# US 10,246,464 B2 · Thienopyrimidine and thienopyridine compounds and methods of use thereof

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- Number: US 10,246,464 B2
- Document ID: US10246464B2
- Status: Granted
- Kind: B2
- Application number: 15/509,989
- Filed: 2015-09-08
- Published: 2017-08-31
- Granted: 2019-04-02
- Earliest claimed: 2014-09-09
- Assignees: The Regents of the University of Michigan; Kura Oncology, Inc.
- Applicants: The Regents of the University of Michigan; Kura Oncology, Inc
- Inventors: Jolanta Grembecka; Tomasz Cierpicki; Dmitry Borkin; Jonathan Pollock; Hongzhi Miao; Duxin Sun; Liansheng Li; Tao Wu; Jun Feng; Pingda Ren; Yi Liu
- Web page: https://patentgrep.com/patent/US10246464B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 35/04: specific for metastasis
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07F 9/5325: {Aromatic phosphine oxides or thioxides (P-C aromatic linkage)}
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present disclosure provides compounds and methods for inhibiting the interaction of menin with its upstream or downstream signaling molecules including but not limited to MLL1, MLL2 and MLL-fusion oncoproteins. Compounds of the disclosure may be used in methods for the treatment of a wide variety of cancers and other diseases associated with one or more of MLL1, MLL2, MLL fusion proteins, and menin.

## Claims

### Claim 1

A compound represented by the structure of Formula (4):
or a salt thereof, wherein:
R1, R2, R4, R5, R8, and Ra are independently selected from hydrogen, halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R1, R2, R4, R5, R8, and Ra is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R3 is selected from selected from hydrogen, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —S(O)2R20, —S(O)2N(R20)2, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle; and C3-10 carbocycle and 3- to 10-membered heterocycle; wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R3 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R6 is independently selected at each occurrence from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle, or two substituents on the same carbon atom of an C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle; and C3-10o carbocycle and 3- to 10-membered heterocycle; wherein any C3-10 carbocycle and 3- to 10-membered heterocycle of R6 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)22, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R20 at each occurrence is independently selected from hydrogen; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR30, —SR30, —N(R30)2, —N(R30)C(O)R30, —C(O)R30, —C(O)OR30, —C(O)N(R30)2, —OC(O)R30, —S(O)2R30, —S(O)2N(R30)2, —N(R30)S(O)2R30, —NO2, —P(O)(OR30)2, —P(O)(R30)2, —OP(O)(OR30)2, and —CN; and 3- to 10-membered heterocycle and C3-10 carbocycle;
R30 at each occurrence is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Y is N or C(Ra);
L is absent or selected from alkylene and heteroalkylene;
s is selected from 0, 1, 2, 3, and 4;
R7a is -G-V-R9a:
G is selected from alkylene, heteroalkylene, C3-12 carbocycle, 3- to 12-membered heterocycle, and combinations thereof, wherein G is optionally substituted with one or more R32 groups;
V is selected from a C3-12 carbocycle, and 3- to 12-membered heterocycle;
wherein V is optionally substituted with one or more R32 groups;
R9a is selected from halogen, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)OR20, —OC(O)R20, —N(R20)S(O)2R20, —NO2, =S, =N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; C3-10 carbocycle and 3- to 10-membered heterocycle; or two R32 on the same carbon atom can come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl; and
R32 at each occurrence is selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is independently optionally substituted at each occurrence with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C3-10 carbocycle, and 3- to 10-membered heterocycle; C3-10 carbocycle and 3- to 10-membered heterocycle; or two R32 on the same carbon atom can come together to form a C3-10 carbocycle or 3- to 10-membered heterocycle, wherein each C3-10 carbocycle and 3- to 10-membered heterocycle of R32 is independently optionally substituted with one or more substituents selected from halogen, —OR20, —SR20, —N(R20)2, —N(R20)C(O)R20, —C(O)R20, —C(O)OR20, —C(O)N(R20)2, —OC(O)R20, —S(O)2R20, —S(O)2N(R20)2, —N(R20)S(O)2R20, —NO2, ═O, ═S, ═N(R20), —P(O)(OR20)2, —P(O)(R20)2, —OP(O)(OR20)2, —CN, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

### Claim 2 (depends on 1)

The compound or salt of claim 1, wherein R1 and R2 are independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, and C2-6 haloalkynyl.

### Claim 3 (depends on 2)

The compound or salt of claim 2, wherein R1 is selected from halogen, C1-6 haloalkyl, C2-6 haloalkenyl, and C2-6 haloalkynyl.

### Claim 4 (depends on 3)

The compound or salt of claim 3, wherein R1 is selected from —CH2CF3 and —CH2CHF2.

### Claim 5 (depends on 2)

The compound or salt of claim 2, wherein R2 is selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-6 alkyl, and C1-6 alkoxy.

### Claim 6 (depends on 5)

The compound or salt of claim 5, wherein R2 is hydrogen.

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein R3, R4, and R5 are each hydrogen.

### Claim 8 (depends on 1)

The compound or salt of claim 1, wherein R6, at each occurrence, is independently selected from halogen, —OH, C1-6 alkyl, and C1-6 alkoxy.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein R8 is selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, and C2-6 haloalkynyl.

### Claim 10 (depends on 9)

The compound or salt of claim 9, wherein R8 is —CN.

### Claim 11 (depends on 1)

The compound or salt of claim 1, wherein Y is N.

### Claim 12 (depends on 1)

The compound or salt of claim 1, wherein L is absent.

### Claim 13 (depends on 1)

The compound or salt of claim 1, wherein G is alkylene optionally substituted with one or more R32 groups.

### Claim 14 (depends on 13)

The compound or salt of claim 13, wherein G is selected from:

### Claim 15 (depends on 1)

The compound or salt of claim 1, wherein V is selected from azetidine, oxetane, piperidine, oxane, piperazine, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, morpholine, thiomorpholine, azepane, and homopiperazine, any one of which is optionally substituted with one or more R32 groups.

### Claim 16 (depends on 1)

The compound or salt of claim 1, wherein V is selected from phenyl, pyridine, pyrazine, pyrimidine, pyridazine, naphthalene, anthracene, quinoline, isoquinoline, quinoxaline, acridine, quinazoline, cinnoline, phthalazine, furan, dihydrofuran, thiophene, dihydrothiophene, imidazole, imidazoline, oxazole, oxazoline, pyrrole, dihydropyrrole, thiazole, dihydrothiazole, pyrazole, dihydropyrazole, isoxazole, dihydroisoxazole, isothiazole, dihydroisothiazole, benzofuran, isobenzofuran, indole, isoindole, benzothiophene, benzimidazole, purine, indazole, benzoxazole, benzisoxazole, and benzothiazole, any one of which is optionally substituted with one or more R32 groups.

### Claim 17 (depends on 1)

The compound or salt of claim 1, wherein R9a is

### Claim 18

A compound selected from:
or a salt thereof.

### Claim 19 (depends on 1)

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

### Claim 20 (depends on 1)

A method for the treatment of a disease, comprising administering a compound of claim 1, or a salt thereof, to a subject suffering from said disease, wherein said disease is leukemia, hematologic malignancies, solid tumor cancer, glioma, or diabetes.