WO2013027168A1 - Novel heterocyclic compounds as bromodomain inhibitors - Google Patents

Novel heterocyclic compounds as bromodomain inhibitors Download PDF

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WO2013027168A1
WO2013027168A1 PCT/IB2012/054211 IB2012054211W WO2013027168A1 WO 2013027168 A1 WO2013027168 A1 WO 2013027168A1 IB 2012054211 W IB2012054211 W IB 2012054211W WO 2013027168 A1 WO2013027168 A1 WO 2013027168A1
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methyl
oxo
hydroxy
methylquinolin
tetrahydroquinazolin
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PCT/IB2012/054211
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French (fr)
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Paul Vincent Fish
Andrew Simon Cook
Christopher Phillips
Andrew Frank BENT
James Edward John Mills
Nunzio Sciammetta
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Pfizer Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel heterocyclic compounds which are effective as bromodomain inhibitors.
  • the present invention also relates to compositions comprising bromodomain inhibitors, and to methods for preparing such compounds.
  • the invention further relates to the use of these compounds to treat diseases or disorders that are bromodomain-dependent.
  • Bromodomain-containing proteins are of substantial biological interest, as
  • the BET family (BRD2, BRD3, BRD4 and BRDT) shares a common domain architecture featuring two amino-terminai bromodomains that exhibit high levels of sequence
  • BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008, 30, 51 -60). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4- NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al.
  • BRD-NUT fusion proteins contribute to carcinogensesis (Oncogene 2008, 27, 2237-2242).
  • BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division— suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al. Ce// 2004 117, 349-60).
  • BRD4 appears to be involved in the recruitment of the pTEF-P complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Ce// 2009 138, 129-145).
  • Bromodomain-containing protein 4 is a member of the BET family that in yeast and animals contains two tandem bromodomains (BDI and BDII) and an extraterminal (ET) domain.
  • BRD4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin.
  • four BET proteins (BRD2, BRD3, BRD4 and BRDT) exhibit similar gene arrangements, domain organizations, and some functional properties (Wu, S. et al., J. Biol. Chem. 2007, 282, 13141 -13145).
  • bromodomain binding agents e.g., WO 2009/084693, JP 2008/15631 1 , WO 2012/075383, WO 201 1/054553, WO
  • the present invention provides compounds of Formula (I):
  • L is -NR1 SO2- or -SO2NR2-;
  • Ri is H or alkyl, or taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl, wherein said
  • heterocycloalkyl is optionally substituted with one, two, three, four or five R9;
  • R 2 is H or alkyl;
  • Q is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with R 3 ;
  • R3 is independently selected from the group consisting of hydroxy, halogen, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, oxo, alkylsulfonyl, amino, alkylamino, dialkylannino and amido, wherein each hydroxy, alkyl, haloalkyi, alkyoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, oxo, alkylsulfonyl, amino, alkylamino, dialkylannino and amido is further optionally substituted with hydroxy, oxo, carboxy, carboxyalkyi, hydroxyalkyi, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyi, amino, alkylamino, dialkylannino, amido alkylamido, dialkylamido, halogen, alkyl
  • R 9 is independently selected from the group consisting of halogen, alkyl, haloalkyi, hydroxy, alkoxy, haloalkoxy, amino, alkylamino and dialkylannino;
  • A is N;
  • B is N or C
  • X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO 2 NR 2 - where R 2 is H, Q is 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
  • the present invention also provides compounds of Formula
  • L is -NR1 SO2- or -SO2NR2-;
  • Ri and R 2 are each independently H or alkyl
  • R , R 5 , R 6 , R7 and Rs are each independently selected from the group consisting of H, hydroxy, halogen, alkyl, alkoxy, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, haloalkyi, cyano, alkylsulfonyl, amino, alkyamino and dialkylamino; wherein each hydroxy, aryl, heteroaryl, cycloalkyi or heterocycloalkyi is optionally substituted with alkyl;
  • A is N;
  • B is N or C
  • X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO 2 NR 2 — where R 2 is H, R 4 or R 5 are each 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the present invention also provides a method of treating a disease or a disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).
  • the present invention further provides a method of inhibiting the bromodomain in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I)
  • the present invention is related to novel heterocyclic compounds of Formula (I), which are effective as bromodomain inhibitors.
  • the present invention is also related to compositions comprising bromodomain inhibitors, and to methods for preparing such compounds.
  • the heterocyclic compounds of the invention and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, or prodrugs show utility for inhibiting the bromodomain and treating diseases that are bromodomain-dependent.
  • alkyl whether used alone or as part of a substituent group refers to a saturated straight and branched carbon chain having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • Designated numbers of carbon atoms e.g. C-i-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl- containing substituent.
  • alkyl groups include methyl, ethyl, n- propyl, / ' so-propyl, n-butyl, sec-butyl, / ' so-butyl, te/t-butyl, and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Ci -6 alkyl) 2 , the alkyl groups may be the same or different.
  • alkoxy refers to groups of formula -Oalkyl. Designated numbers of carbon atoms (e.g. -OC-i-6) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, / ' so-propoxy, n-butoxy, sec-butoxy, / ' so-butoxy, te/t-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted.
  • alkenyl and alkynyl groups refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond (“alkenyl”) or at least one carbon-carbon triple bond (“alkynyl”). Where so indicated, alkenyl and alkynyl groups can be optionally substituted.
  • alkenyl groups include ethenyl, 3-propenyl, 1 -propenyl (also 2-methylethenyl), isopropenyl (also 2- methylethen-2-yl), buten-4-yl, and the like.
  • alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1 -yl, and 2-methyl-hex-4-yn-1 -yl.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1 , 2, or 3) double or triple bonds.
  • Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Where so indicated, cycloalkyl rings can be optionally substituted.
  • Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1 H- indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydro-azulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1 H-fluorenyl.
  • cycloalkyl also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1 .1 ]hexanyl, bicyclo[2.2.1 ]heptanyl, bicyclo[3.1 .1 ]heptanyl, 1 ,3- dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
  • Haloalkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms.
  • halogen refers to F, CI, Br and I.
  • Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2 CF 3 ).
  • the halogens can be the same (e.g., CHF 2 , -CF 3 ) or different (e.g., CF 2 CI).
  • haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen.
  • haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl,
  • aryl wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons.
  • Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1 -yl or naphthylen-2-yl). Where so indicated, aryl groups may be optionally substituted with one or more substituents.
  • Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
  • heterocyclydoalkyi is defined herein as a group having one or more rings ⁇ e.g., 1 , 2 or 3 rings) and having from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic.
  • the non-heteroatom bearing ring may be aryl (e.g., indolinyl,
  • heterocydoalkyi groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heterocydoalkyi group can be oxidized (e.g., N ⁇ O " , S(O), SO 2 ). Where so indicated, heterocydoalkyi groups can be optionally substituted.
  • Non-limiting examples of monocyclic heterocydoalkyi groups include, for example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5- tetrahydro-1 H-azepinyl, 2,3-dihydro-1 H-indole, and 1 ,2,3,
  • heteroaryl whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzo-thiophenyl, indolyl).
  • exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heteroaryl group can be oxidized (e.g., N ⁇ O " , S(O), SO 2 ). Where so indicated, heteroaryl groups can be substituted.
  • Non-limiting examples of monocyclic heteroaryl rings include, for example: 1 ,2,3,4-tetrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, triazinyl, thiazolyl, 1 /-/-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl.
  • heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- c/]pyrimidinyl, pyrido[2,3-c/]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 H-indolyl, 4,5,6,7- tetrahydro-1 -H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl.
  • heteroaryl group as described above is C-i-C 5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • C 1 -C5 heteroaryl examples include, but are not limited to for example, triazinyl, thiazol-2- yl, thiazol-4-yl, imidazol-1 -yl, 1 /-/-imidazol-2-yl, 1 /-/-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin- 2-yl, pyridin-3-yl, and pyridin-4-yl.
  • fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring.
  • 1 ,2,3,4- tetrahydroquinoline having the formula:
  • aryl ring When a ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:
  • heteroarylene whether used alone or as part of another group, is defined herein as a divalent single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms), wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic.
  • the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro- 5/-/-cyclopentapyrimidinylene) or aryl (e.g., benzofuranylene, benzothiophenylene, indolylene).
  • exemplary heteroarylene groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • One or more N or S atoms in a heteroarylene group can be oxidized (e.g., N ⁇ O " , S(O), SO 2 ). Where so indicated, heteroarylene groups can be substituted.
  • Non-limiting examples of monocyclic heteroarylene rings include, for example: 1 ,2,3,4-tetrazolylene, [1 ,2,3]triazolylene, [1 ,2,4]triazolylene, triazinylene, thiazolylene, 1 /-/-imidazolylene, oxazolylene, furanylene, thiopheneylene, pyrimidinylene, and pyridinylene.
  • heteroarylene rings containing 2 or more fused rings include: benzofuranylene, benzothiophenylene, benzoxazolylene, benzthiazolylene, benztriazolylene, cinnolinylene, naphthyridinylene, phenanthridinylene, 7/-/-purinylene, 9/-/-purinylene, 5H-pyrrolo[3,2- c/]pyrimidinylene, 7H-pyrrolo[2,3-c/]pyrimidinylene, pyrido[2,3-c ]pyrimidinylene, 2- phenylbenzo[d]thiazolylene, 1 H-indolylene, 4,5,6,7-tetrahydro-1 -H-indolylene,
  • quinoxalinylene 5-methylquinoxalinylene, quinazolinylene, quinolinylene, and
  • heteroarylene group as described above is C-i-C 5 heteroarylene, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S).
  • N nitrogen
  • O oxygen
  • S sulfur
  • C-i-C 5 heteroarylene examples include, but are not limited to for example, triazinylene, thiazol-2-ylene, thiazol-4-ylene, imidazol-1 -ylene, 1 /-/-imidazol-2-ylene, 1 /-/-imidazol-4-ylene, isoxazolin-5-ylene, furan-2-ylene, furan-3-ylene, thiophen-2-ylene, thiophen-4-ylene, pyrimidin-2-ylene, pyrinnidin-4-ylene, pyrimidin-5-ylene, pyridin-2-ylene, pyridin-3-ylene, and pyridin-4-ylene.
  • carbocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms.
  • a carbocyclic ring may be monocyclic, bicyclic or tricyclic.
  • a carbocyclic ring typically contains from 3 to 10 carbon ring atoms and is monocyclic or bicyclic.
  • heterocyclic ring refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms, in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur.
  • a heterocyclic ring may be monocyclic, bicyclic or tricyclic.
  • a heterocyclic ring typically contains from 3 to 10 ring atoms and is monocyclic or bicyclic.
  • amino refers to -NH 2 .
  • alkylamino refers to -N(H)alkyl.
  • alkylamino substituents include methylamino, ethylamino, and propylamino.
  • dialkylamino refers to -N(alkyl) 2 where the two alkyls may be the same or different.
  • dialkylamino substituents include dimethylamino, diethylamino, ethylmethylamino, and dipropylamino.
  • halogen refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
  • sulfonyl refers to -SO 2 -.
  • treat and “treating,” as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer.
  • therapeutically effective refers to a substance or an amount that elicits a desirable biological activity or effect.
  • subject or “patient” are used interchangeably and refer to mammals such as human patients and non-human primates, as well as
  • the term "subject” or "patient” as used herein means any mammalian patient or subject to which the compounds of the invention can be administered.
  • accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
  • substituted is used throughout the specification.
  • the term “substituted” is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1 -10) hydrogen atoms replaced by a substituent as defined herein below.
  • Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent.
  • substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like.
  • a two hydrogen atom replacement includes carbonyl, oximino, and the like.
  • Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like.
  • any number of its hydrogen atoms can be replaced, as described above.
  • difluoromethyl is a substituted Ci alkyl
  • trifluoromethyl is a substituted Ci alkyl
  • 4-hydroxyphenyl is a substituted aryl ring
  • (N,N-dimethyl-5-amino)octanyl is a substituted Cs alkyl
  • 3-guanidinopropyl is a substituted C3 alkyl
  • 2-carboxy-3- fluoropyridinyl is a substituted heteroaryl.
  • C -6 alkyl is specifically intended to individually disclose C-i , C 2 , C 3 , C 4 , C5 , C6 , C1 -C6 , C 1 -C5 , Ci-C 4 , C 1 -C3, C1 -C2, C2-C6 , C2-C5 , C2"C 4 , C2-C3, C3-C6 , C3-C5 ,
  • asymmetric atom also referred as a chiral center
  • some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers.
  • the present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and
  • Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis.
  • the present invention also includes cis and trans or E/Z isomers of compounds of Formula (I) containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin- layer chromatography, and high-performance liquid chromatography.
  • BTD4 refers to Bromodomain-containing protein 4, which is a member of the BET family.
  • the BET family comprises BRD2, BRD3, BRD4 and BRDT.
  • mammal refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
  • a TIMP1 modulator refers to encompasses either a decrease or an increase in activity or expression depending on the target molecule.
  • a TIMP1 modulator is considered to modulate the expression of TIMP1 if the presence of such TIMP1 modulator results in an increase or decrease in TIMP1 expression.
  • skin aging includes conditions derived from intrinsic chronological aging (for example, deepened expression lines, reduction of skin thickness, inelasticity, and/or unblemished smooth surface), those derived from photoaging (for example, deep wrinkles, yellow and leathery surface, hardening of the skin, elastosis, roughness, dyspigmentations (age spots) and/or blotchy skin), and those derived from steroid-induced skin thinning.
  • other therapeutic agents refers to any therapeutic agent that has been used, is currently used or is known to be useful for treating a disease or a disorder encompassed by the present invention.
  • solvate means a physical association of a compound with one or more solvent molecules, whether organic or inorganic, including water ('hydrate').
  • solvent molecules whether organic or inorganic, including water ('hydrate').
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil.
  • a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
  • a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
  • the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of the invention (e.g. a compound of Formula (I)) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • salts of the compounds of this invention are non-toxic “pharmaceutically acceptable salts.”
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic,
  • benzenesulfonic benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic,
  • Suitable organic acids generally include but are not limited to aliphatic, cydoaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, .beta.-hydroxybutyric acid, galactarate,
  • cyclopentanepropionate dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3- phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, ⁇ , ⁇ '-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • secondary, tertiary or quaternary amine salts such as tromethamine, diethylamine, ⁇ , ⁇ '-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
  • Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C.sub.1 - C.sub.6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
  • lower alkyl (C.sub.1 - C.sub.6) halides e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • prodrug refers to a pharmacologically inactive derivative of a parent "drug” molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release or convert the prodrug into the active drug.
  • Prodrugs are designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability.
  • Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug).
  • Some preferred prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions.
  • Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation).
  • Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21 - 24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352- 401 , Academic Press, San Diego, CA (1992)).
  • Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide).
  • a suitable alcohol e.g., a lower alkanol
  • amides prepared by reaction of the parent acid compound with an amine e.g., a lower alkylamide
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder.
  • a therapeutically effective amount preferably refers to the amount of a therapeutic agent that increases peak air flow by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
  • Bromodomain inhibitors may be used in the treatment of a wide variety of chronic autoimmune and inflammatory diseases such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and
  • Bromodomain inhibitors may be used in the treatment of a variety of diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the treatment of viral infections.
  • Bromodomain inhibitors may be used in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.
  • Bromodomain inhibitors may be used in the treatment of diseases or disorders which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic
  • SIRS inflammatory response syndrome
  • multi-organ dysfunction syndrome toxic shock syndrome
  • acute lung injury ARDS (adult respiratory distress syndrome)
  • acute renal failure fulminant hepatitis
  • burns acute pancreatitis
  • post-surgical syndromes sarcoidosis
  • Herxheimer reactions encephalitis, myelitis, meningitis, malaria
  • SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
  • Bromodomain inhibitors may be used in the treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • ischaemia-reperfusion injury such as myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
  • Bromodomain inhibitors may be used in the treatment of disorders of lipid
  • APO-A1 metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
  • Bromodomain inhibitors may be used in the treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be used in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses.
  • Bromodomain inhibitors may be used in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
  • the disease or disorder for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia.
  • the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality.
  • the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome).
  • the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock or
  • the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain inhibitor is indicated for the treatment of burns.
  • the disease or disorder for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus.
  • a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
  • Bromodomain inhibitors may be used in the treatment of cancer, including
  • hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.
  • the compounds described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosol ization or inhalation spray, rectally,
  • parenteral intracisternally, intravaginally, intraperitoneally, bucally, intrathecally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired.
  • parenteral as used herein includes
  • Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
  • compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein.
  • delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
  • the compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
  • compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder.
  • Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
  • Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate bromodomain activity, or to alleviate symptoms of diseases associated with bromodomains activity or susceptible to bromodomain activity modulation.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
  • kits that include one or more compounds of the invention are provided.
  • Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for treating a chronic autoimmune and/or inflammatory condition and cancer by administering an effective amount of a compound of the present invention.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide, such
  • excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound.
  • excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • a "pharmaceutically/therapeutically effective amount” means an amount which is capable of providing a therapeutic and/or prophylactic effect.
  • the specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated.
  • a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50- 100 mg/kg of body weight of an active compound of the invention.
  • Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg.
  • Factors such as clearance rate, half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
  • IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. The value depends on the assay used.
  • One aspect of the invention relates to compounds of Formula (I):
  • dotted line may be a single bond or a double bond
  • L is -NR1SO2- (Q is bound to the N) or -SO 2 NR 2 - (Q is bound to the S);
  • Ri is H or alkyl, or taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl, wherein said
  • heterocycloalkyl is optionally substituted with R 9 ;
  • R 2 is H or alkyl
  • Q is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with R 3 ;
  • R 3 is independently selected from the group consisting of hydroxy, halogen, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or cyano, oxo, alkylsulfonyl, amino, alkylamino, dialkylamino and amido, wherein each hydroxy, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, oxo, alkylsulfonyl, amino, alkylamino, dialkylamino or amido is further optionally substituted with hydroxy, oxo, carboxy, carboxyalkyi, hydroxyal
  • R 9 is independently selected from the group consisting of halogen, alkyl, haloalkyi, hydroxy, alkoxy, haloalkoxy, amino, alkylamino and dialkylamino;
  • A is N;
  • B is N or C
  • X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO 2 NR 2 - where R 2 is H, Q is 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
  • the present invention relates to any of the aforementioned compounds, wherein L is -NHSO2-.
  • the present invention relates to any of the aforementioned compounds, wherein L is -SO 2 NH-
  • the present invention relates to any of the aforementioned compounds, wherein Ri is H.
  • the present invention relates to any of the aforementioned compounds, wherein R-i is Ci -6 alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein R-i is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein Ri taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl. In certain embodiments, the present invention relates to any of the aforementioned
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is C h alky!.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 , 2, 3, 4 or 5 R 3 .
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 , 2 or 3 R3.
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 R 3 .
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 2 R 3 .
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 3 R 3 .
  • the present invention relates to any of the aforementioned compounds, wherein Q is substituted with at least one hydroxy, halogen or C h alky!.
  • the present invention relates to any of the aforementioned compounds, wherein Q is aryl.
  • the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with hydroxy, halogen or Ci -6 alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with cyano. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with aryl, heteroaryl or cycloalkyi.
  • the present invention relates to any of the aforementioned compounds, wherein Q is heteroaryl.
  • the present invention relates to any of the aforementioned compounds, wherein Q is heteroaryl optionally substituted with hydroxy, halogen or alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein Q is cycloalkyi .
  • the present invention relates to any of the aforementioned compounds, wherein Q is heterocycloalkyl
  • the present invention relates to any of the aforementioned compounds, wherein Q is azetidin-1 -yl, pyrrol id in-1 -yl, piperidin-1 -yl or azepan-1 -yl, optionally substituted with substituents independently selected from the group consisting of C-i-6alkyl, hydroxy, halogen, alkoxy, amino, alkylamino and dialkylamino.
  • the present invention relates to any of the aforementioned compounds, wherein B is N.
  • the present invention relates to any of the aforementioned compounds, wherein B is C.
  • the present invention relates to any of the aforementioned compounds, wherein the dotted line is a single bond.
  • the present invention relates to any of the aforementioned compounds, wherein the dotted line is a double bond.
  • the present invention relates to any of the aforementioned compounds, wherein B is N; and the dotted line is a single bond.
  • the present invention relates to any of the aforementioned compounds, wherein X is H.
  • the present invention relates to any of the aforementioned compounds, wherein X is C h alky!.
  • the present invention relates to any of the aforementioned compounds, wherein X is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is H.
  • the present invention relates to any of the aforementioned compounds, wherein Y is C h alky!.
  • the present invention relates to any of the aforementioned compounds, wherein Y is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein Z is H.
  • the present invention relates to any of the aforementioned compounds, wherein Z is Ci -6 alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein Z is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein Y is methyl; B is N; the dotted line is a single bond; and L is - SO 2 NR 2 -.
  • the present invention relates to any of the aforementioned compounds, wherein Y is methyl; B is C; the dotted line is a double bond; and L is - SO 2 NR 2 -.
  • the present invention also provides compounds of Formula
  • L is -NR1 SO2- or -SO2NR2-;
  • Ri is H or alkyl
  • R2 is H or alkyl
  • R , R 5 , R 6 , R7 and Rs are each independently selected from the group consisting of H, hydroxy, halogen, alkyl, alkoxy, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, haloalkyi, cyano, alkylsulfonyl, amino, alkyamino and dialkylamino; wherein each hydroxy, aryl, heteroaryl, cycloalkyi or heterocycloalkyi is optionally substituted with alkyl;
  • A is N;
  • B is N or C
  • X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO 2 NR 2 - where R 2 is H, R 4 or R 5 are each 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
  • the present invention relates to any of the aforementioned compounds, wherein L is -NHSO 2 -
  • the present invention relates to any of the aforementioned compounds, wherein L is -SO2NH-.
  • the present invention relates to any of the aforementioned compounds, wherein R-i is H.
  • the present invention relates to any of the aforementioned compounds, wherein Ri is Chalky!.
  • the present invention relates to any of the aforementioned compounds, wherein R-i is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein R-i taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyi
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 2 is Ci -6 alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R 2 is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein R 4 , R 5 , R6 , R7 and Rs are each independently H, hydroxy, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, haloalkyl or cyano.
  • the present invention relates to any of the aforementioned compounds, wherein R is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 5 is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 6 is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 7 is H.
  • the present invention relates to any of the aforementioned compounds, wherein R 8 is H.
  • the present invention relates to any of the aforementioned compounds, wherein B is N.
  • the present invention relates to any of the aforementioned compounds, wherein B is C.
  • the present invention relates to any of the aforementioned compounds, wherein the dotted line is a single bond.
  • the present invention relates to any of the aforementioned compounds, wherein the dotted line is a double bond.
  • the present invention relates to any of the aforementioned compounds, wherein X is H.
  • the present invention relates to any of the aforementioned compounds, wherein X is Chalky! .
  • the present invention relates to any of the aforementioned compounds, wherein X is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is H.
  • the present invention relates to any of the aforementioned compounds, wherein Y is C h alky!.
  • the present invention relates to any of the aforementioned compounds, wherein Y is methyl.
  • the present invention relates to any of the aforementioned compounds, wherein Z is H.
  • the present invention relates to any of the aforementioned compounds, wherein Z is Ci -6 alkyl.
  • the present invention relates to any of the aforementioned compounds, wherein Z is methyl.
  • the compounds include:
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a method of treating a disease or a disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of any one of the aforementioned compounds or aforementioned pharmaceutical composition.
  • the present invention relates to any of the aforementioned methods, wherein the disease or disorder is selected from the group consisting of chronic autoimmune disease, inflammatory disease and cancer.
  • the present invention relates to any of the aforementioned methods, wherein the treatment of a disease or a disorder further comprises administering an additional therapeutic agent.
  • Another aspect of the invention relates to a method for inhibiting bromodomain in a cell, comprising contacting the cell with a therapeutically effective amount of any one of the aforementioned compounds or aforementioned pharmaceutical composition.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by
  • GC chromatography
  • GPC gel-permeation chromatography
  • Preparation of the compounds can involve protection and deprotection of various chemical groups.
  • the chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes.
  • Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • the compounds of these teachings can be prepared by methods known in the art.
  • the reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds of the present invention can be prepared according to the methods illustrated in the following Synthetic Schemes.
  • DAD diode array detector
  • DBTTBP di-tert-butyl(2 ⁇ 4 ⁇ 6'-tnisopropyl-3,4,5,6-tetramethyl-[1 ,1 '-biphenyl]-2-yl) ⁇
  • DMEDA A/ 1 ,A/ 2 -dimethylethane-1 ,2-diamine
  • DMSO dimethyl sulfoxide
  • EDTA ethylenediaminetetracetic acid
  • ELSD evaporative light scattering detection
  • HCI hydrochloric acid
  • KF-AI 2 O 3 potassium fluoride on aluminum oxide
  • KNO 3 potassium nitrate
  • MgSO 4 magnesium sulfate
  • Na 2 SO 4 sodium sulfate
  • NBS /V-bromosuccinimide
  • Pd/C palladium on carbon
  • Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium
  • MS mass spectra, MS (m/z), were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI).
  • ESI electrospray ionisation
  • APCI atmospheric pressure chemical ionisation
  • HPLC High Performance Liquid Chromatography
  • Detection was achieved using a Shimadzu SPD-20AV or Waters 2998 PDA wavelength absorbance detector set at 220 or 200 nm followed in series by a Shimadzu MS201 OEV or Waters 3100 mass spectrometer.
  • the Shimadzu MS201 OEV MS was tuned with the following parameters:
  • the fraction collection was triggered by both MS.
  • the Waters 3100 MS was tuned with the following parameters:
  • Desolvation gas 800 (L/H)
  • Source Temp 130 °C.
  • the fraction collection was triggered by MS or by UV.
  • Quality control (QC) analysis was performed using a LCMS method. Acidic runs were carried out on a Shimadzu XB-C18 (2.1 x 30 mm, 5 ⁇ ), X-Bridge (50 x 4.6 mm, 5 ⁇ ), Gemini NX C18 (50 x 4.6, 3 ⁇ ), or Gemini NX C18 (50 x 4.6, 5 ⁇ ). A flow rate of 1 .0-1 .2 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B:
  • acetonitrile + 0.1 % modifier (v/v).
  • the modifier was trifluoroacetic acid.
  • a Shimadzu 20AB pump ran a gradient elution from 0% to 98% B over 2 min followed by a 1 min hold at 95% B. Detection was achieved using a Shimadzu 10A detector set at 220 or 260 nm followed in series by a Shimadzu MS2010EV or Applied Biosystem API 2000 mass spectrometer in parallel.
  • the Shimadzu MS2010EV MS was tuned with the following parameters:
  • ES+ Cone voltage 25 v
  • ES- Cone voltage -30 v
  • Desolvation gas Nitrogen Source Temp: 250°C. Scan range 100-1000 Da
  • Scan range 100-800 Da
  • the modifier was formic acid, for basic run the modifier was diethylamine.
  • Detection was achieved using a Waters 2487 dual wavelength absorbance detector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.
  • the PL 2100 ELSD was set at 30°C with 1 .6 L/min supply of Nitrogen.
  • the Waters ZQ MS was tuned with the following parameters:
  • the fraction collection was triggered by both MS and ELSD.
  • Quality control (QC) analysis was performed using a LCMS method. Acidic runs were carried out on a Sunfire C18 (4.6 x 50 mm, 5 ⁇ ), basic runs were carried out on a Xterra C18 (4.6 x 50 mm, 5 ⁇ ), both from Waters. A flow rate of 1 .5 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v). For acidic runs the modifier was formic acid, for basic run the modifier was ammonia. A Waters 1525 binary LC pump ran a gradient elution from 5% to 95% B over 3 min followed by a 1 min hold at 95% B.
  • Detection was achieved using a Waters MUX UV 2488 detector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel.
  • the PL 2100 ELSD was set at 30°C with 1 .6 L/min supply of Nitrogen.
  • the Waters ZQ MS was tuned with the following parameters:
  • Desolvation gas 800 L/hr
  • Source Temp 150°C.
  • reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature.
  • compounds in the genus were prepared by the following schemes.
  • Step 1 Preparation of 3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride, Intermediate 1 : 3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one (5.0g, 30.83 mmol) was added to chlorosulfonic acid (15 mL) at 0 °C. The reaction was permitted to warm to room temperature and the pale orange solution was stirred at room temperature for 2 h. The reaction mixture was quenched by addition of ice and the resultant white solid was removed by filtration.
  • Step 2 Preparation of 3-methyl-2-oxo-/V-phenyl-1 ,2,3,4-tetrahydro- quinazoline-6-sulfonamide (6): A white suspension of Intermediate 1 (200 mg, 0.767 mmol) in DCM (2.0 mL) was treated with pyridine (200 ⁇ , 2.5 mmol, 3.2 equiv.) and aniline (2.2 mmol, 2.9 equiv.). The reaction stirred at room temperature overnight and was then concentrated and slurried with 2M aqueous HCI solution.
  • Step 1 Preparation of 3-methyl-6-nitro-3,4-dihydroquinazolin-2(1 /-/)-one,
  • Step 2 Preparation of 6-amino-3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one,
  • Step 3 Preparation of 2-fluoro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro- quinazolin-6-yl)benzenesulfonamide (10): A solution of Intermediate 3 (100 mg, 0.42 mmol,) in DCM (10 ml_) was treated with pyridine (200 ⁇ _, 2.5 mmol, 5.9 equiv.) and 2- fluorobenzene-1 -sulfonyl chloride (0.63 mmol, 1 .5 equiv). The reaction was stirred at room termperature for 2 h, concentrated, and the residue was partitioned between EtOAc and 2N HCI (aq).
  • Step 1 Preparation of 6-bromo-3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one,
  • Step 2 Method A: Preparation of A/-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide (25): A solution of Intermediate 4 (200 mg, 0.83 mmol) in anhydrous dioxane (10 mL) was treated with benzenesulfonamide (1 .24 mmol, 1 .5 equiv.) and
  • CS2CO3 (405 mg, 1 .24 mmol, 1 .5 equiv.). After degassing with N 2 bubbling, the reaction was treated with DBTTBP (63 mg, 0.132 mmol, 0.16 equiv) and Pd 2 (dba) 3 (83 mg, 0.091 mmol, 0.1 1 equiv). The reaction was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc and filtered through a pad of celite.
  • Step 2 Method B: Preparation of 3-methoxy-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro- quinazolin-6-yl)benzenesulfonamide (27): A solution of Intermediate 4 (200 mg, 0.83 mmol) in anhydrous dioxane (10 mL) was treated with 3-methoxybenzenesulfonamide (1 .66 mmol, 2.0 equiv.), DMEDA (89 ⁇ , 0.83 mmol, 1 equiv.), Cul (158 mg, 0.83 mmol, 1 equiv.), and KF-AI2O3 (40 wt%, 601 mg, 4.1 mmol, 5 equiv).
  • the reaction was heated under N 2 at 1 10 °C for 18 h.
  • the reaction mixture was filtered through celite and after rinsing the celite with EtOAc, the filtrate was concentrated to a blue solid that was then dissolved in MeOH and passed through a 5g SCX cartridge eluting with excess MeOH.
  • the reaction was treated with KF-AI 2 O 3 (40 wt%, 130 mg, 2.23 mmol, 5.0 equiv.) and Cul (84.9 mg, 0.446 mmol, 1 .0 equiv.) and the reaction was placed in a preheated bath at 130 °C. The reaction was heated for 1 .5 h. After cooling, the reaction was filtered through a plug of arbosel and washed with EtOAc. The organic phase was then washed with EDTA solution, dried over MgSO 4 , filtered, and concentrated.
  • KF-AI 2 O 3 40 wt%, 130 mg, 2.23 mmol, 5.0 equiv.
  • Cul 84.9 mg, 0.446 mmol, 1 .0 equiv.
  • Step 1 To sodium (2-formyl)benzenesulfonate (5.0 g, 24.038 mmol), thionyl chloride (19.74 ml, 270.433 mmol) was added at room temperature followed by the addition of catalytic DMF (0.3 mL). The reaction mixture was stirred at room temperature for two minutes and then refluxed for three minutes. The reaction mixture was then cautiously poured into ice water and extracted with hexane. The combined organic layers were washed with brine and dried (Na 2 SO ).
  • Step 2 To a stirred solution of 6-amino-3-methyl-1 H-quinolin-2-one (0.25 g, 1 .44 mmol) in pyridine (5 ml), was added (2-formyl)benzenesulfonyl chloride (0.439 g, 2.155 mmol) and resulting mixture was stirred at room temperature for 3 h. After completion of reaction (by TLC) it was diluted with ethyl acetate and water. Organic layer was separated and aqueous layer was back-extracted with ethyl acetate. Combined organic layer was washed with brine and dried over Na 2 SO 4 .
  • Step 3 To a stirred solution of 2-formyl-N-(3-methyl-2-oxo-1 ,2-dihydro-quinolin-6-yl)- benzene-sulfonamide (0.49 g, 1 .44 mmol) and morpholine (0.13 mL, 1 .44 mmol) in dry THF (30 ml) was added sodium triacetoxyborohydride (456 mg, 2.15 mmol) and the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na 2 SO and
  • Step 4 Sodium borohydride (0.055 g, 1 .46 mmol) was added to a stirred solution of 3-methyl-6-(3-morpholin-4-yl-1 ,1 -dioxo-1 ,3-dihydro-1 A * 6 * -benzo[d]isothiazol-2-yl)-1 H- quinolin-2-one (0.3 g, 0.73 mmol) in dry THF (15 ml_) at room temperature and the reaction mixture was stirred for 2 h. After completion of reaction, it was diluted with ethyl acetate and washed with aqueous NaHCO3 solution, brine and dried over Na 2 SO 4 and concentrated.
  • Step 1 To a stirred solution of 2-mercaptophenol (5g, 39.7 mmol) in DMF (50 ml) was added solid KHCO3 (4.36 g, 43.6 mmol) followed by benzyl bromide (4.7 ml, 39.7 mmol). The reaction mixture was stirred at room temperature for 16h and then filtered through a pad of celite. The precipitate was washed with ether. The combined filtrates were washed with water followed by brine, dried over Na 2 SO , and concentrated.
  • Step 2 To a stirred solution of 2-benzylsulfanyl-phenol (4 g, 18.7 mmol) in acetonitrile (40 ml) was added K 2 CO 3 (3.86 g, 28.03 mmol) followed by methyl
  • Step 3 To a solution of (2-benzylsulfanyl-phenoxy)-acetic acid methyl ester (200 mg, 0.695 mmol) in acetonitrile (7 ml_), acetic acid (0.3 ml) and water (0.2 ml_) was added trichloroisocyanuric acid (325 mg, 1 .39 mmol). The reaction mixture was then stirred at room temperature for 16 h. The solvent was evaporated and the residue was diluted with 25% ethyl acetate in hexane, which gave a white precipitate. The precipitate was filtered and the filtrate was concentrated.
  • Step 4 To a solution of (2-chlorosulfonyl-phenoxy)-acetic acid methyl ester (200 mg, 0.758 mmol) in neat pyridine (7 ml_) was added 6-amino-3-methyl-1 H-quinolin-2-one and the mixture was stirred for 96 h at room temperature. The reaction was diluted with ethyl acetate and then washed with saturated copper sulfate solution followed by 1 N HCI.
  • Tetramethyl-di-t-butyl-XPhos (81 mg, 0.17 mmol) and Pd 2 (dba) 3 (106 mg, 0.1 1 mmol) were added and the mixture was degassed again. The mixture was heated under reflux for 2 h, cooled, filtered through Celite, and concentrated. The residue was partitioned between water and ethyl acetate. The ethyl acetate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative tic to afford 39 (39 mg) as a solid.
  • Step 1 To a stirred solution of 3-methyl-6-nitro-1 H-quinolin-2-one (700 mg, 3.43 mmol) in DMF (15 ml) was added potassium t-butoxide (4.1 ml, 1 M in THF) followed by iodomethane (0.43 ml, 6.86 mmol) with ice cooling. The reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was poured onto crushed ice, and the precipitated solid was collected by filtration, washed with water and dried. The solid was triturated with ether to afford 1 ,3-dimethyl-6-nitro-1 H-quinolin-2-one as an off white solid (500 mg, 67%).
  • Step 2 To a stirred solution of 1 ,3-dimethyl-6-nitro-1 H-quinolin-2-one (500 mg, 2.29 mmol) in THF: EtOH: H 2 O (4:2:1 , 70 ml) were added iron powder (896 mg, 16 mmol) and NH 4 CI (613 mg, 1 1 .47 mmol). The reaction mixture was heated at 50° C for 3 h. The reaction mixture was filtered through a short pad of Celite. The filtrate was evaporated and the residue was diluted with ethyl acetate, washed with water, brine, dried over Na 2 SO 4 and filtered.
  • Step 1 To a stirred solution of 6-bromo-3-methyl-1 H-quinolin-2-one (1 .00 g, 4.2 mmol) in dioxane (20 mL) were added diisopropylethylamine (1 .53 mL, 8.8 mmol),
  • Step 2 To a solution of 6-benzylsulfanyl-3-methyl-1 H-quinolin-2-one (200 mg, 0.71 mmol) in 9 ml_ of acetic acid and 1 ml_ of water was added N-chlorosuccinimide (285 mg, 2.13 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with approximately 30 ml_ of water to yield a light brown precipitate, which was filtered, washed with water and dried to afford 3-methyl-2-oxo-1 ,2-dihydro-quinoline-6-sulfonyl chloride as a pale brown solid (166 mg, 90%).
  • Step 3 To a suspension of 3-methyl-2-oxo-1 ,2-dihydro-quinoline-6-sulfonyl chloride (166 mg, 0.64 mmol) in 5 ml_ of dichloromethane was added pyrrolidine (0.53 ml_, 6.4 mmol) to give a brown solution. The mixture was stirred at room temperature for 30 min, then concentrated in under reduced pressure. The residue was stirred with 2 M HCI , filtered, washed with water, and dried under high vacuum to afford 44 as a light brown solid (160 mg, 85%).
  • Each vial was treated with 12 mg (100 umole) of DMAP, after which the vials were stirred for 16 h at 60 °C.
  • the reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 45 °C).
  • Each of the crude products was dissolved in 1 ml_ of DMSO. 10 ⁇ _ of the DMSO solution was diluted to 200 ⁇ _ with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters
  • reaction mixtures were evaporated in a Thermo Explorer (2 h, 5 torr, at 45 °C). Each of the crude products was dissolved in 1 ml_ of DMSO. 10 ⁇ _ of the DMSO solution was diluted to 200 ⁇ _ with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 90: Calculated molecular weight 346.1 ; found MH+ 347.16.
  • 6-Amino-3-methyl-3,4-dihydro-1 H-quinazolin-2-one 100 ⁇ was charged to each vial.
  • Anhydrous DMA (1 to 2 mL) and triethylamine (300 umol) was added to each vial.
  • Each sulfonyl chloride monomer for example cyclopropanesulfonyl chloride, was added to each vial, after which the vials were stirred for 16 h at room temperature.
  • the reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 40 °C). Each of the crude products was dissolved in 1 mL of DMSO.
  • Step 1 To an ice cold solution of concentrated HNO3 (3 ml) and concentrated H2SO4 (6 ml), 3-methyl-1 H-quinolin-2-one (1 .2 g, 7.55 mmol, Heterocycles, 2005, 65, p. 2095 - 2105) was added in small portions. The mixture was stirred additional 2 h with ice cooling. After completion of reaction (monitored by TLC), the mixture was poured into ice. The solid thus formed was filtered, washed with water and dried to afford 3-methyl-6-nitro- 1 H-quinolin-2-one (0.8 g, 52%) as yellow solid.
  • Step 2 To a degassed solution of 3-methyl-6-nitro-1 H-quinolin-2-one (5 g, 24.63 mmol) in acetic acid (200 ml) was added 10% palladium on carbon (5.22 g). The reaction mixture was placed on a Parr low pressure hydrogenation apparatus and hydrogenated at 50 psi for 3 h. After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite. The filtrate was evaporated under reduced pressure, and the residue was triturated with ethyl acetate to afford 6-amino-3-methyl-1 H-quinolin-2-one (3.1 g, 72%) as a brown solid.
  • Step 1 To a stirred solution of 3-methyl-3, 4-dihydro-1 H-quinazolin-2-one (5 g, 30.8 mmol) in sulfuric acid (25 ml) was added potassium nitrate (3.12 g, 30.86 mmol) in portions at 0 ° C. The reaction mixture was allowed to attain room temperature and was stirred for an additional 3 h, after which it was poured into ice water. The yellow precipitate thus formed was collected by filtration, washed with water and dried. This was purified over neutral alumina to afford 3-methyl-6-nitro-3,4-dihydro-1 H-quinazolin-2-one as a yellow solid (3.5 g, 55 %).
  • Step 2 3-Methyl-6-nitro-3,4-dihydro-1 H-quinazolin-2-one (18 g, 86.95 mmol) was dissolved in acetic acid (250 ml) and hydrogenated over Raney nickel (about 4.0 g) in a Parr low pressure hydrogenation apparatus at 30 psi pressure for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1 M sulfuric acid solution (720 ml) and neutralized it using saturated sodium bicarbonate solution.
  • Recombinant Human Bromodomain (BRD4) was expressed in E. coli cells pNIC-28-Bsa4 with a six-His tag at the N-terminus.
  • the His-tagged Bromodomain was extracted from E. coli cells and then purified by affinity chromatography using a Ni chelate column, eluting with a linear 10-500mM Imidazole gradient. Further purification was completed by S75 16/60 HiLoad size exclusion column. Protein integrity was assessed by SDS-PAGE and electro-spray mass spectrometry using an Agilent 1 100 series LC/MSD TOF. Purified protein was stored at -80'C in 10 mM HEPES pH7.5, 500 mM NaCI and 5% glycerol.

Abstract

Disclosed are compounds of Formula (I): (I) which are useful as bromodomain inhibitors. Pharmaceutical compositions containing compounds of Formula (I) and the use of compounds of Formula (I) to treat diseases or disorders that are bromodomain-dependent are also disclosed. Methods for preparing and using these compounds are further described.

Description

NOVEL HETEROCYCLIC COMPOUNDS AS BROMODOMAIN INHIBITORS
RELATED APPLICATIONS
The present invention claims priority under 35 USC 1 19(e) to United States
Provisional Application No, 61/526,004, filed on August 22, 201 1 , which is hereby incorporated by reference in its entirety.
FIELD
The present invention relates to novel heterocyclic compounds which are effective as bromodomain inhibitors. The present invention also relates to compositions comprising bromodomain inhibitors, and to methods for preparing such compounds. The invention further relates to the use of these compounds to treat diseases or disorders that are bromodomain-dependent.
BACKGROUND
Bromodomain-containing proteins are of substantial biological interest, as
components of transcription factor complexes and determinants of epigenetic memory. The BET family (BRD2, BRD3, BRD4 and BRDT) shares a common domain architecture featuring two amino-terminai bromodomains that exhibit high levels of sequence
conservation, and a more divergent carboxy-termina! recruitment domain (Filippakopoulos, P. et al., Nature 2010, 468, 1067-1073). BRD2 and BRD3 are reported to associate with histones along actively transcribed genes and may be involved in facilitating transcriptional elongation (Leroy et al, Mol. Cell. 2008, 30, 51 -60). It has also been reported that BRD4 or BRD3 may fuse with NUT (nuclear protein in testis) forming novel fusion oncogenes, BRD4- NUT or BRD3-NUT, in a highly malignant form of epithelial neoplasia (French et al. Cancer Res., 2003, 63, 304-307 and French et al. J. Clin. Oncol. 2004, 22, 4135-4139). Data suggests that BRD-NUT fusion proteins contribute to carcinogensesis (Oncogene 2008, 27, 2237-2242). BRD-t is uniquely expressed in the testes and ovary. All family members have been reported to have some function in controlling or executing aspects of the cell cycle, and have been shown to remain in complex with chromosomes during cell division— suggesting a role in the maintenance of epigenetic memory. In addition some viruses make use of these proteins to tether their genomes to the host cell chromatin, as part of the process of viral replication (You et al. Ce// 2004 117, 349-60). BRD4 appears to be involved in the recruitment of the pTEF-P complex to inducible genes, resulting in phosphorylation of RNA polymerase and increased transcriptional output (Hargreaves et al, Ce// 2009 138, 129-145).
Bromodomain-containing protein 4 (BRD4) is a member of the BET family that in yeast and animals contains two tandem bromodomains (BDI and BDII) and an extraterminal (ET) domain. BRD4 is a double bromodomain-containing protein that binds preferentially to acetylated chromatin. In humans, four BET proteins (BRD2, BRD3, BRD4 and BRDT) exhibit similar gene arrangements, domain organizations, and some functional properties (Wu, S. et al., J. Biol. Chem. 2007, 282, 13141 -13145).
Recently, some compounds have been reported as bromodomain binding agents, e.g., WO 2009/084693, JP 2008/15631 1 , WO 2012/075383, WO 201 1/054553, WO
201 1/054841 , WO 201 1/054843, WO 201 1/054844, WO 201 1/054845, WO 201 1/054846, WO 201 1/054848, WO 201 1/143669A and WO 201 1/161031 . However, there remains a need for novel and potent small molecule bromodomain inhibitors that meet the demanding biological and pharmaceutical criteria required to justify the time and expense of human clinical trials. The present invention addresses this and other needs.
SUMMARY
The present invention provides compounds of Formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond; L is -NR1 SO2- or -SO2NR2-;
Ri is H or alkyl, or taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl, wherein said
heterocycloalkyl is optionally substituted with one, two, three, four or five R9; R2 is H or alkyl;
Q is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with R3;
R3 is independently selected from the group consisting of hydroxy, halogen, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyano, oxo, alkylsulfonyl, amino, alkylamino, dialkylannino and amido, wherein each hydroxy, alkyl, haloalkyi, alkyoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, oxo, alkylsulfonyl, amino, alkylamino, dialkylannino and amido is further optionally substituted with hydroxy, oxo, carboxy, carboxyalkyi, hydroxyalkyi, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyi, amino, alkylamino, dialkylannino, amido alkylamido, dialkylamido, halogen, alkyl, haloalkyi, aryl, heteroaryl, heterocycloaklyl or cycloalkyl;
R9 is independently selected from the group consisting of halogen, alkyl, haloalkyi, hydroxy, alkoxy, haloalkoxy, amino, alkylamino and dialkylannino;
A is N;
B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2- where R2 is H, Q is 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
In another embodiment, the present invention also provides compounds of Formula
(la):
Figure imgf000004_0001
(la) or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond; L is -NR1 SO2- or -SO2NR2-;
Ri and R2 are each independently H or alkyl;
R , R5, R6, R7 and Rs are each independently selected from the group consisting of H, hydroxy, halogen, alkyl, alkoxy, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, haloalkyi, cyano, alkylsulfonyl, amino, alkyamino and dialkylamino; wherein each hydroxy, aryl, heteroaryl, cycloalkyi or heterocycloalkyi is optionally substituted with alkyl;
A is N;
B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2— where R2 is H, R4 or R5 are each 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier.
The present invention also provides a method of treating a disease or a disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I).
In another embodiment, the present invention further provides a method of inhibiting the bromodomain in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I)
DETAILED DESCRIPTION
The present invention is related to novel heterocyclic compounds of Formula (I), which are effective as bromodomain inhibitors. The present invention is also related to compositions comprising bromodomain inhibitors, and to methods for preparing such compounds. The heterocyclic compounds of the invention and their polymorphs, solvates, esters, tautomers, diastereomers, enantiomers, or prodrugs show utility for inhibiting the bromodomain and treating diseases that are bromodomain-dependent. Before describing the present invention in detail, it is to be understood that this invention is not limited to specific compositions or process steps, as such may vary. It should be noted that, as used in this specification and the appended claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of
compounds.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention is related. The following terms are defined for purposes of the invention as described herein.
As used herein, unless otherwise noted, "alkyl" whether used alone or as part of a substituent group refers to a saturated straight and branched carbon chain having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C-i-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl- containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n- propyl, /'so-propyl, n-butyl, sec-butyl, /'so-butyl, te/t-butyl, and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Ci-6alkyl)2, the alkyl groups may be the same or different.
As used herein, unless otherwise noted, "alkoxy" refers to groups of formula -Oalkyl. Designated numbers of carbon atoms (e.g. -OC-i-6) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, /'so-propoxy, n-butoxy, sec-butoxy, /'so-butoxy, te/t-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted.
As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond ("alkenyl") or at least one carbon-carbon triple bond ("alkynyl"). Where so indicated, alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1 -propenyl (also 2-methylethenyl), isopropenyl (also 2- methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1 -yl, and 2-methyl-hex-4-yn-1 -yl. As used herein, "cycloalkyl" whether used alone or as part of another group, refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1 , 2, or 3) double or triple bonds. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure. Where so indicated, cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1 H- indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydro-azulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1 H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2.1 .1 ]hexanyl, bicyclo[2.2.1 ]heptanyl, bicyclo[3.1 .1 ]heptanyl, 1 ,3- dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.
"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. As used herein, halogen refers to F, CI, Br and I. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e.g., -CF3, -CF2CF3). The halogens can be the same (e.g., CHF2, -CF3) or different (e.g., CF2CI). Where so indicated, haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl,
trichloromethyl, pentafluoroethyl, and pentachloroethyl groups.
The term "aryl" wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons. Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1 -yl or naphthylen-2-yl). Where so indicated, aryl groups may be optionally substituted with one or more substituents. Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1 ,3,5-trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings.
The term "heterocydoalkyi" whether used alone or as part of another group, is defined herein as a group having one or more rings {e.g., 1 , 2 or 3 rings) and having from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic. In heterocyclyl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be aryl (e.g., indolinyl,
tetrahydroquinolinyl, chromanyl). Exemplary heterocydoalkyi groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in a heterocydoalkyi group can be oxidized (e.g., N→O", S(O), SO2). Where so indicated, heterocydoalkyi groups can be optionally substituted.
Non-limiting examples of monocyclic heterocydoalkyi groups include, for example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5- tetrahydro-1 H-azepinyl, 2,3-dihydro-1 H-indole, and 1 ,2,3,4-tetrahydro-quinoline. Non- limiting examples of heterocyclic groups having 2 or more rings include, for example:
hexahydro-1 H-pyrrolizinyl, 3a,4, 5,6,7, 7a-hexahydro-1 H-benzo[d]imidazolyl, 3a,4, 5,6, 7,7a- hexahydro-1 H-indolyl, 1 ,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1 H-cycloocta[b]pyrrolyl.
The term "heteroaryl" whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H- cyclopentapyrimidine) or aryl (e.g., benzofuranyl, benzo-thiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized (e.g., N→O", S(O), SO2). Where so indicated, heteroaryl groups can be substituted. Non-limiting examples of monocyclic heteroaryl rings include, for example: 1 ,2,3,4-tetrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, triazinyl, thiazolyl, 1 /-/-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- c/]pyrimidinyl, pyrido[2,3-c/]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1 H-indolyl, 4,5,6,7- tetrahydro-1 -H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, and isoquinolinyl.
One non-limiting example of a heteroaryl group as described above is C-i-C5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S). Examples of C 1 -C5 heteroaryl include, but are not limited to for example, triazinyl, thiazol-2- yl, thiazol-4-yl, imidazol-1 -yl, 1 /-/-imidazol-2-yl, 1 /-/-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin- 2-yl, pyridin-3-yl, and pyridin-4-yl.
For the purposes of the present invention, fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1 ,2,3,4- tetrahydroquinoline having the formula:
Figure imgf000009_0001
is, for the purposes of the present invention, considered a heterocycloalkyl group.
Dihydro-5H-cyclopentapyrimidine having the formula:
Figure imgf000009_0002
is, for the purposes of the present invention, considered a heteroaryl group. When a ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:
Figure imgf000010_0001
is, for the purposes of the present invention, considered a heteroaryl group.
The term "heteroarylene" whether used alone or as part of another group, is defined herein as a divalent single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms), wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroarylene groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro- 5/-/-cyclopentapyrimidinylene) or aryl (e.g., benzofuranylene, benzothiophenylene, indolylene). Exemplary heteroarylene groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). One or more N or S atoms in a heteroarylene group can be oxidized (e.g., N→O" , S(O), SO2). Where so indicated, heteroarylene groups can be substituted. Non-limiting examples of monocyclic heteroarylene rings include, for example: 1 ,2,3,4-tetrazolylene, [1 ,2,3]triazolylene, [1 ,2,4]triazolylene, triazinylene, thiazolylene, 1 /-/-imidazolylene, oxazolylene, furanylene, thiopheneylene, pyrimidinylene, and pyridinylene. Non-limiting examples of heteroarylene rings containing 2 or more fused rings include: benzofuranylene, benzothiophenylene, benzoxazolylene, benzthiazolylene, benztriazolylene, cinnolinylene, naphthyridinylene, phenanthridinylene, 7/-/-purinylene, 9/-/-purinylene, 5H-pyrrolo[3,2- c/]pyrimidinylene, 7H-pyrrolo[2,3-c/]pyrimidinylene, pyrido[2,3-c ]pyrimidinylene, 2- phenylbenzo[d]thiazolylene, 1 H-indolylene, 4,5,6,7-tetrahydro-1 -H-indolylene,
quinoxalinylene, 5-methylquinoxalinylene, quinazolinylene, quinolinylene, and
isoquinolinylene.
One non-limiting example of a heteroarylene group as described above is C-i-C5 heteroarylene, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S). Examples of C-i-C5 heteroarylene include, but are not limited to for example, triazinylene, thiazol-2-ylene, thiazol-4-ylene, imidazol-1 -ylene, 1 /-/-imidazol-2-ylene, 1 /-/-imidazol-4-ylene, isoxazolin-5-ylene, furan-2-ylene, furan-3-ylene, thiophen-2-ylene, thiophen-4-ylene, pyrimidin-2-ylene, pyrinnidin-4-ylene, pyrimidin-5-ylene, pyridin-2-ylene, pyridin-3-ylene, and pyridin-4-ylene.
The term "carbocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 carbon ring atoms. A carbocyclic ring may be monocyclic, bicyclic or tricyclic. A carbocyclic ring typically contains from 3 to 10 carbon ring atoms and is monocyclic or bicyclic.
The term "heterocyclic ring" refers to a saturated cyclic, partially saturated cyclic, or aromatic ring containing from 3 to 14 ring atoms, in which at least one of the ring atoms is a heteroatom that is oxygen, nitrogen, or sulfur. A heterocyclic ring may be monocyclic, bicyclic or tricyclic. A heterocyclic ring typically contains from 3 to 10 ring atoms and is monocyclic or bicyclic.
The term "amino" refers to -NH2.
The term "alkylamino" refers to -N(H)alkyl. Examples of alkylamino substituents include methylamino, ethylamino, and propylamino.
The term "dialkylamino" refers to -N(alkyl)2 where the two alkyls may be the same or different. Examples of dialkylamino substituents include dimethylamino, diethylamino, ethylmethylamino, and dipropylamino.
The term "amido" refers to -C(=O)NH2.
The term "halogen" refers to fluorine (which may be depicted as -F), chlorine (which may be depicted as -CI), bromine (which may be depicted as -Br), or iodine (which may be depicted as -I).
The term "azide" refers to -N3.
The term "oxo" or "carbonyl" refers to =O.
The term "carboxy" refers to -CO2H.
The term sulfonyl refers to -SO2-.
The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer. As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.
Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as
experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention.
The term "substituted" is used throughout the specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1 -10) hydrogen atoms replaced by a substituent as defined herein below. Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent. For example, substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like. When a moiety is described as "substituted" any number of its hydrogen atoms can be replaced, as described above. For example, difluoromethyl is a substituted Ci alkyl; trifluoromethyl is a substituted Ci alkyl; 4-hydroxyphenyl is a substituted aryl ring; (N,N-dimethyl-5-amino)octanyl is a substituted Cs alkyl; 3-guanidinopropyl is a substituted C3 alkyl; and 2-carboxy-3- fluoropyridinyl is a substituted heteroaryl.
At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "C -6 alkyl" is specifically intended to individually disclose C-i , C2, C3, C4, C5 , C6 , C1 -C6 , C 1 -C5 , Ci-C4, C 1 -C3, C1 -C2, C2-C6 , C2-C5 , C2"C4, C2-C3, C3-C6 , C3-C5 ,
C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.
Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and
pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present invention also includes cis and trans or E/Z isomers of compounds of Formula (I) containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin- layer chromatography, and high-performance liquid chromatography.
The term "BRD4" refers to Bromodomain-containing protein 4, which is a member of the BET family. The BET family comprises BRD2, BRD3, BRD4 and BRDT.
The term "mammal" as used herein, refers to a human, a non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a therapy which reduces the severity of pathology in one species of mammal is predictive of the effect of the therapy on another species of mammal.
The term "modulate" as used herein, refers to encompasses either a decrease or an increase in activity or expression depending on the target molecule. For example, a TIMP1 modulator is considered to modulate the expression of TIMP1 if the presence of such TIMP1 modulator results in an increase or decrease in TIMP1 expression. The term "skin aging" includes conditions derived from intrinsic chronological aging (for example, deepened expression lines, reduction of skin thickness, inelasticity, and/or unblemished smooth surface), those derived from photoaging (for example, deep wrinkles, yellow and leathery surface, hardening of the skin, elastosis, roughness, dyspigmentations (age spots) and/or blotchy skin), and those derived from steroid-induced skin thinning. The term "other therapeutic agents" as used herein, refers to any therapeutic agent that has been used, is currently used or is known to be useful for treating a disease or a disorder encompassed by the present invention.
The term "solvate" as used herein means a physical association of a compound with one or more solvent molecules, whether organic or inorganic, including water ('hydrate').. As noted above, the compounds of Formula I, or pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of the invention (e.g. a compound of Formula (I)) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic,
benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic,
toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include but are not limited to aliphatic, cydoaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
Specific examples of suitable organic acids include but are not limited to acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, .beta.-hydroxybutyric acid, galactarate,
galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate,
cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, 3- phenylpropionate, picrate, pivalate, thiocyanate, and undecanoate.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, i.e., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
Organic salts may be made from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Ν,Ν'-benzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl (C.sub.1 - C.sub.6) halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (i.e., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (i.e., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), arylalkyl halides (i.e., benzyl and phenethyl bromides), and others.
In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. The term "prodrug" as used herein, refers to a pharmacologically inactive derivative of a parent "drug" molecule that requires biotransformation (e.g., either spontaneous or enzymatic) within the target physiological system to release or convert the prodrug into the active drug. Prodrugs are designed to overcome problems associated with stability, toxicity, lack of specificity, or limited bioavailability. Exemplary prodrugs comprise an active drug molecule itself and a chemical masking group (e.g., a group that reversibly suppresses the activity of the drug). Some preferred prodrugs are variations or derivatives of compounds that have groups cleavable under metabolic conditions. Exemplary prodrugs become pharmaceutically active in vivo or in vitro when they undergo solvolysis under physiological conditions or undergo enzymatic degradation or other biochemical transformation (e.g., phosphorylation, hydrogenation, dehydrogenation, glycosylation). Prodrugs often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism. (See e.g., Bundgard, Design of Prodrugs, pp. 7-9, 21 - 24, Elsevier, Amsterdam (1985); and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352- 401 , Academic Press, San Diego, CA (1992)). Common prodrugs include acid derivatives such as esters prepared by reaction of parent acids with a suitable alcohol (e.g., a lower alkanol), amides prepared by reaction of the parent acid compound with an amine, or basic groups reacted to form an acylated base derivative (e.g., a lower alkylamide).
The term "therapeutically effective amount" as used herein, refers to that amount of the therapeutic agent sufficient to result in amelioration of one or more symptoms of a disorder, or prevent advancement of a disorder, or cause regression of the disorder. For example, with respect to the treatment of asthma, a therapeutically effective amount preferably refers to the amount of a therapeutic agent that increases peak air flow by at least 5%, preferably at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.
Bromodomain inhibitors may be used in the treatment of a wide variety of chronic autoimmune and inflammatory diseases such as rheumatoid arthritis, osteoarthritis, acute gout, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease (Crohn's disease and Ulcerative colitis), asthma, chronic obstructive airways disease, pneumonitis, myocarditis, pericarditis, myositis, eczema, dermatitis, alopecia, vitiligo, bullous skin diseases, nephritis, vasculitis, atherosclerosis, Alzheimer's disease, depression, retinitis, uveitis, scleritis, hepatitis, pancreatitis, primary biliary cirrhosis, sclerosing cholangitis, Addison's disease, hypophysitis, thyroiditis, type I diabetes and acute rejection of transplanted organs.
Bromodomain inhibitors may be used in the treatment of a variety of diseases or disorders related to systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cellular activation and proliferation, lipid metabolism, fibrosis and in the treatment of viral infections.
Bromodomain inhibitors may be used in the treatment of a wide variety of acute inflammatory conditions such as acute gout, giant cell arteritis, nephritis including lupus nephritis, vasculitis with organ involvement such as glomerulonephritis, vasculitis including giant cell arteritis, Wegener's granulomatosis, Polyarteritis nodosa, Behcet's disease, Kawasaki disease, Takayasu's Arteritis, vasculitis with organ involvement and acute rejection of transplanted organs.
Bromodomain inhibitors may be used in the treatment of diseases or disorders which involve inflammatory responses to infections with bacteria, viruses, fungi, parasites or their toxins, such as sepsis, sepsis syndrome, septic shock, endotoxaemia, systemic
inflammatory response syndrome (SIRS), multi-organ dysfunction syndrome, toxic shock syndrome, acute lung injury, ARDS (adult respiratory distress syndrome), acute renal failure, fulminant hepatitis, burns, acute pancreatitis, post-surgical syndromes, sarcoidosis, Herxheimer reactions, encephalitis, myelitis, meningitis, malaria and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex and coronavirus.
Bromodomain inhibitors may be used in the treatment of conditions associated with ischaemia-reperfusion injury such as myocardial infarction, cerebrovascular ischaemia (stroke), acute coronary syndromes, renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardio-pulmonary bypass procedures, pulmonary, renal, hepatic, gastro-intestinal or peripheral limb embolism.
Bromodomain inhibitors may be used in the treatment of disorders of lipid
metabolism via the regulation of APO-A1 such as hypercholesterolemia, atherosclerosis and Alzheimer's disease.
Bromodomain inhibitors may be used in the treatment of viral infections such as herpes virus, human papilloma virus, adenovirus and poxvirus and other DNA viruses. Bromodomain inhibitors may be used in the treatment of fibrotic conditions such as idiopathic pulmonary fibrosis, renal fibrosis, post-operative stricture, keloid formation, scleroderma and cardiac fibrosis.
In one embodiment the disease or disorder for which a bromodomain inhibitor is indicated is selected from diseases associated with systemic inflammatory response syndrome, such as sepsis, burns, pancreatitis, major trauma, haemorrhage and ischaemia. In this embodiment the bromodomain inhibitor would be administered at the point of diagnosis to reduce the incidence of: SIRS, the onset of shock, multi-organ dysfunction syndrome, which includes the onset of acute lung injury, ARDS, acute renal, hepatic, cardiac and gastro-intestinal injury and mortality. In another embodiment the bromodomain inhibitor would be administered prior to surgical or other procedures associated with a high risk of sepsis, haemorrhage, extensive tissue damage, SIRS or MODS (multiple organ dysfunction syndrome). In a particular embodiment the disease or condition for which a bromodomain inhibitor is indicated is sepsis, sepsis syndrome, septic shock or
endotoxaemia. In another embodiment, the bromodomain inhibitor is indicated for the treatment of acute or chronic pancreatitis. In another embodiment the bromodomain inhibitor is indicated for the treatment of burns.
In one embodiment the disease or disorder for which a bromodomain inhibitor is indicated is selected from herpes simplex infections and reactivations, cold sores, herpes zoster infections and reactivations, chickenpox, shingles, human papilloma virus, cervical neoplasia, adenovirus infections, including acute respiratory disease, poxvirus infections such as cowpox and smallpox and African swine fever virus. In one particular embodiment a bromodomain inhibitor is indicated for the treatment of Human papilloma virus infections of skin or cervical epithelia.
Bromodomain inhibitors may be used in the treatment of cancer, including
hematological, epithelial including lung, breast and colon carcinomas, midline carcinomas, mesenchymal, hepatic, renal and neurological tumors.
The compounds described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosol ization or inhalation spray, rectally,
intracisternally, intravaginally, intraperitoneally, bucally, intrathecally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes
subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices.
Methods of formulation are well known in the art and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 21 st Edition (2005), incorporated herein by reference.
Pharmaceutical compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein.
Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
The compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention.
Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles.
Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate bromodomain activity, or to alleviate symptoms of diseases associated with bromodomains activity or susceptible to bromodomain activity modulation.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.
In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for treating a chronic autoimmune and/or inflammatory condition and cancer by administering an effective amount of a compound of the present invention.
The phrase "pharmaceutically acceptable carrier" as used herein means a
pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1 ) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (1 1 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21 ) other non-toxic compatible substances employed in pharmaceutical formulations. A physiologically acceptable carrier should not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
An "excipient" refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound. Examples of excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
A "pharmaceutically/therapeutically effective amount" means an amount which is capable of providing a therapeutic and/or prophylactic effect. The specific dose of compound administered according to this invention to obtain therapeutic and/or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the specific compound administered, the route of administration, the condition being treated, and the individual being treated. A typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50- 100 mg/kg of body weight of an active compound of the invention. Preferred daily doses generally will be from about 0.05 mg/kg to about 20 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg. Factors such as clearance rate, half-life and maximum tolerated dose (MTD) have yet to be determined but one of ordinary skill in the art can determine these using standard procedures.
As used herein, the term "IC50" refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response. The value depends on the assay used.
One aspect of the invention relates to compounds of Formula (I):
Figure imgf000023_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond;
L is -NR1SO2- (Q is bound to the N) or -SO2NR2- (Q is bound to the S);
Ri is H or alkyl, or taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl, wherein said
heterocycloalkyl is optionally substituted with R9;
R2 is H or alkyl;
Q is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, wherein each aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is optionally substituted with R3; R3 is independently selected from the group consisting of hydroxy, halogen, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or cyano, oxo, alkylsulfonyl, amino, alkylamino, dialkylamino and amido, wherein each hydroxy, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, oxo, alkylsulfonyl, amino, alkylamino, dialkylamino or amido is further optionally substituted with hydroxy, oxo, carboxy, carboxyalkyi, hydroxyalkyi, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyi, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, halogen, alkyl, haloalkyi, aryl, heteroaryl, heterocycloalkyl or cycloalkyl;
R9 is independently selected from the group consisting of halogen, alkyl, haloalkyi, hydroxy, alkoxy, haloalkoxy, amino, alkylamino and dialkylamino;
A is N;
B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2- where R2 is H, Q is 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein L is -NHSO2-.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein L is -SO2NH-
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Ri is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R-i is Ci-6alkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R-i is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Ri taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyl. In certain embodiments, the present invention relates to any of the aforementioned
compounds, wherein L and Q taken together
Figure imgf000025_0001
. wherein L is -NR1 SO2 and Ri taken together with Q and the nitrogen to which they are bound forms a pyrrolidinyl).
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 , 2, 3, 4 or 5 R3.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 , 2 or 3 R3.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 1 R3.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 2 R3.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted by 3 R3.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is substituted with at least one hydroxy, halogen or Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is aryl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with hydroxy, halogen or Ci-6alkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with cyano. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is aryl optionally substituted with aryl, heteroaryl or cycloalkyi.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is heteroaryl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is heteroaryl optionally substituted with hydroxy, halogen or alkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is cycloalkyi .
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is heterocycloalkyl,
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Q is azetidin-1 -yl, pyrrol id in-1 -yl, piperidin-1 -yl or azepan-1 -yl, optionally substituted with substituents independently selected from the group consisting of C-i-6alkyl, hydroxy, halogen, alkoxy, amino, alkylamino and dialkylamino.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein B is N.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein B is C.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the dotted line is a single bond.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the dotted line is a double bond.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein B is N; and the dotted line is a single bond.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is Ci-6alkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is methyl; B is N; the dotted line is a single bond; and L is - SO2NR2-.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is methyl; B is C; the dotted line is a double bond; and L is - SO2NR2-.
In another embodiment, the present invention also provides compounds of Formula
(la):
Figure imgf000027_0001
(la) or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond; L is -NR1 SO2- or -SO2NR2-;
Ri is H or alkyl; R2 is H or alkyl;
R , R5, R6, R7 and Rs are each independently selected from the group consisting of H, hydroxy, halogen, alkyl, alkoxy, aryl, heteroaryl, cycloalkyi, heterocycloalkyi, haloalkyi, cyano, alkylsulfonyl, amino, alkyamino and dialkylamino; wherein each hydroxy, aryl, heteroaryl, cycloalkyi or heterocycloalkyi is optionally substituted with alkyl;
A is N;
B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2- where R2 is H, R4 or R5 are each 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein L is -NHSO2-
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein L is -SO2NH-.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R-i is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Ri is Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R-i is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R-i taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocycloalkyi
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is Ci-6alkyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R2 is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R4, R5, R6 , R7 and Rs are each independently H, hydroxy, halogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, haloalkyl or cyano.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R5 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R6 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R7 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein R8 is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein B is N.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein B is C.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the dotted line is a single bond.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein the dotted line is a double bond.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is Chalky! .
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein X is methyl. In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is Chalky!.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Y is methyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is H.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is Ci-6alkyl.
In certain embodiments, the present invention relates to any of the aforementioned compounds, wherein Z is methyl.
In certain embodiments, the compounds include:
6-((3-Hydroxypyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydroquinazolin-2(1 H)-one; 6-((2-(Hydroxymethyl)piperidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro-quinazolin-2(1 H)- one;
6-((3-(Hydroxymethyl)pyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro-quinazolin-2(1 H)- one;
6-((4-(Hydroxyl(pyridin-2-yl)methyl)piperidin-1 -yl)sulfonyl)-3-methyl-3,4- dihydroquinazolin-2(1 H)-one;
3-Methyl-2-oxo-N-phenyl-1 ,2,3,4-tetrahydro-quinazoline-6-sulfonamide;
3- Methyl-6-(pyrrolidin-1 -ylsulfonyl)-3,4-dihydroquinazolin-2(1 H)-one;
2-Chloro-4-fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3-(trifluoromethyl)- benzenesulfonamide;
2-Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro-quinazolin-6-yl)benzenesulfonamide;
2-Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonamide;
4- Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonamide; 3- Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
2- Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2-(trifluoronnethyl)- benzenesulfonamide;
4- Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
4- Cyano-N-(3-methyl-2 -oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide; 4-Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Cyano-N-(3-methyl-2 -oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
4- Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene- sulfonamide;
2,6-Dichloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)- benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-4-(trifluoronnethyl)- benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonannide;
N-Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3-Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro-quinazolin-6- yl)benzenesulfonamide;
N-(2-Methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzene-sulfonannide;
3-Methoxy-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)- benzenesulfonamide;
N-(2-Oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
N-(4-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide
2-Fluoro-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
2-methoxy-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
2-Methyl-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide; N-(3-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2-(morpholin-4- ylmethyl)benzenesulfonannide;
Methyl (2-{[(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)annino]sulfonyl}phenoxy)acetate;
2- (2-Hydroxy-2-methylpropoxy)-N-(3-nnethyl-2-oxo-1 ,2-dihydroquinolin-6- yl)benzenesulfonamide;
(2-{[(3-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)annino]sulfonyl}phenoxy)acetic acid;
N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
3- Methoxy-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7- yl)benzenesulfonamide;
2-Fluoro-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzenesulfonannide;
N-(1 ,3-Dimethyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2-nnethoxybenzenesulfonannide;
2- Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonannide;
3- Methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one;
4- Methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one; N-(2-hydroxy-3-methylquinolin-6-yl)piperidine-1 -sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)pyridine-3-sulfonannide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,3-benzothiazole-6-sulfonamide; 4-{[(2-Hydroxy-3-methylquinolin-6-yl)amino]sulfonyl}benzamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-2,3-dihydro-1 ,4-benzodioxine-6-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -nnethyl-1 H-pyrazole-5-sulfonamide; methyl 3-{[(2-hydroxy-3-methylquinolin-6-yl)amino]sulfonyl}benzoate; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -methyl-1 H-pyrazole-3-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-2,6-dimethylmorpholine-4-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)cyclopropanesulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-3,5-dimethylisoxazole-4-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)azepane-1 -sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-2-oxo-2,3-dihydro-1 ,3-benzoxazole-6- sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2-oxo-1 ,2,3,4-tetrahydroquinoline-6- sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 H-imidazole-4-sulfonannide;
5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)thiophene-2-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,2-dimethyl-1 H-imidazole-4-sulfonannide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2-nnethyl-1 ,3-benzothiazole-5-sulfonamide;
(1 R,2R)-N-(2-Hydroxy-3-methylquinolin-6-yl)-2-phenylcyclopropanesulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-4-nnethyl-3,4-dihydro-2H-1 ,4-benzoxazine-7- sulfonamide;
(1 R,2S)-2-Ethyl-N-(2-hydroxy-3-methylquinolin-6-yl)cyclopropanesulfonannide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -nnethyl-1 H-imidazole-4-sulfonannide;
3-Fluoro-4-{[(2-hydroxy-3-methylquinolin-6-yl)annino]sulfonyl}benzoic acid;
N-(2-Hydroxy-3-methylquinolin-6-yl)morpholine-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 H-pyrazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-3,5-dinnethyl-1 H-pyrazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-3,4-dihydro-2H-1 ,5-benzodioxepine-7- sulfonamide;
5-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methoxybenzenesulfonamide;
3- Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonamide; 2,5-Dichloro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
4- Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
5- Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-1 ,3-dimethyl-1 H-pyrazole-4- sulfonamide;
3-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-4-methoxybenzenesulfonamide;
5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methylbenzenesulfonamide;
2-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-4-methylbenzenesulfonamide; 3-Chloro-5-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methylbenzenesulfonamide;
3,5-Difluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methoxybenzenesulfonamide;
2-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-3-methylbenzenesulfonamide;
2-Chloro-4-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
5-Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
2-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-5-methylbenzenesulfonamide;
2-Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonannide;
2- Methoxy-N-(2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonannide;
N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3- (methylsulfonyl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)biphenyl-3-sulfonannide;
N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2,3-dihydro-1 -benzofuran-5- sulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2,3-dihydro-1 ,4-benzodioxine-6- sulfonamide;
3- Fluoro-4-methoxy-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)cyclopropanesulfonannide;
5-Chloro-2-methoxy-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
2,5-Dichloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
4- fluoro-2-methyl-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
2-Ethoxy-4-methyl-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide; N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2- (trifluoromethoxy)benzenesulfonannide;
2-Methoxy-5-methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide; and
2-Methoxy-4-methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide.
Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the aforementioned compounds and a pharmaceutically acceptable carrier.
Another aspect of the invention relates to a method of treating a disease or a disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of any one of the aforementioned compounds or aforementioned pharmaceutical composition.
In certain embodiments, the present invention relates to any of the aforementioned methods, wherein the disease or disorder is selected from the group consisting of chronic autoimmune disease, inflammatory disease and cancer.
In certain embodiments, the present invention relates to any of the aforementioned methods, wherein the treatment of a disease or a disorder further comprises administering an additional therapeutic agent.
Another aspect of the invention relates to a method for inhibiting bromodomain in a cell, comprising contacting the cell with a therapeutically effective amount of any one of the aforementioned compounds or aforementioned pharmaceutical composition.
Compounds of the present invention can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated.
Optimum reaction conditions can vary with the particular reactants or solvent used. Those skilled in the art will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein.
The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatography such as high-performance liquid chromatograpy (HPLC), gas
chromatography (GC), gel-permeation chromatography (GPC), or thin layer
chromatography (TLC).
Preparation of the compounds can involve protection and deprotection of various chemical groups. The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes.
The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art. Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.
The compounds of these teachings can be prepared by methods known in the art. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature. For example, compounds of the present invention can be prepared according to the methods illustrated in the following Synthetic Schemes.
The description of this invention utilizes a variety of abbreviations well known to those skilled in the art, including the following:
Cs2CO3: cesium carbonate,
Cul: copper (I) iodide;
DAD: diode array detector; DBTTBP:di-tert-butyl(2\4\6'-tnisopropyl-3,4,5,6-tetramethyl-[1 ,1 '-biphenyl]-2-yl)^
DCM: dichloromethane; methylene chloride;
DMA: Λ/,/V-dimethyl acetamide;
DMEDA: A/1,A/2-dimethylethane-1 ,2-diamine;
DMSO: dimethyl sulfoxide;
EDTA: ethylenediaminetetracetic acid;
ELSD: evaporative light scattering detection;
Et3N: triethylamine;
Et2O: diethyl ether;
EtOAc: ethyl acetate;
EtOH: ethanol;
HCI: hydrochloric acid;
H2SO4: sulfuric acid;
IPA: isopropanol;
KF-AI2O3: potassium fluoride on aluminum oxide;
KNO3: potassium nitrate;
LCMS: liquid chromatography mass spectrometry;
MeOH: methanol;
MgSO4: magnesium sulfate;
Na2SO4: sodium sulfate;
NBS: /V-bromosuccinimide;
Pd/C: palladium on carbon;
Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; and
TLC: thin layer chromatography.
1H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations have been used for common solvents: CDCI3, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol.
Mass spectra, MS (m/z), were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). When relevant, and unless stated otherwise, the m/z data provided are for isotopes 19F, 35CI and 79Br.
Certain compounds of the Examples and Preparations were purified using
Preparative High Performance Liquid Chromatography (HPLC). Reversed-phase HPLC conditions were either on Gilson GX281 , Shimadzu CL-2010C, or Agilent 1200 system.
Samples were submitted dissolved in 1 ml_ of DMSO. Depending on the nature of the compounds and the results of a pre-analysis, the purification was performed under a variety conditions at ambient temperature. HPLC was carried out on a Agella Venusil ASB C18 column (21 .2 x 150 mm, 5 μιτι),. A flow rate of 0.5-150 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v). The modifier was formic acid, trifluoroacetate, ammonia acetate, or hydrochloric acid. A Shimadzu MS2010EV MS2525 binary LC or Waters 2545 BGM pump supplied a mobile phase with a composition of 5% B for 1 min then ran from 5% to 98% B over 6 min followed by a 2 min hold at 98% B.
Detection was achieved using a Shimadzu SPD-20AV or Waters 2998 PDA wavelength absorbance detector set at 220 or 200 nm followed in series by a Shimadzu MS201 OEV or Waters 3100 mass spectrometer. The Shimadzu MS201 OEV MS was tuned with the following parameters:
ES+ Cone voltage: 30 v Capillary: 1 .5 kv
Desolvation gas: Nitrogen
Source Temp: 250°C.
Scan range 100-1200 Da
The fraction collection was triggered by both MS.
The Waters 3100 MS was tuned with the following parameters:
ES+ Cone voltage: 35 v Capillary: 3.0 kv
Desolvation gas: 800 (L/H) Source Temp: 130 °C. Scan range 100-800 Da
The fraction collection was triggered by MS or by UV.
Quality control (QC) analysis was performed using a LCMS method. Acidic runs were carried out on a Shimadzu XB-C18 (2.1 x 30 mm, 5 μιτι), X-Bridge (50 x 4.6 mm, 5 μηη), Gemini NX C18 (50 x 4.6, 3 μηη), or Gemini NX C18 (50 x 4.6, 5 μηη). A flow rate of 1 .0-1 .2 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B:
acetonitrile + 0.1 % modifier (v/v). For acidic runs the modifier was trifluoroacetic acid. A Shimadzu 20AB pump ran a gradient elution from 0% to 98% B over 2 min followed by a 1 min hold at 95% B. Detection was achieved using a Shimadzu 10A detector set at 220 or 260 nm followed in series by a Shimadzu MS2010EV or Applied Biosystem API 2000 mass spectrometer in parallel. The Shimadzu MS2010EV MS was tuned with the following parameters:
ES+ Cone voltage: 25 v Capillary: 1 .50 kv ES- Cone voltage:-30 v Capillary:-1 .50 kv Desolvation gas: Nitrogen Source Temp: 250°C. Scan range 100-1000 Da
The Applied Biosystem API 2000 MS was tuned with the following parameters:
ES+ Cone voltage: 50 v Capillary: 1 .50 kv
ES- Cone voltage:-50 v Capillary:-1 .50 kv
Desolvation gas: 40-50 psi
Source Temp: 200°C.
Scan range 100-800 Da
Certain compounds of the Examples and Preparations were purified using
Automated Preparative High Performance Liquid Chromatography (HPLC). Reversed- phase HPLC conditions were on FractionLynx systems.
In the case of the Fractionlynx system, Samples were submitted dissolved in 1 mL of DMSO. Depending on the nature of the compounds and the results of a pre-analysis, the purification was performed under either acidic (Ά-HPLC), or basic ('B-HPLC') conditions at ambient temperature. A-HPLC was carried out on a Sunfire Prep C18 OBD column (19 x 100 mm, 5 μιτι). B-HPLC was carried out on an Xterra Prep MS C18 (19 x 100 mm, 5 μιτι), both from Waters. A flow rate of 18 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v). For acidic runs the modifier was formic acid, for basic run the modifier was diethylamine. A Waters 2525 binary LC pump supplied a mobile phase with a composition of 5% B for 1 min then ran from 5% to 98% B over 6 min followed by a 2 min hold at 98% B.
Detection was achieved using a Waters 2487 dual wavelength absorbance detector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel. The PL 2100 ELSD was set at 30°C with 1 .6 L/min supply of Nitrogen. The Waters ZQ MS was tuned with the following parameters:
ES+ Cone voltage: 30 v Capillary: 3.20 kv
ES- Cone voltage:-30 v Capillary:-3.00 kv
Desolvation gas: 600 L/hr
Source Temp: 120°C.
Scan range 150-900 Da
The fraction collection was triggered by both MS and ELSD.
Quality control (QC) analysis was performed using a LCMS method. Acidic runs were carried out on a Sunfire C18 (4.6 x 50 mm, 5 μιτι), basic runs were carried out on a Xterra C18 (4.6 x 50 mm, 5 μιτι), both from Waters. A flow rate of 1 .5 mL/min was used with mobile phase A: water + 0.1 % modifier (v/v) and B: acetonitrile + 0.1 % modifier (v/v). For acidic runs the modifier was formic acid, for basic run the modifier was ammonia. A Waters 1525 binary LC pump ran a gradient elution from 5% to 95% B over 3 min followed by a 1 min hold at 95% B. Detection was achieved using a Waters MUX UV 2488 detector set at 225 nm followed in series by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel. The PL 2100 ELSD was set at 30°C with 1 .6 L/min supply of Nitrogen. The Waters ZQ MS was tuned with the following parameters:
ES+ Cone voltage: 25 v Capillary: 3.30 kv
ES- Cone voltage:-30 v Capillary:-2.50 kv
Desolvation gas: 800 L/hr Source Temp: 150°C.
Scan range 160-900 Da
SYNTHETIC PROCEDURES
In the tabulated experimental details that follow, the Examples and Preparations were prepared according to the corresponding reference method (i.e. Method A, Method B, Preparation 15, and so on). The skilled person will appreciate that, in the synthesis of any specific Example or Preparation, it may be necessary to make minor variations to the reaction conditions of the reference method (e.g. with regard to solvent, temperature and so on).
The reagents used in the preparation of the compounds of this invention can be either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus were prepared by the following schemes.
GENERAL SYNTHETIC SCHEME(S) FOR THE PREPARATION OF INTERMEDIATES AND COMPOUNDS OF THE INVENTION
According to Scheme 1 -3, the compounds of formula (I) can be prepared, the details of each example is described in the Examples.
Scheme 1 :
Figure imgf000041_0001
Scheme 2:
Figure imgf000041_0002
Scheme 3:
Figure imgf000042_0001
EXAMPLES
The following non-limiting examples are presented merely to illustrate the present invention. The skilled person will understand that there are numerous equivalents and variations not exemplified but which still form part of the present teachings.
EXAMPLE 1
Figure imgf000042_0002
Step 1 : Preparation of 3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazoline-6-sulfonyl chloride, Intermediate 1 : 3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one (5.0g, 30.83 mmol) was added to chlorosulfonic acid (15 mL) at 0 °C. The reaction was permitted to warm to room temperature and the pale orange solution was stirred at room temperature for 2 h. The reaction mixture was quenched by addition of ice and the resultant white solid was removed by filtration. The white solid product was identified as the title compound and was azeotropically dried with DCM (Yield 15%, 1H NMR (400 MHz, DMSO-c/6) δ 9.25 (s, 1 H), 7.36 (m, 2H), 6.69 (d, 1 H, J = 8 Hz), 4.40 (s, 2H), 2.85 (s, 3H); LC/MS [M + H]+ = 261 m/z).
Step 2 Method A: Preparation of A/-cyclohexyl-3-methyl-2-oxo-1 ,2,3,4-tetrahydro- quinazoline-6-sulfonamide (1): A vessel containing cyclohexanamine (75 μιτιοΙ, 1 .0 equiv.) was treated with a 0.12M solution of Intermediate 1 in DCM (90 μιτιοΙ, 1 .2 equiv.) and the solution was cooled to 0 °C. The reaction was then treated with Et3N (225 μιτιοΙ, 3.0 equiv.), warmed to 30 °C, and shaken for 3 h. The reaction was concentrated and the resultant residue purified by Prep-HPLC to give the title compound as product (Yield 32%, LC/MS [M + H]+ = 324 m/z).
EXAMPLE 2
Preparation of 6-((3-hydroxypyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydroquinazolin- 2(1 H)-one (2): The title compound was prepared according to the procedure of Example 1 ; (Yield 28%, LC/MS [M + H]+ = 312 m/z). EXAMPLE 3
Preparation of 6-((2-(hydroxymethyl)piperidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro- quinazolin-2(1 H)-one (3): The title compound was prepared according to the procedure of Example 1 ; (Yield 28%, LC/MS [M + H]+ = 340 m/z).
EXAMPLE 4
Preparation of 6-((3-(hydroxymethyl)pyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro- quinazolin-2(1 H)-one (4): The title compound was prepared according to the procedure of Example 1 ; (Yield 35%, LC/MS [M + H]+ = 326 m/z).
EXAMPLE 5
Preparation of 6-((4-(hydroxyl(pyridin-2-yl)methyl)piperidin-1 -yl)sulfonyl)-3-methyl- 3,4-dihydroquinazolin-2(1 H)-one (5): The title compound was prepared according to the procedure of Example 1 ; (Yield 23%, LC/MS [M + H]+ = 417 m/z).
EXAMPLE 6
Figure imgf000043_0001
Step 2 Method B: Preparation of 3-methyl-2-oxo-/V-phenyl-1 ,2,3,4-tetrahydro- quinazoline-6-sulfonamide (6): A white suspension of Intermediate 1 (200 mg, 0.767 mmol) in DCM (2.0 mL) was treated with pyridine (200 μί, 2.5 mmol, 3.2 equiv.) and aniline (2.2 mmol, 2.9 equiv.). The reaction stirred at room temperature overnight and was then concentrated and slurried with 2M aqueous HCI solution. The product was filtered, rinsed with water, and dried under vacuum to afford the title compound as product (Yield 80%; 1H NMR (400 MHz, DMSO-c/6) δ 10.08 (s, 1 H), 9.60 (s, 1 H), 7.5 (m, 2H), 7.22 (m, 2H), 7.08- 6.99 (m, 3H), 6.82 (d, 1 H, J = 12 Hz), 4.41 (s, 2H), 2.83 (s, 3H); LC/MS [M + H]+ = 318 m/z).
EXAMPLE 7
Preparation of 3-methyl-6-(pyrrolidin-1 -ylsulfonyl)-3,4-dihydroquinazolin-2(1 H)-one (7): The title compound was prepared according to the procedure of Example 6; (Yield 71 %, LC/MS [M + H]+ = 296 m/z). EXAMPLE 8
Step 1 : Preparation of 3-methyl-6-nitro-3,4-dihydroquinazolin-2(1 /-/)-one,
Intermediate 2: 3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one (0.5g, 3.08 mmol) was added to ice-cooled H2SO4 (2 ml_) portionwise to give a yellow solution. Then KNO3 (0.25g, 2.472 mmol, 0.8 equiv) was added portionwise to yield a dark solution and the reaction mixture was permitted to slowly warm to room temperature over 3h. The reaction was poured into ice-water, and the yellow solid was removed by filtration and dried to give the title compound as product (Yield 62%, 1H NMR (400 MHz, DMSO-c/6) δ 9.93 (s, 1 H), 8.06 (m, 2H), 6.90 (d, 1 H, J = 12 Hz), 4.52 (s, 2H), 2.88 (s, 3H); LC/MS [M + H]+ = 208 m/z).
Step 2: Preparation of 6-amino-3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one,
Intermediate 3. Intermediate 2 (3.5g, 16.9 mmol) was dissolved in ethanol (400 ml_) and degassed with N2 gas. Then 10% Pd/C (1 .2g) was added and the reaction was stirred under atmospheric H2 at room temperature for 16 h. The reaction mixture was filtered through a bed of celite, washed with methanol, and concentrated. The crude product was purified by alumina column chromatography to provide the title compound as product (Yield 33%, 1H NMR (400 MHz, DMSO-c/6) δ 8.72 (s, 1 H), 6.47 (m, 1 H), 6.37 (m, 1 H), 6.30 (m, 1 H), 4.65 (br s, 2H), 4.24 (s, 2H), 2.81 (s, 3H); LC/MS [M + H]+ = 178 m/z).
Figure imgf000044_0001
Step 3 Method A: Preparation of 2-chloro-4-fluoro-/V-(3-methyl-2-oxo-1 ,2,3,4- tetrahydroquinazolin-6-yl)benzenesulfonamide (8): A solution of Intermediate 3 (0.1 mmol,) in anhydrous DMA (1 mL) was treated with Et3N (0.3 mmol, 3.0 equiv.) and 2-chloro-4- fluorobenzene-1 -sulfonyl chloride (0.1 mmol, 1 .0 equiv). The reaction was stirred at room termperature for 16 h, concentrated, and purified by Prep-HPLC to provide the title compound as product (Yield 26%, LC/MS [M - H]~ = 368 m/z).
EXAMPLE 9
Preparation of A/-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3- (trifluoromethyl)-benzenesulfonamide (9): The title compound was prepared according to the procedure of Example 8; (Yield 6%, LC/MS [M + H]+ = 386 m/z). EXAMPLE 10
Figure imgf000045_0001
Step 3 Method B: Preparation of 2-fluoro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro- quinazolin-6-yl)benzenesulfonamide (10): A solution of Intermediate 3 (100 mg, 0.42 mmol,) in DCM (10 ml_) was treated with pyridine (200 μΙ_, 2.5 mmol, 5.9 equiv.) and 2- fluorobenzene-1 -sulfonyl chloride (0.63 mmol, 1 .5 equiv). The reaction was stirred at room termperature for 2 h, concentrated, and the residue was partitioned between EtOAc and 2N HCI (aq). The EtOAc was then washed with water, washed with brine, and dried over MgSO . The sample was filtered, concentrated and purified by Auto-HPLC to provide title compound as product (LC/MS [M + H]+ = 336 m/z).
EXAMPLE 11
Preparation of 2-methyl-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (11): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 332 m/z).
EXAMPLE 12
Preparation of 4-methyl-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (12): The title compound was prepared according to the procedure of Example 10; (Yield 57%, 1H NMR (400 MHz, DMSO-c/6) δ 9.82 (s, 1 H), 9.08 (s, 1 H), 7.57 (d, 2H, J = 8 Hz), 7.32 (d, 2H, J = 8 Hz), 6.8 (m, 2H), 6.58 (d, 1 H, J = 12 Hz), 4.28 (s, 2H), 2.80 (s, 3H), 2.33 (s, 3H); LC/MS [M + H]+ = 332 m/z).
EXAMPLE 13
Preparation of 3-chloro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (13): The title compound was prepared according to the procedure of Example 10; (Yield, 72%, LC/MS [M + H]+ = 353 m/z).
EXAMPLE 14
Preparation of 2-chloro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (14): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 353 m/z). EXAMPLE 15
Preparation of A/-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2- (trifluoromethyl)-benzenesulfonannide (15): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 386 m/z).
EXAMPLE 16
Preparation of 4-fluoro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene- sulfonamide (16): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 336 m/z).
EXAMPLE 17
Preparation of 3-fluoro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene- sulfonamide (17): The title compound was prepared according to the procedure of Example 10; (Yield 22%, LC/MS [M + H]+ = 336 m/z).
EXAMPLE 18
Preparation of 3-methyl-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (18): The title compound was prepared according to the procedure of Example 10; (Yield 86%, LC/MS [M + H]+ = 332 m/z).
EXAMPLE 19
Preparation of 4-cyano-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (19): The title compound was prepared according to the procedure of Example 10; (Yield 24%, LC/MS [M + H]+ = 343 m/z).
EXAMPLE 20
Preparation of 4-chloro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (20): The title compound was prepared according to the procedure of Example 10; (Yield 42%, LC/MS [M + H]+ = 353 m/z).
EXAMPLE 21
Preparation of 3-cyano-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (21): The title compound was prepared according to the procedure of Example 10; (Yield 17%, 1H NMR (400 MHz, DMSO-c/6) δ 10.05 (s, 1 H), 9.10 (s, 1 H), 8.10 (m, 2H), 7.90 (m, 1 H), 7.75 (m, 1 H), 6.80 (m, 2H), 6.60 (m, 1 H), 4.25 (s, 2H), 2.80 (s, 3H). EXAMPLE 22
Preparation of 4-methoxy-/V-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (22): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 348 m/z).
EXAMPLE 23
Preparation of 2,6-dichloro-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)- benzenesulfonamide (23): The title compound was prepared according to the procedure of Example 10; (LC/MS [M + H]+ = 387 m/z).
EXAMPLE 24
Preparation of A/-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-4- (trifluoromethyl)-benzenesulfonamide (24): The title compound was prepared according to the procedure of Example 10; (Yield 55%, LC/MS [M + H]+ = 386 m/z).
EXAMPLE 25
Step 1 : Preparation of 6-bromo-3-methyl-3,4-dihydroquinazolin-2(1 /-/)-one,
Intermediate 4: A solution of 3-methyl-3,4-dihydroquinazolin-2(1 H)-one (1 OO.OOg, 61 .655 mmol) in dichloromethane (300 mL) was treated portionwise with N-bromosuccinimide (13.2g, 74.00 mmol, 1 .20 equiv). The red solution was stirred at room temperature under nitrogen for 2 h and a precipitate formed. The orange solid was removed by filtration and the filtrate was washed with water, brine, and dried over Na2SO . This was filtered and concentrated to yield the title compound as a white solid (Yield 84%, 1H NMR (400 MHz, CDCI3) δ 8.20 (br s, 1 H), 7.25 (dd, 1 H, J = 2 Hz, 12 Hz), 7.15 (d, 1 H, J = 2 Hz), 6.62 (d, 1 H, J = 12 Hz), 4.41 (s, 2H), 3.02 (s 3H); LC/MS [M + H]+ = 241 m/z).
Figure imgf000047_0001
Dioxane n
Step 2 Method A: Preparation of A/-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide (25): A solution of Intermediate 4 (200 mg, 0.83 mmol) in anhydrous dioxane (10 mL) was treated with benzenesulfonamide (1 .24 mmol, 1 .5 equiv.) and
CS2CO3 (405 mg, 1 .24 mmol, 1 .5 equiv.). After degassing with N2 bubbling, the reaction was treated with DBTTBP (63 mg, 0.132 mmol, 0.16 equiv) and Pd2(dba)3 (83 mg, 0.091 mmol, 0.1 1 equiv). The reaction was stirred at 100 °C for 16 h. The reaction mixture was diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purified by silica gel flash chromatography (EtOAc/hexanes eluant) to provide title compound as product (Yield 69%, LC/MS [M + H]+ = 318 m/z).
EXAMPLE 26
Preparation of A/-methyl-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzene-sulfonamide (26): The title compound was prepared according to the procedure of Example 25; (Yield 16%, LC/MS [M + H]+ = 332 m/z).
EXAMPLE 27
Figure imgf000048_0001
Dioxane H
Step 2 Method B: Preparation of 3-methoxy-/V-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro- quinazolin-6-yl)benzenesulfonamide (27): A solution of Intermediate 4 (200 mg, 0.83 mmol) in anhydrous dioxane (10 mL) was treated with 3-methoxybenzenesulfonamide (1 .66 mmol, 2.0 equiv.), DMEDA (89 μί, 0.83 mmol, 1 equiv.), Cul (158 mg, 0.83 mmol, 1 equiv.), and KF-AI2O3 (40 wt%, 601 mg, 4.1 mmol, 5 equiv). The reaction was heated under N2 at 1 10 °C for 18 h. The reaction mixture was filtered through celite and after rinsing the celite with EtOAc, the filtrate was concentrated to a blue solid that was then dissolved in MeOH and passed through a 5g SCX cartridge eluting with excess MeOH. The crude material was concentrated and purified by silica gel flash chromatography (MeOH/DCM eluant) to provide the title compound as product (Yield 69%, 1H NMR (400 MHz, DMSO-c/6) δ 9.89 (s, 1 H), 9.10 (s, 1 H), 7.44 (t, 1 H, J = 8 Hz), 7.26-7.15 (m, 3H), 6.82 (m, 2H), 6.62 (d, 1 H, J = 12 Hz), 4.29 (s, 2H), 3.76 (s, 3H), 2.80 (s, 3H); LC/MS [M + H]+ = 348 m/z).
EXAMPLE 28
Figure imgf000048_0002
Dioxane
Preparation of A/-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzene- sulfonamide (28): A solution of 7-bromo-2-methyl-1 ,2-dihydroisoquinolin-3(4H)-one (was prepared following the literature procedure: Ulysse, L. G.; Yang, Q.; McLaws, M. D.; Keefe, D. K.; Guzzo, P. R.; Haney, B. P. Org. Proc. Res. Dev. 2010, 14, 225-228) (200 mg, 0.83 mmol) in anhydrous dioxane was degassed with N2 and then sequentially treated with benzenesulfonamide (262 mg, 1 .67 mmol, 2.0 equiv), Cs2CO3 (543 mg, 1 .67 mmol, 2.0 equiv), DBTTBP (80.3 mg, .017 mmol, 0.20 equiv), and Pd2(dba)3 (153 mg, 0.17 mmol, 0.20 equiv) with degassing after every addition of reagent. The reaction was placed in a pre-heated bath at 1 10 °C for 30 min. After cooling, the crude was partitioned between water and EtOAc, and the organic layer was dried over MgSO . The crude was filtered, concentrated, and purified by silica gel column chromatography (EtOAc/pentane eluant) to afford title compound as product after trituration with Et2O (Yield 19%, LC/MS [M + H]+ = 317 m/z).
EXAMPLE 29
Preparation of 3-methoxy-/V-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)- benzenesulfonamide (29): The title compound was prepared according to the procedure of Example 28; (Yield 28%, LC/MS [M + H]+ = 347 m/z).
EXAMPLE 30
Figure imgf000049_0001
Preparation of A/-(2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonamide (30): A solution of 6-bromoquinolin-2(1 H)-one (100 mg, 0.446 mmol) in anhydrous dioxane was degassed with N2 and then treated with benezenesulfonamide (140 mg, 0.892 mmol, 2.0 equiv.) and DMEDA (48 μί, 0446 mmol, 1 .0 equiv.). After repeating the degassing procedure, the reaction was treated with KF-AI2O3 (40 wt%, 130 mg, 2.23 mmol, 5.0 equiv.) and Cul (84.9 mg, 0.446 mmol, 1 .0 equiv.) and the reaction was placed in a preheated bath at 130 °C. The reaction was heated for 1 .5 h. After cooling, the reaction was filtered through a plug of arbosel and washed with EtOAc. The organic phase was then washed with EDTA solution, dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel column chromatography (EtOAc/pentane eluant) to provide the title compound as product (Yield, 27%, LC/MS [M + H]+ = 301 m/z).
EXAMPLE 31
Preparation of A/-(4-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonamide (31): The title compound was prepared according to the procedure of Example 30; (Yield 25%, LC/MS [M + H]+ = 315 m/z). EXAMPLE 32
Preparation of 2-fluoro-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)benzenesulfonamide (32): To a stirred solution of 6-amino-3-methyl-1 H-quinolin-2-one (200 mg, 1 .15 mmol) in pyridine (10 ml) was added 2-fluorobenzenesulfonyl chloride (0.15 ml, 1 .15 mmol) at room temperature and resulting mixture was stirred for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 1 N HCI, water, brine and dried over Na2SO4. Evaporation of solvent followed by column chromatography (40% ethyl acetate-hexane) afforded 33 (1 10 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 7.12-7.18 (m, 2H), 7.27 (s, 1 H), 7.31 (t, 1 H), 7.40 (t, 1 H), 7.63-7.68 (m, 2H), 7.76 (t, 1 H), 10.48 (s, 1 H), 1 1 .67 (s, 1 H). LCMS: Rt = 6.03 min; m/z 333 [M-H]+ HPLC purity: 93.16%.
EXAMPLE 33
Preparation of 2-methoxy-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)benzenesulfonamide (33): To a stirred solution of 6-amino-3-methyl-1 H-quinolin-2-one (0.2 g, 1 .149 mmol) in pyridine (8 ml), 2-methoxybenzenesulfonyl chloride (0.236 g, 1 .149 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. After completion of reaction (monitored by TLC) the mixture was diluted with cold water and extracted with ethyl acetate. The combined organic layer were washed with 1 N HCI, brine and dried (Na2SO4). Evaporation of the solvent followed by column chromatography (30% ethyl acetate-hexane) afforded the title compound (0.1 g, 46%) as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 2.02 (s, 3H), 3.90 (s, 3H), 6.97 (t, 1 H), 7.08 (d, 1 H), 7.13-7.16 (m, 2H), 7.22 (s, 1 H), 7.53 (t, 1 H), 7.65-7.69 (m, 2H), 9.86 (s, 1 H), 1 1 .62 (s, 1 H). LCMS: Rt = 2.71 min; m/z 345 [M+H]+. HPLC purity: 93.51 %
EXAMPLE 34
Preparation of 2-methyl-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)benzenesulfonamide (34). To a stirred solution of 6-amino-3-methyl-1 H-quinolin-2-one (0.3 g, 1 .724 mmol) in pyridine (10 ml), 2-methylbenzenesulfonyl chloride (0.327 g, 1 .724 mmol) was added at room temperature and the resulting mixture was stirred for 16 h. After completion of reaction (monitored by TLC) the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with 1 N HCI and brine.
Evaporation of solvent followed by column chromatography (40% ethyl acetate-hexane) afforded 34 (0.12 g, 21 %) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 2.58 ( s, 3H), 7.12 (s, 2H), 7.22 (s, 2H), 7.30 (t, 1 H), 7.35 (d, 1 H), 7.47 (t, 1 H), 7.66 (s, 1 H), 7.80 (d, 1 H), 10.25 (s, 1 H), 1 1 .64 (s, 1 H). LCMS: Rt = 2.83 min; m/z 329 [M+H]+. HPLC purity: 96.64%
EXAMPLE 35
Preparation of N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2-(morpholin-4- ylmethyl)benzenesulfonamide (35):
Step 1 : To sodium (2-formyl)benzenesulfonate (5.0 g, 24.038 mmol), thionyl chloride (19.74 ml, 270.433 mmol) was added at room temperature followed by the addition of catalytic DMF (0.3 mL). The reaction mixture was stirred at room temperature for two minutes and then refluxed for three minutes. The reaction mixture was then cautiously poured into ice water and extracted with hexane. The combined organic layers were washed with brine and dried (Na2SO ). Evaporation of solvent followed by column chromatography (10% ethyl acetate-hexane) afforded (2-formyl)benzenesulfonyl chloride (2.3 g, 47%) as yellowish liquid. 1H NMR (400 MHz, CDCI3): δ 7.81 -7.84 (m, 1 H), 7.89 (t, 1 H), 8.14-8.19 (m, 2H), 10.90 (s, 1 H).
Step 2: To a stirred solution of 6-amino-3-methyl-1 H-quinolin-2-one (0.25 g, 1 .44 mmol) in pyridine (5 ml), was added (2-formyl)benzenesulfonyl chloride (0.439 g, 2.155 mmol) and resulting mixture was stirred at room temperature for 3 h. After completion of reaction (by TLC) it was diluted with ethyl acetate and water. Organic layer was separated and aqueous layer was back-extracted with ethyl acetate. Combined organic layer was washed with brine and dried over Na2SO4. Solvent was evaporated under reduced pressure to afford 2-formyl-N-(3-methyl-2-oxo-1 ,2-dihydro-quinolin-6-yl)- benzenesulfonamide (0.3 g, 61 %) as a brown solid. It was used in the next step without further purification. LCMS: Rt = 2.55 min; m/z 341 [M-H]+
Step 3: To a stirred solution of 2-formyl-N-(3-methyl-2-oxo-1 ,2-dihydro-quinolin-6-yl)- benzene-sulfonamide (0.49 g, 1 .44 mmol) and morpholine (0.13 mL, 1 .44 mmol) in dry THF (30 ml) was added sodium triacetoxyborohydride (456 mg, 2.15 mmol) and the resulting mixture was stirred at room temperature for 16 h. After completion of the reaction, it was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO and
evaporated under reduced pressure to afford 3-methyl-6-(3-morpholin-4-yl-1 ,1 -dioxo-1 ,3- dihydro-1 A*6*-benzo[d]isothiazol-2-yl)-1 H-quinolin-2-one (300 mg, 51 %). LCMS: Rt = 2.87 min; m/z 410 [M-H]+
Step 4: Sodium borohydride (0.055 g, 1 .46 mmol) was added to a stirred solution of 3-methyl-6-(3-morpholin-4-yl-1 ,1 -dioxo-1 ,3-dihydro-1 A*6*-benzo[d]isothiazol-2-yl)-1 H- quinolin-2-one (0.3 g, 0.73 mmol) in dry THF (15 ml_) at room temperature and the reaction mixture was stirred for 2 h. After completion of reaction, it was diluted with ethyl acetate and washed with aqueous NaHCO3 solution, brine and dried over Na2SO4 and concentrated. The crude material was purified by preparative TLC to afford 35 (0.03 g, 10%) as off white solid. 1H NMR (400 MHz, DMSO): δ 2.04 (s, 3H), 2.47 (m, 4H), 3.57-3.59 (m, 4H), 3.89 (s, 2H), 7.01 (dd,1 H), 7.12-7.13 (m, 2H), 7.38 (t, 1 H), 7.59 (t, 1 H), 7.67 (s, 1 H), 7.73 (t, 2H), 10.32 (br s, 1 H), 1 1 .68 (s, 1 H). LCMS: Rt = 2.72 min; m/z 414.6 [M+H]+. HPLC purity: 98.15%
EXAMPLE 36
Preparation of methyl (2-{[(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)amino]sulfonyl}phenoxy)acetate (36):
Step 1 : To a stirred solution of 2-mercaptophenol (5g, 39.7 mmol) in DMF (50 ml) was added solid KHCO3 (4.36 g, 43.6 mmol) followed by benzyl bromide (4.7 ml, 39.7 mmol). The reaction mixture was stirred at room temperature for 16h and then filtered through a pad of celite. The precipitate was washed with ether. The combined filtrates were washed with water followed by brine, dried over Na2SO , and concentrated. The residue was purified by column chromatography (100-200 mesh silica, 2% ethyl acetate in hexane) to afford 2-benzylsulfanyl-phenol (5 g, 58%) as colorless liquid. 1H NMR (400 MHz, DMSO- d6): δ 9.82 (s, 1 H), 7.33-7.19 (m, 5H), 7.16 (d, 1 H), 7.02 (t, 1 H), 6.82 (d, 1 H), 6.72 (t, 1 H), 4.1 1 (s, 2H). LCMS: Rt = 3.75; m/z 215.2 (M-H)+
Step 2: To a stirred solution of 2-benzylsulfanyl-phenol (4 g, 18.7 mmol) in acetonitrile (40 ml) was added K2CO3 (3.86 g, 28.03 mmol) followed by methyl
bromoacetate (2.66 ml, 28 mmol). The reaction mixture was refluxed for 16 h and then cooled to room temperature. The solvent was evaporated and the residue was extracted with EtOAc, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (100-200 mesh silica, 4% EtOAc in hexane) to afford (2-benzylsulfanyl-phenoxy)-acetic acid methyl ester (4 g, 74%) as white solid. 1H NMR (400 MHz, CDCI3): δ 7.30-7.23 (m, 5H), 7.20 (d, 1 H), 7.15 (t, 1 H), 6.89 (t, 1 H), 6.73 (d, 1 H), 4.70 (s, 2H), 4.14 (s, 2H), 3.80 (s, 3H). LCMS: Rt = 3.89; m/z 288.6 (M+H)+
Step 3: To a solution of (2-benzylsulfanyl-phenoxy)-acetic acid methyl ester (200 mg, 0.695 mmol) in acetonitrile (7 ml_), acetic acid (0.3 ml) and water (0.2 ml_) was added trichloroisocyanuric acid (325 mg, 1 .39 mmol). The reaction mixture was then stirred at room temperature for 16 h. The solvent was evaporated and the residue was diluted with 25% ethyl acetate in hexane, which gave a white precipitate. The precipitate was filtered and the filtrate was concentrated. The residue was purified by column chromatography (100-200 mesh silica, 15% EtOAc in hexane) to afford (2-chlorosulfonyl-phenoxy)-acetic acid methyl ester (0.17 g, 92%) as a colorless liquid. 1H NMR (400 MHz, CDCI3): δ 7.99 (d, 1 H), 7.64 (t, 1 H), 7.15 (t, 1 H), 6.97 (d, 1 H), 4.88 (s, 2H), 3.81 (s, 3H). LCMS: Rt = 3.06; m/z 282 (M+NH4)+
Step 4: To a solution of (2-chlorosulfonyl-phenoxy)-acetic acid methyl ester (200 mg, 0.758 mmol) in neat pyridine (7 ml_) was added 6-amino-3-methyl-1 H-quinolin-2-one and the mixture was stirred for 96 h at room temperature. The reaction was diluted with ethyl acetate and then washed with saturated copper sulfate solution followed by 1 N HCI. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified by column chromatography (100-200 mesh silica, using a gradient of 30 to 70 % ethyl acetate-hexane) to afford 36 (100 mg, 33%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1 1 .64 (s, 1 H), 9.62 (s, 1 H), 7.64-7.63 (m, 2H), 7.50 (t, 1 H), 7.32 (s, 1 H), 7.22 (d, 1 H), 7.07 (t, 2H), 6.99 (t, 1 H), 5.03 (s, 2H), 3.73 (s, 3H), 2.03 (s, 3H). LCMS: Rt = 6.26; m/z 403.0 (M+H)+. HPLC purity = 92.74%
EXAMPLE 37
Preparation of 2-(2-hydroxy-2-methylpropoxy)-N-(3-methyl-2-oxo-1 ,2- dihydroquinolin-6-yl)benzenesulfonamide (37): To an ice cooled solution of 36 (200 mg, 0.5 mmol) in THF (5 ml) was added MeLi (1 .6 M in Et2O, 1 .86 ml, 2.98 mmol) drop-wise at 0 C and the mixture was stirred for 1 h. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over anhydrous Na2SO . Evaporation of the solvent followed by preparative TLC (100% ethyl acetate) afforded 37(25 mg, 12%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 1 1 .64 (s, 1 H), 9.30 (br s, 1 H), 7.64 (s, 1 H), 7.59-7.52 (m, 2H), 7.27 (d, 1 H), 7.20 (d, 1 H), 7.16-7.14 (m, 1 H), 7.09 (d, 1 H), 6.96 (t, 1 H), 5.42 (br s, 1 H), 3.99 (s, 2H), 2.03 (s, 3H), 1 .33 (s, 6H). LCMS: Rt = 2.79; m/z 401 (M-H)+. HPLC purity = 90.61 %
EXAMPLE 38
Preparation of (2-{[(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)amino]sulfonyl}phenoxy)acetic acid (38): To a solution of 36 (60 mg, 0.15 mmol) in a mixed solvent (THF-MeOH, 1 :1 , 2 ml) was added 1 N KOH solution (0.2 ml, 0.2 mmol) and then reaction mixture was allowed to stir for 2 h at room temperature. TLC monitoring showed the reaction to be completed. The solvent was evaporated and the residue was stirred with ethyl acetate and acidified with 1 N HCI. The organic layer was separated, dried over sodium sulfate and then concentrated. The residue was triturated and washed with pentane-Et2O mixture (1 :1 ), after which purification by prep HPLC gave 38 (17 mg, 29%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 1 1 .59 (s, 1 H), 7.60 (s, 1 H), 7.52-7.47 (m, 2H), 7.30 (s, 1 H), 7.18 (d, 1 H), 7.10 (d, 1 H), 7.05 (d, 1 H), 6.92 (t, 1 H), 4.52 (s, 2H), 1 .99 (s, 3H). LCMS: Rt = 2.33; m/z 389.0 (M+H)+. HPLC purity = 98.13%
EXAMPLE 39
Preparation of N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonamide (39): To a stirred solution of 6-bromo-3-methyl-1 H-quinolin-2-one (0.25 g, 1 mmol, Chem. Pharm. Bull. 1987, 35, p. 2819 - 2824) in 5 mL of dioxane was added benzenesulfonamide (250 mg, 1 .6 mmol), cesium carbonate (516 mg, 1 .6 mmol) and the mixture was degassed under argon. Tetramethyl-di-t-butyl-XPhos (81 mg, 0.17 mmol) and Pd2(dba)3 (106 mg, 0.1 1 mmol) were added and the mixture was degassed again. The mixture was heated under reflux for 2 h, cooled, filtered through Celite, and concentrated. The residue was partitioned between water and ethyl acetate. The ethyl acetate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative tic to afford 39 (39 mg) as a solid. 1H NMR (400 MHz, DMSO-d6): 51 1 .66 (s, 1 H), 10.15 (s, 1 H), 7.69 (t, 3 H), 7.58 (t, 1 H), 7.52 (t, 1 H), 7.24 (s, 1 H), 7.12 (s, 1 H), 2.03 (s, 3 H). LCMS: Rt = 2.68; m/z 315 (M+H)+. HPLC purity = 99.69%
EXAMPLE 40
Preparation of 3-methoxy-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7- yl)benzenesulfonamide (40): The title compound was prepared according to the procedure of Example 39; from 3-methoxybenzenesulfonamide and 7-bromo-2-methyl-1 ,2- dihydroisoquinolin-3(4H)-one (Org. Process Res. Dev. 2010, 14, p. 225 - 228). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.91 (s, 3 H) 3.30 (s, 2 H) 3.39 (s, 2 H) 3.76 (s, 3 H) 6.96 (dd, J=8.40, 2.15 Hz, 1 H) 7.00 (d, J=1 .95 Hz, 1 H) 7.04 (d, J=8.40 Hz, 1 H) 7.16 (ddd, J=8.30, 2.64, 0.98 Hz, 1 H) 7.26 (dd, J=2.34, 1 .76 Hz, 1 H) 7.31 (ddd, J=7.71 , 1 .66, 0.98 Hz, 1 H) 7.45 (t, J=8.01 Hz, 1 H) 10.23 (s, 1 H); MS - m/z 347 (MH+)
EXAMPLE 41
Preparation of 2-fluoro-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7- yl)benzenesulfonamide (41): The title compound was prepared according to the procedure of Example 39; from 2-fluorobenzenesulfonamide and 7-bromo-2-methyl-1 ,2- dihydroisoquinolin-3(4H)-one. 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.04 (s, 3 H) 3.48 (s, 2 H) 4.45 (d, J=0.78 Hz, 2 H) 7.00 - 7.04 (m, 2 H) 7.06 (s, 1 H) 7.20 - 7.29 (m, 2 H) 7.55 - 7.64 (m, 1 H) 7.81 (td, J=7.61 , 1 .76 Hz, 1 H); LCMS: Retention time 3.65 min, m/z = 335 (MH+)
EXAMPLE 42
Preparation of N-(1 ,3-dimethyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2- methoxybenzenesulfonamide (42):
Step 1 : To a stirred solution of 3-methyl-6-nitro-1 H-quinolin-2-one (700 mg, 3.43 mmol) in DMF (15 ml) was added potassium t-butoxide (4.1 ml, 1 M in THF) followed by iodomethane (0.43 ml, 6.86 mmol) with ice cooling. The reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was poured onto crushed ice, and the precipitated solid was collected by filtration, washed with water and dried. The solid was triturated with ether to afford 1 ,3-dimethyl-6-nitro-1 H-quinolin-2-one as an off white solid (500 mg, 67%). 1H NMR (400 MHz, CDCI3): δ 8.60 (s, 1 H), 8.33 (d, 1 H), 7.80 (s, 1 H), 7.68 (d, 1 H), 3.69 (s, 3H), 2.15 (s, 3H). LCMS: Rt = 2.88 min; m/z 219 [M-H]+
Step 2: To a stirred solution of 1 ,3-dimethyl-6-nitro-1 H-quinolin-2-one (500 mg, 2.29 mmol) in THF: EtOH: H2O (4:2:1 , 70 ml) were added iron powder (896 mg, 16 mmol) and NH4CI (613 mg, 1 1 .47 mmol). The reaction mixture was heated at 50° C for 3 h. The reaction mixture was filtered through a short pad of Celite. The filtrate was evaporated and the residue was diluted with ethyl acetate, washed with water, brine, dried over Na2SO4 and filtered. The solvent was evaporated under reduced pressure to afford 6-amino-1 ,3- dimethyl-1 H-quinolin-2-one as a yellow solid (350 mg, 81 %). 1H NMR (400 MHz, CDCI3): δ 7.54 (s, 1 H), 7.21 (d, 1 H), 6.87 (dd, 1 H), 6.72 (d, 1 H), 5.02 (s, 2H), 3.56 (s, 3H), 2.08 (s, 3H). LCMS: Rt = 1 .76 min; m/z 189 [M-H]+ Step 3: To a stirred solution of 6-amino-1 ,3-dimethyl-1 H-quinolin-2-one (350 mg, 1 .86 mmol) in dichloromethane (50 ml) was added triethylamine (0.78 ml, 5.58 mmol) followed by 2-methoxybenzenesulfonyl chloride (461 mg, 2.23 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. It was diluted with water and extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over Na2SO and concentrated under reduced pressure. The residue was purified by flash chromatography (70-80% -ethyl acetate-hexane) to afford 42 as an off-white solid (390 mg, 59%). 1H NMR (400 MHz, CDCI3): δ 9.98 (s, 1 H), 7.72 (d, 1 H), 7.64 (s, 1 H), 7.53 (t, 1 H), 7.34-7.26 (m, 3H), 7.15 (d, 1 H), 6.99 (t, 1 H), 3.91 (s, 3H), 3.52 (s, 3H), 2.05 (s, 3H). LCMS: Rt = 2.88 min; m/z 359 [M-H]+. HPLC : 99.56%.
EXAMPLE 43
Preparation of 2-methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide (43): To a stirred solution of 6-amino-3-methyl-3, 4-dihydro-1 H- quinazolin-2-one (17 g, 72 mmol) in 12 mL of pyridine was added 2- methoxybenzenesulfonyl chloride in 6 mL of dichloromethane dropwise with cooling in ice. The mixture was allowed to warm to room temperature for 1 h. After completion of the reaction, the solvents were evaporated and the residue was treated with water and filtered. The precipitate was dissolved in 9/1 dichloromethane - methanol, dried with Na2SO4, and concentrated. The residue was purified by chromatography on alumina to afford 43 as an off white solid (14.9 g). 1H NMR (400 MHz, DMSO-d6): δ 9.64 (s, 1 H), 9.09 (s, 1 H), 7.68 (d, 1 H), 7.52 (t, 1 H), 7.14 (d, 1 H), 6.97 (t, 1 H), 6.85 (s, 2 H), 6.59 (d, 1 H), 4.25 (s, 2 H), 3.91 (s, 3 H), 2.78 (s, 3 H). LCMS: Rt = 2.64; m/z 348 (M+H)+. HPLC purity = 998.73%
EXAMPLE 44
Preparation of 3-methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one (44):
Step 1 : To a stirred solution of 6-bromo-3-methyl-1 H-quinolin-2-one (1 .00 g, 4.2 mmol) in dioxane (20 mL) were added diisopropylethylamine (1 .53 mL, 8.8 mmol),
Pd2(dba)3 (192 mg, 0.21 mmol), and Xantphos (243 mg, 0.42 mmol). The mixture was degassed, then benzyl mercaptan (0.49 mL, 4.2 mmol) was added under nitrogen and the mixture was heated at 1 10 C overnight. The mixture was allowed to cool and evaporated directly onto silica. Chromatography afforded a dark brown solid. This was triturated in 8 mL of methanol and allowed to stand overnight. Filtration afforded 6-benzylsulfanyl-3-methyl- 1 H-quinolin-2-one as a brown solid (1 .0 g, 85%). Step 2: To a solution of 6-benzylsulfanyl-3-methyl-1 H-quinolin-2-one (200 mg, 0.71 mmol) in 9 ml_ of acetic acid and 1 ml_ of water was added N-chlorosuccinimide (285 mg, 2.13 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with approximately 30 ml_ of water to yield a light brown precipitate, which was filtered, washed with water and dried to afford 3-methyl-2-oxo-1 ,2-dihydro-quinoline-6-sulfonyl chloride as a pale brown solid (166 mg, 90%).
Step 3: To a suspension of 3-methyl-2-oxo-1 ,2-dihydro-quinoline-6-sulfonyl chloride (166 mg, 0.64 mmol) in 5 ml_ of dichloromethane was added pyrrolidine (0.53 ml_, 6.4 mmol) to give a brown solution. The mixture was stirred at room temperature for 30 min, then concentrated in under reduced pressure. The residue was stirred with 2 M HCI , filtered, washed with water, and dried under high vacuum to afford 44 as a light brown solid (160 mg, 85%).
EXAMPLE 45
Preparation of 4-methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one (45): The title compound was prepared according to the procedure of Example 39; from 6-bromo-4- methylquinolin-2(1 H)-one (Synthesis, 201 1 , p. 934 - 942).
EXAMPLE 46
Preparation of N-(2-hydroxy-3-methylquinolin-6-yl)piperidine-1 -sulfonamide (46): This compound was prepared in a parallel synthesis format according to the following procedure.
A 0.2 M solution of 6-amino-3-methyl-1 H-quinolin-2-one in anhydrous pyridine was prepared (Solution A). A 0.2 M solution of each sulfonyl chloride monomer, for example piperidine 1 -sulfonyl chloride, in anhydrous pyridine was likewise prepared. These sulfonyl chloride solutions were prepared freshly just before use. Solution A (500 uL, 100 μιτιοΐβ) was added to each reaction vial, followed by 500 μί (1 equivalent, 100 umole) of sulfonyl chloride solution, with each sulfonyl chloride being unique to each vial in the library. Each vial was treated with 12 mg (100 umole) of DMAP, after which the vials were stirred for 16 h at 60 °C. The reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 45 °C). Each of the crude products was dissolved in 1 mL of DMSO. 10 μί of the DMSO solution was diluted to 200 μί with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 46: Calculated molecular weight 321 .1 1 ; found MH+ 322.05.
EXAMPLES 47 to 73
Compounds 47 to 73 were prepared in a parallel synthesis format according to the procedure of Example 46. Chemical name, calculated molecular weight and found MH+ for compounds 47 to 73 are shown in the table below.
Figure imgf000058_0001
N-(2-hydroxy-3-methylquinolin-6-yl)-2-oxo-2,3-
371 .06 372.18 dihydro-1 ,3-benzoxazole-6-sulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-2-oxo-
296.08 297.21 1 ,2,3,4-tetrahydroquinoline-6-sulfonannide
N-(2-hydroxy-3-methylquinolin-6-yl)-1 H-
304.06 305.17 imidazole-4-sulfonannide
5-chloro-N-(2-hydroxy-3-methylquinolin-6-
353.99 355.12 yl)thiophene-2-sulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-1 ,2-
332.09 333.21 dimethyl-1 H-imidazole-4-sulfonannide
N-(2-hydroxy-3-methylquinolin-6-yl)-2-methyl-
385.06 386.19 1 ,3-benzothiazole-5-sulfonamide
(1 R,2R)-N-(2-hydroxy-3-methylquinolin-6-yl)-2-
354.1 355.24 phenylcyclopropanesulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-4-methyl- 3,4-dihydrc-2H-1 ,4-benzoxazine-7- 385.1 1 386.23 sulfonamide
(1 R,2S)-2-ethyl-N-(2-hydroxy-3-methylquinolin-
306.1 307.21 6-yl)cyclopropanesulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-1 -nnethyl-
318.08 319.2 1 H-imidazole-4-sulfonannide
3-fluoro-4-{[(2-hydroxy-3-methylquinolin-6-
376.05 377.15 yl)amino]sulfonyl}benzoic acid
N-(2-hydroxy-3-methylquinolin-6-
323.09 324.21 yl)morpholine-4-sulfonannide
N-(2-hydroxy-3-methylquinolin-6-yl)-1 H-
304.06 305.21 pyrazole-4-sulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-3,5-
332.09 333.21 dimethyl-1 H-pyrazole-4-sulfonamide
N-(2-hydroxy-3-methylquinolin-6-yl)-3,4-
386.09 387.24 dihydro-2H-1 ,5-benzodioxepine-7-sulfonamide EXAMPLE 74
Preparation of 5-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-2- methoxybenzenesulfonamide (74): This compound was prepared in a parallel synthesis format according to the following procedure.
A 0.2 M solution of 6-amino-3-methyl-1 H-quinolin-2-one in anhydrous 1 :1 pyridine- DMF was prepared (Solution A). A 0.2 M solution of each sulfonyl chloride monomer, for example piperidine 1 -sulfonyl chloride, in anhydrous 1 :1 pyridine-DMF was likewise prepared. These sulfonyl chloride solutions were prepared freshly just before use. Solution A (500 uL, 100 umole) was added to each reaction vial, followed by 500 uL (1 equivalent, 100 umole) of sulfonyl chloride solution, with each sulfonyl chloride being unique to each vial in the library. Each vial was treated with 12 mg (100 umole) of DMAP, after which the vials were stirred for 16 h at 60 °C. The reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 45 °C). Each of the crude products was dissolved in 1 ml_ of DMSO. 10 μΙ_ of the DMSO solution was diluted to 200 μΙ_ with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters
Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 74: Calculated molecular weight 362.07; found MH+ 363.16.
EXAMPLES 75 to 80 and 82 to 89
Compounds 75 to 80 and 82 to 89 were prepared in a parallel synthesis format according to the procedure of Example 74. Chemical name, calculated molecular weight and found MH+ for compounds 75 to 80 and 82 to 89 are shown in the table below.
Figure imgf000060_0001
3-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-
79 362.07 363.12
4-methoxybenzenesulfonamide
5-chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-
80 362.05 363.16
2-methylbenzenesulfonamide
2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-
82 346.08 347.16
4-methylbenzenesulfonannide
3-chloro-5-fluoro-N-(2-hydroxy-3-
83 methylquinolin-6-yl)-2- 380.04 381 .12 methylbenzenesulfonannide
3,5-difluoro-N-(2-hydroxy-3-methylquinolin-6-
84 350.05 351 .12 yl)benzenesulfonamide
5-chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-
85 378.04 379.1 1
2-methoxybenzenesulfonamide
2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-
86 346.08 347.16
3-methylbenzenesulfonannide
2-chloro-4-fluoro-N-(2-hydroxy-3-
87 366.02 367.09 methylquinolin-6-yl)benzenesulfonannide
5-chloro-2-fluoro-N-(2-hydroxy-3-
88 366.02 367.07 methylquinolin-6-yl)benzenesulfonannide
2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-
89 346.08 347.16
5-methylbenzenesulfonannide
EXAMPLE 90
Preparation of 2-methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinolin-6- yl)benzenesulfonamide (90): This compound was prepared in a parallel synthesis format according to the following procedure.
A 0.2 M solution of each amine monomer, for example 6-amino-3-methyl-3,4- dihydro-1 H-quinolin-2-one, in anhydrous pyridine was prepared (Solution A), with each amine being unique to each vial in the library. A 0.2 M solution of 2- methoxybenzenesulfonyl chloride in anhydrous pyridine was prepared just before use. Solution A (400 uL, 80 umole) was added to each reaction vial, followed by 400 uL (1 equivalent, 80 umole) of sulfonyl chloride solution. Each vial was treated with 10 mg (80 umole) of DMAP, after which the vials were stirred for 16 h at 60 °C. The reaction mixtures were evaporated in a Thermo Explorer (2 h, 5 torr, at 45 °C). Each of the crude products was dissolved in 1 ml_ of DMSO. 10μΙ_ of the DMSO solution was diluted to 200 μΙ_ with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 90: Calculated molecular weight 346.1 ; found MH+ 347.16.
EXAMPLE 91
Preparation of 2-methoxy-N-(2-oxo-1 ,2,3,4-tetrahydroquinolin-6- yl)benzenesulfonamide (91): The title compound was prepared according to the procedure of Example 90; from 6-amino-3,4-dihydro-1 H-quinolin-2-one, as prepared according to Archiv der Pharmazie, 2008, 341 , p. 794 - 799. Calculated molecular weight 332.08; found MH+ 333.1 .
EXAMPLE 92
Preparation of N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3- (methylsulfonyl)benzenesulfonamide (92): This compound was prepared in a parallel synthesis format according to the following procedure.
A 0.2 M solution of 6-amino-3-methyl-3,4-dihydro-1 H-quinazolin-2-one in anhydrous pyridine was prepared (Solution A). A 0.2 M solution of each sulfonyl chloride monomer, for example 3-methanesulfonyl-benzenesulfonyl chloride, in anhydrous pyridine was likewise prepared. These sulfonyl chloride solutions were prepared freshly just before use. Solution A (500 uL, 100 umole) was added to each reaction vial, followed by 500 uL (1 equivalent, 100 umole) of sulfonyl chloride solution. Each vial was treated with 12 mg (100 umole) of DMAP, after which the vials were stirred for 16 h at 60 °C. The reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 45 °C). Each of the crude products was dissolved in 1 mL of DMSO. 10μί of the DMSO solution was diluted to 200 μί with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 92: Calculated molecular weight 395.06; found MH+ 396.05.
EXAMPLES 93 to 96
Compounds 93 to 96 were prepared in a parallel synthesis format according to the procedure of Example 92. Chemical name, calculated molecular weight and found MH+ for compounds 93 to 96 are shown in the table below. Calculated
Found
Example Chemical Name molecular
MH+ weight
N-(3-methyl-2-oxo-1 ,2,3,4-
93 tetrahydroquinazolin-6-yl)biphenyl-3- 393.1 1 394.21
sulfonamide
N-(3-methyl-2-oxo-1 ,2,3,4-
94 tetrahydroquinazolin-6-yl)-2,3-dihydro-1 - 359.09 360.16
benzofuran-5-sulfonamide
N-(3-methyl-2-oxo-1 ,2,3,4-
95 tetrahydroquinazolin-6-yl)-2,3-dihydro-1 ,4- 375.09 376.14
benzodioxine-6-sulfonamide
3-fluoro-4-methoxy-N-(3-methyl-2-oxo-
96 1 ,2,3,4-tetrahydroquinazolin-6- 365.08 366.14
yl)benzenesulfonamide
EXAMPLE 97
Preparation of N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)cyclopropanesulfonamide (97): This compound was prepared in a parallel synthesis format according to the following procedure.
6-Amino-3-methyl-3,4-dihydro-1 H-quinazolin-2-one (100 μιτιοΙ) was charged to each vial. Anhydrous DMA (1 to 2 mL) and triethylamine (300 umol) was added to each vial. Each sulfonyl chloride monomer, for example cyclopropanesulfonyl chloride, was added to each vial, after which the vials were stirred for 16 h at room temperature. The reaction mixtures were evaporated in a Thermo Explorer (2 hr, 5 torr, at 40 °C). Each of the crude products was dissolved in 1 mL of DMSO. 10 μί of the DMSO solution was diluted to 200 μί with DMSO for QC analysis and the remaining amount was submitted for prep-HPLC purification on a Waters Autopurification System using a gradient of 0.05% formic acid in water and acetonitrile. Product fractions were evaporated to dryness and weighed. For 97: Calculated molecular weight 281 .08; found M-H+ 280.26.
EXAMPLES 98 to 104
Compounds 98 to 104 were prepared in a parallel synthesis format according to the procedure of Example 97. Chemical name, calculated molecular weight and found MH+ for compounds 98 to 104 are shown in the table below. Calculated
Found
Example Chemical Name molecular
M-H+ weight
5-chloro-2-methoxy-N-(3-methyl-2-oxo-
98 1 ,2,3,4-tetrahydroquinazolin-6- 381 .05 380.28 yl)benzenesulfonamide
2,5-dichloro-N-(3-methyl-2-oxo-1 , 2,3,4-
99 tetrahydroquinazolin-6- 385.01 384.23 yl)benzenesulfonamide
4-fluoro-2-methyl-N-(3-methyl-2-oxo-1 , 2,3,4-
100 tetrahydroquinazolin-6- 349.09 348.31 yl)benzenesulfonamide
2-ethoxy-4-methyl-N-(3-methyl-2-oxo-1 , 2,3,4-
101 tetrahydroquinazolin-6- 375.13 376.4 yl)benzenesulfonamide
N-(3-methyl-2-oxo-1 ,2,3,4-
102 tetrahydroquinazolin-6-yl)-2- 401 .07 402.35
(trifluoronnethoxy)benzenesulfonannide
2-methoxy-5-methyl-N-(3-methyl-2-oxo-
103 1 ,2,3,4-tetrahydroquinazolin-6- 361 .1 1 362.31 yl)benzenesulfonamide
2-methoxy-4-methyl-N-(3-methyl-2-oxo-
104 1 ,2,3,4-tetrahydroquinazolin-6- 361 .1 1 362.36 yl)benzenesulfonamide
PREPARATION OF INTERMEDIATES
Some of the intermediates referred to in the Examples above can be prepared as outlined below.
Preparation of 6-Amino-3-methyl-1 H-quinolin-2-one
Step 1 : To an ice cold solution of concentrated HNO3 (3 ml) and concentrated H2SO4 (6 ml), 3-methyl-1 H-quinolin-2-one (1 .2 g, 7.55 mmol, Heterocycles, 2005, 65, p. 2095 - 2105) was added in small portions. The mixture was stirred additional 2 h with ice cooling. After completion of reaction (monitored by TLC), the mixture was poured into ice. The solid thus formed was filtered, washed with water and dried to afford 3-methyl-6-nitro- 1 H-quinolin-2-one (0.8 g, 52%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.1 1 (s, 3H), 7.41 (d, 1 H), 7.98 (s, 1 H), 8.26 (dd, 1 H), 8.58 (d, 1 H), 12.30 (s, 1 H). LCMS: Rt = 2.72 min; m/z 203 [M-H]+
Step 2: To a degassed solution of 3-methyl-6-nitro-1 H-quinolin-2-one (5 g, 24.63 mmol) in acetic acid (200 ml) was added 10% palladium on carbon (5.22 g). The reaction mixture was placed on a Parr low pressure hydrogenation apparatus and hydrogenated at 50 psi for 3 h. After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite. The filtrate was evaporated under reduced pressure, and the residue was triturated with ethyl acetate to afford 6-amino-3-methyl-1 H-quinolin-2-one (3.1 g, 72%) as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 2.06 (s, 3H), 6.93-6.97 (m, 2H), 7.12 (d, 1 H), 7.63 (s, 1 H), 1 1 .58 (s, 1 H). LCMS: Rt = 1 .38 min; m/z 175 [M+H]+
Preparation of 6-Amino-3-methyl-3,4-dihydro-1 H-quinolin-2-one
A solution of 3-methyl-6-nitro-3,4-dihydro-1 H-quinolin-2-one (9.6 g, 46 mmol, Bioorg. Med. Chem. 2003, 1 1 , p. 4949 - 4958) in 25 ml_ of acetic acid was hydrogenated over Raney nickel at atmospheric pressure for 18 h at room temperature. After completion of the reaction (monitored by TLC), the mixture was filtered through a short pad of Celite. The filtrate was evaporated under reduced pressure, and the residue was triturated with ether and pentane, filtered and dried to afford 6-amino-3-methyl-3,4-dihydro-1 H-quinolin-2-one (7.9 g, 76%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 1 .08 (d, 3 H), 2.36 (m, 2 H), 2.71 (m, 1 H), 6.31 (m, 2 H), 6.55 (d, 1 H), 9.61 (s, 1 H). LCMS: Rt = 2.04 min; m/z 177 [M+H]+
Preparation of 6-Amino-3-methyl-3,4-dihydro-1 H-quinazolin-2-one
Step 1 : To a stirred solution of 3-methyl-3, 4-dihydro-1 H-quinazolin-2-one (5 g, 30.8 mmol) in sulfuric acid (25 ml) was added potassium nitrate (3.12 g, 30.86 mmol) in portions at 0 °C. The reaction mixture was allowed to attain room temperature and was stirred for an additional 3 h, after which it was poured into ice water. The yellow precipitate thus formed was collected by filtration, washed with water and dried. This was purified over neutral alumina to afford 3-methyl-6-nitro-3,4-dihydro-1 H-quinazolin-2-one as a yellow solid (3.5 g, 55 %). 1H NMR (400 MHz, DMSO): δ 2.87 (s, 3H), 4.52 (s, 2H), 6.89-6.91 (m, 1 H), 8.05 (s, 1 H), 8.07(d, 1 H), 9.95 (s,1 H). LCMS (M-H) = 206.0
Step 2: 3-Methyl-6-nitro-3,4-dihydro-1 H-quinazolin-2-one (18 g, 86.95 mmol) was dissolved in acetic acid (250 ml) and hydrogenated over Raney nickel (about 4.0 g) in a Parr low pressure hydrogenation apparatus at 30 psi pressure for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1 M sulfuric acid solution (720 ml) and neutralized it using saturated sodium bicarbonate solution. The precipitate thus formed was collected by filtration, washed with cold water and dried to afford 6-amino-3-methyl-3,4-dihydro-1 H- quinazolin-2-one (13.6 g, 88%) as a brown solid. 1H NMR (400 MHz, DMSO): δ 2.81 (s, 3H), 4.24 (s, 2H), 4.65 (s,2H), 6.30 (s,1 H), 6.36 (d, 1 H), 6.47 (s,1 H), 8.72 (s, 1 H). LCMS (M+H) = 178.0
ALPHA SCREEN BINDING ASSAY
The binding of the compounds of Formula (I) to Bromodomain BRD4 was assessed using a 384-well Alpha Screen assay.
Receptor Source: Recombinant Human Bromodomain (BRD4) was expressed in E. coli cells pNIC-28-Bsa4 with a six-His tag at the N-terminus. The His-tagged Bromodomain was extracted from E. coli cells and then purified by affinity chromatography using a Ni chelate column, eluting with a linear 10-500mM Imidazole gradient. Further purification was completed by S75 16/60 HiLoad size exclusion column. Protein integrity was assessed by SDS-PAGE and electro-spray mass spectrometry using an Agilent 1 100 series LC/MSD TOF. Purified protein was stored at -80'C in 10 mM HEPES pH7.5, 500 mM NaCI and 5% glycerol.
Buffer: 50mM Hepes pH7.4, 0.1 M NaCI, 0.1 % BSA, 0.05% Chaps
Dilutions: For IC50 determination a 12 point through plate dose response curve was constructed using a top concentration of 4 mM in 100% DMSO. The plates were
subsequently diluted 1 :25 in assay buffer (as described above) to give 4% DMSO final. The assay was run in 384-well white low volume Proxiplates (Perkin Elmer) and 4 μΙ_ of compound or DMSO vehicle was transferred into the plate using a Cy-Bio 384 liquid handling system.
Protocol: The reaction was run in a total volume of 20 μΐ. and all reagents were diluted in the standard assay buffer (as described above). The BRD4 protein - 4 μΙ_ (50 nM FAC) was added to plates containing compound/ control and incubated for 30 minutes at room temperature. Following this, 4 μ[_ of H4KAc4 peptide (custom biotinylated peptide, 50nM FAC) was added and the plates incubated for a further 30 minutes prior to the addition of 8 μΐ. of the alpha screen beads at 0.0664 μg bead per well (Streptavidin donor beads, Ni chelate acceptor beads, Perkin Elmer). Plates are left in the dark for one hour prior to reading on an Envision reader (Perkin Elmer).
Data analysis: Data analysis and quality control used proprietary in house plate based pharmacology software in conjunction with Spotfire. All IC50 data was fitted using a full four parameter logistic equation.
SUMMARY OF B IOLOGICAL DATA
The IC50 data obtained with the Alpha Screen assay described above is provided in the table below.
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000067_0003
57 1 .05 73 1 .06 90 0.24
58 0.06 74 0.09 91 1 .74
59 3.07 75 0.99 92 3.45
60 1 .32 76 0.35 93 2.27
61 2.76 77 1 .17 94 0.75
62 0.92 78 0.65 95 1 .28
63 2.92 79 1 .00 96 1 .22
64 2.92 80 0.25 98 0.06
65 2.60 82 0.29 99 0.25
66 0.66 83 1 .35 100 0.19
67 0.62 84 0.59 101 0.13
68 2.03 85 0.05 102 0.25
69 6.65 86 0.31 103 0.1 1
70 0.33 87 0.16 104 0.14
71 1 .1 1 88 0.26
72 0.40 89 0.18
Variations, modifications, and other implementations of what is described herein will occur to those skilled in the art without departing from the spirit and the essential characteristics of the present teachings. Accordingly, the scope of the present teachings is to be defined not by the preceding illustrative description but instead by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Each of the printed publications, including but not limited to patents, patent applications, books, technical papers, trade publications and journal articles described or referenced in this specification are herein incorporated by reference in their entirety and for all purposes.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
Figure imgf000069_0001
(I)
or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond; L is -NR1SO2- or -SO2NR2-;
Ri is H or alkyl, or taken together with Q and the nitrogen to which they are bound forms a four, five, six, seven or eight-membered heterocydoalkyi, wherein said heterocydoalkyi is optionally substituted with R9;
R2 is H or alkyl;
Q is aryl, heteroaryl, cycloalkyl or heterocydoalkyi, wherein each aryl, heteroaryl, cycloalkyl, or heterocydoalkyi is optionally substituted with R3;
R3 is independently selected from the group consisting of hydroxy, halogen, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocydoalkyi, or cyano, oxo, alkylsulfonyl, amino, alkylamino, dialkylamino and amido, wherein each hydroxy, alkyl, haloalkyi, alkoxy, aryl, heteroaryl, cycloalkyl, heterocydoalkyi, oxo,
alkylsulfonyl, amino, alkylamino, dialkylamino or amido is further optionally substituted with hydroxy, oxo, carboxy, carboxyalkyl, hydroxyalkyl, alkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, amino, alkylamino, dialkylamino, amido, alkylamido, dialkylamido, halogen, alkyl, haloalkyi, aryl, heteroaryl, heterocydoalkyi or cycloalkyl;
R9 is independently selected from the group consisting of halogen, alkyl, haloalkyi, hydroxy, alkoxy, haloalkoxy, amino, alkylamino and dialkylamino;
A is N; B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2- where R2 is H, Q is 2- methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
2. The compound of claim 1 , wherein L is -NHSO2- 3. The compound of claim 1 , wherein L is -SO2NH-.
o
II
•s- II
4. The compound of claim 1 , wherein L and Q taken together is o 5. The compound of claim 1 , 2 or 3, wherein Q is aryl optionally substituted with
hydroxy, halogen or alkyl.
6. The compound of claim 1 , 2 or 3, wherein Q is aryl optionally substituted with cyano.
7. The compound of claim 1 , 2 or 3, wherein Q is aryl optionally substituted with aryl, heteroaryl or cycloalkyl.
8. The compound of claim 1 . 2 or 3, wherein Q is heteroaryl optionally substituted with hydroxy, halogen or alkyl.
9. The compound of any one of claims 1 -8, wherein B is N.
10 A compound of Formula (la):
Figure imgf000070_0001
(la) or a pharmaceutically acceptable salt or solvate thereof, wherein the dotted line may be a single bond or a double bond; L is -NR1 SO2- or -SO2NR2-; Ri and R2 are each independently H or alkyl
R , R5, R6, R7 and R8 are each independently selected from the group consisting of H, hydroxy, halogen, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, haloalkyl, cyano, alkylsulfonyl, amino, alkyamino and dialkylamino; wherein each hydroxy, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with alkyl;
A is N;
B is N or C; and,
X, Y and Z are each independently H or alkyl, with the proviso that when B is N and the dotted line is a double bond, then Y is absent; and with the further proviso that when A and B are both N, X and Z are both H, L is -SO2NR2- where R2 is H, R4 or R5 are each 2-methoxyphenyl, and the dotted line is a single bond, then Y is not methyl.
1 1 . The compound of claim 10, wherein L is -NHSO2-
12. The compound of claim 10, wherein L is -SO2NH-
13. The compound of claim 1 , wherein Y is methyl; B is N and the dotted line is a single bond or B is C and the dotted line is a double bond; and L is -SO2NH-
14. The compound of claim 10, 1 1 or 12, wherein R , R5, R6, R7 and Rs are each
independently H, hydroxy, halogen, alkyl, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, haloalkyl or cyano.
15. A compound selected from the group consisting of:
6-((3-Hydroxypyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydroquinazolin-2(1 H)-one;
6-((2-(Hydroxymethyl)piperidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro-quinazolin-2(1 H)- one;
6-((3-(Hydroxymethyl)pyrrolidin-1 -yl)sulfonyl)-3-methyl-3,4-dihydro-quinazolin-2(1 H)- one;
6-((4-(Hydroxyl(pyridin-2-yl)methyl)piperidin-1 -yl)sulfonyl)-3-methyl-3,4- dihydroquinazolin-2(1 H)-one;
3-Methyl-2-oxo-N-phenyl-1 ,2,3,4-tetrahydro-quinazoline-6-sulfonamide; 3-Methyl-6-(pyrrolidin-1 -ylsulfonyl)-3,4-dihydroquinazolin-2(1 H)-one; 2-Chloro-4-fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3-(trifluoronnethyl)- benzenesulfonamide;
2-Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro-quinazolin-6-yl)benzenesulfonannide;
2- Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide; 4-Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
2- Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2-(trifluoronnethyl)- benzenesulfonamide;
4- Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Fluoro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
4- Cyano-N-(3-methyl-2 -oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide; 4-Chloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3- Cyano-N-(3-methyl-2 -oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
4- Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene- sulfonamide;
2,6-Dichloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)- benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-4-(trifluoronnethyl)- benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonannide;
N-Methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzene-sulfonannide;
3-Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydro-quinazolin-6- yl)benzenesulfonamide;
N-(2-Methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzene-sulfonannide; 3-Methoxy-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)- benzenesulfonamide;
N-(2-Oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
N-(4-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
2-Fluoro-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
2-methoxy-N-(3-nnethyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
2-Methyl-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
N-(3-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2-(nnorpholin-4- ylmethyl)benzenesulfonannide;
Methyl (2-{[(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)annino]sulfonyl}phenoxy)acetate;
2- (2-Hydroxy-2-methylpropoxy)-N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6- yl)benzenesulfonamide;
(2-{[(3-Methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)annino]sulfonyl}phenoxy)acetic acid; N-(3-methyl-2-oxo-1 ,2-dihydroquinolin-6-yl)benzenesulfonannide;
3- Methoxy-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7- yl)benzenesulfonamide;
2-Fluoro-N-(2-methyl-3-oxo-1 ,2,3,4-tetrahydroisoquinolin-7-yl)benzenesulfonannide; N-(1 ,3-Dimethyl-2-oxo-1 ,2-dihydroquinolin-6-yl)-2-nnethoxybenzenesulfonannide;
2- Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)benzenesulfonannide;
3- Methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one;
4- Methyl-6-(pyrrolidin-1 -ylsulfonyl)quinolin-2(1 H)-one; N-(2-hydroxy-3-methylquinolin-6-yl)piperidine-1 -sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)pyridine-3-sulfonannide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,3,5-trimethyl-1 H-pyrazole-4-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,3-benzothiazole-6-sulfonamide; 4-{[(2-Hydroxy-3-methylquinolin-6-yl)amino]sulfonyl}benzamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-2,3-dihydro-1 ,4-benzodioxine-6-sulfonamide; N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -nnethyl-1 H-pyrazole-5-sulfonamide; methyl 3-{[(2-hydroxy-3-methylquinolin-6-yl)annino]sulfonyl}benzoate;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -nnethyl-1 H-pyrazole-3-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2,6-dimethylmorpholine-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)cyclopropanesulfonannide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-3,5-dimethylisoxazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)azepane-1 -sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2-oxo-2,3-dihydro-1 ,3-benzoxazole-6- sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2-oxo-1 ,2,3,4-tetrahydroquinoline-6- sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 H-imidazole-4-sulfonamide;
5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)thiophene-2-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 ,2-dimethyl-1 H-imidazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-2-methyl-1 ,3-benzothiazole-5-sulfonamide;
(1 R,2R)-N-(2-Hydroxy-3-methylquinolin-6-yl)-2-phenylcyclopropanesulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-4-methyl-3,4-dihydro-2H-1 ,4-benzoxazine-7- sulfonamide;
(1 R,2S)-2-Ethyl-N-(2-hydroxy-3-methylquinolin-6-yl)cyclopropanesulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 -methyl-1 H-imidazole-4-sulfonamide;
3-Fluoro-4-{[(2-hydroxy-3-methylquinolin-6-yl)amino]sulfonyl}benzoic acid;
N-(2-Hydroxy-3-methylquinolin-6-yl)morpholine-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-1 H-pyrazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-3,5-dimethyl-1 H-pyrazole-4-sulfonamide;
N-(2-Hydroxy-3-methylquinolin-6-yl)-3,4-dihydro-2H-1 ,5-benzodioxepine-7- sulfonamide;
5-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methoxybenzenesulfonamide; 3- Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonamide; 2,5-Dichloro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
4- Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide;
5- Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-1 ,3-dimethyl-1 H-pyrazole-4- sulfonamide;
3-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-4-methoxybenzenesulfonamide; 5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methylbenzenesulfonamide;
2- Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-4-methylbenzenesulfonamide;
3- Chloro-5-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methylbenzenesulfonamide; 3,5-Difluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide; 5-Chloro-N-(2-hydroxy-3-methylquinolin-6-yl)-2-methoxybenzenesulfonamide; 2-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-3-methylbenzenesulfonamide; 2-Chloro-4-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide; 5-Chloro-2-fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)benzenesulfonannide; 2-Fluoro-N-(2-hydroxy-3-methylquinolin-6-yl)-5-methylbenzenesulfonamide; 2-Methoxy-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonannide;
2- Methoxy-N-(2-oxo-1 ,2,3,4-tetrahydroquinolin-6-yl)benzenesulfonannide;
N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-3- (methylsulfonyl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)biphenyl-3-sulfonannide;
N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2,3-dihydro-1 -benzofuran-5- sulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2,3-dihydro-1 ,4-benzodioxine-6- sulfonamide;
3- Fluoro-4-methoxy-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)cyclopropanesulfonannide; 5-Chloro-2-methoxy-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
2,5-Dichloro-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
4-fluoro-2-methyl-N-(3-nnethyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
2-Ethoxy-4-methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide;
N-(3-Methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6-yl)-2- (trifluoromethoxy)benzenesulfonannide;
2-Methoxy-5-methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide; and
2-Methoxy-4-methyl-N-(3-methyl-2-oxo-1 ,2,3,4-tetrahydroquinazolin-6- yl)benzenesulfonamide.
16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 -15 and a pharmaceutically acceptable carrier.
17. A method of treating a disease or a disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 -15 or a pharmaceutical composition of claim 16.
18. The method of claim 17, wherein the disease or disorder is selected from the group consisting of chronic autoimmune disease, inflammatory disease and cancer.
19. The method of claim 17, wherein the treatment of a disease or a disorder further comprises administering an additional therapeutic agent.
20. A method for inhibiting bromodomain in a cell, comprising contacting the cell with a therapeutically effective amount of a compound of any one of claims 1 -15 or a pharmaceutical composition of claim 16.
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