# US 2020/0399283 A1 · Bruton's tyrosine kinase inhibitors

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- Number: US 2020/0399283 A1
- Document ID: US20200399283A1
- Status: Published application
- Kind: A1
- Application number: 16/748,410
- Filed: 2020-01-21
- Published: 2020-12-24
- Earliest claimed: 2009-09-04
- Assignees: Sunesis Pharmaceuticals, Inc.; Biogen MA Inc.
- Applicants: Sunesis Pharmaceuticals, Inc.; Biogen MA Inc.
- Inventors: Minna BUI; Patrick CONLON; Julio H. CUERVO; Daniel A. ERLANSON; Junfa FAN; Bing GUAN; Brian T. HOPKINS; Tracy J. JENKINS; Gnanasambandam KUMARAVEL; Alexey A. LUGOVSKOY; Doug MARCOTTE; Noel POWELL; Daniel SCOTT; Laura SILVIAN; Art TAVERAS; Deping WANG; Min ZHONG
- Web page: https://patentgrep.com/patent/US20200399283A1

## CPC

- C07D 487/14: Ortho-condensed systems
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 487/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.

## Claims

### Claim 1

A pharmaceutical salt of a compound having the formula:
wherein:
X1 is —O—, —CR5R6—, or —NR7—;
X2 is ═CR8— or ═N—;
p is 0-5;
y is 0, 1, or 2;
z is 0, 1, or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
each R1 is independently halogen, —NO2, —CN, —OR, —SR, —N(R)2, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)N(R)2, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)C(O)N(R)2, —N(R)SO2N(R)2, —N(R)SO2R, —OC(O)N(R)2, or an optionally substituted group selected from C1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, ad sulfur, or:
two R1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, ad sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, ad sulfur, or:
two R1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—S—, or —S—, or:
two R1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R2, R3, R5, R6, and R8 is independently R, halogen, —NO2, —CN, —OR, —SR, —N(R)2, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —S(O)R, —S(O)2R, —C(O)N(R)2, —SO2N(R)2, —OC(O)R, —N(R)C(O)R, —N(R)N(R)2, —N(R)C(═NR)N(R)2, —C(═NR)N(R)2, —C═NOR, —N(R)C(O)N(R)2, —N(R)SO2N(R)2, —N(R)SO2R, or —OC(O)N(R)2; or:
R3 and R4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole, pyrazole, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
each of R and R7 is independently R, —CN, —C(O)R, —CO2R, —C(O)C(O)R, —C(O)CH2C(O)R, —C(O)N(R)2, —S(O)R, —S(O)2R, or —S(O)2N(R)2;
Ring A is
and is optionally substituted,
wherein T is an optionally substituted, bivalent C1-5 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of T are optionally and independently replaced by —C(R)2—, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N2)—;
Ring A2 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L is a covalent bond or an optionally substituted, bivalent C1-7 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are independently replaced by -Cy-, —CR2—, —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—, —SO2—, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N2)—, wherein at least one methylene unit of L is replaced by —N(R)—; and
each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

### Claim at position 2

-4. (canceled)

### Claim 5 (depends on 1)

The pharmaceutical salt of claim 1, wherein L is —NH—C(O)—NH—, —NH—C(O)—, —NH—, or —NHSO2—.

### Claim 6 (depends on 5)

The pharmaceutical salt of claim 5, wherein L is —NH—C(O)—NH— or —NH—.

### Claim 7 (depends on 1)

The pharmaceutical salt of claim 1, wherein L is:
wherein s and t are independently 0, 1, or 2, and the sum of s and t is 0-4.

### Claim at position 6

-15. (canceled)

### Claim 16 (depends on 1)

The pharmaceutical salt of claim 1, wherein the compound is of formula I-a-i, or I-a-ii:

### Claim 17 (depends on 1)

The pharmaceutical salt of claim 1, wherein the compound is of formula I-b-i, or I-b-ii:

### Claim at position 9

-20. (canceled)

### Claim 21 (depends on 1)

The pharmaceutical salt of claim 1, wherein R4 is hydrogen.

### Claim 22

(canceled)

### Claim 23 (depends on 1)

The pharmaceutical salt of claim 1, wherein R1 is halogen, —CN, or optionally substituted C1-6 aliphatic.

### Claim at position 13

-32. (canceled)

### Claim 33 (depends on 1)

The pharmaceutical salt of claim 1, wherein X1 is —CR5R6—.

### Claim at position 15

-50. (canceled)

### Claim 51 (depends on 1)

The pharmaceutical salt of claim 1, wherein Ring A1 is:
and is optionally substituted, wherein q is 0-4.

### Claim 52

(canceled)

### Claim 53 (depends on 51)

The pharmaceutical salt of claim 51, wherein q is 2.

### Claim 54

(canceled)

### Claim 55 (depends on 51)

The pharmaceutical salt of claim 51, wherein the compound is of formula XI:

### Claim 56 (depends on 1)

The pharmaceutical salt of claim 1, wherein Ring A2 is an optionally substituted ring selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

### Claim 57

(canceled)

### Claim 58 (depends on 56)

The pharmaceutical salt of claim 56, wherein Ring A2 is optionally substituted phenyl.

### Claim 59 (depends on 58)

The pharmaceutical salt of claim 58, wherein substituents on Ring A2 are selected from R, halogen, —CN, —CF3, —OH, —OR, —NH2, —N(R)2, —COOH, —SR, —S(O)R, —S(O)2R, —S(O)N(R)2, and —S(O)2N(R)2.

### Claim 60 (depends on 59)

The pharmaceutical salt of claim 59, wherein Ring A2 is of the formula:
wherein Rh is F, Cl, Br, or I.

### Claim 61 (depends on 58)

The pharmaceutical salt of claim 58, wherein the ortho carbons on Ring A2 are independently R, halogen, —CN, —CF3, —OH, —OR, —NH2, —N(R)2, or —COOH.

### Claim at position 27

-63. (canceled)

### Claim 64 (depends on 61)

The pharmaceutical salt of claim 61, wherein Ring A2 is selected from:

### Claim 65 (depends on 64)

The pharmaceutical salt of claim 64, wherein Ring A2 is:

### Claim 66 (depends on 1)

The pharmaceutical salt of claim 1, wherein the compound is a compound as shown in Table 1.

### Claim at position 31

-74. (canceled)