Compounds useful as inhibitors of atr kinase

Abstract

The present invention relates to pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors. The compounds of this invention have formula III: wherein the variables are as defined herein.

1 . A compound of formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         L 2  is C 1-10  aliphatic chain where up to 3 methylene units of said chain are optionally replaced with —O—, —S—, —N(R′)—, or —CO—; 
         R′ is H or C 1-4 alkyl; 
         m is 0 or 1; 
         R 2  is -Q or -Q-Q 1 ; 
         Q is a 3-8 membered monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently and optionally substituted with 1-4 J Q  groups; 
         Q is optionally fused to Q 1  to form a fused bicyclic ring Q-Q 1 ; or Q and Q 1  are optionally joined together at a carbon atom to form a spirocyclic bicyclic ring Q-Q 1 ; or Q and Q 1 , taken together, form a bridged bicyclic ring Q-Q 1  wherein said bridge is 1-3 atoms long; 
         Q 1  is a 3-8 membered monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q 1  is independently and optionally substituted with 1-4 J Q1  groups; 
         L is —C(O)NH— or —C(O)N(C 1-6 alkyl)-; 
         n is 0 or 1; 
         R 1  is a 5-6 membered monocyclic aryl or heteroaryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein said monocyclic aryl or heteroaryl ring is optionally fused to another ring to form a 8-10 membered bicyclic aryl or heteroaryl ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R 1  is optionally substituted with 1-5 J 1  groups; 
         each J Q , J Q1 , and J 1  is independently halo, —CN, —NO 2 , V—R, or —(V 2 ) m -Q 3 ; 
         V is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O) 2 ; V is optionally substituted with 1-6 occurrences of J V ; 
         V 2  is a C 1-10 aliphatic chain wherein 0-3 methylene units are optionally and independently replaced with oxygen, nitrogen, sulfur, C(O), S(O), or S(O) 2 ; V is optionally substituted with 1-6 occurrences of J V2 ; 
         m is 0 or 1; 
         Q 3  is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q 3  is optionally substituted with 1-5 J Q3 ; 
         each J V  and J V2  is independently halogen, CN, NH 2 , NO 2 , C 1-4 aliphatic, NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , OH, O(C 1-4 aliphatic), CO 2 H, CO(C 1-4 aliphatic), CO 2 (C 1-4 aliphatic), C(O)NH 2 , C(O)NH(C 1-4 aliphatic), C(O)N(C 1-4 aliphatic) 2 , NHCO(C 1-4 aliphatic), N(C 1-4 aliphatic)CO(C 1-4 aliphatic), SO 2 (C 1-4 aliphatic), NHSO 2 (C 1-4 aliphatic), or N(C 1-4 aliphatic)SO 2 (C 1-4 aliphatic), wherein said C 1-4 aliphatic is optionally substituted with halo; 
         J Q3  is halo, oxo, CN, NO 2 , X—R, or —(X) p -Q 4 , 
         p is 0 or 1; 
         X is C 1-10 aliphatic; wherein 1-3 methylene units of said C 1-6 aliphatic are optionally replaced with —NR, —O—, —S—, C(O), S(O) 2 , or S(O); wherein X is optionally and independently substituted with 1-4 occurrences of NH 2 , NH(C 1-4 aliphatic), N(C 1-4 aliphatic) 2 , halogen, C 1-4 aliphatic, OH, O(C 1-4 aliphatic), NO 2 , CN, CO(C 1-4 aliphatic), CO 2 H, CO 2 (C 1-4 aliphatic), C(O)NH 2 , C(O)NH(C 1-4 aliphatic), C(O)N(C 1-4 aliphatic) 2 , SO(C 1-4 aliphatic), SO 2 (C 1-4 aliphatic), SO 2 NH(C 1-4 aliphatic), SO 2 NH(C 1-4 aliphatic), NHC(O)(C 1-4 aliphatic), N(C 1-4 aliphatic)C(O)(C 1-4 aliphatic), NHSO 2 (C 1-4 aliphatic), or N(C 1-4 aliphatic)SO 2 (C 1-4 aliphatic), wherein said C 1-4 aliphatic is optionally substituted with 1-3 occurrences of halo; 
         Q 4  is a 3-8 membered saturated or unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 8-10 membered saturated or unsaturated bicyclic ring having 0-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q 4  is optionally substituted with 1-5 J Q4 ; 
         each J V , J V2 ′ and J Q4  is independently halo, CN, or C 1-4 alkyl wherein up to 2 methylene units are optionally replaced with O, N, S, C(O), S(O), or S(O) 2 ; 
         R is H or C 1-4 alkyl wherein said C 1-4 alkyl is optionally substituted with 1-4 halo. 
       
     
     
         2 . The compound of  claim 1 , wherein m is 0. 
     
     
         3 . The compound of  claim 2 , wherein n is 0. 
     
     
         4 . The compound of any one of  claims 1 - 3 , wherein R 1  is isoxazolyl or oxadiazolyl. 
     
     
         5 . The compound of  claim 4 , wherein R 1  is optionally substituted with one occurrence of J 1 . 
     
     
         6 . The compound of  claim 5 , wherein J 1  is —(V 2 ) m -Q 3  wherein m is 0. 
     
     
         7 . The compound of  claim 6 , wherein J 1  is phenyl. 
     
     
         8 . The compound of  claim 7 , wherein J Q3  is halo or X—R. 
     
     
         9 . The compound of  claim 5 , wherein J 1  is phenyl optionally substituted with CH 2 NHCH 3 , methyl, or fluoro. 
     
     
         10 . The compound of  claim 1 , wherein n is 1. 
     
     
         11 . The compound of  claim 10 , wherein L is —C(O)NH— and R 1  is phenyl. 
     
     
         12 . The compound of  claim 2 , wherein Q is aromatic. 
     
     
         13 . The compound of  claim 12 , wherein R 2  is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or thienyl. 
     
     
         14 . The compound of  claim 13 , wherein R 2  is pyridinyl. 
     
     
         15 . The compound of  claim 1 , wherein Q is nonaromatic. 
     
     
         16 . The compound of  claim 15 , wherein R 2  is 1,2,3,6-tetrahydropyridinyl or N-alkyl pyridone. 
     
     
         17 . The compound of any one of  claims 1 - 16 , wherein J Q  is V—R or —(V 2 ) m -Q 3 . 
     
     
         18 . The compound of  claim 17 , wherein V is S(O) 2  or C(O); and V 2  is S(O) 2  or C(O). 
     
     
         19 . The compound of  claim 18 , wherein R is C 1-4 alkyl and Q 3  is a 3-7 membered saturated or unsaturated monocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 
     
     
         20 . The compound of  claim 1 , wherein n is 0 or 1; L is —C(O)NH—; R 1  is phenyl, oxadiazolyl, or isoxazolyl; m is 0; R 2  is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thienyl, or 1,2,3,6-tetrahydropyridinyl; and J Q  is V—R or —(V 2 ) m -Q 3  wherein V is SO 2  or CO, R is C 1-4 alkyl; V 2  is S(O) 2  or C(O); and Q 3  is a 5-7 membered monocyclic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur. 
     
     
         21 . The compound of  claim 1 , wherein n is 0 or 1; L is —C(O)NH—; R 1  is phenyl, oxadiazolyl, or isoxazolyl; J 1  is phenyl optionally substituted with CH 2 NHCH 3 , methyl, or fluoro; m is 0; R 2  is phenyl, pyridinyl, pyrazinyl, thienyl, or 1,2,3,6-tetrahydropyridinyl; and J Q  is SO 2 (furanyl), CO(homopiperazinyl), or SO 2 (C 1-6 alkyl). 
     
     
         22 . The compound of  claim 1  selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 22  and a pharmaceutically acceptable carrier. 
     
     
         24 . A method for treating cancer in a patient comprising administering a compound of any one of  claims 1 - 22  or a pharmaceutically acceptable derivative thereof. 
     
     
         25 . The method of  claim 24 , further comprising administering to said patient an additional therapeutic agent selected from a DNA-damaging agent; wherein said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said compound as a single dosage form or separately from said compound as part of a multiple dosage form. 
     
     
         26 . The method of  claim 25 , wherein said DNA-damaging agent is selected chemotherapy or radiation treatment. 
     
     
         27 . The method of  claim 25 , wherein said DNA-damaging agent is selected from ionizing radiation, radiomimetic neocarzinostatin, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, an alkyl sulphonates, an antimetabolite, or an antibiotic. 
     
     
         28 . The method of  claim 27 , wherein said DNA-damaging agent is selected from ionizing radiation, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, or an antibiotic. 
     
     
         29 . The method of  claim 28 , wherein said platinating agent is selected from Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, Lobaplatin, Triplatin Tetranitrate, Picoplatin, Satraplatin, ProLindac and Aroplatin; said Topo I inhibitor is selected from Camptothecin, Topotecan, Irinotecan/SN38, Rubitecan and Belotecan; said Topo II inhibitor is selected from Etoposide, Daunorubicin, Doxorubicin, Aclarubicin, Epirubicin, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin and Teniposide; said antimetabolite is selected from Aminopterin, Methotrexate, Pemetrexed, Raltitrexed, Pentostatin, Cladribine, Clofarabine, Fludarabine, Thioguanine, Mercaptopurine, Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine, Cytarabine, Gemcitabine, Azacitidine and Hydroxyurea; said alkylating agent is selected from Mechlorethamine, Cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Melphalan, Prednimustine, Bendamustine, Uramustine, Estramustine, Carmustine, Lomustine, Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin, Busulfan, Mannosulfan, Treosulfan, Carboquone, ThioTEPA, Triaziquone, Triethylenemelamine, Procarbazine, Dacarbazine, Temozolomide, Altretamine, Mitobronitol, Actinomycin, Bleomycin, Mitomycin and Plicamycin. 
     
     
         30 . The method of  claim 29 , wherein said platinating agent is selected from Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, or Satraplatin; said Topo I inhibitor is selected from Camptothecin, Topotecan, irinotecan/SN38, rubitecan; said Topo II inhibitor is selected from Etoposide; said antimetabolite is selected from methotrexate, pemetrexed, Thioguanine, Fludarabine, Cladribine, Cytarabine, gemcitabine, 6-Mercaptopurine, or 5-Fluorouracil; said alkylating agent is selected from nitrogen mustards, nitrosoureas, triazenes, alkyl sulfonates, Procarbazine, or aziridines; and said antibiotic is selected from Hydroxyurea, Anthracyclines, Anthracenediones, or  Streptomyces  family. 
     
     
         31 . The method of  claim 28  wherein said DNA-damaging agent is a platinating agent or ionizing radiation. 
     
     
         32 . The method of any one of  claims 24 - 31 , wherein said cancer is a solid tumor selected from the following cancers: Oral: buccal cavity, lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum, Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
 Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis, Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; undifferentiated thyroid cancer, medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma.   
     
     
         33 . The method of  claim 32 , wherein said cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer. 
     
     
         34 . A method of promoting cell death in cancer cells comprising administering to a patient a compound of any one of  claims 1 - 22 . 
     
     
         35 . A method of preventing cell repair from DNA damage comprising administering to a patient a compound of any one of  claims 1 - 22 . 
     
     
         36 . A method of inhibiting ATR in a biological sample comprising the step of contacting a compound of any one of  claims 1 - 22  with said biological sample. 
     
     
         37 . The method of  claim 36 , wherein said biological sample is a cell. 
     
     
         38 . A method of sensitizing cells to DNA damaging agents comprising administering to a patient a compound of any one of  claims 1 - 22 . 
     
     
         39 . The method of any one of  claims 24 - 38 , wherein said cell is a cancer cell having defects in the ATM signaling cascade. 
     
     
         40 . The method of  claim 39 , wherein said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1 or H2AX. 
     
     
         41 . The method of any one of  claims 24 - 38 , wherein said cell is a cancer cell expressing DNA damaging oncogenes. 
     
     
         42 . The method of  claim 41 , wherein said cancer cell has altered expression or activity of one or more of the following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb. 
     
     
         43 . Use of a compound of any one of  claims 1 - 22  as a radio-sensitizer or a chemo-sensitizer. 
     
     
         44 . Use of a compound according to any one of  claims 1 - 22  as a single agent (monotherapy) for treating cancer. 
     
     
         45 . Use of according to any one of  claims 1 - 22  for treating patients having cancer with a DNA-damage response (DDR) defect. 
     
     
         46 . The use according to  claim 45 , wherein said defect is a mutation or loss of ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1, MDC1, or H2AX.