IDO inhibitors

• US 9,790,169 B2
• Filed: 04/01/2016
• Issued: 10/17/2017
• Est. Priority Date: 04/03/2015
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Syngene International Limited (Biocon Incorporated), Bristol-Myers Squibb Company
• Inventors: Balog, James Aaron, Cherney, Emily Charlotte, Guo, Weiwei, Huang, Audris, Markwalder, Jay A., Seitz, Steven P., Shan, Weifang, Williams, David K., Murugesan, Natesan, Nara, Susheel Jethanand, Roy, Saumya, Thangavel, Soodamani, Sistla, Ramesh Kumar, Cheruku, Srinivas, Thangathirupathy, Srinivasan, Kanyaboina, Yadagiri, Pulicharla, Nagalakshmi
• Primary Examiner(s): Ward, Paul V
• Application Number:
  US15/088,211
• Publication Number:
  US 20160289171A1
• Time in Patent Office: 564 Days
• Field of Search: None
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/382 having six-membered rings, e.g. thioxanthenes thiothixene A61K31/496
• CPC Class Codes: A61K 31/397 having four-membered rings, e.g. azetidine
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 229/42 : with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
• CPC Class Codes: C07C 233/81 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/38 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/56 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 255/57 : containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
• CPC Class Codes: C07C 255/58 : containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 275/30 : being further substituted by halogen atoms, or by nitro or nitroso groups
• CPC Class Codes: C07C 275/40 : being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 275/42 : being further substituted by carboxyl groups
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 207/08 : with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 207/12 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 211/08 : with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/10 : with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 239/47 : One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
• CPC Class Codes: C07D 265/30 : not condensed with other rings
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 277/64 : with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/22 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 309/04 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/14 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 317/46 : condensed with one six-membered ring
• CPC Class Codes: C07D 335/02 : not condensed with other rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or inflammatory disorders utilizing the compounds of the invention.

Claims

1. A compound of formula I

2. The compound according to claim 1 wherein R^x and R^y are H, methyl, or methoxy.

3. The compound according to claim 1 wherein R² and R³ are each independently H, methyl, ethyl, methoxymethyl, haloalkyl, or alkoxy.

4. The compound according to claim 1, wherein R¹ is —

COOH, —

CONHSO₂R¹⁴, —

NHSO₂R¹⁴, —

CHCF₃OH, or is selected from the group consisting of

5. The compound according to claim 4, wherein R¹ is —

COOH, —

CONHSO₂R¹⁴, —

NHSO₂R¹⁴, —

CHCF₃OH,

6. The compound according to claim 5 wherein R¹ is —

COOH.

7. The compound according to claim 1 wherein:

R⁴ is optionally substituted C₁ to C₆ alkyl, optionally substituted C₃ to C₆ cycloalkyl;

or selected from the group consisting of optionally substituted tetrahydropyranyl, optionally substituted azetidinyl, optionally substituted morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted piperazinyl, or an optionally substituted heterocyclic ring selected from

8. The compound according to claim 1, wherein R⁵ is —

H, optionally substituted C₁ to C₆ alkyl, or optionally substituted C₃ to C₆ cycloalkyl.

9. The compound according to claim 1, wherein R⁴ is C₁ to C₆ alkyl optionally substituted with hydroxyl;

C₃ to C₆ cycloalkyl, optionally substituted with at least one of C₁ to C₆ alkyl, hydroxyl, and/or alkoxy;

azetidinyl optionally substituted with hydroxyl, halo, or alkoxy;

tetrahydropyranyl;

morpholinyl optionally substituted with at least one of at least one of C₁ to C₆ alkyl and/or phenyl;

piperidinyl optionally substituted with at least one of C₁ to C₆ alkyl, phenyl and/or benzyl;

cyclohexyl;

pyrrolidinyl optionally substituted with at least one of —

OH, hydroxyalkyl, methoxyalkyl and/or haloalkyl;

piperazinyl optionally substituted with at least one of C₁ to C₄ alkyl and/or —

COOR¹³;

10. The compound according to claim 1, wherein R⁴ is optionally substituted C₁ to C₆ alkyl.

11. The compound according to claim 1, wherein R⁴ is optionally substituted tetrahydropyranyl.

12. The compound according to claim 1 wherein R⁴ is optionally substituted morpholinyl.

13. The compound according to claim 1 wherein R⁴ is optionally substituted piperidinyl.

14. The compound according to claim 1 wherein R⁴ is optionally substituted pyrrolidinyl.

15. The compound according to claim 1, wherein R⁴ and R⁵ are taken together with the nitrogen to which they are attached to form an optionally substituted heterocyclyl selected from the group consisting of morpholinyl, piperidinyl, azetidinyl, piperazinyl,

16. The compound according to claim 1, wherein R⁶ is optionally substituted phenyl;

optionally substituted pyrimidinyl;

optionally substituted pyridyl;

optionally substituted pyrazinyl, optionally substituted pyridazinyl, an optionally substituted heterocyclic ring selected from the group consisting of

17. The compound according to claim 1, wherein R⁶ is phenyl optionally substituted with from 1 to 3 substituents selected from C₁ to C₆ alkyl, —

CN, halo, alkoxy, haloalkoxy, and/or —

SO₂-alkyl.

18. The compound according to claim 1, wherein R⁶ is pyrimidinyl optionally substituted with at least one of C₁ to C₆ alkyl, C₁ to C₆ alkoxy, —

CN, and/or amino.

19. The compound according to claim 1, wherein R⁶ is pyridyl, optionally substituted with at least one of alkoxy, amino, and/or CONH₂.

20. The compound according to claim 1, wherein:

Y is CH or CF;

V is CH or CF;

R¹ is —

COOH;

R² and R³ are independently hydrogen, optionally substituted C₁ to C₆ alkyl, C₃ to C₆ cycloalkyl, phenyl, or R² and R³ join together with the carbon to which they are attached to form tetrahydropyranyl;

R⁴ is H, optionally substituted C₁ to C₆ alkyl, tetrahydropyranyl, optionally substituted cyclohexyl,

26. A method of inhibiting activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition comprising one or more compounds of claim 1 and a pharmaceutical carrier.

21. A compound that is

(S)-3-(4-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)(isobutyl)amino)-3-((2-methylbenzo[d]thiazol -5-yl)amino)phenyl)pentanoic acid;

(S)-3-(3-((2,2-difluorobenzo[d][1,3] dioxol-5-yl)amino)-4-((1,1-dioxidotetrahydro -2H-thiopyran-4-yl)(isobutyl)amino)phenyl)pentanoic acid;

(S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-fluorophenyl) amino)phenyl)pentanoic acid;

(S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-difluoromethody)phenyl)amino)phenyl)pentanoic acid;

(S)-3-(3-((4-cyanophenyl)amino)-4-(cyclohexyl(2-hydroxy-2-methylpropyl) amino)phenyl)pentanoic acid;

(S)-3-(4-(cyclohexyl(2-hydroxy-2-methylpropyl)amino)-3-((4-ethylphenyl) amino)phenyl)pentanoic acid;

(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-(p-tolylamino)phenyl)-4-methoxybutanoic acid;

(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4-ethylphenyl)amino)phenyl)-4-methoxybutanoic acid;

(S)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4-fluorophenyl)amino)phenyl)-4-methoxybutanoic acid;

(S)-3-(3-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid;

3-(3-((4-chlorophenyl) amino)-4-(cyclohexyl (isobutyl)amino)phenyl) pentanoic acid;

3-(4-(cyclohexyl(isobutyl) amino)-3-((4-ethylphenyl) amino)phenyl)pentanoic acid;

3-(3-((4-chloro-3-fluorophenyl)amino)-4-(cyclohexyl(isobutyl) amino)phenyl)pentanoic acid;

3-(4-(cyclohexyl(isobutyl) amino)-3-((4-fluorophenyl) amino)phenyl)pentanoic acid;

3-(4-(cyclohexyl(isobutyl) amino)-3-((4-(trifluoromethoxy)phenyl) amino)phenyl)pentanoic acid;

3-(4-(cyclohexyl(isobutyl) amino)-3-((4-ethoxyphenyl)amino) phenyl)pentanoic acid;

3-(3-((4-cyanophenyl) amino)-4-(cyclohexyl (isobutyl)amino)phenyl) pentanoic acid;

(R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl) amino)phenyl)pentanoic acid;

(R)-3-(3-((4-ethoxyphenyl) amino)-4-(ethyl (tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid;

(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4-(2,2,2-trifluoroethoxy) phenyl)amino)phenyl)pentanoic acid;

(R)-3-(3-((4-(cyclopropylmethoxy) phenyl)amino)-4-(ethyl(tetrahydro-2 H-pyran-4-yl) amino)phenyl)pentanoic acid;

(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((4-ethylphenyl)amino) phenyl)pentanoic acid;

(R)-3-(4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-3-((6-methoxypyridin-3-yl)amino)phenyl)pentanoic acid;

(R)-3-(4-(ethyl(tetrahydro-2 H-pyran-4-yl)amino)-3-((2-methoxypyrimidin-5-yl) amino)phenyl)pentanoic acid;

(R)-3-(3-((2-(cyclopropylmethoxy) pyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl) amino)phenyl) pentanoic acid;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21 that is (S)-3-(3-((4-chlorophenyl) amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino) phenyl)-4-methoxybutanoic acid

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21 that is 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-ethylphenyl) amino)phenyl)pentanoic acid

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

24. The compound of claim 21 that is (R)-3-(3-((2-Ethoxypyrimidin-5-yl)amino)-4-(ethyl(tetrahydro-2H-pyran-4-yl)amino)phenyl)pentanoic acid and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

25. The compound of claim 21 that is 3-(4-(cyclohexyl(isobutyl) amino)-3-((4-fluorophenyl) amino)phenyl)pentanoic acid and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.