# US 10,870,652 B2 · Compounds and methods for modulating bruton's tyrosine kinase

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,870,652 B2
- Document ID: US10870652B2
- Status: Granted
- Kind: B2
- Application number: 16/083,409
- Filed: 2017-03-10
- Published: 2019-04-11
- Granted: 2020-12-22
- Earliest claimed: 2016-03-11
- Assignees: Corvus Pharmaceuticals, Inc.
- Applicants: Corvus Pharmaceuticals, Inc.
- Inventors: Ryan Hudson; Anne-Marie Beausoleil; Richard A. Miller; Erik Verner
- Web page: https://patentgrep.com/patent/US10870652B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein, inter alia, are compounds and methods for modulating Bruton's Tyrosine Kinase.

## Claims

### Claim 1

A compound having the formula:
wherein,
R1 is independently halogen, —CX13, —CHX12, —CH2X1, —OCX13, —OCH2X1, —OCHX12, —CN, —SOn1R1D, —SOv1 NR1AR1B, —NHC(O)NR1AR1B, —N(O)m1, —NR1AR1B, —C(O)R1C, —C(O)—OR1C, —C(O)NR1AR1B, —OR1D, —NR1ASO2R1D, —NR1AC(O)R1C, —NR1AC(O)OR1C, —NR1AOR1C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
z1 is an integer from 0 to 5;
R2 is independently halogen, —CX23, —CHX22, —CH2X2, —OCX23, —OCH2X2, —OCHX22, —CN, —SOn2R2D, —SOv2 NR2AR2B, —NHC(O)NR2AR2B, —N(O)m2, —NR2AR2B, —C(O)R2C, —C(O)—OR2C, —C(O)NR2AR2B, —OR2D, —NR2ASO2R2D, —NR2AAC(O)R2C, —NR2AC(O)OR2C, —NR2AOR2C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
z2 is an integer from 0 to 4;
R3 is hydrogen or —NH2;
Y1 is N;
Y2 is N;
L1 is a bond, —S(O)2—, —S(O)2-Ph-, —NR—, —O—, —S—, —C(O)—, —C(O)NR—, —NR6C(O)—, —NR6C(O)NH—, —NHC(O)NR—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R6 is hydrogen, halogen, —CX63, —CHX62, —CH2X6, —OCX63, —OCH2X6, —OCHX62, —CN, —Sn6R6D, —SOv6 NR6AR6B, —NHC(O)NR6AR6B, —N(O)m6, —NR6AR6B, —C(O)R6C, —C(O)—OR6C, —C(O)NR6AR6B, —OR6D, —NR6ASO2R6D, —N6AC(O)R6C, —N6AC(O)OR6C, —NR6AOR6C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
L2 is a bond, —S(O)2—, —S(O)2-Ph-, —NR7A—, —O—, —S—, —C(O)—, —C(O)NR7A—, —NR7C(O)—, —NR7C(O)NH—, —NHC(O)NR—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R7 is hydrogen, halogen, —CX73, —CHX72, —CH2X7, —OCX73, —OCH2X7, —OCHX72, —CN, —SOn7R7D, —SOv7 NR7AR7B, —NHC(O)NR7AR7B, —N(O)m7, —NR7AR7B, —C(O)R7C, —C(O)—OR7C, —C(O)NR7AR7B, —OR7D, —NR7ASO27D, —NR7AC(O)R7C, —NR7AC(O)OR7C, —NR7AOR7C, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
E is:
R15 is independently hydrogen, halogen, CX153, —CHX152, —CH2X15, —CN, —SOn15R15D, —SOv15 NR15AR15B, —NHNR15AR15B, —ONR15AR15B, —NHC═(O)NHNR15AR15B, —NHC(O)NR15AR15B, —N(O)m15, —NR15AR15B, —C(O)R15C, —C(O)—OR15C, —C(O)NR15AR15B, —OR15D, —NR15ASO2R15D, —NR15AC(O)R15C, —NR15AC(O)OR15C, —NR15AOR15C, —OCX153, —OCHX152, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R16 is independently hydrogen, halogen, CX163, —CHX162, —CH2X16, —CN, —SOn16R16D, —SOv16 NR16AR16B, —NHNR16AR16B, —ONR16AR16B, —NHC═(O)NHNR16AR16B, —NHC(O)NR16AR16B, —N(O)m16, —NR16AR16B, —C(O)R16C, —C(O)—OR16C, —C(O)NR16AR16B, —OR16D, —NR16ASO2R16D, —NR16AC(O)R16C, —NR16AC(O)OR16C, —NR16AOR16C, —OCX163, —OCHX162, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R17 is independently hydrogen, halogen, CX173, —CHX172, —CH2X17, —CN, —SOn17R17D, —SOv17 NR17AR17B, —NHNR17AR17B, —ONR17AR17B, —NHC═(O)NHNR17AR17B, —NHC(O)NR17AR17B, —N(O)m17, —NR17AR17B, —C(O)R17C, —C(O)—OR17C, —C(O)NR17AR17B, —OR17D, —NR17ASO2R17D, —NR17AC(O)R17C, —NR17AC(O)OR17C, —NR17AOR17C, —OCX173, —OCHX172, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
R8 is independently hydrogen, —CX183, —CHX182, —CH2X18, —C(O)R18C, —C(O)OR18C, —C(O)NR18AR18B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
Each R1A, R1B, R1C, R1D, R2A, R2B, R2C, R2D, R6A, R6B, R6C, R6D, R7A, R7B, R7C, R7D, R15A, R15B, R15C, R15D, R16A, R16B, R16C, R16D, R17A, R17B, R17C, R17D, R18A, R18B, and R18C is independently hydrogen, —CX3, —CN, —COOH, —CONH2, —CHX2, —CH2X, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R2A and R2B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R6A and R6B substituents bond the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R7A and R7B substituents bonded to the same nitrogen atom may optionally be joined form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R15A and R18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R16A and R16B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R17A and R17B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R18A and R18B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
each X, X1, X2, X6, X7, X15, X16, X17, and X18 is independently —F, —Cl, —Br, or —I;
n1, n2, n6, n7, n15, n16, and n17 are independently an integer from 0 to 4; and
m1, m2, m6, m7, m15, m16, m17, v1, v2, v6, v7, v15, v16, and v17 are independently an integer from 1 to 2.

### Claim 2 (depends on 1)

The compound of claim 1 having the formula:

### Claim 3 (depends on 1)

The compound of claim 1 having the formula:

### Claim 4 (depends on 1)

The compound of claim 1, wherein R3 is hydrogen.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R3 is —NH2.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is independently halogen, —CX13, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —OCX13, —OCHX12, —CHX12, —CH2X1, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; two adjacent R1 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein z1 is 0, 1 or 2.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2 is independently halogen, —CX23, —CN, —OH, —NH2, —COOH, —CONH2, —N2, —SH, —OCX23, —OCHX22, —CHX22, —CH2X2, substituted or unsubstituted C1-C8 alkyl, or substituted or unsubstituted 2 to 8 membered heteroalkyl; two adjacent R2 substituents may optionally be joined to form a substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein z2 is 0, 1 or 2.

### Claim 10 (depends on 1)

The compound of claim 1, wherein L1 is a bond, —S(O)2—, —S(O)2-Ph-, substituted or unsubstituted C1-C8 alkylene, substituted or unsubstituted 2 to 8 membered heteroalkylene, substituted or unsubstituted C3-C8 cycloalkylene, substituted or unsubstituted 3 to 8 membered heterocycloalkylene, substituted or unsubstituted phenylene, or substituted or unsubstituted 5 to 6 membered heteroarylene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein L1 is a bond.

### Claim 12 (depends on 1)

The compound of claim 1, wherein L1 is an unsubstituted methylene.

### Claim 13 (depends on 1)

The compound of claim 1, wherein L2 is —NR7A— or substituted or unsubstituted heterocycloalkylene comprising a ring nitrogen bonded directly to E.

### Claim 14 (depends on 1)

The compound of claim 1, wherein L2 is —NR7A—.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R7 is hydrogen, substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 2 to 6 membered heteroalkyl.

### Claim 16 (depends on 1)

The compound of claim 1, wherein L2 is substituted or unsubstituted heterocycloalkylene.

### Claim 17 (depends on 1)

The compound of claim 1, wherein L2 is substituted or unsubstituted azepanylene, substituted or unsubstituted piperidinylene, or substituted or unsubstituted pyrrolidinylene.

### Claim 18 (depends on 1)

The compound of claim 1, wherein E is:

### Claim 19 (depends on 1)

The compound of claim 1, wherein R15, R16, R17, and R18 are hydrogen.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R1 is independently halogen.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R2 is independently halogen.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound has the formula:

### Claim 23 (depends on 1)

The compound of claim 1, wherein the compound is capable of entering the central nervous system of a patient following administration outside of the central nervous system.

### Claim 24 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

### Claim 25 (depends on 1)

A method of treating a lymphoma or multiple sclerosise, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

### Claim 26 (depends on 1)

A Bruton's tyrosine kinase protein covalently bonded to a compound of claim 1.

### Claim 27 (depends on 1)

The compound of claim 1, wherein -L1-L2-E is:

### Claim 28 (depends on 25)

The method of claim 25, wherein the lymphoma is diffuse large B-cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or follicular lymphoma.