# US 2023/0054084 A1 · Compounds and methods of use

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- Number: US 2023/0054084 A1
- Document ID: US20230054084A1
- Status: Published application
- Kind: A1
- Application number: 17/772,465
- Filed: 2020-10-28
- Published: 2023-02-23
- Earliest claimed: 2019-10-28
- Assignees: Tango Therapeutics, Inc.
- Applicants: Tango Therapeutics, Inc.
- Inventors: Kevin M. Cottrell; John P. Maxwell; Douglas A. Whittington
- Web page: https://patentgrep.com/patent/US20230054084A1

## CPC

- A61K 31/4725: containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5386: spiro-condensed or forming part of bridged ring systems
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 471/08: Bridged systems
- C07D 498/08: Bridged systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof: wherein X1, X2, X3, X4, X5, A, L, R1, R2, R5, m and n are as defined herein. Compounds of the present invention are contemplated useful for the prevention and treatment of a variety of conditions.

## Claims

### Claim 1

A compound of Formula (I)
or a pharmaceutically acceptable salt thereof;
wherein:
X1, X2, X3, X4 and X5 are each independently N or CRx;
L is a bond, —C(═O)—, —NH— or —O—;
Ring A is a carbocycle, heterocycle or a 5-6 membered monocyclic heteroaryl;
R1 is a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, —C1-C6 heteroalkyl, C3-C9 carbocyclyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each Rx is independently selected from hydrogen, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2 wherein each alkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl is optionally substituted;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

### Claim 2 (depends on 1)

The compound of claim 1 wherein the compound is of Formula (Ia):

### Claim 3 (depends on 1)

The compound of claim 1 wherein the compound is of Formula (II):

### Claim 4 (depends on 1, 2, 3)

The compound of any one of claims 1-3 wherein the compound is of Formula (IIa):

### Claim 5

A compound of Formula (VI)
or a pharmaceutically acceptable salt thereof,
wherein:
X1, X2, X3, X4 and X5 are each independently N or CRx;
L is a bond, —C(═O)—, —NH— or —O—;
Ring A is a carbocycle, heterocycle or a 5-6 membered monocyclic heteroaryl;
R1 is a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, —C1-C6 heteroalkyl, C3-C9 carbocyclyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each Rx is independently selected from hydrogen, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2 wherein each alkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl is optionally substituted;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
m is 0, 1, 2 or 3; and
n is 0, 1, 2 or 3.

### Claim 6 (depends on 5)

The compound of claim 5 wherein the compound is of Formula (VIa):

### Claim 7 (depends on 5)

The compound of claim 5 wherein the compound is of Formula (VIb):

### Claim 8 (depends on 5)

The compound of claim 5 wherein the compound is of Formula (VII):

### Claim 9 (depends on 5, 6, 7, 8)

The compound of any one of claims 5-8 wherein the compound is of Formula (VIIa):

### Claim 10 (depends on 5, 6, 7, 8)

The compound of any one of claims 5-8 wherein the compound is of Formula (VIIb):

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10 wherein X1 is N and X2, X3 and X4 are CRx.

### Claim 12 (depends on 11)

The compound of claim 11 wherein the compound is of Formula (IIa1):

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10 wherein X1 and X3 are N and X2 and X4 are CRx.

### Claim 14 (depends on 13)

The compound of claim 13 wherein the compound is of Formula (IIa2):

### Claim 15 (depends on 13)

The compound of claim 13 wherein the compound is of Formula (VIIa1):

### Claim 16 (depends on 13)

The compound of claim 13 wherein the compound is of Formula (VIIb1):

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10 wherein X1, X2, X3 and X4 are CRx.

### Claim 18 (depends on 17)

The compound of claim 17 wherein the compound is of Formula (IIa3)

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The compound of any one of claims 1-10 wherein X3 is N and X1, X2 and X4 are CRx.

### Claim 20 (depends on 19)

The compound of claim 19 wherein the compound is of Formula (IIa4)

### Claim 21 (depends on 1)

The compound of claim 1 wherein the compound is of Formula (III)

### Claim 22 (depends on 21)

The compound of claim 21 wherein the compound is of Formula (IIIa)

### Claim 23 (depends on 21, 22)

The compound of claim 21 or 22 wherein X2 is N, and X3, X4, and X5 are CRx.

### Claim 24 (depends on 23)

The compound of claim 23, wherein the compound is of Formula (IIIa1):

### Claim 25 (depends on 21, 22)

The compound of claim 21 or 22 wherein X2, X3, X4 and X5 are CRx.

### Claim 26 (depends on 25)

The compound of claim 25, wherein the compound is of Formula (IIIa2):

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1 to 26 wherein L is —NH—.

### Claim 28 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (IIa1i):

### Claim 29 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (IIa2i):

### Claim 30 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (IIa3i)

### Claim 31 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (IIa4i)

### Claim 32 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (VIIa1i):

### Claim 33 (depends on 27)

The compound of claim 27 wherein the compound is of Formula (VIIb1i):

### Claim 34 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1 to 26 wherein L is a bond.

### Claim 35 (depends on 34)

The compound of claim 34 wherein the compound is of Formula (IIa3ii)

### Claim 36 (depends on 34)

The compound of claim 34, wherein the compound is of Formula (IIIa1i):

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1 to 26, wherein L is —O—.

### Claim 38 (depends on 37)

The compound of claim 37, wherein the compound is of Formula (IIIa2i):

### Claim 39 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26)

The compound of any one of claims 1 to 26 wherein L is —C(═O)—.

### Claim 40 (depends on 39)

The compound of claim 39, wherein the compound is of Formula (IIIa2ii):

### Claim 41 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)

The compound of any one of claims 1 to 40, wherein Rx is H, N(R3)2, NHR3, N(CH3)R3, OR3, C1-C6 alkyl, optionally substituted —C3-C9 carbocyclyl or optionally substituted-3-10-membered heterocyclyl.

### Claim 42 (depends on 41)

The compound of claim 41, wherein Rx is —C3-C9 carbocyclyl or 3-10 membered heterocyclyl substituted with 0-1 instances of R7, wherein R7 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 or —S(═O)2N(R3)2.

### Claim 43 (depends on 42)

The compound of claim 42, wherein R7 is —C1-C6 alkyl or —C(═O)R3.

### Claim 44 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)

The compound of any one of claims 1 to 43, wherein Rx is a 4-7 membered monocyclic heterocyclyl or 7-10 membered bridged bicyclic heterocyclyl.

### Claim 45 (depends on 44)

The compound of claim 44, wherein Rx is a 7-8 membered bridged bicyclic heterocyclyl or 6 membered monocyclic heterocyclyl; wherein the 7-8 membered bridged bicyclic heterocyclyl or 6 membered monocyclic heterocyclyl contains 1 or 2 heteroatoms independently selected from O and N.

### Claim 46 (depends on 45)

The compound of claim 45, wherein Rx is selected from piperidinyl, piperazinyl, morpholinyl, 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, and 3-azabicyclo[3.2.1]octanyl.

### Claim 47 (depends on 41)

The compound of claim 41 wherein Rx is H.

### Claim 48 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The compound of any one of claims 1 to 47, wherein ring A is a 4-6 membered monocyclic heterocyclyl, containing 1 or 2 heteroatoms independently selected from O and N.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)

The compound of any one of claims 1 to 48, wherein ring A is piperidinyl, piperazinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, azetidinyl, tetrahydropyranyl, 1,4-dioxan-2-yl or morpholinyl.

### Claim 50 (depends on 49)

The compound of claim 49 wherein ring A is piperidinyl.

### Claim 51 (depends on 49)

The compound of claim 49 wherein ring A is oxetanyl.

### Claim 52 (depends on 49)

The compound of claim 49 wherein ring A is tetrahydropyranyl.

### Claim 53 (depends on 49)

The compound of claim 49 wherein ring A is morpholinyl.

### Claim 54 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The compound of any one of claims 1 to 47 wherein ring A is a 7-12 membered bicyclic heterocyclyl.

### Claim 55 (depends on 54)

The compound of claim 54, wherein A is a 7-9 membered bridged bicyclic or spirocyclic heterocyclyl containing one or two heteroatoms independently selected from O and N.

### Claim 56 (depends on 55)

The compound of claim 55 wherein ring A is selected from:

### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The compound of any one of claims 1 to 47 wherein ring A is a 5-6 membered monocyclic heteroaryl.

### Claim 58 (depends on 57)

The compound of claim 57 wherein ring A is pyridinyl (e.g., 3-pyridinyl).

### Claim 59 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47)

The compound of any one of claims 1 to 47 wherein ring A is a 3-8 membered carbocycle.

### Claim 60 (depends on 59)

The compound of claim 59, wherein ring A is a 6-8 membered spirocarbocycle.

### Claim 61 (depends on 59)

The compound of claim 59 wherein ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2.3]hexyl or spiro[3.3]heptyl.

### Claim 62 (depends on 59)

The compound of claim 59 wherein ring A is cyclobutyl.

### Claim 63

A compound of Formula (IV) or a pharmaceutically acceptable salt thereof, wherein:
R1 is a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, C3-C9 carbocyclyl, 3-10 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
each R8 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R8 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
m is 0, 1, 2 or 3; and
p is 0, 1, 2 or 3.

### Claim 64 (depends on 63)

The compound of claim 63, wherein the compound is of Formula (IVa)

### Claim 65

A compound of Formula (V) or a pharmaceutically acceptable salt thereof, wherein
X6 is N, NH, CHRx or CRx;
R1 is a 5-6 membered heteroaryl substituted with 0-3 instances of R4;
each R2 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroaryl alkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each R3 is independently selected from H, C1-C6 alkyl, —C1-C6 heteroalkyl, C3-C9 carbocyclyl, 3-10 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted;
each R4 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2;
each Rx is independently selected from hydrogen, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, cycloalkylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 and —S(═O)2N(R3)2 wherein each alkyl, carbocyclyl, heterocyclyl, heterocyclylalkyl, cycloalkylalkyl is optionally substituted;
each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R5 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
each R8 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3, —S(═O)2N(R3)2, or two R8 can be taken together with the atoms to which they are attached to form a —C3-C9 carbocyclyl or a 3-10 membered heterocyclyl;
m is 0, 1, 2 or 3; and
p is 0, 1, 2 or 3.

### Claim 66 (depends on 65)

A compound of claim 65 wherein the compound is of Formula (Va)

### Claim 67 (depends on 66)

A compound of claim 66 wherein the compound is of Formula (Va1)

### Claim 68 (depends on 66)

A compound of claim 66 wherein the compound is of Formula (Va2)

### Claim 69 (depends on 66)

A compound of claim 66 wherein the compound is of Formula (Va3)

### Claim 70 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69)

The compound of any one of claims 1 to 69, wherein R1 is a 5-membered heteroaryl substituted with 0-3 instances of R4.

### Claim 71 (depends on 70)

The compound of claim 70, wherein R1 is selected from:

### Claim 72 (depends on 71)

The compound of claim 71, wherein R1 is:

### Claim 73 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69)

The compound of any one of claims 1 to 69, wherein R1 is a 6-membered heteroaryl (e.g., pyridyl) substituted with 0-3 instances of R4.

### Claim 74 (depends on 73)

The compound of claim 73, wherein R1 is:

### Claim 75 (depends on 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 73)

The compound of any one of claims 11 to 70 and 73, wherein R4 is C1-C6 alkyl.

### Claim 76 (depends on 75)

The compound of claim 75, wherein R4 is methyl.

### Claim 77 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)

The compound of any one of claims 1 to 76 wherein n is 0.

### Claim 78 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76)

The compound of any one of claims 1 to 76 wherein n is 1.

### Claim 79 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)

The compound of any one of claims 1 to 78 wherein R2 is arylalkyl or heteroarylalkyl.

### Claim 80 (depends on 79)

The compound of claim 79, wherein R2 is benzyl or pyridinylmethyl (e.g., pyridin-4-ylmethyl).

### Claim 81 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)

The compound of any one of claims 1 to 78, wherein R2 is —C(═O)OR3, or —C(O)R3.

### Claim 82 (depends on 81)

The compound of claim 81, wherein R2 is —C(═O)CH3, —C(O)cyclopropyl, —C(O)cyclobutyl, —C(O)tBu, —C(O)iPr, —C(O)Pr, —C(O)tBu, or —C(═O)OMe.

### Claim 83 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The compound of any one of claims 1 to 81, wherein R3 is C3-C7 carbocyclyl, C1-C6 alkyl or C1-C6 heteroalkyl.

### Claim 84 (depends on 83)

The compound of claim 83, wherein R3 is C1-C3 alkyl, C1-C6 heteroalkyl (e.g., —(CH2)2OCH3) or C3-C7 cycloalkyl.

### Claim 85 (depends on 81)

The compound of claim 81, wherein R2 is —C(═O)R3.

### Claim 86 (depends on 85)

The compound of claim 85 wherein R3 is optionally substituted aryl.

### Claim 87 (depends on 86)

The compound of claim 86, wherein R3 is phenyl substituted with 0-2 instances of —OMe or halo.

### Claim 88 (depends on 85)

The compound of claim 85 wherein R3 is C3-C9 carbocyclyl or 3-10 membered heterocyclyl wherein each carbocyclyl and heterocyclyl is optionally substituted;

### Claim 89 (depends on 88)

The compound of claim 88 wherein R3 is C3-C9 carbocyclyl or 3-10 membered heterocyclyl wherein each carbocyclyl and heterocyclyl is optionally substituted with 0-2 instances of R7, wherein each R7 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, —OR3, —N(R3)2, —C(═O)R3, —C(═O)OR3, —NR3C(═O)R3, —NR3C(═O)OR3, —C(═O)N(R3)2, —OC(═O)N(R3)2, —S(═O)R3, —S(═O)2R3, —SR3, —S(═O)(═NR3)R3, —NR3S(═O)2R3 or —S(═O)2N(R3)2.

### Claim 90 (depends on 89)

The compound of claim 89 wherein R3 is a monocyclic or bicyclic 3-10 membered heterocyclyl (e.g., morpholine, piperidine, piperazine, azepane, 8-azabicyclo[3.2.1]octane, 3-oxa-8-azabicyclo[3.2.1]octane) substituted with one instance of methyl, ethyl, hydroxy or methoxy.

### Claim 91 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90)

The compound of any one of claims 1 to 90 wherein m is 0.

### Claim 92 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90)

The compound of any one of claims 1 to 90 wherein m is 1 and each R5 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, —OR3, —N(R3)2, —CO(R3), —NR3(CO)R3, —(CO)N(R3)2.

### Claim 93 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)

The compound of any one of claims 63 to 92 wherein p is 0.

### Claim 94 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)

The compound of any one of claims 63 to 92 wherein p is 1 and each R8 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, —OR3, —N(R3)2, —CO(R3), —NR3(CO)R3, —(CO)N(R3)2.

### Claim 95 (depends on 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92)

The compound of any one of claims 63 to 92 wherein p is 2 and each R8 is independently selected from ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 carbocyclyl, 3-10 membered heterocyclyl, —OR3, —N(R3)2, —CO(R3), —NR3(CO)R3, —(CO)N(R3)2.

### Claim 96 (depends on 94, 95)

The compound of claim 94 or 95 wherein R8 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl).

### Claim 97 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96)

The compound of any one of claims 1 to 96 wherein the compound is selected from Table 1.

### Claim 98 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97)

A pharmaceutical composition comprising a compound of any one of claims 1 to 97 and a pharmaceutically acceptable carrier.

### Claim 99 (depends on 98)

The pharmaceutical composition of claim 98, further comprising a second therapeutic agent.

### Claim 100 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97)

A method of treating an MTAP-deficient and/or an MTA-accumulating disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 97 or a pharmaceutically acceptable composition of claim 95.

### Claim 101 (depends on 100)

The method of claim 100 wherein the compound or composition is administered in combination with a second therapeutic agent.

### Claim 102 (depends on 99)

A method of treating an MTAP-deficient and/or an MTA-accumulating disease in a subject in need thereof by administering to the subject a therapeutically effective amount of a pharmaceutically acceptable composition of claim 99.

### Claim 103 (depends on 100, 101, 102)

The method of any one of claims 100 to 102 wherein the disease is a proliferating disease.

### Claim 104 (depends on 103)

The method of claim 103 wherein the disease is an MTAP-deficient and/or MTA-accumulating cancer.

### Claim 105 (depends on 104)

The method of claim 104 wherein the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary tract, liver, soft tissue, pleura and large intestine or sarcoma.

### Claim 106 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)

A method of treating a cancer in a subject in need thereof comprising the steps of:
a) assessing the level of MTAP and/or MTA in a test sample obtained from said subject, wherein the MTA level can be assessed directly (e.g., by ELISA or LC-MS/MS) or indirectly (e.g., by SDMA-modified protein ELISA or IHC, or by RNA splicing);
b) comparing the test sample with a reference, wherein MTAP deficiency and/or MTA accumulation in said test sample compared to the reference indicates the cancer in said subject will respond to therapeutic treatment with a PRMT5 inhibitor; and
c) administering a therapeutically effective amount of a compound of any one of claims 1 to 97 or composition of claim 98 or 99 to the subject identified in step b).