# US 10,479,778 B2 · Substituted pyrroles active as kinases inhibitors

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- Number: US 10,479,778 B2
- Document ID: US10479778B2
- Status: Granted
- Kind: B2
- Application number: 15/599,025
- Filed: 2017-05-18
- Published: 2017-09-07
- Granted: 2019-11-19
- Earliest claimed: 2012-08-02
- Assignees: Nerviano Medical Sciences S.R.L.
- Applicants: NERVIANO MEDICAL SCIENCES S.r.l.
- Inventors: Maria Gabriella Brasca; Simona Bindi; Marina Caldarelli; Marcella Nesi; Sten Christian Orrenius; Achille Panzeri
- Web page: https://patentgrep.com/patent/US10479778B2

## CPC

- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/52: Purines, e.g. adenine
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 473/00: Heterocyclic compounds containing purine ring systems
- C07D 487/04: Ortho-condensed systems
- C07F 5/04: Esters of boric acids
- C07F 7/083: {Syntheses without formation of a Si-C bond}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- 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 pyrrole compounds which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular Jak family 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:
Ring W is a pyrrole;
R1 is a substituted aryl;
R2 is CN or CONR6R7 wherein 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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, 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 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R3 is hydrogen, halo or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R4 is an optionally substituted heteroaryl group selected from
wherein:
R8 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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl, COR9, CONR10R11 and SO2R12,
wherein:
R9 is a group optionally substituted 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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;
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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, 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 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S;
R12 is a group optionally substituted 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, aryl-alkyl, heteroaryl, heteroaryl-alkyl, heterocyclyl and heterocyclyl-alkyl;
R5 is hydrogen, halo or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound of the formula (I), as defined in claim 1, wherein R2 is CN.

### Claim 3 (depends on 1)

A compound of the formula (I), as defined in claim 1, wherein R2 is CONR6R7, wherein R6 and R7 are as defined in claim 1.

### Claim 4

A compound or a pharmaceutically acceptable salt thereof which is selected from the group consisting of:
1-(5-Chloro-2-methylphenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carbonitrile (compd 63);
1-(5-Chloro-2-ethylphenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carbonitrile (compd 68);
1-[2-Chloro-5-(trifluoromethyl)phenyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carbonitrile (compd 72);
3-(5-Chloro-2-methylphenyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 123);
3-(5-Chloro-2-ethylphenyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 124);
3-[2-Ethyl-5-(trifluoromethyl)phenyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 125);
3-(5-Chloro-2-methylphenyl)-N-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 129);
3-(5-Chloro-2-ethylphenyl)-N-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 130);
3-[2-Ethyl-5-(trifluoromethyl)phenyl]-N-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 131);
2-(5-Chloro-2-methylphenyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 191);
2-(5-Chloro-2-ethylphenyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 199);
2-[2-Chloro-5-(trifluoromethyl)phenyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 206);
2-[2-Methyl-5-(trifluoromethyl)phenyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 213);
2-[2-Ethyl-5-(trifluoromethyl)phenyl]-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 220);
1-(5-Chloro-2-methylphenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 229);
1-(5-Chloro-2-methylphenyl)-4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 234);
1-(5-Chloro-2-ethylphenyl)-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 237);
1-(5-Chloro-2-ethylphenyl)-4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 241);
1-[2-Chloro-5-(trifluoromethyl)phenyl]-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-2-carboxamide (compd 244);
4-(5-Chloro-2-methylphenyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 270);
2-(5-Chloro-2-ethylphenyl)-N-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 303);
2-[2-Methyl-5-(trifluoromethyl)phenyl]-N-methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 318); and
2-[2-Ethyl-5-(trifluoromethyl)phenyl]-N-methyl-5-(7H-pyrrolo[2,3-]pyrimidin-4-yl)-1H-pyrrole-3-carboxamide (compd 323).

### Claim 5 (depends on 1)

A process for preparing a compound of formula (I) as defined in claim 1 or the pharmaceutically acceptable salts thereof wherein the process comprises:
Step 1: reaction of a compound of formula (II)
wherein R1 and R3 are as defined in claim 1 and PG is a protecting group being benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
alternatively:
Step 1a: reaction of a halo compound of formula (III)
wherein R1 and R3 are as defined in claim 1, X is halogen, and PG is a protecting group being 2-(trimethylsilyl)ethoxymethyl or tert-butyloxycarbonyl,
with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 2: metal-catalyzed coupling reaction of the resultant compound of formula (IV)
wherein R1 and R3 are as defined in claim 1 and PG is a protecting group being 2-(trimethylsilyl)ethoxymethyl, tert-butyloxycarbonyl, or benzenesulfonyl with a halo compound of formula (V)
R4-x (V)
wherein R4 is as defined in claim 1 and X is halogen;
Step 3: deprotection of the resultant compound of formula (VI)
wherein R1, R3 and R4 are as defined in claim 1 and PG is a protecting group being 2-(trimethylsilyl)ethoxymethyl, tert-butyloxycarbonyl, or benzenesulfonyl to give a compound of formula (Ia)
wherein R1, R3 and R4 are as defined in claim 1, R2 is CN and R5 is hydrogen;
alternatively
Step 4: reaction of a compound of formula (VII)
wherein R1 and R3 are as defined in claim 1 and PG is a protecting group being benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 5: metal-catalyzed coupling reaction of the resultant compound of formula (VIII)
wherein R1 and R3 are as defined in claim 1 and PG is a protecting group being benzenesulfonyl with a halo compound of formula (V), as defined above;
Step 6: hydrolysis under basic conditions of the resultant carboxylic ester of formula (IX)
wherein R1, R3, and R4 are as defined in claim 1 and PG is as defined above;
Step 7: amidation of the resultant carboxylic acid of formula (X)
wherein R1, R3 and R4 are as defined in claim 1, through reaction with an amine of formula (XI)
NHR6R7 (XI)
wherein R6 and R7 are as defined in claim 1, to give a compound of formula (Ia)
wherein R2 is CONR6R7, R5 is hydrogen, R1, R3, R4, R6 and R7 are as defined in claim 1;
alternatively
Step 8: reaction of a halo compound of formula (XII)
wherein R1, R3 and R5 are as defined in claim 1 and X is halogen with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 9: metal-catalyzed coupling reaction of the resultant compound of formula (XIII)
wherein R1, R3 and R5 are as defined in claim 1, with a halo compound of formula (V), as defined above, to give a compound of formula (Ib)
wherein R1, R3, R4 and R5 are as defined in claim 1 and R2 is CN;
alternatively
Step 10: reaction of a compound of formula (XIV)
wherein R1, R3 and R5 are as defined in claim 1, with a halo compound of formula (V), as defined above, in the presence of a base or metal-catalyzed to give a compound of formula (Ic)
wherein R1, R3, R4 and R5 are as defined in claim 1 and R2 is CN;
alternatively
Step 11: reaction of a compound of formula (XV)
wherein R1 and R5 are as defined in claim 1 and PG is a protecting group being benzenesulfonyl with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 12: metal-catalyzed coupling reaction of the resultant compound of formula (XVI)
wherein R1 and R5 are as defined in claim 1 and PG is a protecting group being benzenesulfonyl with a halo compound of formula (V), as defined above;
Step 13: hydrolysis under basic conditions of the resultant carboxylic ester of formula (XVII)
wherein R1, R4 and R5 are as defined in claim 1 and PG is a protecting group as defined above;
Step 14: amidation of the resultant carboxylic acid of formula (XVIII)
wherein R1, R4 and R5 are as defined in claim 1, through reaction with an amine of formula (XI), as defined above, to give a compound of formula (Id)
wherein R1, R2, R4 and R5 are as defined in claim 1 and R3 is hydrogen;
alternatively
Step 15: reaction of a halo compound of formula (XIX)
wherein R1, R3 and R5 are as defined in claim 1, PG is a protecting group being tert-butyloxycarbonyl and X is halogen with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxyborolane;
Step 16: metal-catalyzed coupling reaction of the resultant compound of formula (XX)
wherein R1, R3 and R5 are as defined in claim 1 and PG is a protecting group being tert-butyloxycarbonyl, with a halo compound of formula (V), as defined above;
Step 17: deprotection of the resultant compound of formula (XXI)
wherein R1, R3, R4 and R5 are as defined in claim 1 and PG is a protecting group being tert-butyloxycarbonyl;
Step 18: reaction of the resultant compound of formula (XXII)
wherein R1, R3, R4 and R5 are as defined in claim 1, with an amine of formula (XI), as defined above, in the presence of triphosgene, to give a compound of formula (Ie)
wherein R2 is CONR6R7 and R1, R3, R4, R5, R6 and R7 are as defined above;
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 6 (depends on 5)

A process for preparing a compound of formula (I) according to claim 5, wherein the optional conversion of a compound of formula (I) into another compound of formula (I) is carried out by one or more of the following reactions:
conv.1) converting a compound of the formula (I), wherein R2 is CN, into the corresponding compound of formula (I), wherein R2 is CONH2, by hydrolyzing in acidic conditions,
conv.2) converting a compound of the formula (I), wherein R2 is CONH2, into the corresponding compound of formula (I), wherein R2 is CONR6R7 wherein R6 and R7 are independently hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, straight or branched C3-C6 alkenyl, straight or branched C2-C6 alkynyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, aryl, aryl-alkyl, heteroaryl, heteroaryl-alkyl, 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 7 membered heterocyclyl group optionally containing one additional heteroatom selected from N, O and S, but not both hydrogen
by exhaustive tert-butoxycarbonylation of a compound of the formula (I), treatment with an amine derivative of formula (XXIII)
NHR6R7 (XXIII)
wherein R6 and R7 are as defined above but not both hydrogen and deprotection of tert-butoxycarbonyl protecting groups;
conv.3) converting a compound of the formula (Ia), wherein R5 is hydrogen or (Id) wherein R3 is hydrogen, into the corresponding compound of formula (Ia) or (Id), wherein R5 or R3 respectively is an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, cycloalkyl-alkyl, heterocyclyl and heterocyclyl-alkyl,
by treatment with optionally substituted alkyl halide of the formula R5X (XXIV) or R3X (XXV), wherein R5 or R3 respectively is an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C7 cycloalkyl, heterocyclyl and heterocyclyl-alkyl, and X is halogen.

### Claim 7 (depends on 1)

A method for treating a disease, the disease selected from the group consisting of transplant rejection, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, atopic dermatitis, solid tumors, myelofibrosis, myeloproliferative disorders, polycythemia vera (PV), essential thrombocythemia (ET), acute myeloid leukemia (AML), chronic myelogenous leukemias (CML), and acute lymphoblastic leukemia (ALL), 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 wherein the mammal in need thereof is a human.

### Claim 9 (depends on 7)

The method according to claim 7 wherein said disease is selected from a carcinoma; hematopoietic tumors of lymphoid lineage; hematopoietic tumors of myeloid lineage; tumors of mesenchymal origin; and tumors of the central and peripheral nervous system.

### Claim 10 (depends on 7)

The method according to claim 7 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 11 (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 12 (depends on 11)

A pharmaceutical composition, according to claim 11, further comprising one or more chemotherapeutic agents.

### Claim 13 (depends on 1)

An in vitro method for inhibiting the JAK family 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 14 (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 15 (depends on 7)

The method according to claim 7, wherein said solid tumors are selected from melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoxanthoma, thyroid follicular cancer, Kaposi's sarcoma, and mesothelioma.

### Claim 16 (depends on 9)

The method according to claim 9, wherein: said carcinoma is selected from bladder, breast, brain, colon, kidney, liver, lung, small cell lung cancer, head and neck, esophagus, gall-bladder, ovary, uterine, pancreas, stomach, cervix, thyroid, prostate, skin, and squamous cell carcinoma; said hematopoietic tumors of lymphoid lineage are selected from leukaemia, T and B acute lymphoblastic leukemia (ALL), 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; said hematopoietic tumors of myeloid lineage are selected from acute and chronic myelogenous leukemias, acute megakaryoblastic leukemia, myelodysplastic syndrome, promyelocytic leukemia, Primary myelofibrosis and myelofibrosis secondary to PV, and ET; said tumors of mesenchymal origin are selected from sarcoma, fibrosarcoma and rhabdomyosarcoma; and said tumors of the central and peripheral nervous system are selected from astrocytoma neuroblastoma, glioma and schwannomas.