Substituted 2-morpholinopyridine derivatives as ATR kinase inhibitors

Abstract

To provide new anti-cancer therapies and, in particular, ATR kinase inhibitor-based anti-cancer therapies.SOLUTION: Disclosed are compounds of formula (I) below or pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical compositions containing the compounds of formula (I) and methods for their preparation. The compounds of formula (I) may be inhibitors of Ataxia-telangiectasia and RAD-3 -related protein kinase (ATR) and used for the treatment of diseases or conditions such as cancers.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to compounds and pharmaceutical compositions, their preparation and use in the treatment of diseases or conditions, such as cancer, in particular ataxia telangiectasia and diseases or conditions (e.g., cancer) that depend on the activity of RAD3-related protein (ATR) kinase. [Background technology]

[0002] DNA damage occurs continuously within cells as a result of environmental insults, including ultraviolet light, X-rays, and endogenous stressors such as reactive oxygen species and base hydrolysis. Cancer cells frequently suffer from DNA damage, which is inherently induced by the high rate of DNA replication within the cell. Several DNA damage response (DDR) pathways have evolved in a highly systematic manner to aid in DNA damage repair and function as cellular checkpoints that halt replication of cells with damaged DNA, thereby allowing repair functions to occur before the damaged DNA is inherited by daughter cells. Each identified DNA repair pathway senses and repairs different but overlapping types of DNA damage.

[0003] One of the key DDR proteins that functions as a critical cell cycle checkpoint is the ataxia telangiectasia mutated and rad3-related (ATR) kinase, which is related to the phosphoinositide 3-kinase-related protein kinase (PIKK) family. ATR is activated by single-stranded (ss) DNA damage that occurs during stalled replication forks or nucleotide excision repair, but also by double-strand breaks following DNA end resection during homologous recombination. ATR, along with a cofactor called ATR-interacting protein (ATRIP), is recruited to DNA damage sites by binding to RPA proteins that coat ssDNA. The ATR / ATRIP complex is then activated by the recruitment of additional factors, the 9-1-1 complex (RAD9, RAD1, and HUS1). The 9-1-1 complex subsequently recruits the TOPBP1 protein, representing a critical step for the activation of downstream phosphorylation cascades that result in cell cycle arrest. The primary target of ATR kinase is CHK1, which, upon phosphorylation, targets both cdc25 protein and Wee1, leading to inhibition of cyclin-dependent kinase activity and cell cycle arrest at S phase or G2 / M.

[0004] ATR is essential for cell division and has therefore been identified as an important cancer target. While ATR-deficient mice are embryonic lethal, adult mice with a conditional ATR knockout are viable due to its effects on rapidly proliferating tissues and stem cell populations. ATR-deficient mouse embryonic stem cells divide only once or twice before dying, suggesting that ATR is required for the maintenance of dividing cells. Interestingly, mice carrying a hypomorphic ATR mutation that reduces ATR expression to 10% of normal levels showed reduced H-rasG12D-induced tumor growth with minimal impact on proliferating normal cells, such as bone marrow or intestinal epithelial cells. Therefore, cancer cells with high levels of replication stress due to oncogenic mutations, dysfunctional G1 / S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM), or defects affected by DNA-damaging agents (e.g., radiation therapy or chemotherapy) are more dependent on ATR for DNA repair and survival. Collectively, these results strengthen the rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the possibility of a therapeutic window spanning healthy proliferating cells. Summary of the Invention [Problem to be solved by the invention]

[0005] There is a need for new anticancer therapies, particularly those based on ATR inhibitors. [Means for solving the problem]

[0006] In one aspect, the present invention provides a compound of formula (I):

[0007] [ka]

[0008] [In the formula,

[0009] [ka]

[0010] is a double bond, and each Y is independently N or CR 4 or

[0011] [ka]

[0012] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y )2, where each R Y are independently H or optionally substituted C 1-6 is alkyl; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and; R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl; Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl; Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 is aryl; R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Q is an optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 is arylene; and X is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments,

[0014] [ka]

[0015] is a double bond. In some embodiments,

[0016] [ka]

[0017] is a single bond. In some embodiments, the compound has formula (II):

[0018] [ka]

[0019] [In the formula, Each Y is independently N or CR 4 and the remaining variables are as described in relation to formula (I), or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, in the compound of Formula (I) or (II): Each Y is independently N or CR 4 and; R1 is H or optionally substituted C 1-6 is alkyl; R 2 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, or -SO2R 5A and; R 3 is optionally replaced by C 1-9 is heteroaryl; Each R 4 are independently hydrogen or optionally substituted C 1-6 is alkyl; Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 is cycloalkyl; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6Alkyl, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 Forming a heterocyclyl.

[0021] In some embodiments, the compound has formula (Ia):

[0022] [ka]

[0023] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (Ib):

[0024] [ka]

[0025] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (IA):

[0026] [ka]

[0027] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (IA-a):

[0028] [ka]

[0029] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (IB):

[0030] [ka]

[0031] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (IB-a):

[0032] [ka]

[0033] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has the formula (IC):

[0034] [ka]

[0035] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has the formula (IC-a):

[0036] [ka]

[0037] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has the formula (ID):

[0038] [ka]

[0039] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments, the compound has formula (ID-a):

[0040] [ka]

[0041] or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 1 is methyl.

[0042] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, or -SO2R 5A is.

[0043] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is optionally replaced by C 3-8 In some embodiments, R 2 is the formula (A):

[0044] [ka]

[0045] [In the formula, n is 0, 1, 2, or 3; R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, and each R A are independently H or alkyl, or both R A together with the atoms to which they are bonded, C 2-9 forming a heterocyclyl.

[0046] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is the formula (B):

[0047] [ka]

[0048] [In the formula, R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, and each R Aare independently H or alkyl, or both R A together with the atoms to which they are bonded, C 2-9 forming a heterocyclyl.

[0049] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is an optionally substituted non-aromatic C 2-9 In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is an optionally substituted non-aromatic bridged C 2-9 In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is an optionally substituted non-aromatic spiro C 2-9 It is a heterocyclyl.

[0050] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 is -QR 5B In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), Q is an optionally substituted C 2-9 In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 5B is a hydroxyl.

[0051] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 2 teeth,

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] is. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 is an optionally substituted monocyclic C ring containing at least one nitrogen atom 1-9 In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 is an optionally substituted monocyclic C ring containing two nitrogen atoms 1-9 In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 is expressed by the formula (C):

[0056] [ka]

[0057] wherein A is an optionally substituted monocyclic C 1-9is a heteroaryl ring. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 is expressed as formula (C1):

[0058] [ka]

[0059] [In the formula, R 8 is hydrogen, halogen, or optionally substituted C 1-6 is an alkyl group. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), A is an optionally substituted monocyclic C ring containing two nitrogen atoms. 1-9 It is a heteroaryl ring.

[0060] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 teeth,

[0061] [ka]

[0062] is. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 3 teeth,

[0063] [ka]

[0064] is. In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), R 4 is hydrogen.

[0065] In some embodiments of any of Formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a), X is hydrogen.

[0066] In some embodiments, the compound is selected from the group consisting of Compounds 1-152 (e.g., Compounds 1-140) and pharmaceutically acceptable salts thereof (e.g., Compounds 1, 2, 3, 4, 5, 6, 7, 8, 43, 45, 47, 48, 49, 52, 53, 55, 57, 58, 59, 61, 62, 63, 73, 74, 77, 80, 81, 82, 84, 86, 87, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 300, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 130, 131, 132, 133, 135, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, and pharmaceutically acceptable salts thereof).

[0067] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, hi some embodiments, the compound of the present invention is isotopically enriched with deuterium.

[0068] In a further aspect, the present invention provides methods for inhibiting ATR kinase in a cell expressing ATR kinase by contacting the cell with a compound of the present invention. In some embodiments, the cell is in vitro. In some embodiments, the cell is in a subject.

[0069] In yet another aspect, the present invention provides a method of treating a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention. In some embodiments, the subject is suffering from a disease or condition with symptoms of cellular hyperproliferation (e.g., the disease or condition is cancer or a premalignant or precancerous condition) and is in need of treatment. In some embodiments, the cancer is carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma.

[0070] In some embodiments, the cancer is selected from the group consisting of medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, and pulmonary carcinoma. basocellulare), basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebrumoid carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, endometrial carcinoma, cribriform carcinoma, armor-like carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma , encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, childhood embryonic carcinoma, carcinoma in situ in situ), intraepithelial carcinoma, intraepithelial carcinoma carcinoma, Chromosome pecker carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), nodular carcinoma (tuberous carcinoma), verrucous carcinoma, and choriocarcinoma.

[0071] In some embodiments, the cancer is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cell, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0072] In some embodiments, the cancer is selected from the group consisting of non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0073] In some embodiments, the cancer is a melanoma selected from the group consisting of acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0074] In some embodiments, the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer.

[0075] In some embodiments, the cancer is Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, carcinoma, malignant pancreatic cancer, malignant carcinoid, bladder cancer, precancerous skin lesion, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasm, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0076] In some embodiments, the subject is suffering from a precancerous condition and is in need of treatment. The present invention is also described by the following listed clauses.

[0077] 1. Formula (I):

[0078] [ka]

[0079] [In the formula,

[0080] [ka]

[0081] is a double bond, and each Y is independently N or CR 4 or

[0082] [ka]

[0083] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y )2, where each R Y are independently H or optionally substituted C 1-6 is alkyl; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and; R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl; Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl; Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 is aryl; R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Q is an optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 is arylene; X is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0084] 2.

[0085] [ka]

[0086] is a double bond. 3.

[0087] [ka]

[0088] The compound of clause 1, wherein is a single bond. 4. The compound has the formula (II):

[0089] [ka]

[0090] [In the formula, Each Y is independently N or CR 4 and; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and; R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl; Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl; Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 is aryl; R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Q is an optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 is arylene; X is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0091] 5. The compound has formula (Ia):

[0092] [ka]

[0093] or a pharmaceutically acceptable salt thereof. 6. The compound has the formula (IA):

[0094] [ka]

[0095] or a pharmaceutically acceptable salt thereof. 7. The compound has the formula (IA-a):

[0096] [ka]

[0097] or a pharmaceutically acceptable salt thereof. 8. The compound has formula (IB):

[0098] [ka]

[0099] or a pharmaceutically acceptable salt thereof. 9. The compound has the formula (IB-a):

[0100] [ka]

[0101] or a pharmaceutically acceptable salt thereof. 10. The compound has formula (IC):

[0102] [ka]

[0103] or a pharmaceutically acceptable salt thereof. 11. The compound has the formula (IC-a):

[0104] [ka]

[0105] or a pharmaceutically acceptable salt thereof. 12.R 1 12. The compound of any one of clauses 1 to 11, wherein is methyl. 13.R 2 is optionally replaced by C1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, or -SO2R 5A 13. The compound of any one of clauses 1 to 12, wherein

[0106] 14.Each R 5A are independently optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 14. The compound of any one of clauses 1 to 13, wherein the compound is cycloalkyl. 15.Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 A compound according to any one of clauses 1 to 13, forming a heterocyclyl.

[0107] 16.R 2 is optionally replaced by C 3-8 16. The compound of any one of clauses 1 to 15, wherein the compound is cycloalkyl. 17.R 2 alkylsulfonyl, cyano, -CON(R A )2, C optionally substituted by hydroxy, or alkoxy 3-8 cycloalkyl, and each R Aare independently H or alkyl; or both R A together with the atoms to which they are bonded, C 2-9 A compound of clause 16, forming a heterocyclyl.

[0108] 18.R 2 But, formula (A):

[0109] [ka]

[0110] [In the formula, n is 0, 1, 2, or 3; R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, and each R A are independently H or alkyl, or both R A together with the atoms to which they are bonded, C 2-9 16. A compound of clause 16, wherein the group:

[0111] 19.R 2 But, equation (B):

[0112] [ka]

[0113] [In the formula, R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, and each R A are independently H or alkyl; or both R A together with the atoms to which they are bonded, C2-9 16. A compound according to any one of clauses 1 to 15, wherein the group:

[0114] 20.R 7 is alkylsulfonyl, cyano, or -CON(R A 20. A compound according to clause 18 or 19, wherein 21.R 2 is optionally replaced by C 1-6 13. The compound of any one of clauses 1 to 12, wherein the alkyl is alkyl.

[0115] 22.R 2 is optionally substituted tertiary C 3-6 22. The compound of clause 21, wherein the compound is alkyl. 23.R 2 is an optionally substituted non-aromatic C 2-9 16. The compound of any one of clauses 1 to 15, which is heterocyclyl.

[0116] 24.R 2 is an optionally substituted non-aromatic bridged C 2-9 The compound of clause 23 which is heterocyclyl. 25.R 2 is an optionally substituted non-aromatic spiro C 2-9 The compound of clause 23 which is heterocyclyl.

[0117] 26.R 2 is optionally replaced by C 3-8 16. The compound of any one of clauses 1 to 15, wherein the compound is cycloalkyl. 27.R 2 is an optionally substituted spiro C 3-8 The compound of clause 26, which is cycloalkyl.

[0118] 28.R 2 Ga-QR 5B 13. The compound of any one of clauses 1 to 12, wherein 29. Q is optionally replaced by C 1-9 The compound of clause 28 which is a heteroarylene.

[0119] 30. Q is optionally replaced by C 3-8 The compound of clause 28, which is a cycloalkylene. 31. Q is optionally replaced by C 2-9 The compound of clause 28 which is a heterocyclylene.

[0120] 32. Q is optionally replaced by C 6-10 The compound of clause 28 which is an arylene. 33.R 5B is optionally replaced by C 1-6 33. The compound of any one of clauses 28 to 32, wherein the compound is alkyl.

[0121] 34.R 5B 33. The compound of any one of clauses 28 to 32, wherein is hydroxyl. 35.R 5B is optionally replaced by C 6-10 33. The compound of any one of clauses 28 to 32, wherein the compound is aryl.

[0122] 36.R 5B is optionally replaced by C 1-9 33. The compound of any one of clauses 28 to 32, which is heteroaryl. 37.R 5B -N(R 5 33. The compound of any one of clauses 28 to 32, wherein

[0123] 38.Each R 5 A compound of clause 37, wherein is hydrogen. 39.R 5B 33. The compound of any one of clauses 28 to 32, wherein is optionally substituted alkoxy.

[0124] 38.R 5B -SO2N(R 6 33. The compound of any one of clauses 28 to 32, wherein 39.Each R 6 A compound of clause 38, wherein is hydrogen.

[0125] 40.R5B Ga-SO2R 5A 33. The compound of any one of clauses 28 to 32, wherein 41.R 5A is optionally replaced by C 1-6 The compound of clause 40, wherein the compound is alkyl. 42.R 2 but,

[0126] [ka]

[0127] [ka]

[0128] [ka]

[0129] 16. The compound of any one of clauses 1 to 15, 43.R 2 but,

[0130] [ka]

[0131] [ka]

[0132] [ka]

[0133] The compound of clause 42. 44.R 2 but,

[0134] [ka]

[0135] The compound of clause 42. 45.R 2 but,

[0136] [ka]

[0137] [ka]

[0138] [ka]

[0139] The compound of clause 42. 46.R 2 but,

[0140] [ka]

[0141] The compound of clause 42. 47.R 2 but,

[0142] [ka]

[0143] The compound of clause 42. 48.R 2 but,

[0144] [ka]

[0145] The compound of clause 42. 49.R 2 but,

[0146] [ka]

[0147] The compound of clause 42. 50.R 2 but,

[0148] [ka]

[0149] The compound of clause 42. 51.R 2 but,

[0150] [ka]

[0151] The compound of clause 42. 52.R 2 but,

[0152] [ka]

[0153] The compound of clause 42. 53.R 2 but,

[0154] [ka]

[0155] The compound of clause 42. 54.R 2 but,

[0156] [ka]

[0157] The compound of clause 42. 55.R 2 but,

[0158] [ka]

[0159] The compound of clause 42. 56.R 2 but,

[0160] [ka]

[0161] The compound of clause 42. 57.R 2 but,

[0162] [ka]

[0163] The compound of clause 42. 58.R 2 but,

[0164] [ka]

[0165] The compound of clause 42. 59.R 2 but,

[0166] [ka]

[0167] The compound of clause 42. 60.R 2 but,

[0168] [ka]

[0169] The compound of clause 42. 61.R 2 but,

[0170] [ka]

[0171] The compound of clause 42. 62.R 2 but,

[0172] [ka]

[0173] The compound of clause 61. 63.R 2 but,

[0174] [ka]

[0175] The compound of clause 42. 64.R 2 but,

[0176] [ka]

[0177] The compound of clause 42. 65.R 2 but,

[0178] [ka]

[0179] The compound of clause 42. 66.R2 but,

[0180] [ka]

[0181] The compound of clause 42. 67.R 2 but,

[0182] [ka]

[0183] The compound of clause 42. 68.R 2 but,

[0184] [ka]

[0185] The compound of clause 42. 69.R 2 but,

[0186] [ka]

[0187] The compound of clause 42. 70.R 3 is a monocyclic C ring containing at least one nitrogen atom, optionally substituted 1-9 69. The compound of any one of clauses 1 to 69, which is heteroaryl.

[0188] 71.R 3 is an optionally substituted monocyclic C ring containing two nitrogen atoms; 1-9 The compound of clause 70, which is heteroaryl. 72.R 3 But, formula (C):

[0189] [ka]

[0190] wherein A is an optionally substituted monocyclic C 1-9 70. The compound of claim 70, wherein the ring is a heteroaryl ring. 73.R 3 But, equation (C1):

[0191] [ka]

[0192] [In the formula, R 8 is hydrogen, halogen, or optionally substituted C 1-6 70. A compound of claim 70, wherein the group is alkyl. 74.R 8 Compounds of clause 73, wherein is hydrogen or a halogen.

[0193] 75. A is an optionally substituted monocyclic C ring containing two nitrogen atoms 1-9 75. The compound of any one of clauses 72 to 74, which is a heteroaryl ring. 76.R 3 but,

[0194] [ka]

[0195] 76. The compound of any one of clauses 1 to 75, 77.R 3 but,

[0196] [ka]

[0197] The compound of Article 76. 78.R 3 but,

[0198] [ka]

[0199] The compound of Article 76. 79.R 3 but,

[0200] [ka]

[0201] The compound of Article 76. 80.R 3 but,

[0202] [ka]

[0203] The compound of Article 76. 81.R 4 81. The compound of any one of clauses 1 to 80, wherein is hydrogen. 82.R 4 81. The compound of any one of clauses 1 to 80, wherein is halogen.

[0204] 83.R 4 is optionally replaced by C 2-6 The compound of any one of clauses 1 to 80, wherein the compound is alkenyl. 84. The compound of any one of clauses 1 to 80, wherein X is hydrogen.

[0205] 85. A compound selected from the group consisting of compounds 1 to 152 and pharmaceutically acceptable salts thereof. 87. The compound, Compounds 1, 2, 3, 4, 5, 6, 7, 8, 24, 43, 45, 47, 48, 49, 52, 53, 55, 57, 58, 59, 61, 62, 63, 73, 74, 77, 80, 81, 82, 84 , 86, 87, 92, 93, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 150, 151, and pharmaceutically acceptable salts thereof.

[0206] 88. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 6, 8, 43, 48, 92, 126, 128, 130, 131, 141, 142, 143, 145, 150, and pharmaceutically acceptable salts thereof.

[0207] 89. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 2, 4, 7, 47, 49, 63, 86, and pharmaceutically acceptable salts thereof. 90. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 57, 62, 73, 74, 80, 81, 82, 84, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 137, 138, 144, 146, 147, 148, 151, and pharmaceutically acceptable salts thereof.

[0208] 91. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 57, 62, 87, 93, 94, 95, 99, 100, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 118, 119, 120, 121, 122, 123, 135, 147, 148, and pharmaceutically acceptable salts thereof.

[0209] 92. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 61, 105, 107, 110, 112, 113, and pharmaceutically acceptable salts thereof. 93. The compound of clause 56, wherein said compound is selected from the group consisting of compounds 121, 122, and pharmaceutically acceptable salts thereof.

[0210] 94. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 125, 127, 129, 138, 139, 140, 144, 146, 151, and pharmaceutically acceptable salts thereof.

[0211] 95. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 58, 123, and pharmaceutically acceptable salts thereof. 96. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 1, 3, 5, 59, 77, 97, 98, 101, 102, 103, 104, 106, 114, 115, 132, 133, and pharmaceutically acceptable salts thereof.

[0212] 97. The compound of clause 85, wherein said compound is selected from the group consisting of compounds 45, 52, 55, and pharmaceutically acceptable salts thereof. 98. The compound of clause 85, wherein said compound is Compound 1 or a pharmaceutically acceptable salt thereof.

[0213] 99. The compound of clause 85, wherein said compound is Compound 2 or a pharmaceutically acceptable salt thereof. 100. The compound of clause 85, wherein said compound is compound 3 or a pharmaceutically acceptable salt thereof.

[0214] 101. The compound of clause 85, wherein said compound is compound 4 or a pharmaceutically acceptable salt thereof. 102. The compound of clause 85, wherein said compound is compound 5 or a pharmaceutically acceptable salt thereof.

[0215] 103. The compound of clause 85, wherein said compound is compound 6 or a pharmaceutically acceptable salt thereof. 104. The compound of clause 85, wherein said compound is compound 7 or a pharmaceutically acceptable salt thereof.

[0216] 105. The compound of clause 85, wherein said compound is compound 8 or a pharmaceutically acceptable salt thereof. 106. The compound of clause 85, wherein said compound is compound 9 or a pharmaceutically acceptable salt thereof.

[0217] 107. The compound of clause 85, wherein said compound is compound 86 or a pharmaceutically acceptable salt thereof. 108. The compound of clause 85, wherein said compound is compound 99 or a pharmaceutically acceptable salt thereof.

[0218] 109. The compound of clause 85, wherein said compound is compound 100 or a pharmaceutically acceptable salt thereof. 110. The compound of clause 85, wherein said compound is compound 115 or a pharmaceutically acceptable salt thereof.

[0219] 111. The compound of clause 85, wherein said compound is compound 120 or a pharmaceutically acceptable salt thereof. 112. The compound of clause 85, wherein said compound is compound 121 or a pharmaceutically acceptable salt thereof.

[0220] 113. The compound of clause 85, wherein said compound is compound 125 or a pharmaceutically acceptable salt thereof. 114. The compound of clause 85, wherein said compound is compound 126 or a pharmaceutically acceptable salt thereof.

[0221] 115. The compound of clause 85, wherein said compound is compound 138 or a pharmaceutically acceptable salt thereof. 116. The compound of clause 85, wherein said compound is compound 139 or a pharmaceutically acceptable salt thereof.

[0222] 117. The compound of clause 85, wherein said compound is compound 140 or a pharmaceutically acceptable salt thereof. 118. The compound of clause 85, wherein said compound is compound 142 or a pharmaceutically acceptable salt thereof.

[0223] 119. The compound of clause 85, wherein said compound is compound 144 or a pharmaceutically acceptable salt thereof. 120. The compound of clause 85, wherein said compound is compound 147 or a pharmaceutically acceptable salt thereof.

[0224] 121. The compound of clause 85, wherein said compound is compound 148 or a pharmaceutically acceptable salt thereof. 122. The compound of clause 85, wherein said compound is compound 150 or a pharmaceutically acceptable salt thereof.

[0225] 123. The compound of clause 85, wherein said compound is compound 151 or a pharmaceutically acceptable salt thereof. 124. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 123 and a pharmaceutically acceptable excipient.

[0226] 125. The pharmaceutical composition of clause 124, wherein said compound is isotopically enriched with deuterium. 126. A method of inhibiting ATR kinase in a cell expressing ATR kinase, the method comprising contacting said cell with a compound of any one of clauses 1 to 123.

[0227] 127. The method of clause 126, wherein said cells are in vitro. 128. The method of clause 126, wherein the cell is in a subject. 129. A method of treating a subject in need thereof, comprising administering to said subject a compound of any one of clauses 1 to 123 or a pharmaceutical composition of clause 124 or 125.

[0228] 130. The method of clause 128 or 129, wherein the subject is suffering from a disease or condition having a symptom of cellular hyperproliferation and is in need of treatment. 131. The method of clause 130, wherein said disease or said condition is cancer.

[0229] 132. The method of clause 131, wherein said cancer is a solid tumor. 133. The method of clause 131, wherein said cancer is carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma.

[0230] 134. The cancer is medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma basocellulare), basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebrumoid carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, endometrial carcinoma, cribriform carcinoma, armor-like carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma , encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, childhood embryonic carcinoma, carcinoma in situ in situ), intraepithelial carcinoma, intraepithelial carcinoma carcinoma, Chromosome pecker carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous 132. The method of clause 131, wherein the carcinoma is selected from the group consisting of: myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0231] 135. The cancer is chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, or rhabdomyosarcoma. 132. The method of clause 131, wherein the sarcoma is selected from the group consisting of: kinsarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cell, immunoblastic sarcoma of T cell, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0232] 136. The cancer is non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukemic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia 132. The method of clause 131, wherein the leukemia is selected from the group consisting of leukemia, lymphocytic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0233] 137. The method of clause 136, wherein said cancer is chronic lymphocytic leukemia. 138. The method of clause 131, wherein said cancer is lymphoma. 139. The method of clause 138, wherein the lymphoma is non-Hodgkin's lymphoma, Hodgkin's disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) / follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), or extranodal NK / T-cell lymphoma, nasal type.

[0234] 140. The method of clause 139, wherein said lymphoma is mantle cell lymphoma. 141. The method of clause 131, wherein said cancer is a melanoma selected from the group consisting of acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentiginous malignant melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0235] 142. The method of clause 131, wherein said cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer.

[0236] 143. The method of clause 131, wherein said cancer is prostate cancer. 144. The method of clause 131, wherein said cancer is ampullary cancer. 145. The method of clause 131, wherein said cancer is colon cancer.

[0237] 146. The method of clause 131, wherein said cancer is lung cancer. 147. The method of clause 131, wherein said cancer is non-small cell lung cancer. 148. The method of clause 131, wherein said cancer is ovarian cancer.

[0238] 149. The method of clause 131, wherein said cancer is pancreatic cancer. 150. The method of clause 131, wherein said cancer is Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, carcinoma, malignant insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasm, medullary thyroid carcinoma, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, or prostate cancer.

[0239] 151. The method of clause 129, wherein the subject is suffering from a precancerous condition and in need of treatment. Abbreviation Abbreviations and terms commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology, and medicine and familiar to those skilled in the art are used herein. Representative abbreviations and definitions are provided below.

[0240] Ac is acetyl [CH3C(O)-], Ac2O is acetic anhydride; AcOH is acetic acid; APC is antigen-presenting cell; aq. is aqueous; 9-BBN is 9-borabicyclo[3.3.1]nonane; BINAP is (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl); Bn is benzyl; BOC is tert-butyloxycarbonyl; CDI is carbonyldiimidazole; DCM is dichloromethane; DIAD is diisopropyl azodicarboxylate; DIBAL is diisobutylaluminum hydride DIPEA is diisopropylethylamine; DMA is dimethylacetamide; DMAP is 4-dimethylaminopyridine; DMF is N,N-dimethylformamide; DMSO is dimethyl sulfoxide; dppf is 1,1'-bis(diphenylphosphino)ferrocene; EDAC (or EDC) is 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide HCl; ESI is electrospray ionization mass spectrometry; Et2O is diethyl ether; Et3N is triethyl amine; Et is ethyl; EtOAc is ethyl acetate; EtOH is ethanol; 3-F-Ph is 3-fluorophenyl; HATU is (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCl is hydrochloric acid; HOBt is 1-hydroxybenzotriazole; HPLC is high performance liquid chromatography; LCMS is HPLC with mass spectral detection; LiHMDS is lithium bis(trimethylsilyl) ) amide; LG is a leaving group; M is molar; mCPBA is metachloroperbenzoic acid; mmol is millimolar; Me is methyl; MeCN is acetonitrile; MeOH is methanol; Ms is methanesulfonyl; MS is mass spectrometry; N is normal; NaHMDS is sodium hexamethyldisilazide; NaOAc is sodium acetate; NaOtBu is sodium tert-butoxide; NMO is N-methylmorpholine N-oxide; NMP is N-methylpyrrolidinone;NMR is nuclear magnetic resonance spectroscopy; Pd2(dba)3 is tris(dibenzylideneacetone)dipalladium; PdCl2(PPh3)2 is dichlorobis-(triphenylphosphine)palladium; PG indicates an unspecified protecting group; Ph is phenyl; PhMe is toluene; PPh3 is triphenylphosphine; PMB is paramethoxybenzyl; rt is room temperature; RBF is round-bottom flask; RuPhos Pd G1 is chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II); SEM is [2-(trimethylsilyl)ethoxy]methyl; SFC is supercritical fluid chromatography; S; N Ar is nucleophilic aromatic substitution; TBAB is tetrabutylammonium bromide; TBAF is tetrabutylammonium fluoride; TBS is tert-butyldimethylsilyl; tBu is tert-butyl; Tf is triflate; TFA is trifluoroacetic acid; THF is tetrahydrofuran; THP is tetrahydropyran; TLC is thin layer chromatography; TMAD is tetramethylazodicarboxamide; TMS is trimethylsilyl; TPAP is tetrapropylammonium perruthenate; Ts is p-toluenesulfonyl; UPLC is ultra performance liquid chromatography.

[0241] definition As used herein, the term "aberrant" refers to something that differs from normal. When used to describe enzyme activity, abnormal refers to activity that is greater than or less than the average of a normal control or a normal, non-diseased control sample. Abnormal activity can refer to an amount of activity that results in a disease, where returning the abnormal activity to a normal or non-disease-related amount (e.g., by administering a compound described herein or using a method described herein) results in alleviation of the disease or one or more disease symptoms. Abnormal activity can be measured by measuring the modification of the enzyme's substrate, and a difference in activity of two-fold or greater can be considered abnormal. Abnormal activity can also refer to increased dependence on a particular signaling pathway as a result of a defect in another complementary pathway.

[0242] As used herein, the term "acyl" refers to the group -C(=O)-R, where R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl. Acyl can be optionally substituted as described herein for each individual R group.

[0243] The term "adenocarcinoma," as used herein, refers to a malignant tumor arising from glandular cells lining organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colon cancer.

[0244] The term "alkanoyl," as used herein, represents a hydrogen or alkyl group attached to the parent molecular group through a carbonyl group and is exemplified by formyl (i.e., a carboxaldehyde group), acetyl, propionyl, butyryl, and isobutyryl. Unsubstituted alkanoyl groups contain 1 to 7 carbons. Alkanoyl groups can be unsubstituted or substituted as described herein for the alkyl group (e.g., optionally substituted C1-7 alkanoyl). The suffix "-(o)yl" can be attached to other groups defined herein, such as aryl, cycloalkyl, and heterocyclyl, to define "aryloyl," "cycloalkanoyl," and "(heterocyclyl)oyl." These groups represent a carbonyl group substituted with aryl, cycloalkyl, or heterocyclyl, respectively. Each of "aryloyl", "cycloalkanoyl", and "(heterocyclyl)oyl" may be optionally substituted as defined for "aryl", "cycloalkyl", or "heterocyclyl".

[0245] The term "alkenyl," as used herein, refers to a monovalent, straight- or branched-chain, acyclic hydrocarbon group containing one, two, or three carbon-carbon double bonds. Non-limiting examples of alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl groups may be optionally substituted as defined herein for alkyl.

[0246] As used herein, unless otherwise specified, the term "alkoxy" refers to a group of the formula -OR, where R is C 1-6represents a chemical substituent of a group (which is an alkyl group). In some embodiments, alkyl groups can be further substituted as defined herein. The term "alkoxy" can be combined with other terms defined herein, such as aryl, cycloalkyl, or heterocyclyl, to define "arylalkoxy," "cycloalkylalkoxy," and "(heterocyclyl)alkoxy" groups, which represent alkoxy groups substituted with aryl, cycloalkyl, or heterocyclyl, respectively. Each of "arylalkoxy," "cycloalkylalkoxy," and "(heterocyclyl)alkoxy" can be optionally substituted, at each individual moiety, as defined herein.

[0247] As used herein, the term "alkoxyalkyl" refers to a group of the formula -LOR, where L is C 1-6 alkylene and R is C 1-6 An optionally substituted alkoxyalkyl is an alkoxyalkyl optionally substituted as described herein for alkyl.

[0248] The term "alkyl," as used herein, refers to a straight- or branched-chain acyclic saturated hydrocarbon group, which, if unsubstituted, has from 1 to 12 carbons, unless otherwise specified. In certain preferred embodiments, unsubstituted alkyls have from 1 to 6 carbons. Alkyl groups are exemplified by methyl, ethyl, n-propyl and isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, neopentyl, and the like, and may be optionally substituted, where valences permit, with one, two, three, or, for alkyl groups of two or more carbons, four or more, substituents independently selected from the group consisting of amino, aryl, aryloxy, azido, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heterocyclyl, (heterocyclyl)oxy, heteroaryl, hydroxy, nitro, thiol, silyl, cyano, alkylsulfonyl, alkylsulfinyl, alkylsulfenyl, =0, =S, -SOR (where R is amino or cycloalkyl), and =NR' (where R' is H, alkyl, aryl, or heterocyclyl). Each of the substituents may itself be unsubstituted or, where valences permit, substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0249] The term "alkylene" as used herein refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.

[0250] As used herein, the term “alkylamino” refers to a group of the formula —N(R N1 )2 or -NHR N1 (In the formula, R N1 is alkyl). The alkyl portion of an alkylamino may be optionally substituted as defined for alkyl. Each optional substituent of a substituted alkylamino may itself be unsubstituted or, to the extent valence allows, substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0251] As used herein, the term "alkylsulfenyl" refers to a group of formula -S-(alkyl), which may be optionally substituted as defined for alkyl.

[0252] The term "alkylsulfinyl" as used herein represents a group of the formula -S(O)-(alkyl), which may be optionally substituted as defined for alkyl.

[0253] The term "alkylsulfonyl," as used herein, represents a group of formula -S(O)-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

[0254] The term "alkynyl," as used herein, refers to a monovalent straight or branched chain hydrocarbon group of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, and is exemplified by ethynyl, 1-propynyl, and the like. Alkynyl groups can be unsubstituted or substituted (e.g., optionally substituted alkynyl) as defined for alkyl.

[0255] As used herein, the term "amino" refers to -N(R N1 )2, and when amino is unsubstituted, R N1 are both H; if the amino is substituted, each R N1 are independently H, -OH, -NO2, -N(R N2 )2, -SO2OR N2 , -SO2R N2 , -SOR N2 , -COOR N2 , an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, arylalkyl, aryloxy, cycloalkyl, cycloalkenyl, heteroalkyl, or heterocyclyl, provided that at least one R N1 is not H, but each R N2is independently H, alkyl, or aryl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group. In some embodiments, amino may be unsubstituted amino (i.e., —NH) or substituted amino (e.g., —NHR N1 ), in which case R N1 are independently -OH, SO2OR N2 , -SO2R N2 , -SOR N2 , -COOR N2 , optionally substituted alkyl, or optionally substituted aryl, and each R N2 may be an optionally substituted alkyl or an optionally substituted aryl. In some embodiments, the substituted amino may be an alkylamino, where the alkyl group is optionally substituted as described herein for alkyl. In some embodiments, the amino group is -NHR N1 and R N1 is an optionally substituted alkyl.

[0256] The term "aryl," as used herein, refers to a monocyclic, bicyclic, or polycyclic carbocyclic ring system having one or two aromatic rings. Aryl groups can contain 6 to 10 carbon atoms. All atoms in an unsubstituted carbocyclic aryl group are carbon atoms. Non-limiting examples of carbocyclic aryl groups include phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like. Aryl groups can be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfinyl, alkylsulfenyl, alkylsulfonyl, amino, aryl, aryloxy, azido, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heteroalkyl, heterocyclyl, (heterocyclyl)oxy, hydroxy, nitro, thiol, silyl, and cyano. Each of the substituents may itself be unsubstituted or may be substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0257] As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group. The aryl and alkyl portions may be optionally substituted as described herein, as may the individual groups.

[0258] The term "arylene," as used herein, refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

[0259] The term "aryloxy," as used herein, unless otherwise specified, represents a chemical substituent of formula -OR, where R is an aryl group. In an optionally substituted aryloxy, the aryl group is optionally substituted as described herein for aryl.

[0260] As used herein, the term "ATR inhibitor" refers to an inhibitor that, when contacted with the enzyme ATR kinase, whether in vitro, in cell culture, or in an animal, reduces the activity of ATR kinase and reduces the IC of ATR kinase. 50 The IC50 of ATR kinase is 10 μM or less (e.g., 5 μM or less or 1 μM or less). 50 The IC50 of ATR kinase can be 100 nM or less (e.g., 10 nM or less, or 1 nM or less), and can be as low as 100 pM or 10 pM. 50 is 1 nM to 1 μM (for example, 1 nM to 750 nM, 1 nM to 500 nM, or 1 nM to 250 nM).

[0261] As used herein, the term "ATR kinase" refers to ataxia-telangiectasia- and RAD-3-related protein kinase. The term "azido" as used herein refers to an -N3 group.

[0262] The term "cancer," as used herein, refers to any type of cancer, neoplasm, or malignant tumor found in mammals (e.g., humans), including leukemia, carcinoma, and sarcoma. Non-limiting examples of cancers that can be treated with the compounds or methods provided herein include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, and pancreatic cancer. Additional non-limiting examples may include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, cancer, malignant insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasms, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, and prostate cancer.

[0263] The term "carbocyclic" as used herein refers to an optionally substituted C3-16 monocyclic, bicyclic, or tricyclic structure in which the ring is formed by carbon atoms, which may be aromatic or non-aromatic. Carbocyclic structures include cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, and certain aryl groups.

[0264] The term "carbonyl" as used herein refers to a -C(O)- group. The term "carcinoma," as used herein, refers to a malignant new growth composed of epithelial cells that tend to infiltrate surrounding tissues and give rise to metastases. Non-limiting examples of carcinomas that can be treated with the compounds or methods provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma, thyroid ... basocellulare), basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebrumoid carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, endometrial carcinoma, cribriform carcinoma, armor-like carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma , encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, childhood embryonic carcinoma, carcinoma in situ in situ), intraepithelial carcinoma, intraepithelial carcinoma carcinoma, Chromosome pecker carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0265] As used herein, the term "cyano" refers to a -CN group. As used herein, unless otherwise specified, the term "cycloalkenyl" refers to a non-aromatic carbocyclic group having at least one double bond and 3 to 10 carbons in the ring (e.g., C 3-10

[0023] Cycloalkenyl groups refer to cycloalkenyl groups. Non-limiting examples of cycloalkenyl groups include cycloprop-1-enyl, cycloprop-2-enyl, cyclobut-1-enyl, cyclobut-1-enyl, cyclobut-2-enyl, cyclopent-1-enyl, cyclopent-2-enyl, cyclopent-3-enyl, norbornen-1-yl, norbornen-2-yl, norbornen-5-yl, and norbornen-7-yl. Cycloalkenyl groups can be unsubstituted or substituted (e.g., optionally substituted cycloalkenyl), as described for cycloalkyl.

[0266] The term "cycloalkenylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkenyl group, each as defined herein. The cycloalkenyl and alkyl portions may be substituted as individual groups as defined herein.

[0267] The term "cycloalkoxy," as used herein, unless otherwise specified, refers to a chemical substituent of formula -OR, where R is a cycloalkyl group. In some embodiments, the cycloalkyl group can be further substituted as defined herein.

[0268] As used herein, unless otherwise specified, the term "cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbons (e.g., C 3-C10Cycloalkyl groups refer to groups having cyclic or bicyclic ring structures, such as bicyclo[pqO]alkyl, where p and q are each independently 1, 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively, bicyclic cycloalkyl groups can include bridged cycloalkyl structures, e.g., bicyclo[pqr]alkyl, where r is 1, 2, or 3 and p and q are each independently 1, 2, 3, 4, 5, or 6, provided that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. Cycloalkyl groups can also be spirocyclic groups, e.g., spiro[pq]alkyl, where p and q are each independently 2, 3, 4, 5, 6, or 7, provided that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl, 2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl, 7-bicyclo[2.2.1.]heptyl, and decalinyl. A cycloalkyl group can be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents (e.g., optionally substituted cycloalkenyl), which substituents are independently alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silyl; cyano; =0; =S; -SOR (where R is amino or cycloalkyl); =NR' (where R' is H, alkyl, aryl, or heterocyclyl); or -CON(R A )2(in the formula, each R A are independently H or alkyl, or both R Aare selected from the group consisting of: and together with the atom to which they are attached form a heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each respective group.

[0269] The term "cycloalkylalkyl," as used herein, refers to an alkyl group substituted with a cycloalkyl group, each as defined herein. The cycloalkyl and alkyl portions may be optionally substituted like the individual groups described herein.

[0270] The term "cycloalkylene" as used herein refers to a divalent cycloalkyl group. An optionally substituted cycloalkylene is an optionally substituted cycloalkylene as described herein for cycloalkyl.

[0271] The term "cycloalkynyl," as used herein, unless otherwise specified, refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having 8 to 12 carbons. A cycloalkynyl can include one transannular bond or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononynyl, cyclodecynyl, and cyclodecadiynyl. Cycloalkynyl groups can be unsubstituted or substituted (e.g., optionally substituted cycloalkynyl) as defined for cycloalkyl.

[0272] "Disease" or "condition" refers to a condition or state of a patient or subject that can be treated by the compounds or methods provided herein. The term "halo" as used herein refers to a halogen selected from bromine, chlorine, iodine, and fluorine.

[0273] The term "heteroalkyl," as used herein, refers to an alkyl, alkenyl, or alkynyl group that is interrupted once by one or two heteroatoms; twice, independently each time, by one or two heteroatoms; three times, independently each time, by one or two heteroatoms; or four times, independently each time, by one or two heteroatoms. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group contains two adjacent oxygen or sulfur atoms. Heteroalkyl groups can be unsubstituted or substituted (e.g., optionally substituted heteroalkyl). When a heteroalkyl is substituted and a substituent is attached to a heteroatom, the substituent is selected according to the nature and valence of the heteroatom. Thus, substituents attached to a heteroatom can include, where valence permits, ═O, —N(R N2 )2, -SO2OR N3 , -SO2R N2 , -SOR N3 , -COOR N3 , an N-protecting group, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, or cyano, wherein each R N2 is independently H, alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl, and each R N3 is independently alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted with unsubstituted substituent(s) as defined herein for each group. When a heteroalkyl is substituted and the substituent is bonded to a carbon atom, the substituent is selected from those described for alkyl, unless the substituent on the carbon atom bonded to the heteroatom is Cl, Br, or I. It is understood that the carbon atom is at the terminal end of the heteroalkyl group.

[0274] The term "heteroarylalkyl," as used herein, refers to an alkyl group substituted with a heteroaryl group, each as defined herein. The heteroaryl and alkyl portions may be optionally substituted as individual groups described herein.

[0275] The term "heteroarylene" as used herein refers to a divalent heteroaryl. An optionally substituted heteroarylene is an optionally substituted heteroarylene as described herein for heteroaryl.

[0276] The term "heteroaryloxy," as used herein, refers to the structure --OR, where R is heteroaryl. Heteroaryloxy may be optionally substituted as defined for heterocyclyl.

[0277] The term "heterocyclyl," as used herein, unless otherwise specified, refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having a fused, bridged, and / or spiro 3-, 4-, 5-, 6-, 7-, or 8-membered ring containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having a fused or bridged 5-, 6-, 7-, or 8-membered ring containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless otherwise specified. A heterocyclyl can be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyls have zero or one double bond, non-aromatic 6- and 7-membered heterocyclyl groups have zero to two double bonds, and non-aromatic 8-membered heterocyclyl groups have zero to two double bonds and / or zero or one carbon-carbon triple bond. Heterocyclyl groups, unless otherwise specified, contain 1 to 16 carbon atoms. Certain heterocyclyl groups can contain up to 9 carbon atoms. Non-aromatic heterocyclyl groups include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, etc. When a heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, such structure is an aromatic heterocyclyl (i.e., heteroaryl).Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, quinazolinyl, quinolinyl, thiadiazolyl (e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term "heterocyclyl" also refers to heterocyclic compounds having bridged polycyclic structures in which one or more carbon and / or heteroatoms bridge two non-adjacent members of a monocyclic ring, such as quinuclidine, tropane, or diaza-bicyclo[2.2.2]octane. The term "heterocyclyl" includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles is fused to one, two, or three carbon rings, such as an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocycle. Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. Heterocyclyl groups can be unsubstituted or substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfinyl, alkylsulfenyl, alkylsulfonyl, amino, aryl, aryloxy, azido, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkynyl, halo, heteroalkyl, heterocyclyl, (heterocyclyl)oxy, hydroxy, nitro, thiol, silyl, cyano, =0, =S, =NR', where R' is H, alkyl, aryl, or heterocyclyl. Each of the substituents can itself be unsubstituted or substituted with the unsubstituted substituent(s) defined herein for each respective group.

[0278] The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with a heterocyclyl group, each as defined herein. The heterocyclyl and alkyl portions may be optionally substituted as individual groups described herein.

[0279] The term "heterocyclylene" as used herein refers to a divalent heterocyclyl. An optionally substituted heterocyclylene is an optionally substituted heterocyclylene as described herein for heterocyclyl.

[0280] The term "(heterocyclyl)oxy," as used herein, unless otherwise specified, represents a chemical substituent of formula -OR, where R is a heterocyclyl group. The (heterocyclyl)oxy may be optionally substituted as defined for heterocyclyl.

[0281] The terms "hydroxyl" and "hydroxy", used interchangeably herein, refer to an --OH group. The term "isotopically enriched" as used herein refers to a pharmaceutical active agent in which the isotopic content of one isotope at a given position in the molecule is at least 100 times greater than the natural abundance of this isotope.For example, an isotopically enriched composition for deuterium includes an active agent in which the abundance of deuterium at the position of at least one hydrogen atom is at least 100 times greater than the natural abundance of deuterium.Preferably, the isotopic enrichment of deuterium is at least 1000 times greater than the natural abundance of deuterium.More preferably, the isotopic enrichment of deuterium is at least 4000 times (for example, at least 4750 times, for example, up to 5000 times) greater than the natural abundance of deuterium.

[0282] The term "leukemia," as used herein, broadly refers to a progressive, malignant disease of the blood-forming organs, generally characterized by the incorrect proliferation and development of white blood cells and their precursors in the blood and bone marrow. Leukemias are generally classified clinically based on (1) the duration and nature of the disease (acute or chronic); (2) the cell types involved: bone marrow (myeloid), lymph (lymphoid), or monocytic; and (3) the increased or absent number of leukemic or nonleukemic (subleukemic) abnormal cells. Exemplary leukemias that can be treated with the compounds or methods provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, acute myelocy ... Leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.

[0283] The term "lymphoma" as used herein refers to cancer arising from cells of immune origin. Non-limiting examples of T-cell and B-cell lymphomas include non-Hodgkin's lymphoma and Hodgkin's disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom's macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL) / follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia / lymphoma (ATLL), or extranodal NK / T-cell lymphoma, nasal type.

[0284] As used herein, the term "melanoma" is intended to mean a tumor originating from the melanocyte system in the skin and other organs. Melanomas that can be treated with the compounds or methods provided herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0285] The term "nitro" as used herein refers to the group --NO.sub.2. The term "oxo," as used herein, refers to a divalent oxygen atom (eg, the structure of oxo may be depicted as ═O).

[0286] The term "Ph" as used herein refers to phenyl. As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a government regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablets, capsules, caplets, gelcaps, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate embolic material and in a solvent system suitable for intravenous use); or any other formulation described herein.

[0287] The terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used interchangeably herein, refer to any ingredient (e.g., a vehicle capable of suspending or dissolving an active compound) other than the compounds described herein that has the properties of being non-toxic and non-inflammatory to a patient. Excipients can include, for example, anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (pigments), emollients, emulsifiers, bulking agents (diluents), film-forming agents or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or water for hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0288] As used herein, the term "pharmaceutically acceptable salt" means that the salt is suitable for use in contact with the tissues of humans and animals, within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or can be prepared separately by reacting the free base with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, Examples of the salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate.Representative alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, such as, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

[0289] As used herein, the terms "premalignant" or "precancerous" refer to a condition that is not malignant but has a tendency to become malignant. Non-limiting examples of premalignant conditions include myelodysplastic syndromes, colonic polyps, actinic keratosis of the skin, cervical dysplasia, pulmonary metaplasia, and leukoplakia.

[0290] As used herein, the term "protecting group" refers to a group intended to prevent a hydroxy, amino, or carbonyl group from participating in one or more undesired reactions during chemical synthesis. As used herein, the term "O-protecting group" refers to a group intended to prevent a hydroxy or carbonyl group from participating in one or more undesired reactions during chemical synthesis. As used herein, the term "N-protecting group" refers to a group intended to prevent a nitrogen-containing (e.g., amino, amido, NH heterocycle, or hydrazine) group from participating in one or more undesired reactions during chemical synthesis. Commonly used O-protecting and N-protecting groups are described in Greene, "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York, 1999), which are incorporated herein by reference. Exemplary O-protecting and N-protecting groups include alkanoyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-isopropylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylphenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl.

[0291] Exemplary O-protecting groups for protecting carbonyl-containing groups include, but are not limited to, acetals, acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and 1,3-dithiolanes.

[0292] Other O-protecting groups include substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., For example, trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenylmethylsilyl; carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

[0293] Other N-protecting groups include protected or unprotected D-amino acids, L-amino acids, or chiral auxiliaries such as D,L-amino acids, such as alanine, leucine, and phenylalanine; sulfonyl-containing groups, such as benzenesulfonyl and p-toluenesulfonyl; carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethylbenzyloxycarbonyl, ... t-butyloxycarbonyl, diisopropyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; aryl-alkyl groups, such as benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl, and the like; silyl alkyl acetal groups, such as [2-(trimethylsilyl)ethoxy]methyl; and silyl groups, such as trimethylsilyl, and the like. Useful N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0294] The term "tautomer" refers to structural isomers that are readily interconvertible, often by migration of a proton. Tautomers are distinct chemical species that can be distinguished by differences in spectroscopic properties but are usually inseparable from one another. Non-limiting examples of tautomers include ketone-enol, enamine-imine, amide-imidic acid, nitroso-oxime, ketene-ynol, and amino acid-ammonium carboxylate.

[0295] In general, the term "sarcoma" refers to a tumor composed of dense, solid cells that are composed of a substance like embryonic connective tissue and are usually embedded in a fibrous or homogeneous substance. Non-limiting examples of sarcomas that can be treated with the compounds or methods provided herein include, for example, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, and Ewing's sarcoma. , fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemia sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0296] The term "subject," as used herein, refers to a human or non-human animal (e.g., a mammal) that has been determined by a qualified professional (e.g., a doctor or nurse) to be suffering from or at risk for a disease or condition, with or without clinical testing(s) of a sample(s) from the subject, as known in the art. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases with symptoms of cellular hyperproliferation, such as cancer.

[0297] As used herein, "treatment" or "treating" refers to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent, or cure a disease or condition. This term encompasses active treatment (treatment directed at ameliorating the disease or condition); causal treatment (treatment directed at the cause of the associated disease or condition); symptomatic treatment (treatment designed to alleviate the symptoms of the disease or condition); preventative treatment (treatment directed at minimizing or partially or completely suppressing the onset of the associated disease or condition); and adjunctive treatment (treatment used to supplement another therapy). [Effects of the Invention]

[0298] According to the present invention, an anti-cancer therapy based on an ATR inhibitor can be provided. DETAILED DESCRIPTION OF THE INVENTION

[0299] In general, the present invention provides compounds, pharmaceutical compositions containing the same, methods for preparing the compounds, and methods of use. The compounds of the present invention can be ATR kinase inhibitors. Such compounds can be used to inhibit ATR kinase in cells, e.g., in the cells of a subject. The subject can be in need of treatment for a disease or condition, e.g., a disease or condition with symptoms of cellular hyperproliferation, e.g., cancer. The ATR kinase inhibitory activity of the compounds disclosed herein is useful for treating subjects in need of cancer treatment. Non-limiting examples of cancers that can be treated using the compounds disclosed herein are provided in Foote et al., J. Med. Chem., 61:9889-9907, 2018; Wengner et al., Mol. Cancer Ther., doi:10.1158 / 1535-7163.MCT-19-0019; and Dillon and Harrington, "Targeting ATR for Cancer Therapy: ATR-Targeted Drug Candidates" in Targeting the DNA Damage Response for Anti-Cancer Therapy, Eds.: Pollard and Curtin; Humana Press, Cham (2018), pp. 99-127.

[0300] The present invention relates to a compound of formula (I):

[0301] [ka]

[0302] [In the formula,

[0303] [ka]

[0304] is a double bond, and each Y is independently N or CR 4 or

[0305] [ka]

[0306] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y )2, where each R Y are independently H or optionally substituted C 1-6 is alkyl; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and; R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl; Each R 4 are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl; Each R 5 are independently hydrogen, optionally substituted C1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 is aryl; R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Q is an optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8Cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 is arylene; and X is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

[0307] The compounds of the present invention are, for example, compounds of formula (II):

[0308] [ka]

[0309] [In the formula, Each Y is independently N or CR 4 and; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 is optionally replaced by C 2-9 Heterocyclyl, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, halogen, -N(R 5 )2, -OR 5 , -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A , or -QR 5B and; R 3 is optionally replaced by C 1-9 Heteroaryl or optionally substituted C 1-9 Heteroaryl C 1-6 is alkyl; Each R 4are independently hydrogen, halogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 alkenyl, or optionally substituted C 2-6 is alkynyl; Each R 5 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 6-10 is aryl; R 5B is hydroxyl, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, -SO2R 5A or optionally substituted alkoxy; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkoxyalkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 3-8 cycloalkyl, or optionally substituted C 1-9heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Q is an optionally substituted C 2-9 Heterocyclylene, optionally substituted C 3-8 Cycloalkylene, optionally substituted C 1-9 heteroarylene, or optionally substituted C 6-10 is arylene; X is hydrogen or halogen] or a pharmaceutically acceptable salt thereof.

[0310] In some embodiments, in the compound of Formula (II), (I), or (Ib), Each Y is independently N or CR 4 and; R 1 is H or optionally substituted C 1-6 is alkyl; R 2 is optionally replaced by C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted C 2-9 Heterocyclyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, optionally substituted C 1-9 Heteroaryl C 1-6 Alkyl, -N(R 5 )2, -CON(R 6 )2, -SO2N(R 6 )2, or -SO2R 5A and; R 3 is optionally replaced by C 1-9 is heteroaryl; Each R 4 are independently H or optionally substituted C 1-6 is alkyl; Each R 5 are independently hydrogen, optionally substituted C 1-6Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 Aryl, optionally substituted C 1-9 Heteroaryl, or -SO2R 5A and each R 5A are independently optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 cycloalkyl; or both R 5 together with the atoms to which they are attached, optionally substituted C 2-9 forming a heterocyclyl; Each R 5A are independently optionally substituted C 1-6 Alkyl or optionally substituted C 3-8 is cycloalkyl; Each R 6 are independently hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 6-10 Aryl C 1-6 Alkyl, optionally substituted C 6-10 aryl, or optionally substituted C 1-9 heteroaryl; or both R 6 together with the atoms to which they are attached, optionally substituted C 2-9 Forming a heterocyclyl.

[0311] The compounds of the present invention are, for example, compounds of formula (Ia):

[0312] [ka]

[0313] [In the formula, Y, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compounds of the present invention are, for example, compounds of formula (Ib):

[0314] [ka]

[0315] [In the formula, Y, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compounds of the present invention are, for example, compounds of formula (IA):

[0316] [ka]

[0317] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (IA) can be, for example, the compound of formula (IA-a):

[0318] [ka]

[0319] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compounds of the present invention are, for example, compounds of formula (IB):

[0320] [ka]

[0321] [In the formula, R1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (IB) is, for example, the compound of formula (IB-a):

[0322] [ka]

[0323] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compounds of the present invention are, for example, compounds of formula (IC):

[0324] [ka]

[0325] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (IC) is, for example, the compound of formula (IC-a):

[0326] [ka]

[0327] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compounds of the present invention are, for example, compounds of formula (ID):

[0328] [ka]

[0329] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. The compound of formula (ID) is, for example, a compound of formula (ID-a):

[0330] [ka]

[0331] [In the formula, R 1 , R 2 , R 3 , and R 4 is as described for formula (I), or a pharmaceutically acceptable salt thereof. Preferably, R 1 is methyl.

[0332] In the compounds of the present invention, R 2 is, for example, optionally substituted C 3-8 For example, R 2 is the formula (A):

[0333] [ka]

[0334] [In the formula, n is 0, 1, 2, or 3; R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, and each R Aare independently H or alkyl, or both R A together with the atoms to which they are bonded, C 2-9 It can be a group of the formula: forming a heterocyclyl.

[0335] In the compounds of the present invention, R 2 is, for example, optionally substituted C 1-6 Alkyl (e.g., optionally substituted tertiary C 3-6 alkyl). For example, R 2 is the formula (B):

[0336] [ka]

[0337] [In the formula, R 7 is hydrogen, alkylsulfonyl, cyano, -CON(R A )2, -SON(R A )2, optionally replaced by C 1-9 heteroaryl, hydroxy, or alkoxy, where each R A are independently H or alkyl, or both R A together with the atoms to which they are bonded, C 2-9 It can be a group of the formula: forming a heterocyclyl.

[0338] In the compounds of the present invention, R 2 is, for example, an optionally substituted non-aromatic C 2-9 It may be a heterocyclyl. In the compounds of the present invention, R 2 For example,

[0339] [ka]

[0340] [ka]

[0341] [ka]

[0342] It could be. In the compounds of the present invention, R 3 is, for example, an optionally substituted monocyclic C ring containing at least one nitrogen atom (e.g., two nitrogen atoms). 1-9 For example, R 3 is expressed by the formula (C):

[0343] [ka]

[0344] wherein A is an optionally substituted monocyclic C 1-9 is a heteroaryl ring. In some compounds of the invention, A may be, for example, a group of formula (C1):

[0345] [ka]

[0346] [In the formula, R 8 is hydrogen, halogen, or optionally substituted C 1-6 It can be a group of the formula: In the compounds of the present invention, R 3 For example,

[0347] [ka]

[0348] It could be. In the compounds of the present invention, R 3 For example,

[0349] [ka]

[0350] It could be. In the compounds of the present invention, R 4 can be, for example, hydrogen. The compound of the invention can be, for example, a compound listed in Table 1 below, or a pharmaceutically acceptable salt thereof.

[0351] [Table 1-1]

[0352] [Table 1-2]

[0353] [Table 1-3]

[0354] [Table 1-4]

[0355] [Table 1-5]

[0356] [Table 1-6]

[0357] [Table 1-7]

[0358] [Table 1-8]

[0359] [Table 1-9]

[0360] [Table 1-10]

[0361] [Table 1-11]

[0362] The present invention includes (where possible) individual diastereomers, enantiomers, epimers, and atropisomers of the compounds disclosed herein, as well as mixtures of diastereomers and / or enantiomers thereof, including racemic mixtures. While the specific stereochemistry disclosed herein is preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures thereof, may also have utility in treating ATR-mediated disorders. Inactive or less active diastereoisomers and enantiomers may be useful, for example, for scientific studies related to the receptor and activation mechanisms.

[0363] It is understood that a particular molecule may exist in more than one tautomeric form, and the invention includes all tautomers, even if only one tautomer is shown in the examples.

[0364] The present invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions containing the compounds and a pharmaceutically acceptable carrier. Such compounds are particularly useful, for example, in certain types of cancer and for slowing the progression of cancer after it has developed in a patient.

[0365] The compounds disclosed herein can be used in pharmaceutical compositions containing (a) the compound(s) or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier. The compounds can be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients. The compounds can be used in pharmaceutical compositions in which the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, are the only active ingredient.

[0366] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers The compounds disclosed herein may contain, for example, one or more stereocenters and may exist as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and / or enantiomers. The present invention includes all such isomeric forms of the compounds disclosed herein. All possible stereoisomers (e.g., enantiomers and / or diastereomers) in mixtures and as pure or partially purified compounds are intended to be included within the scope of the present invention (i.e., all possible combinations of stereocenters, either as pure compounds or in mixtures).

[0367] Some of the compounds described herein may contain bonds that are rotationally hindered, which can be advantageous in that two individual rotamers, or atropisomers, can be separated and detected as having different biological activities. All possible atropisomers are intended to be encompassed within the scope of the present invention.

[0368] Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. One example is a ketone and its enol form, known as keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed by the present invention.

[0369] Compounds disclosed herein that possess one or more asymmetric centers can be separated into diastereoisomers, enantiomers, etc. by methods well known in the art. Alternatively, enantiomers and other compounds containing chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and / or reagents of known configuration.

[0370] Metabolites-prodrugs The present invention includes therapeutically active metabolites, which are themselves encompassed within the scope of the claims. The present invention also includes prodrugs, which are compounds that are converted to the claimed compounds during or after administration to a patient. The claimed chemical structures of this use may themselves be prodrugs in some cases.

[0371] Isotopically enriched derivatives The present invention includes molecules that are isotopically enriched at one or more positions within the molecule, and therefore, compounds enriched with deuterium are encompassed within the scope of the claims.

[0372] Methods for preparing the compounds of the present invention The compounds of the invention can be prepared using reactions and techniques known in the art and those described herein.

[0373] Method A The compounds of the present invention can be prepared as shown in Scheme A and described herein. Commercially available 4-cyano-7-azaindole can be hydrolyzed to the acid and esterified under standard conditions. Regiospecific chlorination of the 6-position can be achieved by oxidation of the 7-aza with an oxidizing agent, such as mCPBA, followed by chlorination with mesyl chloride. The indole nitrogen can be protected with a suitable protecting group (PG), such as SEM or THP. The 6-chloro can be optionally catalyzed by palladium(0) or copper(I)-catalyzed S NThe ester can then be derivatized by reduction to the alcohol with a suitable reducing agent, e.g., LiBH4 or DIBAL-H, activated by forming a mesylate or iodo group, and displaced with sodium methanesulfinate to form a methyl sulfone. Benzylic cyclopropanation can be achieved using dibromoethane in the presence of a base and a phase transfer catalyst. Deprotection of the azaindole then provides the key intermediate, which can be converted to the appropriate aryl or heteroaryl iodide (R 3 -I) to form the compounds of the present invention. 3 may require a deprotection step using acid, base, and / or fluoride conditions to provide the compounds of the invention.

[0374] [ka]

[0375] Method B Compounds of the present invention can also be prepared as shown in Scheme B and described herein. Commercially available 4-chloro-7-azaindole can be activated for nucleophilic substitution by oxidation of the 7-aza group and methylation with dimethyl sulfate. Addition of an appropriately substituted morpholine followed by in situ elimination of methanol affords 6-morpholinoazaindole. An aryl or heteroaryl group (R 3 ) can be attached via a copper-mediated arylation reaction. Depending on the nature of the heteroaryl group, placement of a protecting group may be required prior to this coupling reaction. The 4-chloro group can be derivatized in several different ways to obtain compounds of the invention. For example, palladium- or copper-mediated coupling can be used to add R 2 An aryl or heteroaryl group can be introduced at the R 2 is a substituted amine, S NChloride displacement can be achieved under Ar or Buchwald-type coupling conditions. Sulfides can also be used to displace the 4-chloro group, which can be optionally oxidized to form sulfones. R 3 If carries a protecting group, a deprotection step using acid, base, and / or fluoride conditions may be required to obtain the compounds of the invention.

[0376] [ka]

[0377] Method C The compounds of the present invention can be prepared from key intermediate A, which is shown in Scheme C and can be prepared as described herein. Protected 5-aminopyrazoles can be prepared by condensing the appropriate aldehyde with hydrazine hydrate and acrylonitrile. Subsequent condensation with a dialkyl oxaloacetate in refluxing acetic acid generates the substituted azaindazole. Activation of the hydroxyl group with triflic anhydride followed by nucleophilic displacement with a morpholine derivative generates key intermediate A.

[0378] [ka]

[0379] Method D Intermediate A can be converted to compounds of the invention by conversion to an alkyl ester as shown in Scheme D and described herein. For example, treatment of intermediate A with a reducing group such as DIBAL-H, LiBH, or NaBH generates a primary alcohol, which can be activated with a reagent such as MsCl or TsCl. Displacement of the leaving group with an alkyl sulfonate provides a benzyl sulfone, which can be alkylated under basic conditions with an alkyl halide. Subsequent deprotection and arylation as described in Method A provides compounds of the invention.

[0380] [ka]

[0381] Method E Compounds of the invention can be prepared from intermediate A, as shown in Scheme E and described herein. Intermediate A can be treated with an alkylating agent, such as methylmagnesium bromide, to convert the alkyl ester group to a tertiary alcohol. This material can be deprotected and arylated as described in Method A to provide compounds of the invention.

[0382] [ka]

[0383] Method F The compounds of the present invention can be prepared from intermediate A, shown in Scheme F and described herein. Intermediate A can be deprotected under acidic conditions and then arylated under copper-catalyzed conditions. The ester group can then be reduced and activated with an agent, such as mesyl chloride or tosyl chloride, optionally in the presence of lithium iodide. Subsequent displacement with sodium cyanide provides arylacetonitriles, exemplary compounds of the present invention. These compounds can be alkylated with alkyl halides in the presence of a base to provide dialkylated arylacetonitriles, compounds of the present invention. When R X is a dihaloalkane, the corresponding cyclic derivatives are formed in which the two R groups form 3- to 7-membered rings. Alternatively, primary alcohols can be coupled with cyanohydrins under Mitsunobu conditions to directly provide nitrile derivatives. The nitriles can also be hydrolyzed to primary amides under basic conditions or in the presence of a metal catalyst to provide compounds of the present invention.

[0384] [ka]

[0385] Method G Compounds of the invention can be prepared as shown in Scheme G and described herein. N-protected 5,7-dichloro-3H-imidazo[4,5-b]pyridine is treated with an arylboronic acid under palladium catalysis to afford the appropriate R 2 The second chloro substituent can be introduced by optionally palladium(0) or copper(I) catalyzed S N Under Ar conditions, the morpholine can be suitably substituted and removed. Removal of the protecting group and subsequent arylation as described in Method A provides compounds of the invention.

[0386] [ka]

[0387] Method H Compounds of the invention are shown in Scheme H and can be prepared as described herein. Addition of an alkyl Grignard reagent to a protected azaindole as described in Method A generates a tertiary alcohol. Removal of the protecting group on the azaindole followed by arylation as described in Method A provides compounds of the invention.

[0388] [ka]

[0389] Method I The compounds of the present invention can be prepared from intermediate A, as shown in Scheme I and described herein. The ester of intermediate A can be hydrolyzed to the corresponding acid, followed by treatment with the amide under amide-forming conditions using a suitable coupling reagent, such as EDC or HATU. Deprotection of the azaindole then provides the key intermediate, which can be coupled to a suitable aryl or heteroaryl iodide (R 3 -I) to form the compounds of the present invention. 3may require a deprotection step using acid, base, and / or fluoride conditions to provide the compounds of the invention.

[0390] [ka]

[0391] Method J Compounds of the invention can be prepared as shown in Scheme J and described herein. The ester intermediate from Method F can be hydrolyzed to the corresponding acid under standard conditions, for example, with aqueous LiOH or NaOH. This acid can be coupled with a hydrazine using an activating agent, such as CDI or EDC, to generate a hydrazide. This can be formylated (R=H) or acylated (R=alkyl, aryl) to generate a diacylhydrazine, which can be cyclized to generate compounds of the invention. Cyclization with POCl3 generates an oxadiazole. Cyclization with Lawesson's reagent generates a thiadiazole. Protecting groups can be added to facilitate this cyclization, such as R. 3 may require a deprotection step using acid, base, and / or fluoride conditions to provide the compounds of the invention.

[0392] [ka]

[0393] Method K Compounds of the invention can be prepared as shown in Scheme K and described herein. 5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridine can be prepared by the optional palladium(0) or copper(I) catalyzed Scheme K. N The triazolyl nitrogen can be substituted with an appropriate aryl or heteroaryl iodide (R 3 -I) and derivatized by palladium- or copper-catalyzed coupling with the appropriate R 3The 7-chloro group can be introduced. Regiospecific chlorination at the 7-position can be achieved by 3-azaoxidation with an oxidizing agent, such as mCPBA, followed by chlorination with mesyl chloride. The 7-chloro group can be derivatized in several different ways to obtain compounds of the invention. For example, palladium- or copper-mediated coupling can be used to introduce R 2 An aryl or heteroaryl group can be introduced at the R 2 is a substituted amine, S N Chloride displacement can be achieved under Ar or Buchwald-type coupling conditions. Sulfides can also be used to displace the 4-chloro group, which can be optionally oxidized to form sulfones. Protecting groups to facilitate this cyclization are available as R 3 may require a deprotection step using acid, base, and / or fluoride conditions to provide the compounds of the invention.

[0394] [ka]

[0395] Method L 2,6-Difluoro-4-iodopyridine can be formylated by metallation with a strong base and trapping with a suitable formylating agent, such as ethyl formate. The resulting aldehyde can be condensed with an appropriately substituted pyrazole hydrazine to form the corresponding hydrazine, which can be cyclized to the azaindazole by heating to elevated temperatures. The fluorine substituent on the azaindazole can be converted to S N Elimination with an appropriately substituted morpholine under Ar conditions affords key intermediate B. Protection of the pyrazole NH with an appropriate protecting group affords key intermediate C, usually as a mixture of N-protected regioisomers.

[0396] [ka]

[0397] Method M Compounds of the invention can be prepared as shown in Scheme M and described herein by treating key intermediate C with an arylboronic acid under palladium catalysis to afford the appropriate R 2 A protecting group can be introduced. Removal of the protecting group affords the compounds of the invention.

[0398] [ka]

[0399] Method N Compounds of the invention are shown in Scheme N and can be prepared as described herein. Metallation of key intermediate C with an alkyllithium or alkylmagnesium halide can generate an aryllithium or arylmagnesium bromide, which can be added to an appropriate ketone to generate a tertiary alcohol derivative. If the ketone contains deuterium enrichment at one or more positions, the resulting product will also be isotopically enriched in deuterium. Removal of the protecting group affords the compounds of the invention. Alternatively, if no protecting group is present, key intermediate B can be used to carry out this chemistry and directly afford compounds of the invention.

[0400] [ka]

[0401] Method O Compounds of the invention can be prepared as shown in Scheme O and described herein. Key intermediate C is treated with a carbon-, nitrogen-, or sulfur-based nucleophile to remove the iodo group and form the appropriate R 2 A protecting group can be introduced. Removal of the protecting group affords the compounds of the invention.

[0402] [ka]

[0403] Method P Compounds of the invention can be prepared as shown in Scheme P and described herein. Treatment with a brominating agent introduces a bromine atom at the 3-position of the azaindazole ring to provide compounds of the invention. Treatment with an alkylstannane, vinylstannane, or arylstannane under Pd catalysis provides compounds of the invention.

[0404] [ka]

[0405] Method Q Compounds of the invention can be prepared as shown in Scheme Q and described herein. 2,6-difluoro-4-iodonicotinaldehyde is cyclized with hydrazine to form 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine, followed by S-reaction with a substituted morpholine. N The resulting intermediate can be subjected to a second S-reaction with 2-cyanopropane under basic conditions. N Ar reaction can be performed to give the disubstituted azaindazole ring system. Ullmann coupling at the NH of the azaindazole followed by deprotection gives the compounds of the present invention.

[0406] [ka]

[0407] Method R Compounds of the invention are shown in Scheme R and can be prepared as described herein. Intermediate C can be converted to a boronic acid reagent by treatment with bis(pinacolato)diboron, a palladium catalyst, and base. This boronic acid can then be treated with an aryl halide or aryl triflate under palladium catalysis to afford the appropriate R 2 A protecting group can be introduced. Removal of the protecting group affords the compounds of the invention.

[0408] [ka]

[0409] Method S Compounds of the invention can be prepared as shown in Scheme R and described herein. Intermediate C can be chlorinated at the 5-position. The resulting intermediate can be treated with an arylboronic acid or arylboronic ester under palladium catalysis to afford the appropriate R 2 A protecting group can be introduced. Removal of the protecting group affords the compounds of the invention.

[0410] [ka]

[0411] Method T The compounds of the present invention can be prepared as shown in Scheme T and described herein. 2,6-Difluoro-4-iodo-pyridine-3-carboxaldehyde can be treated with a substituted morpholine to selectively remove the 6-fluoro substituent. Oxidation of the aldehyde is followed by hydrazide formation with a suitably protected heterocyclic hydrazine. The hydrazide can be cyclized under basic conditions to form an iodopyrazolopyridinone ring system. This intermediate can then be converted to an S-type nucleophile by a carbon, oxygen, or sulfur nucleophile. N Ar reaction or, preferentially, palladium-catalyzed treatment with arylboronic acids to afford the appropriate R 2 Subsequent removal of the protecting group provides the compounds of the invention.

[0412] [ka]

[0413] Treatment method The compounds of the present invention can be used to treat a disease or condition mediated by ATR kinase in a subject by administering an effective amount of a compound of the present invention to the subject.

[0414] The disease or condition may have a symptom of cellular hyperproliferation. For example, the disease or condition may be cancer. The cancer may be, for example, carcinoma, sarcoma, adenocarcinoma, lymphoma, leukemia, or melanoma. The cancer may be, for example, a solid tumor.

[0415] Non-limiting examples of cancer include prostate cancer, breast cancer, ovarian cancer, multiple myeloma, brain cancer, glioma, lung cancer, salivary gland cancer, gastric cancer, thymic epithelial carcinoma, thyroid cancer, leukemia, melanoma, lymphoma, gastrointestinal cancer, pancreatic cancer, kidney cancer, bladder cancer, colon cancer, and liver cancer.

[0416] Non-limiting examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, and basal cell carcinoma. basocellulare), basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebrumoid carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, endometrial carcinoma, cribriform carcinoma, armor-like carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma , encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, childhood embryonic carcinoma, carcinoma in situ in situ), intraepithelial carcinoma, intraepithelial carcinoma carcinoma, Chromosome pecker carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tuberous carcinoma, verrucous carcinoma, and choriocarcinoma.

[0417] Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

[0418] Non-limiting examples of leukemias include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross' leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphoma, and leukemia. Leukemias include lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

[0419] Non-limiting examples of melanoma include acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

[0420] The compounds of the present invention can be administered by a route selected from the group consisting of oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, intratumoral, and topical administration.

[0421] The method of the present invention may include a step of identifying a subject as a candidate for ATR inhibitor therapy. For example, a subject can be identified as a candidate for ATR inhibitor therapy by determining whether or not the subject has (i) a cancer associated with a defect in the ATM signaling cascade; (ii) a cancer, cancer cells, or cells with a genetically abnormal expression of a cancer-promoting gene or an oncogene; (iii) a cancer, cancer cells, or cells with one or more defects in a protein or gene involved in base excision repair; (iv) a cancer associated with a defect in a protein or gene involved in homologous recombination; (v) a cancer associated with a defect in a protein or gene involved in sensitivity to an ATR inhibitor or genetic perturbation of ATR; or (vi) a cancer associated with a gene or protein characteristic involved in sensitivity to an ATR inhibitor.

[0422] The compounds, compositions, and methods described can be used to treat subjects with cancers associated with abnormalities in the ATM signaling cascade. For example, abnormalities in the ATM signaling cascade can be, for example, alterations in the expression or activity of one or more of the following proteins / genes, including, but not limited to, ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, H2AX, MCPH1 / BRIT1, CTIP, and SMC1. Abnormalities in ATM signaling can be identified as follows: A 20% or greater change in CHK2 phosphorylation can be indicative of abnormalities in the ATM signaling cascade. Alternatively, abrogation of cell arrest in the G1 and S phases of the cell cycle in response to double-stranded DNA breaks can be indicative of abnormalities in the ATM signaling cascade.

[0423] The compounds, compositions, and methods described can be used to treat subjects with cancer, cancer cells, or cells with aberrant expression of cancer-promoting proteins or oncogenes. For example, cancer cells may have genetic abnormalities that cause altered expression or activity of one or more of the following proteins / genes: KRAS, NRAS, HRAS, BRAF, MYC, MOS, E2F, CDC25A, CDC4, CDK2, CCNE1, CCNA1, DNAPK, APOBEC3, CDC6, and RB1.

[0424] The compounds, compositions, and methods described can be used to treat subjects with cancer, cancer cells, or cells with one or more abnormalities in proteins or genes involved in base excision repair. For example, abnormalities in base excision repair proteins can be altered expression or activity of one or more of the following proteins / genes, including but not limited to: UNG, SMUG1, MBD4, TDG, OGG1, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylase); APE1, APEX2 (AP endonuclease); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 cofactor); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly(ADP-ribose) polymerase); PolB, PolG (polymerase); FEN1 (endonuclease) or aprataxin.

[0425] The described compounds, compositions, and methods can be used to treat subjects having cancer, cancer cells, or cells with one or more abnormalities in proteins or genes involved in homologous recombination. For example, the abnormality in homologous recombination can be an alteration in the expression or activity of one or more of the following proteins / genes, including, but not limited to, BRCA1, BRCA2, MRE11, RAD50, RAD51, RAD52, RAD54L, NBN, ATM, H2AX, PALB2, RPA, BRIP1, BARD1, ATR, ATRX, CHK1, CHK2, MDM2, MDM4, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, and FANCL.

[0426] The described compounds, compositions, and methods can be used to treat subjects with cancer, cancer cells, or cells with one or more abnormalities in proteins or genes involved in sensitivity to ATR inhibitors or genetic perturbation of the ATR signaling pathway. For example, the abnormality in a gene involved in sensitivity to ATR inhibitors or genetic perturbation of ATR can be altered expression or activity of one or more of the following proteins / genes: ATR, CHK1, ERCC1, ERCC2, RAD17, RAD1, RAD9A, ERCC4, ATM, FANCE, GCP3, IDH1, PALB2, PMS2, ARID1A, SLX4, MSH4, RRM2, POLA, POLD1, RRM1, WEE1, CLSPN, PGBD5, XRCC1, XRCC3, XRCC5, KDM5D, CDC6, SLFN11, TLK1, and TLK2.

[0427] There are many methods known in the art for determining whether tumors have abnormalities in proteins or genes.For example, tumor samples can be subjected to sequencing of each designated gene (such as UNG, PARP1, or LIG1) either in genomic DNA or mRNA product to determine whether there are mutations that are predicted to regulate the function or expression of gene products.In addition to mutational inactivation, tumor cells can regulate genes by hypermethylating their promoter regions, thereby reducing gene expression.This is most commonly assessed using methylation-specific polymerase chain reaction (PCR), which quantifies the methylation level of the promoter of the target base excision repair gene.Analysis of DNA repair gene promoter methylation is commercially available.

[0428] Gene expression levels can be assessed by directly quantifying the levels of each gene's mRNA and protein products using standard techniques, such as quantitative reverse transcriptase-linked polymerase chain reaction (RT-PCR), RNA-Seq gene expression analysis, and immunohistochemistry (IHC) for protein expression. Gene amplification leading to aberrant protein overexpression or gene deletion leading to underexpression (respectively) can also be measured by FISH (fluorescence in situ hybridization) analysis using probes specific for the gene of interest.

[0429] The above methods (gene sequence, promoter methylation, and mRNA expression) can also be used to characterize the status (e.g., expression or mutation) of other genes or proteins of interest, such as DNA-damaging oncogenes expressed in tumors or due to defects in cellular DNA repair pathways.

[0430] The described compounds, compositions, and methods can be used to treat subjects suffering from cancers with genetic traits that are associated with sensitivity to ATR inhibitors. In some embodiments, the genetic traits are one or more of the following: cellular transformation in the absence of HTERT and / or ATRX mRNA or protein expression; the presence of C-circle or partial double-stranded and circular extrachromosomal telomeric repeats (ECTRs); the presence of telomeres of different lengths; and cells with selective elongation of telomeres (ALT), characterized by positive staining indicating the presence of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs).

[0431] There are several methods for determining ALT characteristics in cells. Non-limiting examples of these methods include: HTERT and ATRX expression can be measured by Western blot, immunohistochemistry (IHC), or mRNA expression (qRT-PCR) assay. The presence of C-rings can be measured by PCR assay, and the presence of telomeres of different lengths can be measured by telomere restriction fragment analysis (TRF), which uses terminal restriction fragment length distribution to measure the heterogeneity of the telomere length range in a cell population. Staining for the presence of APB can be performed using IHC by co-staining with probes for telomeric DNA and PML protein.

[0432] Pharmaceutical Composition The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biologically compatible form suitable for in vivo administration. Pharmaceutical compositions typically include a compound described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may also include one or more additional pharmaceutically active agents described herein.

[0433] The compounds described herein can also be used in the form of a free base, a salt, a zwitterion, a solvate, or a prodrug, or a pharmaceutical composition thereof. All forms are within the scope of the present invention. As will be understood by those skilled in the art, the compounds, salts, zwitterions, solvates, prodrugs, or pharmaceutical compositions thereof can be administered to patients in various forms depending on the selected route of administration. The compounds used in the methods described herein can be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via a patch, via a pump, or transdermally, and pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and topical modes of administration. Parenteral administration can be by continuous infusion over a selected period of time.

[0434] For human use, the compounds of the invention can be administered alone or in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Thus, pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and adjuvants that facilitate processing of the compounds of the invention into formulations and that can be used in pharmaceutically acceptable carriers.

[0435] The present invention also includes pharmaceutical compositions that may contain one or more pharmaceutically acceptable carriers. In preparing the pharmaceutical compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, it can be a solid, semi-solid, or liquid substance (e.g., normal saline) that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, and soft and hard gelatin capsules. As is known in the art, the type of diluent can vary depending on the intended route of administration. The resulting composition may also contain additional agents, such as preservatives.

[0436] Excipients or carriers are selected based on the mode and route of administration.Suitable pharmaceutical carriers and pharmaceutical essentials used in pharmaceutical preparations are described in the well-known reference books in the field, Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and USP / NF (United States Pharmacopoeia and National Formulary).Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.Preparation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methylbenzoate and propylhydroxybenzoate; sweeteners; and flavoring agents. Other exemplary excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

[0437] These pharmaceutical compositions can be prepared by conventional methods, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. Methods for preparing formulations well known in the art are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988-1999, Marcel Dekker, New York. Suitable formulations depend on the selected route of administration. The formulation and preparation of such compositions are well known to those skilled in the art of pharmaceutical formulation. When preparing a formulation, the active compound can be milled to an appropriate particle size before being combined with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size can be adjusted by milling to, for example, about 40 mesh, allowing for a more uniform distribution in the formulation.

[0438] Dosage The dosage of the compound used in the methods described herein, or its pharmaceutically acceptable salt or prodrug, or pharmaceutical composition thereof, can vary depending on many factors, such as the pharmacodynamic properties of the compound; the method of administration; the recipient's age, health, and weight; the nature and severity of symptoms; the frequency of treatment, and, if applicable, the type of concurrent treatment; and the clearance rate of the compound in the treated animal. Those skilled in the art can determine the appropriate dosage based on the above factors. The compound used in the methods described herein is initially administered at an appropriate dosage, and the dosage can be adjusted as necessary depending on the clinical response. In general, an appropriate daily dose of the compound of the present invention is considered to be the amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally vary depending on the above factors.

[0439] The compounds of the present invention can be administered to a patient in a single dose or multiple doses. When multiple doses are administered, the doses can be separated from each other, for example, by 1 to 24 hours, 1 to 7 days, 1 to 4 weeks, or 1 to 12 months. The compounds can be administered according to a schedule or without a set schedule. The active compounds can be administered, for example, once, twice, three, four, five, six, seven, eight, nine, ten, eleven, or twelve times daily; every two, three, four, five, or six days; once, two, three, four, five, six, or seven times weekly; once, two, three, four, five, or six times monthly; or once, two, three, four, five, six, seven, eight, nine, ten, eleven, or 12 times yearly. It should be understood that specific dosage regimens for a particular subject will need to be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the compositions.

[0440] Although the appropriate amount and dosing regimen will ultimately be determined by the attending physician, an effective amount of a compound of the present invention can be, for example, a total daily dose, e.g., 0.05 mg to 3000 mg, of any of the compounds described herein. Alternatively, the dose can be calculated using the patient's body weight. Such dose ranges can include, for example, 10 to 1000 mg (e.g., 50 to 800 mg). In some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the compound is administered.

[0441] In the methods of the present invention, the duration over which multiple doses of a compound of the present invention are administered to a patient can vary. For example, in some embodiments, doses of a compound of the present invention are administered to a patient over a period of 1 to 7 days; 1 to 12 weeks; or 1 to 3 months. In some embodiments, the compound is administered to a patient over a period of, for example, 4 to 11 months or 1 to 30 years. In some embodiments, the compound is administered to a patient at the onset of symptoms. In any of these embodiments, the amount of compound administered can vary over the course of administration. If the compound is administered daily, it can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times daily.

[0442] formulation Using any of the methods described herein, a compound identified as capable of treating any of the conditions described herein can be administered to a patient or animal in unit dosage form with a pharmaceutically acceptable diluent, carrier, or excipient. Chemical compounds for use in such therapy can be prepared and isolated by any standard techniques known to those skilled in the art of medicinal chemistry. Conventional pharmaceutical practice can be used to provide suitable formulations or compositions for administering the identified compound to a patient suffering from a disease or condition. Administration may begin before the patient exhibits symptoms.

[0443] Exemplary routes of administration of a compound (e.g., a compound of the present invention) or a pharmaceutical composition thereof used in the present invention include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intraorbital, intraventricular, intraspinal, intraperitoneal, intranasal, inhalation, and topical administration. The compound is preferably administered with a pharmaceutically acceptable carrier. Pharmaceutical formulations of the compounds described herein formulated for treating the disorders described herein are also part of the present invention.

[0444] Oral administration formulation Pharmaceutical compositions contemplated by the present invention include those formulated for oral administration ("oral dosage forms"), which may be in the form of, for example, tablets, capsules, liquid solutions or suspensions, powders, or liquid crystals or solid crystals, which contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients. Such excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugars, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricants, glidants, and antiadherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, buffering agents, and the like.

[0445] Formulations for oral administration may also be present as chewable tablets, as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. Powders, granules, and pellets can be prepared using the ingredients described above for tablets and capsules in conventional manner, for example, using a mixer, fluidized bed apparatus, or spray-drying apparatus.

[0446] Controlled-release compositions for oral use can be constructed to release the active drug by controlling the dissolution and / or diffusion of the active drug substance. Achieving controlled release and a targeted plasma concentration versus time profile can be accomplished by any of several means. In one example, controlled release is achieved by appropriate selection of various formulation parameters and ingredients, including, for example, various types of controlled-release compositions and coatings. Examples include single- or multi-unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches, and liposomes. In some embodiments, the compositions include a biodegradable, pH-, and / or temperature-sensitive polymer coating.

[0447] Dissolution or diffusion controlled release can be achieved by suitable coating of tablets, capsules, pellets, or granules of the compound, or by incorporating the compound in a suitable matrix. Controlled release coatings can include one or more of the coating materials mentioned above and / or, for example, shellac, beeswax, glycowax, castor oil wax, carnauba wax, stearyl alcohol, glyceryl monostearate, glyceryl distearate, glycerol palmitostearate, ethyl cellulose, acrylic resin, dl-polylactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinylpyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate, and / or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methylcellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and / or halogenated fluorocarbons.

[0448] Liquid forms into which the compounds and compositions of the present invention can be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions using edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical vehicles.

[0449] Parenteral administration formulations The compounds described herein for use in the methods of the present invention can be administered in pharmaceutically acceptable parenteral (e.g., intravenous or intramuscular) formulations described herein. Pharmaceutical formulations can also be administered parenterally (intravenously, intramuscularly, subcutaneously, etc.) in dosage forms or formulations containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants. In particular, formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. For example, to prepare such compositions, the compounds of the present invention can be dissolved or suspended in a parenterally acceptable liquid vehicle. Acceptable vehicles and solvents that can be used include water, water adjusted to an appropriate pH with an appropriate amount of hydrochloric acid, sodium hydroxide, or a suitable buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Aqueous formulations can also contain one or more preservatives, such as methyl, ethyl, or n-propyl p-hydroxybenzoate. Additional information regarding parenteral formulations can be found, for example, in the United States Pharmacopeia-National Formulary (USP-NF), which is incorporated herein by reference.

[0450] Parenteral formulations are classified into five general types of preparations identified by the USP-NF as suitable for parenteral administration: (1) "Drug injection solution": a liquid preparation of a drug substance (e.g., a compound of the present invention) or a solution thereof; (2) "Injectable drug": A drug substance (e.g., a compound of the present invention) as a dry solid combined with a sterile vehicle suitable for parenteral administration as a drug injection; (3) "Drug Injectable Emulsion": A liquid preparation of a drug substance (e.g., a compound of the present invention) dissolved or dispersed in a suitable emulsion vehicle; (4) "Drug Injectable Suspension": A liquid preparation of a drug substance (e.g., a compound of the present invention) suspended in a suitable liquid medium; (5) "Drug for injectable suspension": Any drug substance (e.g., a compound of the present invention) as a dry solid combined with a sterile vehicle suitable for parenteral administration as a drug for injectable suspension.

[0451] Exemplary formulations for parenteral administration include aqueous solutions of the compound, suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), as well as in oils. Under normal storage and use conditions, these preparations may contain preservatives to prevent the growth of microorganisms. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0452] Formulations for parenteral administration may contain, for example, excipients such as sterile water or saline, polyalkylene glycols such as polyethylene glycol, vegetable oils, or hydrogenated naphthalene. Biocompatible, biodegradable lactide polymers, lactide / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of the compounds. Other potentially useful parenteral compound delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Inhalation formulations may contain excipients such as lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate, and deoxycholate, or oily solutions for administration in the form of nasal drops or as gels.

[0453] Parenteral formulations can be formulated for immediate release or sustained / extended release of the compound. Exemplary formulations for parenteral release of the compound include aqueous solutions, powders for reconstitution, co-solvent solutions, oil / water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels.

[0454] combination The compounds of the present invention may be administered in combination with one or more additional agents, e.g. (a) cytotoxic agents; (b) antimetabolites; (c) alkylating agents; (d) anthracyclines; (e) antibiotics; (f) antimitotic agents; (g) hormone therapy; (h) signal transduction inhibitors; (i) Gene expression regulators; (j) apoptosis inducers; (k) angiogenesis inhibitors; (l) immunotherapeutic agents; (m) DNA damage repair inhibitors; or combinations of these can be administered to a subject in combination with

[0455] Cytotoxic agents include, for example, actinomycin-D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, Mycobacterium bovis (BCG), bendamustine, bexarotene, bevacizumab, bleomycin, bortezomib, busulfan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, and crizastatin. Intaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubicin, 1-dehydrotestosterone, denileukin, dexamethasone, dexrazoxane, dihydroxyanthracin dione, disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, Floxuridine, fludarabine, fluorouracil (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferon, interferon alpha-2a, interferon alpha-2b, ixabepilone, lactate dehydrogenase A (LDH-A), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine , melphalan, 6-mercaptopurine, mesna, methotrexate, methoxsalen, metoprine, metronidazole, mithramycin, mitomycin-C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprelvekin, oxaliplatin, paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, porfimer sodium, procaine, procarbazine, propranolol,The agent may be puromycin, quinacrine, radicicol, a radioisotope, raltitrexed, rapamycin, rasburicase, salinosporamide A, sargramostim, sunitinib, temozolomide, teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

[0456] The antimetabolite can be, for example, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuridine, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof.

[0457] The alkylating agent can be, for example, mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamineplatinum(II) (DDP) cisplatin, altretamine, cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozotocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectedin, semustine, or a combination thereof.

[0458] The anthracycline can be, for example, daunorubicin, doxorubicin, acarrubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof.

[0459] Antibiotics include, for example, dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticarcillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, cephalosporins, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demecloxacillin, The anti-inflammatory drug may be iclin, minocycline, oxytetracycline, tetracycline, penicillin, amoxicillin, cephalexin, erythromycin, clarithromycin, azithromycin, ciprofloxacin, levofloxacin, ofloxacin, doxycycline, clindamycin, metronidazole, tigecycline, chloramphenicol, metronidazole, tinidazole, nitrofurantoin, vancomycin, teicoplanin, telavancin, linezolid, cycloserine, rifamycin, polymyxin B, bacitracin, viomycin, capreomycin, quinolone, daunorubicin, doxorubicin, 4'-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin-c, mitoxantrone, or a combination thereof.

[0460] The antimitotic agent can be, for example, vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoids, dolastatins, cryptophycins, or combinations thereof.

[0461] The signal transduction inhibitor can be, for example, imatinib, trastuzumab, erlotinib, sorafenib, sunitinib, temsirolimus, vemurafenib, lapatinib, bortezomib, cetuximab, panitumumab, matuzumab, gefitinib, STI 571, rapamycin, flavopiridol, imatinib mesylate, vatalanib, semaxinib, motesanib, axitinib, afatinib, bosutinib, crizotinib, cabozantinib, dasatinib, entrectinib, pazopanib, lapatinib, vandetanib, or a combination thereof.

[0462] Gene expression regulator can be, for example, siRNA, shRNA, antisense oligonucleotide, HDAC inhibitor, or a combination thereof.HDAC inhibitor can be, for example, trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinaline, mocetinostat, gibinostat, resminostat, abexinostat, xinostat, rosirinostat, pracinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or a combination thereof.Antisense oligonucleotide can be, for example, custorisen, apatursen, AZD9150, travedersen, EZN-2968, LErafAON-ETU, or a combination thereof. The siRNA can be, for example, ALN-VSP, CALAA-01, Atu-027, SPC2996, or a combination thereof.

[0463] The hormone therapy can be, for example, a luteinizing hormone-releasing hormone (LHRH) antagonist. The hormone therapy can be, for example, farmagon, leuproline, goserelin, buserelin, flutamide, bicalutamide, ketoconazole, aminoglutethimide, prednisone, hydroxylprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxyfene, 4-hydroxybenzoates, benzocaine, benzodiazepine ... It may be droxitamoxifen, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, triptorelin, histrelin, abiraterone, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, tretinoin, fenretinide, troxacitabine, or a combination thereof.

[0464] The apoptosis-inducing agent can be, for example, recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof.

[0465] The angiogenesis inhibitor can be, for example, sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof. The immunotherapeutic agent may be, for example, a monoclonal antibody, a cancer vaccine (e.g., a dendritic cell (DC) vaccine), an oncolytic virus, a cytokine, adoptive T cell therapy, Mycobacterium Calmette-Guérin (BCG), GM-CSF, thalidomide, lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody may be, for example, anti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody can be, for example, alemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, adotrastuzumab emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituximab, pertuzumab, tositumomab, gemtuzumab, ozogamicin, tositumomab, or a combination thereof. The cancer vaccine may be, for example, Sipuleucel-T, BioVaxID, NeuVax, DCVax, SuVaxM, CIMAvax®, Provenge®, hsp110 chaperone complex vaccine, CDX-1401, MIS416, CDX-110, GVAX pancreatic vaccine, HyperAcute™ pancreatic vaccine, GTOP-99 (MyVax®), or Imprime PGG®. The oncolytic virus may be, for example, talimogene laherparepvec. The cytokine may be, for example, IL-2, IFNα, or a combination thereof. The adoptive T cell therapy may be, for example, tisagenlecleucel, axicabtageneciloreucel, or a combination thereof.

[0466] DNA damage repair inhibitors can be, for example, PARP inhibitors, cell checkpoint kinase inhibitors, or combinations thereof.PARP inhibitors can be, for example, olaparib, rucaparib, veliparib (ABT-888), niraparib (ZL-2306), iniparib (BSI-201), talazoparib (BMN 673), 2X-121, CEP-9722, KU-0059436 (AZD2281), PF-01367338, or combinations thereof.Cell checkpoint kinase inhibitors can be, for example, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737, or combinations thereof. [Example]

[0467] The following examples are intended to illustrate the present invention. They are not meant to limit the invention in any way. Example 1. Preparation of Compounds compound 1 Step 1. A suspension of 4-chloro-7-azaindole (25 g) in DMA (140 mL) was purged with vacuum / N2 gas (3 cycles). Next, zinc powder (1.07 g), zinc cyanide (11.26 g), dppf (2.72 g), and Pd2(dba)3 (2.39 g) were added. The mixture was again purged with vacuum / N2 gas (3 cycles) and heated to 120 °C for 4 h. The reaction mixture was cooled to 100 °C, and water (428 mL) was added over 30 min. The mixture was then cooled to room temperature over 2 h. The crude product was filtered and washed with water (2 × 95 mL), then added to 3 N HCl (150 mL), and the mixture was stirred at room temperature for 2 h. Insoluble material was removed by filtration. 50% aqueous NaOH was added to the filtrate until a pH of 12 was reached. Filtration and drying gave 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (11.6 g) as a tan solid.

[0468] Step 2. A mixture of 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (10.4 g) and NaOH (29 g) in water (100 mL) and EtOH (100 mL) was heated to reflux for 18 hours. After cooling to room temperature, the mixture was treated with concentrated HCl to a pH of approximately 2. The solid was collected by filtration and dried under high vacuum to give 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (11.8 g) as a tan solid.

[0469] Step 3. To EtOH (120 mL) at 0°C was added thionyl chloride (12.4 mL) dropwise. After stirring the mixture at room temperature for 30 minutes, 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (12.0 g) was added, and the reaction mixture was heated to reflux for 8 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue thus obtained was suspended in water (150 mL), and the pH was adjusted to pH 9 with saturated aqueous K2CO3. The mixture was extracted with EtOAc (2 x 150 mL). The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness to give ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (10.5 g) as a tan solid.

[0470] Step 4. To a mixture of ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (9.5 g) in EtOAc (95 mL) was added mCPBA (15.5 g) portionwise at 0° C. The reaction mixture was warmed to room temperature and stirred for 3 hours. The precipitate was filtered and washed with EtOAc (3×30 mL), and the residue was dried under high vacuum to give 4-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (8.8 g) as a pale yellow solid.

[0471] Step 5. To a solution of 4-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (25.5 g) in DMF (250 mL) was added methanesulfonyl chloride (11.5 mL) dropwise. The mixture was then heated to 80°C for 1 hour, cooled to room temperature, and additional methanesulfonyl chloride (11.5 mL) was added. The mixture was again heated at 80°C for 1 hour. After cooling to 0°C, the reaction mixture was poured into ice water (480 mL) with vigorous stirring. The mixture was then stirred at 0°C for 2 hours. The precipitate was filtered and washed with water (3 x 200 mL). The residue was dried under high vacuum to give ethyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (25.0 g) as a beige solid, which was used in the subsequent step without further purification.

[0472] Step 6. To a solution of ethyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (25 g) in DMF (250 mL) at 0 °C was added NaH (6.68 g) over 45 min, followed by stirring at 0 °C for 1 h. SEM-Cl (23.6 mL) was added over 20 min, and the mixture was stirred at 0 °C for 1 h. Water (300 mL) was added slowly, and the mixture was extracted with EtOAc (2 × 200 mL), then washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (15–30% EtOAc / hexanes) to give ethyl 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (32.4 g) as an orange oil.

[0473] Step 7. To a solution of ethyl 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (32.3 g) in toluene (150 mL) was added (R)-3-methylmorpholine (12.4 mL), BINAP (3.4 g), and cesium carbonate (89 g). The mixture was degassed (three vacuum / argon cycles), palladium acetate (1.0 g) was added, and the reaction mixture was degassed again before being heated to 120 °C for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc (500 mL) and filtered through a pad of diatomaceous earth, washing with EtOAc (2 x 250 mL). The filtrate was concentrated to dryness under reduced pressure and purified by silica gel chromatography (0–40% EtOAc / hexanes) to afford ethyl (R)-6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (26 g) as a yellow oil.

[0474] Step 8. To a solution of ethyl (R)-6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (4.9 g) in 80 mL of THF was added MeOH (0.048 mL). The reaction mixture was heated to 65 °C, and then a solution of 2 M LiBH in 9 mL of THF was added dropwise over 1 h. The reaction mixture was stirred at 65 °C for 18 h. After cooling to room temperature, acetone (2 mL) was added and stirred at room temperature for 30 min. The mixture was diluted with a 1:1 saturated aqueous solution of NH Cl / water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (5-50% EtOAc / hexanes) to give (R)-(6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (3.9 g) as a yellow gum.

[0475] Step 9. To a solution of (R)-(6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (7.5 g) in dichloromethane (70 mL) was added triethylamine (2.8 mL) followed by methanesulfonyl chloride (1.55 mL) at 0° C. The reaction mixture was stirred at room temperature for 90 minutes and then diluted with dichloromethane (100 mL) and water (100 mL). The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness to give (R)-(6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl methanesulfonate (9 g) as a yellow gum, which was used in the subsequent step without further purification.

[0476] Step 10. To a solution of (R)-(6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methyl methanesulfonate (9 g) in dioxane (80 mL) was added LiI (5.3 g). The mixture was heated to 100° C. under argon for 2.5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and water (100 mL). The layers were partitioned, and the aqueous layer was extracted with EtOAc (80 mL). The combined organic extracts were washed with 2 M sodium bisulfite (80 mL), water (80 mL), brine (80 mL), dried over MgSO, filtered, and concentrated to give (R)-4-(4-(iodomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (9.6 g) as a dark oil, which was used directly in the subsequent step without further purification.

[0477] Step 11. To a solution of (R)-4-(4-(iodomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (9.6 g) in DMF (80 mL) was added sodium methanesulfinate (2.4 g). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL), the layers were partitioned, and the aqueous layer was extracted with EtOAc (80 mL). The combined organic extracts were washed with aqueous sodium thiosulfate (80 mL), water (80 mL), and brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10-90% EtOAc / hexanes) to give (R)-3-methyl-4-(4-((methylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (7.5 g) as a gray-green gum.

[0478] Step 12. To a solution of (R)-3-methyl-4-(4-((methylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (7.5 g) in toluene (80 mL) was added TBAB (1 g) and 50% NaOH (36 mL), followed by 1,2-dibromoethane (2 mL). The mixture was heated to 65° C. for 18 hours. Then, while the mixture was stirred at 65° C., additional 1,2-dibromoethane (16 mL) was added via syringe pump over 18 hours. The reaction mixture was aged at 65° C. for an additional 18 hours before being cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and water (150 mL), the layers were partitioned, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (10–80% EtOAc / hexanes) to give (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (5.4 g) as a yellow foam.

[0479] Step 13. To a solution of (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (5.4 g) in dichloromethane (50 mL) was added TFA (18 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 18 hours. Toluene (40 mL) was added and the mixture was concentrated. The residue was diluted with dioxane (40 mL) and the pH of the mixture was adjusted to pH 10 by adding 3N NaOH. The mixture was heated to 80° C. for 3 hours and then cooled to room temperature. The mixture was diluted with EtOAc (150 mL) and water (150 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (30-100% EtOAc / hexanes) to give (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (1.65 g) as a pale yellow foam.

[0480] Step 14. To a solution of 3-iodo-1H-pyrazole (2.5 g) in DMF (25 mL) was added cesium carbonate (9.43 g) at 0 °C. SEM-Cl (2.8 mL) was added over 15 min. The mixture was stirred at room temperature for 18 h. Water (60 mL) was added slowly, and the mixture was partitioned with EtO (60 mL). The aqueous layer was extracted with EtO (30 mL), and the combined organic extracts were washed with water (3 × 50 mL), brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (0–30% EtOAc / hexanes) to give 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (3.3 g) as a colorless liquid. H-NMR indicated a 1:1 ratio of two regioisomers.

[0481] Step 15. To (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (100 mg), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (145 mg), cesium carbonate (244 mg), and L-proline (21 mg) in a microwave vessel was added NMP (1 mL), followed by CuBr (20 mg). The vessel was capped and degassed (3 cycles of vacuum / argon) before being heated to 150 °C for 4 h. After cooling to room temperature, the reaction mixture was quenched with 20 mL of NH4Cl:HO:NH4OH (4:3:1) and EtOAc (15 mL), filtered through diatomaceous earth, and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (20–100% EtOAc / hexanes) to give (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (25 mg) as a mixture of regioisomers.

[0482] Step 16. To a solution of (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (25 mg) in dichloromethane (1 mL) was added TFA (0.2 mL). The reaction mixture was stirred at room temperature for 18 hours. Toluene (10 mL) was added and the volatiles were removed under reduced pressure. The residue was dissolved in dioxane (3 mL) and saturated aqueous NaHCO3 (3 mL), and the mixture was heated to 65°C for 18 hours and then to 80°C for 18 hours. After cooling to room temperature, the mixture was extracted with dichloromethane (2 x 15 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography (20–100% EtOAc / hexanes) to give the desired product, which was suspended in CH3CN (1 mL) and water (1 mL) and lyophilized to give (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (15 mg) as a pale yellow foam. 1 H NMR(400MHz,CDCl3):δ7.66(d;J=3.74Hz;1H);7.62(d;J=2.36Hz;1H);6.98(s;1H) );6.78(s;1H);6.59(d;J=3.76Hz;1H);4.32-4.37(m;1H);4.05-4.09(m;1H);3.87 -3.91(m;1H);3.83-3.84(m;2H);3.64-3.71(m;1H);3.28-3.35(m;1H);2.83(s;3H) );1.93-1.96(m;2H);1.39-1.42(m;2H);1.29(d;J=6.71Hz;3H).MS:[M+1]:402.2.

[0483] Intermediate A

[0484] [ka]

[0485] Step 1. To a cooled (0°C) solution of acrylonitrile (12.4 mL) in THF (75 mL) was added hydrazine monohydrate (8.7 mL) dropwise over 30 minutes to maintain an internal temperature below 10°C. The resulting mixture was stirred in an ice bath for 30 minutes and then warmed to room temperature for 3 hours. The mixture was cooled again in an ice bath and 2,4-dimethoxybenzaldehyde (31 g) was added over 10 minutes. The resulting mixture was stirred in an ice bath for 25 minutes and warmed to room temperature for 1 hour, then concentrated in vacuo and placed under high vacuum with stirring overnight to remove water.

[0486] The resulting residue was dissolved in n-BuOH (70 mL) and treated with NaOMe (20.4 g), resulting in a dark color and exotherm. The mixture was heated to reflux for 1 h, cooled to room temperature, and poured into brine. EtOAc was added, and the organic layer was separated, washed with brine, dried over MgSO, filtered through a pad of diatomaceous earth, and concentrated in vacuo. The material was placed under high vacuum to remove residual n-BuOH. This procedure was repeated on the same scale, and the combined material was purified by eluting with 1:1 EtOAc / hexanes on silica gel to give 35 g of 1-(2,4-dimethoxybenzyl)-1H-pyrazol-5-amine.

[0487] Step 2. To a solution of 1-(2,4-dimethoxybenzyl)-1H-pyrazol-5-amine (14 g) in AcOH (140 mL) was added diethyl oxalacetate sodium salt (16.1 g). The resulting suspension was placed in an oil bath and heated to reflux for 2 hours. The reaction was cooled in an ice bath and then slowly added to 440 mL of cold water via a dropping funnel with rapid stirring. The resulting suspension was stirred for 2 hours, filtered, rinsed with water, and air-dried overnight to give 19.2 g of ethyl 1-(2,4-dimethoxybenzyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate as a yellow solid.

[0488] Step 3. To a suspension of ethyl 1-(2,4-dimethoxybenzyl)-6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (11.0 g) in acetonitrile (100 mL) at 0 °C, pyridine (1.8 mL) was added, followed by triflic anhydride (3.8 mL) at a rate such that the internal temperature remained below 5 °C. The reaction mixture was allowed to warm to room temperature over 1 h, quenched with water (100 mL), and extracted with dichloromethane (2 × 100 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 10 g of ethyl 1-(2,4-dimethoxybenzyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate as a yellow solid, which was used in the subsequent step without further purification.

[0489] Step 4. To a solution of crude ethyl 1-(2,4-dimethoxybenzyl)-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (10 g) in DMF (100 mL) was added (R)-3-methylmorpholine (6.8 g) and pyridine (2.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 days and then diluted with water (100 mL) and EtOAc (120 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by ISCO CombiFlash (120 g column) eluting with 10-100% EtOAc / hexanes to give 5.8 g of ethyl (R)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (Intermediate A) as a yellow gum. LCMS (+ESI): m / z = 441.1 [M+H].

[0490] compound 2 Step 1. To a solution of Intermediate A (400 mg) in THF (4 mL) at -78 °C, MeMgBr (3M / EtO, 1 mL) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with cold saturated aqueous NH4Cl and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by ISCO CombiFlash (40 g column) eluting with 10-100% EtOAc / hexane to afford 380 mg of (R)-2-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol as a yellow oil.

[0491] Step 2. To a solution of (R)-2-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol (380 mg) in dichloromethane (4 mL) was added TFA (1.36 mL) at room temperature, and the solution was stirred for 18 hours. The volatiles were removed under reduced pressure, and the residue was suspended in EtOAc (30 mL) and washed with saturated aqueous NaHCO. The aqueous layer was extracted with EtOAc (20 mL), and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 160 mg of (R)-2-(6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol.

[0492] Step 3. (R)-2-(6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol (160 mg), SEM-protected 3-iodopyrazole (376 mg), CS2CO3 (475 mg), L-proline (13 mg), CuBr (13 mg), and NMP (3 mL) were placed in a microwave tube. The vessel was then capped, degassed (3 cycles of vacuum / argon), and heated to 150 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 mL) and then purified by ISCO CombiFlash (24 g column) eluting with 10-100% EtOAc / hexanes to give 100 mg of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol as a yellow gum. 1H-NMR and LCMS showed two regioisomers of the N-protected pyrazole by SEM.

[0493] Step 4. To a solution of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol (100 mg) in dichloromethane (1 mL) at room temperature was added TFA (0.211 mL) and the reaction mixture was stirred for 18 hours. Toluene (10 mL) was added and the volatiles were removed under reduced pressure. The flask was placed under high vacuum to remove residual TFA. The residue was diluted with dioxane (3 mL) and 1 N NaOH (1 mL) was added. The reaction mixture was heated to reflux for 3 hours, cooled to room temperature, and then diluted with EtOAc (20 mL) and water (20 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (12 g column) eluting with 40-100% EtOAc / hexanes. The desired product fractions were combined and concentrated to dryness. The residue was diluted with CHCN (1 mL) and water (1 mL) and lyophilized to afford 22 mg of the desired product, (R)-2-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol, as a colorless foam. Purity by HPLC at 254 nm: 93.0%, 1 H NMR(400MHz,CDCl3):δ8.12(s;1H);7.63(d;J=2.10Hz;1H);6.83(s;1H);6.72(s;1H);4.45-4.49(m;1H);4.02-4.09(m;2H) );3.77-3.86(m;3H);3.66(td;J=11.90;3.16Hz;1H);3.39(td;J=12.73;3.87Hz;1H);1.73(s;6H);1.35(d;J=6.74Hz;3H).

[0494] compound 3 Step 1. To a solution of Intermediate A (3.4 g) in THF (35 mL) was added MeOH (0.062 mL). The reaction mixture was heated to 65° C., and then a solution of 2 M LiBH4 in THF (5.8 mL) was added dropwise over 1 h. The reaction mixture was stirred at 65° C. for 4 h and then cooled to room temperature. Acetone (1 mL) was added and stirred at room temperature for 30 min. The mixture was diluted with a 1:1 saturated aqueous solution of NH4Cl / water (80 mL) and EtOAc (80 mL). The layers were partitioned, and the aqueous layer was extracted with EtOAc (40 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by ISCO CombiFlash (80 g column) eluting with 30–100% EtOAc / hexanes to give (R)-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)methanol and (R)-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-2H-pyrazolo[3,4-b]pyridin-4-yl)methanol as colorless foams (separable mixture of regioisomers).

[0495] Step 2. To a solution of (R)-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-2H-pyrazolo[3,4-b]pyridin-4-yl)methanol (600 mg) in dichloromethane (7 mL) was added triethylamine (0.141 mL) followed by methanesulfonyl chloride (0.254 mL) at 0° C. The reaction mixture was stirred at room temperature for 90 minutes and then diluted with dichloromethane (40 mL) and water (40 mL). The layers were partitioned, the aqueous layer was extracted with dichloromethane (30 mL), and the combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness to provide 700 mg of methyl (R)-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-2H-pyrazolo[3,4-b]pyridin-4-yl)methanesulfonate, which was used in the subsequent step without further purification.

[0496] Step 3. To a solution of (R)-(1-(2,4-dimethoxybenzyl)-6-(3-methylmorpholino)-2H-pyrazolo[3,4-b]pyridin-4-yl)methyl methanesulfonate (700 mg) in dioxane (7 mL) was added LiI (393 mg). The mixture was heated to 50° C. under argon for 2.5 hours. After cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and water (50 mL). The layers were partitioned, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with 2 M sodium bisulfite (50 mL), water (50 mL), and brine (50 mL), then dried over MgSO, filtered, and concentrated to dryness under reduced pressure to give 760 mg of (R)-4-(2-(2,4-dimethoxybenzyl)-4-(iodomethyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine, which was used directly in the subsequent step without further purification.

[0497] Step 4. To a solution of (R)-4-(2-(2,4-dimethoxybenzyl)-4-(iodomethyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (790 mg) in DMF (8 mL) was added sodium methanesulfinate (190 mg). The reaction mixture was stirred at room temperature for 2 h and then diluted with EtOAc (40 mL) and water (40 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with aqueous sodium thiosulfate (50 mL), water (50 mL), and brine, then dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. The residue was adsorbed onto silica gel and purified by Isco CombiFlash (40 g column) eluting with 30-100% EtOAc / hexanes to give 640 mg of (R)-4-(2-(2,4-dimethoxybenzyl)-4-((methylsulfonyl)methyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine as a colorless foam.

[0498] Step 5: To a solution of (R)-4-(1-(2,4-dimethoxybenzyl)-4-((methylsulfonyl)methyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (640 mg) in toluene (3 mL) was added TBAB (45 mg) and 1,2-dibromoethane (0.156 mL), followed by 50% NaOH (2.9 mL). The reaction mixture was heated to 60° C. for 2 h. Additional 1,2-dibromoethane (0.5 mL) was added, and the mixture was again heated at 60° C. for 18 h. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and water (25 mL), the layers were partitioned, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness under reduced pressure. The residue was adsorbed onto silica gel and purified by ISCO CombiFlash (24 g column) eluting with 30-100% EtOAc / hexanes to give 510 mg of (R)-4-(1-(2,4-dimethoxybenzyl)-4-(1-methylsulfonyl)cyclopropyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine as a pale yellow foam.

[0499] Step 6. (R)-3-Methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine: To a solution of (R)-4-(1-(2,4-dimethoxybenzyl)-4-(1-methylsulfonyl)cyclopropyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (510 mg) in dichloromethane (5 mL) was added TFA (1.6 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 5 h. Toluene (10 mL) was added to the reaction mixture, and the volatiles were removed in vacuo followed by co-evaporation with toluene (10 mL). The residue was dissolved in EtOAc (50 mL) and saturated aqueous NaHCO (40 mL) with vigorous stirring. The layers were partitioned, and the aqueous layer was extracted with EtOAc (30 mL). The combined extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness in vacuo to give 350 mg of (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine as a pale yellow foam, which was used in the next step without further purification.

[0500] Step 7. (R)-3-Methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine (160 mg), pyrazole (310 mg), CS2CO3 (390 mg), L-proline (11 mg), CuBr (11 mg), and NMP (2 mL) were placed in a microwave tube. The vessel was capped and degassed (three vacuum / argon cycles) before heating to 150 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 mL) and NH4Cl:HO:NH4OH (4:3:1, 20 mL) and then filtered through diatomaceous earth. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (24 g column) eluting with 20–100% EtOAc / hexanes to give (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine and the corresponding SEM-pyrazole regioisomer.

[0501] Step 8. To a solution of (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine (37 mg) in dichloromethane (1 mL) was added TFA (0.319 mL) and the reaction mixture was stirred for 18 hours. Toluene (10 mL) was added and the volatiles were removed under reduced pressure. The residue was dissolved in dioxane (3 mL) and saturated aqueous NaHCO (3 mL) and the mixture was heated to 65° C. for 4 hours and then to 80° C. for 18 hours. After cooling to room temperature, the mixture was extracted with dichloromethane (2×15 mL) and the combined organic extracts were washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by flash chromatography on a silica gel column eluted with EtOAc and 5% MeOH / EtOAc. The resulting residue was suspended in CHCN (2 mL) and water (2 mL) and lyophilized to give 23 mg of (R)-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine as a pale yellow foam. 1 H NMR(400MHz,CDCl3):δ8.11(s;1H);7.70(d;J=2.26Hz;1H);6.93(d;J=2.26Hz;1H);6.84(s;1H);4.41-4.43(m;1H);4.06-4.09(m;2H);3.77-3 .87(m;2H);3.61-3.68(m;1H);3.33-3.40(m;1H);2.85(s;3H);1.97-2. 00(m;2H);1.41-1.44(m;2H);1.35(d;J=6.78Hz;3H).[M+1]:m / z403.1.

[0502] compound 4 Step 1. To a solution of intermediate A (5.8 g, 13.167 mmol) in dichloromethane (60 mL) was added TFA (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 hours. Toluene (60 mL) was added, and the volatiles were removed under vacuum and by co-evaporation with toluene (20 mL). The residue was dissolved in dichloromethane (300 mL) and then treated with saturated aqueous NaHCO3 (200 mL) with vigorous stirring. The layers were separated, and the aqueous layer was extracted with dichloromethane (150 mL). The combined extracts were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo to give 3.8 g of ethyl (R)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate as a yellow solid, which was used in the next step without further purification.

[0503] Step 2. A mixture of (R)-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (3.8 g), pyrazole (6.37 g), CS2CO3 (10.7 g), L-proline (300 mg), CuBr (292 mg), and NMP (40 mL) was degassed (three vacuum / argon cycles) and heated to 150 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with 10% citric acid to adjust the pH to approximately 6-7, and EtOAc (350 mL) was added. The mixture was filtered through diatomaceous earth and washed with EtOAc. The layers were partitioned, and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-10% MeOH / dichloromethane, to give 3.6 g of (R)-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy))methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and its SEM regioisomer as yellow oils.

[0504] Step 3. To a solution of (R)-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.6 g) in DMF (36 mL) was added potassium carbonate (2.7 g) followed by iodomethane (0.6 mL). The reaction mixture was stirred at room temperature for 18 hours. EtOAc (50 mL) and water (50 mL) were added, the layers were separated, and the aqueous layer was extracted with EtOAc (40 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by ISCO CombiFlash (80 g column) eluting with 0-70% EtOAc / hexanes to give 2.2 g of methyl (R)-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate as a yellow solid.

[0505] Step 4. To a solution of methyl (R)-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (2.2 g) in THF (20 mL) and MeOH (0.038 mL) was added lithium borohydride (3.4 mL) at room temperature. The mixture was heated to 65° C. for 4 hours and then cooled to room temperature. Acetone (1 mL) was added and stirred for 30 minutes. The mixture was diluted with (1:1) NHCl / water (50 mL) and then extracted with EtOAc (2×40 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness in vacuo to provide 2 g of (R)-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)methanol, which was used without further purification.

[0506] Step 5. To a solution of (R)-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)methanol (2 g) in dichloromethane (20 mL) was added EtN (0.69 mL) followed by MsCl (0.38 mL) at 0 °C. The reaction was then stirred at room temperature for 2 h. The mixture was diluted with dichloromethane (60 mL) and water (60 mL). The layers were partitioned and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo to give 2.3 g of methyl (R)-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)methanesulfonate, which was used in the subsequent step without further purification.

[0507] Step 6. To a solution of (R)-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)methyl methanesulfonate (2.3 g) in DMF (18 mL) at room temperature was added NaCN (325 mg). The reaction mixture was stirred for 18 hours and then diluted with EtOAc (40 mL) and water (40 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by ISCO CombiFlash (24 g column) eluting with 20–100% EtOAc / hexanes to give 440 mg of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)acetonitrile.

[0508] Step 7. To a solution of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)acetonitrile (430 mg) in THF (5 mL) was added iodomethane (0.148 mL) followed by the dropwise addition of potassium tert-butoxide (2.37 mL) over 10 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, then poured into saturated aqueous NH4Cl and extracted with EtOAc (2×35 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (24 g Gold SiO column) eluting with 10–90% EtOAc / hexanes to give 140 mg of (R)-2-methyl-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanenitrile.

[0509] Step 8. To a solution of (R)-2-methyl-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanenitrile (90 mg) in EtOH / HO (2 mL / 0.4 mL) was added hydrido(dimethylphosphinite-kP) [hydrogen bis(dimethylphosphinite-kP)]platinum(II) (4 mg). The mixture was heated to 80 °C, then cooled and concentrated to dryness. The residue was purified by adsorption onto silica via ISCO CombiFlash (12 g Gold SiO column) eluting with 30-100% EtOAc / hexanes to give 82 mg of (R)-2-methyl-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanamide as a colorless solid.

[0510] Step 9. To a solution of (R)-2-methyl-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanamide (81 mg) in dichloromethane (2 mL) was added TFA (0.30 mL) and the reaction mixture was stirred at room temperature for 18 hours. Additional TFA (0.5 mL) was added and the mixture was stirred for 6 hours. Toluene (10 mL) was added and the volatiles were removed under reduced pressure. The residue was diluted with 5 mL of MeOH / water (85:15) and stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in EtOAc (25 mL) and treated with saturated aqueous NaHCO3 (20 mL). The layers were partitioned and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness in vacuo. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (12 g Gold SiO column) eluting with 80–100% EtOAc / hexanes to afford 23 mg of (R)-2-methyl-2-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanamide as a colorless foam. 1 H NMR(400MHz,DMSO):δ12.80(s;1H);7.90(s;1H);7.83(s;1H);7.06(s;1H);7.02(s ;1H);6.76-6.77(m;1H);6.65(s;1H);4.47-4.50(m;1H);4.06(d;J=13.56Hz;1H); 3.99(d;J=11.46Hz;1H);3.78(d;J=11.34Hz;1H);3.63-3.66(m;1H);3.47-3.53(m ;1H);3.17-3.23(m;1H);1.54(s;6H);1.22(d;J=6.68Hz;3H).MS(+ESI):m / z370.2.

[0511] compound 5 Step 1. To a solution of (R)-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazole[3,4-b]pyridin-4-yl)methanol (115 mg) obtained from Step 5 of Example 4 and 2-hydroxyisobutyronitrile (0.07 mL) in dry toluene (10 mL) were added tributylphosphine (0.2 mL) and TMAD (133.6 mg), and the resulting mixture was stirred at room temperature for 1 hour, then diluted with water and extracted with EtOAc. The organic extract was dried and concentrated to dryness and then purified by Combi-Flash (12 g column) eluting with 10-80% EtOAc / hexanes to give 110 mg of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)acetonitrile as a pale yellow oil.

[0512] Step 2: To a solution of (R)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)acetonitrile (68 mg) in toluene (2 mL) was added tetrabutylammonium bromide (9.66 mg) and 50% NaOH (0.5 mL), followed by 1,5-dibromopentane (0.027 mL). The mixture was heated to 65° C. for 2 hours, then diluted with water and extracted with EtOAc. The combined organic extracts were dried over NaSO, concentrated to dryness, and purified by Combi-Flash (4 g column) eluting with 20–80% EtOAc / hexanes to give 54 mg of (R)-1-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexane-1-carbonitrile as a pale yellow oil.

[0513] Step 3. To a solution of (R)-1-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexane-1-carbonitrile (54 mg) in dichloromethane (2 mL) was added TFA (0.27 mL). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The residue was dissolved in 5 mL of MeOH / HO (85:15), stirred at room temperature for 18 hours, and concentrated. The residue was dissolved in EtOAc (25 mL) and saturated aqueous NaHCO (25 mL) was added. The layers were partitioned, and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (4 g column) eluting with 30-100% EtOAc / hexanes to give 11 mg of (R)-1-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclohexane-1-carbonitrile as an off-white foam. 1 H NMR(400MHz,CDCl3):δ1.37(d;3H);1.96(d;5H);2.09(t;2H);2.29(d;2H);3.39(td;1H);3.65(td;1 H);3.87-3.77(m;2H);4.08(d;3H);4.49(d;1H);6.82(s;1H);6.99(d;1H);7.80(d;1H);8.22(s;1H).

[0514] compound 6 Step 1. To a mechanically stirred suspension of 4-chloro-1H-pyrrolo[2,3-b]pyridine (35 g) in EtOAc (600 mL) at 0 °C, mCPBA (51.41 g) was added portionwise over 30 minutes. The reaction mixture was then stirred at room temperature for 18 hours, and the solid was collected by filtration and washed with n-heptane (350 mL). The residue was dried under high vacuum to give 62 g of 4-chloro-1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate as a gray solid.

[0515] Step 2. To a mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (30 g) in acetonitrile (300 mL) was added dimethyl sulfate (9.6 mL) and the reaction mixture was heated to 60° C. for 18 hours. After cooling to room temperature, (R)-3-methylmorpholine (14 g) was added, followed by diisopropylethylamine (48.2 mL), and the reaction mixture was heated to 60° C. for 18 hours. After cooling to room temperature, the volatiles were removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 10-40% EtOAc / hexane to afford 12 g of (R)-4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine as a light gray solid.

[0516] Step 3. A mixture of (R)-4-(4-chloro-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (11.64 g), iodopyrazole (15.11 g), CuI (81 mg), trans-N,N-dimethylcyclohexane-1,2-diamine (0.66 mL), and KPO (17.23 g) in dioxane (110 mL) was purged with argon three times and heated to 110 °C for 18 h. The mixture was cooled and filtered through a pad of silica gel, eluting with EtOAc (700 mL). The filtrate was concentrated to dryness in vacuo and then purified by flash chromatography on silica gel, eluting with 10–25% EtOAc / hexane. Pure fractions were combined and concentrated to give 19.3 g of (R)-4-(4-chloro-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine as a mixture of SEM regioisomers.

[0517] Step 4. To a solution of (R)-4-(4-chloro-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (5.0 g), bis(pinacolato)diboron (4.25 g), Pd(dba) (510 mg), and tricyclohexylphosphine (780 mg) in dioxane (70 mL) was added potassium acetate (3.32 g). The mixture was purged with argon and heated to 100° C. overnight, then cooled, diluted with ethyl acetate, and filtered through a pad of diatomaceous earth. The filtrate was concentrated to dryness, and the reaction conditions were resubmitted. After overnight, the reaction mixture was diluted with ethyl acetate, filtered through a pad of diatomaceous earth, and concentrated to dryness. Purification by column chromatography eluting with 0-50% ethyl acetate / hexanes gave 4.38 g of (R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine as a yellow powder.

[0518] Step 5. To a 1-dram vial containing (R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (106 mg), 2-bromophenylmethylsulfone (93 mg), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg) was added dioxane (1 mL) and 2 N NaCO (250 μL). The mixture was evacuated and purged with argon (3 times) and heated at 120 °C for 24 h, then cooled and partitioned between water and ethyl acetate. The organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified on a Redisep Gold Column (12 g) using 0-100% ethyl acetate / hexanes to give 76 mg of (R)-3-methyl-4-(4-(2-(methylsulfonyl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine.

[0519] Step 6: To a solution of (R)-3-methyl-4-(4-(2-(methylsulfonyl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (76 mg) in dichloromethane (2 mL) was added TFA (0.45 mL). The reaction was stirred overnight at room temperature, then concentrated, redissolved in 85 / 15 MeOH / HO, and stirred for an additional 4 h. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The crude material was purified on a Redisep column (24 g) eluting with 40-60% ethyl acetate / hexanes to give 58 mg of (R)-3-methyl-4-(4-(2-(methylsulfonyl)phenyl)-1-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine.1 H NMR(d6-DMSO)δ12.7(s,1H),8.2(d1H),7.8(m,1H),7.7(m,2H),7.6(m1H),7.5(m1H),7.0(s,1H) ,6.7(s,1H),4.3(m,1H),4.0(m,1H),3.7(m,2H),3.5(m,1H),3.2(m,1H),2.9(s,3H),1.2(d3H).

[0520] compound 7 Step 1. To a solution of 4-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide 3-chlorobenzoate (508 mg) in acetonitrile (10 mL) was added 3-chlorobenzoic acid (275 mg) and dimethyl sulfate (0.29 mL), and the reaction was heated at 60° C. for 36 hours. After cooling, (R)-3-methylmorpholine (423 mg) and DIPEA (1.45 mL) were added, and the reaction was heated at 60° C. for 26 hours. The reaction mixture was concentrated and purified by silica gel chromatography using 40-100% ethyl acetate / hexanes to afford 243 mg of (R)-4-(4-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine.

[0521] Step 2. To a 100 mL flask containing (R)-4-(4-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (2.08 g) was added 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.79 g) in dioxane (20 mL). The mixture was sparged with argon, and ground KPO (2.9 g) was added, followed by trans-N,N'-dimethylcyclohexane-1,2-diamine (111 mg) and CuI (15 mg). The reaction was heated at 100 °C for 44 h, then filtered through diatomaceous earth and rinsed with ethyl acetate. The filtrate was washed with water, and the organic layer was dried over NaSO, filtered, and concentrated. Purification on a Redisep Gold column (80 g) eluting with 0–100% ethyl acetate / hexanes afforded 2.53 g of (R)-3-methyl-4-(6-(1-(methylsulfonyl)cyclopropyl)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)thio)pyrimidin-4-yl)morpholine as a mixture of regioisomers.

[0522] Step 3. To a solution of (R)-4-(4-chloro-3-methyl-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (138 mg) in THF (1 mL) was added isobutyronitrile (350 μL), followed by LiHMDS (1 M in THF, 2.7 mL). The mixture was heated in a microwave at 100° C. for 15 minutes, then cooled and partitioned between saturated aqueous NH4Cl and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification on a Redisep Gold column (24 g) using 0–100% ethyl acetate / hexanes gave 136 mg of (R)-2-methyl-2-(3-methyl-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)propanenitrile as an oil.

[0523] Step 4. To a solution of (R)-2-methyl-2-(3-methyl-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)propanenitrile (135 mg) in dichloromethane (1 mL) was added TFA (250 μL). The reaction was stirred at room temperature for 3 days, then concentrated and partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 times). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification on a Redisep Gold column (12 g) using 30–100% ethyl acetate / hexanes gave 15 mg of (R)-2-methyl-2-(3-methyl-6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)propanenitrile. 1 H NMR(d6-DMSO)δ12.7(s,1H),7.8(s,1H),7.6(s,1H),6.9(s,1H),6.6(s,1H),5.7(s,1H),4.4(m,1 H),4.0(m,1H),3.9(m,1H),3.8(m,1H),3.7(m,1H),3.5(m,1H),3.2(m,1H),2.6(s,3H),1.2(d3H).

[0524] compound 8 Step 1. To a solution of 5,7-dichloro-3H-imidazo[4,5-b]pyridine (457 mg) and 2-(chloromethoxy)ethyl-trimethyl-silane (516 μL) in DMF (8 mL) was added diisopropylethylamine (509 μL) and the mixture was stirred at room temperature for 1 h. Water and EtO were added and the phases were separated. The aqueous phase was extracted with EtO (twice), and the combined organic extracts were washed with brine, dried over NaSO, filtered, and evaporated under reduced pressure. The crude mixture was purified using silica gel chromatography eluting with 0-70% EtOAc / hexanes to afford 473 mg of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyltrimethylsilane (tentative assignment) and 120 mg of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-1-yl)methoxy]ethyltrimethylsilane (tentative assignment). Major isomer: 1 H NMR (400MHz, CDCl3) δ8.22(s,1H),7.35(s,1H),5.64(s,2H),3.69-3.48(m,2H),0.99-0.85(m,2H),-0.04(s,9H).LCMS:318.12(M+H). Minor isomer: 1 H NMR (400MHz, CDCl3) δ8.21(s,1H),7.30(s,1H),5.74(s,2H),3.68-3.42(m,2H),1.05-0.84(m,2H),-0.07(s,9H). LCMS:319.97(M+H). LCMS:318.25(M+H).

[0525] Step 2. Under nitrogen, to a solution of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane (90 mg), KPO (2 M, 424 μL), and (2-methylsulfonylphenyl)boronic acid (68 mg) in dioxane (1 mL) was added Pd(dppf)Cl·CHCl (31 mg) and stirred at 80 °C overnight. Water was added along with EtOAc, and the phases were separated. The aqueous phase was extracted with EtOAc (twice), and the combined organic extracts were washed with brine, dried over NaSO, filtered, and evaporated under reduced pressure. The crude mixture was purified using silica gel chromatography eluting with 0–100% EtOAc / hexanes to afford 2-[[7-chloro-5-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl-trimethyl-silane as a 1:1 mixture of regioisomers. 1 H NMR(400MHz,CDCl3)δ8.22(dd,J=7.7,1.6Hz,1H),8.14(s,1H),7.79-7.64(m,2H),7.41(dd,J=7.3,1. 6Hz,1H),7.33(s,1H),5.67(s,2H),3.77-3.63(m,2H),3.03(s,3H),1.04-0.91(m,2H),-0.03(s,9H). LCMS:437.94(M+H).

[0526] Step 3. To a solution of 2-[[7-chloro-5-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl-trimethyl-silane (640 mg) in dry dioxane (1 mL) was added cesium carbonate (952 mg), RuPhos Pd G1 methyl t-butyl ether adduct (119 mg), and (3R)-3-methylmorpholine (332 μL). The mixture was purged with nitrogen and then heated to 100 °C in a sealed vial for 16 h. Water and EtOAc were added, and the phases were separated. The aqueous phase was extracted with EtOAc (twice), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was dissolved in DMSO and purified using reverse phase chromatography to give 490 mg of trimethyl-[2-[[5-[(3R)-3-methylmorpholin-4-yl]-7-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl]silane. 1 H NMR(400MHz,CDCl3)δ8.21(dd,J=7.9,1.4Hz,1H),7.95(s,1H),7.68(td,J=7.5,1.4Hz,1H),7.59(td,J=7 .7,1.5Hz,1H),7.52(dd,J=7.5,1.4Hz,1H),6.62(s,1H),5.56(d,J=2.3Hz,2H),5.06(s,1H),4.33(d,J=13 .2Hz,1H),4.03(dd,J=11.4,3.6Hz,1H),3.93(dd,J=11.4,3.1Hz,1H),3.84-3.71(m,2H),3.63-3.53(m,2 H),3.49(td,J=6.5,5.5,3.8Hz,1H),3.32(s,3H),1.34(d,J=6.7Hz,3H),0.97-0.83(m,2H),-0.06(s,9H). LCMS:505.19(M+H).

[0527] Step 4. To a solution of trimethyl-[2-[[5-[(3R)-3-methylmorpholin-4-yl]-7-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl]silane (55 mg) in dichloromethane (1 mL) was slowly added TFA (250 μL), and the mixture was stirred at room temperature overnight. Additional TFA (250 μL) was added, and the mixture was stirred over the weekend. The volatiles were removed under reduced pressure, and the crude residue was dissolved in EtOAc and treated with a saturated solution of NaHCO3, after which the layers were separated. The aqueous layer was extracted with EtOAc (twice), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified using reverse phase chromatography to give 31 mg of (3R)-3-methyl-4-[7-(2-methylsulfonylphenyl)-3H-imidazo[4,5-b]pyridin-5-yl]morpholine. 1 H NMR(400MHz,CDCl3)δ8.23(dd,J=7.9,1.4Hz,1H),7.74(s,1H),7.70(td,J=7.5,1.4Hz, 1H),7.63(td,J=7.7,1.5Hz,1H),7.48(dd,J=7.5,1.4Hz,1H),6.73(s,1H),4.25(q,J=7. 0Hz,1H),4.02(dd,J=11.4,3.6Hz,1H),3.92-3.84(m,1H),3.80(d,J=2.1Hz,2H),3.64(t d,J=11.7,3.0Hz,1H),3.27(td,J=12.5,3.8Hz,1H),2.97(s,3H),1.27(d,J=6.7Hz,3H). LCMS:374.08(M+H).

[0528] Step 5. Under nitrogen, copper bromide (45 mg) was added to a solution of (3R)-3-methyl-4-[5-(2-methylsulfonylphenyl)-3H-imidazo[4,5-b]pyridin-7-yl]morpholine (290 mg), 2-[(3-iodopyrazol-1-yl)methoxy]ethyl-trimethyl-silane (510 mg), 3-(1,1-difluoroethyl)benzenesulfinic acid (54 mg), and cesium carbonate (634 mg) in NMP (3.5 mL), and the mixture was heated at 120 °C overnight. The mixture was cooled, treated with saturated aqueous NH4Cl, water, and ammonium hydroxide (4:1:3), and extracted with EtOAc. The aqueous phase was extracted with EtOAc (twice), and the combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using reverse phase chromatography to give 220 mg of trimethyl-[2-[[3-[5-[(3R)-3-methylmorpholin-4-yl]-7-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]pyrazol-1-yl]methoxy]ethyl]silane as a mixture of regioisomers. LCMS: 569.38 (M+H).

[0529] Step 6. To a solution of trimethyl-[2-[[3-[5-[(3R)-3-methylmorpholin-4-yl]-7-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]pyrazol-1-yl]methoxy]ethyl]silane (14 mg) in dichloromethane (1 mL) was added TFA (56 μL), and the mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the mixture was dissolved in dioxane (1 mL), basified to pH 10 using 3N NaOH, and heated at 80 °C for 3 h. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (twice), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DMSO and purified using reverse phase chromatography to give 3.7 mg of (3R)-3-methyl-4-[7-(2-methylsulfonylphenyl)-3-(1H-pyrazol-3-yl)imidazole[4,5-b]pyridin-5-yl]morpholine. 1H NMR(400MHz,DMSO-d6)δ13.03(s,1H),8.47(s,1H),8.14(dd,J=7.8,1.5Hz,1H),7.96(d ,J=2.3Hz,1H),7.80(dtd,J=21.7,7.5,1.5Hz,2H),7.52(dd,J=7.4,1.5Hz,1H),6.97(d ,J=2.2Hz,1H),6.79(s,1H),4.42-4.32(m,1H),3.99(d,J=11.8Hz,2H),3.82-3.65(m,2 H),3.54(td,J=11.7,3.0Hz,1H),3.19(s,3H),3.18-3.07(m,1H),1.19(d,J=6.6Hz,3H). LCMS:438.94(M+H).

[0530] Intermediate C Step 1. To a solution of 3-aminopyrazole (24.7 g, 297 mmol) in 6 N HCl (181 mL) at −5° C. was added a 1 M aqueous solution of NaNO (300 mL, 297 mmol). Next, a solution of SnCl (113 g, 595 mmol) in concentrated HCl (510 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure to give 3-hydrazinylidene-3H-pyrazole as a light brown solid, which was used directly without further purification. 1 H NMR (400MHz, DMSO-d6, δppm): 9.90 (s, 3H), 7.65 (d, J = 2.4Hz, 1H), 5.81 (d, J = 2.3Hz, 1H).

[0531] Step 2. A 500 mL RBF was charged with 2,6-difluoro-4-iodopyridine (17 g, 70.5 mmol) and anhydrous THF (255 mL). The yellow reaction mixture was cooled to -78 °C, and commercial LDA (1.0 M in THF / hexanes, 84.7 mL, 84.7 mmol) was added dropwise at a rate that maintained the internal temperature below -68 °C. The light brown solution was stirred at -78 °C for 1 h, after which ethyl formate (8.5 mL, 105.678 mmol) was added over 10 min. The reaction was monitored by TLC and was complete after 30 min. Formic acid (5.3 mL, 140.5 mmol) was added dropwise, and the mixture was stirred at -78 °C for 10 min before being diluted with EtOAc (150 mL). The mixture was warmed to 0 °C, and water (100 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (150 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 19 g of 2,6-difluoro-4-iodo-pyridine-3-carbaldehyde as a light brown solid. 1 H NMR: (400MHz, CDCl3), δ10.11(s, 1H), 7.54(d; J=2.87Hz; 1H).

[0532] Step 3. To a suspension of 3-hydrazinylidene-3H-pyrazole (12.5 g, 94.3 mmol) in 95% EtOH (70 mL) was added 2,6-difluoro-4-iodo-pyridine-3-carbaldehyde (4.4 g, 16.3 mmol), and the mixture was stirred at room temperature for 15 minutes. Most of the volatiles were then removed under reduced pressure. The orange mixture was dissolved in EtOAc and NaHCO and stirred at room temperature for 15 minutes, resulting in vigorous gas evolution. The phases were separated, and the aqueous phase was extracted three times with EtOAc. The combined organic extracts were washed with water and brine, then dried over MgSO, filtered, and evaporated under reduced pressure to give (E)-3-((2-(1H-pyrazol-3-yl)hydrazinylidene)methyl)-2,6-difluoro-4-iodopyridine (5.5 g, 15.9 mmol) as a yellow / orange solid. 1 H NMR (400MHz, DMSO-d6) 12.02 (s, 1H), 10.89 (s, 1H), 7.92 (s, 1H), 7.82 (d, 1H), 7.54 (s, 1H), 5.97 (s, 1H).

[0533] Step 4. A solution of (E)-3-((2-(1H-pyrazol-3-yl)hydrazinylidene)methyl)-2,6-difluoro-4-iodopyridine (8.6 g, 24.7 mmol) in NMP (115 mL) was divided into 20 mL batches and heated in a microwave reactor at 200° C. for 20 minutes. The combined mixture was then added dropwise to water with vigorous stirring to give a cloudy mixture, which was stirred at room temperature for 5 minutes and then cooled to 0° C. The precipitate was filtered, washed with water, and dried in a Buchner funnel for 1 hour and under reduced pressure for 1 hour to give 6-fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine (6.8 g, 20.7 mmol) as a light brown powder. 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H), 8.29(s,1H), 7.95(t,1H), 7.71(d,1H), 6.67(t,1H).

[0534] Step 5. A solution of 6-fluoro-4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridine (6.8 g, 20.7 mmol) and (R)-3-methylmorpholine (1.24 mL, 7.23 mmol) in DMSO (35 mL) was sealed in a thick-walled tube and heated at 120 °C for 45 min. The mixture was then added dropwise to a water-filled Erlenmeyer flask with vigorous stirring. The cloudy mixture was stirred at room temperature for 5 min and then at 0 °C for 20 min. The precipitate was filtered through a Buchner funnel, washed with water, and dried on the Buchner funnel overnight to give (R)-4-(4-iodo-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (6.9 g, 16.8 mmol) (Intermediate B).

[0535] Step 6. To a solution of intermediate B (2.00 g, 4.88 mmol) in DMF (20 mL) was added 2-(chloromethoxy)ethyltrimethylsilane (1.04 mL, 5.8 mmol), followed by diisopropylethylamine (1.28 mL, 7.3 mmol), and the resulting mixture was stirred for 40 minutes. The mixture was partitioned between EtOAc and water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were washed with water (twice) and brine, then dried over Na2SO4, filtered, and evaporated. Purification by silica gel chromatography (gradient 0-80% EtOAc / hexanes) gave 2-[[3-[4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyltrimethylsilane (0.67 g, 1.25 mmol) and 2-[[5-[4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyltrimethylsilane (0.17 g, 0.31 mmol).

[0536] compound 86 Step 1. In a round-bottom flask, 2,6-difluoro-4-iodo-pyridine-3-carbaldehyde (1.76 g, 6.54 mmol) was dissolved in DME (15 mL) and hydrazine hydrate (535 μL, 65% purity, 7.1 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours. Water was added to the heterogeneous yellow solution, which was stirred at room temperature for 30 minutes. The resulting solid was then filtered, rinsed with water, and dried under vacuum overnight to give 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine.

[0537] Step 2. In a RBF, 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (2.18 g, 8.29 mmol) was dissolved in DMSO (30 mL). To this solution, (3R)-3-methylmorpholine (3.43 g, 33.94 mmol, 3.85 mL) was added, and the reaction mixture was stirred at 120 °C overnight. After that, the reaction mixture was slowly cooled to room temperature. Water was added slowly over 5-10 minutes, the flask was placed in an ice bath, and the solution was stirred for 1 hour. The resulting solid was then collected by filtration, washed with water, air-dried under suction for 1 hour, and dried under vacuum overnight to give (3R)-4-(4-iodo-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methyl-morpholine (2.12 g, 6.16 mmol).

[0538] Step 3. In a RBF, 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (1.54 g, 5.86 mmol) was dissolved in DMF (40 mL) and cooled to 0 °C. To this solution was added 60 wt% sodium hydride (281.0 mg, 7.03 mmol, 60% purity), and the reaction mixture was stirred at 0 °C for 30 minutes. Next, SEM-Cl (1.46 g, 8.78 mmol, 1.55 mL) was added, and the solution was stirred at 0 °C for 5 minutes, then allowed to warm to room temperature and stirred for an additional hour. Saturated NH Cl was added, followed by water, and the mixture was stirred for 30 minutes. The resulting solid was filtered and dried under vacuum overnight to give 2-[(6-fluoro-4-iodo-pyrazolo[3,4-b]pyridin-2-yl)methoxy]ethyl-trimethyl-silane as a mixture of SEM regioisomers.

[0539] Step 4. In a RBF, 2-[[4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]methoxy]ethyl-trimethyl-silane (103 mg, 217.11 μmol) was dissolved in THF (1 mL). To this solution, 2-methylpropanenitrile (150.15 mg, 2.17 mmol, 195 μL) was added, followed by LiHMDS (1 M, 1.09 mL). The reaction mixture was stirred at 20 °C for 15 min and then heated to 100 °C under microwave irradiation for 12 min. Water was added along with EtOAc, and the phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic phase was washed with a saturated aqueous solution of brine, then dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified using a 15.5 g Gold C18 Isco column and elution with 10-100% water / MeCN to give 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]propanenitrile.

[0540] Step 5. In a RBF, 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4-yl]propanenitrile (690 mg, 1.66 mmol) was dissolved in DCM (30 mL) and TFA (3.80 mL, 50 mmol) was added. The reaction mixture was stirred overnight at room temperature, and then the volatiles were removed in vacuo. The crude material was dissolved in 1 mL of DMSO and purified using a 15.5 g Gold C18 Isco column and eluted with 5–100% water / MeCN to give 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[3,4-b]pyridin-4-yl]propanenitrile.

[0541] Step 6. A solution of 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1H-pyrazolo[3,4-b]pyridin-4-yl]propanenitrile (100 mg, 0.35 mmol), 5-iodo-3-methyl-1-tetrahydropyran-2-yl-pyrazole (205 mg, 0.7 mmol), cesium carbonate (285 mg, 0.87 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (100 mg, 0.70 mmol) in NMP (1.2 mL) was flushed with nitrogen for 5 minutes, followed by the addition of copper iodide (67 mg, 0.35 mmol). The mixture was heated to 120 °C for 16 hours. Water was added, and the mixture was stirred for 30 minutes. The resulting solid was collected by filtration and dried under vacuum for 1 hour. The solid was then dissolved in 1 mL of DMSO and purified by reverse-phase Combiflash (5 to 100% water / MeCN over 20 CV) to give 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]propanenitrile.

[0542] Step 7. In a round-bottom flask, 2-methyl-2-[6-[(3R)-3-methylmorpholin-4-yl]-1-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-yl)pyrazolo[3,4-b]pyridin-4-yl]propanenitrile (42 mg, 93 μmol) was dissolved in MeOH (0.5 mL). To this solution, HCl in MeOH (1.25 M, 112 μL) was added, and the reaction mixture was stirred at 60° C. for 1 h. The volatiles were evaporated under reduced pressure, and the crude material was purified using a 15.5 g Gold C18 Isco column and elution with 5-100% water / MeCN to give compound 86. 1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),8.27(s,1H),6.73(s,1H),6.49(d,J=2. 0Hz,1H),4.46(s,1H),4.09-4.00(m,1H),3.97(dd,J=11.4,3.5Hz,1H),3.76( d,J=11.4Hz,1H),3.64(dd,J=11.5,3.1Hz,1H),3.49(td,J=11.9,3.1Hz,1H), 3.19(td,J=12.6,3.8Hz,1H),2.30(s,3H),1.85(s,6H),1.20(d,J=6.7Hz,3H).

[0543] compound 99 Step 1. A solution of 2-[[5-[4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (500 mg, 0.92 mmol) in THF (8 mL) was cooled to -78 °C and slowly treated with nBuLi (2.5 M, 0.48 mL). The mixture was allowed to stir for 40 min. Next, a solution of tetrahydropyran-3-one (27 μL, 2.78 mmol) in THF (1.5 mL) was added to the mixture. The flask was removed from the dry ice bath and stirring was continued for 1 h. Next, the mixture was quenched with saturated NH4Cl solution, EtOAc was added, and the phases were separated. The aqueous phase was extracted twice more with EtOAc, and the combined organic extracts were washed with saturated brine, then dried over Na2SO4, filtered, and evaporated under reduced pressure to give 3-[6-[(3R)-3-methylmorpholin-4-yl]-1-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyrazolo[3,4-b]pyridin-4-yl]tetrahydropyran-3-ol.

[0544] Step 2. A solution of 3-[6-[(3R)-3-methylmorpholin-4-yl]-1-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyrazolo[3,4-b]pyridin-4-yl]tetrahydropyran-3-ol (168 mg, 0.325 mmol), triethylsilane (291 mg, 2.50 mmol, 0.4 mL), DCM (1 mL), and TFA (5.96 g, 52.3 mmol, 4 mL) was stirred at room temperature for 10 minutes. The volatiles were removed under reduced pressure, and the residue was purified using reverse-phase chromatography to give a mixture of compound 99 and compound 100, which were separated by SFC.

[0545] compound 121 Step 1. A solution of intermediate C (200 mg, 0.37 mmol) in THF (4 mL) was cooled to -78 °C and slowly treated with nBuLi (2.5 M, 0.19 mL). The mixture was stirred for 40 min, and then a solution of 8-oxabicyclo[3.2.1]octan-3-one (27 μL, 1.2 mmol) in THF (0.4 mL) was added. The flask was then removed from the dry ice bath and allowed to warm to room temperature over 1.5 h. The mixture was then quenched with saturated NH4Cl solution and extracted with EtOAc. The aqueous phase was extracted twice more with EtOAc, and the combined organic extracts were washed with saturated brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was used in the next step without further purification.

[0546] Step 2. A solution of 3-[6-[(3R)-3-methylmorpholin-4-yl]-1-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyrazolo[3,4-b]pyridin-4-yl]-8-oxabicyclo[3.2.1]octan-3-ol (100 mg, 0.18 mmol) and triethylsilane (0.23 mL, 1.42 mmol) in DCM (1 mL) was treated with TFA (2.3 mL, 30 mmol) at room temperature and stirred for 10 min. The volatiles were removed under reduced pressure, and the residue was purified using silica gel chromatography eluting with 0-10% MeOH followed by reverse-phase chromatography eluting with 0-100% MeCN / HO to give compound 121. 1H NMR(400MHz,DMSO-d6)δ12.79(s,1H),8.04(s,1H),7.83(s,1H),6.80(s,1H),6 .78(s,1H),5.33(s,1H),4.49-4.40(m,3H),4.05-3.91(m,2H),3.77(d,J=11.4H) z,1H),3.64(dd,J=11.5,3.1Hz,1H),3.49(td,J=11.7,2.9Hz,1H),3.23-3.11( m,1H),2.43-2.31(m,4H),1.81(dd,J=20.9,11.5Hz,4H),1.20(d,J=6.6Hz,3H).

[0547] compound 125 Step 1. To a solution of 2-amino-3-bromopyridine (1.0 g, 5.8 mmol) in DCM (10 mL) at room temperature, di-tert-butyl dicarbamate (2.65 g, 12.1 mmol) and DMAP (35 mg, 0.29 mmol) were added, followed by the slow addition of EtN (1.8 mL, 12.9 mmol). The reaction mixture was stirred at room temperature for 18 h and then partitioned between water (50 mL) and DCM (40 mL). The aqueous layer was extracted with DCM (40 mL), and the combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated in vacuo. The residue was purified by adsorption onto silica gel via Combi-Flash (80 g Gold SiO) eluting with a gradient of 100% hexane to 35% EtOAc / hexane over 25 min to give 1.8 g of di-tert-butyl (3-bromopyridin-2-yl)dicarbamate as a colorless solid. MS (+ESI) m / z 395.1 / 397.1 (M+Na).

[0548] Step 2. Di-tert-butyl (3-bromopyridin-2-yl)dicarbamate (150 mg, 0.40 mmol), bis(pinacolato)diboron (204 mg, 0.80 mmol), and potassium acetate (120 mg, 1.21 mmol) were dissolved in dry DMF (1 mL) followed by Pd(dppf)Cl.CHCl (33 mg, 0.04 mmol). The reaction was purged with argon and then heated to 85 °C for 16 h. The mixture was diluted with EtOAc and filtered through a Celite pad. Evaporation of the volatiles afforded tert-butyl (tert-butoxycarbonyl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate, which was used without further purification.

[0549] Step 3. 2-[[3-[4-Iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyltrimethylsilane (120 mg, 0.22 mmol), KPO (142 mg, 0.66 mmol), Pd(dppfCl).CHCl (9 mg, 0.011 mmol), and tert-butyl (tert-butoxycarbonyl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (186 mg, 0.44 mmol) were dissolved in dry DMF (2 mL). The reaction was purged with argon and heated to 85 °C for 16 h. The product was purified by combiflash (C18, 26 g) using 5-100% MeCN in HO (0.1% formic acid) for 20 min to give tert-butyl (R)-(tert-butoxycarbonyl)(3-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-2-yl)carbamate (35 mg).

[0550] Step 4. To a solution of tert-butyl (R)-(tert-butoxycarbonyl)(3-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-2-yl)carbamate (35 mg, 0.05 mmol) in DCM (1.5 mL) was added TFA (0.40 mL, 5.2 mmol) and EtSiH (0.03 mL, 0.17 mmol) and the reaction was stirred for 1.5 h. The volatiles were evaporated and the residue was purified by combi-flash (SiO, 4 g) using 0–100% hexanes in EtOAc for 15 min to give (R)-3-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)pyridin-2-amine (18 mg).

[0551] compound 126 Step 1. (R)-4-(4-iodo-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine (Intermediate C, 700 mg, 1.30 mmol), (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid (492 mg, 1.68 mmol), 2 M K2CO3 (2 mL, 4 mmol), Pd(PPh3)4 (75 mg, 0.065 mmol), and dioxane (7 mL) were placed in a microwave tube. The tube was sealed and flushed with N2 (three cycles of vacuum / N2). The mixture was heated to 100 °C for 5 h. LCMS indicated a complete reaction. After cooling to room temperature, the mixture was diluted with EtOAc (40 mL) and water (40 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (70 mL). The combined organic layers were washed with brine, dried over MgSO, filtered, and concentrated to dryness. The residue was purified by adsorption onto silica gel via ISCO CombiFlash (40 g column, Si02 Gold) eluting with 20-100% EtOAc / hexanes to afford 700 mg of (R)-N-(tert-butyl)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)benzenesulfonamide.

[0552] Step 2. To a solution of (R)—N-(tert-butyl)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)benzenesulfonamide (700 mg, 1.12 mmol) and triethylsilane (0.68 mL, 4.26 mmol) in DCM (10 mL) was added TFA (9 mL, 118 mmol) at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The volatiles were removed in vacuo and the residue was dissolved in TFA (10 mL). The mixture was stirred at room temperature for 18 hours, then heated to 40° C. for 1 hour and to 50° C. for 1 hour. The volatiles were removed under reduced pressure and co-evaporated with DCM (3 times). The residue was purified by adsorption to silica gel via ISCO CombiFlash (24 g column, Gold SiO2) eluting with 30-100% EtOAc / hexanes. The desired product fractions were combined and concentrated to dryness under reduced pressure. The residue was dissolved in CH3CN (3 mL) and water (5 mL) and lyophilized to afford 350 mg of (R)-2-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)benzenesulfonamide as a pale yellow foam. +ESI [M+1]: 440.2. Purity by HPLC at 254 nm: >99%, 10-90% CH3CN / HO (+0.1% formic acid) over 20 min. 1 H NMR(400MHz,DMSO):δ12.83(s;1H);8.11-8.13(m;1H);7.86(s;1H);7.68-7.72( m;2H);7.61(s;1H);7.50-7.52(m;1H);7.42(s;2H);6.83(s;1H);6.80(s;1H);4. 33-4.38(m;1H);4.08(d;J=13.32Hz;1H);3.97-4.00(m;1H);3.73-3.76(m;1H); 3.64-3.68(m;1H);3.49-3.55(m;1H);3.15-3.21(m;1H);1.22(d;J=6.61Hz;3H).

[0553] compound 138 Step 1. (3R)-4-[4-iodo-1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-morpholine (500 mg, 0.943 mmol), bis(pinacolato)diboron (359 mg, 1.41 mmol), and potassium acetate (324 mg, 3.30 mmol) were combined in DMF (5 mL), and the solution was degassed by bubbling N through the mixture with sonication for 10 minutes. Next, Pd(dppf)Cl.DCM (69 mg, 0.0943 mmol) was added, and the mixture was again degassed for 5 minutes. The reaction was then heated to 95 °C for 2 hours. The mixture was cooled to room temperature and partitioned between EtOAc and water (3 volumes each). The organic layer was washed with water (2 × 3 volumes), dried over NaSO, and concentrated to dryness. The product was then purified by combiflash (0-100% EtOAc / hexanes).

[0554] Step 2. To a solution of (3R)-4-[1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[3,4-b]pyridin-6-yl]-3-methyl-morpholine (220 mg, 0.415 mmol) and 3-bromo-6-(trifluoromethyl)pyridin-2-amine (200 mg, 0.830 mmol) in DMF (9 mL) was added aqueous KCO (1.1 mL, 1.24 mmol), followed by Pd(dppf)Cl-DCM complex (68 mg, 0.083 mmol). The reaction was heated to 110 °C in a microwave for 10 min. The mixture was cooled to room temperature and partitioned between EtOAc and water (3 volumes each). The organic layer was washed with water (2 x 3 vol), dried over Na2SO4 and concentrated to dryness. The product was then purified by combiflash (0-100% EtOAc / hexanes).

[0555] Step 3. 3-[1-[2-[(4-Methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-4-yl]-6-(trifluoromethyl)pyridin-2-amine (120 mg, 0.213 mmol) was dissolved in trifluoroacetic acid (3.0 mL, 0.21 mmol) and the reaction was stirred for 2 h. The reaction was evaporated to dryness, the residue was dissolved in DMSO (1 mL), and the product was purified by reverse-phase combiflash (5-95% MeCN / water). +ESI [M+1]: 445. Purity by HPLC at 0.254 nm: >99%, 10-90% CH3CN / HO (+0.1% formic acid) for >20 min. 1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.84(brm,2H),7.72(d,J=7.5Hz,1H) ,7.09(d,J=7.5Hz,1H),6.86-6.77(m,2H),6.45(s,2H),4.48(s,1H),4.11(d ,J=13.4Hz,1H),4.07-3.93(m,1H),3.75(d,J=11.3Hz,1H),3.64(d,J=9.8Hz ,1H),3.49(t,J=11.1Hz,1H),3.20(t,J=12.6Hz,1H),1.20(d,J=6.9Hz,3H).

[0556] compound 139 Step 1. To a solution of [1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-4-yl]boronic acid (250 mg, 0.558 mmol) and 3-bromo-6-methyl-pyridin-2-amine (0.33 mL, 1.12 mmol) in DMF (9 mL) was added KCO (1.1 mL, 1.67 mmol) and flushed with nitrogen, followed by the addition of Pd(dppf)Cl-DCM complex (91 mg, 0.11 mmol). The reaction was heated in a microwave at 100 °C for 10 minutes, after which the mixture was cooled to room temperature and partitioned between EtOAc and water (3 volumes each). The organic layer was washed with water (2 × 3 volumes), dried over NaSO, and concentrated to dryness. The product was then purified by combiflash (0-100% EtOAc / hexanes).

[0557] Step 2. 3-[1-[2-[(4-Methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-4-yl]-6-methyl-pyridin-2-amine (250 mg, 0.490 mmol) was dissolved in trifluoroacetic acid (4.0 mL, 0.49 mmol), and the reaction was heated to 60 °C and monitored by UPLC-MS. After 1 h, the reaction was cooled to room temperature and evaporated to dryness the next day. The product was purified by reverse-phase chromatography (5-95% MeCN / water). +ESI [M+1]: 391.0. Purity by HPLC at 254 nm: >99%, 10-90% CH3CN / HO (+0.1% formic acid) over 20 min. 1 H NMR(400MHz,DMSO-d6)δ12.81(s,1H),7.84(br,2H),7.59(br,1H),6.82-6.76 (m,2H),6.68(s,1H),4.46(s,1H),4.09(d,J=13.3Hz,1H),3.97(d,J=10.2Hz, 1H),3.75(d,J=11.3Hz,1H),3.64(d,J=11.8Hz,1H),3.49(t,J=10.6Hz,1H),3 .19(t,J=13.0Hz,1H),2.55-2.50(m,3H),2.38(s,3H),1.22(d,J=6.6Hz,3H).

[0558] compound 149 Step 1. To a solution of intermediate C (690 mg, 1.28 mmol) in chloroform (10 mL) was added N-chlorosuccinimide (170 mg, 1.27 mmol) and stirred at room temperature overnight. The solution was heated to 65 °C for 1 hour, and then an additional 138 mg of N-chlorosuccinimide was added and stirred at 65 °C for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography eluting with 0-100% EtOAc / hexane to give 2-[[5-[5-chloro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (240 mg).

[0559] Step 2. To a solution of 2-[[5-[5-chloro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethyl-silane (107 mg, 0.187 mmol) and 4,4,5,5-tetramethyl-2-[2-(trifluoromethyl)phenyl]-1,3,2-dioxaneborolane (0.33 mL, 0.382 mmol) in 1,4-dioxane (1 mL) was added KPO (0.50 mL, 0.560 mmol). After flushing the vial with nitrogen, Pd(dppf)Cl (30 mg, 0.0373 mmol) was added and heated to 110 °C in a microwave oven for 3 h. The solution was diluted with water and DCM and filtered through a phase separator. The aqueous phase was washed twice with DCM and the combined organic extracts were evaporated under reduced pressure. The product was used in the next reaction without further purification.

[0560] Step 3. To a solution of crude 2-[[5-[5-chloro-6-[(3R)-3-methylmorpholin-4-yl]-4-[2-(trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyl-trimethylsilane (110 mg, 0.186 mmol) in DCM (1 mL) was added 0.2 mL of triethylsilane and 1 mL of TFA. The resulting solution was stirred at room temperature for 1 h, and the solvent was removed under reduced pressure. The residue was purified using reverse-phase chromatography eluting with 0-100% MeCN / HO, followed by further purification using normal-phase chromatography eluting with 0-10% MeOH / DCM to give the desired product as a 1:1 mixture of atropisomers, which was used for biological testing. Further purification using chiral SFC affords two separated atropisomers (4.0 mg, 6.8% and 4.7 mg, 8.0%, respectively). Mass Spectrometry: m / z: 463.2. compound 150 Step 1. 2,6-Difluoro-4-iodo-pyridine-3-carboxaldehyde (9.00 g, 33.5 mmol) was dissolved in DMSO (330 mL) and (3R)-3-methylmorpholine (3.8 mL, 33.3 mmol) was added. The solution was heated at 120 °C for 2 h. The solution was cooled and added dropwise to water (1.5 L) with vigorous stirring. Ice was then added and the suspension was stirred for an additional 2 h. The solid was filtered and dried under house vacuum for 15 h. The resulting beige solid (10.9 g) was dissolved in a minimal amount of DCM and purified by silica gel chromatography (0–100% EtOAc / hexanes gradient) to give 2-fluoro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carbaldehyde (6.36 g, 18.16 mmol) as a beige solid.

[0561] Step 2. To a solution of 2-fluoro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carbaldehyde (5.86 g, 16.7 mmol) in tert-butanol (20 mL) and water (6.5 mL) was added 2-methyl-2-butene (82 mL, 164 mmol), sodium chlorite (7.56 g, 83.6 mmol), and monobasic sodium phosphate dihydrate (2.64 g, 16.9 mmol) at room temperature. The resulting mixture was stirred at room temperature for 15 hours. A saturated aqueous solution of sodium sulfite was slowly added, followed by formic acid until an acidic pH was reached. EtOAc was added, and the phases were separated. The aqueous phase was extracted three times with EtOAc, and the combined organic extracts were dried over MgSO, filtered, and evaporated under reduced pressure to give a beige solid. This material was triturated with EtO for 30 minutes and then filtered to give 2.06 g of an off-white solid. The filtrate was concentrated and purified on a 100 g C18 column using a 0-100% MeCN / water gradient to give an additional 2.83 g of a beige solid, for a total of 4.89 g of 2-fluoro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylic acid.

[0562] Step 3. To a solution of 2-fluoro-4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carboxylic acid (4.89 g, 13.4 mmol) in DMF (67 mL) was added azaniumyl-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ammonium dichloride (4.65 g, 16.0 mmol), followed by 2,6-lutidine (12 mL, 100 mmol). HATU (6.17 g, 16.2 mmol) was then added, and the reaction mixture was stirred at room temperature for 1 hour. The solution was then added dropwise to water (400 mL) with vigorous stirring to give a suspension, which was stirred for 1 hour and then filtered. The resulting solid was dried under vacuum for 15 hours to give 2-fluoro-4-iodo-N'-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carbohydrazide (7.48 g, 13.2 mmol) as a beige solid.

[0563] Step 4. 2-Fluoro-4-iodo-N'-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]pyridine-3-carbohydrazide (2.00 g, 3.53 mmol) was dissolved in DMF (70 mL) and NaH (285 mg, 7.13 mmol) was added. The mixture was stirred at room temperature for 10 minutes and then slowly heated to 60 °C over 30 minutes. Water, brine, and EtOAc were added and the phases were separated. The aqueous phase was extracted three times with EtOAc, and the combined organics were dried over MgSO, filtered, and evaporated under reduced pressure. The resulting material was purified by silica gel chromatography (0-10% MeOH / DCM gradient) to afford 4-iodo-1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-3-one (1.19 g, 2.18 mmol) as a brown solid.

[0564] Step 5. To a solution of 4-iodo-1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]-2H-pyrazolo[3,4-b]pyridin-3-one (100 mg, 0.183 mmol) and 2-trifluoromethylphenylboronic acid (87 mg, 0.43 mmol) in 1,4-dioxane (1.8 mL) was added K2CO3 (0.28 mL, 0.55 mmol). After flushing the mixture with nitrogen for 5 minutes, Pd(dppf)Cl2 (30 mg, 0.037 mmol) was added and then heated to 110 °C under microwave irradiation for 15 minutes. Water was added along with DCM, and the phases were separated. The aqueous phase was extracted three times with DCM, and the organic extracts were combined, dried over MgSO, filtered, and evaporated under reduced pressure to give 1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3R)-3-methylmorpholin-4-yl]-4-[2-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-3-one (103 mg, 0.182 mmol) as a black solid, which was used in the next step without purification.

[0565] Step 6. The crude material from Step 5 was dissolved in trifluoroacetic acid (2.0 mL) and stirred at 60° C. for 1.5 hours, then concentrated in vacuo. The resulting material was dissolved in DMSO (1 mL) and purified by silica gel chromatography (0 to 100% MeCN / water gradient) to afford 6-[(3R)-3-methylmorpholin-4-yl]-1-(1H-pyrazol-5-yl)-4-[2-(trifluoromethyl)phenyl]-2H-pyrazolo[3,4-b]pyridin-3-one (35 mg, 0.079 mmol) as a beige solid. 1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),10.86(s,1H),7.84(d,J=7.8Hz,1H),7.79-7.75(m,1H),7.7 3(t,J=7.5Hz,1H),7.65(t,J=7.6Hz,1H),7.47(d,J=7.0Hz,1H),6.76(s,1H),6.48(d,J=5.5Hz,1H) ,4.44-4.33(m,1H),4.12-4.03(m,1H),4.01-3.91(m,1H),3.73(d,J=11.4Hz,1H),3.65(dd,J=11. 4,2.7Hz,1H),3.57-3.46(m,1H),3.17(td,J=12.7,12.2,3.5Hz,1H),1.20(dd,J=10.9,6.6Hz,3H).

[0566] Example 2. ATR / ATRIP enzyme アッセイ The AlphaScreen system was used to detect ATR kinase activity and measure phosphorylation of the substrate protein p53. Recombinant purified ATR / ATRIP (Eurofins, catalog no. 14-953) was mixed with serially diluted compounds in 10% DMSO at a final concentration of 0.63 nM in assay buffer (50 mM Hepes pH 7.4, 0.1 mM vanadate, 0.5 mM DTT, 0.1 mM EGTA, 5 mM MnCl2, 0.01% Brij-30, 1% glycerol, 0.05% BSA). The final DMSO concentration was 1.25%. A premix of GST-tagged p53 (full length, Enzo Life Sciences, catalog number BML-FW9370) and adenosine 5′-triphosphate, ATP (Sigma-Aldrich, catalog number 10519979001, Roche Diagnostic) in assay buffer was added to the enzyme:compound mixture for final concentrations of 25 nM GST-p53 and 3 μM ATP. The reaction proceeded for 1 hour at room temperature and was then stopped by adding a premix of phospho-p53 (Ser15) antibody (New England Biolabs, catalog no. 9284S) at a final dilution of 1:3000, glutathione donor beads (PerkinElmer Life Sciences, catalog no. 6765301) at a final bead concentration of 14.3 μg / mL, and protein A acceptor beads (PerkinElmer Life Sciences, catalog no. 670137) at a final bead concentration of 14.3 μg / mL in buffer (50 mM Tris, 60 mM EDTA, pH 7.4, and 0.1% BSA). The plate was incubated in the dark at room temperature for 4 hours and read on a BMG Polarstar using an AlphaScreen proprietary filter. The assay was performed in a 96-well format using white polypropylene half-area plates (Costar, catalog no. 3693). IC was calculated using a four-parameter fit algorithm. 50 value was determined.

[0567] Example 3. ATR assay in HeLa cells HeLa S3 cells were seeded in a 384-plate format at a density of 16K cells per well in 25 μL of standard medium F-12K with 10% FBS and incubated overnight at 37°C and 5% CO2. The medium was then replaced with 20 μL of Opti-MEM (phenol red-free) per well, and 5 μL of serially diluted compound was added to the assay plate to achieve a final DMSO concentration of 0.5%. After incubating the cells and compound at room temperature for 20 minutes, 5 μL of gemcitabine was added to a final concentration of 1.5 μM. The plate was incubated for 3.5–4 hours at 37°C and 5% CO2. The medium was removed, and the cells were lysed in 15 μL of PerkinElmer lysis buffer for 10–20 minutes. Next, 4 μL of the lysate was transferred to a proximity white plate 384 format (PerkinElmer Life Sciences, catalog number 6008280). Quantification of CHK1 phosphorylation at Ser345 was performed using Alphascreen SureFire CHK1 p-Ser345 (PerkinElmer Life Sciences, Cat. No. TGRCHK1S10K) and Alphascreen Protein A (PerkinElmer Life Sciences, Cat. No. 67060617C). Plates were read on an Envision using AlphaScreen-specific filters. IC was calculated using a four-parameter fit algorithm. 50 value was determined.

[0568] Exemplary prepared compounds and their activity in the ATR / ATRIP enzyme assay are shown in Table 2 below.

[0569] [Table 2-1]

[0570] [Table 2-2]

[0571] [Table 2-3]

[0572]

Table 2-4

[0573]

Table 2-5

[0574]

Table 2-6

[0575]

Table 2-7

[0576]

Table 2-8

[0577]

Table 2-9

[0578]

Table 2-10

[0579]

Table 2-11

[0580]

Table 2-12

[0581]

Table 2-13

[0582] [Table 2-14]

[0583] [Table 2-15]

[0584] [Table 2-16]

[0585] [Table 2-17]

[0586] In Table 2, the "Method" column indicates the preparative method described above that was used to prepare the compound. Exemplary prepared compounds and their ATR inhibitory activity in the HeLa S3 whole cell assay are shown in Table 3 below.

[0587] [Table 3-1]

[0588] [Table 3-2]

[0589] [Table 3-3]

[0590] [Table 3-4]

[0591] [Table 3-5]

[0592] [Table 3-6]

[0593] [Table 3-7]

[0594] [Table 3-8]

[0595] [Table 3-9]

[0596] [Table 3-10]

[0597] [Table 3-11]

[0598] [Table 3-12]

[0599] [Table 3-13]

[0600] In Table 3, the "Method" column indicates the preparative method described above that was used to prepare the compound. Other embodiments Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the embodiments of the invention that are apparent to those skilled in the art are intended to be within the scope of the present invention.

[0601] Other embodiments are within the scope of the claims. The technical concepts that can be understood from the above-described embodiment will be described below as supplementary notes. [Appendix 1] Formula (I): [ka] [In the formula, [ka] is a double bond, and each Y is independently N or CR 4 or [ka] is a single bond, and each Y is independently NR Y , carbonyl, or C(R Y ) 2 In that case, each R Y are independently H or optionally substituted C 1-6 is alkyl; R 1 is optionally replaced by C 1-6 is alkyl or H; R 2 teeth, [ka] [ka]

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Claims

1. in the manufacture of a medicament for treating a subject in need thereof, 【Chemical 1】 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the subject is in need of treatment for a disease or condition having a symptom of cellular hyperproliferation, a pre-malignant condition, or cancer.

2. The cancer is Medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, lobular carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basal cell carcinoma basocellulare), basaloid cell carcinoma, basal squamous cell carcinoma, bronchioloalveolar epithelial carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebrumoid carcinoma, Cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedo carcinoma, endometrial cancer, cribriform carcinoma, armor-shaped carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, hard carcinoma, embryonal carcinoma , encephaloid carcinoma, epidermoid carcinoma, adenoid carcinoma, exophytic carcinoma, ulcerative carcinoma, fibrous carcinoma, colloid carcinoma, colloid carcinoma, giant cell carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, pilomatric carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hürthle cell carcinoma, hyaline carcinoma, adrenoid carcinoma, childhood embryonic carcinoma, carcinoma in situ in situ), intraepithelial carcinoma, intraepithelial carcinoma carcinoma), chrome pecker carcinoma, Klutzycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, malignant melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma, mucous cell carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucosal carcinoma carcinoma), myxomatous carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, medullary carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, squamous cell carcinoma, stringy carcinoma, angioectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma (carcinoma tuberosum), tuberous carcinoma, verrucous carcinoma, and choriocarcinoma; a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, liposarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma; adenocarcinoma, Non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, non-leukemic leukemia, leukocytic leukemia, basophilic leukemia, blastic leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia a leukemia selected from the group consisting of myeloma, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myeloblastic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Leder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia; a melanoma selected from the group consisting of acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma; The use according to claim 1, wherein

3. The cancer is selected from the group consisting of prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, gastric cancer, uterine cancer, medulloblastoma, ampullary cancer, colorectal cancer, pancreatic cancer, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary myeloma, and ovarian cancer.

2. The use of claim 1, wherein the cancer is erythroglobulinemia, primary brain tumor, malignant insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesion, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, pancreatic endocrine or exocrine neoplasm, medullary thyroid carcinoma, medullary thyroid carcinoma, colorectal cancer, papillary thyroid carcinoma, or hepatocellular carcinoma.

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