# US 10,308,660 B2 · Compounds and compositions for inhibiting the activity of SHP2

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- Number: US 10,308,660 B2
- Document ID: US10308660B2
- Status: Granted
- Kind: B2
- Application number: 15/736,989
- Filed: 2016-06-15
- Published: 2018-09-06
- Granted: 2019-06-04
- Earliest claimed: 2015-06-19
- Assignees: Novartis AG
- Applicants: Zhuoliang Chen; Jorge Garcia Fortanet; Matthew J. LaMarche; Martin Sendzik; Victoriano Tamez, Jr.; Bing Yu
- Inventors: Zhuoliang Chen; Jorge Garcia Fortanet; Matthew J. LaMarche; Martin Sendzik; Victoriano Tamez, Jr.; Bing Yu
- Web page: https://patentgrep.com/patent/US10308660B2

## CPC

- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- A61P 35/00: Antineoplastic agents
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds of formula I: in which X1, X2, X3, Y1, Y2, Y3, R1, R2, R3a, R4a, R4b, R5a, R5b, R6a and R6b are defined in the Summary of the Invention; capable of inhibiting the activity of SHP2. The invention further provides a process for the preparation of compounds of the invention, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the management of diseases or disorders associated with the aberrant activity of SHP2.

## Claims

### Claim 1

A compound of formula I:
in which:
X1 is selected from N and CH;
X2 is CR3b;
X3 is selected from S and a bond;
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy and hydroxy;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6-10aryl and C6-10aryl-C0-1alkoxy;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkyl, —NH(C3-5cycloalkyl), C1-3alkoxy and hydroxy;
R1 is selected from hydrogen, halo, halo-substituted-C1-2alkyl, halo-substituted-C1-2alkoxy, C1-2alkyl-hydroxy and cyano; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from 1,3-dioxole, phenyl, pyridine, cyclopentene, dihydrofuran, dihydropyrane; wherein said 1,3-dioxole, phenyl, pyridine, cyclopentene, 2,3-dihydrofuran, 2,3-dihydropyrrole, or dihydropyrane can be unsubstituted or substituted 1 to 2 halo groups;
R2 is selected from hydrogen and halo;
R3a is selected from hydrogen, methyl and halo-substituted-C1-2alkyl;
R3b is selected from hydrogen, methyl and amino;
R4a and R4b are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R4a and R4b cannot both be OH; with the proviso that R4a and R4b cannot be OH and F simultaneously;
R5a is selected from amino and amino-methyl;
R5b is selected from OH, amino, fluoro, C1-6alkyl, methoxy-carbonyl, C3-6cycloalkyl-C1-3alkyl, hydroxy-substituted C1-3alkyl, C1-2alkoxy-substituted C1-3alkyl and a 5 to 6 member heteroaryl ring containing 1 to 4 heteroatoms selected from O, S and N; wherein said C1-6alkyl or C1-2alkoxy-substituted C1-3alkyl of R5b is unsubstituted or substituted with 1-3 fluorines; with the proviso that if R5a is amino, R5b cannot be OH, amino or fluoro; or R5a and R5b, together with the carbon atom to which R5a and R5b are attached, form a group selected from:
wherein *C represents the carbon atom to which R5a and R5b are attached; R10 is amino; R11a is selected from hydrogen, hydroxy, fluoro, C1-3alkyl and hydroxy-methyl; R11b is selected from fluoro, methyl and hydrogen; with proviso that R11a and R11b cannot both be OH and fluoro simultaneously; R11c is selected from hydrogen, C1-3alkyl and hydroxy-methyl; R12 is selected from hydrogen, halo, hydroxy, C1-3alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkoxy and C1-3alkoxy; R13 is selected from hydrogen, halo and C1-3alkyl; R14 is selected from hydrogen and fluoro; with proviso that R12 and R13 cannot both be OH and fluoro simultaneously; R15 is selected from hydrogen and fluoro; and
R6a and R6b are each independently selected from hydrogen, hydroxy and fluoro; with proviso that R6a and R6b cannot both be OH; with proviso that R6a and R6b cannot both be OH and fluoro simultaneously; or the pharmaceutically acceptable salts thereof; with the proviso that a compound of formula I does not include a compound selected from:

### Claim 2 (depends on 1)

The compound of claim 1 of formula Ia:
in which:
X3 is selected from S;
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, amino, halo, C1-3alkyl, and C1-3alkoxy;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6-10aryl and C6-10aryl-C0-1alkoxy; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from, cyclopentene, 2,3-dihydrofuran, 2,3-dihydropyrrole;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy and hydroxy;
R1 is selected from hydrogen, halo, halo-substituted-C1-2alkyl;
R2 is selected from hydrogen and chloro;
R4a is selected from hydrogen, hydroxy and fluoro;
R6b is selected from hydrogen, hydroxy and fluoro;
R10 is amino; and
R11c is selected from hydrogen and C1-3alkyl; or the pharmaceutically acceptable salts thereof.

### Claim 3 (depends on 2)

The compound of claim 2 in which:
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, halo and amino;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, halo-substituted-C1-2alkyl, C1-2alkoxy, cyclopropyl, cyclopentyl, cyclopentyl-methoxy, halo-substituted-C1-2alkoxy, phenyl, methoxy-ethoxy, tetrahydro-2H-pyran-4-yl, morpholino, phenoxy and benzoxy;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-2alkoxy, cyclopropyl, trifluoromethyl, trifluoromethyl-sulfanyl, isopropyl and hydroxy;
R1 is selected from hydrogen, halo, trifluoromethyl, trifluoromethoxy, C1-2alkyl and cyano;
R2 is selected from hydrogen, fluoro and chloro;
R4a is hydrogen;
R6b is hydrogen;
R10 is amino; and
R11c is selected from hydrogen, methyl and ethyl; or the pharmaceutically acceptable salts thereof.

### Claim 4 (depends on 3)

The compound of claim 3, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 5 (depends on 1)

The compound of claim 1 of formula Ia:
in which:
X3 is a bond;
Y1 is CR7; wherein R7 is selected from hydrogen, chloro and fluoro;
Y2 is CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6aryl and C6aryl-C0-1alkoxy;
Y3 is selected from CR9; wherein R9 is selected from hydrogen, chloro, fluoro and methyl;
R1 is selected from hydrogen, chloro, fluoro;
R2 is hydrogen;
R4a is selected from hydrogen, hydroxy and fluoro;
R6b is selected from hydrogen, hydroxy and fluoro;
R10 is amino; and
R11c is selected from hydrogen, C1-3alkyl and hydroxy-methyl; or the pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 5)

The compound of claim 5, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 7 (depends on 1)

The compound of claim 1 of formula Ib:
in which:
X3 is S;
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, amino, halo, C1-3alkyl, and C1-3alkoxy;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6-10aryl and C6-10aryl-C0-1alkoxy; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from, cyclopentene, 2,3-dihydrofuran, 2,3-dihydropyrrole;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy and hydroxy;
R1 is selected from hydrogen, halo, halo-substituted-C1-2alkyl;
R2 is selected from hydrogen and halo;
R3a is selected from hydrogen and methyl;
R4a is selected from hydrogen, hydroxy and fluoro;
R5b is C1-6alkyl;
R6b is selected from hydrogen, hydroxy and fluoro; or the pharmaceutically acceptable salts thereof.

### Claim 8 (depends on 7)

The compound of claim 7 in which:
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, halo and amino;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, cyano, halo-substituted-C1-2alkyl, C1-2alkoxy and halo-substituted-C1-2alkoxy;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-2alkoxy and hydroxy;
R1 is selected from halo, trifluoromethyl, trifluoromethoxy, C1-2alkyl, nitro, hydroxy and cyano; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from 1,3-dioxolane and pyridine; wherein said 1,3-dioxolane or pyridine can be unsubstituted or substituted 1 to 2 halo groups;
R2 is selected from hydrogen, fluoro and chloro;
R3 is selected from hydrogen and methyl;
R4a is hydrogen;
R5b is methyl;
R6b is hydrogen; or the pharmaceutically acceptable salts thereof.

### Claim 9 (depends on 8)

The compound of claim 8, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 10 (depends on 1)

The compound of claim 1 of formula Ib:
in which:
X3 is a bond;
Y1 is CR7; wherein R7 is selected from hydrogen, chloro and fluoro;
Y2 is CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6aryl and C6aryl-C0-1alkoxy;
Y3 is selected from CR9; wherein R9 is selected from hydrogen, chloro, fluoro and methyl;
R1 is selected from hydrogen, chloro, fluoro;
R2 is hydrogen;
R4a is selected from hydrogen, hydroxy and fluoro;
R5b is C1-6alkyl;
R6b is selected from hydrogen, hydroxy and fluoro; or the pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 10)

The compound of claim 10, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 12 (depends on 1)

The compound of claim 1 of formula Ic:
in which:
X1 is selected from N and CH;
X3 is S;
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6-10aryl and C6-10aryl-C0-1alkoxy; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from, cyclopentene, 2,3-dihydrofuran, 2,3-dihydropyrrole;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy and hydroxy;
R1 is selected from hydrogen, halo, halo-substituted-C1-2alkyl and halo-substituted-C1-2alkoxy;
R2 is selected from hydrogen and halo;
R3a is selected from hydrogen and methyl;
R3b is selected from hydrogen and methyl;
R4a is selected from hydrogen, hydroxy and fluoro;
R5b is C1-6alkyl;
R6b is selected from hydrogen, hydroxy and fluoro.

### Claim 13 (depends on 12)

The compound of claim 12 in which:
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, halo and amino;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, cyano, halo-substituted-C1-2alkyl, C1-2alkoxy and halo-substituted-C1-2alkoxy;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-2alkoxy and hydroxy;
R1 is selected from halo, trifluoromethyl, trifluoromethoxy, C1-2alkyl and cyano;
R2 is selected from hydrogen, fluoro and chloro;
R3 is selected from hydrogen and methyl;
R4a is hydrogen;
R6b is hydrogen; or the pharmaceutically acceptable salts thereof.

### Claim 14 (depends on 13)

The compound of claim 13, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 15 (depends on 1)

The compound of claim 1 of formula Id:
in which:
X1 is selected from N and CH;
X3 is S;
Y1 is selected from N and CR7; wherein R7 is selected from hydrogen, amino, halo, C1-3alkyl, and C1-3alkoxy;
Y2 is selected from N and CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6-10aryl and C6-10aryl-C0-1alkoxy; or R1 and R8 together with the carbon atoms to which R1 and R8 are attached form a ring selected from, cyclopentene, 2,3-dihydrofuran, 2,3-dihydropyrrole;
Y3 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkyl, C1-3alkoxy and hydroxy;
R1 is selected from hydrogen, halo, halo-substituted-C1-2alkyl and cyano;
R2 is selected from hydrogen and halo;
R3a is selected from hydrogen, methyl and halo-substituted-C1-2alkyl;
R4a is selected from hydrogen, hydroxy and fluoro;
R6b is selected from hydrogen, hydroxy and fluoro;
R10 is amino;
R11a is selected from hydrogen, hydroxy, fluoro, C1-3alkyl and hydroxy-methyl;
R11b is selected from fluoro, methyl and hydrogen; with proviso that R11a and R11b cannot both be OH and fluoro simultaneously;
R12 is selected from hydrogen, halo, hydroxy, C1-3alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkoxy and C1-3alkoxy;
R13 is selected from hydrogen, halo and C1-3alkyl; with proviso that R12 and R13 cannot both be OH and fluoro simultaneously;
R14 is selected from hydrogen and fluoro;
R15 is selected from hydrogen and fluoro; or the pharmaceutically acceptable salts thereof.

### Claim 16 (depends on 15)

The compound of claim 15, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 17 (depends on 1)

The compound of claim 1 of formula Id:
in which:
X1 is selected from N and CH;
X3 is a bond;
Y1 is CR7; wherein R7 is selected from hydrogen, chloro and fluoro;
Y2 is CR8; wherein R8 is selected from hydrogen, halo, amino, dimethyl-amino, cyano, C3-6cycloalkyl, C1-4alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkyl-sulfanyl, C1-3alkoxy, halo-substituted-C1-3alkoxy, C1-3alkoxy-C1-3alkoxy, C6aryl and C6aryl-C0-1alkoxy;
Y3 is selected from CR9; wherein R9 is selected from hydrogen, chloro, fluoro and methyl;
R1 is selected from hydrogen, chloro, and fluoro;
R2 is hydrogen;
R3a is methyl;
R3b is amino;
R4a is selected from hydrogen, hydroxy and fluoro;
R6b is selected from hydrogen, hydroxy and fluoro;
R10 is amino;
R11a is selected from hydrogen, hydroxy, fluoro, C1-3alkyl and hydroxy-methyl;
R11b is selected from fluoro, methyl and hydrogen; with proviso that R11a and R11b cannot both be OH and fluoro simultaneously;
R12 is selected from hydrogen, halo, hydroxy, C1-3alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkoxy and C1-3alkoxy;
R13 is selected from hydrogen, halo and C1-3alkyl; with proviso that R12 and R13 cannot both be OH and fluoro simultaneously;
R14 is selected from hydrogen and fluoro;
R15 is selected from hydrogen and fluoro; or the pharmaceutically acceptable salts thereof.

### Claim 18 (depends on 17)

The compound of claim 17, or a pharmaceutically acceptable salt thereof, selected from:

### Claim 19 (depends on 1)

The compound of claim 1 of formula Ie:
in which:
X1 is selected from N and CH;
Y1 is selected from CR7; wherein R7 is selected from hydrogen, halo and amino;
Y2 is CR8; wherein R8 is selected from hydrogen, halo, amino, cyano, halo-substituted-C1-3alkyl, C1-3alkoxy and halo-substituted-C1-3alkoxy;
Y3 is selected from CR9; wherein R9 is selected from hydrogen, amino, halo, C1-3alkoxy, and hydroxy;
R1 is selected from halo-substituted-C1-2alkyl, halo-substituted-C1-2alkoxy, C1-2alkyl and cyano;
R2 is selected from hydrogen and halo;
R3a is selected from hydrogen, and methyl;
R3b is selected from hydrogen and methyl;
R4a is selected from hydrogen, hydroxy and fluoro; R6b is selected from hydrogen, hydroxy and fluoro;
R10 is amino;
R11a is selected from hydrogen, hydroxy, fluoro, C1-3alkyl and hydroxy-methyl;
R11b is selected from fluoro, methyl and hydrogen;
R11c is selected from hydrogen, C1-3alkyl and hydroxy-methyl;
R12 is selected from hydrogen, halo, hydroxy, C1-3alkyl, halo-substituted-C1-3alkyl, halo-substituted-C1-3alkoxy and C1-3alkoxy;
R13 is selected from hydrogen, halo and C1-3alkyl; with proviso that R12 and R13 cannot both be OH and fluoro simultaneously; or the pharmaceutically acceptable salts thereof.

### Claim 20 (depends on 19)

The compound of claim 19, or a pharmaceutically acceptable salt thereof, selected from: