Compounds, compositions and methods of use

A method for modulating TDP-43 inclusion formation in a subject, the method comprising administering to the subject a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is aryl or heteroaryl;
• Ring B is 6-membered aryl or 5- or 6-membered heteroaryl;
• R″ is H or C(O)R1;
• R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7;
• each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R8;
• R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R9;
• or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9;
• each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9;
• each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7;
• or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7;
• each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Rc, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10;
• each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11;
• each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11;
• or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11;
• each R11 is independently C1-C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro;
• n is 0, 1, 2, 3, 4, or 5;
• and
• p is 0, 1, or 2;
• provided that Ring B is not
• wherein the connection to C(O)R1 and N(R5)S(O)2— is as shown.

A method for treating a B-cell or T-cell lymphoma in a subject in need thereof with a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is aryl or heteroaryl;
• Ring B is 6-membered aryl or 5- or 6-membered heteroaryl;
• R″ is H or C(O)R1;
• R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7;
• each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R8;
• R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R9;
• or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9;
• each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9;
• each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7;
• or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7;
• each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Re, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10;
• each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11;
• each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11;
• or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11;
• each R11 is independently C1-C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro;
• n is 0, 1, 2, 3, 4, or 5;
• and
• p is 0, 1, or 2.

A method for treating a neurodegenerative disease selected from the group consisting of frontotemporal dementia caused by mutations in the progranulin protein or tau protein (e.g., progranulin-deficient FTLD), frontotemporal dementia with inclusion body myopathy (IBMPFD), frontotemporal dementia with motor neuron disease, bovine spongiform encephalopathy, Kuru, scrapie, Lewy Body disease, diffuse Lewy body disease (DLBD), polyglutamine (polyQ)-repeat diseases, progressive bulbar palsy (PBP), psuedobulbar palsy, spinal and bulbar muscular atrophy (SBMA), primary lateral sclerosis, HIV-associated dementia, progressive spinobulbar muscular atrophy (e.g., Kennedy disease), post-polio syndrome (PPS), pantothenate kinase-associated neurodegeneration (PANK), Lytigo-bodig (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-Parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Apler's disease, Krabbe's disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne syndrome, Kearns-Sayre syndrome, Gerstmann-Straussler-Scheinker syndrome and other transmissible spongiform encephalopathies, hereditary spastic paraparesis, Leigh's syndrome, demyelinating diseases, neuronal ceroid lipofuscinoses, epilepsy, tremors, depression, mania, anxiety and anxiety disorders, sleep disorders (e.g., narcolepsy, fatal familial insomnia), acute brain injuries (e.g., stroke, head injury) or autism in a subject in need thereof with a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is aryl or heteroaryl;
• Ring B is 6-membered aryl or 5- or 6-membered heteroaryl;
• R″ is H or C(O)R1;
• R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7;
• each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R8;
• R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R9;
• or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9;
• each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9;
• each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7;
• or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7;
• each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Re, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10;
• each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11;
• each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11;
• or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11;
• each R11 is independently C1-C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro;
• n is 0, 1, 2, 3, 4, or 5;
• and
• p is 0, 1, or 2;
• provided that Ring B is not
• wherein the connection to C(O)R1 and N(R5)S(O)2— is as shown.

A method for treating a musculoskeletal disease in a subject in need thereof with a compound of Formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• Ring A is aryl or heteroaryl;
• Ring B is 6-membered aryl or 5- or 6-membered heteroaryl;
• R″ is H or C(O)R1;
• R1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —NRBC(O)RD, or —SRE, each of which is optionally substituted with 1-5 R7;
• each R is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, halo, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —NRBC(O)RD, —NRBC(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R8;
• R5 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —ORA, or —SRE, each of which is optionally substituted with 1-5 R9;
• or R5, together with the nitrogen atom to which it is attached, forms a heterocyclyl or heteroaryl ring with Ring A, optionally substituted with 1-3 R9;
• each R6 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, cyano, hydroxy, halo, —ORA, —NRBRC, —C(O)RD, —C(O)ORA, —C(O)NRBRC, —SRE, —S(O)RE, —S(O)2RE, —NRBS(O)2RE, or —S(O)2NRBRC, each of which is optionally substituted with 1-5 R9;
• each RA, RB, RC, RD, or RE is independently H, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, each of which is optionally substituted with 1-4 occurrences of R7;
• or RB and RC, together with the atoms to which each is attached, form a heterocyclyl ring optionally substituted with 1-4 R7;
• each R7, R8, or R9 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, —ORa, —NRbRc, —C(O)Rd, —C(O)ORa, —C(O)NRbRc, —NRbC(O)Rd, —NRbC(O)NRbRc, —SRe, —S(O)Re, —S(O)2Re, —NRbS(O)2Re, or —S(O)2NRbRc, each of which is optionally substituted with 1-5 R10;
• each R10 is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, hydroxy, cyano, or nitro, each of which is optionally substituted with 1-4 R11;
• each Ra, Rb, Rc, Rd, or Re is H, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted with R11;
• or RB and RC, together with the atoms to which each is attached, form a cycloalkyl or heterocyclyl ring optionally substituted with 1-4 R11;
• each R11 is independently C1-C6 alkyl, halo, hydroxy, cycloalkyl, alkoxy, keto, cyano, or nitro;
• n is 0, 1, 2, 3, 4, or 5;
• and
• p is 0, 1, or 2.