Phosphatidylinositol 3-kinase (PI3K) is a family of lipid kinases that phosphorylate phosphatidylinositol at the 3′ position of the inositol ring. PI3K is comprised of several classes of genes, including Class IA, IB, II and III and some of these classes contain several isoforms (reviewed in Engelman et al., Nature Review Genetics 7:606-619 (2006)). Adding to the complexity of this family is the fact that PI3Ks function as heterodimers, comprising a catalytic domain and a regulatory domain. The PI3K family is structurally related to a larger group of lipid and serine/threonine protein kinases known as the phosphatidylinositol 3-kinase like kinases (PIKKs), which also includes DNA-PK, ATM, ATR, mTOR, TRRAP and SMG1.
PI3K is activated downstream of various mitogenic signals mediated through receptor tyrosine kinases, and subsequently stimulates a variety of biological outcomes; including increased cell survival, cell cycle progression, cell growth, cell metabolism, cell migration and angiogenesis (reviewed in Cantley, Science 296:1655-57 (2002); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005); Engelman et al., Nature Review Genetics 7:606-619 (2006)). Thus, PI3K hyper-activation is associated with a number of hyper-proliferative, inflammatory, or cardiovascular disorders; including cancer, inflammation, and cardiovascular disease.
There are a number of genetic aberrations that lead to constitutive PI3K signaling; including activating mutations in PI3K itself (Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005); reviewed in Bader et al., Nature Reviews Cancer 5:921-9 (2005)); RAS (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)) and upstream receptor tyrosine kinases (reviewed in Zwick et al., Trends in Molecular Medicine 8:17-23 (2002)) as well as inactivating mutations in the tumor suppressor PTEN (reviewed in Cully et al., Nature Reviews Cancer 6:184-92 (2006)). Mutations in each of these gene classes have proven to be oncogenic and are commonly found in a variety of cancers.
The molecules defined within this invention inhibit the activity of PI3K, and therefore may be useful for the treatment of proliferative, inflammatory, or cardiovascular disorders. Cases where PI3K pathway mutations have been linked to proliferative disorders where the molecules defined within this invention may have a therapeutic benefit include benign and malignant tumors and cancers from diverse lineage, including but not limited to those derived from colon (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), liver (reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), intestine (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), stomach (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), esophagus (Phillips et al., International Journal of Cancer 118:2644-6 (2006)); pancreas (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)); skin (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), prostate (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), lung (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), breast (Samuels et al., Science 304:554 (2004); Isakoff et al., Can Res 65:10992-1000 (2005); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), endometrium (Oda et al., Can Res 65:10669-73 (2005); reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), cervix (reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); ovary (Shayesteh et al., Nature Genetics 21:99-102 (1999); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), testes (Moul et al., Genes Chromosomes Cancer 5:109-18 (1992); Di Vizio et al., Oncogene 24:1882-94 (2005)), hematological cells (reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)), pancreas (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)), thyroid (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003); reviewed in Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); brain (Samuels et al., Science 304:554 (2004); reviewed in Karakas et al., British Journal of Cancer 94: 455-59 (2006)), bladder (Lopez-Knowles et al., Cancer Research 66:7401-7404 (2006); Hennessy et al., Nature Reviews Drug Discovery 4:988-1004 (2005)); kidney (reviewed in Downward Nature Reviews Cancer 3:11-22 (2003)) and Head and Neck (reviewed in Engelman et al., Nature Reviews Genetics 7:606-619 (2006)).
Other classes of disorders with aberrant PI3K pathway signaling where the molecules defined within this invention may have a therapeutic benefit include inflammatory and cardiovascular diseases, including but not limited to allergies/anaphylaxis (reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), acute and chronic inflammation (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006); reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)), rheumatoid arthritis (reviewed in Rommel et al., Nature Reviews Immunology 7:191-201 (2007)); autoimmunity disorders (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), thrombosis (Jackson et al., Nature Medicine 11:507-14 (2005); reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), hypertension (reviewed in Ruckle et al., Nature Reviews Drug Discovery 5:903-12 (2006)), cardiac hypertrophy (reviewed in Proud et al., Cardiovascular Research 63:403-13 (2004)), and heart failure (reviewed in Mocanu et al., British Journal of Pharmacology 150:833-8 (2007)).
Vacuolar Protein Sorting 34 (VPS34) is the sole Class III PI3K family member. VPS34 functions in the formation and trafficking of multiple intracellular vesicles, including vacuoles, endosomes, multivessicular bodies, lysosomes and autophagosomes (reviewed in Backer Biochem J 2008; Yan and Backer Biochem J 2007). VPS34 carries out these activities by phosphorylating PtdIns forming PtdIns3P, resulting in the recruitment and localization of a variety of FYVE and PX domain containing effector proteins that facilitate vesicular formation, elongation and movement. At a cellular level, inhibition of VPS34 results in defects in protein sorting and autophagy. Broadly defined, autophagy is a regulated process whereby cells catabolize subcellular components targeted for degradation by enclosing them in double-membrane vesicles which then fuse with lysosomes. Autophagy has been best characterized as occurring during times of nutrient deprivation, but also plays a role in normal cellular and tissue homeostasis and functions, including the development of multiple tissue types, the immune response, clearance of neuronal aggregates and tumor suppression. In addition to functioning in vesicle formation and movement, VPS34 may also participate in several signal transduction pathways (reviewed in Backer Biochem J 2008). Given that VPS34 plays an important role in many critical cellular processes including autophagy, inhibitors of VPS34 may have therapeutic application in a number of diseases, including but not limited to cancer, muscular disorders, neurodegeneration, inflammatory disease, infectious disease and other age related illnesses (reviewed in Shintani and Klionshy Science 2004; Kondo et al Nat Rev Cancer 2005; Delgato et al Immunol Rev 2009).
Clearly, it would be beneficial to provide novel PI3K inhibitors that possess good therapeutic properties, especially for the treatment of proliferative, inflammatory, or cardiovascular disorders.
1. General Description of Compounds of the Invention:
This invention provides compounds that are inhibitors of PI3K, and accordingly are useful for the treatment of proliferative, inflammatory, or cardiovascular disorders. The compounds of this invention are represented by formula IA or IB:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is CY, —C(O)N(R3)2, —C(O)OR3, —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR3N(R3)2, —C(═N—NH2)NH2, —C(═N)N(R3)2, wherein:                CY is an optionally substituted group selected from:        
wherein:                G2 is N═, ═N, or —N(R3′), wherein:        each occurrence of R3 and R3′ is independently hydrogen or an optionally substituted C1-6 aliphatic, wherein:        X1, X2, and X3, are each independently N, NR3′, O, S, or CR4, provided that only one of X1, X2, or X3 may be O, S, or NR3′;        X8, X9, X10, and X11 are each independently N, or CR4, provided no more than two occurrences of X8, X9, X10, and X11 are N;        each occurrence of R4 is independently hydrogen, —CN, halogen, —Z3—R6, or an optionally        substituted group selected from C1-6 aliphatic, or 3-10-membered cycloaliphatic,        wherein:                    Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R4a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, —N(R4a)C(O)—, —N(R4a)CO2—, —S(O)2NR4a—, —N(R4a)S(O)2—, —OC(O)N(R4a)—, —N(R4a)C(O)NR4a—, —N(R4a)S(O)2N(R4a)—, or —OC(O)—;            R4a is hydrogen or an optionally substituted C1-4 aliphatic, and            R6 is hydrogen or an optionally substituted group selected from C1-6 aliphatic,                        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                    or wherein two adjacent occurrences of R3′ or R4, taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        Y10 is —OR4′ or —N(R4′)2;        Y11 is O or N—R4′;        each occurrence of R4′ is independently hydrogen or an optionally substituted C1-6 aliphatic;        
Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                each occurrence of R2 is independently —R12a, -T2-R12d, or —V2-T2-R12d, and:        each occurrence of R12a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —N(R12e)C(O)N(R12e)—, —N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and                        
T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-C4aliphatic group;
n is 0 to 4;
W is selected from —C(R7)2—, —C(═C(R7)2)—, —C(R7)2O—, —C(R7)2NR7a—, —N(R7b)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR7a—, or —N(R7a)C(O)—, wherein:                each occurrence of R7 is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R7b)2, —OR7a, —SR7a, halo, or —CN;        each occurrence of R7a is independently hydrogen or optionally substituted C1-6 aliphatic;        each occurrence of R7b is independently hydrogen, optionally substituted C1-6 aliphatic, —C(O)R7a, or —S(O)2R7a; or        wherein any two occurrences of R7, R7a, or R7b taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        or wherein any two occurrences of R7a and R2, or R7b and R2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
G1 is N or —CR8, wherein R8 is H, —CN, halogen, -Z-R9, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R8a)—, —S—, —S(O)—, S(O)2—, —C(O)—, —CO2—, —C(O)NR8a—, —N(R8a)C(O)—, —N(R8a)CO2—, —S(O)2NR8a—, —N(R8a)S(O)2—, —OC(O)N(R8a)—, —N(R8a)C(O)NR8a—, —N(R8a)S(O)2N(R8a)—, or —OC(O)—;                    R8a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and HY is an optionally substituted group selected from:        

wherein each occurrence of X4, X5, X6, and X7 is independently —CR10 or N, provided no more than two occurrences of X4, X5, X6, and X7 are N;
each occurrence of Q1 and Q2 is independently S, O or —NR5;
each occurrence of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9 is independently —CR10 or N, provided no more than two occurrences of Y6, Y7, Y8, and Y9 are N;                or wherein two adjacent occurrences of X4 and X5, X6 and X7, Y1 and Q1, Y3 and Q2, or Y4 and Y5 taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;wherein R10 is —R10b, —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:        V1 is —NR11—, —NR11—C(O)—, —NR11—C(S)—, —NR11—C(NR11)—, —NR11C(O)OR10a—, —NR11C(O)NR11—, —NR11C(O)SR10a—, —NR11C(S)OR10a—, —NR11C(S)NR11—, —NR11C(S)SR10a—, —NR11C(NR11)OR10a—, —NR11C(NR11)NR11—, —NR11S(O)2—, —NR11S(O)2NR11—, —C(O)—, —CO2—, —C(O)NR11—, —C(O)NR11O—, —SO2—, or —SO2NR11—;        each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R11)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R11)—, —S(O)2N(R11)—, —OC(O)N(R11)—, —N(R11)C(O)—, —N(R11)SO2—, —N(R11a)C(O)O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R11)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, N(R11)2, —OR10a, —S(O)2R10a, —C(O)R10a, —C(O)OR10a, —C(O)N(R11)2, —S(O)2N(R11)2, —OC(O)N(R11)2, —N(R11)C(O)R10a, —N(R11)SO2R10a, —N(R11)C(O)OR10a, —N(R11)C(O)N(R11)2, or —N(R11)SO2N(R11)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or        R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
each occurrence of R11 is independently hydrogen, —C(O)R11a, —CO2R11a, —C(O)N(R11a)2, —C(O)N(R11a)—OR11a, —SO2R11a, —SO2N(R11a)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
each occurrence of R5 is independently hydrogen, —C(O)R5a, —CO2R5a, —C(O)N(R5b)2, —SO2R5a, —SO2N(R5b)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        wherein each occurrence of R5b is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R5b taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that:        a. when G1 is N, W is NH, and R1 is CONH2, then HY is other than optionally substituted 4,5,6,7-tetrahydro-4-hydrazinylidene-1-H-indolyl, 4,5,6,7-tetrahydro-4-hydrazinylidene-1-H-indazolyl, a 4,5,6,7-tetrahydro-4-oxo-1H-indazol-1-yl, or a 4,5,6,7-tetrahydro-4-oxo-1H-indol-1-yl group; and        b. the compound is other than 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(1-piperazinyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-[4-(2,2,2-trifluoroacetyl)-1-piperazinyl]phenyl]amino]-, or 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(methylsulfonyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(1-piperazinyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-[4-[4-(2,2,2-trifluoroacetyl)-1-piperazinyl]phenyl]amino]-, or 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(methylsulfonyl)phenyl]amino]-.        
In another aspect, the compounds of this invention are represented by formula IA or IB:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is CY, —C(O)N(R3)2, —C(O)OR3, —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR3N(R3)2, —C(═N—NH2)NH2, —C(═N)N(R3)2, wherein:                CY is        
                 wherein:        G2 is N═, ═N, or —N(R3′), wherein:        each occurrence of R3 and R3′ is independently hydrogen or an optionally substituted C1-6 aliphatic, wherein:        X1, X2, and X3, are each independently N, NR3′, O, S, or CR4, provided that only one of X1, X2, or X3 may be O, S, or NR3′;                    each occurrence of R4 is independently hydrogen, —CN, halogen, -Z3-R6, or an optionally substituted group selected from C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:            Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R4a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C2—, —C(O)NR4a—, —N(R4a)C(O)—, —N(R4a)CO2—, —S(O)2NR4a—, —N(R4a)S(O)2—, —OC(O)N(R4a)—, —N(R4a)C(O)NR4a—, —NR4a)S(O)2N(R4a)—, or —OC(O)—;            R4a is hydrogen or an optionally substituted C1-4 aliphatic, and            R6 is hydrogen or an optionally substituted group selected from C1-6 aliphatic,                        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                    or wherein two adjacent occurrences of R3′ or R4, taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                        
Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                each occurrence of R2 is independently —R12a, -T2-R12d, or V2-T2-R12d, and:        each occurrence of R12a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12c—, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;        each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;        each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —N(R12e)C(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and        
T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group;
n is 0 to 4;
W is selected from —C(R7)2—, —C(═C(R7)2)—, —C(R7)2O—, —C(R7)2NR7a—, —O—, —N(R7b)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR7a—, or —N(R7a)C(O)—, wherein:                each occurrence of R7 is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R7b)2, —SR7a, halo, or —CN;        each occurrence of R7a is independently hydrogen or optionally substituted C1-6 aliphatic;        each occurrence of R7b is independently hydrogen, optionally substituted C1-6 aliphatic, —C(O)R7a, or —S(O)2R7a; or        wherein any two occurrences of R7, R7a, or R7b taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        or wherein any two occurrences of R7a and R2, or R7b and R2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
G1 is N or —CR8, wherein R8 is H, —CN, halogen, -Z-R9, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R8a)—, —S—, —S(O)—, S(O)2—, —C(O)—, —CO2—, —C(O)NR8a—, —NR8a)C(O)—, —NR8a)CO2—, —S(O)2NR8a—, NR8a)S(O)2—, —OC(O)N(R8a)—, —N(R8a)C(O)NR8a—, —N(R8a)S(O)2N(R8a)—, or —OC(O)—;                    R8a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and HY is an optionally substituted group selected from:        

wherein each occurrence of X4, X5, X6, and X7 is independently —CR10 or N, provided no more than two occurrences of X4, X5, X6, and X7 are N;
each occurrence of Q1 and Q2 is independently S, O or —NR5;
each occurrence of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, and Y9 is independently —CR10 or N, provided no more than two occurrences of Y6, Y7, Y8, and Y9 are N;                or wherein two adjacent occurrences of X4 and X5, X6 and X7, Y1 and Q′, Y3 and        
Q2, or Y4 and Y5 taken together with the atom to which they are bound, form an optionally substituted fused group selected from 5-6-membered aryl, or 5-6-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
wherein R10 is —R10b, —V1—R10c, -T1-R10b, or —V1-T1-R10b wherein:
                V1 is —NR11—, —NR11—C(O)—, —NR11—C(S)—, —NR11—C(NR11)—, —NR11C(O)OR10a—, —NR11C(O)NR11—, —NR11C(O)SR10a—, —NR11C(S)OR10a—, —NR11C(S)NR11—, —NR11C(S)SR10a—, —NR11C(NR11)OR10a—, —NR11C(NR11)NR11—, —NR11S(O)2—, —NR11S(O)2NR11—, —C(O)—, —CO2—, —C(O)NR11, —C(O)NR11O—, —SO2—, or —SO2NR11—;        each occurrence of R10a is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        T1 is an optionally substituted C1-C6alkylene chain wherein the alkylene chain optionally is interrupted by —N(R11)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R11)—, —S(O)2N(R11)—, —OC(O)N(R11)—, —N(R11)C(O)—, —N(R11)SO2—, —N(R11a)C(O) O—, —NR10aC(O)N(R10a)—, —N(R10a)S(O)2N(R10a)—, —OC(O)—, or —C(O)N(R11)—O— or wherein T1 forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        each occurrence of R10b is independently hydrogen, halogen, —CN, —NO2, —N(R11)2, —OR10a, —SR10a, —S(O)2R10a, —C(O)R10a, —C(O)R10a, —C(O)N(R11)2, —S(O)2N(R11)2, —OC(O)N(R11)2, —N(R11)C(O)R10a, —N(R11)SO2R10a, —N(R11)C(O)OR10a, —N(R11)C(O)N(R11)2, or —N(R11)SO2N(R11)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
each occurrence of R10c is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or R10a and R10c taken together with a nitrogen atom to which they are bound form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each occurrence of R11 is independently hydrogen, —C(O)R11a, —CO2R11a, —C(O)N(R11a)2, —C(O)N(R11a)—OR11a, —SO2R11a, —SO2N(R11a)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                wherein each occurrence of R11a is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
each occurrence of R5 is independently hydrogen, —C(O)R5a, —CO2R5a, —C(O)N(R5b)2, —SO2R5a, —SO2N(R5b)2, or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                wherein each occurrence of R5a is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        wherein each occurrence of R5b is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or two occurrences of R5b taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;provided that:        a. when G1 is N, W is NH, and R1 is CONH2, then HY is other than optionally substituted 4,5,6,7-tetrahydro-4-hydrazinylidene-1-H-indolyl, 4,5,6,7-tetrahydro-4-hydrazinylidene-1-H-indazolyl, a 4,5,6,7-tetrahydro-4-oxo-1H-indazol-1-yl, or a 4,5,6,7-tetrahydro-4-oxo-1H-indol-1-yl group; and        b. the compound is other than 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(1-piperazinyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-[4-(2,2,2-trifluoroacetyl)-1-piperazinyl]phenyl]amino]-, or 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(methylsulfonyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(1-piperazinyl)phenyl]amino]-, 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-[4-[4-(2,2,2-trifluoroacetyl)-1-piperazinyl]phenyl]amino]-, or 4-Oxazolecarboxamide, 2-(1H-indazol-4-yl)-5-[[4-(methylsulfonyl)phenyl]amino]-        
In another aspect, the compounds of this invention are represented by formula IA or IB:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is —C(O)N(R3)2, —C(O)OR3, —C(O)(NH)OH, —C(═NH)NHOH, —C(O)NR3N(R3)2, —C(═N—NH2)NH2, —C(═N)N(R3)2;                each occurrence of R3 is independently hydrogen or an optionally substituted C1-6 aliphatic;        
Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                each occurrence of R2 is independently —R12a, -T2-R12d, or —V2-T2-R12d, and:        each occurrence of R12a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12)2, —S(O)2N(R12b)2, —OC(O)NR12b)2, —N(R12e)C(O)R12b, —N(R12c)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —N(R12e)C(O)N(R12e), —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and                        
T2 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group;
n is 0 to 4;
W is selected from —C(R7)2—, —C(═C(R7)2)—, —C(R7)2O—, —C(R7)2NR7a—, —O—, —N(R7b)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR7a—, or —N(R7a)C(O)—, wherein:                each occurrence of R7 is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R7b)2, —OR7a, —SR7a, halo, or —CN;        each occurrence of R7a is independently hydrogen or optionally substituted C1-6 aliphatic;        each occurrence of R7b is independently hydrogen, optionally substituted C1-6 aliphatic, —C(O)R7a, or —S(O)2R7a; or        wherein any two occurrences of R7, R7a, or R7b taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        or wherein any two occurrences R7a and R2, or R7b and R2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
G1 is N or —CR8, wherein R8 is H, —CN, halogen, -Z-R9, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R8a)—, —S—, —S(O)—, S(O)2—, —C(O)—, —CO2—, —C(O)NR8a—, —N(R8a)C(O)—, —N(R8a)CO2—, —S(O)2NR8a—, —N(R8a)S(O)2—, OC(O)N(R8a)—, —N(R8a)C(O)NR8a—, —N(R8a)S(O)2N(R8a)—, or —OC(O)—;                    R8a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and HY is        

wherein each occurrence of R14 is independently —R14a or -T1-R14d, wherein:                each occurrence of R14a, as valency and stability permit, is independently fluorine, ═O, ═S, —CN, —NO2, —R14c—, —N(R14b)2, —OR14b—, —SR14c, —S(O)2R14c, —C(O)R14b, —C(O)OR14b, —C(O)N(R14b)2, —S(O)2N(R14b)2, —OC(O)N(R14b)2, —N(R14e)C(O)R14b, —N(R14e)SO2R14c, —N(R14e)C(O)OR14b, —N(R14e)C(O)N(R14b)2, or —N(R14e)SO2N(R14b)2, or two occurrences of R14b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;        each occurrence of R14b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14e is independently hydrogen or an optionally substituted C1-6 aliphatic group; and        T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R14a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R14a)—, —S(O)2N(R14a)—, —OC(O)N(R14a)—, —N(R14a)C(O)—, —N(R14a)SO2—, —N(R14a)C(O)O—, —NR14a C(O)N(R14a)—, —N(R14a)S(O)2N(R14a)—, —OC(O)—, or —C(O)N(R14a)—O— or wherein T1 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        
n is 0-6;
m is 1 or 2; and
p is 0, 1, or 2.
In some embodiments for compounds described directly above, HY is
wherein both occurrences of m are 1.
In other embodiments for compounds described directly above, HY is
wherein both occurrences of m are 1, and R1 is COOH.
In yet another aspect, the compounds of this invention are represented by formula IA or IB:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is CY, wherein:                CY is an optionally substituted group selected from:        
wherein:                each occurrence of R3 is independently hydrogen or an optionally substituted C1-6 aliphatic, wherein:        X8, X9, X10, and X11 are each independently N, or CR4, provided no more than two occurrences of X8, X9, X10, and X11 are N;        each occurrence of R4 is independently hydrogen, —CN, halogen, -Z3—R6, or an optionally substituted group selected from C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                    Z3 is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R4a)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —CO2—, —C(O)NR4a—, —N(R4a)C(O)—, —N(R4a)CO2—, —S(O)2NR4a—, —N(R4a)S(O)2—, —OC(O)N(R4a)—, —N(R4a)C(O)NR4a—, —N(R4a)S(O)2N(R4a)—, or —OC(O)—;            R4a is hydrogen or an optionally substituted C1-4 aliphatic, and            R6 is hydrogen or an optionally substituted group selected from C1-6 aliphatic,                        3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        Y10 is —OR4′ or —N(R4′)2;        Y11 is O or N—R4′;        each occurrence of R4′ is independently hydrogen or an optionally substituted C1-6 aliphatic;        
Ring A is a group selected from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;                each occurrence of R2 is independently R12a, -T2-R12d, —V2—R12d, and:        each occurrence of R12a is independently halogen, —CN, —NO2, —R12c, —N(R12b)2, —OR12b, —SR12c, —S(O)2R12c, —C(O)R12b, —C(O)OR12b, —C(O)N(R12b)2, —S(O)2N(R12b)2, —OC(O)N(R12b)2, —N(R12e)C(O)R12b, —N(R12e)SO2R12c, —N(R12e)C(O)OR12b, —N(R12e)C(O)N(R12b)2, or —N(R12e)SO2N(R12b)2, or two occurrences of R12b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;                    each occurrence of R12b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;            each occurrence of R12e is independently hydrogen or an optionally substituted C1-6 aliphatic group;            each occurrence of V2 is independently —N(R12e)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R12e)—, —S(O)2N(R12e)—, —OC(O)N(R12e)—, —N(R12e)C(O)—, —N(R12e)SO2—, —N(R12e)C(O)O—, —N(R12e)C(O)N(R12e)—, —N(R12e)SO2N(R12e)—, —OC(O)—, or —C(O)N(R12e)—O—; and                        
T2 is an optionally substituted C1-C6alkylene chain wherein the alkylene chain optionally is interrupted by —N(R13)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R13)—, —S(O)2N(R13)—, —OC(O)N(R13)—, —N(R13)C(O)—, —N(R13)SO2—, —N(R13)C(O)O—, —N(R13)C(O)N(R13)—, —N(R13)S(O)2N(R13)—, —OC(O)—, or —C(O)N(R13)—O— or wherein T3 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring, wherein R13 is hydrogen or an optionally substituted C1-4aliphatic group;
n is 0 to 4;
W is selected from —C(R7)2—, —C(═C(R7)2)—, —C(R7)2O—, —C(R7)2NR7a—, —N(R7b)—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)NR7a—, or —N(R7a)C(O)—, wherein:                each occurrence of R7 is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, —N(R7b)2, —OR7a, —SR7a, halo, or —CN;        each occurrence of R7a is independently hydrogen or optionally substituted C1-6 aliphatic;        each occurrence of R7b is independently hydrogen, optionally substituted C1-6 aliphatic, —C(O)R7a, or —S(O)2R7a; or        wherein any two occurrences of R7, R7a, or R7b taken together with the atom to which they are bound, form an optionally substituted group selected from a 3-6-membered cycloaliphatic ring, 6-10-membered aryl, 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        or wherein any two occurrences of R7a and R2, or R7b and R2 taken together with the nitrogen atom to which they are bound, form an optionally substituted group selected from 3-6-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        
G1 is N or —CR8, wherein R8 is H, —CN, halogen, -Z-R9, C1-6 aliphatic, or 3-10-membered cycloaliphatic, wherein:                Z is selected from an optionally substituted C1-3 alkylene chain, —O—, —N(R8a)—, —S—, —S(O)—, S(O)2—, —C(O)—, —CO2—, —C(O)NR8a—, —N(R8a)C(O)—, —N(R8a)CO2—, —S(O)2NR8a—, —N(R8a)S(O)2—, —OC(O)N(R8a)—, —N(R8a)C(O)NR8a—, —N(R8a)S(O)2N(R8a)—, or —OC(O)—;                    R8a is hydrogen or an optionally substituted C1-4 aliphatic, and                        R9 is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and            HY is

wherein each occurrence of R14 is independently —R14a or -T1-R14d, wherein:                each occurrence of R14a, as valency and stability permit, is independently fluorine, ═O, ═S, —CN, —NO2, —R14c, —N(R14b)2, —OR14b, —SR14c, —S(O)2R14c, —C(O)R14b, —C(O)OR14b, —C(O)N(R14b)2, —S(O)2N(R14b)2, —OC(O)N(R14b)2, —N(R14e)C(O)R14b, —N(R14e)SO2R14c, —N(R14e)C(O)OR14b, —N(R14e)C(O)N(R14b)2, or —N(R14e)SO2N(R14b)2, or two occurrences of R14b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 4-7-membered heterocyclyl ring having 0-1 additional heteroatoms selected from nitrogen, oxygen, or sulfur;        each occurrence of R14b is independently hydrogen or an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14c is independently an optionally substituted group selected from C1-C6 aliphatic, 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14d is independently hydrogen or an optionally substituted from 3-10-membered cycloaliphatic, 4-10-membered heterocyclyl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 6-10-membered aryl, or 5-10-membered heteroaryl having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;        each occurrence of R14e is independently hydrogen or an optionally substituted C1-6 aliphatic group; and        T1 is an optionally substituted C1-C6 alkylene chain wherein the alkylene chain optionally is interrupted by —N(R14a)—, —O—, —S—, —S(O)—, —S(O)2—, —C(O)—, —C(O)O—, —C(O)N(R14a)—, —S(O)2N(R14a)—, —OC(O)N(R14a)—, —N(R14a)C(O)—, —N(R14a)SO2—, —N(R14a)C(O)O—, —NR14a C(O)N(R14a)—, —N(R14a)S(O)2N(R14a)—, —OC(O)—, or —C(O)N(R14a)—O— or wherein T1 or a portion thereof optionally forms part of an optionally substituted 3-7 membered cycloaliphatic or heterocyclyl ring;        
n is 0-6;
m is 1 or 2;
p is 0, 1, or 2.
In some embodiments for compounds described directly above, G1 is N.
In some embodiments for compounds described directly above, CY is
wherein X8 and X11 are N, X9 and X10 are CR4, and Y11 is O.
In some embodiments for compounds described directly above, HY is
wherein both occurrences of m are 1.
In some embodiments for compounds described directly above, HY is pyridyl optionally additionally substituted with one or more occurrences of R10.