# US 8,785,440 B2 · Bruton's tyrosine kinase inhibitors

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- Number: US 8,785,440 B2
- Document ID: US8785440B2
- Status: Granted
- Kind: B2
- Application number: 13/393,192
- Filed: 2010-09-03
- Published: 2012-06-21
- Granted: 2014-07-22
- Earliest claimed: 2009-09-04
- Assignees: Biogen Idec MA Inc.; Sunesis Pharmaceuticals, Inc.
- Applicants: 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
- 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/US8785440B2

## 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 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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or 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, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or 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, or 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, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each of R4 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 A1 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, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or 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, or sulfur, or a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 2)

The compound of claim 2, wherein L is —NH—C(O)—NH—or —NH—.

### Claim 4 (depends on 1)

The compound 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 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

The compound of claim 1, wherein R4 is hydrogen.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

The compound of claim 1, wherein X1 is —CR5R6—.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 10)

The compound of claim 10, wherein q is 2.

### Claim 12 (depends on 10)

The compound of claim 10, wherein the compound is of formula XI:

### Claim 13 (depends on 1)

The compound 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, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 14 (depends on 13)

The compound of claim 13, wherein Ring A2 is optionally substituted phenyl.

### Claim 15 (depends on 14)

The compound of claim 14, 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, —S(O)2N(R)2.

### Claim 16 (depends on 15)

The compound of claim 15, wherein Ring A2 is of the formula:
wherein Rh is F, Cl, Br, or I.

### Claim 17 (depends on 14)

The compound of claim 14, wherein the ortho carbons on Ring A2 are independently R, halogen, —CN, —CF3, —OH, —OR, —NH2, —N(R)2, or —COOH.

### Claim 18 (depends on 14)

The compound of claim 14, wherein Ring A2 is selected from:

### Claim 19 (depends on 18)

The compound of claim 18, wherein Ring A2 is:

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.