IP Library › Granted Patent US 12662491

Granted Patent B2

US 12662491 · App. 17/908,576 · Granted Jun 23, 2026

Compounds targeting RNA-binding proteins or RNA-modifying proteins

Inventors: Anna M. Ericsson (Shrewsbury, MA); Shomir Ghosh (Brookline, MA); Darren Martin Harvey (Acton, MA)

C07D498/04 A61K31/4709 A61K31/497 A61K31/4985 A61K31/501 A61K31/506 C07D401/04 C07D401/14 C07D405/14 C07D471/04 C07D487/08

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Quick Facts

Patent No.: US 12662491
App. No.: 17/908,576
Granted: Jun 23, 2026
Kind: B2

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Abstract

The invention relates to a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, compositions comprising the same and methods of preparing and using the same. The variables are described herein.

Claims (205)

1 . A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W is —CH 2 Y—R 3 , —S(O) 2 R 3 , —SCH 2 R 3 , Y—R 3 , —OC(═O)NR 11 R 12 or —N(C═O)NR 11 R 12 ;

V is —C(═O)—, —S(═O) 2 — or CR 13 R 14 ;

X is CR 4 R 5 , NR 6 or O;

Y is O;

Z is CR 8 or N;

R 1 is halo, —CN, —OR 1a , —C≡CH, a C 3-6 carbocyclyl, or a C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R 10 ;

R 1a is H or C 1-6 alkyl optionally substituted with one or more R 10 ;

R 10 , for each occurrence, is independently selected from halo, —CN and —OR 10a ;

R 10a , for each occurrence, is independently selected from H and C 1-6 alkyl;

R 2 is —CN, —CHR z CN, —C(O)NH 2 , —CHR z C(O)NH 2 , 3- to 12-membered carbocyclyl, —(CHR z )—(3- to 12-membered carbocyclyl), 3- to 12-membered heterocyclyl, or —(CHR z )-(3 to 12-membered heterocyclyl), wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R 2 or in the group represented by R 2 are optionally substituted with one or more R 20 , and R z is H or methyl;

R 20 , for each occurrence, is independently selected from H, halo, CN, oxo, —C(O)R 20a , —C(O) 2 R 20a , —C(O)NR 20a , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —N(R 20a )S(O) 2 R 20a , —OR 20a , —OC(O)R 20a , —OC(O)N(R 20a ) 2 , —SR 20a , —S(O) 2 R 20a , —S(O)N(R 20a ) 2 , —S(O) 2 N(R 20a ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R 20 are each optionally substituted with one or more R 25 ;

R 20a , for each occurrence, is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R 20a are each optionally substituted with one or more R 25 , or two R 20a together with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —C═O, —C(O)O(C 1 -C 6 alkyl), 4- to 6-membered heterocyclyl optionally substituted with OH, —N(R 25a ) 2 , or —OR 25a , or phenyl optionally substituted with C 1-6 alkyl, halo, —N(R 25a ) 2 or —OR 25a ;

R 25a is H, C 1-6 alkyl; or two R 25a together with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl, wherein the C 1-6 alkyl is optionally substituted with —OCH 3 ;

R 3 is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R 3 are optionally substituted with one or more R 30 ;

R 30 , for each occurrence, is independently selected from H, halo, oxo, —CN, —C(O)R 30a , —C(O) 2 R 30a , —C(O)NR 30a , —N(R 30a ) 2 , —N(R 30a )C(O)R 30a , —N(R 30a )C(O) 2 R 30a , —N(R 30a )C(O)N(R 30a ) 2 , —N(R 30a )S(O) 2 R 30a , —OR 30a , —OC(O)R 30a , —OC(O)N(R 30a ) 2 , —SR 30a , —S(O) 2 R 30a , —S(O)N(R 30a ) 2 , —S(O) 2 N(R 30a ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R 30 are each optionally substituted with one or more R 35 ;

R 30a , for each occurrence, is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R 30a are each optionally substituted with one or more R 35 ;

R 35 , for each occurrence, is independently H, —NH 2 , C 1-6 alkyl, halo or —OR 35a ; and

R 35a is H or C 1-6 alkyl;

R 4 , R 5 , R 15 , R 16 , R 17 and R 18 are each independently selected from H, C 1-6 alkyl, halo, —CN, —OR 4a , —NHC(O)CH 3 , 4- to 6-membered carbocyclyl, or 4- to 6-membered heterocyclyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, and wherein the heterocyclyl and carbocyclyl are optionally substituted with halo, —CN, —OR 4a , C 1 -C 6 alkyl or ═O (when the carbocyclyl or heterocyclyl are non-aromatic), or wherein R 15 and R 16 taken together or R 17 and R 18 taken together are ═NOH or ═NHOCH 3 ;

R 4a is H or C 1-6 alkyl, optionally substituted with one or more halo;

R 6 is H or C 1-6 alkyl optionally substituted with one or more substituents independently selected from halo, —CN and —OR 6a ;

R 6a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 8 is H, halo, —CN, —OR 8a or C 1-6 alkyl optionally substituted with one or more halo;

R 8a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 9 , R 13 and R 14 are each independently selected from H, C 1-6 alkyl, and C 3-6 cycloalkyl, wherein the C 1-6 alkyl and the C 3-6 cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, —CN, —OR 9a and C 1-6 alkyl optionally substituted with one or more halo;

R 9a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 11 and R 12 are each independently H or C 1-6 alkyl, or R 11 and R 12 together with the nitrogen atom from which they are attached form a 4- to 7-membered monocyclic heterocyclyl optionally substituted with one or more substituents independently selected from C 1-6 alkyl, halo, —OH, and C 1-6 alkoxy;

or any two of R 4 , R 5 , R 9 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 together form a —C 1-5 alkylene-, optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl, provided that R 4 and R 5 , R 13 and R 14 , R 15 and R 16 and R 17 and R 18 taken together form a —C 3-5 alkylene-, optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl;

or R 4 and R 15 taken together with their intervening carbon atoms form phenyl or a 6 membered heteroaryl; and

R a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one or more halo;

R 19a and R 19b are each independently H or C 1-6 alkyl optionally substituted with one or more halo, or R 19a and R 19b together with the carbon atom from which they are attached form —C(═O); or

one R 20 group and one R 30 group taken together form —O—CH 2 CH 2 —O— or —O—CH 2 CH 2 —NH—; and

n1 is 0, 1 or 2; and

n2 is 0, 1 or 2, provided when X is NR 6 or O, n1 and n2 cannot be 0.

2 . The compound of claim 1 , represented by Formula (I′):

or a pharmaceutically acceptable salt thereof, wherein:

W is Y—R 3 , —OC(═O)NR 11 R 12 or —N(C═O)NR 11 R 12 ;

V is —C(═O)—, —S(═O) 2 — or CR 13 R 14 ;

X is CR 4 R 5 , NR 6 or O;

Y is O;

Z is CR 8 or N;

R 1 is halo, CN, —OR 1a , —C≡CH, or a C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R 10 ;

R 1a is H or C 1-6 alkyl optionally substituted with one or more R 10 ;

R 10 , for each occurrence, is independently selected from halo, CN and OR 10a ;

R 10a , for each occurrence, is independently selected from H and C 1-6 alkyl;

R 2 is a 3 to 12-membered carbocyclyl or a 3 to 12-membered heterocyclyl, wherein the 3 to 12-membered carbocyclyl and the 3 to 12-membered heterocyclyl represented by R 2 are optionally substituted with one or more R 20 ;

R 20 , for each occurrence, is independently selected from H, halo, CN, oxo, —C(O)R 20a , —C(O) 2 R 20a , —C(O)NR 20a , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )C(O) 2 R 20a , —N(R 20a )C(O)N(R 20a ) 2 , —N(R 20a )S(O) 2 R 20a , —OR 20a , —OC(O)R 20a , —OC(O)N(R 20a ) 2 , —SR 20a , S(O) 2 R 20a , —S(O)N(R 20a ) 2 , —S(O) 2 N(R 20a ) 2 , C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered monocyclic heterocyclyl represented by R 20 are each optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —N(R 25a ) 2 , —OR 25a , phenyl optionally substituted with C 1-6 alkyl, halo, —N(R 25a ) 2 or —OR 25a ; and

R 25a is H or C 1-6 alkyl;

R 35 , for each occurrence, is independently H, C 1-6 alkyl, halo or —OR 35a ; and

R 35a is H or C 1-6 alkyl;

R 4 , R 5 , R 15 , R 16 , R 17 and R 18 are each independently selected from H, C 1-6 alkyl, halo, —CN and —OR 4a , wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ;

R 4a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 6 is H or C 1-6 alkyl wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ;

R 6a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 8 is H, halo, CN, —OR 8a or C 1-6 alkyl optionally substituted with one or more halo;

R 8a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 9 , R 13 and R 14 are each independently selected from H, C 1-6 alkyl and C 3-6 cycloalkyl, wherein the C 1-6 alkyl and the C 3-6 cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, —OR 9a and C 1-6 alkyl optionally substituted with one or more halo;

R 9a is H or C 1-6 alkyl optionally substituted with one or more halo;

or any two of R 4 , R 5 , R 9 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 together form a —C 3-5 alkylene-, [—C 1-5 alkylene-]optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl, provided that R 4 and R 5 , R 13 and R 14 , R 15 and R 16 and R 17 and R 18 taken together form a —C 3-5 alkylene-, optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl;

R a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one or more halo;

R 19a and R 19b are each independently H or C 1-6 alkyl optionally substituted with one or more halo or R 19a and R 19b together with the carbon atom from which they are attached form —C(═O)—;

n1 is 0, 1 or 2; and

n2 is 0, 1 or 2, provided when X is NR 6 or O, n1 and n2 cannot be 0.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (Ia) or (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

X is CR 4 R 5 , NR 6 or O;

Y is O;

Z is CR 8 or N;

R 1 is halo, CN, —OR 1a , —C≡CH, or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R 10 ;

R 1a is H or C 1-6 alkyl optionally substituted with one or more R 10 ;

R 10 , for each occurrence, is independently selected from halo, CN and OR 10a ;

R 10a , for each occurrence, is independently selected from H and C 1-6 alkyl;

R 20a , for each occurrence, is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl and 4- to 7-membered monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 -cycloalkyl and 4- to 7-membered monocyclic heterocyclyl represented by R 20a are each optionally substituted with one or more R 25 , or two R 20a together with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —N(R 25a ) 2 , —OR 25a , phenyl optionally substituted with C 1-6 alkyl, halo, —N(R 25a ) 2 or —OR 25a ; and

R 25a is H or C 1-6 alkyl;

R 35 , for each occurrence, is independently H, C 1-6 alkyl, halo or —OR 35a ; and

R 35a is H or C 1-6 alkyl;

R 4 and R 5 are each independently selected from H, C 1-6 alkyl, halo, —CN and —OR 4a , wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ;

R 4a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 6 is H or C 1-6 alkyl optionally substituted with one or more substituents independently selected from halo, CN and —OR 6a ;

R 6a is H or C 1-6 alkyl optionally substituted with one or more halo;

R 8 is H, halo, CN, —OR 8a or C 1-6 alkyl optionally substituted with one or more halo;

R 8a is H or C 1-6 alkyl optionally substituted with one or more halo;

n1 is 0, 1 or 2; and

n2 is 0, 1 or 2,

or, for formula (Ia), any two of R 4 , R 5 , R 9 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 together form a —C 1-5 alkylene- optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl, provided that R 4 and R 5 , R 13 and R 14 , R 15 and R 16 and R 17 and R 18 taken together form a —C 3-5 alkylene-, optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl; wherein R a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one or more halo.

4 . The compound of 3, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IIIa), (IIIb), (III-1a) or (III-1b):

or a pharmaceutically acceptable salt thereof.

5 . The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is Cl, Br, CN, —OR 9 or C 1-6 alkyl;

R 2 is C 3-8 cycloalkyl, phenyl, a 4 to 6-membered saturated monocyclic heterocyclyl, a 7 to 10-membered saturated or partially saturated bicyclic heterocyclyl, a 5 or 6-membered monocyclic heteroaryl or a 9 to 10-membered bicyclic heteroaryl, each of which is optionally substituted with one to three R 20 ;

R 20 , for each occurrence, is independently selected from H, halo, —CN, oxo, —C(O)R 20a , —C(O)NR 20a , —N(R 20a ) 2 , —N(R 20a )C(O)R 20a , —N(R 20a )S(O) 2 R 20a , —OR 20a , C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, and 4- to 7-membered saturated monocyclic heterocyclyl represented by R 20 are each optionally substituted with one or two R 25 ;

R 20a , for each occurrence, is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl represented by R 20a is optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —N(R 25a ) 2 , —OR 25a , phenyl optionally substituted with C 1-6 alkyl, halo, —N(R 25a ) 2 or —OR 25a ; and

R 25a is H or C 1-6 alkyl;

R 3 is phenyl, a 5 or 6-membered monocyclic heteroaryl or a 9 or 10-membered bicyclic heteroaryl, wherein the phenyl, 5 or 6-membered monocyclic heteroaryl and 9 or 10-membered bicyclic heteroaryl represented by R 3 are each optionally substituted with one to three R 30 ,

R 30 , for each occurrence, is H, halo, CN, —C(O)NR 30a , —N(R 30a ) 2 , —N(R 30a )C(O)R 30a , —N(R 30a )S(O) 2 R 30a , —OR 30a , or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one to three R 35 ;

R 30a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one to three R 35 ;

R 35 , for each occurrence, is independently H, halo and —OR 35a ; and

R 35a is H or C 1-3 alkyl; and

R 8 is H, halo, or OR 8a .

6 . The compound of claim 5 , a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (Va), or (Vb):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2.

7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (V-1a) or (V-1b):

or a pharmaceutically acceptable salt thereof.

8 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VAa), (VBa), (VCa), or (VDa):

or a pharmaceutically acceptable salt thereof.

9 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VAb), (VBb), (VCb) or (VDb):

or a pharmaceutically acceptable salt thereof.

10 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R 20 .

11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIIA-1a), (VIIB-1a), (VIIC-1a), or (VIID-1a):

or a pharmaceutically acceptable salt thereof, wherein:

R 30 is H, halo, CN, —OR 30a , or C 1-6 alkyl optionally substituted with one to three halo; and R 30a is H or C 1-6 alkyl optionally substituted with one to three halo; and

R 2 is phenyl or a 6-membered monocyclic heteroaryl containing 1 to 3 nitrogen atoms, wherein the phenyl and the 6-membered monocyclic heteroaryl are each optionally substituted with one to three R 20 ;

R 20 , for each occurrence, is independently selected from halo, and —N(R 20a ) 2 ; and

R 20a , for each occurrence, is independently selected from H and C 1-3 alkyl, or two R 20a together with the nitrogen atom from which they are attached form a 4- to 7-membered heterocyclyl optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —N(R 25a ) 2 , or —OR 25a ; and

R 25a is H or C 1-6 alkyl.

12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (VIIA-1b), (VIIB-1b), (VIIC-1b) or (VIID-1b):

or a pharmaceutically acceptable salt thereof.

13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

R 30 is halo or C 1-3 alkyl;

R 2 is phenyl, pyridinyl or pyrazinyl, each of which is optionally substituted with —N(R 20a ) 2 ; and

R 20a , for each occurrence, is H or methyl, or two R 20a together with the nitrogen atom from which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with one R 25 ;

R 25 is —N(R 25a ) 2 ; and

R 25a is H or Me.

14 . The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein, for formula (Va), (i) R 4 , R 5 , R 13 , R 14 , R 17 and R 18 are all H, and R 9 is C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and the C 3-6 cycloalkyl are each optionally substituted with one or more substituents independently selected from halo, CN, —OR 9a and C 1-6 alkyl optionally substituted with one or more halo; wherein R 9a is H or C 1-6 alkyl optionally substituted with one or more halo; (ii) R 5 , R 9 , R 13 , R 14 , R 17 and R 18 are all H, and R 4 is C 1-6 alkyl, halo, —CN or —OR 4a , wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ; and R 4a is H or C 1-6 alkyl optionally substituted with one or more halo; or (iii) R 4 , R 5 , R 14 , R 17 and R 18 are all H, and R 13 and R 9 together form a —C 1-3 alkylene optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl; wherein R a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one or more halo.

15 . A compound represented by Formula (IV-1a):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is F, Cl, CN or CH 3 ;

R 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, 2-azaspiro[3.3]heptanyl, 1H-indolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1H-benzo[d]imidazolyl, 1,3,4-thiadiazoly, indolinyl, tetrahydro-2H-pyranyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxetanyl, tetrahydro-2H-pyranyl, 1H-benzo[d]imidazolyl, 1H-indazolyl, isochromanyl, and 1,3-dihydroisobenzofuranyl, each of which is optionally substituted with one or two R 20 ;

R 20a , for each occurrence, is independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl represented by R 20a is optionally substituted with one or more R 25 ;

R 25 , for each occurrence, is independently H, C 1-6 alkyl, halo, —N(R 25a ) 2 , —OR 25a , phenyl optionally substituted with C 1-6 alkyl, halo, —N(R 25a ) 2 or —OR 25a ; and

R 25a is H, C 1-6 alkyl, or C 1-6 alkyl substituted with —OCH 3 ;

R 3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-imidazo[4,5-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, 3H-imidazo[4,5-b]pyridinyl,or 1H-imidazo[4,5-c]pyridinyl, each of which is optionally substituted with one to three R 30 ;

R 30a , for each occurrence, is independently H, C 1-6 alkyl optionally substituted with one to three R 35 or C 3-6 cycloalkyl;

R 35 , for each occurrence, is independently H, halo or —OR 35a ; and

R 35a is H or C 1-3 alkyl;

R 4 is H, halo, —CN, —OR 4a , C 1-6 alkyl, pyridinyl, or pyrazolyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ; wherein the pyridinyl, or pyrazolyl is optionally substituted with —OH, —C 1 -C 6 alkyl or —O—C 1 -C 6 alkyl; and

R 4a is H, C 1-6 alkyl optionally substituted with one or more halo, or C 3 -C 6 cycloalkyl;

R 5 is H or halo, or R 4 and R 5 taken together are ═NOH, or ═NHOCH 3 , or R 4 and R 5 taken together with the carbon to which they are connected form a C 3 -C 6 cycloalkyl, or R 5 and R 13 taken together with their intervening atoms form a cyclopropyl; and;

R 8 , R 13 and R 14 are each H;

R 9 is H, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, or R 9 and R 13 together form a —C 1-3 alkylene- optionally substituted with one or more substituents independently selected from halo, —OR a , —N(R a ) 2 and C 1-6 alkyl; wherein R a , for each occurrence, is independently H or C 1-6 alkyl optionally substituted with one or more halo;

R 17 is H, halo or C 1-6 alkyl; and

R 18 is H, —OH, —O(C 1 -C 6 alkyl) or C 1-6 alkyl, or R 17 and R 18 taken together are ═NOH or ═NHOCH 3 .

16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):

wherein:

R 1 is F, Cl, CN or CH 3 ,

R 20 , for each occurrence, is independently selected from —F, —OH, —Cl, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 N(CH 3 ) 2 , —OCH 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OH, —OCH 2 CH 2 N(CH 3 ) 2 , (4-methoxybenzyl)oxy, oxo, —C(O)CH 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 2 OCH 3 ), —NHCH 2 CH 2 OMe, —NHCH 2 CH 2 N(CH 3 ) 2 , —NHSO 2 CH 3 , —NHSO 2 CH 2 CH 3 , —NHC(O)CH 3 , azetidin-yl, 3-aminoazeitidin-1-yl, piperidin-1-yl, morpholinyl, pyrrolidin-1-yl; and 3-(dimethylamino)azetidin-1-yl or

R 3 is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-imidazo[4,5-b]pyridinyl; 1H-pyrrolo[3,2-b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R 30 ;

R 30 , for each occurrence, is H, F, Cl, Br, CN, —OCH 3 , —O(cyclopropyl), —NH 2 , —NH(CH 3 ) 2 , —CH 3 , —CH 2 CH 3 or —CF 3 ;

R 4 is H, halo, —CN, OR 4a , C 1-6 alkyl, pyridinyl, or pyrazolyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from halo, CN and —OR 4a ; wherein the pyridinyl, or pyrazolyl is optionally substituted with —OH, —CH 3 or —OCH 3 ; and

R 4a is H, —CH 3 , or —CH 2 CH 3 optionally substituted with one or more halo, or cyclopropyl;

R 5 is H or F, or R 4 and R 5 taken together are ═NHOCH 3 , or R 4 and R 5 taken together with the carbon to which they are connected form cyclopropyl, or R 5 and R 13 taken together with their intervening atoms form a cyclopropyl; and

R 8 , R 13 and R 14 are all H;

R 9 is H or —CH 3 , or R 9 and R 13 together form a —C 2 alkylene-;

R 17 is H, F or —CH 3 ; and

R 18 is H, —OH, —OCH 3 or —CH 3 , or R 17 and R 18 taken together are ═NHOCH 3 .

17 . A compound represented by Formula (IV-1a):

or a pharmaceutically acceptable salt thereof wherein:

R 1 is F or Cl;

R 2 is selected from pyridinyl, pyriminidinyl and pyridazinyl, each of which is substituted with R 20 ;

R 20 , for each occurrence, is independently selected from —NH 2 , —NHCH 3 , N(CH 3 ) 2 , and 4- to 7-membered saturated monocyclic heterocyclyl, wherein the 4- to 7-membered saturated monocyclic heterocyclyl represented by R 20 substituted with —N(R 25a ) 2 ;

each R 25a is independently H, C 1-6 alkyl, or C 1-6 alkyl substituted with —OCH 3 ;

R 3 is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl or 3H-imidazo[4,5-b]pyridinyl, each of which is optionally substituted with one to three R 30 ;

R 30 , for each occurrence, is H, halo, C 1 -C 6 alkyl, —N(R 30a ) 2 and —OR 30a ;

R 30a , for each occurrence, is independently H, C 1-6 alkyl or C 3-6 cycloalkyl;

R 4 is H, halo, —OR 4a , C 1-6 alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl, or pyrazolyl is optionally substituted with —OH, —C 1 -C 6 alkyl or —O—(C 1 -C 6 alkyl);

R 4a is H, C 1-6 alkyl or C 3 -C 6 cycloalkyl;

R 5 is H or halo, or R 4 and R 5 taken together are ═NOH or ═NHOCH 3 , or R 4 and R 5 taken together with the carbon to which they are connected form a C 3 -C 6 cycloalkyl, or R 5 and R 13 taken together with their intervening atoms form a cyclopropyl; and;

R 8 , R 13 and R 14 are each H;

R 9 is H or C 1 -C 6 alkyl;

R 17 is H, halo, C 1 -C 6 alkoxy or C 1-6 alkyl;

R 18 is H, or C 1-6 alkyl.

18 . The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula (IV-1a):

wherein:

R 1 is F or Cl;

R 2 is selected from pyridinyl, pyrimidinyl and pyridazinyl, each of which is substituted with R 20 ;

R 20 is —NH 2 , —NHCH 3 , N(CH 3 ) 2 , 3-(dimethylamino)azetidin-1-yl or

R 3 is pyridinyl, 1H-imidazo[4,5-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, 1H-pyrrolo[3,2-b]pyridinyl, or 3H-imidazo[4,5-b]pyridinyl each of which is optionally substituted with one to three R 30 ;

R 30 , for each occurrence, is H, Cl, CH 3 , —OCH 3 , —O(cyclopropyl), —NH 2 , —NHCH 3 or —N(CH 3 ) 2 ;

R 4 is H, F, OH, —OCH 3 , —O-(cyclopropyl), —C 1 -C 3 alkyl, pyridinyl, or pyrazolyl, wherein the pyridinyl or pyrazolyl is optionally substituted with —OH, —CH 3 or —OCH 3 ;

R 8 , R 13 and R 14 are each H;

R 9 is H or —CH 3 ;

R 17 is H, F, —OCH 3 or —CH 3 ; and

R 18 is H or —CH 3 .

19 . A pharmaceutical composition, comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.