Compounds useful as inhibitors of atr kinase

Abstract

The present invention relates to 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 of 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 I: or a pharmaceutically acceptable salt, wherein the variables R 1 , R 2 , R 3 , and R 4 are as defined herein.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or prodrug thereof, wherein:
 R 1  is independently selected from -(L 1 ) n -W or M; 
 M and L 1  are a C 1-8 aliphatic wherein up to three methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —, each M and L 1  is optionally substituted with 0-3 occurrences of J LM ; 
 J LM  is independently selected from halo, —CN, or a C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; 
 n is independently selected from 0 or 1; 
 W is independently selected from a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein W is optionally substituted with 0-5 occurrences of J W ; 
 J W  is independently selected from —CN, halo, —CF 3 ; a C 1-4 aliphatic wherein up to two methylene units are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; 
 two occurrences of J W  on the same atom, together with atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; or two occurrences of J W , together with W, form a 6-10 membered saturated or partially unsaturated bridged ring system; 
 R 2  is independently selected from H; halo; —CN; a C 1-2 alkyl optionally substituted with 1-3 occurrences of fluoro; or a C 1-3 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z ; 
 R 3  is independently selected from H; halo; C 1-4 alkyl optionally substituted with 1-3 occurrences of halo; C 3-4 cycloalkyl; 3-4 membered heterocyclyl; —CN; or a C 1-3 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z ; 
 R 4  is independently selected from -(L 2 ) k -Q 1  or T; 
 L 2  and T are each independently a C 1-10 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; each L 2  and T is optionally substituted with 0-5 occurrences of J LT ; 
 J LT  is independently selected from —CN; halo or a C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; 
 k is 0 or 1; 
 Q 1  is independently selected from a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen or sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein Q 1  is independently substituted with 0-5 occurrences of J Q ; 
 J Q  is independently selected from —CN; halo; ═O; Q 2 ; or a C 1-8 aliphatic chain wherein up to three methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; each occurrence of J Q  is optionally substituted by 0-3 occurrences of J R ; or two occurrences of J Q  on the same atom, taken together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the ring formed by two occurrences of J Q  is optionally substituted with 0-3 occurrences of J X ; or 
 two occurrences of J Q , together with Q 1 , form a 6-10 membered saturated or partially unsaturated bridged ring system; 
 Q 2  is independently a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur 
 J R  is independently selected from —CN, halo; ═O; →O; Q 3 ; or a C 1-6 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —S—, —C(O)—, or —S(O) z —; each J R  is optionally substituted with 0-3 occurrences of J P ; or two occurrences of J R  on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; wherein the ring formed by two occurrences of J R  is optionally substituted with 0-3 occurrences of J X ; or 
 two occurrences of J R , together with Q 2 , form a 6-10 membered saturated or partially unsaturated bridged ring system; 
 Q 3  is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring having 0-3 heteroatoms selected from oxygen, nitrogen, or sulfur; or a 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic ring having 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur; 
 J X  is independently selected from —CN, halo or a C 1-4 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; or 
 J P  is independently selected from —CN; ═O; halo; a C 1-6 aliphatic chain wherein up to two methylene units of the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O) z —; or a 3-6 membered non-aromatic ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; each J P  is optionally substituted with 0-3 occurrences of J M ; or two occurrences of J P  on the same atom, together with the atom to which they are joined, form a 3-6 membered ring having 0-2 heteroatoms selected from oxygen, nitrogen, or sulfur; or two occurrences of J P , together with Q 3 , form a 6-10 membered saturated or partially unsaturated bridged ring system; 
 J M  is independently selected from halo or C 1-6 aliphatic; 
 z is 0, 1 or 2; and 
 R is independently selected from H or C 1-4 aliphatic. 
 
     
     
         2 .- 59 . (canceled) 
     
     
         60 . The compound of  claim 1  independently selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         61 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         62 . A method for treating cancer in a patient comprising administering a compound of  claim 1  or a pharmaceutically acceptable derivative thereof. 
     
     
         63 . The method of  claim 62 , further comprising administering to said patient an additional therapeutic agent independently 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. 
     
     
         64 . The method of  claim 63 , wherein said DNA-damaging agent is selected chemotherapy or radiation treatment. 
     
     
         65 . The method of  claim 64 , wherein said DNA-damaging agent is independently 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, or an antibiotic. 
     
     
         66 . The method of  claim 65 , wherein said DNA-damaging agent is independently selected from ionizing radiation, a platinating agent, a Topo I inhibitor, a Topo II inhibitor, an antimetabolite, an alkylating agent, or an alkyl sulphonates. 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 66 , wherein said platinating agent is independently 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. 
     
     
         69 . The method of  claim 68 , wherein said platinating agent is independently 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. 
     
     
         70 . (canceled) 
     
     
         71 . The method of  claim 66 , wherein the antimetabolite is gemcitabine. 
     
     
         72 . The method of  claim 66 , wherein the DNA-damaging agent is ionizing radiation. 
     
     
         73 . The method of  claim 66 , wherein the DNA-damaging agent is a platinating agent independently selected from Cisplatin or Carboplatin. 
     
     
         74 . The method of  claim 66 , wherein the DNA-damaging agent is a Topo II inhibitor selected from Etoposide. 
     
     
         75 . The method of  claim 66 , wherein the DNA-damaging agent is an alkyating agent selected from Temozolomide. 
     
     
         76 . The method of  claim 66 , wherein the DNA-damaging agent is independently selected from one or more of the following: Cisplatin, Carboplatin, gemcitabine, Etoposide, Temozolomide, or ionizing radiation. 
     
     
         77 . The method of  claim 62 , 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/Female: 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; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; and Adrenal glands: neuroblastoma. 
     
     
         78 . (canceled) 
     
     
         79 . (canceled) 
     
     
         80 . The method of  claim 76 , wherein said cancer is selected from non-small cell lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, or ovarian cancer. 
     
     
         81 . (canceled) 
     
     
         82 . A method of treating pancreatic cancer comprising administering to a patient a compound of a compound of  claim 1  in combination with an additional therapeutic agent selected from Gemcitabine, radiation therapy, or both Gemcitabine and radiation therapy together. 
     
     
         83 . A method of increasing the sensitivity of pancreatic cancer cells to a cancer therapy selected from chemotherapy or radiation therapy by administering to a patient a compound of  claim 1 . 
     
     
         84 . The method of  claim 83 , wherein the chemotherapy is gemcitabine. 
     
     
         85 . The method of  claim 83 , wherein the cancer therapy is gemcitabine. 
     
     
         86 . The method of  claim 83 , wherein the cancer therapy is radiation. 
     
     
         87 . The method of  claim 83 , wherein the cancer therapy is gemcitabine and radiation. 
     
     
         88 . A method of inhibiting phosphorylation of Chk1 (Ser 345) in a pancreatic cancer cell comprising administering a compound of  claim 1  in combination with gemcitabine (100 nM) and/or radiation (6 Gy). 
     
     
         89 . A method of sensitizing pancreatic cancer cells to chemoradiation by administering a compound of  claim 1  in combination with chemoradiation. 
     
     
         90 . (canceled) 
     
     
         91 . A method of radiosensitizing hypoxic pancreatic cancer cells by administering a compound of  claim 1  in combination with radiation therapy. 
     
     
         92 . A method of sensitizing hypoxic pancreatic cancer cells by administering a compound of  claim 1  in combination with chemotherapy. 
     
     
         93 . (canceled) 
     
     
         94 . A method of disrupting damage-induced cell cycle checkpoints by administering a compound of  claim 1  in combination with radiation therapy and/or gemcitabine. 
     
     
         95 . A method of inhibiting repair of DNA damage by homologous recombination in a pancreatic cancer cell by administering a compound of  claim 1  in combination with radiation therapy and/or gemcitabine. 
     
     
         96 . (canceled) 
     
     
         97 . (canceled) 
     
     
         98 . (canceled) 
     
     
         99 . A method of treating non-small cell lung cancer comprising administering to a patient a compound of  claim 1  in combination with one or more of the following additional therapeutic agents: Cisplatin or Carboplatin, Etoposide, and ionizing radiation. 
     
     
         100 . (canceled) 
     
     
         101 . A method of promoting cell death in cancer cells comprising administering to a patient a compound of  claim 1 . 
     
     
         102 . A method of preventing cell repair from DNA damage comprising administering to a patient a compound of  claim 1 . 
     
     
         103 . A method of inhibiting ATR in a biological sample comprising the step of contacting a compound of  claim 1  with said biological sample. 
     
     
         104 . (canceled) 
     
     
         105 . A method of sensitizing cells to DNA damaging agents comprising administering to a patient a compound of  claim 1 . 
     
     
         106 .- 118 . (canceled) 
     
     
         119 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula 6: 
       
       
         
           
           
               
               
           
         
         under suitable conditions to form an amide bond, wherein: 
         J is H or Cl; and 
         R 1 , R 2 , R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         120 .- 124 . (canceled) 
     
     
         125 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula 9: 
       
       
         
           
           
               
               
           
         
         under suitable condensation conditions to form a pyrimidine ring, wherein R 1 , R 2 , R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         126 . (canceled) 
     
     
         127 . (canceled) 
     
     
         128 . A process for preparing a compound of formula I: 
       
         
           
           
               
               
           
         
         comprising reacting a compound of formula 5: 
       
       
         
           
           
               
               
           
         
         under suitable conditions to form an amide bond, wherein R 1 , R 2 , R 3  and R 4  are as defined in  claim 1 .