# US 2014/0155421 A1 · Substituted pyrimidinyl-pyrroles active as kinase inhibitors

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- Number: US 2014/0155421 A1
- Document ID: US20140155421A1
- Status: Published application
- Kind: A1
- Application number: 14/112,559
- Filed: 2012-04-05
- Published: 2014-06-05
- Earliest claimed: 2011-04-19
- Assignees: Nerviano Medical Sciences S.R.L.
- Inventors: Maria Gabriella Brasca; Tiziano Bandiera; Jay Aaron Bertrand; Paola Gnocchi; Danilo Mirizzi; Marcella Nesi; Achille Panzeri
- Web page: https://patentgrep.com/patent/US20140155421A1

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07F 5/025: {Boronic and borinic acid compounds}
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention relates to substituted pyrimidinyl-pyrrole compounds of formula (I) which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Janus kinases. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing such compounds or the pharmaceutical compositions containing them.

## Claims

### Claim 1

A compound of formula (I):
wherein:
R1 and R2 are independently halogen, nitro, cyano, OR5, NR6R7 or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, wherein:
R5 is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl;
R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R6 and R7, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R3 is NR8R9 wherein:
R8 and R9 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R8 and R9, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R4 is hydrogen, an optionally substituted straight or branched C1-C6 alkyl or NR10R11, wherein:
R10 and R11 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C2-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl and heterocyclyl-alkyl, or R10 and R11, taken together with the nitrogen atom to which they are bonded, may form an optionally substituted 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is hydrogen or an optionally substituted straight or branched C1-C6 alkyl;
or a pharmaceutically acceptable salt thereof, with the proviso that the following compounds are excluded:
5-(2-amino-pyrimidin-4-yl)-2-(5-fluoro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2,5-difluoro-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2,5-dimethyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(5-chloro-2-fluoro-phenyl)-1H-pyrrole-3-carboxamide,
5-(2-amino-pyrimidin-4-yl)-2-(2-fluoro-5-methyl-phenyl)-1H-pyrrole-3-carboxamide and
5-(2-amino-pyrimidin-4-yl)-2-(2-chloro-5-fluoro-phenyl)-1H-pyrrole-3-carboxamide.

### Claim 2 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
R4 is NR10R11, wherein R10 and R11 are independently hydrogen or an optionally substituted straight or branched C1-C6 alkyl.

### Claim 3 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
R3 is NR8R9, wherein R8 and R9 are independently hydrogen or an optionally substituted straight or branched C1-C6 alkyl.

### Claim 4 (depends on 1)

A compound of formula (I) as defined in claim 1 wherein:
R12 is hydrogen.

### Claim 5

A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2,5-dichlorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-cyanophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-bromo-2-fluorophenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(hydroxymethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(2-chloro-5-methoxyphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethoxy)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(propan-2-yl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2,5-bis(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[5-chloro-2-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-cyano-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(piperidin-1-yl)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-phenyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(furan-2-ylmethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(3-hydroxypropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methoxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-fluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
N-(2-Aminoethyl)-5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-[2-(methylamino)ethyl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-benzyl-2-(5-chloro-2-methylphenyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2-methylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-N-(2,2-dimethylpropyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-ethyl-1H-pyrrole-3-carboxamide,
5-(2-aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-N,N-dimethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-[2-chloro-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-hydroxyphenyl)-1H-pyrrole-3-carboxamide,
2-(5-chloro-2-methylphenyl)-5-[2-(methylamino)pyrimidin-4-yl]-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
5-(Pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carboxamide,
2-(5-Chloro-2-methylphenyl)-5-(2-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-ethylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-ethyl-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-(2-hydroxyethyl)-1H-pyrrole-3-carboxamide,
5-(2-Aminopyrimidin-4-yl)-N-methyl-2-[2-methyl-5-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxamide and
5-(2-Aminopyrimidin-4-yl)-2-[2-ethyl-5-(trifluoromethyl)phenyl]-N-methyl-1H-pyrrole-3-carboxamide.

### Claim 6 (depends on 1)

A process for preparing a compound of formula (I) as defined in claim 1 or the pharmaceutically acceptable salts thereof, characterized in that the process comprises the following steps:
Step 1: metal-catalyzed coupling reaction of a halo derivative of formula (II)
with a substituted aryl boronic acid of formula (IIIa) or an aryl boronic-ester of formula (IIIb):
wherein R1 and R2 are as defined in claim 1;
Step 2: hydrolysis of the resulting carboxylic ester of formula (IV)
wherein R1 and R2 are as defined above, through basic hydrolysis;
Step 3: amidation of the resulting carboxylic acid of formula (V)
wherein R1 and R2 are as defined above, through reaction with a derivative of formula (VI)
NHR8R9 (VI)
wherein R8 and R9 are as defined in claim 1, to give a compound of formula (I)
wherein R1 and R2 are as defined above, R3 is as defined in claim 1, R4 is NH2 and R12 is hydrogen;
or
Step 3a: direct amidation of the carboxylic ester of formula (IV) as defined above through reaction with a derivative of formula (VI) as defined above to give a compound of formula (I)
wherein R1, R2 and R3 are as defined above, R4 is NH2 and R12 is hydrogen;
alternatively,
Step 4: metal-catalyzed coupling reaction of a halo derivative of formula (VII)
wherein R3 is as defined above, with a substituted aryl boronic acid of formula (IIIa) or an aryl boronic-ester of formula (IIIb)
wherein R1 and R2 are as defined above, to give a compound of formula (I)
wherein R1, R2 and R3 are as defined above, R4 is NH2 and R12 is hydrogen;
alternatively
Step 5: reacting a pyrrole of the formula (VIII)
wherein R1 and R2 are as defined above, with acetyl chloride in the presence of a Lewis acid or in the presence of zinc metal;
Step 6: reacting the resultant compound of the formula (IX)
wherein R1 and R2 are as defined above, with a dialkyl acetal of N,N-dimethylformamide;
Step 7: reacting the resultant enaminone of the formula (X)
wherein R1 and R2 are as defined above, with an optionally substituted guanidine of formula (XI) or a salt thereof
wherein R4 is NR10R11, and R10 and R11 are as defined in claim 1;
Step 8: hydrolizing in acidic conditions the cyano group of the resultant compound of the formula (XII)
wherein R4 is NR10R11, wherein R10 and R11 are as defined in claim 1, and R1 and R2 are as defined above, so as to obtain the compound of the formula (I)
wherein R1 and R2 are as defined above, R3 is NH2, R4 is NR10R11, wherein R10 and R11 are as defined above, and R12 is hydrogen;
alternatively
Step 9: reacting the enaminone of the formula (X) as defined above, with an optionally substituted amidine of the formula (XIII), or a salt thereof
wherein R4 is hydrogen or optionally substituted straight or branched (C1-C6);
Step 10: hydrolizing the cyano group of the resultant compound of the formula (XIV)
wherein R1 and R2 are as defined above and R4 is hydrogen or optionally substituted straight or branched (C1-C6) alkyl, in acidic conditions, so as to obtain the compound of the formula (I)
wherein R1 and R2 as defined above, R3 is —NH2, R4 is hydrogen or optionally substituted straight or branched (C1-C6) alkyl, and R12 is hydrogen;
optionally converting a compound of the formula (I) into another different compound of the formula (I), and, if desired, converting a compound of the formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into the free compound (I).

### Claim 7 (depends on 1)

A method for treating a disease caused by and/or associated with a dysregulated protein kinase activity which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined in claim 1.

### Claim 8 (depends on 7)

The method according to claim 7 for treating a disease caused by and/or associated with a dysregulated JAK family kinase activity.

### Claim 9 (depends on 7)

The method according to claim 7 wherein the disease is selected from the group consisting of cancer, cell proliferative disorders, viral infections, immune-related disorders, neurodegenerative disorders and cardiovascular diseases.

### Claim 10 (depends on 9)

The method according to claim 9 wherein the cancer is selected from the group consisting of carcinoma such as bladder, breast, brain, colon, kidney, liver, lung, including small cell lung cancer, head and neck, esophagus, gall-bladder, ovary, uterine, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage including leukaemia, T and B acute lymphoblastic leukemia (ALL), including DS-ALL, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Multiple Myeloma, hairy cell lymphoma, Burkett's lymphoma and mantle cell lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, acute megakaryoblastic leukaemia, myelodysplastic syndrome and promyelocytic leukaemia, myeloproliferative disorders like Polycythemia Vera (PV), Essential Thrombocythemia (ET), Primary myelofibrosis and myelofibrosis secondary to PV and ET, chronic myelomonocytic leukemia; tumors of mesenchymal origin, including sarcoma, fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma neuroblastoma, glioma and schwannomas; other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma, mesothelioma.

### Claim 11 (depends on 9)

The method according to claim 9 wherein the cell proliferative disorder is selected from the group consisting of benign prostate hyperplasia, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis and post-surgical stenosis and restenosis.

### Claim 12 (depends on 9)

The method according to claim 9 wherein the viral infections comprise the prevention of AIDS development in HIV-infected individuals.

### Claim 13 (depends on 9)

The method according to claim 9 wherein the immune-related disorders is selected from the group consisting of transplant rejection, skin disorders like psoriasis, allergies, asthma and autoimmune-mediated diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease and amyotrophic lateral sclerosis.

### Claim 14 (depends on 9)

The method according to claim 9 wherein the neurodegenerative disorders is selected from the group consisting of Alzheimer's disease, degenerative nerve diseases, encephalitis, Stroke, Parkinson's Disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease, Pick's Disease and other.

### Claim 15 (depends on 9)

The method according to claim 9 wherein the cardiovascular diseases is selected from the group consisting of atherosclerosis primary or secondary to diabetes, heart attack and stroke.

### Claim 16 (depends on 10)

The method according to claim 10 further comprising subjecting the mammal in need thereof to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent.

### Claim 17 (depends on 7)

The method according to claim 7 wherein the mammal in need thereof is a human.

### Claim 18 (depends on 7)

The method according to claim 7 which provides tumor angiogenesis and metastasis inhibition.

### Claim 19 (depends on 1)

An in vitro method for inhibiting the JAK1, JAK2, JAK3 kinase protein activity which comprises contacting the said protein with an effective amount of a compound of formula (I) as defined in claim 1.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and at least one pharmaceutically acceptable excipient, carrier and/or diluent.

### Claim 21 (depends on 20)

A pharmaceutical composition according to claim 20 further comprising one or more chemotherapeutic agents.

### Claim 22 (depends on 1)

A product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.

### Claim at position 23

-25. (canceled)

### Claim 26

An intermediate of formula (IIIa):
wherein
R1 is ethyl and R2 is chlorine or CF3,
or
R1 is isopropyl and R2 is chlorine.