Tricyclic pkmyt1 kinase inhibitors

Abstract

The present disclosure relates generally to compounds and compositions thereof for inhibition of PKMYT1.

Description

Attorney Docket No.18407-20019.40 TRICYCLIC PKMYT1 KINASE INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 470,553 filed June 2, 2023, the entire contents of which are incorporated herein by reference. FIELD

[0002] The present disclosure relates generally to compounds and compositions thereof for inhibition of PKMYT1 kinase. BACKGROUND

[0003] The WEE1 family of threonine / tyrosine kinases is comprised of the WEE1, PKMYT1, and WEE1b kinases. WEE1 and PKMYT1 are ubiquitously expressed in eukaryotic somatic cells and are important regulators of the cell cycle. WEE1b is primarily expressed in germline cells to regulate meiosis (Luserna di Rora et. al., 2020; Ayeni and Campbell 2014). PKMYT1 is also reported to regulate progression through the meiotic cell cycle in X. Laevis, D. melanogaster and C. elegans and likely most other eumetazoa (Aiba et al., 2022; Ruiz et. al., 2010; Varadarajan et al., 2016; Jin et al., 2005; Burrows et. al., 2006; Lamitina and L’Hernault, 2002; Chu et. al., 2021). During the somatic cell cycle, PKMYT1 and WEE1 play partially redundant roles in inhibiting cyclin dependent kinase 1 (CDK1) at the growth phase 2 (G2) / mitosis (M) cell cycle transition to prevent premature entry into mitosis. WEE1’s primary substrate is tyrosine 15 of CDK1 and PKMYT1 predominantly phosphorylates threonine 14. Phosphorylation of either site negatively impacts CDK1 activity, thereby slowing progression to G2 and M to allow sufficient time for DNA replication and DNA damage repair (Wells et. al., 1999; Gallo et. al., 2022; Hughes 2013).

[0004] Cancer cells often harbor deleterious mutations in genes coding for factors involved in the multiple pathways comprising the DNA damage response (DDR). These genetic alterations result in the induction of replication stress rendering cancer cells dependent upon the remaining intact semi-redundant DDR pathways not impacted by mutation (Curtin, 2012; O’Connor, 2015). This dependency creates what is known as a synthetic lethal condition in which targeting the remaining intact pathway(s) can substantially reduce the cancer cell’s ability to repair their DNA leading to catastrophic DNA damage and ultimately cell death. In contrast, normal wildtype cells possessing a fully competent DDR 1 ny-2729143Attorney Docket No.18407-20019.40 can survive treatment (Ashworth et al., 2011). Replication stress often derives from cancer- associated mutations in an array of substituents of the DDR as well as checkpoint regulators including but not limited to: ATM, ATR, BAP1, BRCA1, BRCA2, CCNE1, FBXW7, CDK12, BLM, CHEK1, CHEK2, RAD51, or MYC (Collet et al., 2022, Shao et al., 2022, Shah et al., 2021).

[0005] Cyclin E (CCNE1) amplification is a common alteration that induces replication stress and is frequently found in specific histological cancer types (Yao et. al., 2022; Llobet et. al., 2020 Fagundes and Teixeira 2021). Cell cycle progression and proliferation are tightly regulated by a family of Cyclin-Dependent kinases (CDKs) that partner with and are activated by specific cyclin regulatory subunits at critical checkpoints throughout the cell cycle. These active kinase complexes then phosphorylate and regulate substrates critically involved in a particular cell cycle phase specific for that kinase. The modified substrates either halt cell cycle progression or license cells to progress to the next phase of the cell cycle. Cyclin E is the activating subunit for CDK2 which is a critical regulator of the growth phase 1 (G1) / S phase of the cell cycle. Cyclin E expression peaks in late G1 engaging and activating CDK2 to drive progression from G1 to the S phase. This is a key cell cycle transition when active Cyclin E-CDK2 initiates an E2F-dependent transcriptional program required for DNA synthesis. In addition to activating transcription of S-phase critical proteins, Cyclin E-CDK2 phosphorylates proteins required to license pre-formed replication complexes on DNA replication origins that are essential for replication initiation. A precisely defined level of CDK2 activity is required to effectively regulate these processes. This level is determined by the expression of Cyclin E which is tightly regulated. However, in the context of Cyclin E amplification, excessive overproduction results in high levels of Cyclin E-Cdk2 activity that then exerts detrimental effects on cell cycle progression, DNA synthesis and repair. Resultant hyper-phosphorylation of Cyclin E-CDK2 substrates interferes with pre- initiation complex formation and results in unregulated activation of DNA replication origins, insufficient nucleotide biosynthesis and an imbalance of DNA replication versus transcription (Kok et. al., 2020; Geng et. al., 2003; Tanaka and Diffley, 2002). Cyclin E-CDK2 hyper- activity also induces precocious cell cycle progression into mitosis. Therefore, the cumulative impact of Cyclin E overexpression is altered cell cycle timing, replication stress and genomic instability resulting in unregulated proliferation and increased DNA damage, both of which are hallmarks of cancer cells (Fagundes and Teixeira 2021; Chu et al., 2021; Yao et al., 2022; Zeng et al., 2023; Kok et al., 2020; Geng et. al., 2003). 2 ny-2729143Attorney Docket No.18407-20019.40

[0006] In a CRISPR-Cas9 dropout screen seeking to identify factors synthetic lethal with Cyclin E amplification, PKMYT1 was identified as one of the top scoring hits. Further analysis of the cancer dependency map (DepMap) database revealed that Cyclin E amplified cancer cell lines generally exhibited an enhanced dependency on PKMYT1. These findings were additionally confirmed in a complementary fashion by employing small molecule inhibitors of PKMYT kinase activity (Gallo et al., 2022). In total, these data support the hypothesis that replication stress induced by Cyclin E overexpression creates a synthetic lethal dependency on PKMYT1 to delay progression to mitosis ensuring sufficient time to resolve unrepaired DNA lesions (Gallo et al., 2022). These results indicate that cancer cells harboring Cyclin E amplification, or potentially other types of replication stress induced by genomic alterations or therapeutic interventions, might also be sensitive to PKMYT1 inhibition while preserving healthy proliferating cells. Accordingly, given the promise of targeting PKMYT1 for the treatment of tumor types experiencing replication stress, small molecule inhibitors of PKMYT1 are indicated for the treatment of these tumors.

[0007] As with other synthetic lethal targets such as PARP1 / 2, PKMYT1 inhibitors in combination with therapeutic agents that elicit DNA damage such as chemotherapies or regulators of the DDR may represent an additional and important therapeutic opportunity to address a broader range of cancers that harbor both an intact DDR and regulatory network (Gallo et al., 2022). For example, therapies that induce double-stranded DNA breaks (e.g., topoisomerase I and II inhibitors) or DNA adducts (e.g., platinum-based drugs or alkylating agents) or interfere with DNA replication (e.g., anti-metabolites, nucleoside analogs) have potential to synergize with PKMYT1 inhibition irrespective of tumor mutational status. In addition, PKMYT1 inhibitor combinations with small molecule inhibitors of factors that regulate various repair pathways of DNA damage response also have the potential to elicit an important therapeutic benefit (Gallo et al., 2022).

[0008] Accordingly, there is a need in the art for new PKMYT1 inhibitors. BRIEF SUMMARY

[0009] In one aspect, provided herein is a compound of Formula (AA) 3 ny-2729143Attorney Docket No.18407-20019.40Formula (AA) or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6alkyl, or halogen; each R9is independently H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; each R2is independently H, C1-C6alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5); each R7is independently H or hydroxyl; and each R8is independently H or C1-C6alkyl. 4 ny-2729143Attorney Docket No.18407-20019.40

[0010] In some embodiments, the compound of Formula (AA) is a compound of Formula (AI), Formula (AII), Formula (AIII), Formula (AIV), Formula (AV), or Formula (AVI)or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; Z1is independently N, CR3, or CHR3; Z2is independently N, O, S, or CR3; each Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; each R1is independently H, C1-C6 alkyl, or halogen; 5 ny-2729143Attorney Docket No.18407-20019.40 each R9is independently H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; each R2is independently H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5); each R7is independently H or hydroxyl; and each R8is independently H or C1-C6alkyl.

[0011] In one aspect, provided herein is a compound of Formula (A)Formula (A) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Ring A is C5-C6 aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6 alkyl, or halogen; each R2is independently H, C1-C6alkyl, or halogen; 6 ny-2729143Attorney Docket No.18407-20019.40 each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0012] In some embodiments, the compound of Formula (A) is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI)7 ny-2729143Attorney Docket No.18407-20019.40 Formula (V) Formula (VI) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; Z1is independently N, CR3, or CHR3; Z2is independently N, O, S, or CR3; each Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; each R1is independently H, C1-C6alkyl, or halogen; each R2is independently H, C1-C6alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2 or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; and each R6is independently hydroxyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0013] In some embodiments, the compound of Formula (A) is a compound of Formula (I’), Formula (II’), Formula (III’), Formula (IV’), Formula (V), or Formula (VI)8 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; each Z1, Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; Z2is independently N, O, S, or CR3; each R1is independently H, C1-C6alkyl, or halogen; each R2is independently H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10- membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2 or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; and each R6is independently hydroxyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 9 ny-2729143Attorney Docket No.18407-20019.40 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0014] In another aspect, provided is a pharmaceutical composition comprising a compound of Formulae (AA), (AI), (AII), (AIII), (AIV), (AV), (AVI), (A), (I), (II), (III), (IV), (V), (VI), or any subformulae thereof as disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof.

[0015] In another aspect, provided is a method of inhibiting kinase activity of a human receptor tyrosine kinase PKMYT1 comprising contacting the PKMYT1 with a therapeutically effective amount of a compound of Formulae (AA), (AI), (AII), (AIII), (AIV), (AV), (AVI), (A), (I), (II), (III), (IV), (V), (VI), or any subformulae thereof as disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a pharmaceutical composition comprising any of the foregoing.

[0016] In another aspect, provided is a method of treating a patient having a cancer, comprising administering to the patient a therapeutically effective amount of a compound of Formulae (AA), (AI), (AII), (AIII), (AIV), (AV), (AVI), (A), (I), (II), (III), (IV), (V), (VI), or any subformulae thereof as disclosed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION

[0017] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments. I. DEFINITIONS

[0018] As used herein, the following definitions shall apply unless otherwise indicated. Further, if any term or symbol used herein is not defined as set forth below, it shall have its ordinary meaning in the art.

[0019] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a 10 ny-2729143Attorney Docket No.18407-20019.40 compound of the present disclosure as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose dc (dc = “directly compressible”), honey dc, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0020] The terms “individual”, “subject” and “patient” refer to mammals and includes humans and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, patient refers to a human.

[0021] As used herein, the term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.

[0022] “Pharmaceutically acceptable” refers to safe and non-toxic, and suitable for in vivo or for human administration.

[0023] As used herein, the term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C1-C6 means one to six carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n- hexyl, n-heptyl, n-octyl, and the like. In some embodiments, the term “alkyl” may encompass 11 ny-2729143Attorney Docket No.18407-20019.40 C1-C6alkyl, C2-C6alkyl, C3-C6alkyl, C4-C6alkyl, C5-C6alkyl, C1-C5alkyl, C2-C5alkyl, C3-C5alkyl, C4-C5 alkyl, C1-C4 alkyl, C2-C4 alkyl, C3-C4 alkyl, C1-C3 alkyl, C2-C3 alkyl, or C1-C2 alkyl.

[0024] As used herein, the term “alkenyl” refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. The group may be in either the cis or trans configuration (Z or E configuration) about the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1- yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl). In some embodiments, the alkenyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon double bond. In other embodiments, the “alkenyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon double bond is located elsewhere along the branched or straight-chain alkyl group.

[0025] As used herein, the term “alkynyl”refers to an unsaturated branched or straight- chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl) and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). In some embodiments, the alkynyl group may be attached to the rest of the molecule by a carbon atom in the carbon-carbon triple bond. In other embodiments, the “alkynyl” may be attached to the rest of the molecule by a saturated carbon atom, and the carbon-carbon triple bond is located elsewhere along the branched or straight- chain alkyl group.

[0026] The term “cycloalkyl”, “carbocyclic”, or “carbocycle” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices. In some embodiments, “cycloalkyl” encompasses C3-C6cycloalkyl, C4-C6cycloalkyl, C5-C6cycloalkyl, C3-C5 cycloalkyl, C4-C5 cycloalkyl, or C3-C4 cycloalkyl. In some embodiments, the term “cycloalkyl” may be further described as a “spirocycloalkyl” or a “fused cycloalkyl”. The term “spirocycloalkyl” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices, wherein the hydrocarbon ring is 12 ny-2729143Attorney Docket No.18407-20019.40 attached to the rest of the molecule at a single ring vertex (e.g. ¸ring carbon atom) by two covalent bonds. The term “fused “cycloalkyl” refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C3-C6 cycloalkyl means 3-6 carbons) and being fully saturated or having no more than one double bond between ring vertices, wherein the hydrocarbon ring is attached to the rest of the molecule at two ring vertices (e.g. two carbon atoms) by two covalent bonds. In some embodiments, “cycloalkyl”, “cycloalkyl”, “carbocyclic”, or “carbocycle” is also meant to refer to bicyclic, polycyclic and spirocyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane, norborene, spirocyclic C5-12 alkane, etc. In addition, one ring of a polycyclic cycloalkyl group may be aromatic, provided the polycyclic cycloalkyl group is bound to the parent structure via a non-aromatic carbon. For example, a 1,2,3,4-tetrahydronaphthalen-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.

[0027] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon radical, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) O, N and S can be placed at any interior position of the heteroalkyl group. The heteroatom Si can be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. A “heteroalkyl” can contain up to three units of unsaturation, and also include mono- and poly-halogenated variants, or combinations thereof. Examples include -CH2-CH2-O-CH3, -CH2-CH2-O-CF3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH═CH-O-CH3, -Si(CH3)3, -CH2-CH═N-OCH3, and -CH═CH═N(CH3)-CH3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0028] The term “heterocycloalkyl”, “heterocyclic”, “heterocyclyl”, or “heterocycle” refers to a cycloalkyl radical group having the indicated number of ring atoms (e.g., 5-6 membered heterocycloalkyl) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally 13 ny-2729143Attorney Docket No.18407-20019.40 oxidized, nitrogen atom(s) are optionally quaternized, as ring atoms. In some embodiments, a “heterocycloalkyl,” “heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic, bridged or fused ring system, spirocyclic or a polycylic ring system. Non-limiting examples of “heterocycloalkyl,” “heterocyclic,” or “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)- dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide, thiomorpholine- S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane and the like. A “heterocycloalkyl,” “heterocyclic,” or “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. In some embodiments, “heterocycloalkyl” encompasses3- to 10- membered heterocycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heterocycloalkyl, 6- to 10-membered heterocycloalkyl, 7- to 10-membered heterocycloalkyl, 8- to 10-membered heterocycloalkyl, 9- to 10-membered heterocycloalkyl, 3- to 9-membered heterocycloalkyl, 4- to 9-membered heterocycloalkyl, 5- to 9-membered heterocycloalkyl, 6- to 9-membered heterocycloalkyl, 7- to 9-membered heterocycloalkyl, 8- to 9-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyl, 4- to 8-membered heterocycloalkyl, 5- to 8-membered heterocycloalkyl, 6- to 8-membered heterocycloalkyl, 7- to 8-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 6- to 7-membered heterocycloalkyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl, 5- to 6-membered heterocycloalkyl, 3- to 10-membered heterocycloalkyl, 4- to 5-membered heterocycloalkyl, or 3- to 4-membered heterocycloalkyl. In other embodiments, “heterocycloalkyl” may be characterized by the number of carbon atoms in the ring, provided that the ring contains at least one heteroatom. For example, in some embodiments, “heterocycloalkyl” encompasses C3-C9 heterocycloalkyl, C3-C8 heterocycloalkyl, C3-C7 heterocycloalkyl, C3-C6 heterocycloalkyl, C3-C5 heterocycloalkyl, C3-C4heterocycloalkyl, C4-C9heterocycloalkyl, C4-C8heterocycloalkyl, C4- C7 heterocycloalkyl, C4-C6 heterocycloalkyl, C4-C5 heterocycloalkyl, C5-C9 heterocycloalkyl, C5-C8 heterocycloalkyl, C5-C7 heterocycloalkyl, C5-C6 heterocycloalkyl, C6-C9 heterocycloalkyl, C6-C8heterocycloalkyl, C6-C7heterocycloalkyl, C7-C9heterocycloalkyl, C7- C8heterocycloalkyl, or C8-C9heterocycloalkyl. It should be recognized that “heterocycloalkyl” as described by the number of ring atoms may also be described by number of carbon atoms in the ring. For example, a piperazinyl ring may be described as a C4 14 ny-2729143Attorney Docket No.18407-20019.40 heterocycloalkyl ring or a 6-membered heterocycloalkyl ring; an azetidinyl or oxetanyl ring may each be described as a C3 heterocycloalkyl ring or a 4-membered heterocycloalkyl ring.

[0029] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “C1-C4 haloalkyl” is mean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

[0030] The term “aryl” means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group, which can be a single ring or multiple rings (up to three rings) which are fused together. In some embodiments, “aryl” encompasses C6-C14aryl, C8-C14aryl, C10-C14aryl, C12-C14aryl, C6-C12aryl, C8-C12aryl, C10-C12aryl, C6-C10aryl, C8-C10aryl, or C6-C8 aryl. In some instances, both rings of a polycyclic aryl group are aromatic (e.g., naphthyl). In other instances, polycyclic aryl groups may include a non-aromatic ring fused to an aromatic ring, provided the polycyclic aryl group is bound to the parent structure via an atom in the aromatic ring. Thus, a 1,2,3,4-tetrahydronaphthalen-5-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered an aryl group. Similarly, a 1,2,3,4-tetrahydroquinolin-8-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl group (wherein the moiety is bound to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term “aryl” does not encompass or overlap with “heteroaryl,” as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some instances, aryl is phenyl or naphthyl. In certain instances, aryl is phenyl.

[0031] The term “heteroaryl” refers to aryl groups (or rings) that contain from one to five heteroatoms selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom as valency permits. In some instances, both rings of a polycyclic heteroaryl group are aromatic. In other instances, polycyclic heteroaryl groups may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to a heteroaryl ring, 15 ny-2729143Attorney Docket No.18407-20019.40 provided the polycyclic heteroaryl group is bound to the parent structure via an atom in the aromatic ring. For example, a 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (wherein the moiety is bound to the parent structure via an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (wherein the moiety is bound to the parent structure via a non-aromatic carbon atom) is not considered a heteroaryl group.

[0032] Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the term “heteroaryl” encompasses 5- to 10-membered heteroaryl, 6- to 10-membered heteroaryl, 7- to 10-membered heteroaryl, 8- to 10-membered heteroaryl, 9- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 6- to 9-membered heteroaryl, 7- to 9- membered heteroaryl, 8- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 6- to 8- membered heteroaryl, 7- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, 6- to 7- membered heteroaryl, or 5- to 6-membered heteroaryl.

[0033] The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. The term “substituted” means that the specified group or moiety bears one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, alkoxycarbonyl, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azido, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo and the like. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some 16 ny-2729143Attorney Docket No.18407-20019.40 embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0034] A dashed bond in a structure indicates that the bond may be present or absent. For example, denotes a bond that is a single bond or a double bond. Likewise, a dashed circle, such as , within a ring structure indicates that the ring is fully saturated, partially unsaturated,or aromatic.

[0035] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0036] As used herein, the term “heteroatom” is meant to include oxygen (O), nitrogen (N), sulfur (S), boron (B), and silicon (Si).

[0037] As used herein, the term “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water. Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0038] The term “co-crystal” as used herein refers to a solid that is a crystalline single phase material composed of two or more different molecular or ionic compounds generally in 17 ny-2729143Attorney Docket No.18407-20019.40 a stoichiometric ratio which are neither solvates nor simple salts. A co-crystal consists of two or more components that form a unique crystalline structure having unique properties. Co- crystals are typically characterized by a crystalline structure, which is generally held together by freely reversible, non-covalent interactions. As used herein, a co-crystal refers to a compound of the present disclosure and at least one other component in a defined stoichiometric ratio that form a crystalline structure.

[0039] As used herein, the term “protecting group” refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups in Organic Synthesis 4thedition, Wiley-Interscience, New York, 2006.

[0040] As used herein, the term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N′- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, 18 ny-2729143Attorney Docket No.18407-20019.40 ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0041] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure.

[0042] Certain compounds of the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., separate enantiomers) are all intended to be encompassed within the scope of the present disclosure.

[0043] The compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or 19 ny-2729143Attorney Docket No.18407-20019.40 mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the present disclosure and include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as2H (“D”),3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36Cl,123I and125I. Certain isotopically labeled compounds of the present disclosure (e.g., those labeled with3H or14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0044] “Treating” or “treatment” of a disease in a patient refers to inhibiting the disease or arresting its development; or ameliorating or causing regression of the disease. As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this disclosure, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delay or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of the present disclosure contemplate any one or more of these aspects of treatment. 20 ny-2729143Attorney Docket No.18407-20019.40

[0045] “Preventing”, “prevention”, or “prophylaxis” of a disease in a patient refers to preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease.

[0046] The phrase “therapeutically effective amount” means an amount of a compound of the present disclosure that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

[0047] The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0048] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the chemical groups represented by the variables are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. II. COMPOUNDS

[0049] In one aspect, provided herein is a compound of Formula (AA) 21 ny-2729143Attorney Docket No.18407-20019.40Formula (AA) or a pharmaceutically acceptable salt thereof, wherein: ring A is C5-C6aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6alkyl, or halogen; each R9is independently H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; each R2is independently H, C1-C6alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5); each R7is independently H or hydroxyl; and each R8is independently H or C1-C6alkyl. 22 ny-2729143Attorney Docket No.18407-20019.40

[0050] In some embodiments, the compound of Formula (AA) is a compound of Formula (A)Formula (A) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: ring A is C5-C6 aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6alkyl, or halogen; each R2is independently H, C1-C6alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2 or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; and each R6is independently hydroxyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0051] In some embodiments, the compound of Formula (AA) is a compound of Formula (AI), Formula (AII), Formula (AIII), Formula (AIV), Formula (AV), or Formula (AVI) 23 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; Z1is independently N, CR3, or CHR3; Z2is independently N, O, S, or CR3; each Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; each R1is independently H, C1-C6 alkyl, or halogen; each R9is independently H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; each R2is independently H, C1-C6 alkyl, or halogen; 24 ny-2729143Attorney Docket No.18407-20019.40 each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5); each R7is independently H or hydroxyl; and each R8is independently H or C1-C6alkyl.

[0052] In some embodiments the compound of Formula (AA) or Formula (A) is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) R1R14 4O R O R25 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; Z1is independently N, CR3, or CHR3; Z2is independently N, O, S, or CR3; each of Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; each R1is independently H, C1-C6 alkyl, or halogen; each R2is independently H, C1-C6alkyl, or halogen; each R3is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0053] In some embodiments, the compound of Formula (AA) is a compound of Formula (AI’), Formula (AII’), Formula (AIII’), Formula (AIV’), Formula (AV), or Formula (AVI) 26 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; each of Z1, Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; Z2is independently N, O, S, or CR3; each R1is independently H, C1-C6alkyl, or halogen; each R9is independently H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; each R2is independently H, C1-C6alkyl, or halogen; 27 ny-2729143Attorney Docket No.18407-20019.40 each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5); each R7is independently H or hydroxyl; and each R8is independently H or C1-C6alkyl.

[0054] In some embodiments, the compound of Formula (AA) or Formula (A) is a compound of Formula (I’), Formula (II’), Formula (III’), Formula (IV’), Formula (V), or Formula (VI) R1R14 4O R O R28 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; each of Z1, Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; Z2is independently N, O, S, or CR3; each R1is independently H, C1-C6 alkyl, or halogen; each R2is independently H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

[0055] In some embodiments, provided herein is a compound of Formula (AI) 29 ny-2729143Attorney Docket No.18407-20019.40

[0056] In some embodiments, the compound of Formula (AI) is a compound of Formula (AI')

[0057] In some embodiments, provided herein is a compound of Formula (AII)

[0058] In some embodiments, the compound of Formula (AII) is a compound of Formula (AII’)

[0059] In some embodiments, provided herein is a compound of Formula (AIII) 30 ny-2729143Attorney Docket No.18407-20019.40

[0060] In some embodiments, the compound of Formula (AIII) is a compound of Formula (AIII’)

[0061] In some embodiments, provided herein is a compound of Formula (AIV)

[0062] In some embodiments, the compound of Formula (AIV) is a compound of Formula (AIV’)

[0063] In some embodiments, provided herein is a compound of Formula (AV) 31 ny-2729143Attorney Docket No.18407-20019.40

[0064] In some embodiments, provided herein is a compound of Formula (AVI)

[0065] In some embodiments, provided herein is a compound of Formula (I) R1R4O

[0066] In some embodiments, the compound of Formula (I) is a compound of Formula (I') 14R O R

[0067] In some embodiments, provided herein is a compound of Formula (II) 32 ny-2729143Attorney Docket No.18407-20019.40 R1R4O

[0068] In some embodiments, the compound of Formula (II) is a compound of Formula (II’) 14R O R

[0069] In some embodiments, provided herein is a compound of Formula (III) 14R O R

[0070] In some embodiments, the compound of Formula (III) is a compound of Formula (III’) R1R4O

[0071] In some embodiments, provided herein is a compound of Formula (IV) 33 ny-2729143Attorney Docket No.18407-20019.40 R14O R

[0072] In some embodiments, the compound of Formula (IV) is a compound of Formula (IV’) R1R4O

[0073] In some embodiments, provided herein is a compound of Formula (V)

[0074] In some embodiments, provided herein is a compound of Formula (VI)

[0075] In some embodiments, is C1-C6 alkyl. In some embodiments, R1is methyl. In some embodiments, R1is halogen. In some embodiments, R1is Cl.

[0076] In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is methyl. In some embodiments, R2is halogen. In some embodiments, R2is Cl. 34 ny-2729143Attorney Docket No.18407-20019.40

[0077] In some embodiments, R7is H. In some embodiments, R7is hydroxyl.

[0078] In some embodiments, R8is H. In some embodiments, R8is C1-C6 alkyl. In some embodiments, R8is methyl.

[0079] In some embodiments R9is H. In some embodiments, R9is hydroxyl. In some embodiments, R1and R9are taken together to form a 5-membered heteroaryl. In some embodiments, R1and R9are taken together to form a pyrazole ring.

[0080] In some embodiments, R1and R2are each C1-C6alkyl. In some embodiments, R1and R2are each methyl.. It will be understood that for the denotes the pointof attachment to the remainder of the molecule. For example, when the35 ny-2729143Attorney Docket No.18407-20019.40

[0082] In some embodiments, Z1is CR3. In some embodiments, Z1is CH. In some embodiments, Z1is N.

[0083] In some embodiments, R4is -NH2. In some embodiments, R4is H.

[0084] In some embodiments, Z2and Z3are CR3, X1is C, X2is N, and Y1is N. In some embodiments, the compound is a compound of Formula (I-A), Formula (II-A), Formula (III- A), or Formula (IV-A).36 ny-2729143Attorney Docket No.18407-20019.40

[0085] In some embodiments of Formula (I-A), Formula (II-A), Formula (III-A), or Formula (IV-A), Z1is N. In some embodiments of Formula (I-A), Formula (II-A), Formula (III-A), or Formula (IV-A), Z1is CR3. In some embodiments of Formula (I-A), Formula (II- A), Formula (III-A), or Formula (IV-A), Z1is CH. In some embodiments of Formula (I-A), Formula (II-A), Formula (III-A), or Formula (IV-A), Z1is CR3, and each R3is H. In some embodiments of Formula (I-A), Formula (II-A), Formula (III-A), or Formula (IV-A), R4is - NH2. In some embodiments of Formula (I-A), Formula (II-A), Formula (III-A), or Formula (IV-A), R4is H.

[0086] In some embodiments, Z2is N, Z3is CR3, X1is C, X2is N, and Y1is N. In some embodiments, the compound is a compound of Formula (I-B), Formula (II-B), Formula (III- B), or Formula (IV-B).

[0087] In some embodiments of Formula (I-B), Formula (II-B), Formula (III-B), or Formula (IV-B), Z1is N. In some embodiments of Formula (I-B), Formula (II-B), Formula (III-B), or Formula (IV-B), Z1is CR3. In some embodiments of Formula (I-B), Formula (II- B), Formula (III-B), or Formula (IV-B), Z1is CH. In some embodiments of Formula (I-B), Formula (II-B), Formula (III-B), or Formula (IV-B), Z1is CR3, and each R3is H. In some embodiments of Formula (I-B), Formula (II-B), Formula (III-B), or Formula (IV-B), R4is - 37 ny-2729143Attorney Docket No.18407-20019.40 NH2. In some embodiments of Formula (I-B), Formula (II-B), Formula (III-B), or Formula (IV-B), R4is H.

[0088] In some embodiments, Z2is CR3, Z3is N, X1is N, X2is C, and Y1is N. In some embodiments, the compound is a compound of Formula (I-B), Formula (II-B), Formula (III- B), or Formula (IV-B).

[0089] In some embodiments of Formula (I-C), Formula (II-C), Formula (III-C), or Formula (IV-C), Z1is N. In some embodiments of Formula (I-C), Formula (II-C), Formula (III-C), or Formula (IV-C), Z1is CR3. In some embodiments of Formula (I-C), Formula (II- C), Formula (III-C), or Formula (IV-C), Z1is CH. In some embodiments of Formula (I-C), Formula (II-C), Formula (III-C), or Formula (IV-C), Z1is CR3, and each R3is H. In some embodiments of Formula (I-C), Formula (II-C), Formula (III-C), or Formula (IV-C), R4is - NH2. In some embodiments of Formula (I-C), Formula (II-C), Formula (III-C), or Formula (IV-C), R4is H.

[0090] In some embodiments, Z2and Z3are CR3, X1is N, X2is C, and Y1is N. In some embodiments, the compound is a compound of Formula (I-D), Formula (II-D), Formula (III- D), or Formula (IV-D). 38 ny-2729143Attorney Docket No.18407-20019.40

[0091] In some embodiments of Formula (I-D), Formula (II-D), Formula (III-D), or Formula (IV-D), Z1is N. In some embodiments of Formula (I-D), Formula (II-D), Formula (III-D), or Formula (IV-D), Z1is CR3. In some embodiments of Formula (I-D), Formula (II- D), Formula (III-D), or Formula (IV-D), Z1is CH. In some embodiments of Formula (I-D), Formula (II-D), Formula (III-D), or Formula (IV-D), Z1is CR3, and each R3is H. In some embodiments of Formula (I-D), Formula (II-D), Formula (III-D), or Formula (IV-D), R4is - NH2. In some embodiments of Formula (I-D), Formula (II-D), Formula (III-D), or Formula (IV-D), R4is H.

[0092] In some embodiments, Z2is N, Z3is CR3, X1is N, X2is C, and Y1is N. In some embodiments, the compound is a compound of Formula (I-E), Formula (II-E), Formula (III- E), or Formula (IV-E).39 ny-2729143Attorney Docket No.18407-20019.40

[0093] In some embodiments of Formula (I-E), Formula (II-E), Formula (III-E), or Formula (IV-E), Z1is N. In some embodiments of Formula (I-E), Formula (II-E), Formula (III-E), or Formula (IV-E), Z1is CR3. In some embodiments of Formula (I-E), Formula (II- E), Formula (III-E), or Formula (IV-E), Z1is CH. In some embodiments of Formula (I-E), Formula (II-E), Formula (III-E), or Formula (IV-E), Z1is CR3, and each R3is H. In some embodiments of Formula (I-E), Formula (II-E), Formula (III-E), or Formula (IV-E), R4is - NH2. In some embodiments of Formula (I-E), Formula (II-E), Formula (III-E), or Formula (IV-E), R4is H.

[0094] In some embodiments, Z5is CR3, Z6is CR3, Z7is CR3, and Z8is N. In some embodiments, the compound is a compound of Formula (V-A) or Formula (VI-A).

[0095] In some embodiments of Formula (V-A) or Formula (VI-A), Z1is N. In some embodiments of Formula (V-A) or Formula (VI-A), Z1is CR3. In some embodiments of Formula (V-A) or Formula (VI-A), Z1is CH. In some embodiments of Formula (V-A) or Formula (VI-A), Z4is N. In some embodiments of Formula (V-A) or Formula (VI-A), Z4is CR3. In some embodiments of Formula (V-A) or Formula (VI-A), Z1is CR3and Z4is N. In some embodiments of Formula (V-A) or Formula (VI-A), Z1is CH and Z4is N. In some embodiments of Formula (V-A) or Formula (VI-A), Z1is CR3, Z4is N, and each R3is H. In 40 ny-2729143Attorney Docket No.18407-20019.40 some embodiments of Formula (V-A) or Formula (VI-A), R4is -NH2. In some embodiments of Formula (V-A) or Formula (VI-A), R4is H.

[0096] In some embodiments, of Formula (AA), Formula (A), or any applicable subformulae thereof, ring A is phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more R3. In some embodiments, ring A is or. In some embodiments ring A is selected from the group consisting of

[0097] In some embodiments of Formula (AA), Formula (A), or any applicable subformulae thereof, . In some embodiments41 ny-2729143Attorney Docket No.18407-20019.40

[0098] It will be understood that for the denotes the point of attachment to Z4of Formula (AA), andto the carbon atthe 4 position relative to Z4of Formula (AA). For example, when the portion of42 ny-2729143Attorney Docket No.18407-20019.40 Formula (AA) is depicted when ring A is indicatedcorresponding structure

[0099] In some embodiments of Formula (AI), Formula (AII), Formula (AIII), Formula (AIV), or any applicable subformulae thereof, is selected form the group,43 ny-2729143Attorney Docket No.18407-20019.40 to Z4of Formula (AA). For example, when the portion of Formula (AI) isdepicted

[0100] In some embodiments of Formula (AV), Formula (AVI), or any applicabledenotes the point of attachment to Z4of Formula (AA), andto the carbon at the 4 position relative to Z4of Formula. For example, when the portion of Formula (AV) is depictedthe corresponding structure44 ny-2729143Attorney Docket No.18407-20019.40

[0101] In some embodiments Z1is N. In some embodiments, Z1is CR3. In some embodiments, Z4is N. In some embodiments Z4is CR3.

[0102] In some embodiments, R3is H. In some embodiments R3is C1-C6 alkyl. In some embodiments R3is -CH3. In some embodiments, each R3is independently selected from H and C1-C6 alkyl. In some embodiments, each R3is independently selected from H and -CH3.

[0103] In some embodiments, each R3is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6alkoxy, wherein each C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is independently optionally substituted by one or more -R6. In some embodiments, each R3is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy. In some embodiments, each R3is independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6alkoxy, wherein each C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is independently substituted by one or more -R6.

[0104] In some embodiments, each R3is independently C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6. In some embodiments, each R3is independently C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. In some embodiments, each R3is independently C3-C8 cycloalkyl, C3- C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein each C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10-membered heteroaryl is independently substituted by one or more -R6.

[0105] In some embodiments, each R3is independently halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), -SO2N(R5)2, or -SO2(R5).

[0106] In some embodiments, each R3is independently selected from H, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, C(O)N(R5)2, 5- to 10-membered heteroaryl, and C3-C8cycloalkyl, wherein each C1-C6 alkoxy and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6. In some embodiments, each R3is independently selected from H, halogen, cyano, C1-C6alkyl, C1-C6alkoxy optionally substituted by one or more - N(R5)2, C(O)N(R5)2, 5- to 10-membered heteroaryl optionally substituted by one or more C1- 45 ny-2729143Attorney Docket No.18407-20019.40 C6alkyl, and C3-C8cycloalkyl, wherein each R5is independently H or C1-C6alkyl. In some embodiments, each R3is independently selected from H, Cl, cyano, CH3, C(O)NH2,

[0107] In some embodiments is halogen. In some embodiments R3is Cl. In some embodiments, R3is C1-C6 alkyl. In some embodiments, R3is methyl. In some embodiments, R3is C1-C6alkoxy optionally substituted by one or more -R6. In some embodiments, R3is C2alkoxy optionally substituted by one or more -R6. In some embodiments, R3is C1-C6 alkoxy optionally substituted by one or more -N(R5)2, wherein each R5is independently C1-C6 alkyl. In some embodiments, R3is C1-C6alkoxy optionally substituted by one or more -N(CH3)2. In some embodiments, R3is , wherein each R5is independently C1-C6alkyl. Insome embodiments, R3is . In some embodiments, R3is C(O)N(R5)2, wherein each R5is independentlyIn some embodiments, R3is C(O)NH2. In some embodiments R3is C3-C8 cycloalkyl. In some embodiments R3is cyclopropyl. In some embodiments, R3is 5- to 10-membered heteroaryl optionally substituted by one or more R6. In some embodiments, R3is 5- to 10-membered heteroaryl optionally substituted by one or more R6, wherein each R6is independently C1-C6 alkyl. In some embodiments, R3is 5- to 10- membered heteroaryl optionally substituted by one or more methyl groups. In some embodiments, R3is 5-membered heteroaryl optionally substituted by one or more R6. In some embodiments, R3is pyrazole optionally substituted by one or more R6. In some embodiments, R3is pyrazole optionally substituted by one or more R6, wherein each R6is independently C1- C6 alkyl. In some embodiments, R3is .

[0108] In some embodiments, each R6is independently hydroxyl, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, or C3-C8 cycloalkenyl. In some embodiments, each R6is independently 4- to 10-memebered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl. In some embodiments, each R6is independently halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), -SO2N(R5)2, or -SO2(R5). 46 ny-2729143Attorney Docket No.18407-20019.40

[0109] In some embodiments, provided is a compound selected from the compounds in Table 1, or pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing. Table 1 Compound Structure Name47 ny-2729143Attorney Docket No.18407-20019.40 7 OH 7-amino-8-(3-hydroxy-2,6- NH48 ny-2729143Attorney Docket No.18407-20019.40 13 7-amino-8-(3-hydroxy-2,6-49 ny-2729143Attorney Docket No.18407-20019.40 20 9-amino-10-(3-hydroxy-2,6-50 ny-2729143Attorney Docket No.18407-20019.40 27 8-amino-5-cyclopropyl-9-51 ny-2729143Attorney Docket No.18407-20019.40 34 7-amino-8-(3-hydroxy-2,6-52 ny-2729143Attorney Docket No.18407-20019.40 41 8-amino-5-methyl-9-(5-53 ny-2729143Attorney Docket No.18407-20019.40 47 7-amino-4-cyano-8-(3-54 ny-2729143Attorney Docket No.18407-20019.40 54 7-amino-8-(2-chloro-3-55 ny-2729143Attorney Docket No.18407-20019.40 60 7-amino-8-(2-chloro-3-

[0110] This disclosure also includes all salts, such as pharmaceutically acceptable salts, of compounds referred to herein. This disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any 56 ny-2729143Attorney Docket No.18407-20019.40 tautomers or other forms, such as N-oxides, solvates, hydrates, or isotopomers, of the compounds described. The present disclosure also includes co-crystals of the compounds described herein. Unless stereochemistry is explicitly indicated in a chemical structure or name, the structure or name is intended to embrace all possible stereoisomers of a compound depicted. In addition, where a specific stereochemical form is depicted, it is understood that other stereochemical forms are also embraced by the invention. All forms of the compounds are also embraced by the invention, such as crystalline or non-crystalline forms of the compounds. Compositions comprising a compound of the invention are also intended, such as a composition of substantially pure compound, including a specific stereochemical form thereof. Compositions comprising a mixture of compounds of the invention in any ratio are also embraced by the invention, including mixtures of two or more stereochemical forms of a compound of the invention in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of a compound are embraced.

[0111] Representative examples of compounds detailed herein, including intermediates and final compounds, are depicted in the tables and elsewhere herein. It is understood that in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual.

[0112] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0113] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, provided are pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein. 57 ny-2729143Attorney Docket No.18407-20019.40

[0114] Any variation or embodiment of Ring A, Q1, Q2, Q3, Q4, R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, X2, Y1, Z1, Z2, Z3, Z4, Z5, Z6, Z7, or Z8, provided herein can be combined with every other variation or embodiment of A, Q1, Q2, Q3, Q4, R1, R2, R3, R4, R5, R6, R7, R8, R9, X1, X2, Y1, Z1, Z2, Z3, Z4, Z5, Z6, Z7, or Z8, as if each combination had been individually and specifically described.

[0115] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. III. PHARMACEUTICAL COMPOSITIONS AND FORMULATIONS

[0116] Any of the compounds described herein may be formulated as a pharmaceutically acceptable composition.

[0117] Pharmaceutical compositions of any of the compounds detailed herein are embraced by this disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a compound as detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation.

[0118] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein are provided, such as compositions of substantially pure compounds. In some embodiments, a composition containing a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, as detailed herein is in substantially pure form. In one variation, “substantially pure” intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a salt thereof. For example, a composition of a substantially pure compound selected from a compound of Table 1 intends a composition that contains no more than 35% impurity, wherein the impurity denotes a compound other than the compound 58 ny-2729143Attorney Docket No.18407-20019.40 of Table 1. In one variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 25% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 20% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains or no more than 10% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 5% impurity. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 3% impurity. In still another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 1% impurity. In a further variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided wherein the composition contains no more than 0.5% impurity. In yet other variations, a composition of substantially pure compound means that the composition contains no more than 15%, no more than 10%, no more than 5%, no more than 3%, or no more than 1% impurity, which impurity may be the compound in a different stereochemical form. For instance, and without limitation, a composition of substantially pure (S) compound means that the composition contains no more than 15% or no more than 10% or no more than 5% or no more than 3% or no more than 1% of the (R) form of the compound.

[0119] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, the present disclosure embraces pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the 59 ny-2729143Attorney Docket No.18407-20019.40 compounds are suitable for any compound or form thereof detailed herein. In some embodiments, the compounds and compositions as provided herein are sterile. Methods for sterilization known in the art may be suitable for any compounds or form thereof and compositions thereof as detailed herein.

[0120] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0121] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining the compound or compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, with a pharmaceutically acceptable carrier. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), which is incorporated herein by reference.

[0122] A compound detailed herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to 60 ny-2729143Attorney Docket No.18407-20019.40 individuals in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid poly-ols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0123] Any of the compounds, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, can be formulated as a 10 mg tablet.

[0124] Compositions comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, provided herein are also described. In one variation, the composition comprises a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.

[0125] Compositions formulated for co-administration of a compound provided herein and one or more additional pharmaceutical agents are also described. The co-administration can be simultaneous or sequential in any order. A compound provided herein may be formulated for co-administration with the one or more additional pharmaceutical agents in the same dosage form (e.g., single tablet or single i.v.) or separate dosage forms (e.g., two separate tablets, two separate i.v., or one tablet and one i.v.). Furthermore, co-administration can be, for example, 1) concurrent delivery, through the same route of delivery (e.g., tablet or i.v.), 2) sequential delivery on the same day, through the same route or different routes of 61 ny-2729143Attorney Docket No.18407-20019.40 delivery, or 3) delivery on different days, through the same route or different routes of delivery. IV. METHODS OF USE

[0126] Compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of Formula (AA) or any variation thereof provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. The compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.

[0127] In one aspect, provided herein is a method of inhibiting PKMYT1 tyrosine kinase enzymatic activity, comprising contacting an effective amount of a compound or composition provided herein, to the PKMYT1 tyrosine kinase. In some embodiments, provided herein is a method of inhibiting PKMYT1 tyrosine kinase in a cell, comprising administering an effective amount of a compound or composition of the disclosure to the cell. In some embodiments, provided herein is a method of inhibiting PKMYT1 tyrosine kinase in an individual in need thereof, comprising administering an effective amount of a compound or composition of the disclosure to the individual. In some variations, the compounds provided herein are selective for inhibiting PKMYT1 tyrosine kinase.

[0128] In some embodiments, the compound or composition described herein is used in a method of treating a disease or disorder mediated by PKMYT1 tyrosine kinase activity. In some embodiments, the compound or composition is administered according to a dosage described herein.

[0129] In another aspect, provided herein is a method of treating a patient having a cancer, comprising administering to the patient a therapeutically effective amount of a compound or composition as provided herein. In some embodiments, the cancer is pancreatic, prostate, bladder, endometrial, lung, colorectal, ovarian, peritoneal, breast, gastric, fallopian tube, or cervical cancer. 62 ny-2729143Attorney Docket No.18407-20019.40

[0130] In some embodiments, the cancer comprises a deleterious mutation related to the DNA damage response (DDR) or a mutation that induces replicative stress. In some embodiments, the deleterious mutation related to DDR is a HR, BER, NHEJ, or NER mutation. In some embodiments, the mutation comprises a mutation to ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, MRE11A, NBN, PALB2, PP2R2ARAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, XRCC2, the FANC family of proteins, a CCNE1 amplification mutation, a FBXW7 deletion or loss of function mutation, or a MYC amplification mutation.

[0131] In some embodiments, the cancer comprises a mutation to a factor involved in regulation of cell cycle progression.

[0132] In some embodiments, the method further comprises administering a therapy that induces DNA damage and / or replicative stress. In some embodiments, the therapy comprises alkylating agents, platinum-based anti-neoplastic agents, anti-metabolites, topoisomerase inhibitors, ionizing radiation, radiomimetics, or other radiotherapies.

[0133] In some embodiments, the method further comprises administering an agent that targets regulation of the DDR or DNA replication. In some embodiments, the agent is an inhibitor of ATR, ATM, DNA-PK, CHK1, CHK2, WEE1, MYT1, or pol-theta.

[0134] In some embodiments, the method further comprises administering an agent that attenuates survival pathway activation in response to DNA damage. In some embodiments, the agent is an inhibitor of EGFR, ErbB2, IGFR1, MET, FGFR1-4, VEGFR2, MEK, ERK, PI3K, AKT, mTORC1, or mTORC2.

[0135] In some embodiments, the method further comprises administering an agent that targets kinase oncogenic drivers that induce replication stress or interfere with the DDR. In some embodiments, the agent is an inhibitor of BCR-ABL, EGFR, ERBB2, FLT3, MET, RET, ALK, NTRK, RET, ROS1, or BRAF.

[0136] In some embodiments, the method further comprises administering a therapy that acts via the induction of an anti-tumor immune response in a manner analogous to PARP1 and / or PARP2 inhibitors. In some embodiments, the therapy is an anti-PD1, an anti-PD-L1, or an anti-CTLA4 therapy. 63 ny-2729143Attorney Docket No.18407-20019.40

[0137] In some embodiments, the method further comprises administering a therapy that induces an anti-tumor immune response. In some embodiments, the therapy comprises a cancer vaccine, a T-cell-based therapy, a T-cell engager bi-specific antibody, or an oncolytic virus. V. DOSING AND ADMINISTRATION

[0138] The dose of a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular cancer, such as type and stage of cancer, being treated. In some embodiments, the amount of the compound, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, is a therapeutically effective amount.

[0139] The compounds provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, may be administered to an individual via various routes, including, e.g., intravenous, intramuscular, subcutaneous, oral, and transdermal.

[0140] The effective amount of the compound may in one aspect be a dose of between about 0.01 and about 100 mg / kg. Effective amounts or doses of the compounds of the present disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the disease to be treated, the subject’s health status, condition, and weight. An exemplary dose is in the range of about from about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily.

[0141] Any of the methods provided herein may in one aspect comprise administering to an individual a pharmaceutical composition that contains an effective amount of a compound provided herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable excipient.

[0142] A compound or composition provided herein may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or 64 ny-2729143Attorney Docket No.18407-20019.40 duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, which in some variations may be for the duration of the individual’s life. In one variation, the compound is administered on a daily or intermittent schedule. The compound can be administered to an individual continuously (for example, at least once daily) over a period of time. The dosing frequency can also be less than once daily, e.g., about a once weekly dosing. The dosing frequency can be more than once daily, e.g., twice or three times daily. The dosing frequency can also be intermittent, including a ‘drug holiday’ (e.g., once daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as about 2 months, about 4 months, about 6 months or more). Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein. VI. ARTICLES OF MANUFACTURE AND KITS

[0143] The present disclosure further provides articles of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co- crystal thereof, or a mixture of any of the foregoing, a composition described herein, or one or more unit dosages described herein in suitable packaging. In certain embodiments, the article of manufacture is for use in any of the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, ampules, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and / or sealed.

[0144] The present disclosure further provides kits for carrying out the methods of the present disclosure, which comprises one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, or a mixture of any of the foregoing, thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for the treatment of any disease or described herein, for example for the treatment of cancer, including pancreatic, prostate, bladder, endometrial, lung, colorectal, ovarian, peritoneal, breast, gastric, fallopian tube, or cervical cancer.

[0145] In some embodiments, the cancer comprises a deleterious mutation related to the DNA damage response (DDR) or a mutation that induces replicative stress. In some 65 ny-2729143Attorney Docket No.18407-20019.40 embodiments, the deleterious mutation related to DDR is a HR, BER, NHEJ or NER mutation. In some embodiments, the mutation comprises a mutation to ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, MRE11A, NBN, PALB2, PP2R2ARAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, XRCC2, the FANC family of proteins, a CCNE1 amplification mutation, a FBXW7 deletion or loss of function mutation, or a MYC amplification mutation.

[0146] In some embodiments, the cancer comprises a mutation to a factor involved in regulation of cell cycle progression.

[0147] The kits optionally further comprise a container comprising one or more additional pharmaceutical agents and which kits further comprise instructions on or in the package insert for treating the subject with an effective amount of the one or more additional pharmaceutical agents.

[0148] In some embodiments, the one or more additional pharmaceutical agents comprise an agent that targets regulation of the DDR or DNA replication. In some embodiments, the agent is an inhibitor of ATR, ATM, DNA-PK, CHK1, CHK2, WEE1, MYT1, or pol-theta.

[0149] In some embodiments, the one or more additional pharmaceutical agents comprise an agent that attenuates survival pathway activation in response to DNA damage. In some embodiments, the agent is an inhibitor of EGFR, ErbB2, IGFR1, MET, FGFR1-4, VEGFR2, MEK, ERK, PI3K, AKT, mTORC1, or mTORC2.

[0150] In some embodiments, the one or more additional pharmaceutical agents comprise an agent that targets kinase oncogenic drivers that induce replication stress or interfere with the DDR. In some embodiments, the agent is an inhibitor of BCR-ABL, EGFR, ERBB2, FLT3, MET, RET, ALK, NTRK, RET, ROS1, or BRAF.

[0151] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit.

[0152] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a 66 ny-2729143Attorney Docket No.18407-20019.40 compound as disclosed herein and / or an additional pharmaceutically active compound useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0153] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to an individual. VII. GENERAL SYNTHETIC METHODS

[0154] The compounds of the present disclosure may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). In the following process descriptions, the symbols when used in the formulae depicted are to be understood to represent those groups described above in relation to the formulae herein.

[0155] The intermediates described in the following preparations may contain a number of nitrogen, hydroxy, and acid protecting groups such as esters. The variable protecting group may be the same or different in each occurrence depending on the particular reaction conditions and the particular transformations to be performed. The protection and deprotection conditions are well known to the skilled artisan and are described in the literature. See. e.g., Greene and Wuts, Protective Groups in Organic Synthesis, (T. Greene and P. Wuts, eds., 2d ed. 1991).

[0156] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et 67 ny-2729143Attorney Docket No.18407-20019.40 al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994).

[0157] The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, to prepare compounds of the invention, or salts thereof. The products of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. The reagents and starting materials are readily available to one of ordinary skill in the art. Others may be made by standard techniques of organic and heterocyclic chemistry which are analogous to the syntheses of known structurally-similar compounds and the procedures described in the Examples which follow including any novel procedures.

[0158] Compounds of Formula (AA), (AI), (AII), (AIII), (AIV), (AV), (AVI), (AI’), (AII’), (AIII’), (AIV’), (A), (I), (II), (III), (IV), (V), (VI), (I’), (II’), (III’), (IV’), (I-A), (II-A), (III-A), (IV-A), (I-B), (II-B), (III-B), (IV-B), (I-C), (II-C), (III-C), (IV-C), (I-D), (II-D), (III- D), (IV-D), (I-E), (II-E), (III-E), (IV-E), (V-A), or (VI-A) can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, and / or Scheme E, wherein X1, X2, Y1, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, R1, R2, R3, R4, R5, and R6are as defined for Formula (A), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), or any applicable variation thereof as detailed herein. 68 ny-2729143Attorney Docket No.18407-20019.40 Scheme A

[0159] As shown in Scheme A, compounds of general formula A-a are reacted with compounds of general formula A-b, for example in the presence of a Pd catalyst (e.g., Pd- PEPPSI-IPentCl 2-methylpyridine), a base (e.g., C2CO3) and a solvent (e.g., dioxane), to provide compounds of general formula A-c, wherein each Rxis independently selected from Cl, Br, and I, and wherein RPGis a protecting group, for example a -CH3group. Compounds 69 ny-2729143Attorney Docket No.18407-20019.40 of general formula A-c are further reacted with malononitrile, for example in the presence of sodium tert-butoxide, Pd(dppf)Cl2·DCM, and DME, to provide compounds of general formula A-d. Compounds of general formula A-d are further reacted, for example in the presence of Ghaffer-Parkins catalyst, EtOH, and H2O, to provide compounds of general formula A-e. Compound of general formula A-e, are deprotected, for example in the presence of, dichloromethane, tribromoborane, and DCM, to provide compounds of general formula A-f. Scheme B

[0160] As shown in Scheme B, compounds of general formula B-a are reacted with DMF-DMA, for example in the presence of EtOH, to provide compounds of general formula B-b, wherein each Rxis independently selected from Cl, Br, and I. Compounds of general 70 ny-2729143Attorney Docket No.18407-20019.40 formula B-b are further reacted with a hydroxylamine salt, for example hydroxylamine hydrochloride, for example in the presence of MeOH, to provide compounds of general formula B-c. Compounds of formula B-c are further cyclized, for example in the presence of TFAA and THF, to provide compounds of general formula B-d. Scheme C

[0161] As shown in scheme C, compounds of general formula C-a are reacted with hydrazine, for example in the presence of H2O and EtOH, to provide compounds of general formula C-b. Compounds of general formula C-b are further cyclized, for example in the presence of trimethyl orthoformate, to provide compounds of general formula C-c. Scheme D

[0162] As shown in scheme D, compounds of general formula D-a are reacted with a compound of formula D-b, for example in the presence of EtOH, to provide compounds of general formula D-c. 71 ny-2729143Attorney Docket No.18407-20019.40 Scheme E

[0163] As shown in scheme E, compounds of general formula E-a are reacted with DMF- DMA, for example in the presence of EtOH, to provide compounds of general formula E-b. Compounds of general formula E-b are further reacted with a hydroxylamine salt, for example hydroxylamine hydrochloride, for example in the presence of MeOH, to provide compounds of general formula E-c. Compounds of general formula E-c are further cyclized, for example in the presence of TFAA and THF, to provide compounds of general formula E- d. 72 ny-2729143Attorney Docket No.18407-20019.40 Scheme F

[0164] As shown in Scheme F, compounds of general formula F-a are reacted with compounds of general formula F-b, for example in the presence of a Pd catalyst (e.g., Pd- PEPPSI-IPentCl 2-methylpyridine), a base (e.g., C2CO3) and a solvent (e.g., dioxane), to provide compounds of general formula F-c, wherein each Rxis independently selected from Cl, Br, and I, and wherein RPGis a protecting group, for example a -CH3group. Compounds 73 ny-2729143Attorney Docket No.18407-20019.40 of general formula F-c are further reacted with malononitrile, for example in the presence of sodium tert-butoxide, Pd(dppf)Cl2 · DCM, and DME, to provide compounds of general formula F-d. Compounds of general formula F-d are further reacted, for example in the presence of Ghaffer-Parkins catalyst, EtOH, and H2O, to provide compounds of general formula F-e. Compound of general formula F-e, are deprotected, for example in the presence of, dichloromethane, tribromoborane, and DCM, to provide compounds of general formula F- f. 74 ny-2729143Attorney Docket No.18407-20019.40 ENUMERATED EMBODIMENTS

[0165] The following enumerated embodiments are representative of some aspects of the invention. Embodiment 1. A compound of Formula (A)Formula (A) or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Ring A is C5-C6aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6 alkyl, or halogen; each R2is independently H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10- membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5). 75 ny-2729143Attorney Docket No.18407-20019.40 Embodiment 2. The compound of embodiment 1, wherein the compound of Formula (A) is a compound of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI)or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, X2is C or when X2is N, X1is C; Y1is independently N or CR3; Z1is independently N, CR3, or CHR3; Z2is independently N, O, S, or CR3; each Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; each R1is independently H, C1-C6 alkyl, or halogen; each R2is independently H, C1-C6alkyl, or halogen; 76 ny-2729143Attorney Docket No.18407-20019.40 each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2or H; each R5is independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5). Embodiment 3. The compound of embodiment 2, wherein the compound is a compound of Formula (I). Embodiment 4. The compound of embodiment 2, wherein the compound is a compound of Formula (II). Embodiment 5. The compound of embodiment 2, wherein the compound is a compound of Formula (III). Embodiment 6. The compound of embodiment 2, wherein the compound is a compound of Formula (IV). Embodiment 7. The compound of embodiment 2, wherein the compound is a compound of Formula (V). Embodiment 8. The compound of embodiment 2, wherein the compound is a compound of Formula (VI). Embodiment 9. The compound of any one of embodiments 1-8, wherein R1is C1-C6 alkyl. Embodiment 10. The compound of embodiment 9, wherein R1is methyl. 77 ny-2729143Attorney Docket No.18407-20019.40 Embodiment 11. The compound of any one of embodiments 1-10, wherein R2is C1-C6alkyl. Embodiment 12. The compound of embodiment 11, wherein R2is methyl. Embodiment 13. The compound of any one of embodiments 1-12, wherein Z1is CR3. Embodiment 14. The compound of any one of embodiments 2-6 and 9-13, wherein Z2and Z3are CR3, X1is C, X2is N, and Y1is N. Embodiment 15. The compound of any one of embodiments 2-6 and 9-13, wherein Z2is N, Z3is CR3, X1is C, X2is N, and Y1is N. Embodiment 16. The compound of any one of embodiments 2-6 and 9-13, wherein Z2is CR3, Z3is N, X1is N, X2is C, and Y1is N. Embodiment 17. The compound of any one of embodiments 2-6 and 9-13, wherein Z2and Z3are CR3, X1is N, X2is C, and Y1is N. Embodiment 18. The compound of any one of embodiments 2-6 and 9-13, wherein Z2is N, Z3is CR3, X1is N, X2is C, and Y1is N. Embodiment 19. The compound of any one of embodiments 2 and 7-13, wherein Z1is CR3, Z4is N, Z5is CR3, Z6is CR3, Z7is CR3, and Z8is N. Embodiment 20. The compound of any one of embodiments 1-19, wherein each R3is independently selected from H and CH3. Embodiment 21. A compound selected from the group consisting of ;78 ny-2729143Attorney Docket No.18407-20019.40 ; ; ,or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof. Embodiment 22. A pharmaceutical composition comprising the compound of any one of embodiments 1 to 21, or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, and at least one pharmaceutically acceptable excipient. Embodiment 23. A method of inhibiting kinase activity of a human receptor tyrosine kinase PKMYT1 comprising contacting the PKMYT1 with a therapeutically effective amount of the compound of any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 21. Embodiment 24. A method of treating a patient having a cancer, comprising administering to the patient a therapeutically effective amount of the compound of any one of embodiments 1 to 21, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of embodiment 22. 79 ny-2729143Attorney Docket No.18407-20019.40 Embodiment 25. The method of embodiment 24, wherein the cancer is pancreatic, prostate, bladder, endometrial, lung, colorectal, ovarian, peritoneal, breast, gastric, fallopian tube, or cervical cancer. Embodiment 26. The method of embodiment 24 or 25, wherein the cancer comprises a deleterious mutation related to the DNA damage response (DDR) or a mutation that induces replicative stress. Embodiment 27. The method of embodiment 26, wherein the deleterious mutation related to DDR is a HR, BER, NHEJ or NER mutation. Embodiment 28. The method of embodiment 26, wherein the mutation comprises a mutation to ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, MRE11A, NBN, PALB2, PP2R2ARAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, XRCC2, the FANC family of proteins, a CCNE1 amplification mutation, a FBXW7 deletion or loss of function mutation, or a MYC amplification mutation. Embodiment 29. The method of embodiment 24 or 25, wherein the cancer comprises a mutation to a factor involved in regulation of cell cycle progression. Embodiment 30. The method of any one of embodiments 24-29, further comprising administering a therapy that induces DNA damage and / or replicative stress. Embodiment 31. The method of embodiment 30, wherein the therapy comprises alkylating agents, platinum-based anti-neoplastic agents, anti-metabolites, topoisomerase inhibitors, ionizing radiation, radiomimetics, or other radiotherapies. Embodiment 32. The method of any one of embodiments 24-29, further comprising administering an agent that targets regulation of the DDR or DNA replication. Embodiment 33. The method of embodiment 32, wherein the agent is an inhibitor of ATR, ATM, DNA-PK, CHK1, CHK2, WEE1, MYT1, or pol-theta. Embodiment 34. The method of any one of embodiments 24-29, further comprising administering an agent that attenuates survival pathway activation in response to DNA damage. 80 ny-2729143Attorney Docket No.18407-20019.40 Embodiment 35. The method of embodiment 34, wherein the agent is an inhibitor of EGFR, ErbB2, IGFR1, MET, FGFR1-4, VEGFR2, MEK, ERK, PI3K, AKT, mTORC1, or mTORC2. Embodiment 36. The method of any one of embodiments 24-29, further comprising administering an agent that targets kinase oncogenic drivers that induce replication stress or interfere with the DDR. Embodiment 37. The method of embodiment 36, wherein the agent is an inhibitor of BCR-ABL, EGFR, ERBB2, FLT3, MET, RET, ALK, NTRK, RET, ROS1, or BRAF. Embodiment 38. The method of any one of embodiments 24-29, further comprising administering a therapy that acts via the induction of an anti-tumor immune response in a manner analogous to PARP1 and / or PARP2 inhibitors. Embodiment 39. The method of embodiment 38, wherein the therapy is an anti-PD1, an anti-PD-L1, or an anti-CTLA4 therapy. Embodiment 40. The method of any one of embodiments 24-29, further comprising administering a therapy that induces an anti-tumor immune response. The method of embodiment 40, wherein the therapy comprises a cancer vaccine, a T-cell- based therapy, a T-cell engager bi-specific antibody, or an oncolytic virus. EXAMPLES

[0166] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0167] Abbreviations used in the Examples include the following: ACN: acetonitrile; APCI: atmospheric pressure chemical ionization; BSA: bovine serum albumin; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF-DMA: dimethylformamide-dimethyl acetal; DMSO: dimethyl sulfoxide; ESI: electrospray ionization; EtOAc: ethyl acetate; EtOH: ethanol or ethyl alcohol;1H NMR: proton nuclear magnetic resonance; HPLC: high- performance liquidKHMDS: Potassium bis(trimethylsilyl)amide; LCMS: liquid chromatography–mass spectrometry; LiHMDS: Lithium bis(trimethylsilyl)amide ; MeOH: methanol or methyl alcohol; MTBE: methyl tert-butyl ether; PBS: phosphate- 81 ny-2729143Attorney Docket No.18407-20019.40 buffered saline; TFA: trifluoroacetic acid; TFAA: trifluoroacetic anhydride; PPA: polyphosphoric acid; FA: formic acid; and THF: tetrahydrofuran. SYNTHETIC EXAMPLES Example 1: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5- a]pyrrolo[3,2-e]pyridine-6-carboxamide (Compound 1) Step 1: Synthesis of 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin- 7-amine

[0168] 6-bromo-7-chloro-1,7a-diazaindene (270 mg, 1.17 mmol) and 3-methoxy-2,6- xylidine (265 mg, 1.5 eq., 1.75 mmol) were dissolved in 1,4-dioxane (5.83 mL, 68.4 mmol) and treated with LiHMDS (410 mg, 2.1 eq., 2.45 mmol) (1M in THF). The reactions were heated to 60 °C and left to stir for 30 minutes. The reaction was then cooled to ambient temperature, poured into sat. aq. NH4Cl, and extracted with MTBE. The organics were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-20% EtOAc in heptane to provide 6-bromo-N-(3- methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-7-amine (464 mg, crude). Mass Spec (APCI): [M+1] = 346.3, 348.3. Step 2: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5- a]pyrrolo[3,2-e]pyridine-6-carbonitrile

[0169] Malononitrile (54.6 mg, 2.2 eq., 826 µmol) and sodium tert-butoxide (126 mg, 3.5 eq., 1.31 mmol) were dissolved in DME (1.88 mL) at ambient temperature. The reactions were left to stir for 10 minutes. Then 6-bromo-N-(3-methoxy-2,6- 82 ny-2729143Attorney Docket No.18407-20019.40 dimethylphenyl)pyrazolo[1,5-a]pyridin-7-amine (130 mg, 375 µmol) in DME (1.88 mL) and Pd(dppf)Cl2 · DCM (30.7 mg, 0.1 eq., 37.5 µmol) were added. The reactions were sealed and heated to 120 °C for 1.5 h. The reaction was then cooled to ambient temperature, filtered, and concentrated. The crude product was purified via reverse phase chromatography, eluting with 15-80% ACN in H2O (w / 0.1% TFA buffer). The desired fractions were diluted with DCM, washed with sat. aq. NaHCO3, dried over MgSO4, filtered and concentrated to provide 7- amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6- carbonitrile (11 mg, 9%). Mass Spec (APCI): [M+1] = 332.4. Step 3: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5- a]pyrrolo[3,2-e]pyridine-6-carboxamide

[0170] 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5-a]pyrrolo[3,2- e]pyridine-6-carbonitrile (11 mg, 33.2 µmol) and Ghaffer-Parkins catalyst (1.42 mg, 0.1 eq., 3.32 µmol) was dissolved in ethanol (332 µL, 5.68 mmol) / water (83 µL, 4.61 mmol) under an atmosphere of nitrogen and let stir at ambient temperature for 4 hours. The reaction was diluted with DCM and washed with water. The organics were dried over MgSO4, filtered, and concentrated to provide 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5- a]pyrrolo[3,2-e]pyridine-6-carboxamide. The product was then passed on to the next step without further purification. Mass Spec (APCI): [M+1] = 350.5. Step 4: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5- a]pyrrolo[3,2-e]pyridine-6-carboxamide (Compound 1) 83 ny-2729143Attorney Docket No.18407-20019.40

[0171] 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5-a]pyrrolo[3,2- e]pyridine-6-carboxamide (10 mg, 28.6 µmol) was dissolved in dichloromethane (572 µL, 8.94 mmol) and treated with tribromoborane (10.8 mg, 1.5 eq., 42.9 µmol) (1M in DCM) at ambient temperature for 20 minutes. The crude mixture was then quenched with MeOH and concentrated. The crude material was purified via reverse phase HPLC, eluting with a gradient of 10-60% ACN in water (w / 0.1% TFA buffer). The desired fractions were diluted with DCM, washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated to provide 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrazolo[1,5-a]pyrrolo[3,2- e]pyridine-6-carboxamide (Compound 1) (5.4 mg, 48% over 2 steps). Mass Spec (APCI): [M+1] = 336.4. 1H NMR (300 MHz, MeOD-d4): δ 7.61 (s, 1H), 7.52 (d, J= 12 Hz, 1H), 7.38- 7.32 (m, 2H), 7.05 (d, J=9 Hz, 1H), 6.92 (d, J=6 Hz. 1H), 6.46 (s, 1H), 2.01 (s, 1H), 1.86 (s, 3H), 1.83 (s, 3H) ppm. Example 2: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 2) Step 1: Synthesis of (E)-N'-(5-bromo-6-chloropyridin-2-yl)-N,N- dimethylmethanimidamide

[0172] To a solution of 5-bromo-6-chloropyridin-2-amine (38.0 g, 183.16 mmol) in EtOH (400.0 mL) was added DMF-DMA (64.6 g, 542.11 mmol) at room temperature. The mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was filtered. The solid was washed with H2O / EtOH and then collected to afford (E)-N'-(5- 84 ny-2729143Attorney Docket No.18407-20019.40 bromo-6-chloropyridin-2-yl)-N,N-dimethylmethanimidamide (50.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 262.0. Step 2: Synthesis of (E)-N'-(5-bromo-6-chloropyridin-2-yl)-N-hydroxyformimidamide

[0173] To a solution of (E)-N'-(5-bromo-6-chloropyridin-2-yl)-N,N- dimethylmethanimidamide (55.0 g, crude) in MeOH (550.0 mL) was added hydroxylamine hydrochloride (71.5 g, 1028.91 mmol) at room temperature. The mixture was stirred at 50 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The solid was washed with H2O, EtOH, Et2O and then collected to afford (E)-N'-(5-bromo-6-chloropyridin- 2-yl)-N-hydroxyformimidamide (40.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 249.9. Step 3: Synthesis of 6-bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine

[0174] To a solution of (E)-N'-(5-bromo-6-chloropyridin-2-yl)-N- hydroxymethanimidamide (25.0 g, crude) in THF (500.0 mL) was added TFAA (126.0 g, 599.9 mmol) at room temperature. The mixture was stirred at 50 °C for 4 h. After the reaction was completed, the resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford 6- bromo-5-chloro-[1,2,4]triazolo[1,5-a]pyridine (5.3.g, 13%) as a white solid. LCMS (ESI, m / z): [M+H]+ = 231.9. 85 ny-2729143Attorney Docket No.18407-20019.40 Step 4: Synthesis of 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a]pyridin-5-amine

[0175] To a solution of 3-methoxy-2,6-dimethylaniline (3.2 g, 24.5 mmol) in dioxane (55.0 mL) was added KHMDS (28.0 mL, 1.0 mol / L in THF) at room temperature under N2. The mixture was stirred at room temperature for 10 min. Then a solution of 6-bromo-5- chloro-[1,2,4]triazolo[1,5-a]pyridine (3.7 g, 15.6 mmol) in dioxane (20.0 mL) was added to the mixture at room temperature. The resulting mixture was stirred at 80 °C for an additional 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (40 / 60, v / v) to afford 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-5- amine (540.0 mg, 10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 347.0. Step 5: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile

[0176] To a solution of malononitrile (260.0 mg, 3.60 mmol) in DME (15.0 mL) was added t-BuONa (489.0 mg, 5.07 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-5-amine (540.0 mg, 1.56 mmol) and Pd(dppf)Cl2 (221.0 mg, 86 ny-2729143Attorney Docket No.18407-20019.40 0.26 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for additional 32 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (90 / 10, v / v) to afford 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (98.0 mg, 18%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 333.1. Step 6: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 2)

[0177] A solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (98.0 mg, 0.29 mmol) in H2SO4 (2.0 mL), H2O (2.0 mL) and CH3SO3H (2.0 mL) was stirred at 40 °C for 40 min. Then methionine (154.0 mg, 1.03 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for additional 16 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 16% B in 10 min; Wave Length: 254 / 220 nm) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine- 6-carboxamide (Compound 2) (10.2 mg, 10%) as a white solid. LCMS (ESI, m / z): [M+H]+= 337.2.1H NMR (400 MHz, DMSO-d6): δ 9.54 (s, 1H), 9.04 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.96 - 6.93 (m, 3H), 6.47 (s, 2H), 1.78 (s, 3H), 1.61 (s, 3H). 87 ny-2729143Attorney Docket No.18407-20019.40 Example 3: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (Compound 3) Step 1: Synthesis of 3-bromo-4-chloro-2-hydrazinylpyridine

[0178] To a solution of 3-bromo-4-chloro-2-fluoropyridine (5.0 g, 23.76 mmol) in EtOH (20.0 mL) was added hydrazine hydrate (3.2 g, 80%) at room temperature. The mixture was stirred at 60 °C for 16 h. After the reaction was completed, the resulting mixture was cooled to room temperature and filtered. The solid was washed EtOH and then collected to afford 3- bromo-4-chloro-2-hydrazinylpyridine (4.7 g, crude) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 221.9. Step 2: Synthesis of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridine

[0179] A solution of 3-bromo-4-chloro-2-hydrazinylpyridine (6.0 g, crude) in trimethyl orthoformate (250.0 mL) was stirred at 90 °C for 16 h. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (10 / 90, v / v) to afford 8-bromo-7-chloro- [1,2,4]triazolo[4,3-a]pyridine (4.3 g, 68%) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 231.9. 88 ny-2729143Attorney Docket No.18407-20019.40 Step 3: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a]pyridin-8-amine

[0180] To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridine (1.0 g, 4.30 mmol) in dioxane (18.0 mL) was added 3-methoxy-2,6-dimethylaniline (810.0 mg, 5.35 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (349.0 mg, 0.41 mmol) and Cs2CO3 (4.1 g, 12.69 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (27 / 73, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[4,3-a]pyridin-8-amine (210.0 mg, 12%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 303.1. Step 4: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile

[0181] To a solution of malononitrile (40.0 mg, 0.60 mmol) in DME (3.0 mL) was added t-BuONa (75.0 mg, 0.78 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- a]pyridin-8-amine (75.0 mg, 0.24 mmol) and Pd(dppf)Cl2(34.0 mg, 0.04 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for an additional 48 h. After the 89 ny-2729143Attorney Docket No.18407-20019.40 reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (93 / 7, v / v) to afford 8-amino-9- (3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7- carbonitrile (87.0 mg, 36%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 333.1. Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide

[0182] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (60.0 mg, 0.18 mmol) in DMSO (3.0 mL) was added K2CO3 (19.3 mg, 0.33 mmol) and H2O2 (1.5 mL, 30%) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-9-(3-methoxy-2,6- dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (55.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 351.1. Step 6: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (Compound 3)90 ny-2729143Attorney Docket No.18407-20019.40

[0183] A solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (55.0 mg, crude) in HBr (3.0 mL, 40% in H2O) was stirred at 80 °C for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined aqueous layer was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH OBD Column 30 x 150 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 2 min, 3% B to 10% B in 10 min; 254 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine- 7-carboxamide (Compound 3) (3.3 mg, 2%) as a white solid. LCMS (ESI, m / z): [M+H]+= 337.2.1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 9.04 (s, 1H), 8.22 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.96 - 6.93 (m, 3H), 6.47 (s, 2H), 1.77 (s, 3H), 1.61 (s, 3H). Example 4: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-imidazo[1,2- a]pyrrolo[2,3-c]pyridine-7-carboxamide (Compound 4) Step 1: Synthesis of 7-chloro-8-iodoimidazo[1,2-a]pyridine

[0184] To a solution of 4-chloro-3-iodopyridin-2-amine (2.0 g, 7.86 mmol) in EtOH (20.0 mL) was added chloroacetaldehyde (12.0 mL, 40%) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 7-chloro-8- iodoimidazo[1,2-a]pyridine (2.0 g, 91%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 278.9. Step 2: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-a]pyridin- 8-amine 91 ny-2729143Attorney Docket No.18407-20019.40

[0185] To a solution of 7-chloro-8-iodoimidazo[1,2-a]pyridine (4.5 g, 16.16 mmol) in 1,4-dioxane (180.0 mL) was added 3-methoxy-2,6-dimethylaniline (3.0 g, 19.84 mmol), XantPhos (16.2 g, 27.99 mmol), Cs2CO3(16.0 g, 49.11 mmol) and Pd2(dba)3(8.5 g, 9.28 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / dichloromethane (1 / 8, v / v) and reverse phase flash column chromatography with H2O / ACN (1 / 1, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2- a]pyridin-8-amine (960.0 mg, 19%) as a white solid. LCMS (ESI, m / z): [M+H]+= 302.1. Step 3: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-imidazo[1,2- a]pyrrolo[2,3-c]pyridine-7-carbonitrile

[0186] To a solution of malononitrile (340.0 mg, 5.15 mmol) in DMF (20.0 mL) was added t-BuONa (500.0 mg, 5.20 mmol) at 0 °C under N2. The resulting mixture was stirred at 0°C for 40 min under N2. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2- a]pyridin-8-amine (230.0 mg, 0.76 mmol) and Pd(dppf)Cl2.CH2Cl2 (260.0 mg, 0.32 mmol) were added to the mixture at room temperature under N2. The resulting mixture was stirred at 150 °C for an additional 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was 92 ny-2729143Attorney Docket No.18407-20019.40 concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with H2O / ACN (1 / 1, v / v) to afford 8-amino-9-(3-methoxy-2,6- dimethylphenyl)-9H-imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carbonitrile (35.0 mg, 13%) as a brown oil. LCMS (ESI, m / z): [M+H]+= 332.1. Step 4: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-imidazo[1,2- a]pyrrolo[2,3-c]pyridine-7-carboxamide (Compound 4)

[0187] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-imidazo[1,2- a]pyrrolo[2,3-c]pyridine-7-carbonitrile (35.0 mg, 0.11 mmol) in H2SO4 / H2O (1.0 mL / 0.1 mL) was added and MeSO2H (3.0 mL) at room temperature. The resulting mixture was stirred at 40 °C for 40 min. Then DL-methionine (80.0 mg, 0.54 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for an additional 5 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19x250 mm, 5 um; Mobile Phase A: Water (10 mmol / L NH3H2O), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 25% B to 35% B in 10 min; Wave Length: 254 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-imidazo[1,2-a]pyrrolo[2,3- c]pyridine-7-carboxamide (Compound 4) (1.0 mg, 2%) as a white solid. LCMS (ESI, m / z): [M+H]+= 336.2.1H NMR (400 MHz, DMSO-d6): δ 9.33 (s, 1H), 8.18 (d, J = 7.2 Hz, 1H), 7.72 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.19 - 7.12 (m, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.98 - 6.92 (m, 1H), 6.90 - 6.81 (m, 2H), 6.31 (s, 2H), 1.76 (s, 3H), 1.67 (s, 3H). 93 ny-2729143Attorney Docket No.18407-20019.40 Example 5: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 5) Step 1: Synthesis of (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N,N- dimethylmethanimidamide

[0188] To a solution of 4-chloro-3-iodopyridin-2-amine (9.0 g, 35.37 mmol) in EtOH (300.0 mL) was added DMF-DMA (12.7 g, 106.58 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N,N- dimethylmethanimidamide (10.5 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 310.0. Step 2: Synthesis of (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N-hydroxymethanimidamide

[0189] To a solution of (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N,N- dimethylmethanimidamide (10.5 g, crude) in MeOH (400.0 mL) was added hydroxylamine hydrochloride (7.1 g, 102.17 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was washed with H2O and then filtered. The solid was collected to afford (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N-hydroxymethanimidamide (5.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 297.9. Step 3: Synthesis of 7-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine 94 ny-2729143Attorney Docket No.18407-20019.40

[0190] To a solution of (E)-N'-(4-chloro-3-iodopyridin-2-yl)-N- hydroxymethanimidamide (4.5 g, crude) in THF (150.0 mL) was added TFAA (30.0 mL) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1, v / v) to afford 7-chloro- 8-iodo-[1,2,4]triazolo[1,5-a]pyridine (1.5 g, 35 %) as a brown oil. LCMS (ESI, m / z): [M+H]+= 279.9. Step 4: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a]pyridin-8-amine

[0191] To a solution of 7-chloro-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (750.0 mg, 2.68 mmol) in dioxane (50.0 mL) was added 3-methoxy-2,6-dimethylaniline (812.0 mg, 5.37 mmol), Cs2CO3(2.6 g, 7.98 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (452.0 mg, 0.54 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 9, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-8-amine (350.0 mg, 43%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 303.1. 95 ny-2729143Attorney Docket No.18407-20019.40 Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile

[0192] To a solution of malononitrile (175.0 mg, 2.65 mmol) in DME (12.0 mL) was added t-BuONa (246.0 mg, 2.56 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-8-amine (350.0 mg, 1.15 mmol) and Pd(dppf)Cl2.CH2Cl2 (207.0 mg, 0.25 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at 100 °C for additional 72 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 8-amino-9-(3- methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (130.0 mg, 33%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 333.1. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide

[0193] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (100.0 mg, 0.30 mmol) in DMSO (2.0 mL) was added H2O2 (2.0 mL, 30%) and K2CO3 (9.0 mg, 0.07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, 96 ny-2729143Attorney Docket No.18407-20019.40 the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-9-(3-methoxy-2,6- dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (100.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 351.1. Step 7: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 5)

[0194] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (100.0 mg, crude) in DCM (2.0 mL) was added a solution of BBr3in DCM (2.0 mL, 1 mol / L) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30x150 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 9% B to 19% B in 10 min; Wave Length: 254 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5- a]pyridine-7-carboxamide (Compound 5) (12.0 mg, 12%) as a white solid. LCMS (ESI, m / z): [M+H]+= 337.1.1H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.52 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.68Hz, 1H), 6.97 - 6.88 (m, 3H), 6.63 (s, 2H), 1.76 (s, 3H), 1.67 (s, 3H). Example 6: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazo[1,2- c]pyrrolo[2,3-e]pyrimidine-3-carboxamide (Compound 6) Step 1: Synthesis of 8-bromo-7-chloroimidazo[1,2-c]pyrimidine 97 ny-2729143Attorney Docket No.18407-20019.40

[0195] To a solution of 5-bromo-6-chloropyrimidin-4-amine (5.0 g, 23.99 mmol) in DMF (200.0 mL) was added 2-chloroacetaldehyde (11.7 g, 40% in water) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford 8-bromo-7- chloroimidazo[1,2-c]pyrimidine (1.8 g, 32%) as a brown solid. LCMS (ESI, m / z): [M+H]+=231.9. Step 2: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2- c]pyrimidin-8-amine

[0196] To a solution of 8-bromo-7-chloroimidazo[1,2-c]pyrimidine (0.8 g, 5.29 mmol) in dioxane (10.0 mL) was added Pd-PEPPSI-IPentCl (400.0 mg, 0.41 mmol) and Cs2CO3(4.2 g, 12.89 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (70 / 30, v / v) to afford 7-chloro-N-(3-methoxy-2,6- dimethylphenyl)imidazo[1,2-c]pyrimidin-8-amine (240.0 mg, 18%) as a brown solid. LCMS (ESI, m / z): [M+H]+=303.1. 98 ny-2729143Attorney Docket No.18407-20019.40 Step 3: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazo[1,2- c]pyrrolo[2,3-e]pyrimidine-3-carbonitrile

[0197] To a solution of malononitrile (162.0 mg, 2.45 mmol) in DME (10.0 mL) were added t-BuONa (261.0 mg, 2.72 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)imidazo[1,2-c]pyrimidin-8- amine (270.0 mg, 0.89 mmol) and Pd(dppf)Cl2 (183.0 mg, 0.25 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at 100 °C for an additional 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (40 / 60, v / v) to afford 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazo[1,2- c]pyrrolo[2,3-e]pyrimidine-3-carbonitrile (160.0 mg, 53%) as a brown solid. LCMS (ESI, m / z): [M+H]+=333.1. Step 4: Synthesis of Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H- imidazo[1,2-c]pyrrolo[2,3-e]pyrimidine-3-carboxamide (Compound 6)

[0198] A solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-imidazo[1,2- c]pyrrolo[2,3-e]pyrimidine-3-carbonitrile (40.0 mg, 0.12 mmol) in H2SO4 / H2O / MeSO2H (1.0 mL / 0.1 mL / 1.5 mL) was stirred at room temperature for 1.5 h. Then DL-methionine (71.8 mg, 0.48 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for 99 ny-2729143Attorney Docket No.18407-20019.40 additional 16 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column19x250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 3% B to 8% B in 10 min; Wave Length: 254 nm) to afford 2- amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-imidazo[1,2-c]pyrrolo[2,3-e]pyrimidine-3- carboxamide (Compound 6) (2.5 mg, 6%) as a white solid. LCMS (ESI, m / z): [M+H]+= 337.1.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.44 (s, 2H), 1.80 (s, 3H), 1.71 (s, 3H). Example 7: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 7) Step 1: Synthesis of 3-bromo-2-chloro-5-methylpyridine 1-oxide

[0199] To a solution of 3-bromo-2-chloro-5-methylpyridine (19.0 g, 92.02 mmol) in DCM (200.0 mL) was added m-CPBA (47.5 g, 275.27 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with dichloromethane / methanol (94 / 6, v / v) to afford 3-bromo-2-chloro-5- methylpyridine 1-oxide (18.0 g, 74%) as a light orange solid. LCMS (ESI, m / z): [M+H]+= 221.9. Step 2: Synthesis of 5-bromo-N-tert-butyl-6-chloro-3-methylpyridin-2-amine 100 ny-2729143Attorney Docket No.18407-20019.40

[0200] To a solution of 3-bromo-2-chloro-5-methylpyridine 1-oxide (18.0 g, 80.91 mmol) in toluene (360.0 mL) was added 2-methylpropan-2-amine (41.6 g, 568.80 mmol). Then a solution of p-Toluenesulfonic anhydride (79.5 g, 243.54 mmol) in DCM (90.0 mL) was dropwise added to the mixture at 0 °C under N2. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 5-bromo-N-tert-butyl-6-chloro-3-methylpyridin-2- amine (6.5 g, 26%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 277.0. Step 3: Synthesis of 5-bromo-6-chloro-3-methylpyridin-2-amine

[0201] A solution of 5-bromo-N-tert-butyl-6-chloro-3-methylpyridin-2-amine (6.5 g, 23.41 mmol) in TFA (60.0 mL) was stirred at 70 °C for 3 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8.0 with saturated NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (3 / 7, v / v) to afford 5-bromo-6-chloro-3-methylpyridin-2-amine (5.0 g, 96%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 220.9. Step 4: Synthesis of N'-(5-bromo-6-chloro-3-methylpyridin-2-yl)-N,N- dimethylmethanimidamide 101 ny-2729143Attorney Docket No.18407-20019.40

[0202] To a solution of 5-bromo-6-chloro-3-methylpyridin-2-amine (5.0 g, 22.58 mmol) in THF (80.0 mL) was added DMF-DMA (10.6 g, 88.95 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford N'-(5-bromo-6-chloro-3- methylpyridin-2-yl)-N,N-dimethylmethanimidamide (5.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 276.0. Step 5: Synthesis of N'-(5-bromo-6-chloro-3-methylpyridin-2-yl)-N- hydroxymethanimidamide

[0203] To a solution of N'-(5-bromo-6-chloro-3-methylpyridin-2-yl)-N,N- dimethylmethanimidamide (5.0 g, crude) in MeOH (50.0 mL) was added hydroxylamine hydrochloride (1.3 g, 18.26 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford N'-(5-bromo-6-chloro-3-methylpyridin-2-yl)-N- hydroxymethanimidamide (4.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 263.9. Step 6: Synthesis of 6-bromo-5-chloro-8-methyl-[1,2,4]triazolo[1,5-a]pyridine

[0204] To a solution of N'-(5-bromo-6-chloro-3-methylpyridin-2-yl)-N- hydroxymethanimidamide (4.0 g, crude) in THF (40.0 mL) was added TFAA (3.5 g, 16.63 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 3 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The 102 ny-2729143Attorney Docket No.18407-20019.40 residue was purified by flash column chromatography with dichloromethane / methanol (99 / 1, v / v) to afford 6-bromo-5-chloro-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (2.0 g, 53%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 245.9. Step 7: Synthesis of 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methyl- [1,2,4]triazolo[1,5-a]pyridin-5-amine

[0205] To a solution of 6-bromo-5-chloro-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (900.0 mg, 3.65 mmol) in dioxane (10.0 mL) was added 3-methoxy-2,6-dimethylaniline (828.0 mg, 5.48 mmol) and LiHMDS (7.7 mL, 1.0 mol / L in THF) at room temperature under N2. The resulting mixture was stirred at 60 °C for 1 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with acetonitrile / water (78 / 22, v / v) to afford 6-bromo-N-(3- methoxy-2,6-dimethylphenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridin-5-amine (600.0 mg, 45%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 361.1. Step 8: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile

[0206] To a solution of malononitrile (384.0 mg, 5.81 mmol) in DME (30.0 mL) was added t-BuONa (479.0 mg, 4.98 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methyl- 103 ny-2729143Attorney Docket No.18407-20019.40 [1,2,4]triazolo[1,5-a]pyridin-5-amine (600.0 mg, 1.66 mmol) and Pd(dppf)Cl2(135.0 mg, 0.17 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for an additional 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with acetonitrile / water (1 / 1, v / v) to afford 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4- methyl-8H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (60.0 mg, 10%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 347.2. Step 9: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 7)

[0207] The solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile (50.0 mg, 0.14 mmol) in H2SO4(1.8 mL), CH3SO3H (4.0 mL) and H2O (0.2 mL) was stirred at 40 °C for 1 h. Then DL- Methionine (65.0 mg, 0.44 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for an additional 16 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Phenyl OBD Column19x250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wave Length: 254 / 220 nm) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 7) (1.4 mg, 2%) as a white solid. LCMS (ESI, m / z): [M+H]+= 351.1.1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.12 - 104 ny-2729143Attorney Docket No.18407-20019.40 8.10 (m, 2H), 7.06 (d, J = 8.4 Hz, 1H), 6.95 - 6.93 (m, 3H), 6.44 (s, 2H), 2.57 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H). Example 8: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carboxamide (Compound 8) Step 1: Synthesis of 4-bromo-1,5-diaza-3-naphthylamine

[0208] 1,5-diaza-3-naphthylamine (311 mg, 2.14 mmol) was dissolved in dimethylformamide (10.7 mL, 138 mmol) under an atmosphere of nitrogen and cooled to 0 °C. NBS (534 mg, 1.4 eq., 3 mmol) dissolved in DMF (4 mL) was then added over 20 minutes. The reaction was then allowed to slowly warm to ambient temperature and stirred for 30 minutes. The reaction was then quenched with sat. aq. Na2S2O3and 1N NaOH. The product was then extracted with DCM. The DCM was then dried over magnesium sulfate, filtered, and concentrated to provide 4-bromo-1,5-diaza-3-naphthylamine (317 mg, 66%). Mass Spec (APCI): [M+1] = 224.0, 226.2. Step 2: Synthesis of 3,4-dibromo-1,5-diazanaphthalene

[0209] 4-bromo-1,5-diaza-3-naphthylamine (316 mg, 1.41 mmol) was dissolved in acetonitrile (9.4 mL, 180 mmol) and cooled to 0 °C. Tert-butyl nitrite (185 µL, 1.1 eq., 1.55 mmol) was added neat. The reaction was left to stir at 0 °C for 5 minutes before copper (I) bromide (303 mg, 1.5 eq., 2.12 mmol) was added. The reaction was then allowed to warm to ambient temperature and stirred overnight. Only half conversion was observed so another portion of the tBuNO and CuBr were added and the reaction left again to stir overnight. The MeCN was stripped in vacuo and the residue poured into 1N aq. NH4OH and extracted with 4:1 DCM / IPA. The crude material was purified via flash column chromatography, eluting 105 ny-2729143Attorney Docket No.18407-20019.40 with 0-50% EtOAc in heptane to provide 3,4-dibromo-1,5-diazanaphthalene (148 mg, 36%). Mass Spec (APCI): [M+1] = 289.1. Step 3: Synthesis of (3-methoxy-2,6-xylyl)(3-bromo-1,5-diaza-4-naphthyl)amine

[0210] 3,4-Dibromo-1,5-diazanaphthalene (125 mg, 434 µmol) and 3-methoxy-2,6- xylidine (72.2 mg, 1.1 eq., 478 µmol) were dissolved in 1,4-dioxane (4.34 mL, 50.9 mmol) and treated with LiHMDS (160 mg, 2.2 eq., 955 µmol) (1M in THF) at ambient temperature. The reaction was allowed to stir for 10 minutes, then quenched with brine. The product was extracted with EtOAc, dried over MgSO4, filtered, and dried. The crude material was purified via flash column chromatography, eluting with 0-40% EtOAc in heptane to provide (3-methoxy-2,6-xylyl)(3-bromo-1,5-diaza-4-naphthyl)amine (76 mg, 44%). Mass Spec (APCI): [M+1] = 358.4. Step 4: Synthesis of 2-mino-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carbonitrile

[0211] Malononitrile (30.8 mg, 2.2 eq., 467 µmol) and NaOtBu (71.4 mg, 3.5 eq., 743 µmol) were dissolved in DME (1.06 mL) at room temperature. The reactions were left to stir for 10 minutes. Then (3-methoxy-2,6-xylyl)(3-bromo-1,5-diaza-4-naphthyl)amine (76 mg, 212 µmol) in DME (1.06 mL) and Pd(dppf)Cl2·DCM (34.6 mg, 0.2 eq., 42.4 µmol) were added. The reactions were sealed and heated to 130 °C for 3 h. The reaction was cooled to ambient temperature, and loaded onto silica gel. The compound was purified via column chromatography, eluting with 0-65% EtOAc in heptane to provide 2-mino-1-(3-methoxy-2,6- 106 ny-2729143Attorney Docket No.18407-20019.40 dimethylphenyl)-1H-pyrrolo[3,2-c][1,5]naphthyridine-3-carbonitrile (41 mg, 56%). Mass Spec (APCI): [M+1] = 344.4. Step 5: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carboxamide

[0212] 2-Amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carbonitrile (20 mg, 58.2 µmol) and Ghaffar-Parkins Catalyst (2.49 mg, 0.1 eq., 5.82 µmol) were dissolved in 4:1 tetrahydrofuran (582 µL, 7.16 mmol) / water (146 µL, 8.08 mmol) and heated to 40 °C overnight. The solvent was concentrated, and the crude material was used in the next step without further purification. Mass Spec (APCI): [M+1] = 362.4. Step 6: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carboxamide (Compound 8)

[0213] Crude 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2- c][1,5]naphthyridine-3-carboxamide from the previous step was dissolved in dichloromethane (582 µL, 9.1 mmol) and cooled to 0 °C. The reaction was treated with BBr3(43.8 mg, 3 eq., 175 µmol) (1M in DCM) and let stir for 10 minutes then allowed to warm to ambient temperature. The reaction was left to stir at ambient temperature for another 4 hours. The reaction was quenched with the addition of methanol. The crude product was purified via reverse phase chromatography, eluting with 10-70% MeCN in H2O (w / 0.1% TFA buffer). The desired fractions were diluted with DCM and washed with sat. aq. NaHCO3to provide 2- 107 ny-2729143Attorney Docket No.18407-20019.40 amino-1-(3-hydroxy-2,6-dimethylphenyl)-1H-pyrrolo[3,2-c][1,5]naphthyridine-3- carboxamide (Compound 8) (11.9 mg, 59% over 2 steps). Mass Spec (APCI): [M+1] = 348.4. 1H NMR (300 MHz, 4:1 CDCl3 / MeOD-d4, residual CHCl3 peak referenced to 7.41 ppm): δ 9.23 (s, 1H), 8.50-8.48 (m, 1H), 8.30-8.27 (m, 1H), 7.40-7.36 (m, 1H), 7.08 (d, J=9 Hz, 1H), 6.95 (d, J=9 Hz, 1H), 1.81 (s, 3H), 1.77 (s, 3H) ppm. Example 9: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carboxamide (Compound 9) Step 1: Synthesis of 4-bromo-1-methyl-1,3-benzodiazol-5-amine

[0214] To a solution of 1-methyl-1,3-benzodiazol-5-amine (2.0 g, 13.55 mmol) in CH3COOH (45.0 mL) was added a solution of Br2 (2.1 g, 13.45 mmol) in CH3COOH (10.0 mL) at 0 °C under N2. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was poured into petroleum ether and then filtered. The solid was dissolved in water. The pH value of the mixture was adjusted to 8.0 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with CH2Cl2 / MeOH (90 / 10, v / v) to afford 4-bromo-1-methyl-1,3- benzodiazol-5-amine (1.2 g, 39%) as a white solid. LCMS (ESI, m / z): [M+H]+= 226.0. Step 2: Synthesis of 4-bromo-5-chloro-1-methyl-1,3-benzodiazole

[0215] To a solution of 4-bromo-1-methyl-1,3-benzodiazol-5-amine (6.5 g, 28.71 mmol) in ACN (100.0 mL) was added t-BuNO2 (2.9 g, 28.89 mmol) and CuCl (3.2 g, 24.95 mmol) at room temperature. The mixture was stirred at 60 °C for 1 h. After the reaction was 108 ny-2729143Attorney Docket No.18407-20019.40 completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with CH2Cl2 / MeOH (85 / 15, v / v) to afford 4-bromo-5-chloro-1-methyl- 1,3-benzodiazole (4.5 g, 63%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 244.9. Step 3: Synthesis of 5-chloro-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H- benzo[d]imidazol-4-amine

[0216] To a solution of 4-bromo-5-chloro-1-methyl-1H-benzo[d]imidazole (1.0 g, 4.10 mmol) in dioxane (20.0 mL) was added 3-methoxy-2,6-dimethylaniline (810.0 mg, 5.35 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (349.0 mg, 0.41 mmol) and Cs2CO3 (4.1 g, 12.69 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (27 / 73, v / v) to afford 5-chloro-N-(3-methoxy-2,6-dimethylphenyl)-1- methyl-1H-benzo[d]imidazol-4-amine (454.0 mg, 35%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 316.1. Step 4: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carbonitrile 109 ny-2729143Attorney Docket No.18407-20019.40

[0217] To a solution of malononitrile (270.0 mg, 3.69 mmol) in DME (15.0 mL) was added t-BuONa (497.0 mg, 5.12 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 5-chloro-N-(3-methoxy-2,6-dimethylphenyl)-1-methyl-1H- benzo[d]imidazol-4-amine (454.0 mg, 1.43 mmol) and Pd(dppf)Cl2 (204.0 mg, 0.22 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for additional 48 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (92 / 8, v / v) to afford 7- amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazo[4,5-g]indole-6- carbonitrile (182.0 mg, 18%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 346.2. Step 5: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carboxamide

[0218] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carbonitrile (182.0 mg, 0.53 mmol) in t-BuOH (4.0 mL) was added t-BuOK (142.0 mg, 1.04 mmol) and carbonylchlorohydridotris(triphenylphosphine)ruthenium(ii) (109.6 mg, 0.11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under O2. After the reaction was completed, the resulting mixture was diluted with water and extracted with 110 ny-2729143Attorney Docket No.18407-20019.40 CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-amino- 8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazo[4,5-g]indole-6- carboxamide (150.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=364.2. Step 6: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carboxamide (Compound 9)

[0219] A solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-g]indole-6-carboxamide (130.0 mg, crude) in HBr (3.0 mL, 40% in H2O) was stirred at 80 °C for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 6% B to 16% B in 10 min; Wave Length: 254 / 220 nm) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methylimidazo[4,5-g]indole-6-carboxamide (Compound 9) (8.7 mg, 7%) as a white solid. LCMS (ESI, m / z): [M+H]+= 350.2.1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 7.90 (s, 1H), 7.60 (s, 1H), 7.36 - 7.22 (m, 2H), 7.14 (s, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.44 (s, 2H), 3.81 (s, 3H), 1.80 (s, 3H), 1.71 (s, 3H). Example 10: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 10) Step 1: Synthesis of 3-bromo-2-chloro-5-nitropyridin-4-amine 111 ny-2729143Attorney Docket No.18407-20019.40

[0220] To a solution of 3-bromo-2-chloropyridin-4-amine (10.0 g, 48.20 mmol) in H2SO4(75.0 mL) was added KNO3(9.8 g, 96.40 mmol) at 0 °C. The resulting mixture was stirred at 90 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with water and then filtered. The solid was washed with water and dried to afford 3-bromo-2- chloro-5-nitropyridin-4-amine (9.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=251.9. Step 2: Synthesis of 5-bromo-6-chloropyridine-3,4-diamine

[0221] To a solution of 3-bromo-2-chloro-5-nitropyridin-4-amine (9.0 g, crude) in HOAc / H2O (90.0 mL / 9.0 mL) was added Fe (10.0 g, 178.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (40 / 60, v / v) to afford 5-bromo-6-chloropyridine-3,4-diamine (4.5 g, 56%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=221.9. Step 3: Synthesis of 7-bromo-6-chloro-3H-imidazo[4,5-c]pyridine

[0222] A solution of 5-bromo-6-chloropyridine-3,4-diamine (4.5 g, 20.22 mmol) in trimethoxymethane (40.0 mL) was stirred at 80 °C for 6 h. After the reaction was completed, 112 ny-2729143Attorney Docket No.18407-20019.40 the resulting mixture was concentrated under reduced pressure to afford 7-bromo-6-chloro- 3H-imidazo[4,5-c]pyridine (4.5 g, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+=231.9. Step 4: Synthesis of 7-bromo-6-chloro-3-methyl-3H-imidazo[4,5-c]pyridine

[0223] To a solution of 7-bromo-6-chloro-3H-imidazo[4,5-c]pyridine (4.5 g, crude) in DMF (45.0 mL) was added K2CO3 (8.0 g, 58.07 mmol) and CH3I (4.1 g, 29.04 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with H2O / ACN (60 / 40, v / v) to afford 7-bromo-6-chloro-3-methyl-3H-imidazo[4,5-c]pyridine (2.2 g, 46%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=245.9.1H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.56 (s,Step 5: Synthesis of 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3H- imidazo[4,5-c]pyridin-7-amine

[0224] To a solution of 7-bromo-6-chloro-3-methyl-3H-imidazo[4,5-c]pyridine (1.8 g, 7.30 mmol) in dioxane (40.0 mL) was added 3-methoxy-2,6-dimethylaniline (1.6 g, 10.95 mmol), Pd2(dba)3(1.3 g, 1.46 mmol), XantPhos (1.7 g, 2.92 mmol) and Cs2CO3(7.1 g, 21.91 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and 113 ny-2729143Attorney Docket No.18407-20019.40 extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (30 / 70, v / v) to afford 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3H- imidazo[4,5-c]pyridin-7-amine (1.7 g, 73%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=317.1. Step 6: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carbonitrile

[0225] To a solution of malononitrile (271.0 mg, 4.10 mmol) in DME (10.0 mL) were added t-BuONa (455.0 mg, 4.73 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h. Then 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3H-imidazo[4,5- c]pyridin-7-amine (500.0 mg, 1.58 mmol) and Pd(dppf)Cl2 (323.0 mg, 0.44 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at 100 °C for additional 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (20 / 80, v / v) to afford 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3- methyl-3,8-dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carbonitrile (400.0 mg, 73%) as a brown solid. LCMS (ESI, m / z): [M+H]+=347.2. Step 7: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 10) 114 ny-2729143Attorney Docket No.18407-20019.40

[0226] A solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3-methyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carbonitrile (50.0 mg, 0.14 mmol) in H2SO4 / H2O / MeSO2H (1.0 mL / 0.1 mL / 1.5 mL) was stirred at room temperature for 1.5 h. Then DL-methionine (71.8 mg, 0.48 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for additional 16 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 19x250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 3% B to 8% B in 10 min; Wave Length: 254 nm) to afford 7-amino-8-(3-hydroxy- 2,6-dimethylphenyl)-3-methyl-3,8-dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6- carboxamide (Compound 10) (5.3 mg, 10%) as a grey solid. LCMS (ESI, m / z): [M+H]+= 351.2.1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 8.60 (s, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.03(s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.44 (s, 2H), 3.89 (s, 3H), 1.77 (s, 3H), 1.69 (s, 3H). Example 11: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-c]pyrimidine-7-carboxamide (Compound 11) Step 1: Synthesis of tert-butyl 2-(5-bromo-6-chloropyrimidin-4-yl)hydrazine-1- carboxylate115 ny-2729143Attorney Docket No.18407-20019.40

[0227] To a solution of 5-bromo-4,6-dichloropyrimidine (10.0 g, 43.88 mmol) in THF (200.0 mL) was added tert-butyl hydrazinecarboxylate (7.0 g, 52.96 mmol) and TEA (14.0 g, 138.34 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford tert-butyl 2-(5-bromo-6-chloropyrimidin-4-yl)hydrazine-1-carboxylate (12.0 g, 84%) as a white solid. LCMS (ESI, m / z): [M+H]+=323.0. Step 2: Synthesis of 5-bromo-4-chloro-6-hydrazineylpyrimidine hydrochloride

[0228] A solution of tert-butyl 2-(5-bromo-6-chloropyrimidin-4-yl)hydrazine-1- carboxylate (12.0 g, 37.08 mmol) in HCl / 1,4-dioxane (200.0 mL, 4.0 mol / L) was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford 5-bromo-4-chloro-6-hydrazineylpyrimidine hydrochloride (7.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+=222.9. Step 3: Synthesis of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine

[0229] A solution of 5-bromo-4-chloro-6-hydrazineylpyrimidine hydrochloride (5.0 g, crude) in trimethoxymethane (50.0 mL) was stirred at 120 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford 8- 116 ny-2729143Attorney Docket No.18407-20019.40 bromo-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (3.8 g, 72%) as a white solid. LCMS (ESI, m / z): [M+H]+=232.9. Step 4: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3- c]pyrimidin-8-amine

[0230] To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-c]pyrimidine (500.0 mg, 2.14 mmol) in dioxane (10.0 ml) was added 3-methoxy-2,6-dimethylaniline (382.0 mg, 2.52 mmol), Pd-PEPPSI-IPentCl (110.0 mg, 0.21 mmol) and Cs2CO3(2.0 g, 6.40 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (75 / 25, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-8- amine (70.0 mg, 10%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=304.1. Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-c]pyrimidine-7-carbonitrile

[0231] To a solution of malononitrile (23.0 mg, 0.34 mmol) in DME (2.0 mL) was added t-BuONa (38.0 mg, 0.39 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-8- 117 ny-2729143Attorney Docket No.18407-20019.40 amine (40.0 mg, 0.13 mmol) and Pd(dppf)Cl2(27.0 mg, 0.03 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for additional 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-e][1,2,4]triazolo[4,3- c]pyrimidine-7-carbonitrile (25.0 mg, 56%) as a brown solid. LCMS (ESI, m / z): [M+H]+=334.1. Step 6: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-c]pyrimidine-7-carboxamide (Compound 11) O OH

[0232] A solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-c]pyrimidine-7-carbonitrile (13.0 mg, 0.03 mmol) in H2SO4 / H2O / MeSO2H (1.0 mL / 0.1 mL / 1.5 mL) was stirred at room temperature for 1.5 h. Then DL-methionine (23.2 mg, 0.15 mmol) was added to the mixture. The resulting mixture was stirred at 40 °C for additional 16 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm, Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 10% B to 20% B in 10 min; Wave Length: 254 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- e][1,2,4]triazolo[4,3-c]pyrimidine-7-carboxamide (Compound 11) (2.2 mg, 16%) as a white solid. LCMS (ESI, m / z): [M+H]+=338.0.1H NMR (400 MHz, DMSO-d6): δ 9.60 (s, 1H), 118 ny-2729143Attorney Docket No.18407-20019.40 9.53 (s, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 7.31 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.82 (s, 2H), 1.80 (s, 3H), 1.71 (s, 3H). Example 12: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide formate (Compound 12) Step 1: Synthesis of 5-bromo-6-chloro-3-iodopyrazin-2-amine

[0233] To a stirred solution of 5-bromo-6-chloropyrazin-2-amine (10.0 g, 47.95 mmol) in HOAc (100 mL) was added NIS (15.0 g, 66.65 mmol) and TFA (3.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (85 / 15, v / v) to afford 5- bromo-6-chloro-3-iodopyrazin-2-amine (12.0 g, 75%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 333.8. Step 2: Synthesis of 5-bromo-6-chloro-3-methylpyrazin-2-amine

[0234] To a solution of 5-bromo-6-chloro-3-iodopyrazin-2-amine (10.0 g, 29.90 mmol) in dioxane (150.0 mL) and H2O (50.0 mL) was added methylboronic acid (4.1 g, 66.66 mmol), Pd(dppf)Cl2 (2.5 g, 2.99 mmol, 0.10 equiv) and K2CO3 (12.4 g, 89.72 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (90 / 10, v / v) to afford 5-bromo-6-chloro-3-methylpyrazin-2-amine (3.6 g, 43%) as a yellow solid. LCMS (ESI, m / z): [M-H]- =221.9. 119 ny-2729143Attorney Docket No.18407-20019.40 Step 3: Synthesis of (E)-N'-(5-bromo-6-chloro-3-methylpyrazin-2-yl)-N,N- dimethylformimidamide

[0235] To a solution of 5-bromo-6-chloro-3-methylpyrazin-2-amine (3.6 g, 16.18 mmol) in MeOH (45.0 mL) was added DMF-DMA (5.0 g, 41.99 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 2 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was washed with Et2O and then filtered. The solid was collected and dried to afford (E)-N'-(5-bromo-6-chloro-3- methylpyrazin-2-yl)-N,N-dimethylformimidamide (3.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M-H]+=277.0. Step 4: Synthesis of (E)-N'-(5-bromo-6-chloro-3-methylpyrazin-2-yl)-N- hydroxymethanimidamide

[0236] To a solution of (E)-N'-(5-bromo-6-chloro-3-methylpyrazin-2-yl)-N,N- dimethylmethanimidamide (3.6 g, crude) in MeOH (50.0 mL) was added hydroxylamine hydrochloride (3.6 g, 51.94 mmol) at room temperature. The resulting mixture was stirred at 75 °C for 2 h. After the reaction was completed, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford (E)-N'-(5-bromo-6-chloro-3- methylpyrazin-2-yl)-N-hydroxymethanimidamide (3.5 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 264.9. Step 5: Synthesis of 6-bromo-5-chloro-8-methyl-[1,2,4]triazolo[1,5-a]pyrazine120 ny-2729143Attorney Docket No.18407-20019.40

[0237] A solution of (E)-N'-(5-bromo-6-chloro-3-methylpyrazin-2-yl)-N- hydroxymethanimidamide (2.7 g, crude) in PPA (25.0 mL) was stirred at 90 °C for 4 h. After the reaction was completed, the pH value of the resulting mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under vacuum. The residue was purified by flash column chromatography with ethyl acetate / petroleum ether (60 / 40, v / v) to afford 6-bromo-5-chloro-8-methyl- [1,2,4]triazolo[1,5-a]pyrazine (1.7 g, 68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 246.9. Step 6: Synthesis of 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methyl- [1,2,4]triazolo[1,5-a]pyrazin-5-amine

[0238] To a solution of 3-methoxy-2,6-dimethylaniline (920.1 mg, 6.3 mmol) in dioxane (55.0 mL) was added LiHMDS (12.3 mL, 1.0 mol / L in THF) at 0oC under N2.The mixture was stirred at 0oC for 20 min. Then 6-bromo-5-chloro-8-methyl-[1,2,4]triazolo[1,5- a]pyrazine (1.5 g, 6.1 mmol) in dioxane (20.0 mL) was added to the mixture at room temperature. The resulting mixture was stirred at 60 °C for additional 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (10 / 90, v / v) to afford 6-bromo-N-(3- methoxy-2,6-dimethylphenyl)-8-methyl-[1,2,4]triazolo[1,5-a]pyrazin-5-amine (400.0 mg, 18%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 362.1. Step 7: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile 121 ny-2729143Attorney Docket No.18407-20019.40

[0239] To a solution of malononitrile (260.0 mg, 3.60 mmol) in DME (15.0 mL) was added t-BuONa (489.0 mg, 5.07 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-8-methyl- [1,2,4]triazolo[1,5-a]pyrazin-5-amine (500.0 mg, 1.38 mmol) and Pd(dppf)Cl2 (221.0 mg, 0.26 mmol) were added to the mixture. The resulting mixture was stirred at 100 °C for additional 48 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (90 / 10, v / v) to afford 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (135.0 mg, 28%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 348.1. Step 8: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide

[0240] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carbonitrile (135.0 mg, 0.39 mmol) in t-BuOH (4.0 mL) was added t-BuOK (70.7 mg, 0.63 mmol) and carbonylchlorohydridotris(triphenylphosphine)ruthenium(ii) (114.9 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h under O2. After the reaction was completed, the resulting mixture was diluted with water and extracted with 122 ny-2729143Attorney Docket No.18407-20019.40 CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-amino- 8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H-pyrrolo[3,2-e][1,2,4]triazolo[1,5- a]pyrazine-6-carboxamide (90.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=366.2. Step 9: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide formate (Compound 12)

[0241] A solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide (80.0 mg, crude) in HBr (3.0 mL, 40% in H2O) was stirred at 80 °C for 2 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with ACN / H2O (0.1% FA) (40 / 60, v / v) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H-pyrrolo[3,2- e][1,2,4]triazolo[1,5-a]pyrazine-6-carboxamide formate (Compound 12) (8.9 mg, 11%) as a white solid. LCMS (ESI, m / z): [M+H]+= 352.1.1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.12 - 8.10 (m, 2H), 7.06 (d, J = 8.4 Hz,- 6.93 (m, 3H), 6.44 (s, 2H), 2.57 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H). Example 13: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 13) Step 1: Synthesis of 3-bromo-2-methylpyridine 1-oxide 123 ny-2729143Attorney Docket No.18407-20019.40

[0242] To a solution of 3-bromo-2-methylpyridine (50.0 g, 290.65 mmol) in DCM (1.2 L) was added m-CPBA (60.5 g, 350.60 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 4 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 3-bromo-2-methylpyridine 1-oxide (30.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 188.0. Step 2: Synthesis of 3-bromo-2-methyl-4-nitropyridine 1-oxide

[0243] To a solution of 3-bromo-2-methylpyridine 1-oxide (30.0 g, crude) in H2SO4 (180.0 mL) was added HNO3 (30.0 mL) at 0 °C. The resulting mixture was stirred at 80 °C for 4 h. After the reaction was completed, the pH value of the mixture was adjusted to 8.0 with saturated NaHCO3(aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 3-bromo-2-methyl-4- nitropyridine 1-oxide (18.0 g, 54%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 232.9. Step 3: Synthesis of 2-methyl-3-(methylamino)-4-nitropyridine 1-oxide

[0244] A solution of 3-bromo-2-methyl-4-nitropyridine 1-oxide (18.0 g, 77.25 mmol) in a solution of CH3NH2 in THF (154.0 mL, 4.0 mol / L) was stirred at room temperature for 8 h. 124 ny-2729143Attorney Docket No.18407-20019.40 After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford 2-methyl-3-(methylamino)-4-nitropyridine 1-oxide (12.0 g, crude) as a red solid. LCMS (ESI, m / z): [M+H]+= 184.1. Step 4: Synthesis of 6-chloro-2-methyl-3-(methylamino)-4-nitropyridine 1-oxide

[0245] To a solution of 2-methyl-3-(methylamino)-4-nitropyridine 1-oxide (10.1 g, crude) in DMF (400.0 mL) was added NCS (7.4 g, 55.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 6-chloro-2-methyl-3- (methylamino)-4-nitropyridine 1-oxide (6.0 g, 50%) as a red solid. LCMS (ESI, m / z): [M+H]+=218.0. Step 5: Synthesis of 6-chloro-N3,2-dimethylpyridine-3,4-diamine

[0246] To a solution of 6-chloro-2-methyl-3-(methylamino)-4-nitropyridine 1-oxide (6.0 g, 27.57 mmol) in EtOH / H2O (200.0 mL / 40.0 mL) were added Fe (6.8 g, 122.50 mmol) and NH4Cl (6.0 g, 112.24 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was diluted with H2O and extracted DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 6-chloro-N3,2-dimethylpyridine-3,4-diamine (7.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=172.1. 125 ny-2729143Attorney Docket No.18407-20019.40 Step 6: Synthesis of tert-butyl (4-amino-6-chloro-2-methylpyridin-3- yl)(methyl)carbamate

[0247] To a solution of 6-chloro-N3,2-dimethylpyridine-3,4-diamine (7.0 g, crude) in butan-1-ol (210.0 mL) was added Boc2O (6.0 g, 60.19 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford tert-butyl (4-amino-6- chloro-2-methylpyridin-3-yl)(methyl)carbamate (7.6 g, 68%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=272.1. Step 7: Synthesis of tert-butyl (4-amino-5-bromo-6-chloro-2-methylpyridin-3- yl)(methyl)carbamate

[0248] To a solution of tert-butyl (4-amino-6-chloro-2-methylpyridin-3- yl)(methyl)carbamate (7.6 g, 28.04 mmol) in toluene (200.0 mL) was added AcOH (7.0 mL) and NBS (6.1 g, 104.03 mmol) at room temperature. The resulting mixture was stirred at room temperature for 8 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford tert-butyl (4-amino-5-bromo-6-chloro-2-methylpyridin-3- yl)(methyl)carbamate (7.0 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 350.0. Step 8: Synthesis of 7-bromo-6-chloro-3,4-dimethyl-3H-imidazo[4,5-c]pyridine 126 ny-2729143Attorney Docket No.18407-20019.40

[0249] A solution of tert-butyl (4-amino-5-bromo-6-chloro-2-methylpyridin-3- yl)(methyl)carbamate (7.0 g, crude) in FA (140.0 mL) was stirred at 100 °C for 8 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 7-bromo-6-chloro-3,4-dimethyl-3H-imidazo[4,5-c]pyridine (3.0 g, 57%) as a white solid. LCMS (ESI, m / z): [M+H]+= 260.0. Step 9: Synthesis of 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3H- imidazo[4,5-c]pyridin-7-amine H2N

[0250] To a solution of 7-bromo-6-chloro-3,4-dimethyl-3H-imidazo[4,5-c]pyridine (500.0 mg, 1.92 mmol)) in dioxane (10.0 mL) was added 3-methoxy-2,6-dimethylaniline (550.0 mg, 3.64 mmol), Cs2CO3(400.0 mg, 1.23 mmol) and Pd-PEPPSI-IHeptCl 3- chloropyridine (300.0 mg, 0.36 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (3 / 1, v / v) to afford 6-chloro-N-(3- methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3H-imidazo[4,5-c]pyridin-7-amine (300.0 mg, 47%) as a white solid. LCMS (ESI, m / z): [M+H]+= 331.1. Step 10: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carbonitrile 127 ny-2729143Attorney Docket No.18407-20019.40

[0251] To a solution of malononitrile (156.0 mg, 2.36 mmol) in DME (10.0 mL) was added t-BuONa (262.0 mg, 2.73 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min under N2. Then 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl- 3H-imidazo[4,5-c]pyridin-7-amine (300.0 mg, 0.91 mmol) and Pd(dppf)Cl2.CH2Cl2(207.0 mg, 0.25 mmol) were added to the mixture at room temperature under N2. The resulting mixture was stirred at 100 °C for additional 16 h under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (3 / 1, v / v) to afford 7-amino-8-(3- methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8-dihydroimidazo[4,5-d]pyrrolo[3,2- b]pyridine-6-carbonitrile (100.0 mg, 30%) as a white solid. LCMS (ESI, m / z): [M+H]+= 361.2. Step 11: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide

[0252] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carbonitrile (100.0 mg, 0.28 mmol) in EtOH / H2O (2.0 mL / 0.5 mL) was added Ghaffar-Parkins catalyst (40.0 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h 128 ny-2729143Attorney Docket No.18407-20019.40 under N2. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8-dihydroimidazo[4,5- d]pyrrolo[3,2-b]pyridine-6-carboxamide (50.0 mg, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 379.2. Step 12: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 13)

[0253] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (50.0 mg, crude) in DCM (3.0 mL) was added a solution of BBr3 in DCM (3.0 mL, 1 mol / L) at 0oC. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3(aq.). The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 2 min, 4% B to 14% B in 10 min; Wave Length: 254 / 220 nm) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-3,4-dimethyl-3,8- dihydroimidazo[4,5-d]pyrrolo[3,2-b]pyridine-6-carboxamide (Compound 13) (11.7 mg, 23%) as a white solid. LCMS(ESI,m / z):[M+H]+=365.1.1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.95 - 6.89 (m, 2H), 6.32 (s, 2H), 4.04 (s, 3H), 2.93 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H). 129 ny-2729143Attorney Docket No.18407-20019.40 Example 14: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carboxamide formic acid (Compound 14) Step 1: Synthesis of Tert-butyl (4-chloro-6-methylpyridin-2-yl)carbamate

[0254] To a solution of 4-chloro-6-methylpyridin-2-amine (50.0 g, 350.66 mmol) in t- BuOH (500.0 mL) was added Boc2O (70.4 g, 322.57 mmol), TEA (106.5 g, 1051.97 mmol) and DMAP (3.1 g, 35.07 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford tert-butyl (4-chloro-6-methylpyridin-2- yl)carbamate (43.0 g, 45%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 243.1. Step 2: Synthesis of Tert-butyl (4-chloro-3-iodo-6-methylpyridin-2-yl)carbamate

[0255] To a solution of tert-butyl (4-chloro-6-methylpyridin-2-yl)carbamate (40.0 g, 165.30 mmol) in THF (800.0 mL) was added TMEDA (48.0 g, 413.00 mmol). Then n-BuLi (168.0 mL, 2.5 mol / L) was dropwise added to the mixture at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h under N2. Then a solution of I2 (52.0 g, 204.88 mmol) in THF (200.0 mL) was dropwise added to the mixture at -78°C under N2. The resulting mixture was stirred at at room temperature for additional 16 h under N2. After the reaction was completed, the resulting mixture was quenched with sodium bisulfite (aq.) at room temperature and then extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with 130 ny-2729143Attorney Docket No.18407-20019.40 petroleum ether / ethyl acetate (3 / 1, v / v) to afford tert-butyl (4-chloro-3-iodo-6-methylpyridin- 2-yl)carbamate (30.0 g, 49%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 369.0. Step 3: Synthesis of 4-chloro-3-iodo-6-methylpyridin-2-amine

[0256] To a solution of tert-butyl (4-chloro-3-iodo-6-methylpyridin-2-yl)carbamate (30.0 g, 81.51 mmol) in CH2Cl2(300.0 mL) was added TFA (100.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 8 with NaHCO3(aq.). The mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 4-chloro-3-iodo-6- methylpyridin-2-amine (20.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 268.9. Step 4: Synthesis of 7-chloro-8-iodo-5-methylimidazo[1,2-a]pyridine

[0257] To a solution of 4-chloro-3-iodo-6-methylpyridin-2-amine (20.0 g, crude) in EtOH (300.0 mL) was added 2-chloroacetaldehyde (20.0 g, 256.41 mmol) at room temperature. The resulting mixture was stirred at 80oC for 4 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was triturated with ethyl ether and then filtered. The solid was collected and dried to afford 7- chloro-8-iodo-5-methylimidazo[1,2-a]pyridine (13.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 292.9. Step 5: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2- a]pyridin-8-amine 131 ny-2729143Attorney Docket No.18407-20019.40

[0258] To a solution of 7-chloro-8-iodo-5-methylimidazo[1,2-a]pyridine (1.6 g, 5.47 mmol) in THF (30.0 mL) was added 3-methoxy-2,6-dimethylaniline (1.3 g, 8.60 mmol), t- BuOK (1.8 g, 16.04 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (460.0 mg, 0.55 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2- a]pyridin-8-amine (600.0 mg, 34%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 316.1. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carbonitrile

[0259] To a solution of malononitrile (525.0 mg, 7.95 mmol) in DMF (20.0 mL) was added t-BuONa (1.5 g, 15.86 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5- methylimidazo[1,2-a]pyridin-8-amine (500.0 mg, 1.58 mmol) and Pd(dppf)Cl2(498.0 mg, 0.68 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at at 150 °C for additional 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column 132 ny-2729143Attorney Docket No.18407-20019.40 chromatography with ACN / H2O (2 / 1, v / v) to afford 8-amino-9-(3-methoxy-2,6- dimethylphenyl)-5-methyl-9H-imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carbonitrile (22.0 mg, 4%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 346.2. Step 7: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carboxamide

[0260] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carbonitrile (22.0 mg, 0.06 mmol) in EtOH / H2O (1.0 mL / 0.3 mL) was added Ghaffar-Parkins catalyst (7.0 mg, 0.02 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino- 9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H-imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7- carboxamide (30.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 364.2. Step 8: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carboxamide formic acid (Compound 14)

[0261] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- imidazo[1,2-a]pyrrolo[2,3-c]pyridine-7-carboxamide (25.0 mg, crude) in DCM (3.0 mL) were added BBr3 (1.0 mL, 1.0 mol / L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C 133 ny-2729143Attorney Docket No.18407-20019.40 for 2 h. After the reaction was completed, the reaction mixture was quenched by MeOH at 0oC. The pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 2 min, 3% B to 13% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H-imidazo[1,2- a]pyrrolo[2,3-c]pyridine-7-carboxamide formic acid (Compound 14) (10.0 mg, 36%) as a white solid. LCMS (ESI, m / z): [M+H]+= 350.1.1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.38 (s, 1H), 7.20J = 0.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.80 (s, 2H), 6.31 - 6.29 (m, 2H), 2.51 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H). Example 15: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 15) Step 1: Synthesis of 2-hydrazinyl-6-methyl-3-nitropyridine

[0262] To a solution of 2-chloro-6-methyl-3-nitropyridine (20.0 g, 115.90 mmol) in EtOH (20.0 mL) was added NH2NH2.H2O (5.0 mL, 80%) at room temperature. The resulting mixture was stirred at 80 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was washed with ether and then filtered. The solid was collected and dried to afford 2-hydrazinyl-6-methyl-3-nitropyridine (21.0 g, crude) as a red solid. LCMS (ESI, m / z): [M+H]+= 169.1. Step 2: Synthesis of 5-methyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine134 ny-2729143Attorney Docket No.18407-20019.40

[0263] A solution of 2-hydrazinyl-6-methyl-3-nitropyridine (9.0 g, crude) in FA (150.0 mL) was stirred at 90 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford 5-methyl-8-nitro-[1,2,4]triazolo[1,5- a]pyridine (15.0 g, crude) as a red oil. LCMS (ESI, m / z): [M+H]+= 179.0. Step 3: Synthesis of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine and 5-methyl- [1,2,4]triazolo[4,3-a]pyridin-8-amine

[0264] To a solution of 5-methyl-8-nitro-[1,2,4]triazolo[1,5-a]pyridine (19.0 g, 106.65 mmol) in MeOH (500.0 mL) was added Pd / C (6.0 g, 10%) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under H2. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (12 / 1, v / v) to afford 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine (2.0 g, 12%) as a brown solid and 5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine (1.9 g, 12%) as a brown solid.

[0265] 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine: (more polar), LCMS (ESI, m / z): [M+H]+= 149.1.1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.58 - 6.56 (m, 1H), 5.67 (s, 2H), 2.55 (s, 3H).

[0266] 5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine: (less polar), LCMS (ESI, m / z): [M+H]+= 149.1.1H NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 6.52 - 6.50 (m, 1H), 6.25 - 6.23 (m, 1H), 5.75 (s, 2H), 2.52 (s, 3H). Step 4: Synthesis of 7-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine135 ny-2729143Attorney Docket No.18407-20019.40

[0267] To a solution of 5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine (6.7 g, 45.22 mmol) in ACN (160.0 mL) was added NBS (7.4 g, 41.58 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 7-bromo-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine (5.4 g, 52%) as an orange solid. LCMS (ESI, m / z): [M+H]+= 227.0. Step 5: Synthesis of 7-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine

[0268] To a solution of 7-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine (500.0 mg, 2.20 mmol) in dioxane (25.0 mL) was added 2-iodo-4-methoxy-1,3-dimethylbenzene (1.5 g, 5.72 mmol), Cs2CO3(2.7 g, 8.29 mmol), XantPhos (220.0 mg, 0.38 mmol) and Pd2(dba)3 (174.0 mg, 0.19 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 7-bromo-N-(3- methoxy-2,6-dimethylphenyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-amine (39.0 mg, 4%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 361.1. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile 136 ny-2729143Attorney Docket No.18407-20019.40

[0269] To a solution of malononitrile (68.0 mg, 1.03 mmol) in DME (10.0 mL) was added t-BuONa (98.0 mg, 1.02 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min. Then 7-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine (120.0 mg, 0.33 mmol) and Pd(dppf)Cl2.CH2Cl2(30.0 mg, 0.04 mmol) were added to the mixture at 0 °C under N2.The resulting mixture was stirred at 80 °C for additional 16 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 8-amino-9-(3- methoxy-2,6-dimethylphenyl)-5-methyl-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7- carbonitrile (80.0 mg, 69%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 347.2. Step 7: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide

[0270] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (80.0 mg, 0.23 mmol) in EtOH / H2O (2.3 mL / 0.6 mL) was added Ghaffar-Parkins catalyst (12.8 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8- amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5- 137 ny-2729143Attorney Docket No.18407-20019.40 a]pyridine-7-carboxamide (80.0 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 365.2. Step 8: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 15)

[0271] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (80.0 mg, crude) in DCM (4.0 mL) was added BBr3(1.3 mL, 1.0 mol / L in DCM) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 1 h under N2. After the reaction was completed, the reaction mixture was quenched by MeOH at 0oC. The mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 2 min, 13% B to 23% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 15) (3.2 mg, 4%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 351.1.1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H), 7.06 (d, J = 8.41H), 6.94 - 6.92 (m, 3H), 6.61 (s, 2H), 2.70 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H). Example 16: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carboxamide (Compound 16) Step 1: Synthesis of 1-amino-3-bromo-2-chloro-5-methylpyridin-1-ium 138 ny-2729143Attorney Docket No.18407-20019.40

[0272] To a solution of 3-bromo-2-chloro-5-methylpyridine (25.0 g, 121.08 mmol) in DCM (250.0 mL) was added amino 2,4,6-trimethylbenzenesulfonate (50.0 g, 232.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (10 / 1, v / v) to afford 1-amino-3-bromo-2-chloro-5-methylpyridin-1-ium (21.2 g, 77%) as a white solid. LCMS (ESI, m / z): [M]+= 220.9 Step 2: Synthesis of ethyl 6-bromo-7-chloro-4-methylpyrazolo[1,5-a]pyridine-3- carboxylate

[0273] To a solution of 1-amino-3-bromo-2-chloro-5-methylpyridin-1-ium (20.2 g, 89.90 mmol) in DMF (200.0 mL) was added ethyl propiolate (8.8 g, 89.70 mmol) and K2CO3 (10.0 g, 72.35 mmol) at 0 °C. The resulting mixture was stirred at 40 °C for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (10 / 1, v / v) to afford ethyl 6- bromo-7-chloro-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (4.1 g, 14%) as a white solid. LCMS (ESI, m / z): [M+H]+= 317.0 Step 3: Synthesis of 6-bromo-7-chloro-4-methylpyrazolo[1,5-a]pyridine 139 ny-2729143Attorney Docket No.18407-20019.40

[0274] A solution of ethyl 6-bromo-7-chloro-4-methylpyrazolo[1,5-a]pyridine-3- carboxylate (4.1 g, 0.31 mmol) in HCl (5.0 mL, 37% in H2O) was stirred at 80°C for 16 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3(aq.) at 0 °C. The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 6-bromo-7-chloro-4-methylpyrazolo[1,5- a]pyridine (4.1 g crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 244.9 Step 4: Synthesis of 6-bromo-N-(3-methoxy-2,6-dimethylphenyl)-4-methylpyrazolo[1,5- a]pyridin-7-amine

[0275] To a solution of 6-bromo-7-chloro-4-methylpyrazolo[1,5-a]pyridine (4.1 g, crude) in dioxane (80.0 mL) was added 3-methoxy-2,6-dimethylaniline (3.7 g, 24.60 mmol) and LiHMDS (49.2 mL, 1 mol / L in THF) at room temperature under N2. The resulting mixture was stirred at 60 °C for 1 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (12 / 1, v / v) to afford 6-bromo-N-(3-methoxy-2,6- dimethylphenyl)-4-methylpyrazolo[1,5-a]pyridin-7-amine (4.1 g, 67%) as an orange solid. LCMS (ESI, m / z): [M+H]+= 360.1. 140 ny-2729143Attorney Docket No.18407-20019.40 Step 5: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carbonitrile

[0276] To a solution of malononitrile (2.2 g, 32.69 mmol) in DMF (35.0 mL) was added t-BuOK (3.7 g, 33.15 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 0.5 h under N2. To the above mixture was added 6-bromo-N-(3- methoxy-2,6-dimethylphenyl)-4-methylpyrazolo[1,5-a]pyridin-7-amine (1.2 g, 3.33 mmol) and Pd(dppf)Cl2 (487.0 mg, 0.66 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for an additional 16 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 7-amino-8-(3- methoxy-2,6-dimethylphenyl)-4-methyl-8H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6- carbonitrile (160.3 mg, 14%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 346.2. Step 6: Synthesis of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carboxamide

[0277] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carbonitrile (160.3 mg, 0.46 mmol) in EtOH (4.0 mL) / H2O (1.0 mL) was added Ghaffar-Parkins catalyst (110.0 mg, 0.25 mmol) at room 141 ny-2729143Attorney Docket No.18407-20019.40 temperature under N2. The resulting mixture was stirred at 40 °C for 16 h under N2. After the reaction was completed, the mixture was concentrated under reduced pressure to afford 7- amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H-pyrazolo[1,5-a]pyrrolo[3,2- e]pyridine-6-carboxamide (160.1 mg, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 364.2. Step 7: Synthesis of 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carboxamide (Compound 16)

[0278] To a solution of 7-amino-8-(3-methoxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carboxamide (160.1 mg, crude) in DCM (5.0 mL) was added BBr3 (2.5 mL, 1 mol / L in DCM) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with MeOH at room temperature. The mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) and then purified by Prep-HPLC with the following conditions :( Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: water (0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 42% B in 10 min; wave length: 254 / 220 nm) to afford 7-amino-8-(3-hydroxy-2,6-dimethylphenyl)-4-methyl-8H- pyrazolo[1,5-a]pyrrolo[3,2-e]pyridine-6-carboxamide (Compound 16) (55.8 mg, 36%) as a light pink solid. LCMS (ESI, m / z): [M+H]+= 350.2.1H NMR (400 MHz, DMSO-d6): δ 9.46 (s, 1H), 7.71 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.83 (s, 2H), 6.47 (d, J = 2.4 Hz, 1H), 6.19 (s, 2H), 2.47 (s, 3H), 1.75 (s, 3H), 1.68 (s, 3H). 142 ny-2729143Attorney Docket No.18407-20019.40 Example 17: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (Compound 17) Step 1: Synthesis of 7-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine

[0279] To a solution of 5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine (7.5 g, 50.62 mmol) in ACN (200.0 mL) was added NBS (7.2 g, 40.45 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (12 / 1, v / v) to afford 7-bromo-5-methyl- [1,2,4]triazolo[4,3-a]pyridin-8-amine (2.6 g, 22%) as an orange solid. LCMS (ESI, m / z): [M+H]+= 227.0. Step 2: Synthesis of 7-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[4,3-a]pyridin-8-amine

[0280] To a solution of 7-bromo-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine (200.0 mg, 0.88 mmol) in dioxane (20.0 mL) was added 2-iodo-4-methoxy-1,3-dimethylbenzene (464.0 mg, 1.77 mmol), Cs2CO3 (860.0 mg, 2.64 mmol), XantPhos (920.0 mg, 1.59 mmol) and Pd2(dba)3(486.0 mg, 0.53 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 7-bromo-N-(3- 143 ny-2729143Attorney Docket No.18407-20019.40 methoxy-2,6-dimethylphenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-8-amine (20.0 mg, 6%) as a white solid. LCMS (ESI, m / z): [M+H]+= 361.1. Step 3: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile

[0281] To a solution of malononitrile (34.0 mg, 0.52 mmol) in DME (10.0 mL) was added t-BuONa (49.0 mg, 0.52 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 40 min. Then 7-bromo-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[4,3-a]pyridin-8-amine (60.0 mg, 0.17 mmol) and Pd(dppf)Cl2.CH2Cl2(15.0 mg, 0.02 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at 80 °C for additional 16 h under N2. After the reaction was completed. the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 8-amino-9-(3- methoxy-2,6-dimethylphenyl)-5-methyl-9H-pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7- carbonitrile (13.0 mg, 22%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 347.2. Step 4: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide

[0282] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (20.0 mg, 0.05 mmol) in EtOH / H2O (0.6 mL / 0.2 mL) was added Ghaffar-Parkins catalyst (4.1 mg, 0.01 mmol) at 144 ny-2729143Attorney Docket No.18407-20019.40 room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H-pyrrolo[2,3- c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (20.0 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 365.2. Step 5: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (Compound 17)

[0283] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (20.0 mg, crude) in DCM (2.0 mL) was added BBr3(0.7 mL, 1.0 mol / L in DCM) at 20 °C under N2. The resulting mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the reaction mixture was quenched with MeOH at 0 °C. The mixture was diluted with H2O and extracted with ethyl acetate. The water layer was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 3% B to 3% B in 2 min, 3% B to 13% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl- 9H-pyrrolo[2,3-c][1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (Compound 17) (2.0 mg, 10%) as a white solid. LCMS (ESI, m / z): [M+H]+= 351.0.1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 9.01 (s, 1H), 7.46 (s, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.96 - 6.90 (m, 3H), 6.46 (s, 2H), 2.67 (s, 3H), 1.81 - 1.60 (m, 6H). 145 ny-2729143Attorney Docket No.18407-20019.40 Example 18: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5- methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8-carboxamide (Compound 18) Step 1: Synthesis of 5-bromo-8-chloroimidazo[1,2-a]pyrazine

[0284] To a solution of 6-bromo-3-chloropyrazin-2-amine (5.0 g, 23.99 mmol) in H2O / THF (66.0 mL / 6.6 mL) was added 2-bromo-1,1-diethoxyethane (4.7 mL) at room temperature. The resulting mixture was stirred at 100 °C for 4 h. After the reaction was completed, the mixture was quenched with NaHCO3(aq.) at 0 °C and then filtered. The solids were collected and purified by flash column chromatography with petroleum ether / ethyl acetate (80 / 20, v / v) to afford 5-bromo-8-chloroimidazo[1,2-a]pyrazine (3.1 g, 55%) as a white solid. LCMS (ESI, m / z): [M+H]+=231.9. Step 2: Synthesis of 8-chloro-5-methylimidazo[1,2-a]pyrazine

[0285] To a solution of 5-bromo-8-chloroimidazo[1,2-a]pyrazine (4.0 g, 17.21 mmol) in 1,4-dioxane / H2O (80.0 mL / 16.0 mL) was added Pd(dppf)Cl2.CH2Cl2(1.4 g, 1.72 mmol), K2CO3(7.2 g, 52.10 mmol) and methylboronic acid (5.2 g, 86.04 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (45 / 55, v / v) to afford 8- chloro-5-methylimidazo[1,2-a]pyrazine (1.0 g, 35%) as a white solid. LCMS (ESI, m / z): [M+H]+=168.0. 146 ny-2729143Attorney Docket No.18407-20019.40 Step 3: Synthesis of 2-(3-methoxy-2,6-dimethylphenyl)-2-(5-methylimidazo[1,2- a]pyrazin-8-yl)acetonitrile

[0286] To a solution of 8-chloro-5-methylimidazo[1,2-a]pyrazine (300.0 mg, 1.79 mmol) in DMSO (10.0 mL) was added 2-(3-methoxy-2,6-dimethylphenyl)acetonitrile (400.0 mg, 2.28 mmol) and NaOH (300.0 mg, 7.50 mmol) at room temperature under N2. The resulting mixture was stirred at 80 °C for 2 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-(3-methoxy-2,6-dimethylphenyl)-2-(5- methylimidazo[1,2-a]pyrazin-8-yl)acetonitrile (500.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=307.1. Step 4: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2- a]pyrrolo[2,1-c]pyrazine-8-carbonitrile

[0287] To a solution of 2-(3-methoxy-2,6-dimethylphenyl)-2-{5-methylimidazo[1,2- a]pyrazin-8-yl}acetonitrile (500.0 mg, crude) in DMSO (10.0 mL) was added 2- bromoacetonitrile (580.0 mg, 4.84 mmol) and K2CO3(542.1 mg, 3.92 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column 147 ny-2729143Attorney Docket No.18407-20019.40 chromatography with petroleum ether / ethyl acetate (56 / 44, v / v) to afford 9-amino-10-(3- methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8-carbonitrile (170.0 mg, 30%) as a brown solid. LCMS (ESI, m / z): [M+H]+=346.2. Step 5: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2- a]pyrrolo[2,1-c]pyrazine-8-carboxamide

[0288] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8-carbonitrile (80.0 mg, 0.23 mmol) in EtOH / H2O (4.0 mL / 1.0 mL) was added Ghaffar-Parkins catalyst (10.0 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-amino-10-(3- methoxy-2,6-dimethylphenyl)-5-methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8-carboxamide (90.1 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+=364.2. Step 6: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5-methylimidazo[1,2- a]pyrrolo[2,1-c]pyrazine-8-carboxamide (Compound 18)

[0289] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8-carboxamide (80.0 mg, crude) in DCM (5.0 148 ny-2729143Attorney Docket No.18407-20019.40 mL) was added BBr3(2.0 mL, 1.0 mol / L in DCM) at room temperature. The resulting mixture was stirred at room temperature for 2 h. After the reaction was completed, the resulting mixture was diluted with NaHCO3 (aq.) and then extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column 19x250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 3% B to 30% B in 10 min; Wave Length: 254 nm) to afford 9-amino-10- (3-hydroxy-2,6-dimethylphenyl)-5-methylimidazo[1,2-a]pyrrolo[2,1-c]pyrazine-8- carboxamide (Compound 18) (18.6 mg, 24%) as an off-white solid. LCMS (ESI, m / z): [M+H]+=350.1.1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.64 (s, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.24 (d, J = 0.8 Hz, 1H), 7.16 (s, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 4.32 (s, 2H), 2.45 (s, 3H), 1.85 (s, 3H), 1.79 (s, 3H). Example 19: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine-8-carboxamide (Compound 19) Step 1: Synthesis of (E)-N'-(6-bromo-3-chloropyrazin-2-yl)-N,N- dimethylmethanimidamide

[0290] To a solution of 6-bromo-3-chloropyrazin-2-amine (20.0 g, 95.95 mmol) in EtOH (200.0 mL) was added DMF-DMA (35.0 g, 293.71 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford (E)-N'-(6-bromo-3-chloropyrazin-2-yl)- N,N-dimethylmethanimidamide (25.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 263.0. Step 2: Synthesis of (E)-N'-(6-bromo-3-chloropyrazin-2-yl)-N- hydroxymethanimidamide 149 ny-2729143Attorney Docket No.18407-20019.40

[0291] To a solution of (E)-N'-(6-bromo-3-chloropyrazin-2-yl)-N,N- dimethylmethanimidamide (25.0 g, crude) in MeOH (500.0 mL) was added NH2OH.HCl (20.0 g, 287.81 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford (E)-N'-(6-bromo-3-chloropyrazin-2-yl)-N-hydroxymethanimidamide (25.0 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 250.9. Step 3: Synthesis of 5-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazine

[0292] To a solution of (E)-N'-(6-bromo-3-chloropyrazin-2-yl)-N- hydroxymethanimidamide (25.0 g, crude) in THF (500.0 mL) was added TFAA (150.0 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was adjusted to pH=7 with saturated NaHCO3(aq.). The mixture was filtered. The solids were collected and dried to afford 5-bromo-8-chloro- [1,2,4]triazolo[1,5-a]pyrazine (9.0 g, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 232.9. Step 4: Synthesis of 8-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrazine

[0293] To a solution of 5-bromo-8-chloro-[1,2,4]triazolo[1,5-a]pyrazine (8.0 g, crude) in 1,4-dioxane / H2O (260.0 mL / 65.0 mL) was added methylboronic acid (11.9 g, 198.80 mmol), K3PO4(23.0 g, 108.36 mmol) and DPEphos Pd G3 (2.4 g, 3.35 mmol) at room temperature 150 ny-2729143Attorney Docket No.18407-20019.40 under N2. The resulting mixture was stirred at 80 °C for 4 h under N2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (12 / 1, v / v) to afford 8-chloro-5- methyl-[1,2,4]triazolo[1,5-a]pyrazine (2.0 g, 34%) as a white solid. LCMS (ESI, m / z): [M+H]+= 169.0. Step 5: Synthesis of 2-(3-methoxy-2,6-dimethylphenyl)-2-{5-methyl-[1,2,4]triazolo[1,5- a]pyrazin-8-yl}acetonitrile

[0294] To a solution of 8-chloro-5-methyl-[1,2,4]triazolo[1,5-a]pyrazine (412.0 mg, 2.44 mmol) in DMSO (20.0 mL) was added 2-(3-methoxy-2,6-dimethylphenyl)acetonitrile (644.0 mg, 3.68 mmol) and NaOH (392.0 mg, 9.80 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 2-(3-methoxy-2,6- dimethylphenyl)-2-{5-methyl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl}acetonitrile (430.0 mg, 57%) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 308.1. Step 6: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[5,1-c]pyrazine-8-carbonitrile151 ny-2729143Attorney Docket No.18407-20019.40

[0295] To a solution of 2-(3-methoxy-2,6-dimethylphenyl)-2-{5-methyl- [1,2,4]triazolo[1,5-a]pyrazin-8-yl}acetonitrile (420.0 mg, 1.37 mmol) in DMSO (10.0 mL) was added 2-bromoacetonitrile (330.0 mg, 2.75 mmol) and K2CO3 (620.0 mg, 4.49 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[5,1-c]pyrazine-8-carbonitrile (50.0 mg, 10%) as a brown oil. LCMS (ESI, m / z): [M+H]+= 347.2. Step 7: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[5,1-c]pyrazine-8-carboxamide

[0296] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine-8-carbonitrile (40.0 mg, 0.12 mmol) in EtOH / H2O (3.2 mL / 0.8 mL) was added Ghaffar-Parkins catalyst (11.0 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[5,1-c]pyrazine-8-carboxamide (50.0 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 365.2. Step 8: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[5,1-c]pyrazine-8-carboxamide (Compound 19) 152 ny-2729143Attorney Docket No.18407-20019.40

[0297] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[5,1-c]pyrazine-8-carboxamide (40.0 mg, crude) in DCM (3.0 mL) was added BBr3(1.5 mL, 1.0 mol / L in CH2Cl2) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 16% B to 26% B in 10 min; Wave Length: 254 nm) to afford 9- amino-10-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2-a][1,2,4]triazolo[5,1- c]pyrazine-8-carboxamide (Compound 19) (5.6 mg, 14%) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 351.2.1H NMR (400 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.84 (s, 1H), 8.20 (s, 1H), 7.32 (s, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.0 Hz 1H), 4.49 (s, 2H), 2.55 (s, 3H), 1.86 - 1.80 (m, 6H). Example 20: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazine-8-carboxamide (Compound 20) Step 1: Synthesis of Tert-butyl 2-(6-bromo-3-chloropyrazin-2-yl)hydrazine-1- carboxylate

[0298] To a solution of 3,5-dibromo-2-chloropyrazine (27.0 g, 99.15 mmol) in THF (500.0 mL) was added DIEA (34.0 g, 263.06 mmol) and tert-butoxycarbohydrazide (13.0 g, 153 ny-2729143Attorney Docket No.18407-20019.40 98.36 mmol) at room temperature. The resulting mixture was stirred at 70 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford tert-butyl 2-(6-bromo-3-chloropyrazin-2-yl)hydrazine-1-carboxylate (15.0 g, 46%) as a colorless oil. LCMS (ESI, m / z): [M+H]+= 323.0. Step 2: Synthesis of 5-bromo-2-chloro-3-hydrazineylpyrazine

[0299] To a solution of N'-(6-bromo-3-chloropyrazin-2-yl)tert-butoxycarbohydrazide (7.0 g, 21.63 mmol) in CH2Cl2 (100.0 mL) was added TFA (50.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. the pH of the residue was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to 5-bromo-2-chloro-3- hydrazineylpyrazine (6.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 222.9. Step 3: Synthesis of 5-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine

[0300] A solution of 5-bromo-2-chloro-3-hydrazinylpyrazine (6.0 g, crude) in trimethoxymethane (100.0 mL) was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was triturated with H2O and then filtered. The solid was collected and dried to afford 5-bromo-8- chloro-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 232.9. 154 ny-2729143Attorney Docket No.18407-20019.40 Step 4: Synthesis of 8-chloro-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine

[0301] To a solution of 5-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (2.0 g, 8.57 mmol) in dioxane / H2O (40.0 mL / 4.0 mL) was added methylboronic acid (2.5 g, 41.76 mmol), K2CO3(3.5 g, 25.32 mmol) and Pd(dppf)Cl2(1.4 g, 1.71 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 10, v / v) to afford 8- chloro-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (100.0 mg, 34%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 169.0. Step 5: Synthesis of 2-(3-methoxy-2,6-dimethylphenyl)-2-(5-methyl-[1,2,4]triazolo[4,3- a]pyrazin-8-yl)acetonitrile

[0302] To a solution of 8-chloro-5-methyl-[1,2,4]triazolo[4,3-a]pyrazine (100 mg, 0.593 mmol) in DMSO (5.0 mL) was added 2-(3-methoxy-2,6-dimethylphenyl)acetonitrile (156.0 mg, 0.89 mmol) and NaOH (90.0 mg, 2.25 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 1 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 9, v / v) to afford 2-(3-methoxy-2,6-dimethylphenyl)-2-(5- 155 ny-2729143Attorney Docket No.18407-20019.40 methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)acetonitrile (100.0 mg, 43%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 308.1. Step 6: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[3,4-c]pyrazine-8-carbonitrile

[0303] To a solution of 2-(3-methoxy-2,6-dimethylphenyl)-2-{5-methyl- [1,2,4]triazolo[4,3-a]pyrazin-8-yl}acetonitrile (80.0 mg, 0.26 mmol) in DMSO (5.0 mL) was added K2CO3(120 mg, 0.86 mmol) and 2-bromoacetonitrile (92.0 mg, 0.76 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 10, v / v) to afford 9- amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2-a][1,2,4]triazolo[3,4- c]pyrazine-8-carbonitrile (60.0 mg, 53%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 347.2. Step 7: Synthesis of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[3,4-c]pyrazine-8-carboxamide

[0304] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazine-8-carbonitrile (60.0 mg, 0.17 mmol) in EtOH / H2O (2.0 mL / 0.7 mL) was added Ghaffar-Parkins catalyst (15.0 mg, 0.04 mmol) at 156 ny-2729143Attorney Docket No.18407-20019.40 room temperature under N2. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 9- amino-10-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2-a][1,2,4]triazolo[3,4- c]pyrazine-8-carboxamide (50.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 365.2. Step 8: Synthesis of 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[1,2- a][1,2,4]triazolo[3,4-c]pyrazine-8-carboxamide (Compound 20)

[0305] To a solution of 9-amino-10-(3-methoxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazine-8-carboxamide (40.0 mg, crude) in DCM (3.0 mL) were added a solution of BBr3in CH2Cl2(1.0 mL, 1.0 mol / L) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction mixture was quenched by MeOH at 0 °C. The pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep Phenyl OBD Column 19x250 mm, 5 um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 10% B to 20% B in 10 min; Wave Length: 254 / 220 nm) to afford 9-amino-10-(3-hydroxy-2,6-dimethylphenyl)-5- methylpyrrolo[1,2-a][1,2,4]triazolo[3,4-c]pyrazine-8-carboxamide (Compound 20) (3.7 mg, 9%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 351.1.1H NMR (400 MHz, DMSO-d6): δ 9.15 - 9.05 (m, 2H), 8.56 (s, 1H), 7.31 (s, 2H), 6.96 (d, J1H), 4.44 (s, 2H), 1.88 (s, 3H), 1.81 (s, 3H), 1.76 (s, 3H). 157 ny-2729143Attorney Docket No.18407-20019.40 Example 21: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carboxamide (Compound 21) Step 1: Synthesis of 5-methylquinolin-8-amine

[0306] To a solution of 5-bromoquinolin-8-amine (16.0 g, 71.73 mmol) in DMF (300.0 mL) was added LiCl (8.7 g, 205.24 mmol), tetramethyltin (12.4 g, 69.56 mmol), XPhos (6.6 g, 13.84 mmol) and XPhos Pd G3 (5.8 g, 6.91 mmol) at room temperature under N2. The resulting mixture was stirred at 70 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 5-methylquinolin-8- amine (7.0 g, 49%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 159.1. Step 2: Synthesis of 7-chloro-5-methylquinolin-8-amine

[0307] To a solution of 5-methylquinolin-8-amine (1.3 g, 8.09 mmol) in DMF (50.0 mL) was added NCS (1.1 g, 8.09 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 7-chloro-5-methylquinolin-8-amine (500.0 mg, 32%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 193.0. Step 3: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylquinolin-8- amine 158 ny-2729143Attorney Docket No.18407-20019.40 O O

[0308] To a solution of 7-chloro-5-methylquinolin-8-amine (200.0 mg, 1.04 mmol) in ACN (10.0 mL) was added 3-methoxy-2,6-dimethylphenylboronic acid (700.0 mg, 3.89 mmol), TEA (300.0 mg, 2.97 mmol) and Cu(acac)2 (480.0 mg, 1.83 mmol) at room temperature under O2. The resulting mixture was stirred at 80 °C for 16 h under O2. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / DCM (3 / 1, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methylquinolin-8-amine (130.0 mg, 38%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 327.1. Step 4: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carbonitrile

[0309] To a solution of malononitrile (320.0 mg, 4.84 mmol) in DME (20.0 mL) was added t-BuONa (540.0 mg, 5.62 mmol) at 0 °C under N2. The resulting mixture was stirred at 0 °C for 0.5 h under N2. Then 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5- methylquinolin-8-amine (600.0 mg, 1.84 mmol) and Pd(dppf)Cl2.CH2Cl2 (419.0 mg, 0.51 mmol) were added to the mixture at 0 °C under N2. The resulting mixture was stirred at 100 °C for additional 72 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / DCM (1 / 1, v / v) to afford 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5- 159 ny-2729143Attorney Docket No.18407-20019.40 methylpyrrolo[3,2-h]quinoline-3-carbonitrile (20.0 mg, 3%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 357.2. Step 5: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carboxamide

[0310] To a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carbonitrile (15.0 mg, 0.04 mmol) in EtOH / H2O (1.5 mL / 0.3 mL) was added Ghaffar-Parkins catalyst (5.0 mg, 0.01 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino-1-(3-methoxy-2,6- dimethylphenyl)-5-methylpyrrolo[3,2-h]quinoline-3-carboxamide (10.0 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 375.2. Step 6: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carboxamide (Compound 21)

[0311] To a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2- h]quinoline-3-carboxamide (10.0 mg, crude) in DCM (1.0 mL) was added a solution of BBr3in DCM (0.5 mL, 1 mol / L) at 0 °C under N2. The resulting mixture was stirred at room 160 ny-2729143Attorney Docket No.18407-20019.40 temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 14% B to 24% B in 10 min; Wave Length: 254 / 220 nm) to afford 2-amino-1- (3-hydroxy-2,6-dimethylphenyl)-5-methylpyrrolo[3,2-h]quinoline-3-carboxamide (Compound 21) (1.2 mg, 6%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 361.0.1H NMR (400 MHz, DMSO-d6): δ 8.31 - 8.23 (m, 3H), 7.98 (s, 1H), 7.20 - 7.17 (m, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.90 - 6.74 (m, 3H), 6.31 (s, 2H), 2.69 (s, 3H), 1.71 (s, 3H), 1.63 (s, 3H). Example 22: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carboxamide (Compound 22) Step 1: Synthesis of 7-chloro-1,6-naphthyridin-5-amine

[0312] A solution of 5,7-dichloro-1,6-naphthyridine (13.0 g, 65.32 mmol) in NH3 / isopropanol (340.0 mL, 3.5 mol / L) was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (5 / 1, v / v) to afford 7-chloro- 1,6-naphthyridin-5-amine (11.0 g, 93%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 180.0. Step 2: Synthesis of 8-bromo-7-chloro-1,6-naphthyridin-5-amine

[0313] To a solution of 7-chloro-1,6-naphthyridin-5-amine (11.0 g, 61.24 mmol) in ACN (250.0 mL) was added NBS (10.8 g, 60.68 mmol) at room temperature. The resulting mixture 161 ny-2729143Attorney Docket No.18407-20019.40 was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with CH2Cl2 / MeOH (9 / 1, v / v) to afford 8-bromo-7-chloro-1,6-naphthyridin- 5-amine (9.6 g, 60%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 257.9. Step 3: Synthesis of 8-bromo-7-chloro-5-iodo-1,6-naphthyridine

[0314] To a solution of 8-bromo-7-chloro-1,6-naphthyridin-5-amine (9.6 g, 37.25 mmol) in ACN (140.0 mL) was added CH2I2(22.3 g, 83.26 mmol) and t-BuNO2(12.4 g, 120.25 mmol) at 0 °C under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ethyl / ethyl acetate (3 / 1, v / v) to afford 8-bromo-7-chloro-5-iodo-1,6-naphthyridine (6.5 g, 47%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 368.8. Step 4: Synthesis of 8-bromo-7-chloro-5-methyl-1,6-naphthyridine

[0315] To a solution of 8-bromo-7-chloro-5-iodo-1,6-naphthyridine (5.3 g, 14.43 mmol) in dioxane / H2O (182.0 mL / 10.0 mL) was added methylboronic acid (5.2 g, 86.87 mmol), K2CO3 (6.3 g, 45.45 mmol) and Pd(dppf)Cl2.CH2Cl2 (2.3 g, 2.89 mmol) at room temperature under N2. The resulting mixture was stirred at 60 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and 162 ny-2729143Attorney Docket No.18407-20019.40 filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ethyl / ethyl acetate (9 / 1, v / v) to afford 8-bromo- 7-chloro-5-methyl-1,6-naphthyridine (2.5 g, 67%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 256.9. Step 5: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1,6- naphthyridin-8-amine

[0316] To a solution of 8-bromo-7-chloro-5-methyl-1,6-naphthyridine (1.0 g, 3.88 mmol) in dioxane (30.0 mL) was added 3-methoxy-2,6-dimethylaniline (958.0 mg, 6.34 mmol), Cs2CO3(3.8 g, 11.66 mmol) and Pd-PEPPSI-IHeptCl 3-chloropyridine (341.0 mg, 0.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1,6-naphthyridin- 8-amine (800.0 mg, 62 %) as a brown solid. LCMS (ESI, m / z): [M+H]+= 328.1. Step 6: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carbonitrile163 ny-2729143Attorney Docket No.18407-20019.40

[0317] To a solution of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1,6- naphthyridin-8-amine (500.0 mg, 1.53 mmol) in DMF (25.0 mL) was added malononitrile (268.0 mg, 4.06 mmol), K2CO3 (1.07 g, 7.75 mmol) and Pd(dppf)Cl2.CH2Cl2 (223.2 mg, 0.31 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1, v / v) to afford 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2- h][1,6]naphthyridine-3-carbonitrile (422.0 mg, 77%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 358.2. Step 7: Synthesis of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carboxamide

[0318] To a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carbonitrile (422.0 mg, 1.18 mmol) in EtOH / H2O (10.0 mL / 2.0 mL) was added Ghaffar-Parkins catalyst (160.0 mg, 0.38 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 2-amino- 1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h][1,6]naphthyridine-3- carboxamide (201.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 376.2. Step 8: Synthesis of 2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carboxamide (Compound 22) 164 ny-2729143Attorney Docket No.18407-20019.40

[0319] To a solution of 2-amino-1-(3-methoxy-2,6-dimethylphenyl)-5-methyl-1H- pyrrolo[3,2-h][1,6]naphthyridine-3-carboxamide (190.0 mg, crude) in DCM (10.0 mL) was added a solution of BBr3 in DCM (5.0 mL, 1 mol / L) at 0 °C. The resulting mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was quenched with water. The pH of the mixture was adjusted to 8 with NaHCO3(aq.). The mixture was extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1 % FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 27% B to 37% B in 10 min; Wave Length: 254 / 220 nm) to afford 2-amino-1-(3-hydroxy-2,6- dimethylphenyl)-5-methyl-1H-pyrrolo[3,2-h][1,6]naphthyridine-3-carboxamide (Compound 22) (22.5 mg, 12%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 362.2.1H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.58 - 8.46 (m, 2H), 8.22 (s, 1H), 7.34 - 6.86 (m, 4H), 6.47 (s, 2H), 2.94 (s, 3H), 1.74 - 1.66 (m, 6H). Example 23: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carboxamide (Compound 23) Step 1: Synthesis of 3-bromo-4-chloro-2-nitroaniline

[0320] To a solution of 3-bromo-2-nitroaniline (25.0 g, 115.19 mmol) in DMF (250.0 mL) was added NCS (16.9 g, 126.71 mmol) at room temperature. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with 165 ny-2729143Attorney Docket No.18407-20019.40 brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 3-bromo-4-chloro-2-nitroaniline (20.0 g, 69%) as a red solid. LCMS (ESI, m / z): [M+H]+= 250.9. Step 2: Synthesis of 3-bromo-4-chlorobenzene-1,2-diamine

[0321] To a solution of 3-bromo-4-chloro-2-nitroaniline (18.0 g, 71.58 mmol) in MeOH (40.0 mL) / H2O (200.0 mL) was added NH4Cl (12.5 g, 80.13 mmol) and Fe (12.0 g, 80.13 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1, v / v) to afford 3-bromo-4-chlorobenzene-1,2-diamine (15.0 g, 83%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 220.9. Step 3: Synthesis of 5-bromo-6-chloroquinoxaline

[0322] To a solution of 3-bromo-4-chlorobenzene-1,2-diamine (14.0 g, 63.21 mmol) in EtOH (100.0 mL) was added 1,4-dioxane-2,3-diol (10.5 g, 87.42 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was filtered. The solid was washed with EtOH and then collected to afford 5-bromo-6-chloroquinoxaline (8.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 243.1. Step 4: Synthesis of 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)quinoxalin-5-amine 166 ny-2729143Attorney Docket No.18407-20019.40 O

[0323] To a solution of 5-bromo-6-chloroquinoxaline (1.0 g, crude) in dioxane (20.0 mL) was added 3-methoxy-2,6-dimethylaniline (750.0 mg, 4.96 mmol), Cs2CO3(4.0 g, 12.28 mmol) and Pd-PEPPSI-IPentCl 2-methylpyridine (o-picoline) (345.0 mg, 0.41 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)quinoxalin-5-amine (600.0 mg, 46%) as a yellow green solid. LCMS (ESI, m / z): [M+H]+= 314.1. Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carbonitrile

[0324] To a solution of 6-chloro-N-(3-methoxy-2,6-dimethylphenyl)quinoxalin-5-amine (200.0 mg, 0.63 mmol) in DMF (10.0 mL) was added malononitrile (140.0 mg, 2.11 mmol), K2CO3(260.0 mg, 1.88 mmol) and Pd(dppf)Cl2(95.0 mg, 0.13 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 8-amino- 167 ny-2729143Attorney Docket No.18407-20019.40 9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[2,3-f]quinoxaline-7-carbonitrile (120.0 mg, 54%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 344.1. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carboxamide

[0325] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carbonitrile (110.0 mg, 0.32 mmol) in EtOH (4.0 mL) / H2O (1.0 mL) was added Ghaffar-Parkins catalyst (27.0 mg, 0.06 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-9-(3- methoxy-2,6-dimethylphenyl)pyrrolo[2,3-f]quinoxaline-7-carboxamide (110.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 362.2. Step 7: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carboxamide (Compound 23)

[0326] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[2,3- f]quinoxaline-7-carboxamide (100.0 mg, crude) in DCM (3.0 mL) were added a solution of BBr3in CH2Cl2(1.0 mL, 1.0 mol / L) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. 168 ny-2729143Attorney Docket No.18407-20019.40 After the reaction was completed, the reaction mixture was quenched by MeOH at 0 °C. The mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: XBridge Prep OBD C18 Column, 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 35% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-amino-9-(3-hydroxy-2,6- dimethylphenyl)pyrrolo[2,3-f]quinoxaline-7-carboxamide (Compound 23) (51.4 mg, 53%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 348.1.1H NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1H), 8.56 (s, 1H), 8.38 - 8.34 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.07 - 6.91 (m, 4H), 6.51 (s, 2H), 1.72 (s, 3H), 1.64 (s, 3H). Example 24: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carboxamide (Compound 24) Step 1: Synthesis of tert-butyl quinazolin-8-ylcarbamate

[0327] To a solution of 8-bromoquinazoline (13.0 g, 62.19 mmol) in dioxane (200.0 mL) was added NH2Boc (21.9 g, 186.56 mmol), K2CO3 (25.8 g, 186.56 mmol), Xphos (11.9 g, 24.87 mmol) and Pd(OAc)2 (2.8 g, 12.44 mmol) at room temperature under N2. The resultingmixture was stirred at 100 °C for 4 h under N2. After the reaction was completed, the mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford tert-butyl quinazolin- 8-ylcarbamate (15.0 g, 80%) as a purple solid. LCMS (ESI, m / z): [M+H]+ = 246.1. Step 2: Synthesis of quinazolin-8-amine 169 ny-2729143Attorney Docket No.18407-20019.40

[0328] To a solution of tert-butyl quinazolin-8-ylcarbamate (15.0 g, 61.15mmol) in CH2Cl2 (100.0 mL) was added TFA (100.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with CH2Cl2. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford quinazolin-8-amine (6.2 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 146.1. Step 3: Synthesis of 7-chloroquinazolin-8-amine

[0329] To a solution of quinazolin-8-amine (6.2 g, crude) in CHCl3 (150.0 mL) was added NCS (5.7 g, 42.70 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) and then purified by Prep-ACHIRAL-SFC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 8% B to 18% B in 10 min; Wave Length: 254 / 220 nm) to afford 7- chloroquinazolin-8-amine (1.6 g, 20%) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 180.0. Step 4: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)quinazolin-8-amine 170 ny-2729143Attorney Docket No.18407-20019.40

[0330] To a solution of 7-chloroquinazolin-8-amine (1.6 g, 8.91 mmol) in CH2Cl2 (50.0 mL) was added Cu(OAc)2 (0.9 g, 4.45 mmol), TEA (2.7 g, 26.72 mmol) and 3-methoxy-2,6- dimethylphenylboronic acid (4.0 g, 22.27 mmol) at room temperature under O2. The resulting mixture was stirred at room temperature for 48 h under O2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 7-chloro- N-(3-methoxy-2,6-dimethylphenyl)quinazolin-8-amine (520.0 mg, 18%) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 314.1. Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carbonitrile

[0331] To a solution of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)quinazolin-8-amine (460.0 mg, 1.47 mmol) in DMF (15.0 mL) were added malononitrile (290.5 mg, 4.40 mmol), K2CO3 (1.0 g, 7.33 mmol) and Pd(dppf)Cl2 (214.5 mg, 0.29 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (2 / 1, v / v) to afford 8-amino- 171 ny-2729143Attorney Docket No.18407-20019.40 9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[3,2-h]quinazoline-7-carbonitrile (250.0 mg, 49%) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 344.1. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carboxamide

[0332] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carbonitrile (100.0 mg, 0.29 mmol) in EtOH / H2O (4.0 mL / 1.0 mL) were added Ghaffar-Parkins catalyst (37.0 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-9-(3- methoxy-2,6-dimethylphenyl)pyrrolo[3,2-h]quinazoline-7-carboxamide (100.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 362.2. Step 7: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carboxamide (Compound 24)

[0333] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)pyrrolo[3,2- h]quinazoline-7-carboxamide (90.0 mg, crude) in DCM (6.0 mL) were added BBr3 (2.0 mL, 1.0 mol / L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the 172 ny-2729143Attorney Docket No.18407-20019.40 reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: (Column: Xselect CSH C18 OBD Column 30x150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 2 min, 8% B to 18% B in 10 min; Wave Length: 254 / 220 nm) to afford 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)pyrrolo[3,2-h]quinazoline- 7-carboxamide (Compound 24) (37.1 mg, 42%) as a yellow solid. LCMS (ESI, m / z): [M+H]+ = 348.1. 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.31 (s, 1H), 8.68 (s, 1H), 8.23 - 8.18 (m, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.08 - 7.05 (m, 3H), 6.92 (d, J = 8.4 Hz, 1H), 6.65 (s, 2H), 1.72 (s, 3H), 1.64 (s, 3H). Example 25: Synthesis of 7-amino-4-cyclopropyl-8-(3-hydroxy-2,6-dimethylphenyl)-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 25) Step 1: Synthesis of 3-bromo-2-chloro-5-cyclopropylpyridine

[0334] To a solution of 3-bromo-2-chloro-5-iodopyridine (20.0 g, 62.82 mmol) in toluene / H2O (200.0 mL / 40.0 mL) were added cyclopropylboronic acid (5.4 g, 62.82 mmol), K2CO3(26.0 g, 188.47 mmol) and Pd(dppf)Cl2(4.6 g, 6.28 mmol) at room temperature under N2. The resulting mixture was stirred at 90 °C for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (5 / 1, v / v) to afford 3-bromo- 2-chloro-5-cyclopropylpyridine (7.0 g, 47%) as an colorless oil. LCMS (ESI, m / z): [M+H]+= 231.9. Step 2: Synthesis of 3-bromo-2-chloro-5-cyclopropylpyridine 1-oxide 173 ny-2729143Attorney Docket No.18407-20019.40

[0335] To a solution of 3-bromo-2-chloro-5-cyclopropylpyridine (6.5 g, 27.95 mmol) in DCM (100.0 mL) were added m-CPBA (15.0 g, 86.92 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (4 / 1, v / v) to afford 3-bromo-2-chloro-5- cyclopropylpyridine 1-oxide (6.0 g, 86%) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 247.9. Step 3: Synthesis of 5-bromo-N-tert-butyl-6-chloro-3-cyclopropylpyridin-2-amine

[0336] To a solution of 3-bromo-2-chloro-5-cyclopropylpyridine 1-oxide (6.0 g, 24.14 mmol) in toluene / DCM (50.0 mL / 20.0 mL) were added 2-methylpropan-2-amine (12.3 g, 169.01 mmol) and Tf2O (27.2 g, 96.58 mmol) at 0 °C under N2. The resulting mixture was stirred at room temperature for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 5-bromo-N-tert-butyl-6-chloro-3- cyclopropylpyridin-2-amine (7.0 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+= 303.0. Step 4: Synthesis of 5-bromo-6-chloro-3-cyclopropylpyridin-2-amine 174 ny-2729143Attorney Docket No.18407-20019.40

[0337] A solution of 5-bromo-N-tert-butyl-6-chloro-3-cyclopropylpyridin-2-amine (6.0 g, crude) in TFA (60.0 mL) was stirred at 70oC for 3 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 8 with NaHCO3 (aq.). The mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (3 / 7, v / v) to afford 5-bromo- 6-chloro-3-cyclopropylpyridin-2-amine (2.0 g, 40%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 247.0. Step 5: Synthesis of N'-(5-bromo-6-chloro-3-cyclopropylpyridin-2-yl)-N,N- dimethylmethanimidamide

[0338] To a solution of 5-bromo-6-chloro-3-cyclopropylpyridin-2-amine (1.8 g, 7.27 mmol) in THF (20.0 mL) was added DMF-DMA (2.6 g, 21.81 mmol) at room temperature. The resulting mixture was stirred at 80oC for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford N'-(5-bromo-6-chloro-3- cyclopropylpyridin-2-yl)-N,N-dimethylmethanimidamide (2.5 g, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 302.0. Step 6: Synthesis of N'-(5-bromo-6-chloro-3-cyclopropylpyridin-2-yl)-N- hydroxymethanimidamide 175 ny-2729143Attorney Docket No.18407-20019.40

[0339] To a solution of N'-(5-bromo-6-chloro-3-cyclopropylpyridin-2-yl)-N,N- dimethylmethanimidamide (2.0 g, crude) in MeOH (20.0 mL) was added hydroxylamine hydrochloride (440 mg, 13.32 mmol) at room temperature. The resulting mixture was stirred at 60oC for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford N'-(5-bromo-6-chloro-3-cyclopropylpyridin-2-yl)-N- hydroxymethanimidamide (3.0 g, crude) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 290.0. Step 7: Synthesis of 6-bromo-5-chloro-8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine

[0340] To a solution of N'-(5-bromo-6-chloro-3-cyclopropylpyridin-2-yl)-N- hydroxymethanimidamide (2.5 g, crude) in THF (50.0 mL) was added TFAA (3.5 g, 16.66 mmol) at room temperature. The resulting mixture was stirred at 60oC for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography with DCM / MeOH (99 / 1, v / v) to afford 6-bromo-5-chloro-8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 42%) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 272.0. Step 8: Synthesis of 6-bromo-8-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-5-amine176 ny-2729143Attorney Docket No.18407-20019.40

[0341] To a solution of 6-bromo-5-chloro-8-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridine (900.0 mg, 3.65 mmol) in dioxane (20.0 mL) was added 3-methoxy-2,6-dimethylaniline (1.1 g, 7.26 mmol) and LiHMDS (10.9 mL, 1.0 mol / L) at room temperature under N2. The resulting mixture was stirred at 60oC for 2 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (10 / 1, v / v) to afford 6-bromo-8- cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5-a]pyridin-5-amine (1.2 g, 84%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 387.1. Step 9: Synthesis of 4-amino-8-cyclopropyl-3-(3-methoxy-2,6-dimethylphenyl)-1,3,10,12- tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5-carbonitrile

[0342] To a solution of 6-bromo-8-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-5-amine (1.2 g, 3.09 mmol) in DMF (40.0 mL) were added malononitrile (615.0 mg, 9.30 mmol), K2CO3(2.1 g, 15.49 mmol) and Pd(dppf)Cl2(250.0 mg, 0.34 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 4-amino-8-cyclopropyl-3-(3-methoxy-2,6- dimethylphenyl)-1,3,10,12-tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5- carbonitrile (150.0 mg, 13%) as a brown solid. LCMS (ESI, m / z): [M+H]+= 373.2. Step 10: Synthesis of 4-amino-8-cyclopropyl-3-(3-methoxy-2,6-dimethylphenyl)- 1,3,10,12-tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5-carboxamide 177 ny-2729143Attorney Docket No.18407-20019.40

[0343] To a solution of 4-amino-8-cyclopropyl-3-(3-methoxy-2,6-dimethylphenyl)- 1,3,10,12-tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5-carbonitrile (140.0 mg, 0.37 mmol) in EtOH / H2O (4.0 mL / 1.0 mL) were added Ghaffar-Parkins catalyst (40.0 mg, 0.09 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 48 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 4-amino-8-cyclopropyl-3-(3-methoxy-2,6-dimethylphenyl)- 1,3,10,12-tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5-carboxamide (200.0 mg, crude) as a brown solid. LCMS (ESI, m / z): [M+H]+= 391.2. Step 11: Synthesis of 7-amino-4-cyclopropyl-8-(3-hydroxy-2,6-dimethylphenyl)-8H- pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6-carboxamide (Compound 25)

[0344] To a solution of 4-amino-8-cyclopropyl-3-(3-methoxy-2,6-dimethylphenyl)- 1,3,10,12-tetraazatricyclo[7.3.0.0^{2,6}]dodeca-2(6),4,7,9,11-pentaene-5-carboxamide (60 mg, 0.15 mmol) in DCM (3.0 mL) were added BBr3(1.0 mL, 1 mol / L in CH2Cl2) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash 178 ny-2729143Attorney Docket No.18407-20019.40 column chromatography with acetonitrile / water (1 / 1, v / v) to afford 7-amino-4-cyclopropyl- 8-(3-hydroxy-2,6-dimethylphenyl)-8H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyridine-6- carboxamide (Compound 25) (6.8 mg, 11%) as an off-white solid. LCMS (ESI, m / z): [M+H]+= 377.2.1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.10 (s, 1H), 7.72 (s, 1H), 7.28 - 6.94 (m,, 1.76 - 1.62 (m, 6H), 1.17 - 1.14 (m, 2H), 1.03 - 0.98 (m, 2H). Example 26: Synthesis of 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 26) Step 1: Synthesis of 2-bromo-4-chloro-6-cyclopropylpyridine

[0345] To a solution of 2,6-dibromo-4-chloropyridine (5.0 g, 18.43 mmol) in toluene / H2O (50.0 mL / 10.0 mL) was added cyclopropylboronic acid (2.3 g, 27.27 mmol), Pd(PPh3)4 (212.3 mg, 0.18 mmol) and Na2CO3 (5.87 g, 55.35 mmol) at room temperature under N2. The resulting mixture was stirred at 110 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (99 / 1, v / v) to afford 2- bromo-4-chloro-6-cyclopropylpyridine (3.0 g, 70%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=231.9. Step 2: Synthesis of tert-butyl (4-chloro-6-cyclopropylpyridin-2-yl)carbamate179 ny-2729143Attorney Docket No.18407-20019.40

[0346] To a solution of 2-bromo-4-chloro-6-cyclopropylpyridine (3.5 g, 15.05 mmol) in dioxane (35.0 mL) was added tert-butyl carbamate (5.3 g, 44.86 mmol), Pd2(dba)3 (1.4 g, 1.51 mmol), XantPhos (1.7 g, 3.01 mmol) and Cs2CO3 (14.7 g, 45.16 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (87 / 13, v / v) to afford tert-butyl (4-chloro-6-cyclopropylpyridin-2-yl)carbamate (2.5 g, 61%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=269.1. Step 3: Synthesis of tert-butyl (4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)carbamate

[0347] To a solution of tert-butyl (4-chloro-6-cyclopropylpyridin-2-yl)carbamate (3.5 g, 13.02 mmol) in THF (35.0 mL) was added TMEDA (7.6 g, 65.12 mmol) and n-BuLi (26.0 mL, 2.5 mol / L in n-hexane) at -78 °C under N2. The resulting mixture was stirred at -78 °C for 1 h under N2. Then a solution of I2 (16.5 g, 65.12 mmol) in THF (35.0 mL) was dropwise added to the mixture at -78 °C under N2. The resulting mixture was stirred at room temperature for additional 1 h. After the reaction was completed, the reaction mixture was quenched with sat. NH4Cl (aq.) at room temperature. The resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (94 / 6, v / v) to afford tert-butyl (4-chloro-6-cyclopropyl-3-iodopyridin-2- yl)carbamate (3.2 g, 62%) as a yellow oil. LCMS (ESI, m / z): [M+H]+=395.0. Step 4: Synthesis of 4-chloro-6-cyclopropyl-3-iodopyridin-2-amine 180 ny-2729143Attorney Docket No.18407-20019.40

[0348] To a solution of tert-butyl (4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)carbamate (3.0 g, 7.60 mmol) in DCM (10.0 mL) was added TFA (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3(aq.). The resulting mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 4-chloro-6-cyclopropyl-3-iodopyridin-2-amine (2.0 g, 89%) as a brown oil. LCMS (ESI, m / z): [M+H]+=294.9. Step 5: Synthesis of (E)-N'-(4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)-N,N- dimethylformimidamide

[0349] To a solution of 4-chloro-6-cyclopropyl-3-iodopyridin-2-amine (2.0 g, 6.79 mmol) in EtOH (20.0 mL) was added DMF-DMA (2.4 g, 20.37 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford (E)-N'-(4-chloro-6- cyclopropyl-3-iodopyridin-2-yl)-N,N-dimethylformimidamide (2.3 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+=350.0. Step 6: Synthesis of (E)-N'-(4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)-N- hydroxyformimidamide181 ny-2729143Attorney Docket No.18407-20019.40

[0350] To a solution of (E)-N'-(4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)-N,N- dimethylformimidamide (2.3 g, crude) in MeOH (20.0 mL) was added hydroxylamine hydrochloride (434.5 mg, 13.14 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford (E)-N'-(4-chloro-6-cyclopropyl-3-iodopyridin- 2-yl)-N-hydroxyformimidamide (2.2 g, crude) as a yellow oil. LCMS (ESI, m / z): [M+H]+=337.9. Step 7: Synthesis of 7-chloro-5-cyclopropyl-8-iodo-[1,2,4]triazolo[1,5-a]pyridine

[0351] To a solution of (E)-N'-(4-chloro-6-cyclopropyl-3-iodopyridin-2-yl)-N- hydroxyformimidamide (3.0 g, crude) in THF (30.0 mL) was added TFAA (3.7 g, 17.78 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. After the reaction was completed, the pH of the mixture was adjusted to 8 with NaHCO3 (aq.). The resulting mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (83 / 17, v / v) to afford 7-chloro-5-cyclopropyl-8-iodo- [1,2,4]triazolo[1,5-a]pyridine (1.9 g, 66%) as a yellow solid. LCMS (ESI, m / z): [M+H]+=319.9. Step 8: Synthesis of 7-chloro-5-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-8-amine182 ny-2729143Attorney Docket No.18407-20019.40

[0352] To a solution of 7-chloro-5-cyclopropyl-8-iodo-[1,2,4]triazolo[1,5-a]pyridine (1.0 g, 3.13 mmol) in dioxane (10.0 mL) was added 3-methoxy-2,6-dimethylaniline (700.3 mg, 4.63 mmol), Pd-PEPPSI-IHeptCl (526.9 mg, 0.63 mmol) and Cs2CO3 (3.0 g, 9.32 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (91 / 9, v / v) to afford 7-chloro-5-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)-[1,2,4]triazolo[1,5- a]pyridin-8-amine (550.7 mg, 51%) as a brown solid. LCMS (ESI, m / z): [M+H]+=343.1. Step 9: Synthesis of 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile

[0353] To a solution of 7-chloro-5-cyclopropyl-N-(3-methoxy-2,6-dimethylphenyl)- [1,2,4]triazolo[1,5-a]pyridin-8-amine (250.8 mg, 0.73 mmol) in DMF (5.0 mL) were added K2CO3(503.0 mg, 3.64 mmol), malononitrile (144.2 mg, 2.18 mmol) and Pd(dppf)Cl2(102.1 mg, 0.15 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (50 / 50, v / v) to afford 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (50.6 mg, 18%) as a brown solid. LCMS (ESI, m / z): [M+H]+=373.2. Step 10: Synthesis of 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide 183 ny-2729143Attorney Docket No.18407-20019.40

[0354] To a solution of 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (100.5 mg, 0.27 mmol) in EtOH / H2O (4.0 mL / 1.0 mL) was added Ghaffar-Parkins catalyst (11.3 mg, 0.03 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (85.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+=391.2. Step 11: Synthesis of 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 26)

[0355] To a solution of 8-amino-5-cyclopropyl-9-(3-methoxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (200.0 mg, 0.51 mmol) in DCM (2.0 mL) was added BBr3(2.0 mL, 1 mol / L in DCM) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was quenched with MeOH at 0 °C. the resulting mixture was diluted with H2O and extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash column chromatography with H2O / ACN 184 ny-2729143Attorney Docket No.18407-20019.40 (60 / 40, v / v) to afford 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 26) (55.1 mg, 29%) as a light yellow solid. LCMS (ESI, m / z): [M+H]+= 377.1.1H-NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.07 (s, 1H), 7.20 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.99 (s, 2H), 6.93 (d, J = 8.4 Hz, 1H), 6.63 (s, 2H), 2.60 - 2.52 (m, 1H), 1.75 (s, 3H), 1.66 (s, 3H), 1.13 - 1.05 (m, 4H). Example 27: Synthesis of 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide: (Compounds 27 and 28) Step 1: Synthesis of 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide:

[0356] The product of 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (50.0 mg, 0.13 mmol) was separated by Prep-Chiral-HPLC with the following conditions (CHIRALPAK IC, 2x25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: MeOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient: 25% B to 25% B in 14 min; Wave Length: 220 / 254 nm; RT1(min): 10.97; RT2(min): 12.64) to afford 8-amino-5-cyclopropyl-9- (3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7- carboxamide (Compound 27) (assumed, 13.8 mg, 54%) as a white solid and 8-amino-5- cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5- a]pyridine-7-carboxamide (Compound 28) (assumed, 5.5 mg, 22%) as a white solid.

[0357] 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 27): RT1(min): 10.97; LCMS (ESI, m / z): [M+H]+=377.2.1H-NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.07 (s, 1H), 7.20 (s, 1H), 7.07 - 6.92 (m, 4H), 6.64 (s, 2H), 2.58 - 2.51 (m, 1H), 1.75 (s, 3H), 1.66 (s, 3H), 1.18 - 1.07 (m, 4H). 185 ny-2729143Attorney Docket No.18407-20019.40

[0358] 8-amino-5-cyclopropyl-9-(3-hydroxy-2,6-dimethylphenyl)-9H-pyrrolo[2,3- c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 28): RT2(min): 12.64; LCMS (ESI, m / z): [M+H]+=377.1.1H-NMR (400 MHz, DMSO-d6): δ 9.49 (s, 1H), 8.07 (s, 1H), 7.20 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.99 (s, 2H), 6.93 (d, J = 8.0 Hz, 1H), 6.63 (s, 2H), 2.60 - 2.52 (m, 1H), 1.75 (s, 3H), 1.66 (s, 3H), 1.16 - 1.02 (m, 4H). Example 28: Synthesis of 8-amino-9-(3-hydroxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compounds 29 and 30) Step 1: Synthesis of (Z)-N'-(4-chloro-3-iodo-6-methylpyridin-2-yl)-N,N- dimethylformimidamide

[0359] To a solution of 4-chloro-3-iodo-6-methylpyridin-2-amine (2.0 g, 7.45 mmol) in EtOH (30.0 mL) was added DMF-DMA (3.0 g, 25.18 mmol) at room temperature. The resulting mixture was stirred at 80oC for 2 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to afford (Z)-N'-(4-chloro-3-iodo-6- methylpyridin-2-yl)-N,N-dimethylformimidamide (2.0 g, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 324.0. Step 2: Synthesis of (Z)-N'-(4-chloro-3-iodo-6-methylpyridin-2-yl)-N- hydroxyformimidamide

[0360] To a solution of (Z)-N'-(4-chloro-3-iodo-6-methylpyridin-2-yl)-N,N- dimethylformimidamide (1.9 g, crude) in methanol (30.0 mL) was added hydroxylamine hydrochloride (1.3 g, 18.71 mmol) at room temperature. The resulting mixture was stirred at 50oC for 3 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The residue was washed with MeOH and then filtered. The solid was 186 ny-2729143Attorney Docket No.18407-20019.40 collected to afford (Z)-N'-(4-chloro-3-iodo-6-methylpyridin-2-yl)-N- hydroxyformimidamide (1.2 g, crude) as a white solid. LCMS (ESI, m / z): [M+H]+= 311.9. Step 3: Synthesis of 7-chloro-8-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

[0361] To a solution of (Z)-N'-(4-chloro-3-iodo-6-methylpyridin-2-yl)-N- hydroxyformimidamide (1.1 g, crude) in THF (20.0 mL) was added TFAA (1.6 g, 7.62 mmol) at room temperature. The resulting mixture was stirred at 50 °C for 4 h. After the reaction was completed, the resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with ethyl ether and then filtered. The solid was collected and dried to afford 7-chloro-8-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (800.0 mg, crude) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 293.9. Step 4: Synthesis of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine O

[0362] To a solution of 7-chloro-8-iodo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine (600.0 mg, 2.04 mmol) in dioxane (20.0 mL) was added 3-methoxy-2,6-dimethylaniline (451.0 mg, 2.98 mmol), Cs2CO3(2.0 g, 6.07 mmol) and {1,3-bis[2,6-bis(pentan-3-yl)phenyl]-4,5- dichloro-2,3-dihydro-1H-imidazol-2-yl}dichloro(2-methyl-1lambda4-pyridin-1-yl)palladium (292.0 mg, 0.35 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under 187 ny-2729143Attorney Docket No.18407-20019.40 reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 1, v / v) to afford 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine (200.0 mg, 30%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 317.1. Step 5: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile

[0363] To a solution of 7-chloro-N-(3-methoxy-2,6-dimethylphenyl)-5-methyl- [1,2,4]triazolo[1,5-a]pyridin-8-amine (200.0 mg, 0.63 mmol) in DMF (10.0 mL) was added malononitrile (125.0 mg, 1.89 mmol), K2CO3 (436.0 mg, 3.15 mmol) and Pd(dppf)Cl2 (205.0 mg, 0.25 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography with petroleum ether / ethyl acetate (1 / 2, v / v) to afford 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl- 9H-pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (110.0 mg, 50%) as a yellow solid. LCMS (ESI, m / z): [M+H]+= 347.2. Step 6: Synthesis of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carboxamide188 ny-2729143Attorney Docket No.18407-20019.40

[0364] To a solution of 8-amino-9-(3-methoxy-2,6-dimethylphenyl)-5-methyl-9H- pyrrolo[2,3-c][1,2,4]triazolo[1,5-a]pyridine-7-carbonitrile (100.0 mg, 0.29 mmol) in EtOH / H2O (3.0 mL / 1.0 mL) was added Ghaffar-Parkins catalyst (30.0 mg, 0.07 mmol) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h under N2. After the reaction was completed, the resulting mixture was diluted with H2O and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhydrous sodi...

Claims

Attorney Docket No.18407-20019.40 CLAIMS What is claimed is:

1. A compound of Formula (AA)or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl or 5- or 6-membered heteroaryl, each of which is optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; R1is H, C1-C6 alkyl, or halogen; R9is H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; R2is H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, -C(O)N(R5)2, -C(O)O(R5), -C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; R4is -NH2 or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, -C(O)N(R5)2, -C(O)O(R5), - C(O)(R5), -SO2N(R5)2, or -SO2(R5); 263 ny-2729143Attorney Docket No.18407-20019.40 R7is H or hydroxyl; and R8is H or C1-C6 alkyl.

2. The compound of claim 1, wherein the compound of Formula (AA) is a compound of Formula (AI), Formula (AII), Formula (AIII), Formula (AIV), Formula (AV), or Formula (AVI)or a pharmaceutically acceptable salt thereof, wherein: each of X1and X2is independently N or C, wherein when X1is N, then X2is C; and when X2is N, then X1is C; Y1is N or CR3; Z1is N, CR3, or CHR3; 264 ny-2729143Attorney Docket No.18407-20019.40 Z2is N, O, S, or CR3; each Z3, Z4, Z5, Z6, Z7, and Z8is independently N or CR3; R1is H, C1-C6 alkyl, or halogen; R9is H or hydroxyl; or R1and R9are taken together to form a 5-membered heteroaryl; R2is H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, -C(O)N(R5)2, -C(O)O(R5), -C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6; R4is -NH2 or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, -C(O)N(R5)2, -C(O)O(R5), - C(O)(R5), -SO2N(R5)2, or -SO2(R5); R7is H or hydroxyl; and R8is H or C1-C6alkyl.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AI).

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AII).

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AIII).

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AIV).

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AV). 265 ny-2729143Attorney Docket No.18407-20019.40 8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (AVI).

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein each R1and R2is independently H, methyl, or Cl.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R1and R2are each methyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R7is H or OH; R8is H or methyl; and R9is H or OH.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R7is H, R8is H, and R9is OH; or R7is OH, R8is H, and R9is H.

13. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt14. any one or a thereof, wherein Z1is N.

15. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Z1is CR3.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein Z1is CR3and the R3of Z1is H. 266 ny-2729143Attorney Docket No.18407-20019.40 17. The compound of any one of claims 2-6 and 9-16, or a pharmaceutically acceptable18. or a19. The compound of any one of claims 2 and 7-16, or a pharmaceutically acceptable salt20. or a267 ny-2729143Attorney Docket No.18407-20019.40 21. The compound of any one of claims 2, 7-16, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Z4is N.

22. The compound of any one of claims 2, 7-16, 19, and 20, or a pharmaceutically acceptable salt thereof, wherein Z4is CR3.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein Z4is CR3and the R3of Z4is selected from the group consisting of H, Cl, methyl, - 24.any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from the group consisting of H, halogen, cyano, C1-C6alkyl, C1-C6alkoxy, -C(O)N(R5)2, 5- to 10-membered heteroaryl, and C3-C8 cycloalkyl, wherein each C1-C6 alkoxy and 5- to 10-membered heteroaryl is independently optionally substituted by one or more -R6.

25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from the group consisting of H, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy optionally substituted by one or more - N(R5)2, -C(O)N(R5)2, 5- to 10-membered heteroaryl optionally substituted by one or more C1-C6alkyl, and C3-C8cycloalkyl, wherein each R5is independently H or C1-C6alkyl.

26. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt thereof, wherein each R3is independently selected from the group consisting of H, Cl, cyano, methyl,27. The any one or a salt thereof, wherein R4is H.

28. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R4is NH2.

29. A compound of Formula (A) 268 ny-2729143Attorney Docket No.18407-20019.40or a pharmaceutically acceptable salt, solvate, hydrate, or co-crystal thereof, wherein: Ring A is C5-C6aryl or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by one or more R3; one of Q1, Q2, Q3, and Q4is N, and the remainder of Q1, Q2, Q3, and Q4are C; each of Z1and Z4is independently N, CR3, or CHR3; each R1is independently H, C1-C6alkyl, or halogen; each R2is independently H, C1-C6 alkyl, or halogen; each R3is independently H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5), wherein each C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10aryl, and 5- to 10- membered heteroaryl is independently optionally substituted by one or more -R6; each R4is independently -NH2 or H; each R5is independently H, C1-C6alkyl, or C3-C8cycloalkyl; and each R6is independently hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, 4- to 10-memebered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, halogen, cyano, -N(R5)2, C(O)N(R5)2, C(O)O(R5), C(O)(R5), - SO2N(R5)2, or -SO2(R5).

30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 269 ny-2729143Attorney Docket No.18407-20019.40 ; ; ; ; ;270 ny-2729143Attorney Docket No.18407-20019.40 OH O NH2; ; ; ; ;271 ny-2729143Attorney Docket No.18407-20019.40 ; ; ; ; ; ;ny-2729143Attorney Docket No.18407-20019.40 ; ; ; ; ;273 ny-2729143Attorney Docket No.18407-20019.40 ; ; ; ; ; and274 ny-2729143Attorney Docket No.18407-20019.40 .

31. A pharmaceutical composition comprising the compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

32. A method of inhibiting kinase activity of a human receptor tyrosine kinase PKMYT1, the method comprising contacting the PKMYT1 with a therapeutically effective amount of the compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 31.

33. A method of treating a cancer in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of the pharmaceutical composition of claim 31.

34. The method of claim 33, wherein the cancer is pancreatic, prostate, bladder, endometrial, lung, colorectal, ovarian, peritoneal, breast, gastric, fallopian tube, or cervical cancer.

35. The method of claim 33 or 34, wherein the cancer comprises a deleterious mutation related to the DNA damage response (DDR) or a mutation that induces replicative stress.

36. The method of claim 35, wherein the deleterious mutation related to DDR is a HR, BER, NHEJ, or NER mutation.

37. The method of claim 35, wherein the mutation comprises a mutation to ATM, ATR, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, MRE11A, NBN, PALB2, PP2R2ARAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, XRCC2, 275 ny-2729143Attorney Docket No.18407-20019.40 the FANC family of proteins, a CCNE1 amplification mutation, a FBXW7 deletion or loss of function mutation, or a MYC amplification mutation.

38. The method of claim 33 or 34, wherein the cancer comprises a mutation to a factor involved in regulation of cell cycle progression.

39. The method of any one of claims 33-38, further comprising administering a therapy that induces DNA damage and / or replicative stress.

40. The method of claim 39, wherein the therapy comprises alkylating agents, platinum- based anti-neoplastic agents, anti-metabolites, topoisomerase inhibitors, ionizing radiation, radiomimetics, or other radiotherapies.

41. The method of any one of claims 33-38, further comprising administering an agent that targets regulation of the DDR or DNA replication.

42. The method of claim 41, wherein the agent is an inhibitor of ATR, ATM, DNA-PK, CHK1, CHK2, WEE1, MYT1, or pol-theta.

43. The method of any one of claims 33-38, further comprising administering an agent that attenuates survival pathway activation in response to DNA damage.

44. The method of claim 43, wherein the agent is an inhibitor of EGFR, ErbB2, IGFR1, MET, FGFR1-4, VEGFR2, MEK, ERK, PI3K, AKT, mTORC1, or mTORC2.

45. The method of any one of claims 33-38, further comprising administering an agent that targets kinase oncogenic drivers that induce replication stress or interfere with the DDR.

46. The method of claim 39, wherein the agent is an inhibitor of BCR-ABL, EGFR, ERBB2, FLT3, MET, RET, ALK, NTRK, RET, ROS1, or BRAF.

47. The method of any one of claims 33-38, further comprising administering a therapy that acts via the induction of an anti-tumor immune response in a manner analogous to PARP1 and / or PARP2 inhibitors.

48. The method of claim 47, wherein the therapy is an anti-PD1, an anti-PD-L1, or an anti-CTLA4 therapy. 276 ny-2729143Attorney Docket No.18407-20019.40 49. The method of any one of claims 33-38, further comprising administering a therapy that induces an anti-tumor immune response.

50. The method of claim 49, wherein the therapy comprises a cancer vaccine, a T-cell- based therapy, a T-cell engager bi-specific antibody, or an oncolytic virus. 277 ny-2729143

Images