# US 10,870,636 B2 · Pyrimidines as EGFR inhibitors and methods of treating disorders

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- Number: US 10,870,636 B2
- Document ID: US10870636B2
- Status: Granted
- Kind: B2
- Application number: 16/290,153
- Filed: 2019-03-01
- Published: 2019-06-27
- Granted: 2020-12-22
- Earliest claimed: 2014-12-23
- Assignees: Dana-Farber Cancer Institute, Inc.
- Applicants: Dana-Farber Cancer Institute, Inc.
- Inventors: Nathanael S. Gray; Pasi Janne; Hwan Geun Choi; Jaebong Jang
- Web page: https://patentgrep.com/patent/US10870636B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/14: for lactation disorders, e.g. galactorrhoea
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 31/18: for HIV
- A61P 31/22: for herpes viruses
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 403/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The application relates to a compound having Formula (I): which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.

## Claims

### Claim 1

A method of treating non-small cell lung cancer comprising administering to a subject in need thereof an effective amount of a compound of Formula I:
or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
Z1 and Z2 are each independently N and Z3 is CR8;
R8 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
R1 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, or halogen;
R2 is H or (C1-C6) alkyl;
R3 is (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen;
R4 is NR9R10 or a 5- to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
R9 is H or (C1-C4) alkyl;
R10 is (C1-C4) alkyl, (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2;
or R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen;
R5 is NR12C(O)R13 or C(O)NR12R13;
R12 is H or (C1-C6) alkyl;
R13 is (C1-C5) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2;
R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula
wherein
X3 is N;
X1, X2, X4, X5 and X6 are each independently CH; and
each R15 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1l -C6) alkyl, N((C1-C6) alkyl)2, or halogen.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is H or NH2.

### Claim 3 (depends on 1)

The method of claim 1, wherein R2 is H.

### Claim 4 (depends on 1)

The method of claim 1, wherein R3 is (C1-C4) alkoxy.

### Claim 5 (depends on 1)

The method of claim 1, wherein R4 is NR9R10.

### Claim 6 (depends on 1)

The method of claim 1, wherein R5 is NR12C(O)R13.

### Claim 7 (depends on 1)

The method of claim 1, wherein R15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R8 is H or halogen.

### Claim 9 (depends on 1)

The method of claim 1, wherein R9 is (C1-C4) alkyl.

### Claim 10 (depends on 1)

The method of claim 1, wherein R10 is (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2.

### Claim 11 (depends on 1)

The method of claim 1, wherein R4 is NR9R10 and R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S-and optionally substituted with one or more R11.

### Claim 12 (depends on 1)

The method of claim 1, wherein R11 is (C1-C4) alkyl, R12 is H, and R13 is (C2-C6) alkenyl.

### Claim 13 (depends on 1)

The method of claim 1, wherein R11 is (C1-C4) alkyl, R12 is (C1-C6) alkyl, and R13 is (C2-C6) alkenyl.

### Claim 14 (depends on 1)

The method of claim 1, wherein at least one of X1, X2, X4, X5 and X6 is CR15.

### Claim 15 (depends on 1)

The method of claim 1, wherein R15 is selected from methyl and CF3.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound is of Formula (Ia):
or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
X1, X2, X4, X5 and X6 are each independently CH or CR15;
R91 is (C1-C4) alkyl;
R101 is (C1-C4) alkyl-NH(C1-C4) alkyl or (C1-C4) alkyl-N((C1-C4) alkyl)2;
or R91 and R101 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11;
each R11 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen; and
R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound is selected from the group consisting of:
N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl) (methyl)amino)-4-methoxyphenyl)acrylamide;
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;
N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;
N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide; and
N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.

### Claim 18 (depends on 1)

The method of claim 1, wherein the non-small cell lung cancer is characterized by a mutation in EGFR selected from the group consisting of T790M, L718Q, L844V, L858R, Del, Del/L718Q, Del/L844V, Del/T790M, L858R/T790M, Del/T790M/L718Q, Del/T790M/L844V, L858R/L844V, L858R/L718Q, L858R/T790M/L718Q, and exon 19 deletion/T790M.