# US 11,306,099 B1 · Compounds and methods for modulating Bruton's Tyrosine Kinase

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- Number: US 11,306,099 B1
- Document ID: US11306099B1
- Status: Granted
- Kind: B1
- Application number: 17/004,943
- Filed: 2020-08-27
- Granted: 2022-04-19
- Earliest claimed: 2016-03-11
- Assignees: Angel Pharmaceutical Co., Ltd.
- Applicants: Angel Pharmaceutical Co., Ltd.
- Inventors: Ryan Hudson; Anne-Marie Beausoleil; Richard A. Miller; Erik Verner
- Web page: https://patentgrep.com/patent/US11306099B1

## 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, —OR1D, or unsubstituted C1-C4 alkyl;
z1 is an integer from 0 to 5;
R2 is independently halogen;
z2 is an integer from 0 to 4;
R3 is hydrogen or —NH2;
Y1 is N or C(R4);
R4 is hydrogen, halogen, —CX43, —CHX42, —CH2X4, —OCX43, —OCH2X4, —OCHX42, —CN, —SOn4R4D, —SOv4NR4AR4B, —NHC(O)NR4AR4B, —N(O)m4, —NR4AR4B, —C(O)R4C, —C(O)—OR4C, —C(O)NR4AR4B, —OR4D, —NR4ASO2R4D, —NR4AC(O)R4C, —NR4AC(O)OR4C, —NR4AOR4C, 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;
Y2 is N;
L1 is a bond or unsubstituted methylene;
L2 is a substituted or unsubstituted heterocycloalkylene;
E is
R15 is hydrogen, halogen, —CX153, —CHX152, —CH2X15, —CN, —SOn15R15D, —SOv15NR15AR15B, 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 hydrogen, halogen, —CX163, —CHX162, —CH2X16, —CN, —SOn16R16D, —SOv16NR16AR16B, 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 hydrogen, halogen, —CX173, —CHX172, —CH2X17, —CN, —SOn17R17D, —SOv17NR17AR17B, 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;
each R1D, R4A, R4B, R4C, R4D, R15A, R15B, R15C, R15D, R16A, R16B, R16C, R16D, R17A, R17B, R17C, and R17D 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; R4A and R4B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; R15A and R15B 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;
each X, X4, X15, X16, and X17 is independently —F, —Cl, —Br, or —I;
n4, n15, n16, and n17 are independently an integer from 0 to 4; and
m4, m15, m16, m17, v4, 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 Y1 is C(R4) and R4 is hydrogen.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R1 is independently —F, —Cl, unsubstituted methoxy, or unsubstituted methyl.

### 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 —F.

### 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 L2 is substituted or unsubstituted pyrrolidinylene.

### Claim 11 (depends on 1)

The compound of claim 1, wherein L2 is unsubstituted azepanylene.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

The compound of claim 1, wherein L2 is

### Claim 14 (depends on 1)

The compound of claim 1, wherein E is:

### Claim 15 (depends on 1)

The compound of claim 1, wherein E is:

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

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

### Claim 18 (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 19 (depends on 1)

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

### Claim 20 (depends on 1)

A method of treating a lymphoma, colorectal cancer, non-small cell lung cancer, glioblastoma, prostate cancer, ovarian cancer, breast cancer, pancreatic cancer, arthritis, Siogren's syndrome, systemic lupus erythematosus, diabetes mellitus type 1, bullous pemphigoid, psoriasis, asthma, atherosclerosis, or multiple sclerosis, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1.

### Claim 21 (depends on 20)

The method of claim 20, wherein the arthritis is rheumatoid arthritis.

### Claim 22 (depends on 20)

The method of claim 20, wherein the lymphoma is diffuse large B-cell lymphoma, Hodgkin lymphoma, chronic lymphocytic leukemia, or follicular lymphoma.

### Claim 23 (depends on 1)

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

### Claim 24 (depends on 1)

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