# US 9,751,892 B2 · IRAK inhibitors and uses thereof

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- Number: US 9,751,892 B2
- Document ID: US9751892B2
- Status: Granted
- Kind: B2
- Application number: 14/857,029
- Filed: 2015-09-17
- Published: 2016-03-10
- Granted: 2017-09-05
- Earliest claimed: 2013-01-10
- Assignees: Nimbus Iris, Inc.
- Applicants: Nimbus Iris, Inc.
- Inventors: Jeremy Robert Greenwood; Geraldine C. Harriman; Rosana Kapeller-Libermann; Craig E. Masse; Shaughnessy Robinson; Donna L. Romero; Mee Shelley; Ronald T. Wester
- Web page: https://patentgrep.com/patent/US9751892B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

## Claims

### Claim 1

A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein:
Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 1-4;
each R1 is Cy;
each Cy is an optionally substituted 4-7 membered saturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 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 a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
m is 0-4;
p is 0-2;
[Ar] is an optionally substituted phenyl or heteroaromatic ring;
L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—; and
each R4 is independently halogen, CN, NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and
wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is of formula II:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The method of claim 2, wherein the compound is of formulae III or IV:
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is of formula XII:
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound is of formulae XIII or XIV:
or a pharmaceutically acceptable salt thereof.

### Claim 6

A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formulae XV-a, XV-b, XV-c, XV-d, XVI-a, XVI-b, XVI-c, XVI-d, XVII-a, XVII-b, or XVII-c:
or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, wherein:
R1 is —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R; or R1 is selected from one of the following formulas:
Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 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 a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
m is 0-4;
p is 0-2;
[Ar] is an optionally substituted phenyl or heteroaromatic ring;
L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 7 (depends on 1)

The method of claim 1, wherein Cy is an optionally substituded ring selected from morpholine, piperidine, or piperazine.

### Claim 8 (depends on 1)

The method of claim 1, wherein L1 is —O—.

### Claim 9 (depends on 1)

The method of claim 1, wherein L1 is —N(R)—.

### Claim 10 (depends on 1)

The method of claim 1, wherein L1 is —NH—.

### Claim 11 (depends on 1)

The method of claim 1, wherein [Ar] is optionally substituted phenyl.

### Claim 12

A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein:
Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-4;
each R1 is independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R; or R1 is selected from one of the following formulas:
or
two R1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 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 a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
m is 0-4;
p is 0-2;
[Ar] is an optionally substituted 6-membered heteroaryl;
L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 13

A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein:
Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
n is 0-4;
each R1 is independently —R, halogen, —CN, —NO2, —OR, —CH2OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)2, Cy, or —NRSO2R; or R1 is selected from one of the following formulas:
or two R1 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Cy is an optionally substituted ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring or a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 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 a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring B is a 4-8 membered partially unsaturated carbocyclic fused ring; or a 4-7 membered partially unsaturated heterocyclic fused ring having 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur; wherein said Ring B may be optionally substituted by one or more oxo, thiono, or imino groups;
m is 0-4;
p is 0-2;
[Ar] is an optionally substituted 5-membered heteroaryl;
L1 is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each L2 is independently a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, —SO2N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO2—;
each R4 is independently halogen, —CN, —NO2, —OR, —SR, —N(R)2, —SO2R, —SO2N(R)2, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)N(R)2, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)2N(R)2, —NRSO2R, or an optionally substituted group selected from C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two -L2(R4)p—R4 groups are taken together with their intervening atoms to form an optionally substituted 4-7 membered fused, spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

### Claim 14 (depends on 13)

The method of claim 13, wherein [Ar] is optionally substituted pyrazole.

### Claim 15 (depends on 13)

The method of claim 13, wherein R1 is —N(R)2 or Cy.

### Claim 16 (depends on 15)

The method of claim 15, wherein R1 is —N(Me)2.

### Claim 17

A method of treating an IRAK-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound selected from the following:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is administered as a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

### Claim 19 (depends on 1)

The method of claim 1, wherein the disorder is mediated by IRAK-1, IRAK-2, or IRAK-4, or a mutant thereof.

### Claim 20 (depends on 6)

The method of claim 6 wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

### Claim 21 (depends on 12)

The method of claim 12, wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

### Claim 22 (depends on 13)

The method of claim 13, wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.

### Claim 23 (depends on 17)

The method of claim 17, wherein the disorder, disease, or condition is a cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hereditary disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, a cardiovascular disorder, or a CNS disorder.