Tricyclic heteroaryl compounds useful as inhibitors of janus kinase

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases, particularly of JAK family kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

1 - 20 . (canceled) 
     
     
         21 . A method of inhibiting JAK kinase activity in an in vitro biological sample comprising contacting said biological sample with a compound having the formula (I-a) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 W is —N(R F )—, —C(X)N(R F )— or —N(R F )C(X)—; 
 X is O, S, [hydrogen, hydrogen] or [hydrogen, R]; 
 X 2  is N or C—R X2  wherein R X2  is hydrogen, halogen, —CN, —NO 2 , —OR X2B —OC(O)R X2B —, —OC(O)OR X2B , —OC(O)NR X2A R X2B , —OC(S)R X2B , —SR X2B , —SC(O)R X2B , —SC(S)R X2B , —C(O)OR X2B , —C(O)NR X2A R X2B , —C(S)NR X2A R X2B , —NR X2A R X2B , —S(O)R X2B , —S(O) 2 R X2B , —S(O) 2 NR X2A R X2B , C 1-4  haloaliphatic, optionally substituted C 3-8  cycloaliphatic, C 1-6  aliphatic; 
 X 4  is N or C—R B4 , X 5  is N or C—R B5 , X 6  is N or C—R B6 , and X 7  is N or C—R B7 , where optionally up to two of X 4 , X 5 , X 6 , and X 7  are N and each of R B4 , R B5 , R B6 , and R B7  is, independently, hydrogen, halogen, —CN, —NO 2 , —OR, —OC(O)R, —OC(O)OR, —OC(O)NRR′, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O) 2 R, —S(O) 2 NRR′, optionally substituted C 1-4  haloaliphatic, C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl; 
 each of R F  and R G  is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 1-4  haloaliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, or when W is N(R F ), R F  and R G  and the intervening atoms together optionally form a N═C bond; 
 R H  is hydrogen, optionally substituted C 1-6  aliphatic, C 1-4  haloaliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl; 
 R X2A  is hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, —C(O)R, —C(O)NRR′, —C(O)OR, —S(O)R, —S(O) 2 R, or —S(O) 2 NRR′; 
 each of R, R′, and R X2B  is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl; 
 each of said heterocyclyl and heteroaryl rings contains one to four heteroatoms independently selected from oxygen, sulfur, or nitrogen; 
 the optional substituents on one or more carbon atoms of each of said aryl and heteroaryl groups are: halogen; —R ∘ ; —OR ∘ ; —SR ∘ ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl optionally substituted with R ∘ ; —O(Ph) optionally substituted with R ∘ ; —(CH 2 ) 1-2 (Ph) optionally substituted with R ∘ ; —CH═CH(Ph) optionally substituted with R ∘ ; —NO 2 ; —CN; —N(R ∘ ) 2 ; —NR ∘ C(O)R ∘ ; —NR ∘ C(S)R ∘ ; —NR ∘ C(O)N(R ∘ ) 2 ; —NR ∘ C(S)N(R ∘ ) 2 ; —NR ∘ C(O)OR ∘ ; —NR ∘ NR ∘ C(O)R ∘ ; —NR ∘ NR ∘ C(O)N(R ∘ ) 2 ; —NR ∘ NR ∘ C(O)OR ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(O)OR ∘ ; —C(O)R ∘ ; —C(S)R ∘ ; —C(O)N(R ∘ ) 2 ; —C(S)N(R ∘ ) 2 ; —B(OR ∘ ) 2 , —OC(O)N(R ∘ ) 2 ; —OC(O)R ∘ ; —C(O)N(OR ∘ )R ∘ ; —C(═NOR ∘ )R ∘ ; —S(O) 2 R ∘ ; —S(O) 2 OR ∘ ; —S(O) 2 N(R ∘ ) 2 ; —S(O)R ∘ ; —NR ∘ S(O) 2 N(R ∘ ) 2 ; —NR ∘ S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(═NH)—N(R ∘ ) 2 ; or —(CH 2 ) 0-2 NHC(O)R ∘ ; -L-R ∘ ; -L-N(R ∘ ) 2 ; -L-SR ∘ ; -L-OR ∘ ; -L-(C 3-10  cycloaliphatic), -L-(C 6-10  aryl), -L-(5-10 membered heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C 1-4  haloalkoxy, C 1-4  haloalkyl, -L-NO 2 , -L-CN, -L-OH, -L-CF 3 ; or two substituents, on the same carbon or on different carbons, together with the carbon or intervening carbons to which they are bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring, wherein L is a C 1-6  alkylene group in which up to three methylene units are replaced by —NH—, —NR ∘ —, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)C(O)—, —C(O)—, —C(O)NH—, —C(O)NR ∘ —, —C(═N—CN)—, —NHC(O)—, —NR ∘ C(O)—, —NHC(O)O—, —NR ∘ C(O)O—, —S(O) 2 NH—, —S(O) 2 NR ∘ —, —NHS(O) 2 —, —NR ∘ S(O) 2 —, —NHC(O)NH—, —NR ∘ C(O)NH—, —NHC(O)NR ∘ —, —NR ∘ C(O)NR ∘ , —OC(O)NH—, —OC(O)NR ∘ —, —NHS(O) 2 NH—, —NR ∘ S(O) 2 NH—, —NHS(O) 2 NR ∘ —, —NR ∘ S(O) 2 NR ∘ —, —S(O)—, or —S(O) 2 —, and wherein each occurrence of R ∘  is independently selected from hydrogen, optionally substituted C 1-6  aliphatic, an unsubstituted 5- to 6-membered heteroaryl or heterocyclic ring, phenyl, or —CH 2 (Ph), or, two independent occurrences of R ∘ , on the same substituent or different substituents, taken together with the atom(s) to which each R ∘  group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein optional substituents on the aliphatic group of R ∘  are selected from —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, —C(O)OH, C(O)O(C 1-4  aliphatic), O(haloC 1-4  aliphatic), or haloC 1-4  aliphatic wherein each of the C 1-4  aliphatic groups of R ∘  is unsubstituted; and 
 the optional substituents on one or more carbon atoms of each of said aliphatic, haloaliphatic, cyclo aliphatic, and heterocyclyl groups are as defined for said aryl and heteroaryl groups and additionally comprise: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHC(O)O(alkyl), ═NNHS(O) 2 (alkyl), or ═NR*, wherein each R* is independently selected from hydrogen or an optionally substituted C 1-6  aliphatic, and where optional substituents on said aliphatic group of R* are selected from —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, —C(O)OH, —C(O)O(C 1-4  aliphatic), —O(halo-C 1-4  aliphatic), and halo(C 1-4  aliphatic), wherein each of the foregoing C 1-4  aliphatic groups of R* is unsubstituted. 
 
     
     
         22 . The method according to  claim 21 , wherein said JAK kinase is JAK-3. 
     
     
         23 . The method according to  claim 21 , wherein said JAK kinase is JAK-2. 
     
     
         24 . A method of treating or lessening the severity of a disease, condition, or disorder in a patient, comprising administering a therapeutically effective amount of a compound having the formula (I-a) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 W is —N(R F )—, —C(X)N(R F )— or —N(R F )C(X)—; 
 X is O, S, [hydrogen, hydrogen] or [hydrogen, R]; 
 X 2  is N or C—R X2 , wherein R X2  is hydrogen, halogen, —CN, —NO 2 , —OR X2B , —OC(O)R X2B , —OC(O)OR X2B , —OC(O)NR X2A R X2B , —OC(S)R X2B , —SR X2B , —SC(O)R X2B , —SC(S)R X2B , —C(O)OR X2B , —C(O)NR X2A R X2B , C(S)NR X2A R X2B , —NR X2A R X2B , —S(O)R X2B , S(O) 2 R X2B , —S(O) 2 NR X2A R X2B , C 1-4  haloaliphatic, optionally substituted C 3-8  cycloaliphatic, C 1-6  aliphatic; 
 X 4  is N or C—R B4 , X 5  is N or C—R B5 , X 6  is N or C—R B6 , and X 7  is N or C—R B7 , where optionally up to two of X 4 , X 5 , X 6 , and X 7  are N and each of R B4 , R B5 , R B6 , and R B7  is, independently, hydrogen, halogen, —CN, —NO 2 , —OR, —OC(O)R, —OC(O)OR, —OC(O)NRR′, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O) 2 R, —S(O) 2 NRR′, optionally substituted C 1-4  haloaliphatic, C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl; 
 each of R F  and R G  is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 1-4  haloaliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, or when W is N(R F ), R F  and R G  and the intervening atoms together optionally form a N═C bond; 
 R H  is hydrogen, optionally substituted C 1-6  aliphatic, C 1-4  haloaliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl; 
 R X2A  is hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl, —C(O)R, —C(O)NRR′, —C(O)OR, —S(O)R, —S(O) 2 R, or —S(O) 2 NRR′; 
 each of R, R′, and R X2B  is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl; 
 each of said heterocyclyl and heteroaryl rings contains one to four heteroatoms independently selected from oxygen, sulfur, or nitrogen; 
 the optional substituents on one or more carbon atoms of each of said aryl and heteroaryl groups are: halogen; —R ∘ ; —OR ∘ ; —SR ∘ ; 1,2-methylenedioxy; 1,2-ethylenedioxy; phenyl optionally substituted with R ∘ ; —O(Ph) optionally substituted with R ∘ ; —(CH 2 ) 1-2 (Ph) optionally substituted with R ∘ ; —CH═CH(Ph) optionally substituted with R ∘ ; —NO 2 ; —CN; —N(R ∘ ) 2 ; —NR ∘ C(O)R ∘ ; —NR ∘ C(S)R ∘ ; —NR ∘ C(O)N(R ∘ ) 2 ; —NR ∘ C(S)N(R ∘ ) 2 ; —NR ∘ C(O)OR ∘ ; —NR ∘ NR ∘ C(O)R ∘ ; —NR ∘ NR ∘ C(O)N(R ∘ ) 2 ; —NR ∘ NR ∘ C(O)OR ∘ ; —C(O)C(O)R ∘ ; —C(O)CH 2 C(O)R ∘ ; —C(O)OR ∘ ; —C(O)R ∘ ; —C(S)R ∘ ; —C(O)N(R ∘ ) 2 ; —C(S)N(R ∘ ) 2 ; —B(OR ∘ ) 2 , —OC(O)N(R ∘ ) 2 ; —OC(O)R ∘ ; —C(O)N(OR ∘ )R ∘ ; —C(═NOR ∘ )R ∘ ; —S(O) 2 R ∘ ; —S(O) 2 OR ∘ ; —S(O) 2 N(R ∘ ) 2 ; —S(O)R ∘ ; —NR ∘ S(O) 2 N(R ∘ ) 2 ; —NR ∘  S(O) 2 R ∘ ; —N(OR ∘ )R ∘ ; —C(═NH)—N(R ∘ ) 2 ; or —(CH 2 ) 0-2 NHC(O)R ∘ ; -L-R ∘ ; -L-N(R ∘ ) 2 ; -L-SR ∘ ; -L-OR ∘ ; -L-(C 3-10  cycloaliphatic), -L-(C 6-10  aryl), -L-(5-10 membered heteroaryl), -L-(5-10 membered heterocyclyl), oxo, C 1-4  haloalkoxy, C 1-4  haloalkyl, -L-NO 2 , -L-CN, -L-OH, -L-CF 3 ; or two substituents, on the same carbon or on different carbons, together with the carbon or intervening carbons to which they are bound, form a 5-7 membered saturated, unsaturated, or partially saturated ring, wherein L is a C 1-6  alkylene group in which up to three methylene units are replaced by —NH—, —NR ∘ —, —O—, —S—, —C(O)O—, —OC(O)—, —C(O)C(O)—, —C(O)—, —C(O)NH—, —C(O)NR ∘ —, —C(═N—CN)—, —NHC(O)—, —NR ∘ C(O)—, —NHC(O)O—, —NR ∘ C(O)O—, —S(O) 2 NH—, —S(O) 2 NR ∘ —, —NHS(O) 2 —, —NR ∘ S(O) 2 —, —NHC(O)NH—, —NR ∘ C(O)NH—, —NHC(O)NR ∘ —, —NR ∘ C(O)NR ∘ , —OC(O)NH—, —OC(O)NR ∘ —, —NHS(O) 2 NH—, —NR ∘ S(O) 2 NH—, —NHS(O) 2 NR ∘ —, —NR ∘ S(O) 2 NR ∘ —, —S(O)—, or —S(O) 2 —, and wherein each occurrence of R ∘  is independently selected from hydrogen, optionally substituted C 1-6  aliphatic, an unsubstituted 5- to 6-membered heteroaryl or heterocyclic ring, phenyl, or —CH 2 (Ph), or, two independent occurrences of R ∘ , on the same substituent or different substituents, taken together with the atom(s) to which each R ∘  group is bound, form a 5-8-membered heterocyclyl, aryl, or heteroaryl ring or a 3- to 8-membered cycloalkyl ring, wherein said heteroaryl or heterocyclyl ring has 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein optional substituents on the aliphatic group of R ∘  are selected from —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, —C(O)OH, C(O)O(C 1-4  aliphatic), O(haloC 1-4  aliphatic), or haloC 1-4  aliphatic, wherein each of the C 1-4  aliphatic groups of R ∘  is unsubstituted; and 
 the optional substituents on one or more carbon atoms of each of said aliphatic, haloaliphatic, cyclo aliphatic, and heterocyclyl groups are as defined for said aryl and heteroaryl groups and additionally comprise: ═O, ═S, ═NNHR*, ═NN(R*) 2 , ═NNHC(O)R*, ═NNHC(O)O(alkyl), ═NNHS(O) 2 (alkyl), or ═NR*, wherein each R* is independently selected from hydrogen or an optionally substituted C 1-6  aliphatic, and where optional substituents on said aliphatic group of R* are selected from —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, —C(O)OH, —C(O)O(C 1-4  aliphatic), —O(halo-C 1-4  aliphatic), and halo(C 1-4  aliphatic), wherein each of the foregoing C 1-4  aliphatic groups of R* is unsubstituted, 
 wherein said disease, condition, or disorder is allergy, asthma, chronic obstructive pulmonary disease (COPD), diabetes, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, perivascular fibrosis, benign prostatic hyperplasia, vascular smooth muscle cell proliferation, endothelial dysfunction, ischemia/reperfusion-induced injury, stroke, baldness, cancer, malignoma, hepatomegaly, hypertension, cardiovascular disease, cardiomegaly, cystic fibrosis, restenosis, psoriasis, inflammation, hypertension, angina pectoris, cerebrovascular contraction, peripheral circulation disorder, premature birth, preterm labor, atherosclerosis, vasospasm, cerebral vasospasm, coronary vasospasm, retinopathy, neurite outgrowth, glaucoma, erectile dysfunction (ED), AIDS, a respiratory syncytial viral (RSV) infection, osteoporosis, Crohn's Disease, colitis, or Raynaud's Disease. 
 
     
     
         25 . The method of  claim 24 , wherein the compound is represented by the formula (I-b) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R H2 , R H3 , R H4 , R H5 , and R H6  is, independently, hydrogen, halogen, —CN, —NO 2 , —OR, —B(OR) 2 , —OC(O)R, —OC(O)OR, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O) 2 R, —S(O) 2 NRR′, optionally substituted C 1-4  haloaliphatic, C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl; and 
 each of R and R′ is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl. 
 
     
     
         26 . The method of  claim 25 , wherein R H4  is —OR, —B(OR) 2 , —OC(O)R, —OC(O)OR, or —OC(S)R; each of R B4 , R B5 , and R B6  is hydrogen; and X 2  is N or C—H. 
     
     
         27 . The method of  claim 26 , wherein R H4  is —OH. 
     
     
         28 . The method of  claim 24 , wherein W is —N(R F )—. 
     
     
         29 . The method of  claim 24 , wherein at least one of R G  or R H  is not hydrogen. 
     
     
         30 . The method of  claim 29 , wherein R H  is an optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl. 
     
     
         31 . The method of  claim 30 , wherein R H  is an optionally substituted C 6-10  aryl or 5- to 8-membered monocyclic heteroaryl. 
     
     
         32 . The method of  claim 31 , wherein the compound is represented by formula (II-d) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 R F  is hydrogen, optionally substituted C 1-6  aliphatic, C 1-4  haloaliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl; 
 each of R H2 , R H3 , R H4 , R H5 , and R H6  is, independently, hydrogen, halogen, —CN, —NO 2 , —OR, —B(OR) 2 , —OC(O)R, —OC(O)OR, —OC(S)R, —SR, —SC(O)R, —SC(S)R, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O)R, —S(O) 2 R, —S(O) 2 NRR′, optionally substituted C 1-4  haloaliphatic, C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, or 5- to 8-membered monocyclic heteroaryl, 8- to 12-membered bicyclic heteroaryl; and 
 each of R and R′ is, independently, hydrogen, optionally substituted C 1-6  aliphatic, C 3-8  cycloaliphatic, C 6-10  aryl, 3- to 8-membered monocyclic heterocyclyl, 8- to 12-membered bicyclic heterocyclyl, 5- to 8-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl. 
 
     
     
         33 . The method of  claim 32 , wherein R H4  is —OR, —B(OR) 2 , —OC(O)R, —OC(O)OR, or —OC(S)R; each of R B4 , R B5 , and R B6  is hydrogen; and X 2  is N or C—H. 
     
     
         34 . The method of  claim 33 , wherein R H4  is —OH. 
     
     
         35 . The method of  claim 34 , wherein the compound is represented by formula (II-f) or (II-g), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 34 , wherein each of R B4 , R B5 , R B6 , and R B7  is hydrogen. 
     
     
         36 . The method of  claim 24 , wherein
 each of R B4 , R B5 , and R B6  is hydrogen; X 7  is N or C—H; X 2  is N or C—H; and each of R B2 , R B3 , R H5 , and R H6  is, independently, hydrogen, halogen, —CN, —NO 2 , —OR, —B(OR) 2 , —OC(O)R, —OC(O)OR, —C(O)OR, —C(O)NRR′, —C(S)NRR′, —NRR′, —S(O) 2 R, —S(O) 2 NRR′, optionally substituted C 1-4  haloaliphatic, C 1-6  aliphatic, C 3-8  cycloaliphatic, wherein each of R and R′ is, independently, hydrogen or optionally substituted C 1-6  aliphatic.   
     
     
         37 . The method of  claim 24 , wherein the compound is any one of the following compounds or a pharmaceutically acceptable salt thereof: