# US 11,999,727 B2 · Compounds and methods of use

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- Number: US 11,999,727 B2
- Document ID: US11999727B2
- Status: Granted
- Kind: B2
- Application number: 17/732,846
- Filed: 2022-04-29
- Published: 2023-04-13
- Granted: 2024-06-04
- Earliest claimed: 2020-07-31
- Assignees: Tango Therapeutics, Inc.
- Applicants: Tango Therapeutics, Inc.
- Inventors: Kevin M. Cottrell; John P. Maxwell
- Web page: https://patentgrep.com/patent/US11999727B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- 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 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 493/10: Spiro-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 498/10: Spiro-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds are provided according to Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof; wherein R1, R2, R3, R4, R6, R7, R8 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:
each R1 is independently selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —N(Ra1)2, —C(═O)Ra1, —C(═O)ORa1, —NRa1C(═O)Ra1, —NRa1C(═O)ORa1, —C(═O)N(Ra1)2, —OC(═O)N(Ra1)2, —S(═O)Ra1, —S(═O)2Ra1, —SRa1, —S(═O)(═NRa1)Ra1, —NRa1S(═O)2Ra1 and —S(═O)2N(Ra1)2;
each R2 is independently selected from halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C1-C6 haloalkoxy, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa2, —N(Ra2)2, —C(═O)Ra2, —C(═O)ORa2, —NRa2C(═O)Ra2, —NRa2C(═O)ORa2, —C(═O)N(Ra2)2, —C(═O)N(ORa2)(Ra2), —OC(═O)N(Ra2)2, —S(═O)Ra2, —S (═O)2Ra2, —SRa2, —S(═O)(═NRa2)Ra2, NRa2S(═O)2Ra2, —S(═O)2N(Ra2)2;
each R3 is independently selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa3, —N(Ra3)2, —C(═O)Ra3, —C(═O)ORa3, —NRa3C(═O)Ra3, —NRa3C(═O)ORa3, —C(═O)N(Ra3)2, —OC(═O)N(Ra3)2, —S(═O)Ra3, —S(═O)2Ra3, —SRa3, —S(═O)(═NRa3)Ra3, —NRa3S(═O)2Ra3 and —S(═O)2N(Ra3)2;
each R4 is independently selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa4, —N(Ra4)2, —C(═O)Ra4, —C(═O)ORa4, —NRa4C(═O)Ra4, —NRa4C(═O)ORa4, —C(═O)N(Ra4)2, —OC(═O)N(Ra4)2, —S(═O)Ra4, —S(═O)2Ra4, —SRa4, —S(═O)(═NRa4)Ra4, —NRa4 and —S(═O)2N(Ra4)2;
each R6 is independently absent or selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C10 carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C6-C10 aryl, 5-10 member heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa6, —N(Ra6)2, —C(═O)Ra6, —C(═O)ORa6, —NRa6C(═O)Ra6, NRa6C(═O)ORa6, —C(═O)N(Ra6)2, —OC(═O)N(Ra6)2, —S(═O)Ra6, —S(═O)2Ra6, —SRa6, —S(═O)(═NRa6)Ra6, NRa6S(═O)2Ra6 and —S(═O)2N(Ra6)2, wherein each alkyl, carbocyclyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted at any available position;
each R7 is independently absent or selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 hydroxyalkyl, haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, 5-6-membered monocyclic heteroaryl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa7, —N(Ra7)2, —C(═O)Ra7, —C(═O)ORa7, —NRa7C(═O)Ra7, —NRa7C(═O)ORa7, —C(═O)N(Ra7)2, —OC(═O)N(Ra7)2, —S(═O)Ra7, —S(═O)2Ra7, —SRa7, —S(═O)(═NRa7)Ra7, —NRa7S(═O)2Ra7 and —S(═O)2N(Ra7)2;
each R8 is independently selected from H, -D, ═O, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, heterocyclylalkyl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa8, —N(Ra8)2, —C(═O)Ra8, C(═O)ORa8, —NRa8C(═O)Ra8, —ORa8, —CH2C(═O)N(Ra8)2, —C(═O)N(Ra8)2, —OC(═O)N(Ra8)2, —CH2C(═O)N(Ra8)2, —S(═O)Ra8, —S(═O)2Ra8, —SRa8, —S(═O)(═NRa8)Ra8, —NRa8S(═O)2Ra and —S(═O)2N(Ra8)2;
each Ra1, Ra2, Ra3, Ra4, Ra6, Ra7 and Ra8 is independently selected from H, C1-C6 alkyl, —C1-C6 heteroalkyl, C3-C9 cycloalkyl, 3-7 membered heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, 5-6 membered heteroaryl, arylalkyl and heteroarylalkyl wherein each alkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl is optionally substituted at any available position; and
n is 0, 1, 2 or 3 provided that:
(i) when R1 is H, R2 is not halo, —OPr, —N(CH3)2 or —CF3;
(ii) when R1 is ORa1, R2 is not —ORa2;
(iii) when R1 is H and R2 is —CH3, R8 groups cannot be taken together to form a ring and R6 is not absent or H, and is not thiazolyl, furanyl or pyrrolyl;
(iv) when R2 is Me, R1 is not piperidine
(v) the compound is not:
A. 5-(2-(5-methyl-2-(p-tolyl)piperidin-1-yl)-2-oxoacetamido)nicotinamide or any of its enantiomers or diastereomers;
B. 2-(2-(4-(2H-tetrazol-5-yl)phenyl)-5-methylpiperidin-1-yl)-N-(5,6-dimethylpyridin-3-yl)-2-oxoacetamide or any of its enantiomers or diastereomers;
C. 2-cyano-5-(2-(5-methyl-2-phenylpiperidin-1-yl)-2-oxoacetamido)nicotinamide or any of its enantiomers or diastereomers.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Ia)

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, —ORa1, —N(Ra1)2, —C(═O)Ra1, —C(═O)ORa1, —NRa1C(═O)Ra1, —NRa1, —C(═O)N(Ra1)2 and —OC(═O)N(Ra1)2, wherein each Ra1 is independently selected from H, —C1-C6 alkyl and —C1-C6 haloalkyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, —C1-C6 alkyl, —C1-C6 haloalkyl, —OH, —O—(C1-C6 alkyl), —O—(C1-C6 haloalkyl), —NH2, —NH—(C1-C6 alkyl) and —N—(C1-C6 alkyl)2.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, -Me, -Et, —CHF2, —OMe, —OEt, —OCHF2, —OCF3, —OH and —NH2.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, haloalkyl, haloalkoxy, —C3-C9 cycloalkyl, 3-6 membered heterocyclyl, —ORa2, N(Ra2)2, —C(═O)Ra2, —C(═O)ORa2, —NRa2C(═O)Ra2, —NRa2C═O)ORa2, —C(═O)N(Ra2)2, —OC(═O)N(Ra2)2, wherein each Ra2 is independently selected from H and —C1-C6 alkyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from halo, —C1-C6 alkyl, —C1-C6 haloalkyl, haloalkoxy, —C3-C9 cycloalkyl, 3-6 membered heterocyclyl, haloalkoxy, —OMe, —C(═O)H, —C(═O)NHOH, and —C(═O)NH2.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from —Cl, -Me, -Et, -iPr, —CF3, —CHF2, —OCHF2, —OCF3, cyclopropyl, oxetan-3-yl, tetrahydrofuran-3-yl, —OMe, —C(═O)H, —C(═O)NHOH, and —C(═O)NH2.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, —OMe, —OEt, —OCF3, —OCHF2, —CHF2, -Me, -Et, —OH and —NH2 and R2 is selected from —Cl, -Me, -Et, -iPr, —CF3, —CHF2, —OCHF2, —OCF3, cyclopropyl, —C(═O)NH2, and —C(═O)H, provided that when R2 is -Me, R1 is NH2.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from H, —CHF2, -Me and —NH2 and R2is selected from —Cl, -Me, -Et, —CF3, —CHF2, —OCHF2 and cyclopropyl, provided that when R2 is -Me, le is NH2.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, —ORa3, —N(Ra3)2, —C(═O)Ra3, —C(═O)ORa3, —NRa3C(═O)Ra3, —NRa3C(═O)ORa3, —C(═O)N(Ra3)2 and —OC(═O)N(R3)2, wherein Ra1 is selected from H and C1-C6 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H, -Me and —NH2.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from H, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, —C1-C6 haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, —ORa4, —N(Ra4)2, —C(═O)Ra4, —C(═O)ORa4, —NRa4C(═O)R44, —NRa4C(═O)ORa4, —C(═O)N(Ra4)2 and —OC(═O)N(Ra4)2, wherein each Ra4 is independently selected from H and —C1-C6 alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is H.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently selected from H, D, halo, —CN, —C1-C6 alkyl, —C1-C6 heteroalkyl, haloalkyl, carbocyclyl, 3-10 membered heterocyclyl, heterocyclylalkyl, C6-C10 aryl, 5-10 member heteroaryl, heteroarylalkyl, arylalkyl, cycloalkylalkyl, —ORa6, —N(Ra6), —C(═O)Ra6, —C(═O)ORa6, —NRa6C(═O)R6, —NRa6C(═O)ORa6, C(═O)N(Ra6)2, —OC(═O)N(Ra6)2, —S(═O)Ra6, —S(═O)2Ra6, —SRa6, S(═O)(═NRa6)Ra6, —NRa6S(═O)2Ra6 and —S(═O)2N(Ra)2, wherein each alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl is substituted at any available position with 0, 1, 2 or 3 instances of R10, wherein:
each R10 is independently selected from -D, ═O, —CN, halo, —C1-C6 alkyl, —C1-C6 heteroalkyl, haloalkyl, —C3-C9 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 5-10 membered heteroaryl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkoxy, —ORb10, —N(Rb10)2, C(═O)Rb10, —C(═O)OR10, —NRb10C(═O)R10, —NRb10C(═O)ORb10, —C(═O)N(Rb10)2, OC(═O)Rb10, —OC(═O)N(Rb10)2, —S(═O)2Rb10, —S(═O)2Rb10, —SRb10, —S(═O)(═NRb10)Rb10, —NRb10S(═O)2Rb10, and —S(═O)2N(Rb10)2, wherein each alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclylalkyl, heterocyclylalkoxy, arylalkyl and heteroarylalkyl of R10 is optionally substituted at any available position; and wherein:
each Rb10 is independently H; —C1-C6 alkyl; —C1-C6 haloalkyl; heteroalkyl substituted with 0 or 1 instance of ═O; C3-C9 cycloalkyl; or 3-10 member heterocyclyl substituted with 0 or 1 instances of ═O, -Me or a combination thereof;
each Ra6 is independently selected from H and —C1-C6 alkyl.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R6 is independently selected from —C1-C6 alkyl, —C3-C10 monocyclic or bicyclic carbocyclyl, 3-10 membered mono or bicyclic heterocyclyl, C6-C10 mono or bicyclic aryl, 5-6 member monocyclic heteroaryl, 8-10 member bicyclic heteroaryl wherein each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2 or 3 instances of R10.

### Claim 17 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and pyrimidin-5-yl substituted with one instance of R10.

### Claim 18 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R6 is selected from 1H-indazol-5-yl, 2H-indazol-5-yl, benzo[d]isothiazol-5-yl, benzo[d]thiazol-5-yl, benzo[b]thiophen-5-yl, benzo[d]oxazol-4-yl, benzo[d]oxazol-5-yl, quinoline-7-yl, 1H-thieno[2,3-c]pyrazol-5-yl, imidazo[1,2-a]pyridin-7-yl, and imidazo[1,5-a]pyridin-6-yl substituted with 0, 1, 2 or 3 instances of R10.

### Claim 19 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R10 is -D, —Cl, —F, -Me, —CH2—OH,

### Claim 20 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from H, halo, —CN, —C1-C6 alkyl, 5-membered heteroaryl, haloalkyl, hydroxyalkyl, —C3-C9 cycloalkyl, —ORa7, —N(Ra7)2 and —C(═O)N(Ra7)2, wherein each Ra7 is independently selected from H and —C1-C6 alkyl.

### Claim 21 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from H and methyl.

### Claim 22 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from H, -D, halo, —CN, —C1-C6 alkyl, —C1-C6 haloalkoxy, arylalkyl, —C(═O)Ra8, —N(Ra8)2, —NRa8C(═O)Ra8, —CH2C(═O)N(Ra8)2 and —ORa8, wherein each Ra8 is independently selected from H, —CF3 and —C1-C6 alkyl.

### Claim 23 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from H, -D, —F, -Me, -Et and —CN.

### Claim 24 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

### Claim 25 (depends on 1)

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

### Claim 26 (depends on 1)

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 claim 1.

### Claim 27 (depends on 26)

The method of claim 26, wherein the compound or composition is administered in combination with a second therapeutic agent.

### Claim 28 (depends on 26)

The method of claim 26, wherein the disease is an MTAP-deficient and/or MTA-accumulating cancer.

### Claim 29 (depends on 28)

The method of claim 28, wherein the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer, bladder cancer, pancreatic cancer, mesothelioma, melanoma, non-small cell lung cancer, 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 30 (depends on 1)

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 or indirectly;
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 claim 1 to the subject identified in step b).