Heterocyclic compounds and uses thereof

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

We claim: 
     
         1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         T is —NHC(O)— or —C(O)NH—; 
         W is CH or N; 
         each of R a , R b , R c , and R d  is independently selected from R, OR, or halogen; 
         each R is independently hydrogen, lower alkyl, or lower haloalkyl; 
         R 1  is a warhead group; 
         R 2  is selected from R, halogen, —N(R)C(O)OR, or 1-imidazoyl substituted with R, or:
 R 1  and R 2  are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with a warhead group and 0-3 groups independently selected from oxo, halogen, CN, or C 1-6  aliphatic; and 
 
         R 3  is selected from hydrogen, lower alkyl, or halogen. 
       
     
     
         2 . The compound according to  claim 1 , wherein said compound is of formula II-a or III-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by cyclopropylene, —NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—, and one or two additional methylene units of L are optionally and independently replaced by —O—, —N(R)—, or —C(O)—; and 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -Q-Z, oxo, halogen, CN, or C 1-6  aliphatic, wherein: 
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN; and 
 
         R 2  is selected from R, halogen, —N(R)C(O)OR, or 1-imidazoyl substituted with R. 
       
     
     
         3 . The compound according to  claim 2 , wherein:
 Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN; and   R 3  is lower alkyl.   
     
     
         4 . The compound according to  claim 3 , wherein L is —NHC(O)CH═CH—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHC(O)CH═CHCH 2 O—, —CH 2 NHC(O)CH═CH—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)(C═N 2 )—, —NHC(O)(C═N 2 )C(O)—, —NHC(O)CH═CHCH 2 N(CH 3 )—, —NHSO 2 CH═CH—, —NHSO 2 CH═CHCH 2 —, —NHC(O)CH═CHCH 2 O—, or —NHC(O)C(═CH 2 )CH 2 —. 
     
     
         5 . The compound according to  claim 2 , wherein L has at least one alkylidenyl double bond. 
     
     
         6 . The compound according to  claim 5 , wherein R 2  is hydrogen, —CF 3 , or 1-imidazoyl substituted with R. 
     
     
         7 . The compound according to  claim 1 , wherein:
 R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO 2 —, —C(═S)—, —C(═NR)—, —O—, —N(R)—, or —C(O)—; and 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -Q-Z, oxo, halogen, CN, or C 1-6  aliphatic, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN. 
 
   
     
     
         8 . The compound according to  claim 7 , wherein:
 L is —C≡C—, —C≡CCH 2 N(isopropyl)-, —NHC(O)C≡CCH 2 CH 2 —, —CH 2 —C≡C—CH 2 —, or —C≡CCH 2 O—; and   Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, phenyl, pyridyl, or an optionally substituted saturated 3-6 membered monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -Q-Z, oxo, halogen, CN, or C 1-6  aliphatic.   
     
     
         9 . The compound according to  claim 1 , wherein:
 R 1  is -L-Y, wherein:
 L is a bivalent C 2-8  straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO 2 —, or —SO 2 N(R)—; and 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -Q-Z, oxo, halogen, CN, or C 1-6  aliphatic, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN. 
 
   
     
     
         10 . The compound according to  claim 9 , wherein:
 L is —NHC(O)-cyclopropylene-SO 2 — and —NHC(O)-cyclopropylene-; and   Y is hydrogen, CN, or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN.   
     
     
         11 . The compound according to  claim 1 , wherein:
 R 1  is -L-Y, wherein:
 L is a covalent bond or a bivalent C 1-8  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO 2 —, or —C(═S)—; 
 Y is selected from: 
   
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 11 , wherein L is a covalent bond, —CH 2 —, —NH—, —CH 2 NH—, —NHCH 2 —, —NHC(O)—, —NHC(O)CH 2 OC(O)—, —CH 2 NHC(O)—, —NHSO 2 —, —NHSO 2 CH 2 —, —NHC(O)CH 2 OC(O)—, or —SO 2 NH—. 
     
     
         13 . The compound according to  claim 1 , wherein:
 R 1  is -L-Y, wherein:
 L is a bivalent C 1-8 , straight or branched, alkylene chain, wherein at least one methylene unit of L is replaced by —C(═N 2 )—, and one or two additional methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —S—, —S(O)—, —SO 2 —, —C(═S)—, —C(═NR)—, —O—, —N(R)—, or —C(O)—; and 
 Y is hydrogen, C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with at 1-4 groups independently selected from -Q-Z, oxo, halogen, CN, or C 1-6  aliphatic, wherein:
 Q is a covalent bond or a bivalent C 1-6  saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN. 
 
   
     
     
         14 . The compound according to  claim 13 , wherein:
 L is —NHC(O)(C═N 2 )— or —NHC(O)(C═N 2 )C(O)—; and   Y is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN, or an optionally substituted saturated 3-6 membered monocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl or pyridyl.   
     
     
         15 . The compound according to  claim 1 , wherein said compound is of formula II-a or III-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 2  are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with a warhead group, wherein the warhead group is -Q-Z, and the ring is further substituted with 0-3 groups independently selected from oxo, halogen, CN, or C 1-6  aliphatic, wherein:
 Q is a bivalent C 2-6  straight or branched, hydrocarbon chain having at least one double bond, and wherein one or two methylene units of Q are independently replaced by —NR—, —NRC(O)—, —C(O)NR—, —S—, —O—, —C(O)—, —SO—, or —SO 2 —; and 
 Z is hydrogen or C 1-6  aliphatic optionally substituted with oxo, halogen, or CN. 
 
       
     
     
         16 . The compound according to  claim 15 , wherein R 1  and R 2  are taken together with their intervening atoms to form, together with the phenyl ring fused thereto, a naphthyl, tetrahydroquinoline, indoline, isoindoline, 1H-indole, or tetrahydroisoquinoline ring. 
     
     
         17 . The compound according to  claim 15 , wherein -Q-Z is —NHC(O)CH═CH 2  or —C(O)CH═CH 2 . 
     
     
         18 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         19 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound according to  claim 1 , wherein said compound is of the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         26 . A composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 
     
     
         27 . The composition according to  claim 26 , in combination with an additional therapeutic agent. 
     
     
         28 . The composition according to  claim 27 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         29 . A method for inhibiting PDGFR, cKit, KDR, or cFMS activity in a biological sample comprising the step of contacting said biological sample with a compound according to  claim 1 , or a composition thereof. 
     
     
         30 . A method for inhibiting PDGFR, c-KIT, KDR, or cFMS activity in a patient comprising the step of administering to said patient a compound according to  claim 1 , or a composition thereof. 
     
     
         31 . A method for inhibiting PDGFR, c-KIT, KDR, or cFMS activity in a patient comprising the step of administering to said patient a compound according to  claim 1 , or a composition thereof, wherein the PDGFR, c-KIT, KDR, or cFMS activity is inhibited irreversibly. 
     
     
         32 . The method according to  claim 31 , wherein the PDGFR, c-KIT, KDR, or cFMS activity is inhibited irreversibly by covalently modifying Cys814 of PDGFR-α, Cys822 of PDGFR-β, Cys1024 of KDR, Cys788 of c-KIT, or Cys774 of cFMS. 
     
     
         33 . A method for treating a PDGFR-, c-KIT-, KDR, or cFMS-mediated disorder in a patient in need thereof, comprising the step of administering to said patient compound according to  claim 1 , or a composition thereof. 
     
     
         34 . A method for treating a PDGFR-, c-KIT-, KDR-, or cFMS-mediated disorder in a patient in need thereof, comprising the step of irreversibly inhibiting PDGFR, c-KIT, KDR, or cFMS, by covalently modifying Cys814 of PDGFR-α, Cys822 of PDGFR-β, Cys1024 of KDR, Cys788 of c-KIT, or Cys774 of cFMS. 
     
     
         35 . A conjugate selected from any of formulae:
 Cys814-linker-inhibitor moiety, wherein the Cys814 is Cys814 of PDGFR-α;   Cys822-linker-inhibitor moiety, wherein the Cys822 is Cys822 of PDGFR-β;   Cys788-linker-inhibitor moiety, wherein the Cys788 is Cys788 of c-KIT;   Cys774-linker-inhibitor moiety, wherein the Cys774 is Cys774 of cFMS; or Cys 1024-linker-inhibitor moiety, wherein the Cys1024 is Cys1024 of KDR.   
     
     
         36 . A conjugate of any of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein the Cys814 is Cys814 of PDGFR-α; the Cys822 is Cys822 of PDGFR-β; the Cys788 is Cys788 of c-KIT; the Cys774 is Cys774 of cFMS and the Cys1024 is Cys1024 of KDR, and: 
         each T is —NHC(O)— or —C(O)NH—; 
         each W is CH or N; 
         each of R a , R b , R c , and R d  is independently selected from R, OR, or halogen; 
         each R is independently hydrogen, lower alkyl, or lower haloalkyl; 
         each R 2  is selected from R, halogen, —N(R)C(O)OR, or 1-imidazoyl substituted with R, or:
 R 1  and R 2  are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with a warhead group and 0-3 groups independently selected from oxo, halogen, CN, or C 1-6  aliphatic; and 
 
         each R 3  is selected from hydrogen, lower alkyl, or halogen. 
       
     
     
         37 . The method according to  claim 33 , wherein the disorder is a carcinoma selected from squamous cell carcinomas, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, GIST, and carcinomas of the lung, breast, ovary, cervix, liver, biliary tract, gastrointestinal tact, pancreas, prostate, and head and neck. 
     
     
         38 . The method according to  claim 37 , wherein the disorder is a condition which includes an accumulation of excess extracellular matrix; a fibrotic condition, e.g., scleroderma, lupus nephritis, connective tissue disease, wound healing, surgical scarring, spinal cord injury, CNS scarring, acute lung injury, pulmonary fibrosis (such as idiopathic pulmonary fibrosis and radiation-induced pulmonary fibrosis), chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute lung injury, drug-induced lung injury, glomerulonephritis, diabetic nephropathy, hypertension-induced nephropathy, alimentary track or gastrointestinal fibrosis, renal fibrosis, hepatic or biliary fibrosis, liver cirrhosis, primary biliary cirrhosis, cirrhosis due to fatty liver disease (alcoholic and. nonalcoholic steatosis), primary sclerosing cholangitis, restenosis, cardiac fibrosis, opthalmic scarring, fibrosclerosis, fibrotic cancers, fibroids, fibroma, fibroadenomas, fibrosarcomas, transplant arteriopathy, and keloid); and other conditions such as cachexia, hypertension, ankylosing spondylitis, demyelination in multiple sclerosis, cerebral angiopathy and Alzheimer's disease. 
     
     
         39 . The method according to  claim 33 , wherein the disorder is AML, chronic myelogenous leukemia (CML), mastocytosis, anaplastic large-cell lymphoma, ALL, gastrointestinal stromal tumor (GIST), T-cell lymphoma, adenoid cytsic carcinoma, angiosarcoma, endometrial carcinoma, small cell lung carcinoma, prostate cancer, ovarian cancer, breast carcinoma, thyroid carcinoma, malignant melanoma or colon carcinoma. 
     
     
         40 . The method according to  claim 33 , wherein the disorder is a cancer such as brain cancer, genitourinary tract cancer, lymphatic system cancer, stomach cancer, cancer of the larynx, lung cancer, pancreatic cancer, breast cancer, Kaposi's sarcoma, and leukemia; endometriosis, benign prostatic hyperplasia; vascular diseases such as restenosis and atherosclerosis; autoimmune diseases such as rheumatoid arthritis and psoriasis; ocular conditions such as proliferative or angiogenic retinopathy and macular degeneration; osteoarthritis, or an inflammatory disease such as contact dermatitis, asthma and delayed hypersensitivity reaction. 
     
     
         41 . The method according to  claim 33 , wherein the disorder is osteoarthritis, osteoporosis, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, allograft rejection, or arteriosclerosis. 
     
     
         42 . The method according to  claim 33 , wherein the disorder is GIST.