RU2806857C2 - Compounds, pharmaceutical compositions, methods for preparing the compounds and their use as atr kinase inhibitors - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: compound of Formula (I), where the values of R¹-R³, X, Y are defined in the claims, and its pharmaceutically acceptable salts. The compounds are inhibitors of ataxia-telangiectasia and RAD-3-related protein kinase (ATR). Also disclosed are pharmaceutical compositions containing a compound of Formula (I) or pharmaceutically acceptable salts thereof.

EFFECT: compounds can be used to treat cancers that depend on ATR kinase activity.

37 cl, 3 tbl, 3 ex

Description

Field of invention

The present invention relates to compounds and pharmaceutical compositions, their preparation and their use for the treatment of a disease or pathological condition, for example cancer, and, in particular, those diseases or pathological conditions (for example, cancers) that depend on the activity of protein kinase associated with ataxia -telangiectasia and RAD-3 (ATR).

State of the art

DNA damage occurs constantly in cells as a result of environmental influences, including ultraviolet radiation, x-rays, and endogenous stressors such as reactive oxygen and base hydrolysis. Cancer cells are susceptible to higher levels of DNA damage, initially caused by higher rates of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to promote repair of damaged DNA and act as a cellular checkpoint to stop the replication of cells with damaged DNA, allowing repair functions to occur before the damaged DNA is transferred further to daughter cells. Each of the identified DNA repair pathways recognizes and repairs different but overlapping types of DNA damage.

One of the major DDR proteins that acts as a key cell cycle checkpoint is ataxia-telangiectasia-mutated rad3-related (ATR) kinase, a member of the phosphoinositide 3-kinase (PIKK) family of protein kinases. ATR is activated by single-stranded (ss) DNA lesions caused by stalled replication forks or during nucleotide excision repair, but is also activated by double-strand breaks following DNA end resection during homologous recombination. ATR is recruited to sites of DNA damage by binding to the RPA protein, which coats ssDNA along with an additional factor called ATR-interacting protein (ATRIP). The ATR/ATRIP complex is then activated by recruiting additional factors to the 9-1-1 complex (RAD 9, RAD1 and HUS1), which subsequently recruit the TOPBP1 protein and represent critical steps for the activation of the downstream phosphorylation cascade, leading to cell cycle arrest. The primary target of ATR kinase is CHK1, which when phosphorylated targets both cdc25 and Wee1 proteins, resulting in inhibition of cyclin-dependent kinase activity and cell cycle arrest in S phase or G2/M.

ATR has been identified as an important cancer target because the protein is essential for cell division. ATR-deficient mice are embryonic lethal, however adult conditional ATR knockout mice are viable, with effects on rapidly proliferating tissues and stem cell populations. Mouse embryonic stem cells lacking ATR will only divide 1-2 times and then die, suggesting that ATR is required to maintain dividing cells. Of interest, mice carrying hypomorphic ATR mutations, which reduce ATR expression to 10% of normal levels, showed reduced H-rasG12D-induced tumor growth with minimal effect on proliferating normal cells, such as bone marrow cells or intestinal epithelial cells. . Cancer cells with high levels of replication stress due to oncogenic mutations, dysfunctional G1/S checkpoint control (eg, p53 loss of function), defects in other DNA repair pathways (eg, ATM), or that are exposed to DNA-damaging agents, e.g. , radiation therapy, or chemotherapeutic agents are thus more dependent on ATR in the context of DNA repair and survival. Taken together, these results highlight the rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential for a therapeutic window over healthy proliferating cells.

There is a need for new anti-cancer therapeutic agents and, in particular, for anti-cancer therapeutic agents based on ATR inhibitors.

Brief description of the invention

In one aspect of the present invention there is provided a compound of formula (I):

,

(I)

or a pharmaceutically acceptable salt thereof,

Where

represents a double bond, and each Y is independently N or CR ⁴ ; or represents a single bond, and each Y independently represents NR ^Y , carbonyl, or C(R ^Y ) ₂ ; wherein each R ^Y independently represents H or optionally substituted C _1-6 alkyl;

R ¹ represents optionally substituted C _1-6 alkyl or H;

R ² is optionally substituted 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, optional 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 , -SO ₂ N(R ⁶ ) ₂ ,-SO ₂ R ^5A , or -QR ^5B ;

R ³ is optionally substituted C _1-9 heteroaryl or optionally substituted C _1-9 heteroaryl C _1-6 alkyl;

each R ⁴ independently represents hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, or optionally substituted C _2-6 alkynyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, or an optionally substituted C _6-10 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 , -SO ₂ N (R ⁶ ) ₂ , -SO ₂ R ^5A , or optionally substituted alkoxy;

each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkoxyalkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, optionally substituted _C6-10 aryl, optionally substituted _{C3- 8} cycloalkyl or optionally substituted C _1-9 heteroaryl; or both R ⁶ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

Q is an optionally substituted _C2-9 heterocyclylene, an optionally substituted _C3-8 cycloalkylene, an optionally substituted _C1-9 heteroarylene, or an optionally substituted _C6-10 arylene; and

X represents hydrogen or halogen.

In some embodiments represents a double bond. In some embodiments represents a single bond.

In some embodiments, the compound is a compound of formula (II):

,

(II)

or a pharmaceutically acceptable salt thereof,

Where

each Y is independently N or CR ⁴ ; and the remaining variables are the same as described for formula (I).

In some embodiments, in a compound of formula (I) or (II):

each Y is independently N or CR ⁴ ;

R ¹ represents H or optionally substituted C _1-6 alkyl;

R ² is optionally substituted 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 , -SO ₂ N(R ⁶ ) ₂ or -SO ₂ R ^5A ;

R ³ represents optionally substituted C _1-9 heteroaryl;

each R ⁴ independently represents hydrogen or optionally substituted C _1-6 alkyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl or an optionally substituted C _3-8 cycloalkyl; And

each R ⁶ independently represents 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 both R ⁶ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl.

In some embodiments, said compound is a compound of formula (I-a):

,

(I-a)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, the compound is a compound of Formula (I-b):

,

(I-b)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, the compound is a compound of formula (IA):

,

(IA)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (IA-a):

(IA-a)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (IB):

(IB)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (IB-a):

(IB-a)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (IC):

(IC)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (IC-a):

(IC-a)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (ID):

(ID)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, said compound is a compound of formula (ID-a):

(ID-a)

or a pharmaceutically acceptable salt thereof, wherein all variables are as described herein.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ¹ represents methyl.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a) R ² is optionally substituted 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, optional substituted C _1-9 heteroaryl C _1-6 alkyl, -N(R ⁵ ) ₂ , -CON(R ⁶ ) ₂ , -SO ₂ N(R ⁶ ) ₂ or -SO ₂ R ^5A ;

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ² represents optionally substituted C _3-8 cycloalkyl. In some embodiments, R ² is a group of formula (A):

,

(A)

Where

n is 0, 1, 2 or 3; And

R ⁷ is hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A is independently H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ² represents a group of formula (B):

,

(B)

where R ⁷ represents hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A independently represents H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

In some embodiments, 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 heterocyclyl. In some embodiments, 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 bridged heterocyclyl. In some embodiments, 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 heterocyclyl.

In some embodiments, 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, 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 heterocyclylene. In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ^5B represents hydroxyl.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ² represents:

, , , , , , , , , , , , , , , , , , , , , , , , , , , -I, -SO ₂ Me, , , -SO ₂ Ph, ,-OMe, , , ,-OCH ₂ CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

In some embodiments, 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 _1-9 heteroaryl containing at least one nitrogen atom. In some embodiments, 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 _1-9 heteroaryl ring containing two nitrogen atoms. In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ³ represents a group of formula (C):

,

(C)

where A represents an optionally substituted monocyclic C _1-9 heteroaryl ring.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ³ represents a group of formula (C1):

,

(C1)

where R ⁸ represents hydrogen, halogen or optionally substituted C _1-6 alkyl.

In some embodiments, 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 _1-9 heteroaryl ring containing two nitrogen atoms.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ³ represents:

, , , , , , , , , , , , , , , or .

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ³ is:

.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), R ⁴ represents hydrogen.

In some embodiments, any of formulas (I), (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and ( ID-a), X represents hydrogen.

In some embodiments, said compound is selected from the group consisting of compounds 1-152 (e.g., compounds 1-140) and pharmaceutically acceptable salts thereof (e.g., the compound is selected from the group consisting of: 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, 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 their pharmaceutically acceptable salts).

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient. In some embodiments, a compound of the present invention is isotopically enriched in deuterium.

In a further aspect, the present invention provides a method of inhibiting ATR kinase in a cell expressing ATR kinase by contacting the cell with a compound of the present invention. In some embodiments, said cell is an in vitro cell. In some embodiments, said cell is located in the subject's body.

In yet another further aspect, the present invention provides a method of treating a subject in need thereof, including administering to said subject an effective amount of a compound of the present invention or a pharmaceutical composition of the present invention.

In some embodiments, the subject suffers from and requires treatment for a disease or condition characterized by the symptom of cell hyperproliferation (eg, the disease or condition is cancer, a premalignant condition, or a precancerous condition). In some embodiments, the cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma.

In some embodiments, the cancer is a carcinoma selected from the group consisting of medullary thyroid carcinoma, hereditary medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma s, alveolar cell carcinoma, basal cell carcinoma, basocellular carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, body carcinoma, cribrous carcinoma, carcinoma en cuirasse, skin carcinoma, columnar cell carcinoma, columnar cell carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ex ulcere carcinoma, fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma , giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Gurthle cell carcinoma, hyaline carcinoma, hypernephroid embryonal carcinoma, early embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intra epithelial carcinoma, carcinoma Krompecher's cell carcinoma, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular cell carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, bone marrow carcinoma, melanotic carcinoma, molle carcinoma, mucinous carcinoma, mucip carcinoma arum, mucocellular carcinoma, mucoepidermoid carcinoma, carcinoma mucosal carcinoma, mucosal carcinoma, myxomatodal carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spiny cell carcinoma, mucinous carcinoma, renal cell carcinoma kidney, reserve cell carcinoma, sarcomatoid carcinoma , Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongy carcinoma, squamous cell carcinoma, squamous cell carcinoma, fiber carcinoma, telangiectatic carcinoma , smooth muscle and vascular tissue carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma and villous carcinoma.

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

In some embodiments, the cancer is a leukemia selected from the group consisting of nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythaemic leukemia, basophilic leukemia for, leukemia blast cells, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia goat, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphocytic leukemia, lymphosarcoma-cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Nägeli leukemia, plasma cell leukemia , multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Reader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia and undifferentiated cell leukemia.

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-Passy melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma and superficial melanoma.

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

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 tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, cancer bladder, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer.

In some embodiments, the subject suffers from a pre-malignant condition and requires treatment for it.

The present invention is also described by the following listed items.

1. Compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof,

Where

represents a double bond, and each Y is independently N or CR ⁴ ; or represents a single bond, and each Y independently represents NR ^Y , carbonyl, or C(R ^Y ) ₂ ; wherein each R ^Y independently represents H or optionally substituted C _1-6 alkyl;

R ¹ represents optionally substituted C _1-6 alkyl or H;

R ² is optionally substituted 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, optional 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 , -SO ₂ N(R ⁶ ) ₂ , -SO ₂ R ^5A , or -QR ^5B ;

R ³ is optionally substituted C _1-9 heteroaryl or optionally substituted C _1-9 heteroaryl C _1-6 alkyl;

each R ⁴ independently represents hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, or optionally substituted C _2-6 alkynyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, or an optionally substituted C _6-10 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 , -SO ₂ N (R ⁶ ) ₂ , -SO ₂ R ^5A , or optionally substituted alkoxy;

each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkoxyalkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, optionally substituted _C6-10 aryl, optionally substituted _{C3- 8} cycloalkyl or optionally substituted C _1-9 heteroaryl; or both R ⁶ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

Q is an optionally substituted _C2-9 heterocyclylene, an optionally substituted _C3-8 cycloalkylene, an optionally substituted _C1-9 heteroarylene, or an optionally substituted _C6-10 arylene; and

X represents hydrogen or halogen.

2. Connection according to claim 1, where represents a double bond.

3. Connection according to claim 1, where represents a single bond.

4. A compound according to claim 1, wherein said compound is a compound of formula (II):

(II)

or a pharmaceutically acceptable salt thereof,

Where

each Y is independently N or CR ⁴ ;

R ¹ represents optionally substituted C _1-6 alkyl or H;

R ² is optionally substituted 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, optional 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 , -SO ₂ N(R ⁶ ) ₂ , -SO ₂ R ^5A , or -QR ^5B ;

R ³ is optionally substituted C _1-9 heteroaryl or optionally substituted C _1-9 heteroaryl C _1-6 alkyl;

each R ⁴ independently represents hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, or optionally substituted C _2-6 alkynyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, or an optionally substituted C _6-10 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 , -SO ₂ N (R ⁶ ) ₂ , -SO ₂ R ^5A , or optionally substituted alkoxy;

each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkoxyalkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, optionally substituted _C6-10 aryl, optionally substituted _{C3- 8} cycloalkyl or optionally substituted C _1-9 heteroaryl; or both R ⁶ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl;

Q is an optionally substituted _C2-9 heterocyclylene, an optionally substituted _C3-8 cycloalkylene, an optionally substituted _C1-9 heteroarylene, or an optionally substituted _C6-10 arylene; and

X represents hydrogen or halogen.

5. A compound according to claim 1, wherein said compound is a compound of formula (I-a):

(I-a)

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, wherein said compound is a compound of formula (IA):

(IA)

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 6, wherein said compound is a compound of formula (IA-a):

(IA-a)

or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1, wherein said compound is a compound of formula (IB):

(IB)

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 8, wherein said compound is a compound of formula (IB-a):

(IB-a)

or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1, wherein said compound is a compound of formula (IC):

(IC)

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 10, wherein said compound is a compound of formula (IC-a):

(IC-a)

or a pharmaceutically acceptable salt thereof.

12. The compound according to any of paragraphs 1-11, where R ¹ represents methyl.

13.Connection according to any one of paragraphs. 1-12, where R ² is optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-9 heteroaryl, optional substituted C _1-9 heteroaryl C _1-6 alkyl, -N(R ⁵ ) ₂ , -CON(R ⁶ ) ₂ , -SO ₂ N(R ⁶ ) ₂ or -SO ₂ R ^5A .

14. A compound according to any one of claims 1-13, wherein each R ^5A independently represents an optionally substituted C _1-6 alkyl or an optionally substituted C _3-8 cycloalkyl.

15. A compound according to any of claims 1-13, wherein each R ⁶ independently represents 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 both R ⁶ , together with the atom to which they are attached, combine to form an optionally substituted C _2-9 heterocyclyl.

16. A compound according to any one of claims 1-15, wherein R ² is an optionally substituted C _3-8 cycloalkyl.

17. A compound according to claim 16, wherein R ² is C _3-8 cycloalkyl, optionally substituted with alkylsulfonyl, cyano, -CON( ^RA ) ₂ , hydroxy or alkoxy, wherein each R ^A is independently H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

18. A compound according to claim 16, where R ² represents a group of formula (A):

,

(A)

Where

n is 0, 1, 2 or 3; And

R ⁷ is hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A is independently H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

19. A compound according to any one of paragraphs 1-15, where R ² represents a group of formula (B):

,

(B)

where R ⁷ represents hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A independently represents H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

20. A compound according to claim 18 or 19, where R ⁷ represents alkylsulfonyl, cyano or -CON( ^RA ) ₂ .

21. A compound according to any one of claims 1-12, wherein R ² represents an optionally substituted C _1-6 alkyl.

22. A compound according to claim 21, where R ² represents an optionally substituted tertiary C _3-6 alkyl.

23. A compound according to any one of claims 1-15, wherein R ² is an optionally substituted non-aromatic C _2-9 heterocyclyl.

24. A compound according to claim 23, wherein R ² is an optionally substituted, non-aromatic, C _2-9 bridged heterocyclyl.

25. A compound according to claim 23, wherein R ² is an optionally substituted, non-aromatic, spiro C _2-9 heterocyclyl.

26. A compound according to any one of claims 1-15, wherein R ² represents an optionally substituted C _3-8 cycloalkyl.

27. A compound according to claim 26, wherein R ² is an optionally substituted spiro C _3-8 cycloalkyl.

28. The connection according to any of paragraphs 1-12, where R ² represents -QR ^5B .

29. A compound according to claim 28, wherein Q is an optionally substituted C _1-9 heteroarylene.

30. A compound according to claim 28, wherein Q is an optionally substituted C _3-8 cycloalkylene.

31. A compound according to claim 28, wherein Q is an optionally substituted C _2-9 heterocyclylene.

32. A compound according to claim 28, wherein Q is an optionally substituted C _6-10 arylene.

33. A compound according to any one of claims 28-32, wherein R ^5B is an optionally substituted C _1-6 alkyl.

34. The compound according to any one of paragraphs 28-32, where R ^5B represents hydroxyl.

35. A compound according to any one of claims 28-32, wherein R ^5B is an optionally substituted C _6-10 aryl.

36. A compound according to any one of claims 28-32, wherein R ^5B is an optionally substituted C _1-9 heteroaryl.

37. The compound according to any one of paragraphs 28-32, where R ^5B represents -N(R ⁵ ) ₂ .

38. The compound according to claim 37, wherein each R ⁵ represents hydrogen.

39. A compound according to any one of paragraphs 28-32, wherein R ^5B is an optionally substituted alkoxy.

38. The compound of any one of paragraphs 28-32, where R ^5B represents -SO ₂ N(R ⁶ ) ₂ .

39. The compound of claim 38, wherein each R ⁶ is hydrogen.

40. The compound according to any one of paragraphs 28-32, where R ^5B represents -SO ₂ R ^5A .

41.Connection according to paragraphs. 40, where R ^5A represents optionally substituted C _1-6 alkyl.

42. The connection according to any of paragraphs 1-15, where R ² represents:

, , , , , , , , , , , , , , , , , , , , , , , , , , , -I, -SO ₂ Me, , , -SO ₂ Ph, , -OMe, , , ,-OCH ₂ CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

43. The connection according to claim 42, where R ² is:

, , , , , , , , , , , , , , , , , , , , , , , , , , , -I, -SO ₂ Me, , , -SO ₂ Ph, ,-OMe, , , ,-OCH ₂ CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

44. The connection according to claim 42, where R ² is:

, , , , , , , , , , , , , , , , , , , , , , , , , or .

45. The connection according to claim 42, where R ² is:

, , , , , , , , , , ,-OCH ₂ CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

46. The connection according to claim 42, where R ² is:

.

47. The connection according to claim 42, where R ² is:

.

48. The connection according to claim 42, where R ² is:

.

49. The connection according to claim 42, where R ² is:

.

50. The compound according to claim 42, where R ² is:

.

51. The connection according to claim 42, where R ² is:

.

52. The compound according to claim 42, where R ² is:

.

53. The connection according to claim 42, where R ² is:

.

54. The connection according to claim 42, where R ² is:

.

55. The compound according to claim 42, where R ² is:

.

56. The compound according to claim 42, where R ² is:

.

57. The compound according to claim 42, where R ² is:

.

58. The connection according to claim 42, where R ² is:

.

59. The compound according to claim 42, where R ² is:

.

60. The connection according to claim 42, where R ² is:

.

61. The connection according to claim 42, where R ² is:

.

62. The connection according to claim 61, where R ² is:

.

63. The compound according to claim 42, where R ² is:

.

64. The connection according to claim 42, where R ² is:

.

65. The compound according to claim 42, where R ² is:

.

66. The compound according to claim 42, where R ² is:

.

67. The compound according to claim 42, where R ² is:

.

68. The compound according to claim 42, where R ² is:

.

69. The compound according to claim 42, where R ² is:

.

70. A compound according to any one of claims 1-69, wherein R ³ is an optionally substituted, monocyclic C _1-9 heteroaryl containing at least one nitrogen atom.

71. A compound according to claim 70, wherein R ³ is an optionally substituted, monocyclic C _1-9 heteroaryl containing two nitrogen atoms.

72. A compound according to claim 70, where R ³ represents a group of formula (C):

,

(C)

where A represents an optionally substituted monocyclic C _1-9 heteroaryl ring.

73. A compound according to claim 70, where R ³ represents a group of formula (C1):

,

(C1)

where R ⁸ represents hydrogen, halogen or optionally substituted C _1-6 alkyl.

74. The compound according to claim 73, where R ⁸ represents hydrogen or halogen.

75. A compound according to any one of claims 72-74, wherein A represents an optionally substituted, monocyclic C _1-9 heteroaryl ring containing two nitrogen atoms.

76. The connection according to any of paragraphs 1-75, where R ³ represents:

, , , , , , , , , , , , , , , or .

77. The compound according to claim 76, where R ³ is:

, , , , , or .

78. The compound according to claim 76, where R ³ is:

, , , , , , , or .

79. The compound according to claim 76, where R ³ is:

, or .

80. Compound according to claim 76, where R ³ is:

.

81. A compound according to any one of paragraphs 1-80, where R ⁴ represents hydrogen.

82. A compound according to any one of claims 1 to 80, wherein R ⁴ is halogen.

83. A compound according to any one of claims 1-80, wherein R ⁴ is optionally substituted C _2-6 alkenyl.

84. A compound according to any one of paragraphs 1-80, where X represents hydrogen.

85. A compound selected from the group consisting of compounds 1-152 and their pharmaceutically acceptable salts.

87. The compound according to claim 85, where the specified compound is selected from the group consisting of:

connections 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.

88. A compound according to claim 85, where the specified compound is selected from the group consisting of compounds 6, 8, 43, 48, 92, 126, 128, 130, 131, 141, 142, 143, 145, 150 and their pharmaceutically acceptable salts .

89. A compound according to claim 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 according to claim 85, where the specified 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.

91. The compound according to claim 85, where the specified 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.

92. A compound according to claim 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 claim 56, wherein said compound is selected from the group consisting of compounds 121, 122 and pharmaceutically acceptable salts thereof.

94. The compound of claim 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.

95. The compound according to claim 85, where the specified compound is selected from the group consisting of compounds 58, 123 and their pharmaceutically acceptable salts.

96. The compound according to claim 85, where the specified 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 their pharmaceutically acceptable salts.

97. A compound according to claim 85, wherein said compound is selected from the group consisting of compounds 45, 52, 55 and pharmaceutically acceptable salts thereof.

98. A compound according to claim 85, wherein said compound is Compound 1 or a pharmaceutically acceptable salt thereof.

99. A compound according to claim 85, wherein said compound is compound 2 or a pharmaceutically acceptable salt thereof.

100. A compound according to claim 85, wherein said compound is compound 3 or a pharmaceutically acceptable salt thereof.

101. A compound according to claim 85, wherein said compound is compound 4 or a pharmaceutically acceptable salt thereof.

102. A compound according to claim 85, wherein said compound is compound 5 or a pharmaceutically acceptable salt thereof.

103. A compound according to claim 85, wherein said compound is compound 6 or a pharmaceutically acceptable salt thereof.

104. A compound according to claim 85, wherein said compound is compound 7 or a pharmaceutically acceptable salt thereof.

105. A compound according to claim 85, wherein said compound is compound 8 or a pharmaceutically acceptable salt thereof.

106. A compound according to claim 85, wherein said compound is compound 9 or a pharmaceutically acceptable salt thereof.

107. A compound according to claim 85, wherein said compound is compound 86 or a pharmaceutically acceptable salt thereof.

108. A compound according to claim 85, wherein said compound is compound 99 or a pharmaceutically acceptable salt thereof.

109. A compound according to claim 85, wherein said compound is compound 100 or a pharmaceutically acceptable salt thereof.

110. A compound according to claim 85, wherein said compound is compound 115 or a pharmaceutically acceptable salt thereof.

111. A compound according to claim 85, wherein said compound is compound 120 or a pharmaceutically acceptable salt thereof.

112. A compound according to claim 85, wherein said compound is compound 121 or a pharmaceutically acceptable salt thereof.

113. A compound according to claim 85, wherein said compound is compound 125 or a pharmaceutically acceptable salt thereof.

114. A compound according to claim 85, wherein said compound is compound 126 or a pharmaceutically acceptable salt thereof.

115. A compound according to claim 85, wherein said compound is compound 138 or a pharmaceutically acceptable salt thereof.

116. A compound according to claim 85, wherein said compound is compound 139 or a pharmaceutically acceptable salt thereof.

117. A compound according to claim 85, wherein said compound is compound 140 or a pharmaceutically acceptable salt thereof.

118. A compound according to claim 85, wherein said compound is compound 142 or a pharmaceutically acceptable salt thereof.

119. A compound according to claim 85, wherein said compound is compound 144 or a pharmaceutically acceptable salt thereof.

120. A compound according to claim 85, wherein said compound is compound 147 or a pharmaceutically acceptable salt thereof.

121. A compound according to claim 85, wherein said compound is compound 148 or a pharmaceutically acceptable salt thereof.

122. The compound of claim 85, wherein said compound is compound 150 or a pharmaceutically acceptable salt thereof.

123. A compound according to claim 85, wherein said compound is compound 151 or a pharmaceutically acceptable salt thereof.

124. A pharmaceutical composition comprising a compound according to any of paragraphs 1-123 and a pharmaceutically acceptable excipient.

125. The pharmaceutical composition according to claim 124, in which the specified compound is isotopically enriched in deuterium.

126. A method of inhibiting ATR kinase in a cell expressing ATR kinase, comprising contacting the cell with a compound according to any one of paragraphs 1-123.

127. The method of claim 126, wherein said cell is an in vitro cell.

128.The method of claim 126, wherein said cell is located in the body of the subject.

129. A method of treating a subject in need thereof, comprising administering to said subject a compound of any one of claims 1 to 123 or a pharmaceutical composition of claim 124 or 125.

130. The method of claim 128 or 129, wherein the subject suffers from and requires treatment for a disease or condition characterized by the symptom of cell hyperproliferation.

131. The method of claim 130, wherein said disease or condition is cancer.

132. The method of claim 131, wherein said cancer is a solid tumor.

133. The method of claim 131, wherein said cancer is a carcinoma, sarcoma, adenocarcinoma, leukemia or melanoma.

134. The method according to claim 131, characterized in that the oncological disease is a carcinoma selected from the group consisting of medullary thyroid carcinoma, hereditary medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basocellular carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebral carcinoma form carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, body carcinoma, cribriform carcinoma, en cuirasse carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, carcinoma ex ulcere, fibrous carcinoma , gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid embryonal carcinoma, early embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular cell carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, bone marrow carcinoma, melanotic carcinoma oma, molle carcinoma, mucinous carcinoma, carcinoma muciparum, mucocellular carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucosal carcinoma, myxomatodal carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma , spiny cell carcinoma, mucus-forming carcinoma, renal cell carcinoma kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, carcinoma from squamous cell carcinoma, fiber carcinoma, telangiectatic carcinoma, smooth muscle fiber and vascular tissue carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma and villous carcinoma.

135. The method according to claim 131, characterized in that the oncological disease is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemeti sarcoma, infiltrating lipoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastosarcoma , botryoid sarcoma, chloroleukemia, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple hemorrhagic sarcoma s, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma, parosteal sarcoma, reticulocytic sarcoma, Routh's sarcoma, serous cyst sarcoma, synovial sarcoma or telangiectaltic sarcoma.

136. The method according to claim 131, characterized in that the oncological disease is a leukemia 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, aleukemic leukemia, leukocythaemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia , acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphocytic leukemia, lymphosarcoma-cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Nägeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Reader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia and undifferentiated cellular leukemia.

137. The method of claim 136, wherein said cancer is chronic lymphocytic leukemia.

138. The method of claim 131, wherein said cancer is lymphoma.

139. The method of claim 138, wherein the lymphoma is non-Hodgkin's lymphoma, Hodgkin's disease, diffuse large B cell lymphoma, follicular lymphoma, mucosal lymphoid tissue (MALT) lymphoma, small cell lymphocytic lymphoma - chronic lymphocytic leukemia, mantle cell lymphoma, Mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma - Waldenström's macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL)/follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), T Enteropathy-associated cell lymphoma (EATL), adult T-cell leukemia/lymphoma (ATLL) or extranodal NK/T-cell lymphoma of the nasal type.

140. The method of claim 139, wherein said lymphoma is mantle cell lymphoma.

141. The method of claim 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-Passy melanoma, juvenile melanoma, type melanoma lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma and superficial spreading melanoma.

142. The method according to claim 131, characterized in that the cancer disease is prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cancer head and neck, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, amplular colon cancer, colorectal cancer and pancreatic cancer.

143. The method of claim 131, wherein said cancer is prostate cancer.

144. The method of claim 131, wherein said cancer is amplular colon cancer.

145. The method of claim 131, wherein said cancer is colorectal cancer.

146. The method of claim 131, wherein said cancer is lung cancer.

147. The method of claim 131, wherein said cancer is non-small cell lung cancer.

148. The method of claim 131, wherein said cancer is ovarian cancer.

149. The method of claim 131, wherein said cancer is pancreatic cancer.

150. The method according to claim 131, characterized in that the oncological disease is Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, oncological disease, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, cancer adrenal cortex, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer.

151.The method of claim 129, wherein the subject suffers from a pre-malignant condition and requires treatment for it.

Abbreviations

This document uses abbreviations and terms that are commonly used in the fields of organic chemistry, medicinal chemistry, pharmacology and medicine and are well known in the practice of these fields. Typical abbreviations and definitions are given below:

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

Definitions

In this context, the term “aberrant” refers to something different from normal. When used to describe enzymatic activity, the term "aberrant" refers to activity that is greater or less than a normal control sample or the average of normal control samples without disease. Aberrant activity may refer to the amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease related amount (e.g., by administering a compound or using a method described herein) results in improvement of the disease or one or more number of symptoms of the disease. Aberrant activity can be measured by measuring modification of the substrate of the enzyme in question; in this case, a difference in activity greater than or equal to a twofold change in activity can be considered as deviating from the norm. Aberrant activity may also refer to increased dependence on a particular signaling pathway as a result of a deficiency in a particular complement pathway.

As used herein, the term "acyl" represents a -C(=O)-R group, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocyclyl. Acyl may be optionally substituted, as described herein, for each corresponding R group.

In this context, the term adenocarcinoma is a malignant neoplasm that arises from the glandular cells lining organs within the body. Non-limiting examples of adenocarcinoma include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer and colorectal cancer.

As used herein, the term "alkanoyl" represents a hydrogen or alkyl group that is attached to the parent molecular group via a carbonyl group, exemplified by formyl (ie, a carboxyaldehyde group), acetyl, propionyl, butyryl and isobutyryl. Unsubstituted alkanoyl groups contain from 1 to 7 carbon atoms. An alkanoyl group may be unsubstituted or substituted (eg, optionally substituted C1-7 alkanoyl) as described herein for an alkyl group. The ending “-oil” may be added to another group as defined herein, such as aryl, cycloalkyl, and heterocyclyl, to define “aryloyl,” “cycloalkanoyl,” and “(heterocyclyl)oil.” These groups are 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", respectively.

As used herein, the term "alkenyl" represents straight or branched acyclic monovalent hydrocarbon groups 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.

As used herein, the term "alkoxy" represents a chemical substituent of the formula -OR, where R represents a C _1-6 alkyl group unless otherwise indicated. In some embodiments, the alkyl group may be further substituted, as defined herein. The term “alkoxy” may be combined with other terms as defined herein, such as aryl, cycloalkyl, or heterocyclyl, to define the groups “arylalkoxy,” “cycloalkylalkoxy,” and “(heterocyclyl)alkoxy.” These groups are alkoxy substituted with aryl, cycloalkyl or heterocyclyl, respectively. Each of "arylalkoxy", "cycloalkylalkoxy" and "(heterocyclyl)alkoxy" may optionally be substituted as defined herein for each individual moiety.

As used herein, the term "alkoxyalkyl" represents a chemical substituent of the formula -LOR, where L is C _1-6 alkylene and R is C _1-6 alkyl. Optionally substituted alkoxyalkyl is alkoxyalkyl that is optionally substituted as described herein for alkyl.

As used herein, the term "alkyl" refers to a straight or branched acyclic saturated hydrocarbon group that, when unsubstituted, has from 1 to 12 carbon atoms, unless otherwise noted. In some preferred embodiments, the unsubstituted alkyl contains from 1 to 6 carbon atoms. Alkyl groups are represented by methyl; ethyl; n- and isopropyl; n-, sec-, iso- and tert-butyl; neopentyl and the like, and may be optionally substituted, as valency permits, with one, two, three or, in the case of alkyl groups of two or more carbon atoms, 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; =O; =S; -SO ₂ R, where R represents amino or cycloalkyl; =NR', where R' represents H, alkyl, aryl or heterocyclyl. Each of the substituents may itself be unsubstituted or, if valence permits, substituted with the unsubstituted substituent(s) defined herein for each respective group.

As used herein, the term "alkylene" refers to a divalent alkyl group. An optionally substituted alkylene is an alkylene that is optionally substituted as described herein for alkyl.

As used herein, the term "alkylamino" refers to a group having the formula -N(R ^N1 ) ₂ or -NHR ^N1 , wherein R ^N1 is alkyl, as defined herein. The alkyl moiety of alkylamino may optionally be substituted as defined for alkyl. Each optional substituent on a substituted alkylamino may itself be unsubstituted or, if valency permits, substituted with unsubstituted substituent(s) defined herein for each respective group.

As used herein, the term "alkylsulfenyl" represents a group of the formula -S-(alkyl). Alkylsulfenyl may be optionally substituted as defined for alkyl.

As used herein, the term "alkylsulfinyl" represents a group of the formula -S(O)-(alkyl). Alkylsulfinyl may be optionally substituted as defined for alkyl.

As used herein, the term "alkylsulfonyl" represents a group of the formula -S(O)2-(alkyl). Alkylsulfonyl may be optionally substituted as defined for alkyl.

As used herein, the term "alkynyl" represents monovalent straight or branched chain hydrocarbon groups containing from two to six carbon atoms with at least one carbon-carbon triple bond, examples being ethynyl, 1-propynyl and the like. Alkynyl groups may be unsubstituted or substituted (eg, optionally substituted alkynyl) as defined for alkyl.

As used herein, the term "amino" represents -N(R ^N1 ) ₂ where, if amino is unsubstituted, both R ^N1 are H; or, if amino is substituted, each R ^N1 is independently H, -OH, -NO ₂ , -N(R ^N2 ) ₂ , -SO ₂ OR ^N2 , -SO ₂ R ^N2 , -SOR ^N2 , -COOR ^N2 , 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, and where each R ^N2 is independently H, alkyl or aryl. Each of the substituents may itself be unsubstituted or substituted by the unsubstituted substituent(s) defined herein for each respective group. In some embodiments, amino is an unsubstituted amino (i.e., -NH ₂ ) or a substituted amino (e.g., NHR ^N1 ), wherein ^RN1 is independently -OH, SO ₂ OR ^N2 , -SO ₂ R ^N2 , -SOR ^N2 , -COOR ^N2 is optionally substituted alkyl or optionally substituted aryl, and each R ^N2 may be optionally substituted alkyl or optionally substituted aryl. In some embodiments, the substituted amino may be an alkylamino, in which alkyl groups are optionally substituted as described herein for alkyl. In some embodiments, the amino group is -NHR ^N1 , wherein R ^N1 is an optionally substituted alkyl.

As used herein, the term "aryl" represents a mono-, bicyclic or polycyclic carbocyclic ring system having one or two aromatic rings. An aryl group may contain from 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, etc. An aryl group may be unsubstituted or substituted by one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; arila; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silila; and cyano. Each of the substituents may itself be unsubstituted or substituted by the unsubstituted substituent(s) defined herein for each respective group.

As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. The aryl and alkyl portions may optionally be substituted as separate groups as described herein.

As used herein, the term "arylene" refers to a divalent aryl group. An optionally substituted arylene is an arylene that is optionally substituted as described herein for aryl.

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

As used herein, the term "ATR inhibitor" represents a compound that, when contacted with an ATR kinase enzyme, whether in vitro, in cell culture, or in an animal, reduces ATR kinase activity such that the ATR kinase _IC50 is measured to be 10 μM or less ( e.g. 5 µM or less or 1 µM or less). For some ATR inhibitors, the ATR kinase IC ₅₀ value may be 100 nM or less (eg, 10 nM or less, or 1 nM or less) and may be as low as 100 pM or 10 pM. Preferably, the IC ₅₀ value of ATR kinase is from 1 nM to 1 μM (eg, from 1 nM to 750 nM, from 1 nM to 500 nM, or from 1 nM to 250 nM).

As used herein, the term “ATR kinase” refers to the protein kinase associated with ataxia-telangiectasia and RAD-3.

As used herein, the term "azido" represents the -N ₃ group.

As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignancy found in mammals (eg, humans), including leukemia, carcinomas and sarcomas. Non-limiting examples of cancer that can be treated with the compound or method provided herein include prostate cancer, thyroid cancer, endocrine 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, stomach cancer, uterine cancer, medulloblastoma, amplular colon 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 tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer , precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer.

As used herein, the term "carbocyclic" represents an optionally substituted C3-16 monocyclic, bicyclic or tricyclic structure in which rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl and some aryl groups.

As used herein, the term "carbonyl" represents a -C(O)- group.

In this context, the term "carcinoma" refers to a malignant neoplasm consisting of epithelial cells that tend to invade surrounding tissues and cause metastases. Non-limiting examples of carcinomas that can be treated with the compound or method provided herein include, for example, a carcinoma selected from the group consisting of medullary thyroid carcinoma, hereditary medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basocellular carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, body carcinoma, cribriform carcinoma, en cuirasse carcinoma, skin carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma cinoma, exophytic carcinoma, ex ulcere carcinoma, fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma cinoma, hypernephroid embryonal carcinoma, early embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular cell carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, carcinoma bone marrow cinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, muciparum carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucosal carcinoma, myxomatodal carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, trans iportal carcinoma, preinvasive carcinoma, spiny cell carcinoma, mucus-forming carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma cell carcinoma, spongy carcinoma, squamous cell carcinoma, squamous cell carcinoma, fiber carcinoma, telangiectatic carcinoma, smooth muscle fiber and vascular tissue carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma and villous carcinoma.

As used herein, the term "cyano" represents the -CN group.

As used herein, the term “cycloalkenyl” refers to a non-aromatic carbocyclic group having at least one double bond on the ring and three to ten carbon atoms (eg, C _3-10 cycloalkenyl), unless otherwise noted. Non-limiting examples of cycloalkenyl 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. The cycloalkenyl group may be unsubstituted or substituted (eg, optionally substituted cycloalkenyl) as described for cycloalkyl.

As used herein, the term “cycloalkenylalkyl” represents an alkyl group substituted with a cycloalkenyl group, each of which is defined herein. The cycloalkenyl and alkyl moieties may be substituted as separate groups as defined herein.

As used herein, the term "cycloalkoxy" represents a chemical substituent of the formula -OR, where R represents a cycloalkyl group unless otherwise indicated. In some embodiments, the cycloalkyl group may be further substituted, as defined herein.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl group containing from three to ten carbon atoms (eg, C _{3-C 10} cycloalkyl), unless otherwise specified. Cycloalkyl groups can be monocyclic or bicyclic. Bicyclic cycloalkyl groups may be of the bicyclo[pq0]alkyl type in which p and q are each independently equal to 1, 2, 3, 4, 5, 6 or 7, provided that the sum of p and q is equal to 2, 3 , 4, 5, 6, 7 or 8. Alternatively, bicyclic cycloalkyl groups may include bridged cycloalkyl structures, for example, bicyclo[pqr]alkyl, in which r is 1, 2 or 3, each of p and q, independently, is 1, 2, 3, 4, 5 or 6, provided that the sum of p, q and r is 3, 4, 5, 6, 7 or 8. The cycloalkyl group may be a spirocyclic group, for example spiro[pq]alkyl wherein 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 may be unsubstituted or substituted (eg, optionally substituted cycloalkyl) with one, two, three, four or five substituents independently selected from the group consisting of: alkyl; alkenyl; alkynyl; alkoxy; alkylsulfinyl; alkylsulfenyl; alkylsulfonyl; amino; arila; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; heteroaryl; hydroxy; nitro; thiol; silila; cyano; =O; =S; -SO ₂ R, where R represents amino or cycloalkyl; =NR', where R' represents H, alkyl, aryl or heterocyclyl; or -CON( ^RA ) ₂ wherein each ^RA is independently H or alkyl, or both ^RAs , together with the atom to which they are attached, combine to form a heterocyclyl. Each of the substituents may itself be unsubstituted or substituted by the unsubstituted substituent(s) defined herein for each respective group.

As used herein, the term “cycloalkylalkyl” represents an alkyl group substituted with a cycloalkyl group, each of which is defined herein. The cycloalkyl and alkyl moieties may optionally be substituted as separate groups as described herein.

As used herein, the term “cycloalkylene” represents a divalent cycloalkyl group. An optionally substituted cycloalkylene is a cycloalkylene that is optionally substituted as described herein for cycloalkyl.

As used herein, the term "cycloalkynyl" refers to a monovalent carbocyclic group having one or two carbon-carbon triple bonds and having from eight to twelve carbon atoms, unless otherwise noted. The cycloalkynyl may include a single transannular linkage or bridge. Non-limiting examples of cycloalkynyl include cyclooctynyl, cyclononinyl, cyclodecynyl and cyclodecadinyl. A cycloalkynyl group may be unsubstituted or substituted (eg, optionally substituted cycloalkynyl) as defined for cycloalkyl.

“Disease” or “pathological condition” refers to the general condition or state of health of a patient or subject that can be treated with the compounds or methods described herein.

As used herein, the term "halo" is a halogen selected from bromine, chlorine, iodine and fluorine.

As used herein, the term “heteroalkyl” refers to an alkyl, alkenyl or alkynyl group interrupted once by one or two heteroatoms; twice, each time independently, with one or two heteroatoms; three times, each time independently, with one or two heteroatoms; or four times, each time independently, with one or two heteroatoms. Each heteroatom is independently O, N, or S. In some embodiments, the heteroatom is O or N. No heteroalkyl group includes two adjacent oxygen or sulfur atoms. A heteroalkyl group may be unsubstituted or substituted (eg, optionally substituted heteroalkyl). When a heteroalkyl is substituted and the substituent is bonded to a heteroatom, the substituent is selected according to the natural properties and valency of the heteroatom. Thus, the substituent associated with the heteroatom, if valency permits, is selected from the group consisting of = O, -N(R ^N2 ) ₂ , -SO ₂ OR ^N3 , -SO ₂ R ^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 is alkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl or heterocyclyl. Each of these substituents may itself be unsubstituted or substituted by the unsubstituted substituent(s) defined herein for each respective group. When a heteroalkyl is substituted and the substituent is bonded to carbon, the substituent is selected from those described for alkyl, provided that the substituent on the carbon atom bonded to the heteroatom is not Cl, Br, or I. It should be understood that the carbon atoms are at the ends of the heteroalkyl groups.

As used herein, the term “heteroarylalkyl” represents an alkyl group substituted with a heteroaryl group, each of which is defined herein. The heteroaryl and alkyl moieties may optionally be substituted as separate groups as described herein.

As used herein, the term “heteroarylene” represents divalent heteroaryl. An optionally substituted heteroarylene is a heteroarylene that is optionally substituted as described herein for heteroaryl.

As used herein, the term “heteroaryloxy” refers to an -OR structure in which R is heteroaryl. Heteroaryloxy may be optionally substituted as defined for heterocyclyl.

As used herein, the term "heterocyclyl" represents a monocyclic, bicyclic, tricyclic or tetracyclic ring system having fused, bridged and/or spiro 3-, 4-, 5-, 6-, 7- or 8-membered rings, unless otherwise noted containing one, two, three or four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, "heterocyclyl" is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system having fused or bridged 5-, 6-, 7-, or 8-membered rings, unless otherwise noted, containing one, two, three, or four heteroatom independently selected from the group consisting of nitrogen, oxygen and sulfur. The heterocyclyl may be aromatic or non-aromatic. Non-aromatic 5-membered heterocyclyl groups 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 triple bond. carbon-carbon bond. Heterocyclyl groups contain from 1 to 16 carbon atoms unless otherwise noted. Some heterocyclyl groups can contain up to 9 carbon atoms. Non-aromatic heterocyclic 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. If the heterocyclic ring system has at least one aromatic resonance structure or at least one aromatic tautomer, the structure is an aromatic heterocyclyl (ie, heteroaryl). Non-limiting examples of heteroaryl groups include benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadolidiazolyl, purazolyl, oxadolidiazolyl, purpyrisolyl, oxadolidiazolyl, quinolinyl, thiadiazolyl (e.g. 1,3 ,4-thiadiazole), thiazolyl, thienyl, triazolyl, tetrazolyl, etc. The term “heterocyclyl” also represents a heterocyclic compound having a bridged polycyclic structure in which one or more carbon atoms and/or heteroatoms connect two non-adjacent members of a monocyclic ring eg quinuclidine, tropanes or diazabicyclo[2.2.2]octane. The term "heterocyclyl" includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings are fused to one, two or three carbocyclic rings, for example, an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic ring . Examples of fused heterocyclyls include 1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran; 2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl group may 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; arila; aryloxy; azido; cycloalkyl; cycloalkoxy; cycloalkenyl; cycloalkynyl; halo; heteroalkyl; heterocyclyl; (heterocyclyl)oxy; hydroxy; nitro; thiol; silila; and cyano; =O; =S; =NR', where R' represents H, alkyl, aryl or heterocyclyl. Each of the substituents may itself be unsubstituted or substituted by the unsubstituted substituent(s) defined herein for each respective group.

As used herein, the term “heterocyclyl alkyl” represents an alkyl group substituted with a heterocyclyl group, each of which is defined herein. The heterocyclyl and alkyl moieties may optionally be substituted as separate groups as described herein.

As used herein, the term “heterocyclylene” represents a divalent heterocyclyl. An optionally substituted heterocyclylene is a heterocyclylene that is optionally substituted as described herein for heterocyclyl.

As used herein, the term "(heterocyclyl)oxy" represents a chemical substituent of the formula -OR, where R represents a heterocyclyl group unless otherwise indicated. (Heterocyclyl)oxy may optionally be substituted using the method described for heterocyclyl.

In this context, the terms "hydroxyl" and "hydroxy" are used interchangeably and represent the -OH group.

As used herein, the term "isotopically enriched" refers to a pharmaceutically active agent with an isotopic abundance of one isotope at a predetermined position in the molecule that is at least 100 times the naturally occurring abundance of that isotope. For example, a composition that is isotopically enriched in deuterium includes an active agent with at least one hydrogen atom position having at least 100 times the deuterium content of the natural deuterium content. Preferably, the deuterium isotopic enrichment is at least 1000 times the natural deuterium abundance. More preferably, the deuterium isotopic enrichment is at least 4,000 times greater (eg, at least 4,750 times, eg, up to 5,000 times) naturally occurring deuterium abundance.

In this context, the term "leukemia" broadly refers to progressive malignant diseases of the hematopoietic organs and is usually characterized by impaired proliferation and development of leukocytes and their precursors in the blood and bone marrow. Clinically, leukemia is usually classified based on (1) the duration and nature of the disease: acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous) or monocytic; and (3) an increase or absence of an increase in the number of abnormal cells in the blood: leukemic or aleukemic (subleukemic). Exemplary leukemias that can be treated with the compound or method described herein include, for example, leukemia selected from the group consisting of non-lymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, T- adult cellular leukemia, aleukemic leukemia, leukocythaemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hematoblastic leukemia for, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphocytic leukemia, lymphosarcoma-cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblast leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia , myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Reader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia and undifferentiated cellular leukemia.

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

In this context, the term "melanoma" means a tumor arising from the melanocytic system of the skin and other organs. Melanomas that can be treated with the compound or method described herein include, for example, acral lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passy melanoma, juvenile melanoma, lentigo maligna type melanoma , malignant melanoma, nodular melanoma, subungual melanoma and superficial spreading melanoma.

In this context, the term "nitro" represents the -NO ₂ group.

In this context, the term "oxo" represents a divalent oxygen atom (for example, the structure of oxo can be demonstrated as =O).

As used herein, the term "Ph" represents phenyl.

As used herein, the term “pharmaceutical composition” represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient and manufactured or marketed with the approval of a government regulatory agency as part of a therapeutic regimen for treating a disease in a mammal. Pharmaceutical compositions may be formulated, for example, for oral administration in unit dosage form (eg, tablet, capsule, capsule, gelatin capsule or syrup); for topical use (eg, as a cream, gel, lotion, or ointment); for intravenous administration (for example, in the form of a sterile solution containing no mechanical impurities, and in the form of a solvent system suitable for intravenous use); or in any other composition described herein.

The terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” are used interchangeably herein and refer to any ingredient other than the compounds described herein (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being non-toxic and non-toxic. cause inflammation in the patient. Excipients may include, for example: anti-blocking agents, antioxidants, binding agents, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, fillers, film formers or coatings, flavorings, flavoring agents, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners or waters for hydration. Examples of 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, hydroxyapilatine. hydroxypropyl methylcellulose, 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, sorbium tol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol.

As used herein, the term "pharmaceutically acceptable salt" represents those salts that are medically suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction, or the like. and correspond to a rational 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. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzenesulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like salts, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine , triethylamine, ethylamine and the like.

As used herein, the term "premalignant" or "precancerous" refers to a condition that is not cancerous but has the potential to become malignant. Non-limiting examples of precancerous conditions include myelodysplastic syndrome, colon polyps, actinic keratosis of the skin, cervical dysplasia, pulmonary metaplasia and leukoplakia.

As used herein, the term "protecting group" represents a group designed to protect a hydroxy, amino or carbonyl from participating in one or more undesired reactions during chemical synthesis. As used herein, the term "O-protecting group" represents a group designed to protect a hydroxy or carbonyl group from participating in one or more unwanted reactions during chemical synthesis. As used herein, the term "N-protecting group" represents a group designed to protect a nitrogen-containing (eg, amino, amido, heterocyclic N-H, or hydrazine) group from participating in one or more undesirable reactions during chemical synthesis. Commonly used O- and N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. Examples of O- and N-protecting groups include alkanoyl, aryloyl or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, tert-butyldimethylsilyl, tri-isopropylsilyloxymethyl, 4,4'-dimethoxytylmethyl, isobutyryl, phenoxyacetyl, 4-isopropylpechenoxyacetyl, dimethylformamidino and 4-nitrobenzoyl.

Examples of O-protecting groups for protecting carbonyl-containing groups include, but are not limited to: acetals, acylas, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolane and 1,3-dithiolane.

Other O-protecting groups include, but are not limited to: substituted alkyl, aryl and arylalkyl ethers (e.g. trityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-( trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; tert-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl and nitrobenzyl); silyl ethers (for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl and diphenylmethylsilyl); carbonates (eg, methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).

Other N-protecting groups include, but are not limited to, chiral auxiliaries such as protected or unprotected D, L or D, L-amino acids such as alanine, leucine, phenylalanine and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl and the like; 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-dimethyl-3,5 dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like, arylalkyl groups such as benzyl, p -methoxybenzyl, 2, 4-dimethoxybenzyl, triphenylmethyl, benzyloxymethyl and the like, silylalkyl acetal groups such as [2-(trimethylsilyl)ethoxy]methyl and silyl groups such as trimethylsilyl and the like. Suitable N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, alanyl, phenylsulfonyl, benzyl, dimethoxybenzyl, [2-(trimethylsilyl)ethoxy]methyl (SEM), tetrahydropyranyl (THP), tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "tautomer" refers to structural isomers that readily transform into each other, often by the movement of a proton. Tautomers are individual chemical compounds that can be identified by various spectroscopic characteristics, but generally cannot be isolated individually. Non-limiting examples of tautomers include ketone-enol, enamine-imine, amide-imidic acid, nitroso-oxime, ketene-inol, and the amino acid ammonium carboxylate.

The term "sarcoma" usually refers to a tumor that is composed of a substance similar to embryonic connective tissue and is usually composed of densely packed cells embedded in a fibrillar or homogeneous substance. Non-limiting examples of sarcomas that can be treated with the compound or method presented herein include, for example, sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma arcoma, Hodgkin's sarcoma, idiopathic multiple pigmentary hemorrhagic sarcoma, B-cell immunoblastic sarcoma, T-cell immunoblastic sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, sino vial sarcoma and telangiectatic sarcomas.

As used herein, the term "subject" represents a human or non-human animal ( eg , mammal) who suffers from or is at risk of a disease or condition, as determined by a qualified professional (eg, physician or nurse practitioner) using known given area of laboratory testing of samples from the subject or without them. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases characterized by hyperproliferation of cells, such as cancer.

As used herein, “treating” and “treating” refers to the conservative treatment of a subject for the purpose of ameliorating, alleviating, stabilizing, preventing, or curing a disease or condition. This term includes active treatment (treatment aimed at improving a disease or condition); etiotropic treatment (treatment aimed at the cause of the associated disease or condition); palliative care (treatment designed to relieve symptoms of a disease or condition); preventive treatment (treatment aimed at minimizing or partially or completely inhibiting the development of an associated disease or condition); and maintenance treatment (treatment given to complement other therapy).

Detailed description of the invention

In general, the present invention provides compounds, pharmaceutical compositions containing them, methods for preparing the compounds, and methods of use. The compounds of the present invention may be ATR kinase inhibitors. These compounds can be used to inhibit ATR kinase in a cell, such as a cell of a subject. The subject may require treatment for a disease or condition, such as a disease or condition with a symptom of cell hyperproliferation, such as cancer. The ATR kinase inhibitory activity of the compounds disclosed herein is useful for treating a subject in need of treatment for cancer. Non-limiting examples of cancers that can be treated using the compounds disclosed herein are presented 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.

The present invention provides a compound of formula (I):

(I)

or a pharmaceutically acceptable salt thereof,

Where

represents a double bond, and each Y is independently N or CR ⁴ ; or represents a single bond, and each Y independently represents NR ^Y , carbonyl, or C(R ^Y ) ₂ ; wherein each R ^Y independently represents H or optionally substituted C _1-6 alkyl;

R ¹ is optionally substituted C _1-6 alkyl or H;

^R2 is optionally substituted _C2-9 heterocyclyl, optionally substituted _C1-6 alkyl, optionally substituted _C3-8 cycloalkyl, optionally substituted _C2-9 heterocyclyl, _C1-6 alkyl, optionally substituted _C6-10 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 , -SO ₂ N(R ⁶ ) ₂ , -SO ₂ R ^5A or -QR ^5B ;

R ³ is optionally substituted C _1-9 heteroaryl or optionally substituted C _1-9 heteroaryl C _1-6 alkyl;

each R ⁴ independently represents hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, or optionally substituted C _2-6 alkynyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, or an optionally substituted C _6-10 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 , -SO ₂ N (R ⁶ ) ₂ , -SO ₂ R ^5A or optionally substituted with alkoxy;

each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkoxyalkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, optionally substituted _C6-10 aryl, optionally substituted _{C3- 8} cycloalkyl or optionally substituted C _1-9 heteroaryl; or both R ⁶ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl;

Q is optionally substituted C _2-9 heterocyclylene, optionally substituted C _3-8 cycloalkylene, optionally substituted C _1-9 heteroarylene or optionally substituted C _6-10 arylene; And

X represents hydrogen or halogen.

The compound of the present invention may be, for example, a compound of formula (II):

(II)

or a pharmaceutically acceptable salt thereof,

Where

each Y is independently N or CR ⁴ ;

R ¹ is optionally substituted C _1-6 alkyl or H;

^R2 is optionally substituted _C2-9 heterocyclyl, optionally substituted _C1-6 alkyl, optionally substituted _C3-8 cycloalkyl, optionally substituted _C2-9 heterocyclyl, _C1-6 alkyl, optionally substituted _C6-10 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 , -SO ₂ N(R ⁶ ) ₂ , -SO ₂ R ^5A or -QR ^5B ;

R ³ is optionally substituted C _1-9 heteroaryl or optionally substituted C _1-9 heteroaryl C _1-6 alkyl;

each R ⁴ independently represents hydrogen, halogen, optionally substituted C _1-6 alkyl, optionally substituted C _2-6 alkenyl, or optionally substituted C _2-6 alkynyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, or an optionally substituted C _6-10 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 , -SO ₂ N (R ⁶ ) ₂ , -SO ₂ R ^5A or optionally substituted with alkoxy;

each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C2-6 alkoxyalkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, optionally substituted _C6-10 aryl, optionally substituted _{C3- 8} cycloalkyl or optionally substituted C _1-9 heteroaryl; or both R ⁶ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl;

Q is optionally substituted C _2-9 heterocyclylene, optionally substituted C _3-8 cycloalkylene, optionally substituted C _1-9 heteroarylene or optionally substituted C _6-10 arylene; And

X represents hydrogen or halogen.

In some embodiments, in a compound of formula (II), (I), or (I-b):

each Y is independently N or CR ⁴ ;

R ¹ represents H or optionally substituted C _1-6 alkyl;

R ² is optionally substituted 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 , -SO ₂ N(R ⁶ ) ₂ or -SO ₂ R ^5A ;

R ³ is optionally substituted C _1-9 heteroaryl;

each R ⁴ independently represents H or optionally substituted C _1-6 alkyl;

each R ⁵ independently represents 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 -SO ₂ R ^5A wherein each R ^5A independently represents an optionally substituted C _1-6 alkyl or an optionally substituted C _3-8 cycloalkyl; or both R ⁵ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl;

each R ^5A independently represents an optionally substituted C _1-6 alkyl or an optionally substituted C _3-8 cycloalkyl; And

each R ⁶ independently represents 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 atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl.

The compound of the present invention may be, for example, a compound of formula (I-a):

(I-a)

or a pharmaceutically acceptable salt thereof, wherein Y, R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of the present invention may be, for example, a compound of formula (I-b):

(I-b)

or a pharmaceutically acceptable salt thereof, wherein Y, R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of the present invention may be, for example, a compound of formula (IA):

(IA)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of formula (IA) may be, for example, a compound of formula (IA-a):

(IA-a)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of the present invention may be, for example, a compound of formula (IB):

(IB)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of formula (IB) may be, for example, a compound of formula (IB-a):

(IB-a)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of the present invention may be, for example, a compound of formula (IC):

(IC)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of formula (IC) may be, for example, a compound of formula (IC-a):

(IC-a)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

The compound of the present invention may be, for example, a compound of formula (ID):

(ID)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

A compound of formula (ID) may be, for example, a compound of formula (ID-a):

(ID-a)

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , and R ⁴ are as described for formula (I).

Preferably, R ¹ is methyl.

In the compounds of the present invention, R ² may be, for example, optionally substituted C _3-8 cycloalkyl. For example, R ² may be a group of formula (A):

,

(A)

Where

n is 0, 1, 2 or 3; And

R ⁷ is hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A is independently H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

In the compound of the present invention, R ² may be, for example, an optionally substituted C _1-6 alkyl (for example, an optionally substituted tertiary C _3-6 alkyl. For example, R ² may be a group of formula (B):

,

(B)

where R ⁷ represents hydrogen, alkylsulfonyl, cyano, -CON( ^RA ) ₂ , -SON( ^RA ) ₂ , optionally substituted C _1-9 heteroaryl, hydroxy or alkoxy, where each R ^A independently represents H or alkyl; or both R ^A , together with the atom to which they are attached, combine to form a C _2-9 heterocyclyl.

In the compounds of the present invention, R ² may be, for example, an optionally substituted non-aromatic C _2-9 heterocyclyl.

In the compounds of the present invention, R ² may be, for example:

, , , , , , , , , , , , , , , , , , , , , , , , , , , -I, -SO ₂ Me, , , -SO ₂ Ph, ,-OMe, , , ,-OCH ₂ CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , r , , , , , , , or .

In the compounds of the present invention, R ³ may be, for example, an optionally substituted monocyclic C _1-9 heteroaryl containing at least one nitrogen atom (eg, two nitrogen atoms). For example, R ³ may be a group of formula (C):

,

(C)

where A optionally represents a substituted monocyclic C _1-9 heteroaryl ring.

In some compounds of the present invention, A may be, for example, a group of formula (C1):

,

(C1)

where R ⁸ represents hydrogen, halogen or optionally substituted C _1-6 alkyl.

In the compounds of the present invention, R ³ may be, for example:

, , , , , , , , , , , , , , , or .

In the compounds of the present invention, R ³ may be, for example:

.

In the compounds of the present invention, R ⁴ may be, for example, hydrogen.

The compound of the present invention may be, for example, the compound shown in Table 1 below or a pharmaceutically acceptable salt thereof.

Table 1

The present invention includes (if any) the individual diastereomers, enantiomers, epimers and atropisomers of the compounds disclosed herein, and mixtures of diastereomers and/or enantiomers thereof, including racemic mixtures. Although the particular stereochemical structures disclosed herein are preferred, other stereoisomers, including diastereomers, enantiomers, epimers, atropisomers, and mixtures thereof, may be useful in the treatment of ATR-mediated diseases. Inactive or less active diastereoisomers and enantiomers can be used, for example, for scientific studies concerning the receptor and the mechanism of activation.

It should be understood that certain molecules can exist in multiple tautomeric forms. The present invention includes all tautomers, although only one tautomer may be shown in the examples.

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

The compounds disclosed herein can be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts 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 also be used in pharmaceutical compositions in which the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is the sole active ingredient.

Optical isomers - Diastereomers - Geometric isomers - Tautomers

The compounds disclosed herein may contain, for example, one or more stereogenic centers and may occur as racemates, racemic mixtures, single enantiomers, single diastereomers, and mixtures of diastereomers and/or enantiomers. The present invention includes all such isomeric forms of the compounds disclosed herein. All possible stereoisomers (eg, 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 stereogenic centers as pure compounds or in mixtures).

Some of the compounds described herein may contain hindered bonds such that two distinct rotomers, or atropisomers, can be separated and are found to have different biological activities that may be advantageous. All possible atropisomers are intended to be included within the scope of the present invention.

Some compounds described herein may contain olefinic double bonds and, unless otherwise noted, are intended to include both E and Z geometric isomers.

Some of the compounds described herein may exist with different hydrogen attachment points, called tautomers. An example is the ketone and its enol form, known as keto-enol tautomers. Individual tautomers, as well as mixtures thereof, are within the scope of the present invention.

Compounds disclosed herein with one or more asymmetric centers can be classified into diastereoisomers, enantiomers, and the like. through methods well known in the art.

Alternatively, enantiomers and other compounds with chiral centers can be synthesized by stereospecific synthesis using optically pure raw materials and/or reagents of known configuration.

Metabolites - Prodrugs

The present invention includes therapeutically active metabolites, and the metabolites themselves are included within the scope of the claims. The present invention also includes prodrugs, which are compounds that are converted to the claimed compounds upon or after administration to a patient. The claimed chemical structures of this application may, in some cases, themselves constitute prodrugs.

Isotopically enriched derivatives

The present invention includes molecules that have been enriched with isotopes at one or more positions in the molecule. Thus, compounds enriched in deuterium are included within the scope of the claims.

Methods for preparing the compound of the present invention

The compounds of the present invention can be prepared using reactions and techniques known in the art and described herein.

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 acid and esterified under standard conditions. Stereospecific chlorination of the 6-position can be achieved by 7-aza-oxidation with an oxidizing agent such as mCPBA followed by chlorination with mesyl chloride. The indole nitrogen may be protected with a suitable protecting group (PG), such as SEM or THP. The 6-chloro may be replaced by a suitably substituted morpholine under S _N Ar conditions, which may optionally be catalyzed by palladium(0) or copper(I). The ester can then be derivatized by reduction to an alcohol with a suitable reducing agent, for example LiBH ₄ or DIBAL-H, activated by formation of a mesylate or iodine group and substituted with sodium methanesulfinate to form methyl sulfone. Cyclopropanation at the benzyl position can be performed using dibromethane in the presence of a base and a phase transfer catalyst. Removal of the azaindole protecting groups then provides a key intermediate that can be derivatized by palladium- or copper-catalyzed coupling reactions with the corresponding aryl iodide or heteroaryl iodide (R ³ -I) to form the compounds of the present invention. In the case where R ³ contains a protecting group to promote the substitution reaction, a deprotection step using acidic, basic and/or fluoride conditions may be required to obtain the compounds of the present invention.

Scheme A

Method B

The 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 through oxidation of the 7-aza group and methylation with dimethyl sulfate. Addition of suitably substituted morpholine followed by in situ elimination of methanol provides 6-morpholinoazaindole. An aryl group or heteroaryl group (R ³ ) can then be added via a copper-mediated arylation reaction. Depending on the nature of the heteroaryl group, the presence of a protecting group may be required prior to this coupling reaction. The 4-chloro group can be derivatized in several different ways to provide the compounds of the present invention. For example, a palladium or copper mediated coupling reaction can be used to install an aryl or heteroaryl group at the R ² position. Alternatively, if R ² is a substituted amine, chloride substitution may occur under S _N Ar or Buchwald coupling conditions. A sulfide can also be used to replace the 4-chloro group, which can optionally be oxidized to form a sulfone. In case R ³ contains a protecting group, a deprotection step using acidic, basic and/or fluoride conditions may be required to obtain the compounds of the present invention.

Scheme B

Method C

The compounds of the present invention can be prepared from the key intermediate A , which can be prepared as shown in Scheme C and described herein. Protected 5-aminopyrazole can be prepared by condensing the corresponding aldehyde with hydrazine hydrate and acrylonitrile. Condensation with the dialkyl oxaloacetate salt in boiling acetic acid then provides the substituted azaindazole. Activation of the hydroxyl group with a triflate anhydride followed by nucleophilic substitution with a morpholine derivative forms the key intermediate A.

Scheme C

Method D

Intermediate A can be converted to the compounds of the present invention by converting an alkyl ester to a group as shown in Scheme D and described herein. For example, treatment of intermediate A with a reducing group, such as DIBAL-H, LiBH ₄ or NaBH ₄ , provides a primary alcohol that can be activated with a reagent, such as MsCl or TsCl. Substitution of the leaving group with an alkyl sulfonate provides a benzyl sulfone, which can be alkylated under basic conditions with an alkyl halide. Deprotection and arylation, as described in Method A, then provides the compounds of the present invention.

Scheme D

Method E

The compound of the present 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 ether group to a tertiary alcohol. This material may be deprotected and arylated as described in Method A to produce the compounds of the present invention.

Scheme E

Method F

The compound of the present invention can be prepared from intermediate A, as 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, for example mesyl chloride or tosyl chloride, optionally in the presence of lithium iodide. Substitution with sodium cyanide then provides arylacetonitrile, an exemplary compound of the present invention. Compounds of this type can be alkylated with an alkyl halide in the presence of a base to provide dialkylated arylacetonitrile, which is the compound of the present invention. If R-X is dihaloalkyl, the corresponding cyclic derivative is formed with two R groups for a 3-7 membered ring. Alternatively, the primary alcohol can be coupled with cyanohydrin under Mitsunobu conditions to directly produce nitrile derivatives. The nitrile can also be hydrolyzed to the primary amide under basic conditions or in the presence of a metal catalyst to produce the compounds of the present invention.

Scheme F

Method G

The compound of the present invention can be prepared as shown in Scheme G and described herein. N-protected 5,7-dichloro-3H-imidazo[4,5-b]pyridine can be treated with arylboronic acid under palladium catalysis to install the appropriate R ² group. The second chlorine substituent may be suitably substituted with a substituted morpholine under S _N Ar conditions, which may optionally be catalyzed by palladium(0) or copper(I). Removal of the protecting group followed by arylation as described in Method A provides the compounds of the present invention.

Scheme G

Method H

The compound of the present invention can be prepared as shown in Scheme H and described herein. An alkyl Grignard reagent is added to the protected azaindole described in Method A to form a tertiary alcohol. Removal of the protecting group on the azaindole followed by arylation as described in Method A provides the compounds of the present invention.

Scheme H

Method I

The compound 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, then treated with an amide under amide formation conditions using a suitable coupling reagent, such as EDC or HATU. Removal of the azaindole protecting groups then provides a key intermediate that can be derivatized by palladium- or copper-catalyzed coupling reactions with the corresponding aryl iodide or heteroaryl iodide (R ³ -I) to form the compounds of the present invention. In the case where R ³ contains a protecting group to provide a substitution reaction, a deprotection step using acidic, basic and/or fluoride conditions may be required to obtain the compounds of the present invention.

Scheme I

Method J

The compound of the present invention can be prepared as shown in Scheme J and described herein. The ester intermediate from Method F can be hydrolyzed to the appropriate acid under standard conditions, for example, aqueous LiOH or NaOH. This acid can be coupled with hydrazine using an activating agent, such as CDI or EDC, to form hydrazine. It can be formylated (R=H) or acylated (R=alkyl, aryl) to give diacylhydrazine, which can be cyclized to give the compounds of the present invention. If cyclization is carried out with POCl ₃ , oxadiazole is formed. If cyclization is carried out with Lawsson's reagent, thiadiazole is formed. In the event that R ³ contains a protecting group to enable these cyclization reactions, a deprotection step using acidic, basic and/or fluoride conditions may be required to produce the compounds of the present invention.

Scheme J

Method K

The compound of the present invention can be prepared as shown in Scheme K and described herein. The 5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridine may be replaced by a suitably substituted morpholine under S _N Ar conditions, which may optionally be catalyzed by palladium(0) or copper(I). Triazolyl nitrogen can be derivatized through palladium- or copper-catalyzed coupling reactions with the corresponding aryl iodide or heteroaryl iodide (R ³ -I) to install the appropriate R ³ group. Stereospecific chlorination of the 7-position can be achieved by 3-aza-oxidation 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 provide the compounds of the present invention. For example, a palladium or copper mediated coupling reaction can be used to install an aryl or heteroaryl group at the R ² position. Alternatively, if R ² is a substituted amine, chloride substitution may occur under S _N Ar or Buchwald coupling conditions. A sulfide can also be used to replace the 4-chloro group, which can optionally be oxidized to form a sulfone. In the event that R ³ contains a protecting group to enable these cyclization reactions, a deprotection step using acidic, basic and/or fluoride conditions may be required to produce the compounds of the present invention.

Scheme K

Method L

2,6-difluoro-4-iodopyridine can be formylated by metalation with a strong base and retention with a suitable formylation agent such as ethyl formate. The resulting aldehyde can be condensed with a suitably substituted pyrazolehydrazine to form the corresponding hydrazine, which is cyclized to azaindazole by heating at high temperature. The fluorine substituent on the azaindazole can be replaced with a suitably substituted morpholine under S _N Ar conditions to yield the key intermediate B . Protection of the pyrazole NH by a suitable protecting group is provided by the key intermediate C , typically as a mixture of N-protected regioisomers.

Scheme L

Method M

The compound of the present invention can be prepared as shown in Scheme M and described herein. Key intermediate C can be treated with arylboronic acid under palladium catalysis to install the appropriate R ² group. Removal of the protecting group provides the compounds of the present invention.

Scheme M

Method N

The compound of the present invention can be prepared as shown in Scheme N and described herein. Key intermediate C can be metalated with an alkyl lithium or alkyl magnesium halide to form aryllithium or aryl magnesium bromide, which can be added to a suitable ketone to form a tertiary alcohol derivative. In the event that a ketone contains one or more deuterium-enriched positions, the resulting isotope will also be enriched in deuterium. Removal of the protecting group provides the compounds of the present invention. Alternatively, this chemistry can be carried out without the presence of a protecting group using key intermediate B to directly provide the compounds of the present invention.

Scheme N

Method O

The compound of the present invention can be prepared as shown in Scheme O and described herein. The key intermediate C can be treated with a carbon, nitrogen or sulfur based nucleophile to replace the iodine group and install a suitable R ² group. Removal of the protecting group provides the compounds of the present invention.

Scheme O

Method P

The compound of the present invention can be prepared as shown in Scheme P and described herein. Treatment with a brominating agent may introduce a bromine atom into the 3-position of the azaindazole ring, providing the compound of the present invention. Treatment with alkyl, vinyl or arylstanne under Pd catalysis conditions provides the compounds of the present invention.

Scheme P

Q method

The compound of the present invention can be prepared as shown in Scheme Q and described herein. 2,6-Difluoro-4-iodonicotinaldehyde can be cyclized with hydrazine to form 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine, which can then be reacted under S _N Ar conditions with a substituted morpholine. The resulting intermediate can be subjected to a second reaction under S _N Ar conditions with 2-cyanopropane under basic conditions to yield a disubstituted azaindazole ring system. (Ullmann coupling on the NH of azaindazole followed by deprotection provides the compounds of the present invention.

Scheme Q

R method

The compound of the present invention can be prepared as shown in Scheme R and described herein. Intermediate C can be converted to a boronate reagent by treatment of bis(pinacolato)diborone, a palladium catalyst and a base. This boronate can then be treated with an aryl halide or triflate with a palladium catalyst to install the appropriate R ² group. Removal of the protecting group provides the compounds of the present invention.

Scheme R

Method S

The compound of the present 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 with a palladium catalyst to install the appropriate R ² group. Removal of the protecting group provides the compounds of the present invention.

Scheme S

Method T

The compound 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 substituted morpholine to selectively replace the 6-fluoro substituent. Oxidation of the aldehyde is accompanied by the formation of a hydrazide with an appropriately protective heterocyclic hydrazine. Hydrazine can be cyclized under basic conditions to form an iodopyrazolopyridinone ring system. This intermediate may be further reacted under S _N Ar conditions with a carboxylic, oxygen or sulfur nucleophile, or it may preferably be treated with a palladium-catalyzed arylboronic acid to install the appropriate R ² group. Subsequent removal of the protecting group provides the compounds of the present invention.

Scheme T

Treatment options

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

The disease or condition may have the symptom of cell 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.

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

Non-limiting examples of carcinomas include medullary thyroid carcinoma, hereditary medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal carcinoma. single cell carcinoma, basocellular carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, body carcinoma, cribriform carcinoma, en cuirasse carcinoma, cutaneous carcinoma, columnar carcinoma, columnar carcinoma cell carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, ex ulcere carcinoma, fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid embryonal carcinoma, early embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulczycki cell carcinoma, large cell carcinoma nomu, lenticular carcinoma, lenticular cell carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, bone marrow carcinoma, melanotic carcinoma, molle carcinoma, mucinous carcinoma, muciparum carcinoma, mucocellular carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucinous carcinoma, myxoma athodal carcinoma, nasopharyngeal carcinoma , oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spiny cell carcinoma, mucinous carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma , scrotal carcinoma, cricoid -cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, squamous cell carcinoma, fibrous carcinoma, telangiectatic carcinoma, smooth muscle fiber and vascular tissue carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma and villous carcinoma.

Non-limiting examples of sarcomas include chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma arcoma, 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, sarcoma y from Kupffer cells, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma and telangiectatic sarcoma.

Non-limiting examples of leukemia include nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, leukocythaemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia , cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia goats, lymphocytic leukemia, lymphogenous leukemia, lymphocytic leukemia, lymphosarcoma-cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Nägeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, leukemia from Reader cells, Schilling leukemia, stem cell leukemia, subleukemic leukemia and undifferentiated cell leukemia.

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

The compound 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 external administration.

The methods of the present invention may include the step of identifying a subject as a candidate for ATR inhibitor therapy. For example, a subject may be identified as a candidate for ATR inhibitor therapy by determining (i) whether the subject has a cancer with defects in the ATM signaling cascade; (ii) whether the subject has cancer, cancer cells, or cells expressing genetic aberrations in cancer driving genes or oncogenes; (iii) the subject has cancer, cancer cells, or cells with one or more defects in a protein or gene involved in base excision repair; (iv) whether the subject has a cancer with defects in a protein or gene involved in homologous recombination; (v) whether the subject has a cancer with protein or gene defects that are associated with sensitivity to ATR inhibitors or a genetic disorder of ATR; or (vi) whether the subject has a cancer with genetic or protein characteristics that affect sensitivity to ATR inhibitors.

The described compounds, compositions and methods can be used to treat a subject having cancer with an aberration in the ATM signaling cascade. For example, an aberration in the ATM signaling cascade may be, for example, altered 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. Aberrations in ATM signaling can be identified as follows: a change in CHK2 phosphorylation of 20% or greater may indicate an aberration in the ATM signaling cascade, or failure of cells to arrest in the G1 and S phases of the cell cycle in response to DNA double-strand breaks may indicate an aberration in ATM signal stage.

The described compounds, compositions and methods can be used to treat a subject with cancer, cancer cells or cells having aberrant expression of cancer targeting proteins or oncogenes. For example, a cancer cell may have a genetic aberration that causes altered expression or activity of one or more of the following proteins/genes, including, but not limited to, KRAS, NRAS, HRAS, BRAF, MYC, MOS, E2F, CDC25A, CDC4, CDK2, CCNE1, CCNA1 , DNAPK, APOBEC3, CDC6 and RB1.

The described compounds, compositions and methods can be used to treat a subject with cancer, cancer cells or cells with one or more aberrations in a protein or gene involved in base excision repair. For example, an aberration in a base excision repair protein may 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 endonucleases); LIG1, LIG3 (DNA ligase I and III); XRCC1 (LIG3 accessory element); PNK, PNKP (polynucleotide kinase and phosphatase); PARP1, PARP2 (poly(ADP-ribose) polymerase); PolB, PolG (polymerases); FEN1 (endonuclease) or Aprataxin.

The described compounds, compositions and methods can be used to treat a subject with cancer, cancer cells or cells with one or more aberrations in a protein or gene involved in homologous recombination. For example, an aberration in homologous recombination may be altered 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.

The described compounds, compositions and methods can be used to treat a subject with cancer, cancer cells or cells with one or more aberrations in a protein or gene involved in sensitivity to ATR inhibitors or a genetic disorder of the ATR signaling pathway. For example, an aberration in genes that are involved in sensitivity to ATR inhibitors or a genetic disorder of ATR may be altered expression or activity of one or more of the following proteins/genes, including, but not limited to, 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

There are many methods known in the art to determine whether a tumor has an aberration in a protein or gene. For example, sequencing of either the genomic DNA or mRNA products of each specified gene (eg, UNG, PARP1, or LIG1) can be performed on a tumor sample to determine whether mutations are present that are expected to modulate the function or expression of the gene product. In addition to mutational inactivation, tumor cells can modulate a gene by hypermethylating its promoter region, which leads to decreased gene expression. This is most often assessed using methylation-specific polymerase chain reaction (PCR) to quantify methylation levels at base excision repair promoters of genes of interest. A DNA repair gene promoter methylation assay is commercially available.

Gene expression levels can be assessed by directly quantifying the levels of mRNA and protein products of each gene using standard techniques, such as quantitative reverse transcriptase-linked polymerase chain reaction (RT-PCR), RNA sequencing for gene expression, and immunohistochotomy (IHC) for protein expression. Gene amplification or deletion resulting in aberrantly overexpressed or underexpressed proteins (respectively) can also be measured by FISH (fluorescence in situ hybridization) analysis using a probe specific to the gene of interest.

The methods described above (gene sequence, promoter methylation, mRNA expression) can also be used to characterize the status (eg, expression or mutation) of other genes or proteins of interest, such as DNA damaging oncogenes expressed by tumors or defects. in cell DNA repair pathways.

The described compounds, compositions and methods can be used to treat a subject suffering from cancer with genetic characteristics that have been implicated in sensitivity to ATR inhibitors. In some embodiments, the genetic characteristic is one or more of the following: alternative lengthening telomere (ALT) cells, characterized by cellular transformation in the absence of HTERT and/or ATRX mRNA or protein expression, the presence of C-circles, or partially double-stranded and circular extrachromosomal telomeric repeats (ECTR), presence of telomeres of variable length, and positive staining for ALT-associated promyelocytic leukemia (PML) nuclear bodies (APB).

There are several ways to characterize ALT in cells. Non-limiting examples of these methods include the following: HTERT and ATRX expression can be measured by Western blotting, immunohistochemistry (IHC), or mRNA expression analysis (qRT-PCR); the presence of C-circles can be measured by PCR analysis, the presence of telomeres of varying lengths can be measured by telomere restriction fragment (TRF) analysis, which measures the heterogeneous range of telomere lengths in a population of cells using the length distribution of telomere terminal restriction fragments; and staining for APB can be performed using IHC by co-staining with a probe for telomeric DNA and PML protein.

Pharmaceutical compositions

The compounds used in the methods described herein are preferably formulated into pharmaceutical compositions for administration to human subjects in a biocompatible form suitable for in vivo administration. Typically, pharmaceutical compositions include a compound described herein and a pharmaceutically acceptable excipient. Certain pharmaceutical compositions may include one or more additional pharmaceutically active agents described herein.

The compounds described herein may also be used in free base form, in the form of their salts, zwitterions, solvates, or as prodrugs or pharmaceutical compositions. All forms are included within the scope of the present invention. The compounds, their salts, zwitterions, solvates, prodrugs or pharmaceutical compositions can be administered to a patient in various forms depending on the chosen route of administration, as will be apparent to one skilled in the art. The compounds used in the methods described herein can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal and local routes of administration. Parenteral administration can be accomplished by continuous infusion over a selected period of time.

For use in humans, a compound of the present invention may be administered alone or in admixture with a pharmaceutical carrier selected taking into account 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 physiologically acceptable carriers, including excipients and auxiliary ingredients, which facilitate the processing of the compounds of the present invention into preparations that can be used in pharmaceuticals.

The present invention also includes pharmaceutical compositions, which may contain one or more pharmaceutically acceptable carriers. In preparing the pharmaceutical composition of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient, or enclosed in such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When the vehicle serves as a diluent, it may be a solid, semi-solid, or liquid material (eg, saline) that acts as a carrier, carrier, or vehicle for the active ingredient. Thus, the compositions may be in the form of tablets, powders, lozenges, sachets, wafers, elixirs, suspensions, emulsions, solutions, syrups, and soft and hard gelatin capsules. As is known in the art, the type of diluent may vary depending on the intended route of administration. The resulting compositions may include additional agents, such as preservatives.

The excipient or carrier is selected based on the mode and method of application. Suitable pharmaceutical carriers, as well as pharmaceutical requirements for the use of therapeutic formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippincott Williams & Wilkins (2005), a well-known reference text in the field and USP /NF (USP and National Formulary). Examples of suitable excipients are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. The compositions may further include the following: lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, for example methyl and propyl hydroxy benzoates; sweeteners; and flavoring agents. Other illustrative excipients are described in Handbook of Pharmaceutical Excipients, 6th Edition, Rowe et al., Eds., Pharmaceutical Press (2009).

These pharmaceutical compositions can be prepared in conventional manner, for example, through conventional processes of mixing, dissolving, granulating, panning, trituration, emulsification, encapsulation, entrapment or lyophilization. Methods for preparing formulations well known in the art can be found, 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. The correct composition depends on the chosen route of administration. The composition and preparation of such a pharmaceutical composition are well known to those skilled in the art of pharmaceutical formulation. When formulated, the active compound may be crushed to obtain a suitable particle size before combining with other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by grinding to provide substantially uniform distribution in the formulation, for example, about 40 mesh.

Dosages

The dosage of the compound used in the methods described herein, or its pharmaceutically acceptable salts or prodrugs, or pharmaceutical compositions thereof, may vary depending on many factors, for example, the pharmacodynamic properties of the compound; administration mode; the age, health and weight of the recipient; the nature and extent of symptoms; frequency of treatment and type of concomitant treatment, if any; and the rate of elimination of the compound by the animal being treated. One skilled in the art can determine the appropriate dosage based on the above factors. The compounds used in the methods described herein can be administered initially at an appropriate dosage, which can be adjusted as needed depending on the clinical response. In general, a suitable daily dose of a compound of the present invention will be that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such effective dose will generally depend on the factors described above.

The compound of the present invention can be administered to a patient in one dose or more doses. If multiple doses are administered, the doses may be separated by, for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The compound may be administered according to a schedule, or the compound may be administered without a predetermined schedule. The active compound can be administered, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times a day, every 2nd, 3rd, 4th, 5th or 6th day, 1, 2, 3, 4, 5, 6 or 7 times a week, 1, 2, 3, 4, 5 or 6 times a month, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times a year. It should be understood that for any particular subject, specific dosage regimens must be adjusted over time in accordance with the individual needs and professional judgment of the person administering or supervising the administration of the composition.

Although the appropriate amount and dosage regimen will ultimately be determined by the attending physician, an effective amount of a compound of the present invention may be, for example, a total daily dose of, for example, 0.05 mg to 3000 mg of any of the compounds described herein . Alternatively, the dosage amount can be calculated using the patient's body weight. Such dosage ranges may include, for example, 10-1000 mg (eg, 50-800 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 compound are administered.

In the methods of the present invention, the time during which multiple doses of a compound of the present invention are administered to a patient may vary. For example, in some embodiments, dosages of the compounds of the present invention are administered to a patient over a period that ranges from 1 to 7 days; 1-12 weeks; or 1-3 months. In some embodiments, the compounds are administered to a patient over a period that is, for example, 4-11 months or 1-30 years. In some embodiments, the compounds are administered to a patient upon the onset of symptoms. In any of these embodiments, the amount of compound administered may vary during the administration period. If the compound is administered daily, administration may occur, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 times per day.

Compositions

A compound identified as capable of treating any of the conditions described herein, using any of the methods described herein, can be administered to patients or animals with a pharmaceutically acceptable diluent, carrier or excipient in a unit dosage form. Chemical compounds for use in such therapy can be prepared and isolated using any standard method 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 patients suffering from a disease or condition. Administration can begin before the patient develops symptoms.

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

Formulations for oral administration

Pharmaceutical compositions provided in the present invention include compositions formulated for oral administration (“oral dosage forms”). oral dosage forms may be presented, for example, in the form of tablets, capsules, liquid solution or suspension, powder, liquid or solid crystals, which contain the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or excipients (for example, sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate ); granulating and disintegrating agents (for example, cellulose derivatives, including microcrystalline cellulose, starches, including potato starch, croscarmellose sodium, alginates or alginic acid); binders (eg, sucrose, glucose, sorbitol, gum 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 release agents (eg magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils or talc). Other pharmaceutically acceptable excipients may include coloring agents, flavoring agents, plasticizers, humectants, buffering agents, and the like.

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

Controlled release compositions for oral administration can be prepared to release active drug by controlling the dissolution and/or diffusion of the active drug. Any of a variety of strategies can be used to achieve controlled release and target plasma concentrations based on the time profile. In one example, controlled release is achieved through appropriate selection of various formulation parameters and ingredients, including, for example, different types of controlled release formulations and coatings. Examples include single-component or multi-component compositions in the form of tablets or capsules, oily solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, patches and liposomes. In some embodiments, the compositions include biodegradable, pH- and/or temperature-sensitive polymer coatings.

Dissolution or diffusion-controlled release can be achieved by appropriate coating of the tablet, capsule, granule or granulate of the compound, or by incorporating the compound into a suitable matrix. The controlled release coating may include one or more of the coating agents mentioned above and/or, for example, shellac, beeswax, glycovax, castor wax, carnauba wax, stearyl alcohol, glycerol monostearate, glycerol distearate, glycerol palmitostearate, ethyl cellulose, acrylic resins , dl-polylactic acid, cellulose acetobutyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-hydroxy methacrylate, methacrylate hydrogels, 1,3-butylene glycol, ethylene glycol methacrylate and/or polyethylene glycols. In a controlled release matrix formulation, 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 fluorocarbon.

Liquid forms into which the compounds and compositions of the present invention may be formulated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil. oil, as well as tinctures and similar pharmaceutical preparations.

Formulations for parenteral administration

Compounds for use in the methods of the present invention described herein can be administered in a pharmaceutically acceptable parenteral (eg, intravenous or intramuscular) formulation as described herein. The pharmaceutical composition can also be administered parenterally (intravenously, intramuscularly, subcutaneously, or the like) 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 injectable solutions, which may contain antioxidants, buffers, bacteriostatic agents and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. For example, to prepare such a composition, the compounds of the present invention can be dissolved or suspended parenterally in an acceptable liquid medium. Among the acceptable carriers and solvents that can be used are water, water adjusted to a suitable pH by adding a suitable amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution and isotonic sodium chloride solution. The aqueous formulation may 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), incorporated herein by reference.

The parenteral formulation may be any of the five general types of drugs defined by the USP-NF as suitable for parenteral administration:

(1) “Drug injection”: a liquid preparation that is a drug substance (eg, a compound of the present invention) or a solution thereof;

(2) “Injectable drug”: a drug substance (eg, a compound of the present invention) in the form of a dry solid that will be combined with a suitable sterile carrier for parenteral administration as an injection of the drug;

(3) “Injectable drug emulsion”: a liquid preparation of a drug substance (eg, a compound of the present invention) that is dissolved or dispersed in a suitable emulsion medium;

(4) "Injectable drug suspension": a liquid preparation of a drug substance (eg, a compound of the present invention) suspended in a suitable liquid medium; And

(5) "Drug for injection suspension": a drug substance (eg, a compound of the present invention) in dry solid form that will be combined with a suitable sterile carrier for parenteral administration as an injectable suspension of the drug.

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

Formulations for parenteral administration may contain, for example, excipients, sterile water or saline, polyalkylene glycols, for example polyethylene glycol, vegetable oils or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers can be used to control the release of compounds. Other potentially suitable parenteral delivery systems for the compounds include ethylene vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Compositions for inhalation may contain excipients, for example lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions for administration in the form of nasal drops or in the form of a gel.

The parenteral formulation may be formulated for immediate release or for sustained/extended release of the compound. Exemplary parenteral compound release formulations include the following: aqueous solutions, reconstitution powders, cosolvent solutions, oil/water emulsions, suspensions, oil-based solutions, liposomes, microspheres, and polymer gels.

Combinations

The compounds of the present invention can be administered to a subject in combination with one or more additional agents, for example:

(a) a cytotoxic agent;

(b) antimetabolite;

(c) an alkylating agent;

(d) anthracycline;

(e) antibiotic;

(f) an antimitotic agent;

(g) hormonal therapy;

(h) a signal transduction inhibitor;

(i) gene expression modulator;

(j) an apoptosis inducer;

(k) angiogenesis inhibitor;

(l) an immunotherapeutic agent;

(m) DNA damage repair inhibitor;

or

their combination.

The cytotoxic agent may be, for example, actinomycin-D, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, amphotericin, amsacrine, arsenic trioxide, asparaginase, azacitidine, azathioprine, bacillus Calmette-Guerin (BCG), bendamustine, bexarotene, bevacuzimab, bleu omycin , bortezomib, busulfan, capecitabine, carboplatin, carfilzomib, carmustine, cetuximab, cisplatin, chlorambucil, cladribine, clofarabine, colchicine, chrysantaspase, cyclophosphamide, cyclosporine, cytarabine, cytochalasin B, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib, daunorubi cin, 1-dehydrotestosterone , denileukin, dexamethasone, dexrazoxane, dihydroxyanthracinedione, disulfiram, docetaxel, doxorubicin, emetine, epirubicin, erlotinib, epigallocatechin gallate, epoetin alfa, estramustine, ethidium bromide, etoposide, everolimus, filgrastim, finasunate, floxuridine, fludarabine, fluorura cyl (5-FU), fulvestrant, ganciclovir, geldanamycin, gemcitabine, glucocorticoids, gramicidin D, histrelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, irinotecan, interferons, interferon alpha-2a, interferon alpha-2b, ixabepilone, lactate dehydrogenase A (LDH-A ), lenalidomide, letrozole, leucovorin, levamisole, lidocaine, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, methoxalen, methoprine, metronidazole, mithramycin, mitomycin-C, mitoxantrone, nandrolone, nelarabine, nilotinib, nofetumomab, oprel vequin, oxaliplatin, paclitaxel, pemetrexed, pentostatin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, pemetrexed disodium, plicamycin, procarolineimer, propranolinimer, sodium, puromycin, quinacrine, radicicol, radioactive isotopes, raltitrexed, rapamycin, rasburicase, sali nosporamide A, sargramostim, sunitinib, temozolomide , teniposide, tetracaine, 6-thioguanine, thiotepa, topotecan, toremifene, trastuzumab, treosulfan, tretinoin, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, or a combination thereof.

Antimetabolites may be, for example, methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, cladribine, pemetrexed, gemcitabine, capecitabine, hydroxyurea, mercaptopurine, fludarabine, pralatrexate, clofarabine, cytarabine, decitabine, floxuri din, nelarabine, trimetrexate, thioguanine, pentostatin, or a combination thereof.

The alkylating agent may be, for example, mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclotosfamide, busulfan, dibrommannite, streptozotocin, mitomycin C, cis-dichlorodiamine platinum(II) (DDP), cisplatin, altretamine , cyclophosphamide, ifosfamide, hexamethylmelamine, altretamine, procarbazine, dacarbazine, temozolomide, streptozocin, carboplatin, cisplatin, oxaliplatin, uramustine, bendamustine, trabectin, semustine, or a combination thereof.

The anthracycline may be, for example, daunorubicin, doxorubicin, aclarubicin, aldoxorubicin, amrubicin, annamycin, carubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, or a combination thereof.

The antibiotic may be, for example, dactinomycin, bleomycin, mithramycin, anthramycin (AMC), ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, nafcillin, oxacillin, piperacillin, pivampicillin, pivmecillinam, ticar cillin, aztreonam, imipenem, doripenem, ertapenem, meropenem, clarithromycin, dirithromycin, roxithromycin, telithromycin, lincomycin, pristinamycin, quinupristin, amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, streptomycin, sulfamethizole, sulfamethoxazole, sulfisoxazole, demeclocycline , 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, rifamycins, polymyxin B, bacitracin, viomycin , capreomycin, quinolones, daunorubicin, doxorubicin, 4'-deoxydoxorubicin, epirubicin, idarubicin, plicamycin, mitomycin-c, mitoxantrone, or a combination thereof.

The antimitotic agent may be, for example, vincristine, vinblastine, vinorelbine, docetaxel, estramustine, ixabepilone, paclitaxel, maytansinoid, dolastatin, cryptophycin, or a combination thereof.

The signal transduction inhibitor may 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.

The gene expression modulator may be, for example, a siRNA, shRNA, an antisense oligonucleotide, an HDAC inhibitor, or a combination thereof. The HDAC inhibitor may be, for example, trichostatin A, trapoxin B, valproic acid, vorinostat, belinostat, LAQ824, panobinostat, entinostat, tacedinalin, mocetionstat, givinostat, resminostat, abexinostat, kizinostat, rosilinostat, practinostat, CHR-3996, butyric acid, phenylbutyric acid, 4SC202, romidepsin, sirtinol, cambinol, EX-527, nicotinamide, or a combination thereof. The antisense oligonucleotide may be, for example, kustirsen, apatorsen, AZD9150, trabadersen, EZN-2968, LErafAON-ETU, or a combination thereof. The SiRNA may be, for example, ALN-VSP, CALAA-01, Atu-027, SPC2996, or a combination thereof.

The hormonal therapy may be, for example, a luteinizing hormone releasing hormone (LHRH) antagonist. Hormonal therapy may be, for example, firmagon, leuproline, goserelin, buserelin, flutamide, bicalutadmide, ketoconazole, aminoglutethimide, prednisone, hydroxyl progesterone caproate, medroxyprogesterone acetate, megestrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, test propionate sterone, fluoxymesterone, flutamide, raloxifene, droloxifene, iodoxifene, 4-hydroxytamoxifene, trioxifene, keoxifene, LY117018, onapristone, toremifine citrate, megestrol acetate, exemestane, fadrozole, vorozole, letrozole, anastrozole, nilutamide, tripterelin, hysterelin, arbiraterone, medroxyprogesterone acetate, diethyl stilbestrol, premarin, fluoxymesterone , tretinoin, fenretinide, troxacitabine, or a combination thereof.

The apoptosis inducers may be, for example, recombinant human TNF-related apoptosis-inducing ligand (TRAIL), camptothecin, bortezomib, etoposide, tamoxifen, or a combination thereof.

Angiogenesis inhibitors may be, for example, sorafenib, sunitinib, pazopanib, everolimus, or a combination thereof.

The immunotherapeutic agent may be, for example, a monoclonal antibody, a cancer vaccine (eg, a dendritic cell (DC) vaccine), an oncolytic virus, a cytokine, adoptive T cell therapy, bacillus Calmette-Guerin (BCG), GM-CSF, thalidomide , lenalidomide, pomalidomide, imiquimod, or a combination thereof. The monoclonal antibody may be, for example, nti-CTLA4, anti-PD1, anti-PD-L1, anti-LAG3, anti-KIR, or a combination thereof. The monoclonal antibody may be, for example, lemtuzumab, trastuzumab, ibritumomab tiuxetan, brentuximab vedotin, trastuzumab, ado-trastuzumab, emtansine, blinatumomab, bevacizumab, cetuximab, pertuzumab, panitumumab, ramucirumab, obinutuzumab, ofatumumab, rituk Simab, 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 Pancreas, HyperAcute™ Pancreas, 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, axicabtagene ciloleucel, or a combination thereof.

The DNA damage repair inhibitor may be, for example, a PARP inhibitor, a cell checkpoint kinase inhibitor, or a combination thereof. The PARP inhibitor may 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 a combination thereof. The cell checkpoint kinase inhibitor may be, for example, MK-1775 or AZD1775, AZD7762, LY2606368, PF-0477736, AZD0156, GDC-0575, ARRY-575, CCT245737, PNT-737, or a combination thereof.

Examples

The following examples are intended to illustrate the present invention. They are not intended to limit the present invention in any way.

Example 1: Getting connections

Connection 1

Step 1: A suspension of 4-chloro-7-azaindole (25 g) in DMA (140 ml) was purged with vacuum/N ₂ gas (3 cycles). Zinc powder (1.07 g), zinc cyanide (11.26 g), dppf (2.72 g) and Pd ₂ (dba) ₃ (2.39 g) were then added. The mixture was again purged with vacuum/N ₂ gas (3 cycles) and heated to 120°C for 4 hours. The reaction mixture was allowed to cool to 100°C and water (428 ml) was added over 30 minutes. The mixture was then cooled to room temperature over 2 hours. The crude product was filtered and washed with water (2 x 95 ml), then added to 3N. HCl (150 ml) and the mixture was stirred at room temperature for 2 hours. Insoluble materials were removed by filtration. 50% aq. was added to the filtrate. NaOH until pH 12. Filtration and drying provided 1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (11.6 g) as a dark solid.

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 until condensation occurred for 18 h. When cooled to room temperature, the mixture was treated with concentrated HCl to pH ~2. The solids were collected by filtration and dried under high vacuum to give 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (11.8 g) as a dark solid.

Step 3: To EtOH (120 ml) at 0°C, thionyl chloride (12.4 ml) was added dropwise and the mixture was left to stir at room temperature for 30 minutes, then 1H-pyrrolo[2,3-b]pyridinium- 4-Carboxylic acid (12.0 g) and the reaction mixture were heated until condensation occurred for 8 hours. While cooling to room temperature, the solvents were removed under reduced pressure. The residue thus obtained was suspended in water (150 ml) and the pH was adjusted to 9 aq. sat. K ₂ CO ₃ . The mixture was extracted with EtOAc (2 x 150 ml). The combined extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness to give ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (10.5 g) as a dark solid.

Step 4: To a mixture of ethyl 1H-pyrrolo[2,3-b]pyridine-4-carboxylate (9.5 g) in EtOAc (95 ml) at 0° C. mCPBA (15.5 g) was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. The precipitate was filtered, washed with EtOAc (3 x 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 light yellow solid.

Step 5: To a solution of 4-(ethoxycarbonyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (25.5 g) in DMF (250 ml), methanesulfonyl chloride (11.5 ml) was added dropwise. The mixture was then heated to 80°C for 1 hour, then cooled to room temperature and additional methanesulfonyl chloride (11.5 ml) was added. The mixture was again heated at 80°C for 1 hour. When cooled to 0°C, the reaction mixture was poured into ice water (480 ml) with vigorous stirring. The mixture was then left to stir 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 next step without further purification.

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, add NaH (6.68 g) over 45 min. followed by stirring at 0°C for 1 hour. SEM-Cl (23.6 ml) was added over 20 minutes. and the mixture was left stirring at 0°C for 1 hour. Water (300 ml) was added slowly and the mixture was extracted with EtOAc (2 x 200 ml), then washed with brine, dried over MgSO ₄ , 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.

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) ( R )-3-methylmorpholine (12.4 ml), BINAP (3.4 g) and cesium carbonate (89 g) were added. The mixture was degassed (3 cycles of vacuum/argon) and palladium acetate (1.0 g) was added and the reaction mixture was degassed again, then heated to 120°C for 4 h. When cooled to room temperature, the mixture was diluted with EtOAc (500 ml), filtered through a pad of diatomaceous earth and washed 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 give ethyl-( R )-6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl )-1H-pyrrolo[2,3-b]pyridine-4-carboxylate (26 g) as a yellow oil.

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) to THF (80 ml) was added MeOH (0.048 ml). The reaction mixture was heated to 65°C, then a solution of 2 M LiBH ₄ in THF (9 ml) was added dropwise over 1 hour. The reaction mixture was stirred at 65°C for 18 hours. While cooling to room temperature, acetone (2 ml) was added ) and stirred at room temperature for 30 min. The mixture was diluted 1:1 aq. sat. NH ₄ Cl/water (100 ml) and extracted with EtOAc (2 x 100 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , 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.

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

Step 10. To a solution of ( R )-(6-(3-methylmorpholino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methylmethanesulfonate ( 9 g) in dioxane (80 ml) was added LiI (5.3 g). The mixture was heated to 100°C for 2.5 hours in an argon atmosphere. While cooling to room temperature, the mixture was diluted with EtOAc (100 ml) and water (100 ml). The layers were separated and the aqueous layer was extracted with EtOAc (80 ml). The combined organic extracts were washed with 2 M sodium hydrogen sulfite (80 ml), water (80 ml), brine (80 ml), dried over MgSO ₄ , 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 alone on next stage without additional purification.

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 separated 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 MgSO ₄ , 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.

Step 12. To a solution of ( R )-3-methyl-4-(4-((methylsulfonyl)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine -6-yl)morpholine (7.5 g) in toluene (80 ml) was added TBAB (1 g) and 50% NaOH (36 ml), followed by 1,2-dibromethane (2 ml). The mixture was heated at 65°C for 18 hours. Additional 1,2-dibromethane (16 ml) was then added via syringe pump over 18 hours while stirring the mixture at 65°C. The reaction mixture was left at 65°C for an additional 18 hours, then cooled to room temperature. The mixture was diluted with EtOAc (200 ml) and water (150 ml), the layers were separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , 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.

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 10 by adding 3N. NaOH. The mixture was heated to 80°C for 3 hours, then cooled to room temperature. The mixture was diluted with EtOAc (150 ml) and water (150 ml). The layers were separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , 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]pyridine -6-yl)morpholine (1.65 g) as a light yellow foam.

Stage 14 . Cesium carbonate (9.43 g) was added to a solution of 3-iodo-1H-pyrazole (2.5 g) in DMF (25 ml) at 0°C. SEM-Cl (2.8 ml) was then added over 15 min. The mixture was left stirring at room temperature for 18 hours. Water (60 ml) was added slowly and the mixture was separated with Et ₂ O (60 ml). The aqueous layer was extracted with Et ₂ O (30 ml) and the combined organic extracts were washed with water (3 x 50 ml), brine, dried over MgSO ₄ , 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. The 1H-NMR spectrum demonstrated a 1:1 ratio of the two regioisomers.

Step 15. To ( R )-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)morpholine (100 mg), 3- NMP (1 ml) was added to iodine-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (145 mg), cesium carbonate (244 mg) and L-proline (21 mg) in a microwave vessel. and then CuBr (20 mg). The vessel was sealed and degassed (3 cycles of vacuum/argon), then heated to 150°C for 4 hours. When cooled to room temperature, the reaction mixture was quenched with 20 ml of NH ₄ Cl:H ₂ O:NH ₄ OH (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 ₄ , 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.

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 volatile components were removed under reduced pressure. The residue was dissolved in dioxane (3 ml) and aqueous saturated NaHCO ₃ solution (3 ml), the mixture was heated to 65°C for 18 hours, then 80°C for 18 hours. When cooled to room temperature, the mixture was extracted with dichloromethane ( 2 x 15 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by silica gel chromatography (20-100% EtOAc/hexanes) to give the desired product. The residue was suspended in CH ₃ CN (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 light yellow foam. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.66 (d; J = 3.74 Hz; 1 H); 7.62 (d; J = 2.36 Hz; 1 H); 6.98(s;1H); 6.78(s;1H); 6.59 (d; J = 3.76 Hz; 1 H); 4.32-4.37 (m; 1 H); 4.05-4.09 (m; 1 H); 3.87-3.91 (m; 1 H); 3.83-3.84 (m; 2 H); 3.64-3.71 (m; 1 H); 3.28-3.35 (m; 1 H); 2.83(s;3H); 1.93-1.96 (m; 2 H); 1.39-1.42 (m; 2 H); 1.29 (d; J = 6.71 Hz; 3 H). MS: [M+1]: 402.2.

Intermediate A

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

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

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

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 and then triflate anhydride (3.8 ml) was added at such a rate that the internal temperature was maintained below 5 °C. The reaction mixture was allowed to warm to room temperature for 1 hour, quenched with water (100 ml) and extracted with dichloromethane (2 x 100 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure to obtain 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 next step without further purification.

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) at 0°C, ( R )-3-methylmorpholine (6.8 g) and pyridine (2.0 ml) were added. The reaction mixture was stirred at room temperature for 5 days, then diluted with water (100 ml) and EtOAc (120 ml). The layers were separated and aq. the layer was extracted with EtOAc (100 ml). The combined organic extracts were washed with brine, dried over MgSO ₄ , 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): mass/charge = 441.1 [M+H]+.

Connection 2

Step 1: To a solution of intermediate A (400 mg) in THF (4 ml) at -78°C was added MeMgBr (3M/Et ₂ O, 1 ml) and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with cooled aq. saturated NH ₄ Cl and extracted with EtOAc (2 X 30 ml). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified by ISCO CombiFlash (40 g column), eluting with 10-100% EtOAc/hexanes to give 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.

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) TFA (1.36 ml) was added at room temperature and the solution was stirred for 18 hours. Volatiles were removed under reduced pressure and the residue was suspended in EtOAc (30 ml) and washed with sat. aq. _NaHCO3 . The aqueous layer was extracted with EtOAc (20 ml) and the combined organic layers were washed with brine, dried over MgSO ₄ , 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.

Step 3: ( R )-2-(6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridin-4-yl)propan-2-ol (160 mg) was charged into a microwave reactor vial. SEM-protected 3-iodopyrazole (376 mg), Cs ₂ CO ₃ (475 mg), L-proline (13 mg), CuBr (13 mg) and NMP (3 ml). The vial was then sealed and degassed (3 vacuum/argon cycles), heated at 150 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (50 ml), then purified using an ISCO CombiFlash (24 g column), eluting with 10-100% EtOAc/hexane isomer mixture to give 100 mg ( 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 in the form of a yellow resin. 1H-NMR and LCMS showed two pyrazole regioisomers N-protected by SEM.

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), TFA (0.211 ml) was added at room temperature and the reaction mixture was stirred for 18 hours. Toluene (10 ml) was added ) and volatile components were removed under reduced pressure. The flask was placed under high vacuum to remove residual TPA. The residue was diluted with dioxane (3 ml) and 1 N was added. NaOH (1 ml). The reaction mixture was refluxed for 3 hours, cooled to room temperature, then diluted with EtOAc (20 ml) and water (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (12 g column), eluting with 40-100% EtOAc/hexane isomer mixture. Fractions containing the desired product were combined and concentrated to dryness. The residue was diluted with CH ₃ CN (1 ml) and water (1 ml) for lyophilization to obtain 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 in the form of a colorless foam. HPLC purity at 254 nm: 93.0%, ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.12 (s; 1 H); 7.63 (d; J = 2.10 Hz; 1 H); 6.83 (s; 1 H); 6.72 (s; 1 H); 4.45-4.49 (m; 1 H); 4.02-4.09 (m; 2 H); 3.77-3.86 (m; 3 H); 3.66 (td; J = 11.90; 3.16 Hz; 1 H); 3.39 (td; J = 12.73; 3.87 Hz; 1 H); 1.73 (s; 6 H); 1.35 (d; J = 6.74 Hz; 3 H).

Connection 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 at 65 °C, then a solution of 2 M LiBH ₄ in THF (5.8 ml) was added dropwise over 1 hour. The reaction mixture was stirred at 65 °C for 4 hours, 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 aq. sat. NH ₄ Cl/water (80 ml) and EtOAc (80 ml). The layers were separated and the aqueous layer was extracted with EtOAc (40 ml). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was purified using ISCO CombiFlash (80 g column), eluting with 30-100% EtOAc/hexane isomer mixture 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 in the form of colorless foams (separable mixture of positional isomers).

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

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) LiI (393 mg) was added to dioxane (7 ml). The mixture was heated at 50 °C for 2.5 h in an argon atmosphere. After cooling to room temperature, the mixture was diluted with EtOAc (50 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with EtOAc (30 ml). The combined organic extracts were washed with 2M sodium hydrogen sulfite (50 ml), water (50 ml) and sodium chloride (50 ml), then dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure to give 760 mg ( R )-4-(2 -(2,4-dimethoxybenzyl)-4-(iodomethyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine, which was used as is in the next step without further purification.

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) sodium methanesulfinate (190 mg) was added to DMF (8 ml). The reaction mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (40 ml) and water (40 ml). The layers were separated and the aqueous layer was extracted with EtOAc (30 ml). The combined organic extracts were washed with aq. sodium thiosulfate (50 ml), water (50 ml) and sodium chloride, then dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was adsorbed onto silica gel for purification using an Isco CombiFlash (40 g column), eluting with 30-100% EtOAc/hexane isomer mixture to give 640 mg of ( R )-4-(2-(2,4-dimethoxybenzyl)-4-( (methylsulfonyl)methyl)-2H-pyrazolo[3,4-b]pyridin-6-yl)-3-methylmorpholine in the form of a colorless foam.

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), then 50% NaOH (2.9 ml) was added. The reaction mixture was heated at 60°C for 2 hours. Additional 1,2-dibromoethane (0.5 ml) was added and the mixture was again heated at 60°C for 18 hours. After cooling to RT, the mixture was diluted with EtOAc (30 ml) and water (25 ml), the layers were separated and the aqueous layer was extracted with EtOAc (20 ml). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. The residue was adsorbed onto silica gel for purification using an ISCO CombiFlash (24 g column), eluting with 30-100% EtOAc/hexane isomer mixture 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 in the form of a light yellow foam.

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) at 0 °C, TFA (1.6 ml) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. Toluene (10 ml) was added to the reaction mixture and volatiles were removed in vacuo, then co-evaporated with toluene (10 ml). The residue was dissolved in EtOAc (50 ml) and saturated aqueous NaHCO ₃ (40 ml) with vigorous stirring. The layers were separated and the aqueous layer was extracted with EtOAc (30 ml). The combined extracts were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , 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 light yellow foam, which was used in the next step without further purification.

Step 7: ( R )-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine (160) was loaded into a microwave reactor vial mg), pyrazole (310 mg), Cs ₂ CO ₃ (390 mg), L-proline (11 mg), CuBr (11 mg) and NMP (2 ml). The vial was sealed and degassed (3 vacuum/argon cycles), then heated to 150 °C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (20 ml) and NH ₄ Cl:H ₂ O:NH ₄ OH ( 4:3:1, 20 ml), 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 saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (24 g column), eluting with 20-100% EtOAc/hexane isomer mixture 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.

Step 8. To a solution of ( R )-3-methyl-4-(4-(1-(methylsulfonyl)cyclopropyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5- yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)morpholine (37 mg) in dichloromethane (1 ml), TFA (0.319 ml) was added and the reaction mixture was stirred for 18 hours. Toluene (10 ml) was added ) and volatile components were removed under reduced pressure. The residue was dissolved in dioxane (3 ml) and saturated aqueous NaHCO ₃ (3 ml), and the mixture was heated at 65 °C for 4 hours, then at 80 °C for 18 hours. After cooling to room temperature, the mixture was extracted with dichloromethane ( 2 X 15 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was purified by flash chromatography on silica gel, eluting with EtOAc and 5% MeOH/EtOAc. The resulting residue was suspended in CH ₃ CN (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: in the form of a light yellow foam. ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.11 (s; 1 H); 7.70 (d; J = 2.26 Hz; 1 H); 6.93 (d; J = 2.26 Hz; 1 H); 6.84 (s; 1 H); 4.41-4.43 (m; 1 H); 4.06-4.09 (m; 2 H); 3.77-3.87 (m; 2 H); 3.61-3.68 (m; 1 H); 3.33-3.40 (m; 1 H); 2.85 (s; 3 H); 1.97-2.00 (m; 2 H); 1.41-1.44 (m; 2 H); 1.35 (d; J = 6.78 Hz; 3 H). [M+1]: m/z 403.1.

Connection 4

Step 1: TFA (20 mL) was added to a solution of intermediate A (5.8 g, 13.167 mmol) in dichloromethane (60 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 hours. Toluene (60 ml) was added to the reaction mixture and volatiles were removed in vacuo, then co-evaporated with toluene (20 ml). The residue was dissolved in dichloromethane (300 ml), then treated with saturated aqueous NaHCO ₃ solution (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 saturated aqueous sodium chloride, dried over MgSO ₄ , 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.

Step 2. Mixture of ethyl ( R )-6-(3-methylmorpholino)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (3.8 g), pyrazole (6.37 g), Cs ₂ CO ₃ (10.7 g), L-proline (300 mg), CuBr (292 mg) and NMP (40 ml) were degassed (3 vacuum/argon cycles), heated at 150 °C for 18 h. After cooling to room temperature, the reaction mixture was diluted with 10% citric acid to adjust the pH to ~6-7 and EtOAc (350 ml) was added. The mixture was filtered through diatomaceous earth and washed with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (150 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , 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 a yellow oil.

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 with potassium carbonate (2.7 g), followed by the addition of 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 saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was purified using ISCO CombiFlash (80 g column), eluting with 0-70% EtOAc/hexane isomer mixture 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.

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 at 65 °C for 4 h, then cooled to room temperature. Acetone (1 ml) was added and stirred for 30 min. The mixture was diluted (1:1) NH ₄ Cl/water (50 ml), then extracted with EtOAc (2 x 40 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo to give 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 in the next step without further purification.

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 with Et ₃ N (0.69 ml) at 0 °C, followed by MsCl (0.38 ml). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (60 ml) and water (60 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 2.3 g 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, which was used in the next step without further purification.

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) was added with NaCN (325 mg) at room temperature. The reaction mixture was stirred for 18 hours, then diluted with EtOAc (40 ml) and water (40 ml). The layers were separated and the aqueous layer was extracted with EtOAc (35 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified using ISCO CombiFlash (24 g column), eluting with 20-100% EtOAc/hexane isomers to give 440 mg ( R )-2-(6-(3-methylmorpholino)-1-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)acetonitrile.

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) at 0 °C was added with iodomethane (0.148 ml) followed by dropwise addition of potassium tert-butoxide (2.37 ml) over 10 min. The reaction mixture was stirred at 0 °C for 1 hour, then poured into aq. sat. NH ₄ Cl and extracted with EtOAc (2 x 35 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (24 g Gold SiO ₂ column), eluting with 10-90% EtOAc/hexane isomer mixture to give 140 mg ( 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.

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/H ₂ O (2 ml/0.4 ml) was added hydrido(dimethylphosphinic acid-kP) [hydrogen bis(dimethylphosphinite- kP)]platinum (II) (4 mg). The mixture was heated at 80 °C, then cooled and concentrated to dryness. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (12 g Gold SiO ₂ column), eluting with 30-100% EtOAc/hexane isomer mixture 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 .

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), TPA (0.30 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. Additional amount was added TFA (0.5 ml) and the mixture was stirred for 6 hours. Toluene (10 ml) was added and volatile components were removed under reduced pressure. The residue was diluted in 5 ml MeOH/water (85:15) and stirred at room temperature for 18 hours. Volatile components were removed under reduced pressure and the residue was dissolved in EtOAc (25 ml) and treated with aq. sat. NaHCO ₃ (20 ml). The layers were separated and the aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness in vacuo. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (12 g Gold SiO ₂ column), eluting with 80-100% EtOAc/hexane isomer mixture to give 23 mg ( R )-2-methyl-2-(6-(3-methylmorpholino )-1-(1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)propanamide in the form of a colorless foam. ¹ H NMR (400 MHz, DMSO): δ 12.80 (s; 1 H); 7.90 (s; 1 H); 7.83 (s; 1 H); 7.06 (s; 1 H); 7.02 (s; 1 H); 6.76-6.77 (m; 1 H); 6.65 (s; 1 H); 4.47-4.50 (m; 1 H); 4.06 (d; J = 13.56 Hz; 1 H); 3.99 (d; J = 11.46 Hz; 1 H); 3.78 (d; J = 11.34 Hz; 1 H); 3.63-3.66 (m; 1 H); 3.47-3.53 (m; 1 H); 3.17-3.23 (m; 1 H); 1.54 (s; 6 H); 1.22 (d; J = 6.68 Hz; 3 H). MS (+ESI): m/z 370.2.

Connection 5

Step 1. 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 from Example 4, Step 5 (115 mg) and 2-hydroxyisobutyronitrile (0.07 ml) in anhydrous 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. Organic extracts were dried and concentrated to dryness, then purified by combi-flash (12 g column), eluting with 10-80% EtOAc/hexane isomer mixture to give 110 mg ( 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 light yellow oil.

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 the addition of 1.5 -dibromopentane (0.027 ml). The mixture was heated at 65 °C for 2 h, then diluted with water and extracted with EtOAc. The combined organic extracts were dried over NaSO ₄ , concentrated to dryness and purified using combi-flash (4 g column), eluting with 20-80% EtOAc/hexane isomer mixture 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 in in the form of a light yellow oil.

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 with TFA (0.27 ml). The reaction mixture was stirred at room temperature for 18 hours, then concentrated under reduced pressure. The residue was dissolved in 5 ml MeOH/H ₂ O) (85:15) and stirred at room temperature for 18 hours and concentrated. The residue was dissolved in EtOAc (25 ml) and aq. sat. NaHCO ₃ (25 ml). The layers were separated and the aqueous layer was extracted with EtOAc (10 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated. The residue was adsorbed onto silica gel for purification using an ISCO CombiFlash (4 g column), eluting with 30-100% EtOAc/hexane 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 in the form of an off-white foam. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.37 (d; 3 H); 1.96 (d; 5 H); 2.09 (t; 2 H); 2.29(d;2H); 3.39 (td; 1 H); 3.65 (td; 1 H); 3.87-3.77 (m; 2 H); 4.08 (d; 3 H); 4.49 (d; 1 H); 6.82 (s; 1 H); 6.99(d;1H); 7.80 (d; 1 H); 8.22 (s; 1 H).

Connection 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 in portions over 30 min. The reaction mixture was then stirred at room temperature. for 18 hours, and the solids were collected by filtration and washed with n-heptane (350 ml). The residue was dried under high vacuum to obtain 62 g of 4-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide 3-chlorobenzoate as a gray solid.

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 at 60 °C for 18 hours. After cooling to room temperature, ( R )-3-methylfoline (14 g) was added followed by diisopropylethylamine (48.2 ml) and the reaction mixture was heated at 60 °C for 18 hours. cooling to RT, volatiles were removed in vacuo and the residue was purified by silica gel column chromatography, eluting with 10-40% EtOAc/hexane isomer mixture to give 12 g of ( R )-4-(4-chloro-1H-pyrrolo [2,3-b]pyridin-6-yl)-3-methylmorpholine as a light gray solid.

Step 3. Mixture of ( R )-4-(4-chloro-1Hpyrrolo[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 K ₃ PO ₄ (17.23 g) in dioxane (110 ml) were purged with 3x argon and heated at 110 °C in for 18 hours. 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, then purified by flash chromatography on silica gel, eluting with 10-25% EtOAc/hexane isomer mixture. The pure fractions were combined and concentrated to give 19.3 g

( 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.

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)diborone (4.25 g), Pd2(dba)3 (510 mg) and tricyclohexylphosphine (780 mg) in dioxane (70 ml) potassium acetate (3.32 g) was added. 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 re-reacted. 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/hexane isomer mixture 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 in the form of a yellow powder.

Step 5. Add 1 dram bottle 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 ), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg), dioxane (1 ml) and 2N Na ₂ CO ₃ (250 μl) were added. The mixture was evacuated, purged with argon (3x) 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 saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified on a Redisep Gold column (12 g) using 0 to 100% ethyl acetate/hexane 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.

Step 6. To a solution of ( R )-3-methyl-4-(4-(2-(methylsulfonyl)phenyl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-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 mixture was stirred at room temperature overnight, then concentrated and redissolved in 85/15 MeOH/H ₂ O and stirred for an additional 4 hours. 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 (3x). The combined organic layers were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified on a Redisep column (24 g) eluting with 40 to 60% ethyl acetate/hexane 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. ^1H NMR (d ₆ -DMSO) δ 12.7 (s, 1H), 8.2 (d 1H), 7.8 (m, 1H), 7.7 (m, 2H), 7.6 (m 1H), 7.5 (m 1H), 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 (d 3H).

Connection 7

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

Step 2: Into a 100 mL flask containing ( R )-4-(4-chloro-3-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-3-methylmorpholine (2.08 g ), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.79 g) in dioxane (20 ml) was added. Argon was bubbled into the mixture and ground K ₃ PO ₄ (2.9 g) was added, followed by trans-N,N'-dimethylcyclohexane-1,2-diamine (111 mg) and CuI (15 mg). The reaction mixture was heated at 100 °C for 44 h, then filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. Purification on a Redisep Gold column (80 g), eluting with 0-100% ethyl acetate/hexane isomer mixture, yielded 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 in the form of a mixture of regioisomers.

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 with isobutyronitrile (350 µl) followed by LiHMDS (1M in THF, 2.7 ml). The mixture was heated in a microwave oven at 100 °C for 15 min, then cooled and distributed between saturated aq. NH ₄ Cl and ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated. Purification on a Redisep Gold column (24 g) using 0-100% ethyl acetate/hexane mixture 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.

Step 4. To a solution of ( R )-2-methyl-2-(3-methyl-6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3 -yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)propanenitrile (135 mg) in dichloromethane (1 ml) was added TFA (250 μl). The reaction mixture was stirred at room temperature for 3 days, then concentrated and partitioned between ethyl acetate and saturated aq. _NaHCO3 . The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. Purification on a Redisep Gold column (12 g) using 30-100% ethyl acetate/hexane mixture resulted in 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. ^1H NMR ( _d6 -DMSO) δ 12.7 (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, 1H), 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 (d 3H).

Connection 8

Step 1. Diisopropylethylamine ( 509 µl) and the mixture was stirred at room temperature for 1 hour. Water and Et ₂ O were added and the phases were separated. The aqueous phase was extracted with Et ₂ O (2x) and the combined organic extracts were washed with saturated aqueous sodium chloride and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified using silica gel chromatography, eluting with 0 to 70% EtOAc/hexane isomer mixture to provide 473 mg of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyltrimethylsilane ( pre-signal assignment) and 120 mg 2-[(5,7-dichloroimidazo[4,5-b]pyridin-1-yl)methoxy]ethyltrimethylsilane (pre-signal assignment). Main isomer: ^1H NMR (400 MHz, _CDCl3 ) δ 8.22 (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: ^1H NMR (400 MHz, _CDCl3 ) δ 8.21 (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).

Step 2. To a solution of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethylsilane (90 mg), K ₃ PO ₄ (2 M, 424 μl) and (2-methylsulfonylphenyl)boronic acid (68 mg) in dioxane (1 ml), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (31 mg) was added under nitrogen atmosphere, then stirred overnight at 80 °C. Water was added along with EtOAc and the phases were separated. The aqueous phase was extracted with EtOAc (2x) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified using silica gel chromatography eluting with 0 to 100% EtOAc/hexane to give 2-[[7-chloro-5-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl] methoxy]ethyl-trimethylsilane in the form of a 1:1 mixture of regioisomers. ^1H NMR (400MHz, _CDCl3 ) δ 8.22 (dd, J = 7.7, 1.6 Hz, 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).

Step 3. To a solution of 2-[[7-chloro-5-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl]methoxy]ethyl-trimethylsilane (640 mg) in anhydrous dioxane (1 ml) cesium carbonate (952 mg), methyl tert-butyl ether adduct of RuPhos Pd G1 (119 mg) and ( 3R )-3-methylmorpholine (332 μl) were added. The mixture was purged with nitrogen, then heated to 100 °C in a closed vial for 16 hours. Water and EtOAc were added and the phases were separated. The aqueous phase was extracted with EtOAc (2x) and the combined organic extracts were washed with saturated aqueous sodium chloride, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was taken up 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.21 (dd, J = 7.9, 1.4 Hz, 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, 2H), 3.49 (td, J = 6.5, 5.5, 3.8 Hz, 1H), 3.32 (s, 3H), 1.34 (d, J = 6.7 Hz , 3H), 0.97 - 0.83 (m, 2H), -0.06 (s, 9H). LCMS: 505.19 (M+H).

Step 4. To a solution of trimethyl-[2-[[5-[(3 R )-3-methylmorpholin-4-yl]-7-(2-methylsulfonylphenyl)imidazo[4,5-b]pyridin-3-yl] methoxy]ethyl]silane (55 mg) in dichloromethane (1 ml), TFA (250 μl) was slowly added and the mixture was stirred overnight at room temperature. Additional TFA (250 μl) was added and the mixture was stirred over the weekend. The volatile components were removed under reduced pressure and the crude residue was dissolved in EtOAc and treated with saturated aqueous NaHCO ₃ solution, then the layers were separated. The aqueous layer was extracted with EtOAc (2x) 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. ^1H NMR (400 MHz, CDCl ₃ ) δ 8.23 (dd, J = 7.9, 1.4 Hz, 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 (kv, 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 (td, J = 11.7, 3.0Hz, 1H), 3.27 (dd, J = 12.5, 3.8Hz , 1H), 2.97 (s, 3H), 1.27 (d, J = 6.7Hz, 3H). LCMS: 374.08 (M + H).

Step 5. 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-trimethylsilane (510 mg), 3-(1,1-difluoroethyl)benzenesulfinic acid (54 mg) and cesium carbonate (634 mg) in NMP (3.5 ml) Copper bromide (45 mg) was added under nitrogen atmosphere and the mixture was heated at 120 °C overnight. The mixture was cooled, treated with saturated aqueous NH ₄ Cl, water and ammonium hydroxide (4:1:3) and extracted with EtOAc. The aqueous phase was extracted with EtOAc (2x) and the combined organic phases were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , 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 in the form of a mixture of regioisomers. LCMS: 569.38 (M+H).

Step 6. To a solution of trimethyl-[2-[[3-[5-[(3 R )-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), TFA (56 μl) was added and the mixture was stirred overnight at room temperature. Volatile components were removed under reduced pressure and the mixture was dissolved in dioxane (1 ml), and basified to pH ~10 using 3 N. NaOH, and heated at 80 °C for 3 h. The mixture was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (2x) and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was taken up 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)imidazo [4,5-b]pyridin-5-yl]morpholine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.03 (s, 1H), 8.47 (s, 1H), 8.14 (dd, J = 7.8, 1.5 Hz, 1H), 7 .96 (d, J = 2.3Hz, 1H), 7.80 (dd, 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, 2H), 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).

Intermediate C

Step 1. To a solution of 3-aminopyrazole (24.7 g, 297 mmol) at -5 °C in 6 N. HCl (181 ml) was added 1M aqueous NaNO ₂ solution (300 ml, 297 mmol). Then a solution of SnCl ₂ (113 g, 595 mmol) in conc. HCl (510 ml) and the resulting mixture was stirred at RT. for 2 hours. The solvents were evaporated under reduced pressure to give 3-hydrazinylidene-3H-pyrazole as a light brown solid, which was used without further purification, ¹ H NMR (400 MHz, DMSO-d ₆ , δ ppm. ): 9.90 (s, 3H), 7.65 (d, J = 2.4 Hz, 1H), 5.81 (d, J = 2.3 Hz, 1H).

Step 2: A flame-dried 500 mL round bottom flask 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/hexane isomer mixture, 84.7 mL, 84.7 mmol) was added dropwise at a rate such that the internal temperature remained below −68 °C. The light brown solution was left to stir at -78 °C for 1 hour and then ethyl formate (8.5 mL, 105.678 mmol) was added over 10 minutes. 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 minutes, then diluted with EtOAc (150 ml). The mixture was allowed to warm 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 saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain 19 g of 2,6-difluoro-4-iodo-pyridine-3-carbaldehyde as a light brown solid. ¹ H NMR: (400 MHz, CDCl ₃ ), δ 10.11 (s, 1 H), 7.54 (d; J = 2.87 Hz; 1 H).

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-iodopyridine-3-carbaldehyde (4.4 g , 16.3 mmol) and the mixture was stirred at room temperature. within 15 min. Most of the volatiles were then removed under reduced pressure. The orange mixture was dissolved in EtOAc and NaHCO ₃ and stirred at room temperature for 15 minutes, which resulted in intense gas evolution. The phases were separated and the aqueous phase was extracted with 3x EtOAc. The combined organic extracts were washed with water and sodium chloride, then dried over MgSO ₄ , filtered and concentrated 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, ^1H NMR (400 MHz, 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).

Step 4: 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 batches of 20 ml, which were heated at 200 ºC in a microwave reactor for 20 minutes. The combined mixtures were then added dropwise to water with vigorous stirring to obtain an opaque mixture, which was stirred for 5 minutes at room temperature, then cooled to 0 °C. The precipitate was filtered, washed with water and dried on a Buchner funnel for 1 hour, and under reduced pressure for 1 hour to obtain 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. ^1H NMR (400 MHz, DMSO- _d6 ) δ 13.13 (s, 1H), 8.29 (s, 1H), 7.95 (t, 1H), 7.71 (d, 1H), 6 .67 (t, 1H).

Step 5: 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 to 120 ºC for 45 min. The mixture was then added dropwise to an Erlenmeyer flask filled with water with vigorous stirring. The opaque mixture was stirred at room temperature for 5 minutes, then for 20 minutes at 0 °C. The precipitate was filtered on a Buchner funnel, and the precipitate was washed with water and dried on a 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.

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 (2x). The combined organic layers were washed with water (2x) and sodium chloride, then dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (0 to 80% EtOAc/hexane isomer gradient) afforded 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-[(3 R )-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl]methoxy]ethyltrimethylsilane (0.17 g, 0.31 mmol).

Connection 86

Step 1: In a round bottom flask, dissolve 2,6-difluoro-4-iodo-pyridine-3-carbaldehyde (1.76 g, 6.54 mmol) in DME (15 ml) and add hydrazine hydrate (535 µl, 65% purity, 7.1 mmol). The reaction mixture was stirred at room temperature. for 4 hours. Water was added to the heterogeneous yellow solution and stirred for 30 minutes at room temperature. The resulting solid was then collected by filtration, washed with water and dried in vacuo overnight to give 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine.

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

Step 3: In a round bottom flask, dissolve 6-fluoro-4-iodo-1H-pyrazolo[3,4-b]pyridine (1.54 g, 5.86 mmol) in DMF (40 ml) and cool to 0 °C. Sodium hydride was added to this solution; 60% wt. (281.0 mg, 7.03 mmol, 60% purity) and the reaction mixture was stirred at 0 °C for 30 minutes. SEM-Cl (1.46 g, 8.78 mmol, 1.55 mL) was then added and the solution was stirred at 0 °C for 5 minutes before being warmed back to room temperature and then stirred for a further 1 hour. Saturated NH ₄ Cl was added first, then water and the mixture was stirred for 30 minutes and the resulting solid was collected by filtration and dried overnight under reduced pressure to give 2-[(6-fluoro-4-iodo-pyrazolo[3,4-b ]pyridin-2-yl)methoxy]ethyl-trimethylsilane in the form of a mixture of SEM regioisomers.

Step 4. 2-[[4-iodo-6-[(3R)-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]methoxy]ethyl-trimethyl- was dissolved in a round bottom flask. silane (103 mg, 217.11 µmol) in THF (1 ml). To this solution was added 2-methylpropanonitrile (150.15 mg, 2.17 mmol, 195 µl) followed by the addition of LiHMDS (1 M, 1.09 ml). The reaction mixture was stirred at 20 °C for 15 min and then heated to 100 °C for 12 min under microwave irradiation. Water was added along with EtOAc and the phases were separated. The aqueous phase was extracted a second time with EtOAc. The combined organic phases were washed with saturated aqueous sodium chloride before drying over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified using a 15.5g Gold C18 Isco column and eluted with 10 to 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.

Step 5. 2-Methyl-2-[6-[(3 R )-3-methylmorpholin-4-yl]-1-(2-trimethylsilylethoxymethyl)pyrazolo[3,4-b]pyridin-4- was dissolved in a round bottom flask. yl]propanenitrile (690 mg, 1.66 mmol) in DCM (30 ml) and TFA (3.80 ml, 50 mmol) was added. The reaction mixture was stirred at room temperature. overnight and then the mixture was concentrated under reduced pressure. The crude product was dissolved in 1 ml DMSO and purified using a 15.5g Gold C18 Isco column and eluted with 5 to 100% water/MeCN to give 2-methyl-2-[6-[( 3R )-3-methylmorpholine-4- yl]-1H-pyrazolo[3,4-b]pyridin-4-yl]propanenitrile.

Step 6. 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), (1S,2S)- N1,N2-dimethylcyclohexane-1,2-diamine (100 mg, 0.70 mmol) in NMP (1.2 ml) was purged with nitrogen for 5 minutes before copper iodide (67 mg, 0.35 mmol) was added. The mixture was heated at 120 °C for 16 hours. Water was added, the mixture was stirred for 30 minutes and the resulting solid was collected by filtration and dried under reduced pressure for 1 hour. The resulting solid was then dissolved in 1 ml DMSO and purified using reflux phase on a Combiflash instrument (5 to 100% water/MeCN at 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.

Step 7. 2-Methyl-2-[6-[(3 R )-3-methylmorpholin-4-yl]-1-(5-methyl-2-tetrahydropyran-2-yl-pyrazol-3-) was dissolved in a round bottom flask. yl)pyrazolo[3,4-b]pyridin-4-yl]propanenitrile (42 mg, 93 µmol) in MeOH (0.5 ml). HCl in MeOH (1.25 M, 112 μL) was added to this solution and the reaction mixture was stirred at 60 °C for 1 h. The volatile components were concentrated under reduced pressure and the crude product was purified using a 15.5g Gold C18 Isco column and eluted with 5 to 100% water/MeCN to give Compound 86 . ^1H NMR (400 MHz, DMSO- _d6 ) δ 12.51 (s, 1H), 8.27 (s, 1H), 6.73 (s, 1H), 6.49 (d, J = 2, 0 Hz, 1H), 4.46 (s, 1H), 4.09 - 4.00 (m, 1H), 3.97 (dd, J = 11.4, 3.5 Hz, 1H), 3, 76 (d, J = 11.4 Hz, 1H), 3.64 (dd, J = 11.5, 3.1 Hz, 1H), 3.49 (td, J = 11.9, 3.1 Hz , 1H), 3.19 (td, J = 12.6, 3.8 Hz, 1H), 2.30 (s, 3H), 1.85 (s, 6H), 1.20 (d, J = 6.7 Hz, 3H).

Connection 99

Step 1. Solution of 2-[[5-[4-iodo-6-[(3 R )-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl ]methoxy]ethyl-trimethylsilane (500 mg, 0.92 mmol) in THF (8 ml) was cooled to -78 °C and nBuLi (2.5 M, 0.48 ml) was added slowly. The mixture was stirred in this form for 40 minutes. A solution of tetrahydropyran-3-one (27 µl, 2.78 mmol) in 1.5 ml THF was then added to the mixture. The flask was removed from the dry ice bath and stirring was continued for 1 hour. The mixture was then quenched with saturated NH ₄ Cl solution and EtOAc was added and the phases were separated. The aqueous phase was extracted two additional times with EtOAc and the combined organic extracts were washed with saturated aqueous sodium chloride before drying over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 3-[6-[( 3R )-3-methylmorpholine -4-yl]-1-[2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]pyrazolo[3,4-b]pyridin-4-yl]tetrahydropyran-3-ol.

Step 2. Solution of 3-[6-[(3 R )-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), in DCM (1 ml), TFA (5.96 g, 52.3 mmol, 4 ml) at room temperature and stirred for 10 minutes. The volatile components were removed under reduced pressure and the residue was purified using reverse phase chromatography to obtain a mixture of compound 99 and compound 100, which was separated by SFC.

Connection 121

Step 1: A solution of Intermediate C (200 mg, 0.37 mmol) in THF (4 mL) was cooled to -78 °C and nBuLi (2.5 M, 0.19 mL) was added slowly. The mixture was stirred for 40 min, then a solution of 8-oxabicyclo[3,2,1]octan-3-one (27 µl, 1.2 mmol) in 0.4 ml THF was added. The flask was removed from the dry ice bath and the mixture was allowed to warm to room temperature over 1.5 hours. The mixture was then quenched with saturated NH ₄ Cl and extracted with EtOAc. The aqueous phase was extracted two additional times with EtOAc and the combined organic extracts were washed with saturated aqueous sodium chloride before being dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was used in the next step without further purification.

Step 2. Solution of 3-[6-[(3 R )-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) were treated with TFA (2.3 ml, 30 mmol) at RT. and stirred for 10 minutes. Volatile components 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/H ₂ O to give compound 121. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.79 (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 = 11.4 Hz, 1H), 3.64 (dd, J = 11.5, 3.1 Hz, 1H), 3.49 (td, J = 11.7, 2.9 Hz, 1H), 3.23 - 3.11 (m, 1H), 2.43 - 2.31 (m, 4H), 1.81 (dd, J = 20.9, 11.5 Hz, 4H), 1.20 (d, J = 6.6 Hz, 3H ).

Connection 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 slow addition of Et ₃ N (1.8 mL, 12.9 mmol). The reaction mixture was stirred at room temperature. for 18 hours 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 saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was adsorbed onto silica gel for purification using Combi-Flash (80 g Gold SiO ₂ ), eluting from 100% hexane to 35% EtOAc/hexane over 25 min to give 1.8 g di-tert-butyl ( 3-bromopyridin-2-yl)dicarbamate as a colorless solid. MS (+ESI) m/z 395.1/397.1 (M+Na)

Step 2. Di-tert-butyl (3-bromopyridin-2-yl)dicarbamate (150 mg, 0.40 mmol), bis(pinacolato)diborone (204 mg, 0.80 mmol) and potassium acetate (120 mg, 1 .21 mmol) was dissolved in anhydrous DMF (1 ml), followed by the addition of Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (33 mg, 0.04 mmol). The reaction mixture was purged with argon and then heated to 85 ºC for 16 hours. The mixture was diluted with EtOAc and filtered through a celite column. The volatile components were concentrated to obtain tert-butyl (tert-butoxycarbonyl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate, which was used in next stage without additional purification.

Step 3. 2-[[3-[4-iodo-6-[(3 R )-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl]pyrazol-1-yl] methoxy]ethyltrimethylsilane (120 mg, 0.22 mmol), K ₃ PO ₄ (142 mg, 0.66 mmol), Pd(dppfCl ₂ ).CH ₂ Cl ₂ (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) was dissolved in anhydrous DMF ( 2 ml). The reaction mixture was purged with argon and heated at 85 ºC for 16 h. The product was purified by combiflash (C18, 26 g) using 5-100% MeCN in H ₂ O (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).

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 Et ₃ SiH (0.03 ml, 0.17 mmol) and the reaction mixture was stirred for 1.5 hours. The volatile components were concentrated and the residue was purified using combi-flash (SiO ₂ , 4 d) using a 0-100% mixture of hexane isomers 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).

Connection 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), 2M K ₂ CO ₃ (2 ml, 4 mmol), Pd(PPh ₃ ) ₄ (75 mg, 0.065 mmol) and dioxane (7 ml). The vial was sealed and purged with N ₂ (3 cycles of reduced pressure/N ₂ ). The mixture was heated at 100 °C for 5 h. LCMS indicated completion of the reaction. After cooling to RT, the mixture was diluted with EtOAc (40 ml) and water (40 ml). The layers were separated and aq. the layer was extracted using EtOAc (70 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO ₄ , filtered and concentrated to dryness. The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (40 g column, SiO ₂ Gold) eluting with 20-100% EtOAc/hexane isomer mixture to give 700 mg ( 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.

Step 2. To a solution of ( R )-N-(tert-butyl)-2-(6-(3-methylmorpholino)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-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) at k.t. TFA (9 mL, 118 mmol) was added. The reaction mixture was stirred at room temperature. for 4 hours. Volatile components were removed under reduced pressure and the residue was dissolved in TFA (10 ml). The mixture was stirred at room temperature. for 18 h, then heated to 40 °C for 1 h and 50 °C for 1 h. Volatiles were removed under reduced pressure and co-evaporated with DCM (3x). The residue was adsorbed onto silica gel for purification using ISCO CombiFlash (24 g Gold SiO ₂ column) eluting with 30-100% EtOAc/hexane isomer mixture. Fractions containing the desired product were combined and concentrated to dryness under reduced pressure. The residue was dissolved in CH ₃ CN (3 ml) and water (5 ml) for lyophilization to obtain 350 mg of ( R )-2-(6-(3-methylmorpholino)-1-(1H-pyrazol-3-yl)-1H -pyrazolo[3,4-b]pyridin-4-yl)benzenesulfonamide in the form of a light yellow foam. +IER [M+1]: 440.2. HPLC purity at 254 nm: >99%, 10-90% CH ₃ CN/H ₂ O (+0.1% formic acid) for 20 min. ¹ H NMR (400 MHz, DMSO): δ 12.83 (s; 1 H); 8.11-8.13 (m; 1 H); 7.86 (s; 1 H); 7.68-7.72 (m; 2 H); 7.61 (s; 1 H); 7.50-7.52 (m; 1 H); 7.42 (s; 2 H); 6.83 (s; 1 H); 6.80 (s; 1 H); 4.33-4.38 (m; 1 H); 4.08 (d; J = 13.32 Hz; 1 H); 3.97-4.00 (m; 1 H); 3.73-3.76 (m; 1 H); 3.64-3.68 (m; 1 H); 3.49-3.55 (m; 1 H); 3.15-3.21 (m; 1 H); 1.22 (d; J = 6.61 Hz; 3 H).

Connection 138

Step 1. (3 R )-4-[4-iodo-1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]pyrazolo[3,4-b]pyridin-6-yl]-3 α-methyl-morpholine (500 mg, 0.943 mmol), bis(pinacolato)diborone (359 mg, 1.41 mmol) and potassium acetate (324 mg, 3.30 mmol) were combined in DMF (5 ml) and this solution was degassed by bubbling N ₂ through the mixture with ultrasonic treatment for 10 minutes. Pd(dppf)Cl ₂ DCM (69 mg, 0.0943 mmol) was then added and the mixture was re-degassed for 5 minutes. The reaction mixture was then heated to 95 ºC 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 x 3 volumes), dried over Na ₂ SO ₄ and concentrated to dryness. The product was then purified using combiflash (0-100% EtOAc/hexane mixture).

Step 2. To a solution of (3 R )-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 aq. K ₂ CO ₃ (1.1 ml, 1.24 mmol) and then Pd(dppf)Cl ₂ -DCM complex (68 mg, 0.083 mmol). The reaction mixture was heated at 110 ºC in a microwave reactor for 10 minutes. 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 volumes), dried over Na ₂ SO ₄ and concentrated to dryness. The product was then purified using combiflash (0-100%EtOAc/hexane mixture).

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 mixture was stirred for 2 hours. The reaction mixture was concentrated to dryness, the residue was dissolved in DMSO (1 ml) and the product was purified using reverse phase on a combiflash instrument (5-95% MeCN/water). +IER [M+1]: 445.0. HPLC purity at 254 nm: >99%, 10-90% CH ₃ CN/H ₂ O (+0.1% formic acid) for 20 min. ^1H NMR (400 MHz, DMSO-d6) δ 12.81 (s, 1H), 7.84 (br.m., 2H), 7.72 (d, J = 7.5 Hz, 1H), 7 .09 (d, J = 7.5 Hz, 1H), 6.86 - 6.77 (m, 2H), 6.45 (s, 2H), 4.48 (s, 1H), 4.11 ( d, J = 13.4 Hz, 1H), 4.07 - 3.93 (m, 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (d, J = 9 .8 Hz, 1H), 3.49 (t, J = 11.1 Hz, 1H), 3.20 (t, J = 12.6 Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H).

Connection 139

Step 1. Into a solution of [1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3 R )-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 K ₂ CO ₃ (1.1 ml, 1.67 mmol) and purged with nitrogen, then Pd(dppf)Cl ₂ -DCM complex (91 mg, 0.11 mmol) was added. The reaction mixture was heated in a microwave reactor at 100 ºC for 10 minutes and then 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 volumes), dried over Na ₂ SO ₄ and concentrated to dryness. The product was then purified using combiflash (0-100%EtOAc/hexane mixture).

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 mixture was heated at 60 ºC and the reaction was monitored with using UHPLC-MS. After 1 hour, the reaction mixture was cooled to room temperature. and the next day concentrated to dryness. The product was purified by reverse phase chromatography (5-95% MeCN/water). +IER [M+1]: 391.0 HPLC purity at 254 nm: >99%, 10-90% CH ₃ CN/H ₂ O (+0.1% formic acid) for 20 min. ^1H NMR (400 MHz, DMSO-d6) δ 12.81 (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 = 13.3 Hz, 1H), 3.97 (d, J = 10.2 Hz , 1H), 3.75 (d, J = 11.3 Hz, 1H), 3.64 (d, J = 11.8 Hz, 1H), 3.49 (t, J = 10.6 Hz, 1H ), 3.19 (t, J = 13.0 Hz, 1H), 2.55 - 2.50 (m, 3H), 2.38 (s, 3H), 1.22 (d, J = 6, 6 Hz, 3H).

Connection 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. during the night. The solution was heated to 65 ^° C for 1 hour, 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 isomer mixture 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-trimethylsilane (240 mg).

Step 2. To a solution of 2-[[5-[5-chloro-4-iodo-6-[(3 R )-3-methylmorpholin-4-yl]pyrazolo[3,4-b]pyridin-1-yl] pyrazol-1-yl]methoxy]ethyl-trimethylsilane (107 mg, 0.187 mmol) and 4,4,5,5-tetramethyl-2-[2-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane ( 0.33 ml, 0.382 mmol) in 1,4-dioxane (1 ml) was added K ₃ PO ₄ (0.50 ml, 0.560 mmol). The vial was purged with nitrogen, then Pd(dppf)Cl ₂ (30 mg, 0.0373 mmol) was added and heated to 110 ^o C for 3 hours in a microwave reactor. 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 concentrated under reduced pressure. The product was used in the next reaction without further purification.

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 hour and the solvent was removed under reduced pressure. The residue was purified using reverse phase chromatography, eluting with 0-100% MeCN/H ₂ O, followed by further purification using normal phase chromatography, eluting with 0-10% MeOH/DCM, to obtain the desired product as a 1:1 mixture atropoisomers, which was used for biological testing. Further purification by SFC resulted in two separate atropisomers (4.0 mg, 6.8% and 4.7 mg, 8.0%, respectively). MS: m/z: 463.2.

Connection 150

Step 1: 2,6-Difluoro-4-iodo-pyridine-3-carboxaldehyde (9.00 g, 33.5 mmol) was dissolved in DMSO (330 ml) and (3 R )-3-methylmorpholine (3.8 ml, 33.3 mmol). The solution was heated at 120 °C for 2 hours. The solution was cooled and added dropwise to water (1.5L) with vigorous stirring. Ice was then added and the suspension was stirred for an additional 2 hours. The solids were filtered and dried under reduced pressure for 15 hours. The resulting beige solid (10.9 g) was dissolved in minimal DCM and purified by silica gel chromatography (0 to 100% EtOAc/hexane isomer 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.

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) at room temperature. 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) were added. The resulting mixture was stirred at room temperature. for 15 hours. Saturated aq. sodium sulfite solution was slowly added to the mixture followed by the addition of formic acid until the pH was acidic. EtOAc was added and the phases were separated. The aqueous phase was extracted 3 times with EtOAc and the combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a beige solid. The resulting material was triturated in Et ₂ O for 30 minutes before filtering to obtain 2.06 g of an almost white solid. The filtrate was concentrated and purified on a 100 g C18 column using a 0 to 100% MeCN/water gradient to provide an additional 2.83 g of beige solid with a total mass of 4.89 g of 2-fluoro-4-iodo-6-[( 3R ) -3-methylmorpholin-4-yl]pyridin-3-carboxylic acid.

Step 3: To 2-fluoro-4-iodo-6-[( 3R )-3-methylmorpholin-4-yl]pyridin-3-carboxylic acid (4.89 g, 13.4 mmol) in DMF (67 ml ) azanium-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]ammonium dichloride (4.65 g, 16.0 mmol) was added 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 RT. within 1 hour. The solution was then added dropwise to water (400 ml) with vigorous stirring to obtain a suspension, which was stirred for 1 hour before filtering. The resulting solid was dried under reduced pressure for 15 hours to give 2-fluoro-4-iodo-N'-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[( 3R )- 3-methylmorpholin-4-yl]pyridinium-3-carbohydrazide (7.48 g, 13.2 mmol) as a beige solid.

Step 4. 2-fluoro-4-iodo-N'-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3 R )-3-methylmorpholin-4-yl]pyridinium- 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, then slowly heated to 60 °C for 30 minutes. Water, sodium chloride solution and EtOAc were added and the phases were separated. The aqueous phase was extracted 3 times with EtOAc and the combined organic layers were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting material was purified by silica gel chromatography (0 to 10% MeOH/DCM gradient) to give 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.

Step 5. To a solution of 4-iodo-1-[2-[(4-methoxyphenyl)methyl]pyrazol-3-yl]-6-[(3 R )-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 K ₂ CO ₃ ( 0.28 ml, 0.55 mmol). The mixture was purged with nitrogen for 5 minutes, then Pd(dppf)Cl ₂ (30 mg, 0.037 mmol) was added and heated to 110 °C for 15 minutes under microwave irradiation. Water was added along with DCM and the phases were separated. The aqueous phase was extracted with 3x DCM and the organic extracts were combined, dried over MgSO ₄ , filtered and concentrated 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. The substance was used in the next step without purification.

Step 6: The crude product from Step 5 was dissolved in trifluoroacetic acid (2.0 ml) and stirred at 60 °C for 1.5 h then concentrated under reduced pressure. The resulting material was dissolved in DMSO (1 ml) and purified by silica gel chromatography (0 to 100% MeCN/water gradient) to give 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 ) δ 12.60 (s, 1H), 10.86 (s, 1H ₎ , 7.84 (d, J = 7.8Hz, 1H), 7.79 - 7 .75 (m, 1H), 7.73 (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).

Example 2: ATR/ATRIP Enzymatic Assay

To determine ATR kinase activity, the AlphaScreen system was used to measure phosphorylation of the p53 substrate protein. Recombinant purified ATR/ATRIP (Eurofins cat. no. 14-953) 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 EDTA, 5 mM MnCl ₂ , 0.01% Brij-30, 1% glycerol, 0.05% BSA) were mixed with the compound serially diluted in 10% DMSO. The final DMSO concentration was 1.25%. To the enzyme: compound mixture was added a pre-prepared mixture of GST-tagged p53 (full length, Enzo Life Sciences, cat. no. BML-FW9370) and adenosine 5'-triphosphate, ATP (Sigma-Aldrich, cat. no. 10519979001, Roche Diagnostic) in assay buffer to a final concentration of 25 nM GST-p53 and 3 μM ATP. The reaction mixture was allowed to proceed at room temperature for 1 hour before being stopped by adding anti-phospho-p53 (Ser 15) antibody premix (New England Biolabs Cat #9284S) at a 1:3000 final dilution, 14.3 µg/ml donor glutathione-coated beads (PerkinElmer Life Sciences cat. no. 6765301) and 14.3 µg/ml acceptor protein A-coated beads (PerkinElmer Life Sciences cat. no. 670137) final concentration of beads in buffer (60 mM EDTA in 50 mM Tris, pH 7.4, and 0.1% BSA). The plates were incubated at room temperature in the dark for 4 hours and read on a BMG Polarstar using dedicated AlphaScreen filters. The assay was performed in a 96-well format using white polypropylene half-area plates (Costar cat. no. 3693). IC ₅₀ values were determined using a 4-parameter fitting algorithm.

Example 3: ATR assay in Hela cells.

HeLa S3 cells were seeded into 384-well plates at a density of 16 thousand cells per 25 μl well in regular F-12K 10% FBS media and incubated overnight at 37 ^o C, 5% CO ₂ . The medium was then replaced with 20 μl per well of Opti-MEM without phenol red and 5 μl of compounds serially diluted to a final concentration in DMSO 0.5% were added to the assay plate. Cells and compounds were incubated at room temperature for 20 minutes before adding 5 μl of gemcitabine to a final concentration of 1.5 μM. The plate was incubated at 37 ^o C, 5% CO ₂ for 3.5 to 4 hours. The medium was removed and cells were lysed in 15 μl of PerkinElmer lysis buffer for 10–20 min; 4 μl of lysates were then transferred to a white 384-well proxi plate (PerkinElmer Life Sciences, cat. no. 6008280). Quantification of CHK1 phosphorylation at Ser345 was performed using Alphascreen SureFire CHK1 p-Ser345 (PerkinElmer Life Sciences, cat. no. TGRCHK1S10K) and protein Alphascreen A. (PerkinElmer Life Sciences, Cat. No. 67060617C) The plate was read on an Envision using dedicated AlphaScreen filters.IC ₅₀ values were determined using a 4-parameter fitting algorithm.

Exemplary compounds obtained and their activities in ATR/ATRIP enzyme assays are presented in Table 2 below.

table 2

In Table 2, the Method column indicates the preparatory method described above used to prepare the compounds.

Examples of the compounds obtained and their ATR inhibitory activity in the HeLa S3 whole cell assay are shown in Table 3 below.

Table 3

Compound Way Structure HeLa S3
ATR IC50 (nM) MS (+IER)
[M+1] 93 N 0.5 478.1 94 N 1.9 494.1 95 N 2.0 485.14 96 N 20 529.28 97 N 0.9 459.18 98 N 1.2 458.92 99 N 3.0 385.17 100 N 2.0 385.03 101 N 1.0 412.92 102 N 0.9 427.19 103 N 1.7 407.87 104 N 2.4 451.22 105 N 1.1 426.06 106 N 3.3 422.08 107 N 2.0 425.13 108 N 1.3 448.9 109 N 17 440.13 110 N 0.7 453.28 111 N 2.4 399.97 112 N 0.8 438.94 113 N 2.1 439.34 114 N 0.8 451.09 115 N 1.5 393.27 116 N 1.2 479.03 117 N 38 424.93 118 N 6.4 426.26 119 N 14 454.27 120 N 1.2 466.16 121 N 0.9 411.32 122 N 1.1 427.12 123 N 0.9 409.13 124 M 63 480.2 125 M eleven 377.1 126 M 17 440.2 127 M 7.0 425.2 128 M 2.4 419.3 129 M eleven 405.20 130 M 13 438.20 131 M 1.8 472.20 132 N 1.9 439.20 133 N 1.5 466.89 134 O 41 385.1 135 N 3.4 413.18 136 O 46 398.18 137 O 2.1 446.37 138 R 9.4 445.0 139 M 4.2 391.0 140 M 7.2 411.1/413.1 141 B 9.3 439.9 142 M 3.6 447.0 143 M 7.2 459.2 144 M 1.3 430.2 145 M 3.8 457.1 146 M 3.1 417.3 147 N 0.8 416.2 148 M 2.5 393.1 149 S 27 463.2, 465.2 150
T 7.8 445.3 151 T 9.1 446.1 152 T 22 455.1

In Table 3, the Method column indicates the preparative method described above that was used to prepare the compounds.

Other embodiments

Various modifications and variations of the described invention will become 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 claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications to the described methods of carrying out the invention that will be apparent to those skilled in the art are intended to be included within the scope of the invention.

Other embodiments are indicated in the claims.

Claims (98)

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein represents a double bond, and each Y is independently N or CR ⁴ ; or represents a single bond, and each Y independently represents NR ^Y , carbonyl, or C(R ^Y ) ₂ ; wherein each R ^Y independently represents H or optionally substituted C _1-6 alkyl; R ¹ represents optionally substituted C _1-6 alkyl or H; R ² is optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-9 heteroaryl, halogen, -N(R ⁵ ) ₂ , -OR ⁵ , CON(R ⁶ ) ₂ , -SO ₂ R ^5A or -QR ^5B ; R ³ represents an optionally substituted monocyclic C _1-9 heteroaryl containing at least one nitrogen atom; each R ⁴ independently represents hydrogen, halogen, C _1-6 alkyl or C _2-6 alkenyl; each R ⁵ independently represents hydrogen, optionally substituted with C _1-6 alkyl C _1-9 heteroaryl or -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl; each R ^5A is independently C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl; R ^5B is hydroxyl, optionally substituted C _1-6 alkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-9 heteroaryl, -CON(R ⁶ ) ₂ , -SO ₂ N(R ⁶ ) ₂ , C( O)OC(CH ₃ ) ₃ or optionally substituted with alkoxy; each R ⁶ independently represents hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _6-10 aryl, C _1-6 alkyl, or optionally substituted C _3-8 cycloalkyl; or both R ⁶ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl; Q is an optionally substituted C _2-9 heterocyclylene, an optionally substituted C _3-8 cycloalkylene, an optionally substituted C _1-9 heteroarylene, or an optionally substituted C _6-10 arylene; And X represents hydrogen or halogen, wherein heterocyclyl, heterocyclylene and heteroaryl each include from one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; wherein each optionally substituted alkyl, alkenyl, alkynyl or alkoxy may be substituted by one or more groups independently selected from amino; alkoxy; cycloalkyl; halogen, heterocyclyl; hydroxy; cyano; alkylsulfonyl; -C (O)NH ₂ or =O; wherein each optionally substituted cycloalkyl or cycloalkylene may be substituted by one or more groups independently selected from alkyl; alkoxy; alkylsulfonyl; cycloalkyl; heteroalkyl; heterocyclyl; hydroxy; cyano -CON( ^RA ) ₂ wherein each R ^A is independently H or alkyl; wherein each optionally substituted heterocyclyl or heterocyclylene may be substituted by one or more groups independently selected from alkyl; alkoxy; cycloalkyl; hydroxy; cyano and =O; And wherein each optionally substituted aryl, arylene, heteroaryl and heteroarylene may be substituted by one or more groups independently selected from alkyl; alkoxy; haloalkyl alkylsulfinyl; alkylsulfonyl; amino; cycloalkyl; halogen and cyano. 2. A compound according to claim 1, characterized in that the compound is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein each Y is independently N or CR ⁴ ; R ¹ represents optionally substituted C _1-6 alkyl or H; R ² is optionally substituted C _2-9 heterocyclyl, optionally substituted C _1-6 alkyl, optionally substituted C _3-8 cycloalkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-9 heteroaryl, halogen, -N(R ⁵ ) ₂ , -OR ⁵ , CON(R ⁶ ) ₂ , -SO ₂ R ^5A or -QR ^5B ; R ³ represents an optionally substituted monocyclic C _1-9 heteroaryl containing at least one nitrogen atom; each R ⁴ independently represents hydrogen, halogen, C _1-6 alkyl or C _2-6 alkenyl; each R ⁵ independently represents hydrogen, optionally substituted C _1-6 alkyl, C _1-9 heteroaryl or -SO ₂ R ^5A ; or both R ⁵ , together with the atom to which they are attached, are combined to form an optionally substituted C _2-9 heterocyclyl; each R ^5A is independently C _1-6 alkyl, C _3-8 cycloalkyl or C _6-10 aryl; R ^5B is hydroxyl, optionally substituted C _1-6 alkyl, optionally substituted C _6-10 aryl, optionally substituted C _1-9 heteroaryl, -CON(R ⁶ ) ₂ , -SO ₂ N(R ⁶ ) ₂ , -C (O)OC(CH ₃ ) ₃ or optionally substituted alkoxy; each ^R6 independently represents hydrogen, optionally substituted _C1-6 alkyl, optionally substituted _C6-10 aryl, _C1-6 alkyl, or optionally substituted _C3-8 cycloalkyl, or both ^R6 , together with the atom to which they are attached , combined to form an optionally substituted C _2-9 heterocyclyl; Q is optionally substituted C _2-9 heterocyclylene, optionally substituted C _3-8 cycloalkylene, optionally substituted C _1-9 heteroarylene or optionally substituted C _6-10 arylene; And X represents hydrogen or halogen; wherein heterocyclyl, heterocyclylene and heteroaryl each include from one to four heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; wherein each optionally substituted alkyl, alkenyl, alkynyl or alkoxy may be substituted by one or more groups independently selected from amino; alkoxy, halo; heterocyclyl; cyano; alkylsulfonyl; -C(O)NH ₂ or =O; wherein each optionally substituted cycloalkyl or cycloalkylene may be substituted by one or more groups independently selected from alkyl; alkoxy; alkylsulfonyl; cycloalkyl; heteroalkyl; heterocyclyl; hydroxy; cyano; and -CON( ^RA ) ₂ wherein each ^RA is independently H or alkyl, or both ^RAs together with the atom to which they are attached combine to form a heterocyclyl; wherein each optionally substituted heterocyclyl or heterocyclylene may be substituted by one or more groups independently selected from alkyl; alkoxy; cycloalkyl; hydroxy; cyano; and =O and wherein each optionally substituted aryl, arylene, heteroaryl and heteroarylene may be substituted by one or more groups independently selected from alkyl; alkoxy; haloalkyl, alkylsulfinyl; alkylsulfonyl; amino; cycloalkyl; halogen; and cyano. 3. A compound according to claim 1, characterized in that the compound is a compound of formula (IB): or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1, characterized in that the compound is a compound of formula (IB-a): or a pharmaceutically acceptable salt thereof. 5. A compound according to claim 1, characterized in that the compound is a compound of formula (I-a): or a pharmaceutically acceptable salt thereof. 6. A compound according to claim 1, characterized in that the compound is a compound of formula (IA): or a pharmaceutically acceptable salt thereof. 7. A compound according to claim 1, characterized in that the compound is a compound of formula (IA-a): I or a pharmaceutically acceptable salt thereof. 8. A compound according to claim 1, characterized in that the compound is a compound of formula (IC): or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 1, characterized in that the compound is a compound of formula (IC-a): or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 1, where R ¹ represents methyl. 11. A compound according to claim 1, where R ² represents an optionally substituted C _2-9 heterocyclyl, an optionally substituted C _1-6 alkyl, an optionally substituted C _3-8 cycloalkyl, an optionally substituted C _6-10 aryl, an optionally substituted C _{1- 9} heteroaryl, N(R ⁵ ) ₂ , -CON(R ⁶ ) ₂ , or SO ₂ R ^5A . 12. A compound according to claim 1, wherein each R ^5A is independently C _1-6 alkyl or C _3-8 cycloalkyl. 13. A compound according to claim 1, wherein each R ⁶ independently represents hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _6-10 aryl C _1-6 alkyl, or both R ⁶ , together with the atom to which they attached, combined to form an optionally substituted C _2-9 heterocyclyl. 14. The connection according to claim 1, where R ² represents: 15. A compound according to claim 1, wherein R ³ is an optionally substituted, monocyclic C _1-9 heteroaryl containing at least one nitrogen atom. 16. The compound according to claim 1, where R ³ is: 17. The compound according to claim 1, where R ⁴ represents hydrogen. 18. The compound according to claim 1, where X represents hydrogen. 19. A connection selected from the group consisting of or a pharmaceutically acceptable salt thereof. 20. Pharmaceutical composition for inhibiting ATR kinase, containing an effective amount of a compound according to any one of paragraphs. 1-19 and a pharmaceutically acceptable excipient. 21. Pharmaceutical composition according to claim 20, characterized in that the composition is isotopically enriched in deuterium. 22. A method of inhibiting ATR kinase in a cell expressing ATR kinase, comprising bringing the cell into contact with a compound according to any one of claims. 1-19. 23. The method of claim 22, wherein the cell is a cell from a subject. 24. Use of the compound according to any one of paragraphs. 1-19 for treating a subject in need of ATR kinase inhibition. 25. Use according to claim 24, characterized in that the subject suffers from and requires treatment of a disease or condition having the symptom of cell hyperproliferation. 26. Use according to claim 25, characterized in that the disease or pathological condition is an oncological disease. 27. Use according to claim 26, characterized in that the oncological disease is carcinoma, sarcoma, adenocarcinoma, leukemia or melanoma. 28. Use according to claim 26, characterized in that the oncological disease is a carcinoma selected from the group consisting of medullary thyroid carcinoma, hereditary medullary thyroid carcinoma, acinar carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basocellular carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebral carcinoma form carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedonal carcinoma, body carcinoma, cribriform carcinoma, en cuirasse carcinoma, cutaneous carcinoma, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, solid carcinoma, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, carcinoma ex ulcere, fibrous carcinoma , gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, giant cell carcinoma, glandular carcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid embryonal carcinoma, early embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher carcinoma, Kulczycki cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular cell carcinoma, lipomatous carcinoma, lymphoepithelial carcinoma, medullary carcinoma, bone marrow carcinoma, melanotic carcinoma oma, molle carcinoma, mucinous carcinoma, carcinoma muciparum, mucocellular carcinoma, mucoepidermoid carcinoma, mucosal carcinoma, mucosal carcinoma, myxomatodal carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma , styloid cell carcinoma, mucus-forming carcinoma, renal cell carcinoma kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simple carcinoma, small cell carcinoma, solanoid carcinoma, spheroid cell carcinoma, spindle cell carcinoma, spongiform carcinoma, squamous cell carcinoma, carcinoma from squamous cell carcinoma, fiber carcinoma, telangiectatic carcinoma, smooth muscle fiber and vascular tissue carcinoma, transitional cell carcinoma, tuberosum carcinoma, tuberous carcinoma, verrucous carcinoma and villous carcinoma. 29. Use according to claim 26, characterized in that the oncological disease is a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemeti sarcoma, infiltrating lipoma, liposarcoma, alveolar soft tissue sarcoma, ameloblastosarcoma , botryoid sarcoma, chloroleukemia, choriocarcinoma, embryonal sarcoma, Wilms tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple hemorrhagic sarcoma s, B-cell immunoblastic sarcoma, immunoblastic T-cell sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer's sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma, parosteal sarcoma, reticulocytic sarcoma, Rouss sarcoma, serous cyst sarcoma, synovial sarcoma or telangiectaltic sarcoma. 30. Use according to claim 26, characterized in that the oncological disease is a leukemia 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, aleukemic leukemia, leukocythaemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, cutaneous leukemia, embryonal leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia , acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphocytic leukemia, lymphosarcoma-cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Nägeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Reader cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia and undifferentiated cellular leukemia. 31. Use according to claim 26, characterized in that the oncological disease is a melanoma selected from the group consisting of acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passy melanoma, juvenile melanoma, melanomas such as lentigo maligna, malignant melanoma, nodular melanoma, subungual melanoma and superficial spreading melanoma. 32. Use according to claim 26, characterized in that the cancer disease is prostate cancer, thyroid cancer, endocrine cancer, brain cancer, breast cancer, cervical cancer, colon cancer, cancer head and neck, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, medulloblastoma, amplular colon cancer, colorectal cancer and pancreatic cancer. 33. Use according to claim 26, characterized in that the oncological disease is Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, oncological disease, malignant pancreatic insulinoma, malignant carcinoid, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary cancer, malignant hypercalcemia, endometrial cancer, cancer adrenal cortex, endocrine or exocrine pancreatic neoplasms, medullary thyroid cancer, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer. 34. Use according to claim 25, characterized in that the subject suffers from and requires treatment of a pre-malignant condition. 35. A compound having the formula: or a pharmaceutically acceptable salt thereof. 36. A compound having the formula: 37. A pharmaceutical composition for inhibiting ATR kinase, containing an effective amount of a compound having the formula: pharmaceutical excipient.