Kras g12c inhibitors

Abstract

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

1 - 36 . (canceled) 
     
     
         37 . A compound of Formula II-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         where the piperazinyl ring is optionally substituted with R 8 ,
 R 1  is —C(O)C(R A ) C(R B ) p  or —SO 2 C(R A ) C(R B ) p ; 
 R 2  is hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl, alkylaminylalkyl, dialkylaminylalkyl, —Z—NR 5 R 10 , heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, or heteroarylalkyl, wherein each of the Z, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, and heteroarylalkyl may be optionally substituted with one or more R 9 ; 
 each Z is C1-C4 alkylene; 
 each R 3  is independently C1-C3 alkyl, oxo, haloalkyl, hydroxyl or halogen; 
 L is a bond, —C(O)—, or C1-C3 alkylene; 
 R 4  is hydrogen, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, aralkyl and heteroaryl may be optionally substituted with one or more R 6 , R 7  or R 8 ; 
 each R 5  is independently hydrogen or C1-C3 alkyl; 
 R 6  is cycloalkyl, heterocyclyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one or more R 7 ; 
 each R 7  is independently halogen, hydroxyl, C1-C6 alkyl, cycloalkyl, alkoxy, haloalkyl, amino, cyano, heteroalkyl, hydroxyalkyl or Q-haloalkyl, wherein Q is O or S; 
 R 8  is oxo, C1-C3 alkyl, C2-C4 alkynyl, heteroalkyl, cyano, —C(O)OR 5 , —C(O)N(R 5 ) 2 , —N(R 5 ) 2 , wherein the C1-C3 alkyl may be optionally substituted with cyano, halogen, —OR 5 , —N(R 5 ) 2 , or heteroaryl; 
 each R 9  is independently hydrogen, oxo, acyl, hydroxyl, hydroxyalkyl, cyano, halogen, C1-C6 alkyl, aralkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, alkoxy, dialkylaminyl, dialkylamidoalkyl, or dialkylaminylalkyl, wherein the C1-C6 alkyl may be optionally substituted with cycloalkyl; 
 each R 10  is independently hydrogen, acyl, C1-C3 alkyl, heteroalkyl or hydroxyalkyl; 
 R 11  is haloalkyl; 
 R A  is absent, hydrogen, deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R 5 ) 2 , or hydroxyalkyl; 
 each R B  is independently hydrogen, deuterium, cyano, C1-C3 alkyl, hydroxyalkyl, heteroalkyl, C1-C3 alkoxy, halogen, haloalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl, —CH 2 NHC(O)C1-C3 alkyl, —CH 2 N(CH 3 )C(O)C1-C3 alkyl, heteroaryl, heteroarylalkyl, dialkylaminylalkyl, or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl, wherein the heteroaryl or the heteroaryl portion of the heteroarylalkyl is optionally substituted with one or more R 7 ; 
 or when   is a double bond and p is two, one R B  is hydrogen and R A  and one R B  and the carbon atoms to which they are attached form a 4-8 membered partially saturated cycloalkyl substituted with oxo; 
 m is zero or an integer between 1 and 2; 
 p is one or two; and wherein, 
 when   is a triple bond then R A  is absent, p equals one and R B  is hydroxyalkyl, 
 
         or when   is a double bond then R A  is present, R B  is present and p equals two, wherein when R A  is hydrogen or C1-C3 alkyl, at least one R B  is deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl, —CH 2 NHC(O)C1-C3 alkyl, —NHC(O)C1-C3 alkyl or heterocyclylalkyl, wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl; or when each R B  is hydrogen, then R A  is deuterium, cyano, halogen, haloalkyl, —C(O)N(R 5 ) 2 , hydroxyalkyl or heteroalkyl. 
       
     
     
         38 . The compound of  claim 37 , wherein R 1  is —C(O)C(R A ) C(R B ) p  and   is a double bond and R A  is hydrogen, p is two and at least one R B  is independently deuterium, cyano, halogen, haloalkyl, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, —ZNR 5 R 11 , —C(O)N(R 5 ) 2 , —NHC(O)C1-C3 alkyl or heterocyclylalkyl wherein the heterocyclyl portion is substituted with one or more substituents independently selected from halogen, hydroxyl, alkoxy and C1-C3 alkyl. 
     
     
         39 . The compound of  claim 37 , wherein R 1  is —C(O)C(R A ) C(R B ) p  and   is a double bond, each R B  is hydrogen, and R A  is deuterium, cyano, halogen, C1-C3 alkyl, haloalkyl, heteroalkyl, —C(O)N(R 5 ) 2 , or hydroxyalkyl. 
     
     
         40 . The compound of  claim 37 , wherein R 2  is heterocyclylalkyl optionally substituted with one or more R 9 . 
     
     
         41 . The compound of  claim 40 , wherein the heterocyclyl portion of the heterocyclylalkyl is pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-oxazepanyl, thiomorpholinyl-1,1-dioxide, 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, or azabicyclo[2.2.1]heptan-2-yl, each optionally substituted with one or more R 9 . 
     
     
         42 . The compound of  claim 41 , wherein each R 9  is independently acyl, oxo, halogen, cyano, C1-C6 alkyl, hydroxyalkyl, heteroalkyl, cycloalkyl, aralkyl or dialkylamidoalkyl. 
     
     
         43 . The compound of  claim 42 , wherein each R 9  is independently C1-C6 alkyl, heteroalkyl, or halogen. 
     
     
         44 . The compound of  claim 40 , wherein the heterocyclyl portion of the heterocyclylalkyl is pyrrolidinyl optionally substituted with one or more R 9 . 
     
     
         45 . The compound of  claim 37 , wherein L is a bond and R 4  is aryl or heteroaryl, each optionally substituted with one or more R 6 , R 7  or R 8 . 
     
     
         46 . The compound of  claim 45 , wherein the aryl or heteroaryl are substituted with one or more R 7  independently selected from hydroxyl, amino, halogen, C1-C3 alkyl, haloalkyl, Q-haloalkyl, cycloalkyl and alkoxy. 
     
     
         47 . The compound of  claim 45 , wherein R 4  is aryl optionally substituted with one or more R 6  or R 7 . 
     
     
         48 . The compound of  claim 47 , wherein R 4  is phenyl or naphthyl, each optionally substituted with one or more R 6  or R 7 . 
     
     
         49 . The compound of  claim 48 , wherein R 4  is optionally substituted with one or more R 7  independently selected from halogen, C1-C6 alkyl, and haloalkyl. 
     
     
         50 . The compound of  claim 37 , wherein m is zero. 
     
     
         51 . A pharmaceutically acceptable salt of a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         52 . A compound of the following structure: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         53 . A pharmaceutically acceptable salt of a compound having the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         54 . A pharmaceutical composition, comprising a therapeutically effective amount of the compound of  claim 37 , and a pharmaceutically acceptable excipient. 
     
     
         55 . A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of the compound of  claim 37 . 
     
     
         56 . A method for treating a cancer comprising administering to a patient having cancer a therapeutically effective amount of the compound of  claim 37 , alone or combined with a pharmaceutically acceptable carrier, excipient or diluents, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), 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 tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; 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 (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); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. 
     
     
         57 . The method of  claim 56 , wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day. 
     
     
         58 . The method of  claim 57 , wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day. 
     
     
         59 . The method of  claim 56 , wherein the cancer wherein the cancer is a KRas G12C-associated cancer. 
     
     
         60 . The method of  claim 56 , wherein the cancer is non-small cell lung cancer. 
     
     
         61 . The method of  claim 56 , wherein the cancer is colorectal cancer. 
     
     
         62 . The method of  claim 56 , wherein the cancer is endometrial cancer. 
     
     
         63 . The method of  claim 56 , wherein the cancer is pancreatic cancer. 
     
     
         64 . A method for treating non-small cell lung cancer comprising administering to a patient having non-small cell lung cancer a therapeutically effective amount of a compound of structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents. 
     
     
         65 . A method for treating colorectal cancer comprising administering to a patient having colorectal cancer a therapeutically effective amount of a compound of structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents. 
     
     
         66 . A method for treating endometrial cancer comprising administering to a patient having endometrial cancer a therapeutically effective amount of a compound of structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents. 
     
     
         67 . A method for treating pancreatic cancer comprising administering to a patient having pancreatic cancer a therapeutically effective amount of a compound of structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents. 
     
     
         68 . A method for treating ovarian cancer comprising administering to a patient having ovarian cancer a therapeutically effective amount of a compound of structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.