylpiperidin-1-yl)-N-(2-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-amine (5 mg, 06%) as a yellow solid: LCMS [M+H] + =479.2.

Step b: 6-(4-Amino-4-methylpiperidin-1-yl)-N-(2-chloropyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-amine (5 mg, 0.013 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (1 mL) at 0-4° C. The resulting yellow-orange mixture was stirred at this temperature for 5 min and heated to 80° C. for 4 hours. After cooling, diethyl ether (2.5 mL) was added to the mixture. The liquid was removed from the resulting precipitate which was triturated with diethyl ether (2 mL). The crude residue was purified by reversed phase chromatography (0 to 50% gradient of acetonitrile/10 mM aqueous ammonium formate) to provide 6-(4-amino-4-methylpiperidin-1-yl)-N-(2-chloropyridin-3-yl)-1H-pyrazolo[3,4-b]pyrazin-3-amine (1.3 mg, 33%) as a brownish solid after lyophilization.

Preparation of 1-(3-((2,3-dichlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine, Compound 13

Step a: 1-(3-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (70 mg, 0.16 mmol), Pd 2 dba 3 (15 mg, 0.02 mmol), XantPhos (19 mg, 0.03 mmol), 2,3-dichlorothiophenol (35 mg, 0.20 mmol) and N,N-diisopropylethylamine (57 μL, 0.33 mmol) were successively added to a 5 mL vial, followed by the addition of dioxane (0.3 mL). The resulting mixture was sealed, degassed with N 2 , and heated under microwave irradiation at 130° C. for 1.5 hours. After cooling, the mixture was filtered through a pad of celite, the cake washed with EtOAc (20 mL), and the filtrate concentrated under reduced pressure. The resulting residue was purified by reversed phase chromatography (35 to 75% gradient of acetonitrile/10 mM aqueous ammonium formate) to give 1-(3-((2,3-dichlorophenyl)thio)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (45 mg, 52%) as a pale orange solid after lyophilization: LCMS [M+H] + =529.4.

Step b: 1-(3-((2,3-Dichlorophenyl)thio)-1-(4-methoxybenzyl)-1-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (45 mg, 0.08 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (2 mL) at room temperature. The resulting yellow-orange mixture was then placed in a preheated oil bath at 70° C., and stirred at this temperature for 1 hr. The mixture was allowed to cool then slowly dropped into diethyl ether (20 mL). The resulting yellow/orange precipitate was filtered through a piece of cotton and the gummy residue redissolved in water (3-4 mL), loaded on a reversed phase chromatography column, and purified using a gradient of acetonitrile/0.1% formic acid in water (0 to 55%) to give 1-(3-((2,3-dichlorophenyl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (27 mg, 77%) as a pale yellow solid.

Preparation of 4-methyl-1-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine, Compound 14

Step a: 1-(3-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (50 mg, 0.12 mmol), 1-methyl-1H-imidazole-2-thiol (40 mg, 0.35 mmol), Pd 2 (dba) 3 (33 mg, 0.06 mmol), and XantPhos (67 mg, 0.12 mmol) were all added to a nitrogen flushed microwave vial. A previously degassed (by sparging) mixture of dioxane (1 mL) and DIPEA (0.04 mL, 0.23 mmol) was added to the flushed microwave vial. The entire mixture was then heated to 110° C. for 1 hour in the microwave. After cooling, the reaction was filtered through a pad of celite, which was washed with MeOH. The filtrate was concentrated under vacuum and the product purified by reverse phased flash chromatography using a 0-60% gradient of MeCN in 10 mM ammonium formate to provide 1-(1-(4-methoxybenzyl)-3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine as a white solid (31.6 mg, 57% yield) after lyophilization: LCMS [M+H] + =465.4.

›ABBREVIATIONS · 51 of 63

Step b: 4-Methyl-1-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine (31.6 mg, 0.07 mmol) was slowly dissolved in 33% hydrobromic acid in acetic acid (2 mL). The resulting mixture was heated at 80° C. for 4 hours. After cooling, diethyl ether (4 mL) was added to the mixture to form a yellow precipitate. After removal of the liquid, the precipitate was triturated with diethyl ether (4 mL), and the resulting solid purified by reversed phase flash chromatography using a 0-60% gradient of MeCN in 10 mM ammonium bicarbonate to provide 4-methyl-1-(3-((1-methyl-1H-imidazol-2-yl)thio)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-amine as a white solid (12 mg, 52% yield) after lyophilization.

Preparation of (1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine, Compound 15

Step a: To a cold (−78° C.) solution of 2,2,6,6-tetramethylpiperidine (1.46 mL, 8.7 mmol) in THF (67 mL) was added n-BuLi (2.5 M, 3.2 mL, 8.1 mmol). After addition, the mixture was warmed up to 0° C., and stirred for 30 min. After cooling again to −78° C., 2,6-dichloropyrimidine (1.0 g, 6.7 mmo) in THF (3 mL) was added dropwise. After stirring at −78° C. for 30 min., 2-phenylacetaldehyde (1.2 mL, 10.1 mmol) was added to the mixture and the reaction stirred at −78° C. for 3 hrs followed by warming to room temperature. The mixture was diluted with saturated aqueous ammonium chloride solution then extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (AcOEt/hexane gradient) to give 1-(3,5-dichloropyrazin-2-yl)-2-phenylethanol (595 mg, 33%) as an orange oil: LCMS [M—H 2 O]+=251.1.

Step b: (1-(3,5-Dichloropyrazin-2-yl)-2-phenylethanol (160 mg, 0.60 mmol) was dissolved in dichloromethane (3 mL). Dess-Martin periodinane (322 mg, 0.82 mmol) was added and the mixture stirred for 2 hours. An aqueous solution of NaHCO 3 and Na 2 S 2 O 3 was added and the mixture stirred until the white solid went into the aqueous phase. The aqueous layer was extracted with DCM (2×) and the combined organics dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 1-(3,5-dichloropyrazin-2-yl)-2-phenylethanone (89 mg, 56%) as a yellow solid: LCMS [M+H] + =267.0.

Step c: To a solution of (1-(3,5-dichloropyrazin-2-yl)-2-phenylethanone (89 mg, 0.33 mmol) in DMAc (1.5 mL) at 0-5° C. was slowly added benzyl ((4-methylpiperidin-4-yl)methyl)carbamate (87 mg, 0.33 mmol, CAS #236406-24-9), followed by the addition of cesium fluoride (152 mg, 1.0 mmol). The mixture was stirred at 75° C. for 3 hr then hydrazine monohydrate (470 μL, 1.0 mmol) was slowly added at 0-5° C. (exothermic). After the addition was complete, the reaction mixture was heated at 90° C. for 1-5 hrs. After cooling to 0° C., water (10 mL) and EtOAc (10 mL) were added and the aqueous layer was extracted with EtOAc (10 mL). The combined organics were washed with water (10 mL), brine (10 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane/EtOAc=1:1, 1:3) to afford benzyl ((1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (53 mg, 32%) as a yellow foam: LCMS [M+H] + =471.2; 1 H-NMR (500 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 8.32 (s, 1H), 7.37-7.27 (m, 7H), 7.27-7.22 (m, 2H), 7.18-7.13 (m, 1H), 5.02 (s, 2H), 4.15 (s, 2H), 3.95-3.84 (m, 2H), 3.52-3.41 (m, 2H), 2.96 (d, J=6.4 Hz, 2H), 1.50-1.41 (m, 2H), 1.34-1.25 (m, 2H), 0.93 (s, 3H).

Step d: HBr in acid acetic (33% wt %, 1.0 mL) was added dropwise to benzyl ((1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (50 mg, 0.11 mmol). The mixture was stirred for 1 hr at room temperature, then diluted with DMF and water, and concentrated under reduced pressure to afford a yellow oil. The residue was dissolved in a minimum of DMF and purified by reversed phase chromatography (C18, 0 to 80% gradient of MeCN/(10 mM NH 4 HCO 3 in water, pH 10) to give (1-(3-benzyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (28 mg, 78%) as a white solid.

Preparation of (4-methyl-1-(3-(1-phenylvinyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine, Compound 16

Step a: Benzyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (100 mg, 0.17 mmol) was dissolved in acetonitrile (1.7 mL) and the mixture degassed with N 2 for 10 min. After this time, (1-phenylvinyl)boronic acid (0.038 g, 0.25 mmol), Pd(dppf)Cl 2 —CH 2 Cl 2 (7.7 mg, 8.47 μmol), and potassium carbonate (70 mg, 0.508 mmol) were added. The reaction vial was sealed and the resulting mixture was heated at 120° C. under microwave irradiation for 45 min. The mixture was concentrated under reduced pressure with silica to give a crude material dry pack which was subsequently purified by flash chromatography using a gradient of ethyl acetate in hexanes (0 to 100%) to afford benzyl ((4-methyl-1-(3-(1-phenylvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (89 mg, 93%) as a yellow oil: LCMS [M+H] + =567.5.

Step b: To a mixture of benzyl ((4-methyl-1-(3-(1-phenylvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (40 mg, 0.071 mmol) in acetic acid (2.7 ml) was added very slowly 33% w/w hydrogen bromide in acetic acid (0.8 mL). The resulting mixture was stirred at room temperature for 2 h. After this time, diethyl ether was added to form a precipitate that was isolated by filtration. The crude product was purified by reversed phase chromatography using a gradient of acetonitrile in 0.1% formic acid in water (0 to 100%) to give (4-methyl-1-(3-(1-phenylvinyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (16 mg, 57%) as yellow formate salt after lyophilization.

Preparation of (4-methyl-1-(3-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine, Compound 17

›ABBREVIATIONS · 52 of 63

Step a: To a mixture of benzyl ((4-methyl-1-(3-(1-phenylvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (40 mg, 0.071 mmol) in methanol/ethyl acetate (0.7 mL, 1:1 ratio) was added palladium on carbon (7.5 mg, 7.06 μmol) and di-tert-butyl dicarbonate (31 mg, 0.141 mmol). The reaction mixture was hydrogenated under 45 psi of H 2 for 18 hrs at room temperature. After this time, the mixture was filtered through a pad of celite, which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford tert-butyl ((4-methyl-1-(3-(1-phenylethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (36 mg, 95%) as a crude intermediate. LCMS [M+H]+=535.5.

Step b: To a mixture of tert-butyl ((4-methyl-1-(3-(1-phenylethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (0.040 g, 0.075 mmol) in dioxane (0.37 mL) was added hydrogen chloride (4M in dioxane) (0.94 mL). After stirring for 3 h at room temperature, the volatiles were removed under reduced pressure and the residue purified by reversed phase chromatography using a gradient of acetonitrile in 0.1% formic acid in water (0 to 100%) to give (4-methyl-1-(3-(1-phenylethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (11 mg, 37%) as a yellow formate salt after lyophilization.

Preparation of (6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone, Compound 18

Step a: To a mixture of benzyl ((4-methyl-1-(3-(1-phenylvinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (160 mg, 0.282 mmol) in acetonitrile (2.8 mL) was added sodium periodate (302 mg, 1.412 mmol) and osmium(VIII) oxide (90 μL, 0.014 mmol). The resulting mixture was stirred for 15 hrs at 60° C. The mixture was cooled to room temperature and concentrated under reduced pressure with silica to give a crude material dry pack. This crude material was purified by flash chromatography using a gradient of ethyl acetate in hexanes (0 to 100%) to give benzyl ((1-(3-benzoyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl) methyl)carbamate (118 mg, 73%) as a yellow oil: LCMS [M+H]+=569.5.

Step b: To a mixture of benzyl ((1-(3-benzoyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (30 mg, 0.053 mmol) in acetic acid (0.53 mL) was added 33% w/w hydrogen bromide in acetic acid (0.60 mL). The resulting mixture was stirred at room temperature for 3 hrs. After this time, the reaction mixture was concentrated under reduced pressure and the residue purified by reversed phase chromatography using a gradient of acetonitrile in 0.1% formic acid in water (0 to 100%) to give (6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone (18 mg, 86%) as a yellow formate salt after lyophilization.

Preparation of 1-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1-phenylethanol, Compound 19

Step a: To a mixture of benzyl ((1-(3-benzoyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (30 mg, 0.053 mmol) in acetic acid (0.53 mL) was added 33% w/w hydrogen bromide in acetic acid (0.60 mL). The resulting mixture is stirred at room temperature for 3 hrs. After this time, diethyl ether was added to form a precipitate that was isolated by filtration to give (6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone hydrobromide as a yellow powder: LCMS [M+H]+=351.2.

Step b: To a mixture of (6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)(phenyl)methanone hydrobromide (18 mg, 0.042 mmol) in anhydrous tetrahydrofuran (2 mL) was added methylmagnesium bromide (3M in diethyl ether) (70 μL, 0.209 mmol). The resulting mixture was stirred for 5 hrs at room temperature then quenched with a sat. aq. NaHCO 3 solution (1 mL) and diluted in DMF (1 mL). The mixture was concentrated under reduced pressure and the residue purified by reversed phase chromatography using a gradient of acetonitrile in 0.1% formic acid in water (0 to 100%) to give 1-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1-phenylethanol (10 mg, 58%) as a yellow powder after lyophilization.

Synthesis of 1-(3-(1H-benzo[d]imidazol-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine, Compound 20

Step a: To a flame-dried, nitrogen-flushed Biotage 0.5-2.0 mL vial equipped with a conic magnetic stirbar and a 14/20 white septa was added 1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (43 mg, 0.10 mmol, 1.0 equiv) and anhydrous dimethylsulfoxide (0.50 mL, 0.20 M). The solution was degassed by flowing nitrogen from a balloon through the solution for 5 min. The following reactants/catalysts were successively added to the vial: copper(II)oxide (2.86 mg, 0.010 mmol, 0.20 equiv), 4,7-di-methoxy-1,10-phenanthroline (9.6 mg, 0.04 mmol, 0.4 equiv), benzimidazole (17.8 mg, 0.150 mmol, 1.5 equiv), PEG-4000 (20 mg), and cesium carbonate (65 mg, 0.20 mmol, 2.0 equiv). The septum was removed from the vial, and a blue microwave cap was rapidly crimped on the vial. The solution was warmed to 130° C. using an oil bath and heated at this temperature for 16 hours. The reaction mixture was cooled and transferred to a 60 mL extraction funnel using dichloromethane, where the reaction was quenched with a saturated aqueous solution of sodium bicarbonate (approx. 10 mL). The aqueous layer was further extracted with dichloromethane (3×10 mL) and the combined organics were combined, washed with brine (3×10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting 1-(3-(1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (LCMS [M+H] + =469) was taken directly to next step.

›ABBREVIATIONS · 53 of 63

Step b: 1-(3-(1H-Benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine (46 mg, 0.100 mmol, 1.0 equiv) was dissolved in anhydrous dichloroethane (1.0 mL, 0.10 M) in a 20 mL scintillation vial. Hydrobromic acid (33% in acetic acid, 1.0 mL) was added and the vial capped firmly with a Teflon cap. The reaction mixture was heated at 80° C. for 16 hours. After cooling, the reaction was quenched by the addition of diethyl ether (10 mL). The resulting suspension was stirred for 10 min and the ether supernatant was disposed of. This trituration step was repeated three times before the evaporation of residual ether was affected with a stream of nitrogen. The resulting solid was dissolved in a minimum of dimethylformamide and aqueous sodium carbonate and purified by reversed C18 chromatography using a SNAP Biotage 12 g column (eluting with acetonitrile/water/0.1% ammonium carbonate) to yield 1-(3-(1H-benzo[d]imidazol-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine as an off-white solid (12 mg, 34%).

Synthesis of 1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine hydrochloride, Compound 23

Step a: tert-Butyl (1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (prepared by the route used for Compound 33) (300 mg, 0.56 mmol, 1.0 eq), 1,2,3,4-tetrahydroquinoline (83 mg, 0.62 mmol, 1.1 eq), RuPhos (26 mg, 56 umol, 0.1 eq), Ruphos Pd G4 (48 mg, 56 umol, 0.1 eq), and t-BuONa (163 mg, 1.7 mmol, 3.0 eq) were taken up in dioxane (10 mL). The mixture was evacuated and backfilled with nitrogen three times before being stirred at 120° C. for 10 hrs. The mixture was concentrated under reduced pressure, diluted with ethyl acetate (70 mL), washed with saturated sodium bicarbonate (30 mL×2), water (30 mL), and brine (30 mL×2). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by silica gel chromatography to afford tert-butyl N-[1-[3-(3,4-dihydro-2H-quinolin-1-yl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-4-piperidyl]carbamate (0.2 g) as a yellow oil and 1-[3-(3,4-dihydro-2H-quinolin-1-yl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-piperidin-4-amine (0.1 g) as a yellow oil.

Step b: tert-Butyl N-[1-[3-(3,4-dihydro-2H-quinolin-1-yl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-4-piperidyl]carbamate (200 mg, 0.34 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethyl sulfonic acid (0.5 mL). The reaction mixture was stirred at 100° C. for 1 hr. before being combined with the product from Step c for purification.

Step c: 1-[3-(3,4-Dihydro-2H-quinolin-1-yl)-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-b]pyrazin-6-yl]-4-methyl-piperidin-4-amine (100 mg, 0.2 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethyl sulfonic acid (0.5 mL) and the mixture stirred at 100° C. for 1 hr. The reaction mixture was combined with the reaction mixture from Step b. The solvent was removed under reduced pressure, the residue was diluted with ethyl acetate (70 mL), and the organics washed with saturated sodium bicarbonate (30 mL×2), water (30 mL), and brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow oil, which was purified by reversed phase prep-HPLC (eluting with acetonitrile/water/0.1% HCl) to afford 1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-amine hydrochloride (16 mg) as a brown solid.

The following compounds were synthesized via the same route as Compound 23, using building blocks that were either commercially available or that are described here. The pyrazolo-pyrazine ring was protected with either PMB (as shown above) or a THP group. The product of Step a could lead to mixture of protected and deprotected amines as seen for Compound 23, or as the fully protected intermediate, in which case Step c was not necessary. Compounds synthesized via Compound 23 method included Compound 21, Compound 22, Compound 27, Compound 28, Compound 29, Compound 30, Compound 31, Compound 32, Compound 34, Compound 35, Compound 36, Compound 37, Compound 38, Compound 43, Compound 47, Compound 56, Compound 59, Compound 60, Compound 61, Compound 62, Compound 64, Compound 67.

Syntheses of rel-(2R,4S)-1-(3-(3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine and rel-(2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine, Compound 24 and Compound 25

Step a: A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (300.0 mg, 822 μmol), tert-butyl (2-methylpiperidin-4-yl)carbamate (176.0 mg, 822 μmol, CAS #1281674-64-3), and diisopropylethylamine (428.0 μL, 2.46 mmol) in dimethylsulfoxide (15.0 mL) was stirred at 80° C. for 3 hrs. The reaction mixture was cooled, diluted with ethyl acetate (100.0 mL), washed with water (50.0 mL×3), brine (30.0 mL), and dried over anhydrous sodium sulfate. The mixture was filtered, and concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (eluting with petroleum ether/ethyl acetate) to afford tert-butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (700.0 mg, combined product) as a yellow solid.

Step b: A mixture of tert-butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (360.0 mg, 663 μmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (88.9 mg, 663 μmol), RuPhos-Pd-G4 (57.0 mg, 66.3 μmol), RuPhos (30.8 mg, 66.3 μmol), and t-BuONa (190.0 mg, 2.0 mmol) in dioxane (20.0 mL) was evacuated and backfilled with nitrogen three times before being stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (eluting with petroleum ether/ethyl acetate, then dichloromethane/methanol) to afford tert-butyl (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (400.0 mg, combined product) as a yellow solid and 1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (300.0 mg, combined product) as a yellow solid.

›ABBREVIATIONS · 54 of 63

Step c: tert-Butyl ((2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (400.0 mg, 861 μmol) was added to 4N HCl/methanol (10.0 mL) and the reaction mixture was stirred at 25° C. for 12 hours. The mixture was concentrated under reduced pressure and purified by reversed phase prep-HPLC (eluting with acetonitrile/water/0.1% ammonium hydroxide) to afford rac-(2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (150.0 mg, combined product) as a yellow solid: LCMS [M+H] + =365.3; 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.26 (s, 1H), 7.91-7.89 (m, 1H), 7.49-7.46 (m, 1H), 6.98-6.94 (m, 1H), 4.86-4.83 (m, 1H), 4.35-4.30 (m, 1H), 3.96-3.93 (m, 2H), 3.04-2.93 (m, 4H), 2.10-2.04 (m, 2H), 1.88-1.73 (m, 2H), 1.40-1.35 (m, 1H), 1.19-1.16 (m, 4H).

Step d: rac-(2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (120.0 mg, 329 μmol) was purified by chiral SFC: column—Chiralpak AD-3 100×4.6 mm I.D, 3 μm; mobile phase A—CO 2 mobile phase B—ethanol (0.1% ethanolamine); gradient: from 5% to 40% of B in 4.5 min and hold 40% for 2.5 min, then 5% of B for 1 min; flow rate: 2.8 mL/min; and column temperature−40° C. rel-(2R,4S)-1-(3-(3,4-Dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (40.9 mg, 112 μmol, e.e.=100%) was obtained as a yellow solid: LCMS [M+H] + =365.3; 1 H-NMR (400 MHz, DMSO-d4): δ 8.26 (s, 1H), 7.91-7.88 (m, 1H), 7.49-7.47 (m, 1H), 6.98-6.94 (m, 1H), 4.86-4.82 (m, 1H), 4.34-4.30 (m, 1H), 3.96-3.92 (m, 2H), 3.07-2.92 (m, 4H), 2.10-2.05 (m, 2H), 1.88-1.73 (m, 2H), 1.39-1.37 (m, 1H), 1.22-1.13 (m, 4H). rel-(2S,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (38.4 mg, 105 μmol, e.e.=91.7%) was obtained as a yellow solid: LCMS [M+H] + =365.3; 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.31 (s, 1H), 7.96-7.94 (m, 1H), 7.55-7.52 (m, 1H), 7.03-6.99 (m, 1H), 4.96-4.88 (m, 1H), 4.40-4.36 (m, 1H), 4.02-3.98 (m, 2H), 3.12-2.97 (m, 4H), 2.15-2.08 (m, 2H), 1.94-1.79 (m, 2H), 1.46-1.43 (m, 1H), 1.28-1.21 (m, 4H).

Synthesis of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methanamine dihydrochloride, Compound 26

Step a: tert-Butyl-((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (prepared via the route used for Compound 33) (200 mg, 376 μmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (55.4 mg, 413 μmol), RuPhos (17.5 mg, 37.6 μmol), RuPhos-Pd-G4 (31.9 mg, 37.6 μmol), and t-BuONa (107 mg, 1.12 mmol) were combined in dioxane (10 mL), and the mixture stirred at 120° C. for 10 hrs. The reaction mixture was concentrated under reduced pressure to give a yellow solid, which was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate=100:0 to 100:50) to provide tert-butyl-((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl))methyl)carbamate (150 mg, 256 μmol) as a yellow solid.

Step b: tert-Butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methyl)carbamate (150 mg, 308 μmol) was taken up in trifluoroacetic acid (5 mL) and trifluoromethylsulfonic acid (0.4 mL) and the mixture was stirred at 85° C. for 30 min. After cooling, the reaction mixture was concentrated under reduced pressure to give a yellow solid which was purified by prep-HPLC (eluting with acetonitrile/water/0.1% hydrochloric acid) to afford (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3-methylpyrrolidin-3-yl)methanamine dihydrochloride (33.5 mg, 25.0% yield, HCl salt) as a yellow solid after lyophilization.

Synthesis of (1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine, Compound 33

Step a: 3,5-Dichloropyrazine-2-carbonitrile (500 mg, 2.9 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate hydrochloride (655 mg, 2.9 mmol, CAS #1158759-03-5), and diisopropylethylamine (1.5 mL, 287 μmol) were taken up in dimethyl sulfoxide (10 mL) and stirred at 70° C. for 1 hr. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL×4), brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The combined organics were concentrated under reduced pressure, and purified by flash silica gel chromatography (eluting with ethyl acetate:petroleum ether=0:100 to 50:100) to afford tert-butyl ((1-(6-chloro-5-cyanopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (900 mg, 86% yield) as a yellow solid.

Step b: tert-Butyl ((1-(6-chloro-5-cyanopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (900 mg, 2.5 mmol), (4-methoxybenzyl)hydrazine (447.0 mg, 2.9 mmol), and triethylamine (1.7 mL, 12.2 mmol) were taken up in ethanol (10 mL) and stirred at 90° C. for 12 hrs. After cooling, the mixture was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether:ethyl acetate=100:0 to 100:80) to afford tert-butyl ((1-(3-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (900 mg, 77% yield) as a yellow solid.

Step c: tert-Butyl ((1-(3-amino-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (900 mg, 1.2 mmol), sodium nitrite (153 mg, 2.2 mmol), and hydrogen bromide (5.4 mL, 48% aq, 46.5 mmol) were taken up in acetonitrile (10.0 mL) and the reaction was stirred at 0° C. for 1 hr. Copper(I) bromide (53.3 mg, 0.37 mmol) was added at 0° C., and then warmed to 25° C. before and stirred for another 1 hr. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography (petroleum ether:ethyl acetate=100:0 to 100:20) to afford tert-butyl ((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (500 mg, 50% yield) as a yellow solid.

›ABBREVIATIONS · 55 of 63

Step d: (1-(3-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (300 mg, 0.67 mmol), 1,2,3,4-tetrahydroquinoline (99 mg, 0.74 mmol), RuPhos (31 mg, 67 μmol), RuPhos-Pd-G4 (58 mg, 67 μmol), and t-BuONa (193 mg, 2.0 mmol) were taken up in dioxane (5 mL) and the mixture evacuated and refilled three times with nitrogen before being stirred at 120° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (petroleum ether:EtOAc=100:0 to 100:30) to afford (1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (60 mg, 13% yield) as a yellow solid.

Step e: (1-(3-(3,4-Dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (60 mg, 0.12 mmol) was added to the mixture of trifluoromethylsulfonic acid (0.2 mL) and trifluoroacetic acid (2.0 mL) and the reaction mixture stirred at 90° C. for 0.5 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, diluted with methanol (5 mL), and the pH adjusted to 9 by adding ammonium hydroxide (aq.). The mixture was purified by prep-HPLC (eluting with acetonitrile and water, both with 0.1% ammonium hydroxide) to afford (1-(3-(3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (4.0 mg, 8.8% yield) as a yellow solid: LCMS [M+H] + =378.1.

The following compounds were synthesized via the same route as Compound 33, using the relevant appropriate building blocks (which were either commercially available or prepared as described in the intermediates section). The pyrazolo-pyrazine ring was protected with either PMB (as shown above) or a THP group. In some cases, other intermediates were prepared using the relevant substituted piperidine or pyrrolidine building blocks. Standard cross coupling conditions apply for Step d, which also included using Pd 2 (dba) 3 , Xantphos, and t-BuONa for the coupling. Compounds synthesized via the method described for Compound 33 include: Compound 40, Compound 41, Compound 44, Compound 45, Compound 46, Compound 48, Compound 49, Compound 50, Compound 52, Compound 57, Compound 59, Compound 61, Compound 63, Compound 65, Compound 66, Compound 67, Compound 68, Compound 69, Compound 70, Compound 72, Compound 73, Compound 75, Compound 77, Compound 78, Compound 81, Compound 83, Compound 84, Compound 85, Compound 86, Compound 87, Compound 88, Compound 89, Compound 90, Compound 91, Compound 92, Compound 93, Compound 94, Compound 96, Compound 106, Compound 117, Compound 118, Compound 120, Compound 121, Compound 122, Compound 123, Compound 124, Compound 125, Compound 126, Compound 127, Compound 130, Compound 131, Compound 132, Compound 133, Compound 134, Compound 135, Compound 136, Compound 163, Compound 164, Compound 165, Compound 169, Compound 170, Compound 173, Compound 182, Compound 184, Compound 185, Compound 186, Compound 187, Compound 188, Compound 189, Compound 190, Compound 191, Compound 192, Compound 193, Compound 195.

Synthesis of 1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-3,4-dihydro-1,5-naphthyridin-2(1H)-one, Compound 39

Step a: tert-Butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (200.0 mg, 368.0 μmol, synthesized via Step a of Compound 486), 3,4-dihydro-1,5-naphthyridin-2(1H)-one (162.0 mg, 1.1 mmol), CuI (7.0 mg, 36.8 μmol), potassium carbonate (152.0 mg, 1.1 mmol), and (1S,2S)—N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (5.2 mg, 36.8 μmol) were taken up in toluene (5 mL). The reaction flask was evacuated and refilled 3 times with nitrogen and the mixture was stirred at 110° C. for 12 hrs. After cooling, the mixture was concentrated under reduced pressure to give a residue that was purified by silica gel chromatography (eluting with petroleum ether:ethyl acetate=10:0 to 10:3) to afford tert-butyl (4-methyl-1-(3-(2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)carbamate (100.0 mg, 48.3% yield) as a yellow solid.

Step b: A flask was charged with tert-butyl N-[4-methyl-1-[3-(2-oxo-3,4-dihydro-1,5-naphthyridin-1-yl)-1-tetrahydropyran-2-yl-pyrazolo[3,4-b]pyrazin-6-yl]-4-piperidyl]carbamate (180.0 mg, 319.9 umol) followed by trifluoroacetic acid (2.0 mL). The reaction mixture was stirred at 50° C. for 12 hrs, cooled, and concentrated under reduced pressure. The residue was purified by prep-HPLC (eluting with acetonitrile/water/0.1% hydrochloric acid) to afford 1-[6-(4-amino-4-methyl-1-piperidyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl]-3,4-dihydro-1,5-naphthyridin-2-one (22.0 mg, 15.9/6 yield, HCl salt) as a yellow solid.

Synthesis of 1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-amine Compound 42

Step a: To a solution of 5-chloro-1,2,3,4-tetrahydro-1,6-naphthyridine (150 mg, 889 μmol, CAS #98490-61-0) and diphenylmethanimine (177 mg, 977 μmol) in toluene (5 mL) was added t-BuONa (170 mg, 1.77 mmol), Pd 2 (dba) 3 (81.3 mg, 177 μmol), and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (110 mg, 177 μmol). The mixture was degassed and purged with nitrogen three times, then stirred at 110° C. for 12 hrs under a nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate=100:0 to 100:100) to afford N-(diphenylmethylene)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-amine (180 mg, 574 μmol, 64.7% yield) as a light yellow solid.

Step b: To a solution of tert-butyl (1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (200 mg, 376 μmol) and N-(diphenylmethylene)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-amine (117 mg, 376 μmol) in dioxane (5 mL) was added RuPhos-Pd-G4 (91.3 mg, 112 μmol), t-BuONa (72.2 mg, 752 μmol), and RuPhos (52.2 mg, 112 μmol). The reaction mixture was purged with nitrogen for 3 min, then stirred at 120° C. for 12 hrs under a nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate=100:0 to 100:80) to afford tert-butyl (1-(3-(5-((diphenylmethylene)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (200 mg, 261 μmol, 69.6% yield) as a yellow gum.

›ABBREVIATIONS · 56 of 63

Step c: A solution of tert-butyl (1-(3-(5-((diphenylmethylene)amino)-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (180 mg, 235 μmol) in trifluoroacetic acid (5 mL) was stirred at 80° C. for 50 h and then 100° C. for 22 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, the residue diluted with methanol and the pH adjusted to 10 with ammonium hydroxide (aq.). The mixture was then purified by prep-HPLC (eluting with acetonitrile/water/0.1% ammonium hydroxide) to afford 1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,6-naphthyridin-5-amine (35.0 mg, 92.2 μmol, 39.2% yield) as an off-white solid.

Separation of (R)-(4-methyl-1-(3-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine, Compound 49 and (S)-(4-methyl-1-(3-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine, Compound 50

(4-methyl-1-(3-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (70 mg, 178 μmol) was synthesized as described above for Compound 33, using as 4-methyl-1,2,3,4-tetrahydroquinoline amine in Step d. This compound was then separated by Chiral-SFC (Column: Chiralcel OJ-3 50×4.6 mm I.D., 3 um Mobile phase: A: CO 2 B:ethanol (0.05% DEA) Gradient: hold 5% for 0.2 min, then from 5% to 40% of B in 1.4 min and hold 40% for 1.05 min, then 5% of B for 0.35 min. Flow rate: 4 mL/min Column temp:40° C.). The absolute configuration of both enantiomers were assigned randomly. (R)-(4-methyl-1-(3-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (18.0 mg, 45.9 μmol, e.e.=100%) was obtained as a yellow solid. LCMS: calc. for C22H 29 N 7 : 391.2, found: [M+H]+ 392.1. (S)-(4-methyl-1-(3-(4-methyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanamine (20.0 mg, 51.0 μmol, e.e.=96.7%) was obtained as a yellow solid. LCMS: calc. for C 22 H 29 N 7 : 391.2, found: [M+H]+ 392.1.

Synthesis of 5-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-amine, Compound 51

Step a: To a solution of 6-bromo-1,2,3,4-tetrahydro-1,5-naphthyridine (30 mg, 140 μmol) and diphenylmethanimine (27.9 mg, 154 μmol) in toluene (5 mL) was added Pd 2 (dba); (12.8 mg, 14.0 μmol), BINAP (8.71 mg, 14.0 μmol), and sodium tert-butoxide (26.8 mg, 280 μmol). The mixture was degassed and purged with nitrogen three times before being stirred at 110° C. for 12 hrs under a nitrogen atmosphere. After cooling, the reaction mixture was concentrated under reduced pressure and the product purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate) to afford N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-amine (230 mg, 733 μmol, 71.4% yield) as a brown solid.

Step b: To a solution of tert-butyl ((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (360 mg, 659 μmol) and N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-amine (226 mg, 724 μmol) in dioxane (10 mL) were added RuPhos (65.9 μmol, 30.7 mg), RuPhos-Pd-G4 (65.9 μmol, 56.0 mg), and sodium tert-butoxide (1.31 mmol, 125 mg). The reaction mixture was evacuated and backfilled with nitrogen three times, followed by stirring at 100° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (eluting with dichloromethane and methanol) to afford tert-butyl ((1-(3-(6-((diphenylmethylene)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (500 mg, 449 μmol, 97.6% yield) as a yellow solid.

Step c: A solution of tert-butyl ((1-(3-(6-((diphenylmethylene)amino)-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (480 mg, 617 μmol) in trifluoroacetic acid (10 mL) and trifluoromethylsulfonic acid (2.0 mL) was stirred at 20° C. for 6 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, diluted with methanol (5.0 mL) and dimethylformamide (5.0 mL) and the pH adjusted to 7-10 with ammonium hydroxide. The reaction mixture was purified by prep-HPLC (eluting with acetonitrile/water/0.1% formic acid) to afford 5-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-2-amine (100 mg, 254 μmol, 41.3% yield) as a yellow solid.

Synthesis of 8-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine, Compound 53

A resealable reaction vial was charged with benzyl (8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-yl)carbamate (131 mg, 0.2124 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (31.3 mg, 0.2336 mmol), sodium 2-methylpropan-2-olate (40.8 mg, 0.4248 mmol), RuPhos/Pd G4 (18.0 mg, 0.02124 mmol), and dioxane (5 mL). Nitrogen gas was bubbled through the mixture for 10 min, the vial sealed, and the mixture stirred at 90° C. for 5 hrs. After cooling, the reaction mixture was diluted with ethyl acetate and brine. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase HPLC (eluting with acetonitrile/water/0.1% ammonium formate) to afford 8-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-8-azaspiro[4.5]decan-1-amine (2 mg) as an amorphous off-white solid after lyophilization.

Synthesis of 1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide, Compound 54

Step a: tert-Butyl (1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (0.2 g, 376.0 μmol), methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (71.9 mg, 375.0 μmol, CAS #177478-49-8), RuPhos (17.5 mg, 37.6 μmol), RuPhos-Pd-G4 (31.9 mg, 37.6 μmol), and t-BuONa (107.0 mg, 1.1 mmol) were taken up in dioxane (10 mL). The reaction mixture was evacuated and backfilled three times with nitrogen before being stirred at 120° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether=0:100 to 30:100) to afford methyl 1-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (180.0 mg, 74.6% yield) as a yellow solid.

›ABBREVIATIONS · 57 of 63

Step b: To methyl 1-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (160.0 mg, 249 μmol) dissolved in methanol (3.0 mL) was added sodium hydroxide (19.9 mg, 498.0 μmol) in water (1.0 mL). The reaction mixture was stirred at 70° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure and diluted with water (20 mL), the pH adjusted to 5 by the addition of 2N hydrochloric acid, and extracted with dichloromethane (30 mL×2). The organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (160.0 mg, 96.1% yield) as a yellow solid.

Step c: To a solution of 1-(6-(4-((tert-butoxycarbonyl)amino)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (150.0 mg, 238.0 μmol) in tetrahydrofuran (12 mL) and dichloromethane (6 mL), and triethylamine (96.3 mg, 952.0 μmol) was added HATU (180.0 mg, 476.0 μmol) in one portion and the reaction mixture stirred for 15 min. Ammonium carbonate (91.3 mg, 952.0 μmol) was added and the mixture was stirred for another 2 hrs. The reaction mixture was diluted with ethyl acetate (30 mL), washed with brine (20 mL×2), and concentrated under reduced pressure to afford tert-butyl (1-(3-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (150.0 mg, crude) as a yellow solid.

Step d: tert-Butyl (1-(3-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl) carbamate (150.0 mg, 239 μmol) and trifluoromethylsulfonic acid (0.2 mL) were combined in trifluoroacetic acid (2.0 mL) and the reaction mixture stirred at 90° C. for 30 min. After cooling, the mixture was concentrated under reduced pressure, diluted with methanol (5.0 mL), and the pH adjusted to 9 by adding ammonium hydroxide. Purification by prep-HPLC (eluting with acetonitrile/water/0.1% hydrochloric acid) afforded 1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (43.2 mg, 44.4% yield) as a yellow solid.

Synthesis of 8-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-oxa-8-azaspiro[4.5]decan-4-amine, Compound 55

A resealable reaction vial was charged with 8-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-N-(4-methoxybenzyl)-1-oxa-8-azaspiro[4.5]decan-4-amine (125 mg, 0.2067 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (30.4 mg, 0.2273 mmol), sodium 2-methylpropan-2-olate (39.7 mg, 0.4134 mmol), RuPhos/Pd G4 (17.5 mg, 0.02067 mmol), and dioxane (5 mL). Nitrogen was bubbled through the mixture for 10 min, the vial was sealed, and the mixture was stirred at 90° C. 3 hrs. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then dissolved in trifluoroacetic acid (3 mL) and heated to 100° C. under microwave irradiation for 1 hr, then at 130° C. for 1 hr. The reaction mixture was diluted with methanol, concentrated under reduced pressure, stripped with methanol, and dissolved in dimethysulfoxide (with 0.2 mL aqueous ammonium hydroxide). The mixture was then purified by reversed phase HPLC (eluting with acetonitrile/water/0.1% ammonium formate) to provide 8-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-1-oxa-8-azaspiro[4.5]decan-4-amine (22 mg) as a yellow solid after lyophilization.

Synthesis of 1-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide, Compound 58

Step a: tert-Butyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (200.0 mg, 359 μmol), methyl 1,2,3,4-tetrahydroquinoline-6-carboxylate (68.6 mg, 359 μmol), RuPhos (33.4 mg, 71.8 μmol), RuPhos-Pd-G4 (61.7 mg, 71.8 μmol), and t-BuONa (68.9 mg, 718 μmol) were combined in dioxane (15.0 mL) and the reaction mixture evacuated and backfilled with nitrogen three times before being stirred at 70° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (eluting with petroleum ether/ethyl acetate) to afford methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (160.0 mg, 72.0% yield) as a yellow solid.

Step b: Methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (160 mg, 258 μmol) was dissolved in methanol (10 mL). Sodium hydroxide (30.9 mg, 774 μmol) and water (2.0 mL) was added and the reaction mixture was stirred at 70° C. for 12 hrs. After cooling, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), the pH adjusted to 5 via the addition of 2N hydrochloric acid, and extracted with dichloromethane (30 mL×2). The combined organics were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (130.0 mg, crude) as a yellow solid.

Step c: 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (130.0 mg, 214 μmol) was dissolved in tetrahydrofuran (10 mL). Ethyl chloroformate (81.1 μL, 642 μmol) was added at 0° C., and the reaction mixture stirred for 15 min. Then triethylamine (88.9 μL, 642 μmol) was added in one portion, and the reaction mixture was warmed to 25° C., and stirred for 12 hrs. After this time, the mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (eluting with dichloromethane and methanol) to afford tert-butyl ((1-(3-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (50.0 mg, 36.4% yield) as a yellow solid.

›ABBREVIATIONS · 58 of 63

Step d: tert-Butyl ((1-(3-(6-carbamoyl-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (50.0 mg, 99.2 μmol) was added to 4N HCl/methanol (5 mL), and the reaction mixture stirred at 25° C. for 2 hrs. After this time, the mixture was concentrated under reduced pressure and purified by prep-HPLC (eluting with acetonitrile/water/0.1% hydrochloric acid) to afford 1-(6-(4-(aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-6-carboxamide (18.0 mg, 52% yield, HCl salt) as a yellow solid.

Synthesis of 2-(1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylic acid, Compound 71

A mixture of tert-butyl (1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)carbamate (100 mg, 0.188 mmol), ethyl 2-(1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylate (54.2 mg, 0.188 mmol), sodium tert-butoxide (36.1 mg, 0.376 mmol), and RuPhos Pd G4 (15.9 mg, 0.019 mmol) in dioxane (5 mL) was degassed with nitrogen in a sealed tube, which was then sealed and stirred at 100° C. for 23 hours. The mixture was concentrated down after filtering through a celite plug with 10% MeOH/DCM (5×5 mL) and then dried before taking up in˜1.5 mL TFA and heating in a microwave at 110° C. for 1 hour. Excess TFA was removed under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with DCM/MeOH). Product-containing fractions were pooled and concentrated in vacuo to yield 2-(1-(6-(4-amino-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-5-yl)thiazole-4-carboxylic acid (5.6 mg) as a yellow solid.

rac-(2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine, Compound 74

Step a: A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (300.0 mg, 822 μmol), tert-butyl (2-methylpiperidin-4-yl)carbamate (176.0 mg, 822 μmol) and DIPEA (428.0 μL, 2.46 mmol) in DMSO (15.0 mL) was stirred at 80° C. for 3 hours. The reaction mixture was diluted with EtOAc (100.0 mL), and the organic layer was separated, washed with H 2 O (50.0 mL×3), brine (30.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 100:10) to afford the product of tert-butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (700.0 mg, combined product) as a yellow solid.

Step b: A mixture of tert-butyl (1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (360.0 mg, 663 μmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (88.9 mg, 663 μmol), RuPhos-Pd-G4 (57.0 mg, 66.3 μmol), RuPhos (30.8 mg, 66.3 μmol) and t-BuONa (190.0 mg, 2.0 mmol) in dioxane (20.0 mL) was evacuated and refilled for 3 times with N 2 and stirred at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography (Petroleum ether:Ethyl acetate=100:0 to 0:100, DCM:MeOH=100:20) to afford the product of tert-butyl (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (400.0 mg) as a yellow solid and 1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (300.0 mg) as a yellow solid. LCMS m/z: 448.9 (M+H)+ and 549.2 (M+H)+.

Step c: rac-Tert-butyl ((2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)carbamate (400.0 mg, 861 μmol) was added in 4N HCl/MeOH (10.0 mL), and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (NH 3 .H 2 O) to afford rac-(2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-amine (150.0 mg) as a yellow solid.

Synthesis of 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N-methyl-1,2,3,4-tetrahydroquinoline-5-carboxamide, Compound 79

Step a: A solution of tert-butyl ((1-(3-bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (150.0 mg, 274.0 μmol), methyl 1,2,3,4-tetrahydroquinoline-5-carboxylate (52.3 mg, 274.0 μmol), RuPhos (25.5 mg, 54.8 umol), RuPhos-Pd-G4 (44.3 mg, 54.8 umol) and t-BuONa (52.6 mg, 548.0 umol) in dioxane (5.0 mL) under N 2 was stirred at 70° C. for 12 h. The reaction mixture was concentrated in vacuo to give crude product. The residue was purified by prep-TLC (petroleum ether:EtOAc=1:1) to give methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150.0 mg, 83.7% yield) as yellow gum. LCMS m/z 656.2 (M+H)+.

Step b: To a solution of methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (150.0 mg, 228.0 μmol) in MeOH/H 2 O (3.0 mL/1.0 mL) was added KOH (38.3 mg, 684.0 umol) and stirred at 25° C. for 12 h. The reaction mixture was stirred at 50° C. for another 2 h. The reaction mixture was concentrated in vacuo to give 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (180.0 mg, crude) as yellow gum. LCMS m/z 642.3 (M+H) + .

Step c: A solution of 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (180.0 mg, 280.0 μmol), methanamine hydrochloride (28.3 mg, 420.0 μmol), HATU (212.0 mg, 560.0 umol) and DIPEA (108.0 mg, 840.0 umol) in DMF (5.0 mL) was stirred at 40° C. for 12 h. On completion, the solution was added into H 2 O (10.0 mL) and then extracted with EtOAc (10.0 mL×2). The combined organic layers were washed with saturated NH 4 Cl (10.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give tert-butyl ((1-(1-(4-methoxybenzyl)-3-(5-(methylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (200.0 mg, crude) as yellow gum. LCMS m/z 622.3 (M+H) + .

›ABBREVIATIONS · 59 of 63

Step d: A solution of tert-butyl ((1-(1-(4-methoxybenzyl)-3-(5-(methylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (200.0 mg, 305.0 μmol) in TFA/TfOH (3.0 mL/0.3 mL) was stirred at 25° C. for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (5.0 mL), and adjusted to pH=7 with NH 3 .H 2 O. The mixture was purified by prep-HPLC (HCl) to give 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N-methyl-1,2,3,4-tetrahydroquinoline-5-carboxamide hydrochloride (24.2 mg, 16.9% yield) as orange solid. LCMS: calc. for C 23 H 30 N 8 O: 434.3, found: [M+H] + 435.1. 1 HNMR (400 MHz, MeOD d 4 ): δ 8.35 (s, 1H), 7.36 (s, J=8.0 Hz, 1H), 7.20-7.26 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.15-4.26 (m, 2H), 4.10-4.15 (m, 2H), 3.60-3.68 (m, 2H), 2.95 (s, 4H), 2.93 (s, 3H), 2.15-2.00 (m, 2H), 1.60-1.72 (m, 4H), 1.24 (s, 3H).

Synthesis of 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N,N-dimethyl-1,2,3,4-tetrahydroquinoline-5-carboxamide, Compound 80

Step a: A solution of 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid (150.0 mg, 233.0 μmol, synthesized via Steps a-b of Compound 79), dimethylamine hydrochloride (28.4 mg, 349.0 μmol), HATU (177.0 mg, 466.0 umol) and DIPEA (90.1 mg, 699.0 umol) in DMF (5.0 mL) was stirred at 50° C. for 3 h. On completion, the reaction mixture was concentrated in vacuo to remove solvent. The residue was washed with water (5.0 mL), filtered and dried to give tert-butyl ((1-(3-(5-(dimethylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (150.0 mg) as yellow solid. LCMS m/z 669.3 (M+H) + .

Step b: A solution of tert-butyl ((1-(3-(5-(dimethylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (150.0 mg, 224.0 μmol) in TFA/TfOH (3.0 mL/0.3 mL) was stirred at 25° C. for 12 h. On completion, the reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (5.0 mL), adjusted pH=7 with NH 3 .H 2 O and purified by prep-HPLC (HCl) to give 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N,N-dimethyl-1,2,3,4-tetrahydroquinoline-5-carboxamide hydrochloride (20.7 mg, 19.1% yield) as orange solid. LCMS: calc. for C 24 H 32 N 8 O: 448.3, found: [M+H] + 449.2. 1 HNMR (400 MHz, Methanol_d 4 ): δ 8.39 (s, 1H), 7.35 (d, 1=8.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.18-4.26 (m, 4H), 3.63-3.90 (m, 2H), 3.16 (s, 3H), 2.95 (s, 5H), 2.60-2.90 (m, 2H), 2.00-2.16 (m, 2H), 1.60-1.71 (m, 4H), 1.24 (s, 3H).

Synthesis of (4-(aminomethyl)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanol dihydrochloride, Compound 82

Step a: A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (300 mg, 822 μmol) and tert-butyl ((4-(hydroxymethyl)piperidin-4-yl)methyl)carbamate (220 mg, 904 μmol) in DIEA (10 mL) was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (Petroleum ether: Ethyl acetate=1:1˜0:1) to afford the product of tert-butyl ((4-(hydroxymethyl)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (340 mg, 70.6% yield) as a yellow solid.

Step b: A mixture of tert-butyl ((4-(hydroxymethyl)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methyl)carbamate (290 mg, 506 μmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (74.6 mg, 556 μmol), RuPhos (47 mg, 101 μmol), RuPhos-Pd-G4 (82.4 mg, 101 μmol) and Cs2CO3 (492 mg, 1.5 mmol) in dioxane (15 mL) was stirred at 70° C. for 12 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography (Ethyl acetate: Methyl alcohol=10:1-20:1) to afford the product of tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(hydroxymethyl)piperidin-4-yl)methyl)carbamate (150 mg, crude) as a yellow solid.

Step c: A mixture of tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-(hydroxymethyl)piperidin-4-yl)methyl)carbamate (150 mg, 155 μmol) in 4M HCl/MeOH (5 mL) was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (HCl) to afford the product of (4-(aminomethyl)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)piperidin-4-yl)methanol dihydrochloride (9.8 mg, 13.5% yield) as a orange solid.

Synthesis of (2R,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol, Compound 95

Step a: The compound (2R,4R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (100 mg, 0.2 mmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (36 mg, 0.3 mmol), RuPhos (10 mg, 0.02 mmol), RuPhos-Pd-G4 (19 mg, 0.02 mmol) and t-BuONa (64 mg, 0.6 mmol) were added in dioxane (10 mL). The mixture was evacuated and refilled 3 times using N 2 gas. The reaction mixture was stirred at 80° C. for 12 hours. The reaction was concentrated to give a residue which was purified by prep-TLC (Ethyl acetate) to afford the product of (2R,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (100 mg, 99% yield) as a yellow oil.

Step b: The compound (2R,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (50 mg, 0.1 mmol) was added to HCl/MeOH (5 mL, 2N). The reaction mixture was stirred at 25° C. for 12 hours. The mixture was then filtered and purified by prep-HPLC (HCl) to give the product of (2R,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (6.3 mg, 15% yield) as a yellow solid.

›ABBREVIATIONS · 60 of 63

Synthesis of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-propylpiperidin-4-yl)methanamine dihydrochloride, Compound 97

Step a: To a solution of 1-benzylpiperidine-4-carbonitrile (2 g, 10.0 mmol) in THE (20 ml) was added NaHMDS (1 M, 19.9 mmol, 19.9 mL) at −40° C., the mixture was stirred at −40° C. for 20 minutes. After n-PrI (2.48 g, 14.9 mmol) was added slowly at −40° C., the reaction was stirred at 20° C. for 2 hours. LCMS showed the product's MS was found. The reaction was quenched by sat. NH4Cl (40 mL), washed with brine (40 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (Petroleum ether/ethyl acetate=20:1) to give 1-benzyl-4-propylpiperidine-4-carbonitrile (2.10 g, 8.66 mmol, 87.1% yield) as a white oil.

Step b: To a solution of 1-benzyl-4-propylpiperidine-4-carbonitrile (1 g, 4.1 mmol) in THF (10.0 mL) was added LiAlH4 (312 mg, 8.2 mmol) and the reaction was stirred at 30° C. for 2 h. TLC (DCM/CH3OH=10/1) showed one new spot with higher polarity was found. The reaction was quenched with NaOH (2 N, 20 mL), filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was separated and the aqueous was extracted with EtOAc (50 mL×2). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give (1-benzyl-4-propylpiperidin-4-yl) methanamine (0.7 g, 69.2% yield) as a white solid.

Step c: A mixture of (1-benzyl-4-propylpiperidin-4-yl) methanamine (0.7 g, 2.8 mmol) in DCM (10.0 mL) added TEA (857 mg, 8.49 mmol) and tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (925 mg, 4.24 mmol) stirred at 25° C. for 2 h. LCMS showed ˜50% desired product formed. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL×2). The organic layer was concentrated and purified by (Petroleum ether/ethyl acetate=10:1) to afford tert-butyl ((1-benzyl-4-propylpiperidin-4-yl) methyl) carbamate (760 mg, 2.19 mmol, 77.5% yield) as a yellow solid.

Step d: To solution of tert-butyl ((1-benzyl-4-ethylpiperidin-4-yl) methyl) carbamate (0.6 g, 1.8 mmol) in MeOH (10 mL) was added 10% Pd/C (10 mg) and stirred at 30° C. for 12 hours under H2 (15 psi). TLC (DCM/CH3OH=10/1) showed the starting material was consumed completely. Pd/C was removed off by filtration and the filtrate was concentrated under reduced pressure to give tert-butyl ((4-ethylpiperidin-4-yl) methyl) carbamate (349 mg, 1.44 mmol, 80.0% yield) as a white oil.

Step e: To a solution of 1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (200 mg, 539 μmol) in DMSO (5 ml) was added DIEA (65.7 mg, 539 umol) and tert-butyl ((4-propylpiperidin-4-yl)methyl)carbamate (207 mg, 808 μmol), the mixture was stirred at 70° C. for 6 hours. TLC (Petroleum ether:EtOAc=1:3) showed most of the product formed. The reaction mixture was quenched by satd. NaCl (40 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (elution: Petroleum ether/ethyl acetate=1:1) to give tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-propylpiperidin-4-yl)methyl)carbamate (105 mg, 177 μmol, 33.0% yield) as a yellow oil.

Step f: To a solution of tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-propylpiperidin-4-yl)methyl)carbamate (100 mg, 169 μmol) in MeOH (5 ml) was added HCl/MeOH (2 mL, 4N)) at 0° C., the mixture was stirred at 30° C. for 6 hours. LCMS showed ˜80% desired product formed. The reaction mixture was concentrated and the residue was purified by prep-HPLC (HCl) to afford the product of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-propylpiperidin-4-yl)methanamine dihydrochloride (25.4 mg, 52.9 μmol, 2HCl salt, 31.3% yield) as a yellow solid.

Synthesis of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-ethylpiperidin-4-yl)methanamine dihydrochloride, Compound 98

Step a: To a solution of 1-benzylpiperidine-4-carbonitrile (2.0 g, 9.98 mmol) in THF (20 ml) was added NaHMDS (1 M, 19.9 mmol, 19.9 mL) at −40° C., the mixture was stirred at −40° C. for 20 min. EtI (2.32 g, 14.9 mmol) was added slowly at −40° C., the reaction mixture was stirred at 20° C. for 2 hours. LCMS showed the product's MS was found. The reaction mixture was quenched by sat. NH4Cl (40 mL), washed with brine (40 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (Petroleum ether/ethyl acetate=20:1) to give 1-benzyl-4-ethylpiperidine-4-carbonitrile (2.10 g, 9.19 mmol, 92.5% yield) as a white oil.

Step b: To a solution of 1-benzyl-4-ethylpiperidine-4-carbonitrile (1 g, 4.37 mmol) in THF (10.0 mL) was added LiAlH4 (664 mg, 17.5 mmol) and the reaction was stirred at 30° C. for 2 h. TLC (DCM/CH3OH=10/1) showed one new spot with higher polarity was found. The reaction was quenched with NaOH (2 N, 40 mL), filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was separated and the aqueous was extracted with EtOAc (50 mL×2). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give (1-benzyl-4-ethylpiperidin-4-yl) methanamine (0.8 g, 3.44 mmol, 79.2% yield) as a white solid.

Step c: A mixture of (1-benzyl-4-ethylpiperidin-4-yl)methanamine (0.9 g, 3.87 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (1.26 g, 5.80 mmol) and TEA (783 mg, 7.74 mmol) in DCM (10.0 mL) was stirred at 26° C. for 2 h. LCMS showed 90% desired product formed. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL×2). The organic layer was concentrated and purified by (Petroleum ether/ethyl acetate=10:1) to afford tert-butyl ((1-benzyl-4-ethylpiperidin-4-yl)methyl)carbamate (1.26 g, 3.78 mmol, 92.5% yield) as a yellow solid.

›ABBREVIATIONS · 61 of 63

Step d: To solution of tert-butyl ((1-benzyl-4-ethylpiperidin-4-yl) methyl) carbamate (1.0 g, 3.00 mmol) in MeOH (10 mL) was added 10% Pd/C (10 mg) and stirred at 30° C. for 12 hours under H2 (15 psi). TLC (DCM/CH3OH=10/1) showed the starting material was consumed completely. Pd/C was removed and the reaction mixture was concentrated under reduced pressure to give tert-butyl ((4-ethylpiperidin-4-yl) methyl) carbamate (0.6 g, 2.47 mmol, 82.5% yield).

Step e: To a solution of tert-butyl ((4-ethylpiperidin-4-yl)methyl)carbamate (150 mg, 618 μmol) in DMSO (5 ml) was added DIEA (150 mg, 1.23 mmol) and 1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydro-1,5-naphthyridine (206 mg, 556 μmol), the mixture was stirred at 70° C. for 2 hours. LCMS showed 59% product formed. The reaction mixture was quenched by sat. NaCl (40 mL), extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The resulting crude material was purified by silica gel chromatography (elution: Petroleum ether/ethyl acetate=1:1) to give tert-butyl((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-ethylpiperidin-4-yl)methyl)carbamate (110 mg, 190 μmol, 30.8% yield) as a yellow oil.

Step f: To a solution of tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-ethylpiperidin-4-yl)methyl)carbamate (110 mg, 190 μmol) in MeOH (5 ml) was added HCl/MeOH (2.0 mL, 4N)) at 0° C., the mixture was stirred at 30° C. for 6 hours. LCMS showed ˜90% the desired product formed. The reaction mixture was concentrated and the residue was purified by prep-HPLC (HCl) to afford the product of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-ethylpiperidin-4-yl)methanamine dihydrochloride (30.8 mg, 66.1 μmol, 2 HCl salt, 34.8% yield) as a yellow solid.

Synthesis of (1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-4-yl)methanol, Compound 99

Step a: To a solution of methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-4-carboxylate (150.0 mg, 228.0 μmol, synthesized as described for Compound 33) in THF (5.0 mL) at 0° C. was added LAH (26.6 mg, 684.0 umol). The reaction mixture was stirred at 0° C. for 1 h. On completion, the reaction mixture was poured into H 2 O (10.0 mL) and then extracted with EtOAc (10.0 mL×2). The combined organic layers were washed with saturated NaCl (20.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give crude product as yellow gum. The residue was purified by flash silica gel chromatography (4 g, Ethyl acetate in Petroleum ether from 0% to 40%) to give tert-butyl ((1-(3-(4-(hydroxymethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (70.0 mg, 48.9% yield) as orange oil.

Step b: A solution of tert-butyl ((1-(3-(4-(hydroxymethyl)-3,4-dihydroquinolin-1(2H)-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (70.0 mg, 111.0 μmol) in TFA/TfOH (2.0 mL/0.2 mL) was stirred at 25° C. for 1 h. On completion, the reaction mixture was concentrated in vacuo to give 2,2,2-trifluoro-N-((1-(3-(4-(hydroxymethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)acetamide (100.0 mg) as brown gum.

Step c: A solution of 2,2,2-trifluoro-N-((1-(3-(4-(hydroxymethyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)acetamide (100.0 mg, 198.0 μmol) and NaOH (15.8 mg, 396.0 umol) in MeOH (3.0 mL) was stirred at 25° C. for 12 h. The reaction mixture was purified by prep-HPLC (HCl) to give (1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinolin-4-yl)methanol hydrochloride (41.5 mg, 47.2% yield) as orange solid.

Synthesis of 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N-methyl-1,2,3,4-tetrahydroquinoline-4-carboxamide, Compound 100

Step a: A solution of methyl 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-4-carboxylate (180.0 mg, 274.0 μmol, synthesized using the method described for Compound 33, using methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate in Step d) and KOH (46.1 mg, 822.0 umol) in MeOH/H 2 O (3.0 mL/5 mL) was stirred at 40° C. for 12 h. The reaction mixture was concentrated in vacuum to give crude product. The residue was purified by flash silica gel chromatography (4 g, MeOH in DCM from 0% to 5%) to give 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (150.0 mg, 85.7% yield) as yellow oil.

Step b: A solution of 1-(6-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (150.0 mg, 233.0 μmol), methanamine in THF (233.0 uL, 466.0 μmol, 2.0 M), HATU (177.0 mg, 466.0 umol) and DIEA (90.1 mg, 699.0 umol) in DMF (5.0 mL) was stirred at 40° C. for 2 h. The solution was added into H 2 O (10.0 mL) and then extracted with EtOAc (10.0 mL×2). The combined organic layers were washed with saturated NaCl (20.0 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give tert-butyl ((1-(1-(4-methoxybenzyl)-3-(4-(methylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (200.0 mg, crude) as orange gum.

Step c: A solution of tert-butyl ((1-(1-(4-methoxybenzyl)-3-(4-(methylcarbamoyl)-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (200.0 mg, 305.0 μmol) in TFA/TfOH (3.0 mL/0.3 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (5.0 mL), adjusted to pH=9 with NH 3 .H 2 O, and purified by prep-HPLC (HCl). 1-(6-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)-N-methyl-1,2,3,4-tetrahydroquinoline-4-carboxamide hydrochloride (46.5 mg, 32.5% yield) was obtained as orange solid.

›ABBREVIATIONS · 62 of 63

Synthesis of (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methanamine, Compound 101

Step a: To a solution of 1-benzylpiperidin-4-one (10.0 g, 52.8 mmol) in MeOH (100.0 mL) at 0° C. was added AcCl (6.2 g, 79.1 mmol) slowly and the reaction was stirred at 0° C. for 2 h. LCMS showed one main peak with desired MS was found. The reaction was diluted with EtOAc (200.0 mL), washed with saturated NaHCO3 (100.0 mL×2) and brine (100.0 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc=2/1) to give 1-benzyl-4,4-dimethoxypiperidine (10.8 g, 87.0% yield) as a colorless oil.

Step b: To a solution of 1-benzyl-4,4-dimethoxypiperidine (5.00 g, 21.2 mmol) and TMSCN (3.15 g, 31.8 mmol) in DCM (50.0 mL) was added ZnI2 (0.66 g, 2.2 mmol) at 0° C., and the reaction was stirred at 25° C. for 12 h. LCMS showed main the starting material remained. Another batch of ZnI2 (9.44 g, 29.6 mmol) was added into reaction and the reaction was stirred at 25° C. for 12 h. TLC showed the starting material was consumed completely. The solid was filtered off and the cake was washed with DCM (100.0 mL). The filtrate was washed with saturated NaHCO 3 (50.0 mL×2). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated in vacuum to give 1-benzyl-4-methoxypiperidine-4-carbonitrile (4.30 g, 88.1% yield) as a golden oil.

Step c: To a solution of 1-benzyl-4-methoxypiperidine-4-carbonitrile (1.00 g, 4.34 mmol) in THF (20.0 mL) was added LAH (247.0 mg, 6.51 mmol) and the reaction was stirred at 30° C. for 2 h. LCMS showed the desired product formed. The reaction was quenched with NaOH (10 N, 4.0 mL), filtered through celite and washed with EtOAc (50.0 mL). The filtrate was concentrated in vacuum to give (1-benzyl-4-methoxypiperidin-4-yl)methanamine (1.05 g, crude) as a golden oil.

Step d: To a solution of (1-benzyl-4-methoxypiperidin-4-yl)methanamine (1.05 g, 4.48 mmol) in DCM (20.0 mL) was added Boc2O (1.95 g, 8.96 mmol) and the reaction was stirred at 20° C. for 2 h. LCMS showed the desired product formed. The reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc=1/1) to give tert-butyl ((1-benzyl-4-methoxypiperidin-4-yl)methyl)carbamate (1.25 g, 83.8% yield) as a golden oil.

Step e: A mixture of tert-butyl ((1-benzyl-4-methoxypiperidin-4-yl)methyl)carbamate (1.2 g, 3.58 mmol) and Pd/C (300.0 mg, 10%) in MeOH (20.0 mL) was hydrogenated under H2 (15 psi) at 20° C. for 12 h. TLC (Petroleum ether/EtOAc=1:1) showed one new spot with larger polarity was found. The reaction mixture was filtered through celite and washed with MeOH (20.0 mL). The filtrate was concentrated in vacuum to afford tert-butyl ((4-methoxypiperidin-4-yl)methyl)carbamate (800.0 mg, 91.5% yield) as a colorless oil.

Step f: A mixture of tert-butyl ((4-methoxypiperidin-4-yl)methyl)carbamate (200.0 mg, 822.0 μmol), 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine (250.0 mg, 685.0 μmol) and TEA (137.0 mg, 1.36 mmol) in NMP (10.0 mL) was stirred at 110° C. for 2 hours. TLC (Petroleum ether/EtOAc=2/1, Rf=0.7) showed the reaction worked completely and one new spot with larger polarity was found. The reaction mixture was diluted with EtOAc (50.0 mL), washed with water (50.0 mL×3). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc=2/1) to afford tert-butyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methyl)carbamate (380.0 mg, 96.9% yield) as a light yellow solid.

Step g: A mixture of tert-butyl ((1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methyl)carbamate (150.0 mg, 262.0 μmol), 1,2,3,4-tetrahydro-1,5-naphthyridine (52.7 mg, 393.0 μmol), t-BuONa (50.3 mg, 524.0 umol), RuPhos (24.4 mg, 52.4 umol) and RuPhos-Pd-G4 (22.2 mg, 26.2 umol) in dioxane (5.0 mL) was stirred at 90° C. for 14 h under N2. LCMS showed 57% of peak with the desired MS was found. This reaction was poured into water (50.0 mL) and extracted with EtOAc (50.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/EtOAc=1/1 to 1/3) to afford tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methyl)carbamate (120.0 mg, 79.4% yield) as a yellow solid.

Step h: A solution of tert-butyl ((1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methyl)carbamate (120.0 mg, 207.0 μmol) in TFA (5.0 mL) was stirred at 20° C. for 12 h. LCMS showed main peak with the desired MS was found. The reaction mixture was evaporated in vacuum. The residue was diluted with MeOH (5.0 mL), basified with NH3.H2O to pH=9 and purified by prep-HPLC (NH3.H2O) to afford (1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methoxypiperidin-4-yl)methanamine (41.5 mg, 50.8% yield) as a yellow solid.

Synthesis of (S)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate, Compound 102, and (R)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate, Compound 103

Step a: To a solution of (1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine (80.0 mg, 197.0 μmol, synthesized as described for Compound 33) and (Boc) 2 O (51.5 mg, 236.0 umol) in DCM (10.0 mL) was added TEA (39.8 mg, 394.0 umol) and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100:0 to 100:50). The product tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (90.0 mg, 90.3% yield) was obtained as a yellow solid.

›ABBREVIATIONS · 63 of 63

Step b: Tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (90.0 mg, 177.0 μmol) was separated by chiral SFC (Column: Chiralcel OJ-250×30 mm i.D., 5 um Mobile phase: A: CO 2 B: ethanol (0.1% NH 3 —H 2 O) Gradient: 30% B, Flow rate: 50 mL/min Column temp: 40° C.). The product of (S)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (45.0 mg) was obtained as a yellow solid. The product of (R)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (55.0 mg) was obtained as a yellow solid. The absolute configuration was arbitrarily assigned.

Step c: A solution of (S)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate (45.0 mg, 88.9 μmol) in HCl (2.0 mL, 4.0 N) was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give rel-(S)-(1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine hydrochloride (35.0 mg, 89.2% yield) was obtained as a yellow solid. LCMS: calc. for C 23 H 31 N 7 : 405.3, found: [M+H]+ 406.0. ee: 100%. 1 HNMR (400 MHz, Methanol_d 4 ): δ 8.25 (s, 1H), 7.18-7.21 (m, 1H), 6.95-7.03 (m, 2H), 6.86-6.90 (m, 1H), 4.16-4.21 (m, 2H), 3.93-4.06 (m, 2H), 3.54-3.62 (m, 2H), 2.93 (s, 2H), 2.78-2.83 (m, 1H), 2.11-2.23 (m, 1H), 1.97-2.06 (m, 2H), 1.83-1.90 (m, 1H), 1.63-1.67 (m, 4H), 1.23 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).

Step c was repeated for (R)-tert-butyl ((1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methyl)carbamate to give rel-(R)-(1-(3-(4-ethyl-3,4-dihydroquinolin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-4-methylpiperidin-4-yl)methanamine hydrochloride (46.0 mg, 96.4% yield) was obtained as a yellow solid. LCMS: calc. for C23H 31 N7: 405.3, found: [M+H]+ 406.0. ee: 93%. 1 HNMR (400 MHz, Methanol_d 4 ): δ 8.23 (s, 1H), 7.16-7.19 (m, 1H), 6.96-7.00 (m, 1H), 6.90-6.93 (m, 1H), 6.82-6.86 (m, 1H), 4.16-4.20 (m, 2H), 3.92-4.00 (m, 2H), 3.53-3.61 (m, 2H), 2.93 (s, 2H), 2.78-2.82 (m, 1H), 2.12-2.20 (m, 1H), 1.96-2.06 (m, 2H), 1.83-1.90 (m, 1H), 1.63-1.67 (m, 4H), 1.23 (s, 3H), 1.05 (t, J=7.2 Hz, 3H).

Synthesis of ((2R,4S)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)methanamine and ((2R,4R)-1-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-yl)methanamine, Compound 104 and Compound 109

Step a: (2R,4R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-ol (600 mg, 1.3 mmol) (formed from the reaction of (2R,4R)-2-methylpiperidin-4-ol and 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazine in DMSO, similar to conditions used for compound 33) was dissolved in DCM (25 mL). Dess-Martin periodinane (687 mg, 1.6 mmol) was added at 0° C. The reaction mixture was stirred at 25° C. for 2 hours. The reaction was quenched with sat, Na2SO3 (10 mL). The sat. NaHCO 3 (20 mL) was added. The partitioned layers were separated. The aqueous phase was extracted with DCM (20 mL×2). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous Na2SO4, filtered and concentrated to give a residue which was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 50/100) to afford the product of (2R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-one (500 mg, 84% yield) as a white solid.

Step b: The compound of TosMIC (263 mg, 1.3 mmol) in THF (2 mL) was added in the solution of t-BuOK (2.3 mL, 2.3 mmol, 1M, in THF) in THF (2 mL) at −78° C., and the mixture was stirred for 15 min. (2R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidin-4-one (0.4 g, 0.9 mmol) in THF (5 mL) was added dropwise at −78° C., and the reaction mixture was stirred at −78° C. for 2 hours. MeOH (5 mL) was added at −78° C. The mixture was heated at 70° C. for 2 h. The reaction mixture was concentrated to give a residue which was diluted with EtOAc (20 mL) and H2O (20 mL), the partitioned layers were separated. The aqueous phase was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (Ethyl acetate/Petroleum ether=0/100 to 50/100) to afford the product of (2R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-2-methylpiperidine-4-carbonitrile (300 mg, 73% yield) as a white solid.

Step c: The compound of (2R)-1-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-

›Tables in the description — 2

Compound	Name	Structure	Building Block
Compound 513	(4-methyl-1-(3- (pyrazolo[1,5- a]pyridin-5-ylthio)- 1H-pyrazolo[3,4- b]pyrazin-6- yl)piperidin-4- yl)methanamine
Compound 514	(1-(3-((4a,8a- dihydroisoquinolin- 6-yl)thio)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-4- methylpiperidin-4- yl)methanamine
Compound 515	(1-(3-((1H- pyrrolo[2,3- b]pyridin-4-yl)thio)- 1H-pyrazolo[3,4- b]pyrazin-6-yl)-4- methylpiperidin-4- yl)methanamine
Compound 516	(1-(3-((8- chloroquinolin-7- yl)thio)-1H- pyrazolo[3,4- b]pyrazin-6-yl)-4- methylpiperidin-4- yl)methanamine

TABLE 2 — SHP2 IC 50 Assay Results

Cmpd.		Cmpd.		Cmpd.		Cmpd.
No.	IC 50	No.	IC 50	No.	IC 50	No.	IC 50
6	A	127	A	247	A	367	A
7	A	128	A	248	A	368	A
8	A	129	A	249	A	369	A
9	A	130	A	250	A	370	A
10	A	131	A	251	A	371	A
11	A	132	A	252	A	372	A
12	B	133	A	253	A	373	A
13	A	134	A	254	A	374	A
14	C	135	A	255	A	375	A
15	B	136	A	256	A	376	A
16	A	137	A	257	A	377	A
17	B	138	A	258	A	378	A
18	B	139	A	259	A	379	A
19	B	140	C	260	A	380	A
20	B	141	C	261	A	381	A
21	A	142	C	262	A	382	A
22	A	143	C	263	A	383	A
23	A	144	C	264	A	384	A
24	A	145	C	265	A	385	C
25	A	146	C	266	A	386	A
26	A	147	C	267	A	387	A
27	C	148	C	268	A	388	B
28	A	149	C	269	A	389	A
29	B	150	A	270	A	390	A
30	B	151	C	271	A	391	A
31	A	152	C	272	A	392	A
32	A	153	C	273	A	393	A
33	A	154	C	274	A	394	A
34	A	155	C	275	A	395	A
35	A	156	C	276	A	396	A
36	B	157	B	277	A	397	A
37	A	158	C	278	A	398	A
38	B	159	B	279	A	399	A
39	B	160	C	280	A	400	A
40	B	161	C	281	A	401	A
41	A	162	C	282	A	402	A
42	B	163	A	283	A	403	A
43	C	164	A	284	A	404	A
44	B	165	A	285	A	405	A
45	A	166	A	286	A	406	A
46	A	167	B	287	A	407	A
47	B	168	B	288	A	408	A
48	A	169	A	289	A	409	A
49	A	170	A	290	A	410	A
50	A	171	B	291	A	411	A
51	A	172	A	292	A	412	A
52	A	173	A	293	A	413	A
53	A	174	C	294	A	414	B
54	A	175	A	295	A	415	A
55	A	176	A	296	A	416	A
56	A	177	A	297	A	417	A
57	A	178	B	298	A	418	A
58	A	179	A	299	A	419	A
59	A	180	A	300	A	420	A
60	A	181	A	301	A	421	A
61	A	182	A	302	A	422	A
62	A	183	A	303	A	423	A
63	A	184	A	304	A	424	A
64	A	185	A	305	A	425	A
65	A	186	A	306	A	426	A
66	A	187	A	307	A	427	A
67	A	188	A	308	A	428	A
68	A	189	A	309	A	429	A
69	A	190	A	310	A	430	A
70	A	191	A	311	A	431	A
71	A	192	A	312	A	432	A
72	A	193	A	313	B	433	A
73	A	194	A	314	A	434	A
74	A	195	A	315	A	435	A
75	A	196	A	316	A	436	A
76	A	197	A	317	A	437	A
77	A	198	A	318	A	438	A
78	A	199	A	319	A	439	A
79	A	200	A	320	A	440	A
80	A	201	C	321	A	441	A
81	A	202	A	322	B	442	A
82	A	203	B	323	A	443	A
83	A	204	B	324	A	444	A
84	A	205	B	325	A	445	A
85	A	206	B	326	A	446	A
86	A	207	A	327	A	447	A
87	A	208	A	328	A	448	A
88	A	209	A	329	A	449	A
89	A	210	B	330	A	450	A
90	B	211	A	331	A	451	A
91	A	212	A	332	A	452	A
92	A	213	A	333	A	453	A
93	A	214	A	334	A	454	A
94	A	215	B	335	A	455	A
95	C	216	A	336	A	456	A
96	A	217	A	337	A	457	A
97	A	218	A	338	A	458	A
98	A	219	A	339	A	459	A
99	A	220	A	340	A	460	A
100	A	221	A	341	A	461	A
101	A	222	B	342	A	462	A
102	A	223	A	343	A	463	A
103	A	224	A	344	A	464	A
104	A	225	A	345	A	465	A
106	A	226	A	346	A	466	A
107	A	227	A	347	A	467	A
108	A	228	A	348	A	468	A
109	B	229	A	349	A	469	A
110	A	230	A	350	A	470	A
111	A	231	A	351	A	471	A
112	A	232	A	352	A	472	B
113	A	233	A	353	A	473	B
114	A	234	A	354	A	474	C
115	A	235	A	355	A	475	B
116	A	236	A	356	A	476	A
117	A	237	A	357	A	477	A
118	A	238	A	358	C	478
119	A	239	A	359	B	479	A
120	A	240	A	360	A	480	A
121	A	241	A	361	A	481	A
122	A	242	A	362	A	482	A
123	A	243	A	363	A	483	A
124	A	244	A	364	A	484	A
125	B	245	A	365	A	485	A
126	A	246	A	366	A	486	A
Cmpd
No.	IC 50
487	C
488	C
489	A
490	C
491	B
492	C
493	A
494	A
495	B
496	A
497	A
498	A
499	A
500	A
501	C
502	A
503	B
504	A
505	B
506	A
507	C
508	B
509	B
510	A
511	A
512	A
513	A
514	A
515	A
516	A
517	A
518	A
519	A
510	A
521	A
522	A
523	A
524	A
525	A
526	A
527	A
528	A
529	A
530	A
531	A
532	A

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3 codes

IPC · International Patent Classification

Section A — Human necessities

A61K31/4985

Section C — Chemistry; metallurgy

C07D487/04
C07D519/00

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