EP2024353A2 - Pyrazole compounds - Google Patents

Pyrazole compounds

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Publication number
EP2024353A2
EP2024353A2 EP07705682A EP07705682A EP2024353A2 EP 2024353 A2 EP2024353 A2 EP 2024353A2 EP 07705682 A EP07705682 A EP 07705682A EP 07705682 A EP07705682 A EP 07705682A EP 2024353 A2 EP2024353 A2 EP 2024353A2
Authority
EP
European Patent Office
Prior art keywords
pyrazol
pyrimidin
cycloheteroalkyl
alkyl
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07705682A
Other languages
German (de)
French (fr)
Inventor
Michael John Agouron Pharmaceuticals Inc.A Pfizer Company BENNET
Sujin Agouron Pharmaceuticals Inc.A Pfizer Company CHO-SCHULTZ
Judith Gall Agouron Pharmaceuticals Inc.A Pfizer Company DEAL
Stephen Joseph Agouron Pharmaceuticals Inc.A Pfizer Company KING
Tami Jo Agouron Pharmaceuticals Inc.A Pfizer Company MARRONE
Cynthia Louise Agouron Pharmaceuticals Inc.A Pfizer Company PALMER
William Henry Agouron Pharmaceuticals Inc.A Pfizer Company ROMINES III
Eugene Yuanjin Agouron Pharmaceuticals Inc.A Pfizer Company RUI
Scott Channing Agouron Pharmaceuticals Inc.A Pfizer Company SUTTON
Luke Raymond Agouron Pharmaceuticals Inc.A Pfizer Company ZEHNDER
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Pfizer Products Inc
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Pfizer Products Inc
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Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of EP2024353A2 publication Critical patent/EP2024353A2/en
Withdrawn legal-status Critical Current

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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/14—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 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
    • C07D405/14—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 three or more hetero rings

Definitions

  • the present invention is directed to compounds, and salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the Raf enzyme.
  • the compounds of the present invention are useful for modulating (e.g. inhibiting) Raf activity and for treating diseases or conditions mediated by Raf, such as for example, disease states associated with abnormal cell growth such as cancer.
  • Erk pathway is an intracellular signal transduction pathway used by nearly all types of human cells to translate extracellular signals to cellular decisions, including proliferation, differentiation, senescence, or apoptosis (Wellbrock et al., Nat. Rev. MoI. Cell Biol. 11 :875-885 (2004)).
  • Ras GTPase which receives signals from membrane receptors and activates the Raf protein kinases, which activate the Mek protein kinases, which in turn activate the Erk protein kinases.
  • Activated Erk kinases phosphorylate a number of nuclear and cytoplasmic targets to initiate various cellular decisions.
  • Raf The biological importance of Raf in the Erk pathway is underscored by the finding that mutated forms of Raf are associated with certain human malignancies (see e.g. Monia et al., Nature Medicine 2:668-675 (1996); Davies et al., Nature 417:949-954 (2002)).
  • Three distinct genes have been identified in mammals that encode Raf proteins; a-Raf, b-Raf and c-Raf (also known as RaM) and isoformic variants that result from differential splicing of mRNA are known (Chong et al., EMBO J. 20:3716-3727 (2001)).
  • the Erk pathway is mutationally activated in a number of human cancers, most often by mutation of the Ras or b-Raf genes. Mutations in Ras and b- Raf genes generally occur in the same tumor types, including cancers of the colon, lung and pancreas and melanoma, but are usually mutually exclusive. This suggests that activation of either Ras or Raf is sufficient for pathway activation and cancer progression.
  • R 1 is H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, -N(R 5a R 5b ), -C(O)N(R 5a R 5b ), (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, or (C 2 to C 9 ) heteroaryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 3 to C 8 ) cycloalkyl, (C 6 to C i4 ) aryl, (C 2 to Cg) cycloheteroalkyl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one
  • R 3 is H, or-NH(CH 2 ) n R 7 ;
  • R 4 is -SR 8 , -OR 8 , H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, -N(R 5a R 5b ), -C(O)N(R 5a R 5b ), (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, or (C 2 to C 9 ) heteroaryl, wherein each of said (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, and (C 2 to C 9 ) heteroaryl is optionally substituted with at least one R 6 group;
  • R 5a and R 5b are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 3 to C 8 ) cycloalkyl is optionally substituted with at least one R 6 group;
  • R 6 is -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, (C 3 to C 8 ) cycloalkyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) heteroaryl, -(CH 2 ) n C
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -N(R 5a R 5b ), (C 2 to C 9 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 8 ) cycloalkyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to Cg) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R
  • R 8 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -(CH 2 ) n -cyano, -(CH 2 ) n -(C 3 to C 8 ) cycloalkyl, -(CH 2 V(C 6 to C 14 ) aryl, -(CH 2 J n -(C 2 to C 9 ) cycloheteroalkyl, or -(CH 2 ) ⁇ -(C 2 to C 9 ) heteroaryl;
  • R 9 is H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 1 to C 8 ) alkoxy, or
  • R 1Oa and R 10b are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl;
  • X is N or CH; m is 0, 1 , 2, or 3; each n is independently 0, 1 , 2, 3, or 4; p is 0, 1 , 2, 3, or 4; or a salt or solvate thereof.
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -N(R 5a R 5b ), (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, and (C 3 to C 8 ) cycloalkyl are optionally substituted with at least one group selected from
  • p is 1 or 2 and R 1 is cyano or (C 1 to C 6 ) alkyl.
  • p is 0 and R 1 is H or (C 1 to C 6 ) alkyl. In a still further aspect p is 0 or 1 and R 1 is (C 2 to C 9 ) cycloheteroalkyl and is optionally substituted with at least one R 6 group. In a still further aspect, the (C 2 to C 9 ) cycloheteroalkyl is selected from the group consisting of:
  • each of said (C 2 to C 9 ) cycloheteralkyl groups are optionally substituted with at least one R 6 group.
  • each R 2 is independently halogen, -OCH 3 , or (C 1 to C 6 ) alkyl.
  • R 2 is independently halogen, -OCH 3 , C 1 alkyl, C 2 alkyl, C 3 alkyl, or C 4 alkyl.
  • m is 1 and the compound of Formula (I) has the following structure:
  • R 2 is Cl or CH 3 .
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (Ci to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, - A -
  • (C 3 to C 8 ) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R 5b ), (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) cycloheteroalkyl.
  • R 3 is -NH(CH 2 ) n R 7 where n is 1 or 2, and R 7 is (C-i to C 6 ) alkyl and is substituted with one -OH group.
  • R 7 is (C-i to C 6 ) alkyl and is substituted with one -OH group.
  • R 3 is a compound of Formula (I), as described above, wherein X is N and R 4 is H, (C 2 to C 9 ) cycloheteroalkyl, -OR 8 , or -N(R 5a R 5b ), wherein said (C 2 to C 9 ) cycloheteroalkyl is optionally substituted with at least one R 6 group.
  • the present invention is a compound of Formula (I)
  • R 1 is H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, -N(R 5a R 5b ),
  • each R 2 is independently H, halogen, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 1 to C 8 ) alkoxy, or cyano;
  • R 3 is H, or -NR 11 (CH 2 ) n R 7 ;
  • R 4 is -SR 8 , -OR 8 , H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, -N(R 5a R 5b ), -C(O)N(R 5a R 5b ), (C 3 to C 8 ) cycloalkyl, (C 6 to C i4 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, or (C 2 to C 9 ) heteroaryl, wherein each of said (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) cycloheteroalkyl, and (C 2 to Cg) heteroaryl is optionally substituted with at least one R 6 group;
  • R 5a and R 5b are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (C 2 to C 9 ) cycloheteroalkyl and (C 3 to C 8 ) cycloalkyl is optionally substituted with at least one R 6 group;
  • R s is -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, cyano, (C 3 to C 8 ) cycloalkyl, (C 2 to C 9 ) cycloheteroalkyl, (C 6 to C 14 ) aryl, (C 2 to C 9 ) heteroaryl, -(CH 2 ) n C(O)R 9 , or -N(R 10a R 10b );
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -N(R 5a R 5b ), (C 2 to C 9 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 8 ) cycloalkyl, or (C 6 to C 14 ) aryl, wherein each of said (C-i to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 3 to C 8 ) cycloalkyl, (C 6 to Cu) aryl, and (C 2 to C 9 ) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R
  • R 9 is H, -OH, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 1 to C 8 ) alkoxy, or
  • R 1Oa and R 1Ob are each independently H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl;
  • R 11 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 8 ) cycloalkyl, or (C 6 to Ci 4 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C-i to C 6 ) alkyl, -N(R 5a R 5b ), (C 3 to C 8
  • R 12 is (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -N(R 5a R 5b ), (C 2 to C 9 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 8 ) cycloalkyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R 5
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, -N(R 5a R 5b ), (C 2 to C 9 ) cycloheteroalkyl, (C 2 to C 9 ) heteroaryl, (C 3 to C 8 ) cycloalkyl, or (C 6 to C 14 ) aryl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 8 ) alkenyl, (C 2 to C 8 ) alkynyl, (C 2 to C 9 ) cycloheteroalkyl, (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) heteroaryl are optionally substituted with at least one group selected from halogen, -OH,
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, and (C 3 to C 8 ) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R 5b ), -OC(O)R 12 , (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) cycloheteroalkyl.
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl,
  • R 3 is -NR 11 (CH 2 ) n R 7 .
  • R 7 is H, (C 1 to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, or (C 3 to C 8 ) cycloalkyl, wherein each of said (C-i to C 6 ) alkyl, (C 2 to C 9 ) cycloheteroalkyl, and (C 3 to C 8 ) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C 1 to C 6 ) alkyl, -N(R 5a R 5b ), -OC(O)R 12 , (C 3 to C 8 ) cycloalkyl, (C 6 to C 14 ) aryl, and (C 2 to C 9 ) cycloheteroalkyl.
  • R 3 is -NH(CH 2 ) n R 7 where n is
  • a further aspect of the present invention is a compound according to Formula (I), as described above, which is selected from the group consisting of: 3-chloro-5-(1-isopropyl-4-pyrimidin-4-yl-1 H-pyrazol- 3-yl)phenol; 3-[4-(2-anilinopyrimidin-4-yl)-1-methyl-1 H-pyrazol-3-yl]-5-chlorophenol; 2-(3-(3-chloro-5- hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile; 2-(3-(3-
  • the compound is selected from the group consisting of 3-chloro-5-(1-isopropyl-4-pyrimidin-4- yl-1 H-pyrazol-3-yl)phenol; 3-[4-(2-anilinopyrimidin-4-yl)-1-methyl-1 H-pyrazol-3-yl]-5-chlorophenol; 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile; 2-(3- (3-Chloro-5-hydroxyphenyl-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile; and 3- [3-(3-hydroxy-5-methylphenyl)-4-(2- ⁇ [(2S)-2-hydroxypropyl]amino ⁇ pyrimidin-4-yl)-1 H-pyrazol
  • the compound is selected from the group consisting of 3-(3-(3- hydroxy-5-methylphenyl)-4-(2-((R)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile; 3- chloro-5-[4-[2-(isobutylamino)pyrimidin-4-yl]-1-(1-methylpiperidin-4-yl)-1 H-pyrazol-3-yl]phenol; 3-chloro-5- ⁇ 4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1H-pyrazol-3-yl ⁇ phenol; 3-chloro-5-[4- ⁇ 2-[(2-hydroxy-2- methylpropyl)amino]pyrimidin-4-yl ⁇ -1-(1-methylpiperidin-4-yl)-1W-pyrazol-3-yl]phenol; and 3-chloro-5- ⁇ 4-[2- (iso)
  • the compound is selected from the group consisting of 3-chloro-5-[4- ⁇ 2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl ⁇ -1- (1-methylpiperidin-4-yl)-1/-/-pyrazol-3-yl]phenol; 3-chloro-5- ⁇ 4-[2-(isobutylamino)pyrimidin-4-yl]-1-methyl- 1H-pyrazol-3-yl ⁇ phenol; ⁇ 3-(3-chloro-5-hydroxyphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H- pyrazol-1-yl ⁇ acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4- ⁇ 2-[(2-hydroxy-1-methylethyl)amino]pyrimidin-4- yl ⁇ -1H-pyrazol-1-yl]acetonitrile; and [4-(2-amino
  • the compound is selected from the group consisting of [3-(3- chloro-5-hydroxyphenyl)-4-(2- ⁇ [(2S)-2-hydroxypropyl]amino ⁇ pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; 3- [4- ⁇ 2-[(2-hydroxyethyl)amino]pyrimidin-4-yl ⁇ -3-(3-hydroxy-5-methylphenyl)-1H-pyrazol-1-yl]propanenitrile; 3- ⁇ 3-(3-hydroxy-5-methylphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H-pyrazol-1- yl ⁇ propanenitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2- ⁇ [(1S)-2-hydroxy-1-methylethyl]amino ⁇ pyrimidin-4-yl)- 1 H-pyrazol-1-yl]acetonitrile
  • a further aspect of the present invention is a compound according to Formula (I), as described above, which is selected from the group consisting of 2-(3-(3-fluoro-5-hydroxyphenyl)-4-(2-((S)-2- hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile, 2-(3-(3-hydroxy-5-methylphenyl)-4-(2- ((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)-acetonitrile, 3-(1-(cyanomethyl)-4-(2-(2- hydroxyethylamino)pyrimidin-4-yl)-1 H-pyrazol-3-yl)-5-hydroxybenzonitrile, 3-(4-(2-((S)-2- hydroxypropylamino)pyrimidin-4-yl)-1-((5-methylisoxazol-3-yl)methyl)-1 H-pyrazol-3-
  • the present invention also relates to a pharmaceutical composition, comprising at least one compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
  • the present invention also relates to a method of treating abnormal cell growth, or any Raf- mediated disease or condition, in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the abnormal cell growth is cancerous.
  • the abnormal cell growth in non-cancerous.
  • the present invention further relates to a method of inhibiting Raf enzymatic activity, comprising contacting a Raf enzyme with a Raf-inhibiting amount of at least one compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the present invention further relates to the use of any of the compounds as described herein, or a salt or solvate thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal.
  • the present invention further relates to methods of making the compounds as described herein using the methods as shown in the specific examples herein and in the general synthetic methods A, B, C, D, and E, as described herein.
  • the present invention further relates to any of the compounds described above, or salts or solvates thereof, for use as a medicament.
  • the present invention further relates to the use of any of the compounds described above, or salts or solvates thereof, for the manufacture of a medicament for the treatment of abnormal cell growth.
  • halo and/or halogen refer to fluorine, chlorine, bromine or iodine.
  • (C 1 to Ce) alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms.
  • Examples of (C 1 to C 6 ) alkyl groups include methyl, ethyl, propyl, 2-propyl, ⁇ -butyl, /so-butyl, ferf-butyl, pentyl, and the like.
  • (C 2 to C 8 ) alkenyl means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond.
  • the carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound.
  • Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl.
  • (C 2 to C 8 ) alkynyl means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond.
  • the carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1- hexyne, 2-hexyne, and 3-hexyne.
  • (C 1 to C 8 ) alkoxy means an O-alkyl group wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic.
  • alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic.
  • examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
  • (C 1 to C 8 ) heteroalkyl refers to a straight- or branched-chain alkyl group having a total of from 2 to 12 atoms in the chain, including from 1 to 8 carbon atoms, and one or more atoms of which is a heteroatom selected from S, O, and N, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms.
  • the S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfides and sulfones, respectively.
  • the (C-i to C 8 ) heteroalkyl groups in the compounds of the present invention can contain an oxo group at any carbon or heteroatom that will result in a stable compound.
  • exemplary (C 1 to C 8 ) heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary, and tertiary alkyl amines, amides, ketones, esters, sulfides, and sulfones.
  • (C 6 to C 14 ) aryl means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl.
  • (C 2 to C 9 ) heteroaryl means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • the heterocyclic groups include benzo-fused ring systems.
  • aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
  • the C 2 to C 9 heteroaryl groups may be C-attached or N-attached where such is possible.
  • a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
  • a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
  • (C 2 to C 9 ) cycloheteroalkyl means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 2 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
  • such C 2 to C 9 cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound.
  • such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible.
  • a C 2 to C 9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone.
  • An example of a 4 membered cycloheteroalkyl group is azetidinyl (derived from azetidine).
  • An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl.
  • An example of a 6 membered cycloheteroalkyl group is piperidinyl.
  • An example of a 9 membered cycloheteroalkyl group is indolinyl.
  • An example of a 10 membered cycloheteroalkyl group is 4H-quinolizinyl.
  • C 2 to Cg cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1 ,3-dioxolany
  • (C 3 to C 8 ) cycloalkyl group means a saturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 8 carbon ring atoms.
  • groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.
  • cyano refers to a -C ⁇ N group.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be “unsubstituted,” or is “substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen.
  • a C 6 aryl group also called “phenyl” herein
  • phenyl is substituted with one additional substituent
  • one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C 6 aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4).
  • the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies.
  • a C 6 aryl group in the present compounds is said to be "disubstituted," one of ordinary skill in the art would understand it to mean that the C 6 aryl has 3 carbon atoms remaining that are unsubstituted.
  • solvate is used to describe a molecular complex between compounds of the present invention and solvent molecules.
  • solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
  • DMSO dimethylsulfoxide
  • hydrate can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate.
  • solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
  • pharmaceutically acceptable salt means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable formulation means a combination of a compound of the invention, or a salt or solvate thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
  • Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art.
  • the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium
  • Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the present invention. Alternatively, such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth.
  • the term "Raf-inhibiting amount” as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit the enzymatic activity of Raf in vivo, such as in a mammal, or in vitro.
  • inhibiting Raf enzyme activity means decreasing the activity or functioning of the Raf enzyme either in vitro or in vivo, such as in a mammal, such as a human, by contacting the enzyme with a compound of the present invention.
  • Raf as used herein means a-Raf, b-Raf, c-Raf, or mutants thereof, or any of the known Raf isoformic splice variants.
  • therapeutically effective amount means an amount of a compound of the present invention, or a salt or solvate thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein.
  • a therapeutically effective amount of a compound of the present invention, or a salt or solvate thereof is a quantity sufficient to modulate or inhibit the activity of the Raf enzyme such that a disease condition that is mediated by activity of the Raf enzyme is reduced or alleviated.
  • treat with reference to abnormal cell growth, or to any Raf mediated disease or condition, in a mammal, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlying disease or condition.
  • abnormal cell growth such as cancer
  • these terms simply mean that the life expectancy of an individual affected with abnormal cell growth will be increased or that one or more of the symptoms of the disease will be reduced.
  • references herein to the inventive compounds include references to salts, solvates, and complexes thereof, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof.
  • compounds of the present invention can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.
  • tumor cells tumor cells
  • tumors that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase
  • benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs any tumors that proliferate by receptor tyrosine kinases; any tumors that proliferate by aberrant serine/threonine kinase activation; benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs
  • tumors both benign and malignant, expressing an activated Ras oncogene
  • tumor cells both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene
  • benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs the abnormal growth of: tumor cells (tumors) that proliferate by expressing a mutated tyros
  • abnormal cell growth also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
  • abnormal cell growth and “hyperproliferative disorder” are used interchangeably in this application.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.
  • racemic or “racemic mixture,” as used herein, refer to a 1:1 mixture of enantiomers of a particular compound.
  • diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
  • the compounds of the present invention are useful for modulating or inhibiting Raf activity.
  • these compounds are useful for the prevention and/or treatment of disease states associated with abnormal cell growth such as cancer, alone or in combination with other anti-cancer agents.
  • ⁇ is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
  • the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g., ' ⁇ ⁇ represents a methyl
  • the compounds of the present invention may have asymmetric carbon atoms.
  • the carbon- carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( ⁇ m ⁇ m ⁇ ), or a dotted wedge ( "'" ).
  • the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
  • the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom.
  • a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
  • the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
  • the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the reacemate using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
  • Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
  • a compound of the invention contains an alkenyl or alkenylene group
  • geometric cisltrans (or Z/E) isomers are possible.
  • the compound contains, for example, a keto or oxime group or an aromatic moiety
  • tautomeric isomerism ('tautomerism') can occur.
  • Examples of tautomerism include keto and enol tautomers.
  • a single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
  • Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
  • the compounds of the present invention may be administered as prodrugs.
  • certain derivatives of compounds of Formula (I) which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as "prodrugs”.
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formula (I) with certain moieties known to those skilled in the art. See, e.g. "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed.
  • prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group.
  • replacement groups are known to those of skill in the art. See, e.g. "Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. It is also possible that certain compounds of Formula (I) may themselves act as prodrugs of other compounds of Formula (I).
  • Salts of the present invention can be prepared according to methods known to those of skill in the art.
  • Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, he
  • the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
  • the acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.
  • the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
  • Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
  • such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
  • the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
  • Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
  • salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
  • they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
  • stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
  • the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid, hydrobro
  • the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas.
  • the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • isotopically-labeled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
  • compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
  • a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., a Raf modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • a therapeutically effective amount i.e., a Raf modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy
  • one compound of the present invention as an active ingredient
  • pharmaceutically suitable carriers which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
  • the pharmaceutical carriers employed may be either solid or liquid.
  • Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties.
  • a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added.
  • CMC carboxy-methylcellulose
  • PG propyleneglycol
  • PEG polyethyleneglycol
  • Gelucire ® a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
  • the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
  • the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
  • a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
  • the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
  • a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid.
  • the agent may be dissolved in a suitable co-solvent or combinations of co-solvents.
  • suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
  • a compound of the present invention is dissolved in DMSO and diluted with water.
  • the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
  • the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
  • Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the compounds of the present invention may also be formulated as a depot preparation.
  • Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for hydrophobic compounds is a co- solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the co-solvent system may be a VPD co-solvent system.
  • VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co- solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity non- polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs.
  • Such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like may be used.
  • the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
  • an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg.
  • the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%.
  • the compounds of the present invention may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.
  • This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the Formula (I), as defined above, or a salt or solvate thereof, that is effective in treating abnormal cell growth.
  • the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of
  • the cancer is selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
  • lung cancer NSCLC and SCLC
  • SCLC central nervous system
  • the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
  • the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, or a combination of one or more of the foregoing cancers.
  • said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
  • This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the present invention, or a salt or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.
  • the anti-tumor agent used in conjunction with a compound of the present invention and pharmaceutical compositions described herein is an anti- angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor.
  • Preferred pan kinase inhibitors include SutentTM (sunitinib), described in U.S. Patent No. 6,573,293 (Pfizer, Inc, NY, USA).
  • Anti-angiogenesis agents include but are not limited to the following agents, such as EGF inhibitors, EGFR inhibitors, VEGF inhibitors, .
  • VEGFR inhibitors TIE2 inhibitors, IGF1 R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix- metalloprotienase 9) inhibitors.
  • VEGF inhibitors include for example, Avastin (bevacizumab), an anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788
  • IM862 Cytran Inc. of Kirkland, Washington, USA
  • angiozyme a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California) and combinations thereof.
  • VEGF inhibitors useful in the practice of the present invention are described in US Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposes. Additional VEGF inhibitors are described in, for example in WO 99/24440, in WO 95/21613, WO 99/61422, U.S. Patent 5,834,504, WO 98/50356, U.S. Patent 5,883,113 U.S. Patent 5,886,020, U.S. Patent 5,792,783, U.S.
  • anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof.
  • Other antiproliferative agents that may be used in combination with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following: U.S. Patent 6,080,769; U.S.
  • Each of the foregoing patents and patent applications is herein incorporated by reference in their entirety.
  • PDGRr inhibitors include but are not limited to those disclosed in international patent application publication numbers WO01/40217 and WO2004/020431 , the contents of which are incorporated in their entirety for all purposes.
  • Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its salts.
  • Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its salts). GARF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 5,608,082 which is incorporated in its entirety for all purposes.
  • COX-II inhibitors which can be used in conjunction with a compound of Formula (I) and pharmaceutical compositions disclosed herein include CELEBREXTM (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1- (4-sulfamoyl-phenyl)-1 H-pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).
  • COX-II CELEBREXTM
  • the anti-tumor agent is celecoxib (U.S. Patent No. 5,466,823), valdecoxib (U.S. Patent No. 5,633,272), parecoxib (U.S. Patent No. 5,932,598), deracoxib (U.S. Patent No. 5,521,207), SD-8381 (U.S. Patent No. 6,034,256, Example 175), ABT-963 (WO 2002/24719), rofecoxib (CAS No. 162011-90-7), MK-663 (or etoricoxib) as disclosed in WO 1998/03484, COX-189 (Lumiracoxib) as disclosed in WO 1999/11605, BMS-347070 (U.S.
  • Patent 6,180,651 NS-398 (CAS 123653-11-2), RS 57067 (CAS 17932-91-3), 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H- pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, or meloxicam.
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • NSAIDs non-steroidal antiinflammatory drugs
  • Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof.
  • Targeted agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include EGFr inhibitors such as lressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc.
  • EGFr inhibitors include lressa, Erbitux, Tarceva and combinations thereof.
  • anti-tumor agents include those selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), CI-1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKM 66 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti- HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibodies (Univers
  • pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
  • Additional erbB2 inhibitors include those disclosed in WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, WO 95/19970, U.S. Patent 5,587,458, and U.S. Patent 5,877,305, each of which is herein incorporated by reference in its entirety.
  • ErbB2 receptor inhibitors useful in the present invention are also disclosed in U.S. Patents 6,465,449, and 6,284,764, and in WO 2001/98277 each of which are herein incorporated by reference in their entirety.
  • anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abareiix, Alimta, EPO 906 (Novartis), discodermolide (XAA- 296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZD-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacei), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations
  • Histerelin histrelin acetate
  • Plenaixis abareiix depot
  • Atrasentan ABT-627
  • Satraplatin JM-216
  • thalomid Thalidomide
  • Theratope Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
  • anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase (ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
  • anti-tumor agents may be selected from the following agents, CeaVac (CEA), NeuTrexin
  • Additional anti-tumor agents may be selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, RSR13
  • Additional anti-tumor agents may be selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel), and combinations thereof.
  • anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901, Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2 inhibitor BMS-387,032, Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438, and combinations thereof.
  • mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors, SAHA (Merck Inc./Aton Pharmaceuticals) and combinations thereof.
  • Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), and Chk1/2 inhibitor XL844 (Exilixis).
  • cytotoxic agents e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein.
  • the invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
  • exemestane Amasin, Pfizer Inc.
  • leuprorelin Louprorelin
  • anastrozole Arimidex, Astrazeneca
  • gosrelin Zoladex, AstraZeneca
  • doxercalciferol
  • the invention also relates to the use of the compounds of the present invention together with hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, CasodexTM(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
  • hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, CasodexTM(4'-cyano-3-(
  • the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • supportive care products e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
  • Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
  • topoisomerase I inhibitors may be utilized as anti-tumor agents: camptothecin; irinotecan HCI (Camptosar); edotecarin; orathecin (Supergen); exatecan (Daiichi); BN-80915 (Roche); and combinations thereof.
  • Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence).
  • Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitoi, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum- coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof. Particularly preferred alkylating agents include Eloxatin (oxalip
  • Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1 , Alimta (premetrexed disodium, LY231514,
  • MTA gemzar
  • Gemzar gemcitabine, EIi Lilly
  • fludarabin 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1 , melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No.
  • Antibiotics include intercalating antibiotics and include, but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
  • Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
  • Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
  • Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
  • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof.
  • agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y- muHMFGI), Provenge (Dendreon) and combinations thereof.
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have antitumor activity.
  • agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
  • Velcade (bortemazib, Millenium), tretinoin, and combinations thereof.
  • Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof.
  • Camptothecin derivatives include but are not limited to camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof.
  • Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof.
  • CTLA4 cytotoxic lymphocyte antigen 4
  • CTLA4 compounds disclosed in U.S. Patent 6,682,736
  • anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors.
  • CTLA4 antibodies that can be used in combination with compounds of the present invention include those disclosed in U.S. Patents 6,682,736 and 6,682,736 both of which are herein incorporated by reference in their entirety.
  • Gene therapy agents may also be employed as anti-tumor agents such as TNFerade (GeneVec), which express TNFalpha in response to radiotherapy.
  • TNFerade GeneVec
  • statins may be used in combination with a compound of the present invention and pharmaceutical compositions thereof.
  • Statins HMG-CoA reducatase inhibitors
  • Atorvastatin LipitorTM, Pfizer Inc.
  • Provastatin Provastatin
  • Lovastatin MevacorTM, Merck Inc.
  • Simvastatin ZaocorTM, Merck Inc.
  • Fluvastatin LescolTM, Novartis
  • Cerivastatin BoycolTM, Bayer
  • Rosuvastatin CrestorTM, AstraZeneca
  • Lovostatin and Niacin Niacin
  • statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof.
  • Other agents useful as anti-tumor agents include Caduet.
  • Ketone 3 can be further transformed to pyrazoles represented by formula 5 through a two step sequence involving enamine formation using N,N-dimethylformamide dimethyl acetal (DMF/DMA) followed by reaction with hydrazine.
  • DMF/DMA N,N-dimethylformamide dimethyl acetal
  • Introduction of the R 3 group on the pyrazole nitrogen can be accomplished through N-alkylation of a suitable alkyl halide (R 3 X), using a suitable base such as K 2 CO 3 , NaOH, DBU, NaH, LiHMDS, or Cs 2 CO 3 .
  • pyrazoles During the alkylation reaction, two regioisomeric pyrazoles are usually formed. Pyrazoles represented by 6 can be separated and purified by silica gel chromatography or preparative HPLC and identified using NMR experiments including nuclear Overhauser effect spectroscopy.
  • the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl.
  • Various methods for phenol deprotection can be employed. These methods are known to those skilled in the art (e.g. see T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3 rd Edition 1999, John Wiley & Sons).
  • Suitable leaving groups include groups such as bromo, chloro, fluoro and methylsulfonyl.
  • displacement of the leaving group can be accomplished using primary or secondary amines in a suitable solvent such as THF, ethanol, 2-propanol, toluene or xylenes at elevated temperatures to afford 2-amino heterocycles represented by 9.
  • the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or methycyclopropane.
  • Various methods for phenol deprotection can be employed and are known to those skilled in the art (e.g. see T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3 rd Edition 1999, John Wiley & Sons).
  • compounds of the general structure represented by 16 and 17 are prepared according to Method C.
  • Preparation of isoxazole 11 is accomplished via the Vilsmeier reaction on 4-methylpyrimidine or picoline followed by condensation with hydroxylamine. Ring-opening of the isoxazole with aqueous sodium hydroxide is followed by condensation with hydrazine to afford aminopyrazole 13.
  • a Sandmeyer reaction converts the amino group to an iodopyrazole (14) and, prior to the Suzuki coupling reaction, the pyrazole NH is either alkylated with a preferred R 3 group or protected with tetrahydropyranyl (THP) group to afford 15.
  • THP tetrahydropyranyl
  • a Suzuki coupling reaction of 15 with a boronic acid or boronic ester completes the synthesis of compounds represented by 16.
  • the THP protecting group is used, it is removed under acidic conditions to afford 17.
  • the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl.
  • Various methods for phenol deprotection can be employed as discussed previously.
  • compounds of the general structure represented by 20 and 22 are prepared according to Method D.
  • Reaction of ketone 3 with carbon disulfide and dibromomethane in the presence of a suitable base such as Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 in a solvent such as DMF or acetone affords dithietane 18.
  • Reaction of 18 with amines at elevated temperatures in a suitable solvent such as toluene or xylenes affords vinylogous amide 19.
  • Reaction of the thiol with an alkyl halide such as methyl iodide under basic conditions is followed by pyrazole formation using either hydrazine or substituted hydrazines to afford 5-aminopyrazoles such as 20.
  • Intermediate 18 can also be reacted with sodium or potassium alkoxides to afford vinylogous ester 21 and these intermediates undergo the same sequence to afford 5-alkoxypyrazoles such as 22.
  • the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl.
  • Various methods for phenol deprotection can be employed as discussed previously.
  • Ketone 23 can be transformed to 3,4,5-trisubstituted pyrazoles by tosylhydrazone formation followed by N-acylation of the tosylhydrazone with acid chlorides to form intermediates such as 25.
  • the addition of 6 N HCI to 25 followed by gentle warming initiates a cyclization reaction and tosyl hydrazone elimination to form pyrazole 26.
  • R 4 group on the pyrazole nitrogen can be accomplished through N-alkylation of a suitable alkyl halide (R 3 X), using a suitable base such as K 2 CO 3 , NaOH, DBU, NaH or Cs 2 CO 3 .
  • a suitable base such as K 2 CO 3 , NaOH, DBU, NaH or Cs 2 CO 3 .
  • the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl.
  • Various methods for phenol deprotection can be employed as described previously.
  • Examples 1 to 25 provide detailed synthetic steps for preparing several specific compounds of the present invention.
  • Table 1 shows additional compounds that were prepared as Examples 26 to 30, and 32 to 127 using the methods described herein.
  • Table 2 shows the biochemical and cellular data for the compounds of Examples 1 30, and 32 to 127. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.
  • Et2 ⁇ diethyl ether
  • DMF ⁇ /, ⁇ /-dimethylformamide
  • THF tetrahydrofuran
  • DCM diichloro-methane
  • DMA dimethyl acetal
  • DBU dimethyl acetal
  • LiHMDS or LHMDS lithium hexamethyldisilazide
  • TBME ferf-butyl methyl ether
  • LDA Lithium Diisopropylamide
  • DMSO dimethylsulfoxide
  • MeOH methanol
  • EtOH ethanol
  • EtOAc ethyl acetate
  • THF tetrahydrofuran
  • Ac acetyl
  • Me methyl
  • Et (ethyl); and Ph phenyl
  • the above compound was prepared as follows according to Method A. To an 8% (v:v) solution of trifluoroacetic acid in dichloromethane (10 mL) was added 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl- 1H-pyrazol-4-yl]pyrimidine (242 mg, 0.43 mmol) and triethylsilane (80 ⁇ L, 58 mg, 0.5 mmol). The mixture was stirred at ambient temperature for 15 hours, then cautiously poured into saturated aqueous sodium hydrogen carbonate (40 mL). After stirring for an additional 45 minutes, the layers were separated and the aqueous phase extracted with dichloromethane (2 x 25 mL).
  • the above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 4-[-3-(3-chloro-5-trityloxyphenyl)-1-ethyl-1 H-pyrazol-4-yl]pyrimidine in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 53% yield.
  • the above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 4-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-1-(pyridin-2-yl)-1 H-pyrazol-4- yl)pyrimidine in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 58% yield.
  • the above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 2-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-4-(pyrimidin-4-yl)-1H-pyrazol-1- yl)propanenitrile in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 37% yield.
  • the above compound was prepared as follows according to Method A. To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1H-pyrazol-4-yl]pyrimidine, (0.31 g, 1.1 mmol), prepared in the same way as in Example 1 except using 4-methylpyrimidine in place of picoline, and cesium carbonate (1.1 g, 3.2 mmol) in N,N-dimethylformamide (11 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g, 1.1 mmol). The mixture was stirred at 70 0 C for 16 hours then concentrated to dryness to furnish 0.50 grams of an oil which was used in the next step without any purification.
  • Method A To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1H-pyrazol-4-yl]pyrimidine, (0.31 g, 1.1 mmol), prepared in the same way as in Example 1 except using 4-methyl
  • the above compound was prepared as follows according to Method A. To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl]pyrimidine (1.0 g, 3.5 mmol) in N,N-dimethylformamide (23 mL) was added lithium bis(trimethylsilyl)amide (3.8 mL, 3.8 mmol) (1 M solution in tetrahydrofuran) dropwise. After stirring for 20 minutes, 1-chloro-3-iodopropane (1.1 mL, 11 mmol) was added and the mixture was allowed to stir for 16 hours.
  • Method A To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl]pyrimidine (1.0 g, 3.5 mmol) in N,N-dimethylformamide (23 mL) was added lithium bis(trimethylsilyl)amide (3.8 mL, 3.8 mmol) (1 M solution
  • the residue was treated with a 10% methanol in dichlororhethane solution, solids filtered and rinsed with the 10% methanol in dichloromethane solution, and filtrate concentrated to dryness.
  • the residue was purified by high performance liquid chromatography to provide the title compound (0.010 g, 5%).
  • the above compound was prepared as follows according to Method B. Boron tribromide (0.52 g. 2.1 mmol) was added to a solution of 4-[-3-(3-chloro-5-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl]-2-(N- phenylamino)pyrimidine (249 mg, 0.64 mmol) in dichloromethane (20 mL) at 0 0 C. The cooling bath was removed and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction was quenched upon addition of an ice/water mixture (20 mL) and ethyl acetate (20 mL).
  • Aqueous methylamine (40% w / w , 0.57 mL, 6.6 mmol) was added to a solution of 4-[3-(3-chloro-5- methoxy-phenyl)-1-methyl-1 H-pyrazol-4-yl]-2-methanesulfonyl-pyrimidine (as obtained in Preparation b-1- b) (250 mg, 0.661 mmol) in dioxane (5 mL). The reaction mixture was stirred in a high pressure vessel at 85 0 C overnight, allowed to cool to room temperature, and concentrated in vacuo.
  • the above compound was prepared as follows according to Method B.
  • a mixture of 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile (2.00 g, 5.14 mmol) and (S)-(+)-1-aminopropan-2-ol (3.86 g, 51.4 mmol) in anhydrous THF (50 mL) was heated to 80 0 C in an oil bath for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate and methanol until homogeneous and was washed with sodium citrate buffer (1M, pH 4.5), and saturated sodium chloride (2 x 50 mL).
  • the above compound was prepared as follows according to Method B. A mixture of 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile (200 mg, 0.510 mmol) and 2-aminoethanol (0.31 mL, 5.1 mmol) were reacted at 80 0 C according to Example 11. After a similar work up, the crude residue was purified by reverse phase HPLC to provide the title compound (91 mg, 48%).
  • the above compound was prepared as follows according to Method B. To a mixture of 3-chloro- 5- ⁇ 4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1 H-pyrazol-3-yl ⁇ phenol (0.15 g, 0.32 mmol) in acetonitrile (4 mL) was added a 51 % aqueous formaldehyde solution (75 mL, 0.95 mmol). The mixture was allowed to stir for 20 minutes then sodium cyanoborohydride (60 mg, 0.95 mmol) was added and the mixture was allowed to stir for 10 minutes. Acetic acid was added dropwise until neutral and the entire mixture was concentrated to dryness.
  • Method B To a mixture of 3-chloro- 5- ⁇ 4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1 H-pyrazol-3-yl ⁇ phenol (0.15 g, 0.32 mmol) in acetonit
  • the above compound was prepared as follows according to Method B. Following the procedure described in Example 17, using 3-chloro-5-(4- ⁇ 2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl ⁇ -1- piperidin-4-yl-1/-/-pyrazol-3-yl)phenol in place of 3-chloro-5- ⁇ 4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin- 4-yl-1 H-pyrazol-3-yl ⁇ phenol, the title compound was obtained in 57% yield.
  • the above compound was prepared as follows according to Method C. Following the procedure described in Example 20, using 2,3-dimethyl-5-(4-(pyrimidin-4-yl)-1H-pyrazol-3-yl)phenol in place of 3-(3- (3-methoxy-2,5-dimethylphenyl)-4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile, the title compound was obtained in 46% yield.
  • the above compound was prepared as follows according to Method C. Boron tribromide (0.084 ml_ of 1.0 M solution in DCM, 0.84 mmol) was added to a solution of 4-(3-(5-fluoro-2-methoxyphenyl)-1- methyl-1W-pyrazol-4-yl)pyrimidine (80 mg, 0.28 mmol) in dichloromethane (2 mL) at 0 0 C. The resulting suspension was stirred at 0 °C for 45 minutes. The reaction was diluted with dichloromethane (10 mL) and quenched by the slow addition of saturated aqueous sodium hydrogen carbonate (10 mL). The resulting mixture was stirred at ambient temperature until two phases were evident.
  • the nitrogen bubbler was removed shortly after the addition and the mixture was sealed and placed in a Biotage InitiatorTM Microwave Synthesizer and heated at 130 0 C for 1 hour. After cooling to ambient temperature, the crude reaction mixture was partitioned between saturated aqueous sodium chloride (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2x50 mL), brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness.
  • aqueous sodium chloride 100 mL
  • ethyl acetate 50 mL
  • the combined organic extracts were washed with water (2x50 mL), brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness.
  • the pyrazole regiochemistry of the major regioisomer was confirmed as drawn above by running a nuclear Overhauser effect (NOE) spectroscopy experiment in C 6 D 6 prior to trityl deprotection.
  • the protected phenol (90.0 mg, 0.147 mmol) was dissolved in DCM (3 mL) and treated with Et 3 SiH (100 ⁇ L) followed by TFA (0.5 mL). After 30 minutes, LC/MS analysis indicated complete deprotection and showed the two regioisomers resolved by LCMS. After removing the solvents, the product was purified via silica gel chromatography, eluting with 60/40, 70/30 then 80/20 EtOAc / Pet Ether.
  • the aqueous layer was further extracted with a 1 :1 mixture of Et 2 O / EtOAc (3 x 75 mL). The combined organic extracts were washed with water (3 x 75 ml_) and brine (1 x 100 mL) then dried over MgSO 4 . The solvents were removed to afford an orange foam (7.3 g, 85%) used in the next step without further purification.
  • the above compound was prepared as follows according to Method D. To a solution of 1-(3- methyl-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone (8 g, 17.0 mmol) in ⁇ /, ⁇ /-dimethylformamide (86 mL) was added cesium carbonate (11.1 g, 2 equiv), followed by carbon disulfide (3.08 mL, 3 equiv) and dibromomethane (3.54 mL, 3 equiv). The mixture was stirred at ambient temperature for 6 hours. The solution was poured into ice water and extracted with a mixture of 50% ethyl acetate and 50% diethyl ether (4x).
  • the pyrazole formed after the two step sequence involving enamine formation using DMF/DMA followed by reaction with hydrazine was alkylated with (2- bromoethoxy)(tert-butyl)dimethylsilane. Both the tetrahyropyran and tertbutyl dimethyl silyl protecting groups are removed in the subsequent oxidation step. Displacement of the sulfone with amines according to Method B gave the final targets.
  • Example 136 was prepared following the procedure described in Example 13 (see also general method B) except 2-(3-(3-hydroxy-4,5-dimethylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1 - yl)acetonitrile was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)-pyrimidin-4-yl)- 1H-pyrazol-yl)propanenitrile and the alkylating step was carried out with bromoacetonitrile.
  • Example 139 2-(3-(3-Flouro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1 H-pyrazol-1- yl)acetonitrile (Example 139) was prepared according to method C except starting with 4-methyl-2- (methylthio)pyrimidine gives 4-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazoi-4-yl)-2-
  • Example b-8-a The title compound was prepared following the procedure described in Example b-8-a except 4- (3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of tert-butyl 3- (3-(3-methoxy-5-methylphenyl)- 4-(2-(methylthio)pyrimidin-4-yl)-1/-/-pyrazol-1-yl)azetidine-1 carboxylate to give 4-(3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine in quantitative yield.
  • Example c-1-c he title compound was prepared following the procedure described in Example c-1-c except 3- fluoro-5-methoxyphenylboronic acid was used in place of 3-methoxy-2,5-dimethylphenylboronic acid and 4-(3-iodo-1-tetrahydro-2/-/-pyran-2-yl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of 4-(3- iodo-1-tetrahydro-2W-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine.
  • the mixture was heated in a microwave at 13O 0 C for 1 hour rather than in an oil bath at 100 0 C for 10 hours.
  • the supernatant solution was decanted into a separate flask.
  • the solids were rinsed with a small amount of DMF and the rinse combined with the supernatant solution.
  • the solvent was removed en vacuo and the residue was taken up in methanol and treated with HCI (4N in dioxane, 4 eq).
  • the mixture was stirred at ambient temperature for 15 minutes then reduced to minimum volume.
  • the residue was triturated with dichloromethane/ te/t-methyl butyl ether ( ⁇ 1 :1) and the solids collected by filtration to yield clean product.
  • Example 140 3-(1-(cyanomethyl)-4-(2-(2-hydroxyethylamino)primidin-4-yl)-1H-pyrazole-3-yl)-5- hydroxybenzonitrile (Example 140) was prepared according to method B and subsequent conversion of the chloro to the cyano following the procedure of Leadbeater and Arvela; JOC 2003, 68, 9122-9125.
  • Example b-6-a The title compound was prepared following the procedure described in Example b-6-a except 4- (3-(3-chloro-4-fluoro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of 3- (3-(3-methyl-5-(trityloxy)phenyl)-4-(2-(methylthio)pyrimidin-4-yl)-1/-/-pyrazol-yl)propanenitrile to give 4-(3- (3-chloro-4-fluoro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine in 73% yield.
  • Example 13 2-(3-(3-chloro-4-fluoro-5- hydroxyphenyl)-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile, starting from methyl 4-fluoro-3-methoxy-5-methylbenzoate and 4-methyl-2-(methylthio)pyrimidine.
  • Raf kinase activity is measured in vitro by determining transfer of radiolabeled 32-P phosphate from ATP to the specific Raf substrate Mek1.
  • Full-length wild type b-Raf is expressed in recombinant form and purified from bacterial or insect cells.
  • Recombinant Mek1 is purified from E. coli bacterial cells.
  • the full-length wild type Mek1 is used as the b-Raf substrate.
  • G2 the full-length K97R Mek1 mutant is used as the b- Raf substrate.
  • In vitro kinase assays are performed in solution containing the following; 50 mM Hepes (pH 7.4), 5 nM b-Raf, 0.8 ⁇ M Mek1 , 10 mM MgCI2, 25 ⁇ M ATP, 0.002% (v/v) Tween-20, 5 ⁇ g/mL leupeptin, 1.2 mM DTT, 2% (v/v) DMSO, 0.2-1.0 ⁇ Ci [ ⁇ - 32 P]ATP per well.
  • the assays are performed in wells of a 96 well polypropylene round bottom plate, each well containing 43.5 ⁇ l_ assay mix and 1.5 ⁇ l_ inhibitor compound or DMSO vehicle. 15 ⁇ L of b-Raf mix is added and the plate is shaken on a plate shaker and preincubated for 10 minutes at ambient temperature.
  • the reaction is started by addition of 15 ⁇ L ATP mix and shaking. The reaction is terminated after 40 minutes by addition of 25 ⁇ L 0.5 M EDTA (pH 7.4).
  • 60 ⁇ L of the stopped reaction is transferred to a well of a 96-well nylon 66 Biodyne A membrane Silent Screen filter plate (Nalge/Nunc: 256081).
  • the wells are filtered and washed five times with 0.85% phosphoric acid.
  • the filter is placed in a tray with about 50 mL 0.85% phosphoric acid and gently rotated for 10 minutes on an orbital shaker. The procedure is repeated once with fresh 0.85% phosphoric acid.
  • Raf kinase activity is calculated from the specific activity of [32-P] ATP, 32-P incorporation into Mek1 , and the concentration of b-Raf.
  • Healthy growing human melanoma A2058 cells (harboring a b-Raf mutation) are used for the assay.
  • A2058 cells are grown in 10% FBS DMEM medium. When the cells are near 85%+ confluence, the cells are rinsed with PBS once and trypsinized with trypsin/EDTA for 3 minutes. The cells are resuspended in 10% FBS DMEM and are centrifuged down at 1000 rpm for 5 minutes. The cells are resuspended in 0.5% FBS DMEM and counted on a cell counter. The cells are seeded at 50,000 cells/well in a volume of 100 ⁇ L/well in 0.5% FBS DMEM in a 96 well flat-bottom plate. The negative control wells receive only 100 ⁇ l_ of 0.5% FBS DMEM medium without cells. The plate is incubated overnight in a cell culture incubator with 5% CO 2 at 37 0 C.
  • testing compounds are prepared in 0.5% FBS DMEM medium and serially diluted at 1:3 for 11 test concentrations. Each concentration of the compounds is tested in duplicate.
  • the compound solutions are added at 25 ⁇ L/well to the corresponding wells in the cell plate, and 25 ⁇ L/well of the vehicle (0.5% DMSO in 0.5% FBS DMEM) is added to the negative control wells (no cells) and the positive control wells (cells without compounds).
  • the plate is incubated for 1 hour in a cell culture incubator with 5% CO 2 at 37 °C. After 1 hour of incubation, the medium is removed, 100 ⁇ L/well of cell lysis buffer is added into the cell plate, and the plate is shaken for 15 minutes at room temperature.
  • the cell lysates are transferred to an ELISA plate (pre-coated with anti-Mek1 anti-body, Cell Signaling #2352), and the plate is incubated with gentle shaking for 2 hours at room temperature. After 2 hours, the contents of the wells are aspirated and the wells are washed 4 times with wash buffer. 100 ⁇ L of phospho-Mek1/2 detection antibody (Cell Signaling #9121) is added into each well and the plate is incubated with gentle shaking for 1 hour at room temperature. After 1 hour, the wells are aspirated and washed 4 times with wash buffer.
  • phospho-Mek1/2 detection antibody Cell Signaling #9121

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Abstract

The present invention is directed to compounds of Formula (I), and to salts and solvates thereof, their synthesis, and their use as Raf inhibitors.

Description

PYRAZOLE COMPOUNDS
This application claims the benefit of U. S. Provisional Application No. 60/782,786 filed March 16, 2006 and U. S. Provisional Application No. 60/886,561 filed January 25, 2007, the contents of which are hereby incorporated by reference in their entireties.
Field of the Invention
The present invention is directed to compounds, and salts and solvates thereof, their synthesis, and their use as modulators or inhibitors of the Raf enzyme. The compounds of the present invention are useful for modulating (e.g. inhibiting) Raf activity and for treating diseases or conditions mediated by Raf, such as for example, disease states associated with abnormal cell growth such as cancer.
Background
The "Erk pathway" is an intracellular signal transduction pathway used by nearly all types of human cells to translate extracellular signals to cellular decisions, including proliferation, differentiation, senescence, or apoptosis (Wellbrock et al., Nat. Rev. MoI. Cell Biol. 11 :875-885 (2004)). One of the invariant components of this pathway is the Ras GTPase, which receives signals from membrane receptors and activates the Raf protein kinases, which activate the Mek protein kinases, which in turn activate the Erk protein kinases. Activated Erk kinases phosphorylate a number of nuclear and cytoplasmic targets to initiate various cellular decisions. The biological importance of Raf in the Erk pathway is underscored by the finding that mutated forms of Raf are associated with certain human malignancies (see e.g. Monia et al., Nature Medicine 2:668-675 (1996); Davies et al., Nature 417:949-954 (2002)). Three distinct genes have been identified in mammals that encode Raf proteins; a-Raf, b-Raf and c-Raf (also known as RaM) and isoformic variants that result from differential splicing of mRNA are known (Chong et al., EMBO J. 20:3716-3727 (2001)). The Erk pathway is mutationally activated in a number of human cancers, most often by mutation of the Ras or b-Raf genes. Mutations in Ras and b- Raf genes generally occur in the same tumor types, including cancers of the colon, lung and pancreas and melanoma, but are usually mutually exclusive. This suggests that activation of either Ras or Raf is sufficient for pathway activation and cancer progression.
Since tumor cells frequently become dependent, or 'addicted' to one or two key signaling pathways for their survival (see, e.g. Jonkers et al., Cancer Cell. 6:535-538 (2004)), the Erk pathway represents a highly attractive target for drug intervention to treat cancer. Protein kinases in general are considered desirable targets for drug therapy, as evidenced by recent successes in targeting growth factor receptor and intracellular tyrosine kinases. Inhibitors of Mek have shown promise in clinical trials, however, there is ample evidence to indicate Mek-independent Raf signaling that may also contribute to cancer progression (Wellbrock et al, Nat. Rev. MoI. Cell Biol. 11 :875-885 (2004)). Therefore, targeting Raf kinases promises an alternative and complementary approach to treating tumors in which Ras or Raf genes are mutated. Summarv
In one embodiment of the present invention is a compound of Formula (I)
(I) wherein: R1 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b), -C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C3 to C8) cycloalkyl, (C6 to Ci4) aryl, (C2 to Cg) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group; each R2 is independently H, halogen, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to
C8) alkoxy, or cyano;
R3 is H, or-NH(CH2)nR7;
R4 is -SR8, -OR8, H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b), -C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group;
R5a and R5b are each independently H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C2 to C9) cycloheteroalkyl and (C3 to C8) cycloalkyl is optionally substituted with at least one R6 group; R6 is -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, -(CH2)nC(O)R9, or -N(R10aR10b);
R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to Cg) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl;
R8 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -(CH2)n-cyano, -(CH2)n-(C3 to C8) cycloalkyl, -(CH2V(C6 to C14) aryl, -(CH2Jn-(C2 to C9) cycloheteroalkyl, or -(CH2)π-(C2 to C9) heteroaryl; R9 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C8) alkoxy, or
-N(R1OaR1Ob);
R1Oa and R10b are each independently H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl;
X is N or CH; m is 0, 1 , 2, or 3; each n is independently 0, 1 , 2, 3, or 4; p is 0, 1 , 2, 3, or 4; or a salt or solvate thereof. In one aspect of this embodiment is a compound according to Formula (I), as described above, wherein R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl.
In a further aspect of this embodiment is a compound of Formula (I), wherein p is 0, 1 , 2, or 3 and R1 is H, -N(R5aR5b), (C1 to C6) alkyl, cyano, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl and (C2 to Cg) heteroaryl is optionally substituted with at least one R6 group. For example, in a further aspect p is 1 or 2 and R1 is cyano or (C1 to C6) alkyl. In a still further aspect, p is 0 and R1 is H or (C1 to C6) alkyl. In a still further aspect p is 0 or 1 and R1 is (C2 to C9) cycloheteroalkyl and is optionally substituted with at least one R6 group. In a still further aspect, the (C2 to C9) cycloheteroalkyl is selected from the group consisting of:
, and wherein each of said (C2 to C9) cycloheteralkyl groups are optionally substituted with at least one R6 group.
In a further aspect of this embodiment is a compound of Formula (I), as described above, wherein m is 1 or 2 and the compound of Formula (I) has the following structure:
For example in one aspect each R2 is independently halogen, -OCH3, or (C1 to C6) alkyl. For example R2 is independently halogen, -OCH3, C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl. In a further aspect m is 1 and the compound of Formula (I) has the following structure:
wherein R2 is Cl or CH3.
In a further aspect of this embodiment is a compound of Formula (I), as described above, wherein X is N and R3 is -NH(CH2)nR7. For example, in one aspect R7 is H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (Ci to C6) alkyl, (C2 to C9) cycloheteroalkyl, - A -
and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl.
In a further aspect R3 is -NH(CH2)nR7 where n is 1 or 2, and R7 is (C-i to C6) alkyl and is substituted with one -OH group. In a further aspect of this embodiment is a compound of Formula (I), as described above, wherein X is N and R4 is H, (C2 to C9) cycloheteroalkyl, -OR8, or -N(R5aR5b), wherein said (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group.
In another embodiment, the present invention is a compound of Formula (I)
(I) wherein:
R1 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b),
-C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group; each R2 is independently H, halogen, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C8) alkoxy, or cyano;
R3 is H, or -NR11(CH2)nR7;
R4 is -SR8, -OR8, H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b), -C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to Ci4) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to Cg) heteroaryl is optionally substituted with at least one R6 group;
R5a and R5b are each independently H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C2 to C9) cycloheteroalkyl and (C3 to C8) cycloalkyl is optionally substituted with at least one R6 group;
Rs is -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, -(CH2)nC(O)R9, or -N(R10aR10b);
R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C-i to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to Cu) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), -OC(O)R12, (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl; R8 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -(CH2)n-cyano, -(CH2Jn-(C3 to C8) cycloalkyl, -(CH2Jn-(C6 to C14) aryl, -(CH2Jn-(C2 to C9) cycloheteroalkyl, or -(CH2Jn-(C2 to C9) heteroaryl;
R9 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C8) alkoxy, or
_N(R10aR10b); R1Oa and R1Ob are each independently H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl;
R11 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to Ci4) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C-i to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl;
R12 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, (C1 to C8) alkoxy, and (C2 to C9) cycloheteroalkyl; X is N or CH; m is O, 1 , 2, or 3; each n is independently 0, 1, 2, 3, or 4; p is 0, 1 , 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
In one aspect of this embodiment is a compound according to Formula (I), as described above, R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), -OC(O)R12, (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl. In a further aspect of this embodiment is a compound of Formula (I), as described above, wherein
X is N and R3 is -NH(CH2JnR7. For example, in one aspect R7 is H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), -OC(O)R12, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl. In a further aspect of this embodiment is a compound of Formula (I), as described above, wherein
X is N and R3 is -NR11(CH2)nR7. For example, in one aspect R7 is H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C-i to C6) alkyl, (C2 to C9) cycloheteroalkyl, and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), -OC(O)R12, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl. In a further aspect R3 is -NH(CH2)nR7 where n is 1 or 2, and R7 is (C1 to C6) alkyl and is substituted with one -OH group.
A further aspect of the present invention is a compound according to Formula (I), as described above, which is selected from the group consisting of: 3-chloro-5-(1-isopropyl-4-pyrimidin-4-yl-1 H-pyrazol- 3-yl)phenol; 3-[4-(2-anilinopyrimidin-4-yl)-1-methyl-1 H-pyrazol-3-yl]-5-chlorophenol; 2-(3-(3-chloro-5- hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile; 2-(3-(3-
Chloro-5-hydroxyphenyl-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1/V-pyrazol-1-yl)acetonitrile; 3-[3-(3- hydroxy-5-methylphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]propanenitrile; 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-((R)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1- yl)propanenitrile; 3-chloro-5-[4-[2-(isobutylamino)pyrimidin-4-yl]-1-(1-methylpiperidin-4-yl)-1 H-pyrazol-3- yl]phenol; 3-chloro-5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1W-pyrazol-3-yl}phenol; 3-chloro- 5-[4-{2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl}-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl]phenol; 3-chloro-5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-methyl-1 H-pyrazol-3-yl}phenol; {3-(3-chloro-5- hydroxyphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1H-pyrazol-1-yl}acetonitrile; [3-(3-chloro-5- hydroxyphenyl)-4-{2-[(2-hydroxy-1-methyIethyl)amino]pyrimidin-4-yl}-1H-pyrazol-1-yl]acetonitrile; [4-(2- aminopyrimidin-4-yl)-3-(3-chloro-5-hydroxyphenyl)-1 H-pyrazol-1-yl]acetonitrile; [3-(3-chloro-5- hydroxyphenyl)-4-(2-{[2-(1 H-imidazol-4-yl)ethyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; [3-(3- chloro-5-hydroxyphenyl)-4-(2-{[(2R)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; [3- (3-chloro-5-hydroxyphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; 3-[4-{2-[(2-hydroxyethyl)amino]pyrimidin-4-yI}-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol-1- yl]propanenitrile; 3-{3-(3-hydroxy-5-methylphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H- pyrazol-1-yl}propanenitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2-{[(1S)-2-hydroxy-1- methylethyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; and [3-(3-chloro-5-hydroxyphenyl)-4-(2- {[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile. For example, in one embodiment the compound is selected from the group consisting of 3-chloro-5-(1-isopropyl-4-pyrimidin-4- yl-1 H-pyrazol-3-yl)phenol; 3-[4-(2-anilinopyrimidin-4-yl)-1-methyl-1 H-pyrazol-3-yl]-5-chlorophenol; 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile; 2-(3- (3-Chloro-5-hydroxyphenyl-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile; and 3- [3-(3-hydroxy-5-methylphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1- yl]propanenitrile. In a further embodiment the compound is selected from the group consisting of 3-(3-(3- hydroxy-5-methylphenyl)-4-(2-((R)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile; 3- chloro-5-[4-[2-(isobutylamino)pyrimidin-4-yl]-1-(1-methylpiperidin-4-yl)-1 H-pyrazol-3-yl]phenol; 3-chloro-5- {4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1H-pyrazol-3-yl}phenol; 3-chloro-5-[4-{2-[(2-hydroxy-2- methylpropyl)amino]pyrimidin-4-yl}-1-(1-methylpiperidin-4-yl)-1W-pyrazol-3-yl]phenol; and 3-chloro-5-{4-[2- (isobutylamino)pyrimidin-4-yl]-1-methyl-1 H-pyrazol-3-yl}phenol. In a further embodiment the compound is selected from the group consisting of 3-chloro-5-[4-{2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl}-1- (1-methylpiperidin-4-yl)-1/-/-pyrazol-3-yl]phenol; 3-chloro-5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-methyl- 1H-pyrazol-3-yl}phenol; {3-(3-chloro-5-hydroxyphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H- pyrazol-1-yl}acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4-{2-[(2-hydroxy-1-methylethyl)amino]pyrimidin-4- yl}-1H-pyrazol-1-yl]acetonitrile; and [4-(2-aminopyrimidin-4-yl)-3-(3-chloro-5-hydroxyphenyl)-1H-pyrazol-1- yljacetonitrile. In a further embodiment the compound is selected from the group consisting of [3-(3- chloro-5-hydroxyphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; 3- [4-{2-[(2-hydroxyethyl)amino]pyrimidin-4-yl}-3-(3-hydroxy-5-methylphenyl)-1H-pyrazol-1-yl]propanenitrile; 3-{3-(3-hydroxy-5-methylphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H-pyrazol-1- yl}propanenitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2-{[(1S)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)- 1 H-pyrazol-1-yl]acetonitrile; and [3-(3-chloro-5-hydroxyphenyl)-4-(2-{[(1R)-2-hydroxy-1- methylethyl]amino}pyrimidin-4-yl)-1H-pyrazol-1-yl]acetonitrile, or a pharmaceutically acceptable salt thereof.
A further aspect of the present invention is a compound according to Formula (I), as described above, which is selected from the group consisting of 2-(3-(3-fluoro-5-hydroxyphenyl)-4-(2-((S)-2- hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile, 2-(3-(3-hydroxy-5-methylphenyl)-4-(2- ((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)-acetonitrile, 3-(1-(cyanomethyl)-4-(2-(2- hydroxyethylamino)pyrimidin-4-yl)-1 H-pyrazol-3-yl)-5-hydroxybenzonitrile, 3-(4-(2-((S)-2- hydroxypropylamino)pyrimidin-4-yl)-1-((5-methylisoxazol-3-yl)methyl)-1 H-pyrazol-3-yl)-5-methylphenol, 5- (4-(2-(isopropylamino)pyrimidin-4-yl)-1-(1-methyl-azetidin-3-yl)-1 H-pyrazol-3-yl)-2,3-dimethylphenol, 5-(1- (2-hydroxyethyl)-4-(2-(2-(1-methyl-pyrrolidin-2-yl)-ethylamino)pyrimidin-4-yl)-1 H-pyrazol-3-yl)-2,3- dimethylphenol, 5-(1-(2-hydroxy-ethyl)-4-(2-((tetrahydrofuran-3-yl)methylamino)pyrimidin-4-yl)-1 H-pyrazol- 3-yl)-2,3-dimethyl-phenol, 3-(4-(2-(isobutylamino)pyrimidin-4-yl)-1-(1-methylazetidin-3-yl)-1H-pyrazol-3-yl)- 5-methylphenol, 2-(3-(3-hydroxy-4,5-dimethylphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H- pyrazol-1-yl)acetonitrile, 3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(2-(pyrazin-2-yl)-ethylamino)pyrimidin- 4-yl)-1 H-pyrazol-3-yl)phenol, 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1 H- pyrazol-1 -yl)-N-methylacetam ide, 2-(3-(3-chloro-4-fluoro-5-hydroxyphenyl)-4-(2-(2- hydroxyethylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile, 2-(3-(3-hydroxy-5-methylphenyI)-4-(2-((2- hydroxyethyl)(methyl)amino)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile, 2-(4-(2-(dimethylamino)pyrimidin- 4-yl)-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol-1-yl)-acetonitrile, (S)-1-(4-(1-(cyanomethyl)-3-(3-hydroxy- 5-methylphenyl)-1 H-pyrazol-4-yl)-pyrimidin-2-ylamino)propan-2-yl 2,6-dimethoxybenzoate, 2-(3-(4-fluoro- 3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile and (S)-1-(4-(1- (cyanomethyl)-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-yl acetate, or a pharmaceutically acceptable salt thereof. In a further embodiment is any of the aspects described above in combination with any of the other aspects described above which is not inconsistent therewith.
The present invention also relates to a pharmaceutical composition, comprising at least one compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. The present invention also relates to a method of treating abnormal cell growth, or any Raf- mediated disease or condition, in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound as described herein, or a pharmaceutically acceptable salt thereof. For example, in one embodiment the abnormal cell growth is cancerous. In a further embodiment, the abnormal cell growth in non-cancerous. The present invention further relates to a method of inhibiting Raf enzymatic activity, comprising contacting a Raf enzyme with a Raf-inhibiting amount of at least one compound as described herein, or a pharmaceutically acceptable salt thereof.
The present invention further relates to the use of any of the compounds as described herein, or a salt or solvate thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal.
The present invention further relates to methods of making the compounds as described herein using the methods as shown in the specific examples herein and in the general synthetic methods A, B, C, D, and E, as described herein. The present invention further relates to any of the compounds described above, or salts or solvates thereof, for use as a medicament. The present invention further relates to the use of any of the compounds described above, or salts or solvates thereof, for the manufacture of a medicament for the treatment of abnormal cell growth.
As used herein, the terms "comprising" and "including" are used in their open, non-limiting sense. The terms "halo" and/or "halogen" refer to fluorine, chlorine, bromine or iodine.
The term "(C1 to Ce)" alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms. Examples of (C1 to C6) alkyl groups include methyl, ethyl, propyl, 2-propyl, π-butyl, /so-butyl, ferf-butyl, pentyl, and the like.
The term "(C2 to C8) alkenyl", as used herein, means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond. The carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl. The term "allyl," as used herein, means a -CH2CH=CH2 group. The term, "C(R)=C(R)," as used herein, represents a carbon-carbon double bond in which each carbon is substituted by an R group.
As used herein, the term "(C2 to C8) alkynyl" means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond. The carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1- hexyne, 2-hexyne, and 3-hexyne.
The term "(C1 to C8) alkoxy", as used herein, means an O-alkyl group wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy. The term "(C1 to C8) heteroalkyl" refers to a straight- or branched-chain alkyl group having a total of from 2 to 12 atoms in the chain, including from 1 to 8 carbon atoms, and one or more atoms of which is a heteroatom selected from S, O, and N, with the proviso that said chain may not contain two adjacent O atoms or two adjacent S atoms. The S atoms in said chains may be optionally oxidized with one or two oxygen atoms, to afford sulfides and sulfones, respectively. Furthermore, the (C-i to C8) heteroalkyl groups in the compounds of the present invention can contain an oxo group at any carbon or heteroatom that will result in a stable compound. Exemplary (C1 to C8) heteroalkyl groups include, but are not limited to, alcohols, alkyl ethers, primary, secondary, and tertiary alkyl amines, amides, ketones, esters, sulfides, and sulfones.
The term "(C6 to C14) aryl", as used herein, means a group derived from an aromatic hydrocarbon containing from 6 to 14 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl. The terms "Ph" and "phenyl," as used herein, mean a -C6H5 group. The term "benzyl," as used herein, means a -CH2C6H5 group.
"(C2 to C9) heteroaryl", as used herein, means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. The heterocyclic groups include benzo-fused ring systems. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The C2 to C9 heteroaryl groups may be C-attached or N-attached where such is possible. For instance, a group derived from pyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached). Further, a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached). "(C2 to C9) cycloheteroalkyl", as used herein, means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 2 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms. Furthermore, such C2 to C9 cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound. For example, such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible. In addition, it is to be understood that when such a C2 to C9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone. An example of a 4 membered cycloheteroalkyl group is azetidinyl (derived from azetidine). An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl. An example of a 6 membered cycloheteroalkyl group is piperidinyl. An example of a 9 membered cycloheteroalkyl group is indolinyl. An example of a 10 membered cycloheteroalkyl group is 4H-quinolizinyl. Further examples of such C2 to Cg cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3- azabicyclo[4.1.0]heptanyl, 3H-indolyl quinolizinyl, 3-oxopiperazinyl, 4-methylpiperazinyl, 4- ethylpiperazinyl, and 1-oxo-2,8,diazaspiro[4.5]dec-8-yl. The term "(C3 to C8) cycloalkyl group" means a saturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 8 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl. The term cyano" refers to a -C≡N group.
The term "substituted," means that the specified group or moiety bears one or more substituents. The term "unsubstituted," means that the specified group bears no substituents. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be "unsubstituted," or is "substituted" with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen. For example, if a C6 aryl group, also called "phenyl" herein, is substituted with one additional substituent, one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C6 aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies. Similarly, if a C6 aryl group in the present compounds is said to be "disubstituted," one of ordinary skill in the art would understand it to mean that the C6 aryl has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies. The term "solvate," is used to describe a molecular complex between compounds of the present invention and solvent molecules. Examples of solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof. The term "hydrate" can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate. Additionally, it is specifically contemplated that in the present invention less than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a hemihydrate. Furthermore, solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
The term "pharmaceutically acceptable salt," as used herein, means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable. The term "pharmaceutically acceptable formulation," as used herein, means a combination of a compound of the invention, or a salt or solvate thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof. Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art. For example, the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as povidone, sodium starch glycolate, sodium carboxymethylcellulose, agar, calcium carbonate, and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Final pharmaceutical forms may be pills, tablets, powders, lozenges, saches, cachets, or sterile packaged powders, and the like, depending on the type of excipient used. Additionally, it is specifically contemplated that pharmaceutically acceptable formulations of the present invention can contain more than one active ingredient. For example, such formulations may contain more than one compound according to the present invention. Alternatively, such formulations may contain one or more compounds of the present invention and one or more additional agents that reduce abnormal cell growth. The term "Raf-inhibiting amount" as used herein, refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit the enzymatic activity of Raf in vivo, such as in a mammal, or in vitro. The amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art. The term "inhibiting Raf enzyme activity," as used herein, means decreasing the activity or functioning of the Raf enzyme either in vitro or in vivo, such as in a mammal, such as a human, by contacting the enzyme with a compound of the present invention.
The term "Raf as used herein means a-Raf, b-Raf, c-Raf, or mutants thereof, or any of the known Raf isoformic splice variants. The term "therapeutically effective amount," as used herein, means an amount of a compound of the present invention, or a salt or solvate thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, a therapeutically effective amount of a compound of the present invention, or a salt or solvate thereof, is a quantity sufficient to modulate or inhibit the activity of the Raf enzyme such that a disease condition that is mediated by activity of the Raf enzyme is reduced or alleviated.
The terms "treat", "treating", and "treatment" with reference to abnormal cell growth, or to any Raf mediated disease or condition, in a mammal, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition, e.g., relieving an inflammatory response without addressing the underlying disease or condition. With regard to abnormal cell growth, such as cancer, these terms simply mean that the life expectancy of an individual affected with abnormal cell growth will be increased or that one or more of the symptoms of the disease will be reduced. Unless indicated otherwise, all references herein to the inventive compounds include references to salts, solvates, and complexes thereof, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof. For example, compounds of the present invention can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates. "Abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), including the abnormal growth of normal cells and the growth of abnormal cells. This includes, but is not limited to, the abnormal growth of: tumor cells (tumors) that proliferate by expressing a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation occurs; any tumors that proliferate by receptor tyrosine kinases; any tumors that proliferate by aberrant serine/threonine kinase activation; benign and malignant cells of other proliferative diseases in which aberrant serine/threonine kinase activation occurs; tumors, both benign and malignant, expressing an activated Ras oncogene; tumor cells, both benign and malignant, in which the Ras protein is activated as a result of oncogenic mutation in another gene; benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy, human papilloma virus (HPV), and restinosis. "Abnormal cell growth" also refers to and includes the abnormal growth of cells, both benign and malignant, resulting from activity of the enzyme farnesyl protein transferase.
The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application.
The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. In particular, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. The terms "racemic" or "racemic mixture," as used herein, refer to a 1:1 mixture of enantiomers of a particular compound. The term "diastereomers", on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
Detailed Description The compounds of the present invention are useful for modulating or inhibiting Raf activity.
Accordingly, these compounds are useful for the prevention and/or treatment of disease states associated with abnormal cell growth such as cancer, alone or in combination with other anti-cancer agents.
In accordance with a convention used in the art, the symbol ^ is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure. In accordance with another convention, in some structural formulae herein the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g., ' <~ represents a methyl
group, "" ^ CH3 r roenprrpesspennttss a ann p etthhwyll π grrnoiulnp, x represents a cyclopentyl group, etc.
The compounds of the present invention may have asymmetric carbon atoms. The carbon- carbon bonds of the compounds of the present invention may be depicted herein using a solid line ( ), a solid wedge ( ~m^mΛ ), or a dotted wedge ( "'" ). The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the reacemate using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art. Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
Where a compound of the invention contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. Examples of tautomerism include keto and enol tautomers. A single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
The compounds of the present invention may be administered as prodrugs. Thus certain derivatives of compounds of Formula (I), which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of Formula (I) with certain moieties known to those skilled in the art. See, e.g. "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entireties. Some examples of such prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group. Further examples of replacement groups are known to those of skill in the art. See, e.g. "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. It is also possible that certain compounds of Formula (I) may themselves act as prodrugs of other compounds of Formula (I).
Salts of the present invention can be prepared according to methods known to those of skill in the art. Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogenphosphate, edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methane- sulfonate, methylsulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
If the inventive compound is a base, the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the inventive compound is an acid, the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulas. The invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulfur, such as 35S. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, 3H, and carbon-14, 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.
The compounds of the present invention may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable. Pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
To treat or prevent diseases or conditions mediated by Raf, a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., a Raf modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
The pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like. Further additives or excipients may be added to achieve the desired formulation properties. For example, a bioavailability enhancer, such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol), may be added. Gelucire®, a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
If a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge. The amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension. If a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations. The inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
To obtain a stable water-soluble dose form, a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable co-solvent or combinations of co-solvents. Examples of suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, a compound of the present invention is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
Proper formulation is dependent upon the route of administration selected. For injection, the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A pharmaceutical carrier for hydrophobic compounds is a co- solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. The proportions of a co- solvent system may be suitably varied without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity non- polar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients. These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Furthermore, additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol® Transcutol® and the like may be used.
Further, the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
It will be appreciated that the actual dosages of the agents of this invention will vary according to the particular agent being used, the particular composition formulated, the mode of administration, and the particular site, host, and disease being treated. Those skilled in the art using conventional dosage- determination tests in view of the experimental data for a given compound may ascertain optimal dosages for a given set of conditions. For oral administration, an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals. Furthermore, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500mg. Additionally, the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, or from about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%. The compounds of the present invention, or salts or solvates thereof, may be administered to a mammal suffering from abnormal cell growth, such as a human, either alone or as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, or four times a day, or even more frequently.
Those of ordinary skill in the art will understand that with respect to the compounds of the present invention, the particular pharmaceutical formulation, the dosage, and the number of doses given per day to a mammal requiring such treatment, are all choices within the knowledge of one of ordinary skill in the art and can be determined without undue experimentation.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal, including a human, comprising administering to said mammal an amount of a compound of the Formula (I), as defined above, or a salt or solvate thereof, that is effective in treating abnormal cell growth. In one embodiment of this method, the abnormal cell growth is cancer, including, but not limited to, mesothelioma, hepatobiliary (hepatic and billiary duct), a primary or secondary CNS tumor, a primary or secondary brain tumor, lung cancer (NSCLC and SCLC), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.
In one embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), cancer of the head or neck, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, breast cancer, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, non hodgkins's lymphoma, spinal axis tumors, or a combination of one or more of the foregoing cancers.
In another embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
In another embodiment of the present invention the cancer is selected from lung cancer (NSCLC and SCLC), ovarian cancer, colon cancer, rectal cancer, or a combination of one or more of the foregoing cancers.
In another embodiment of said method, said abnormal cell growth is a benign proliferative disease, including, but not limited to, psoriasis, benign prostatic hypertrophy or restinosis.
This invention also relates to a method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of the present invention, or a salt or solvate thereof, that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens. In one embodiment of the present invention the anti-tumor agent used in conjunction with a compound of the present invention and pharmaceutical compositions described herein is an anti- angiogenesis agent, kinase inhibitor, pan kinase inhibitor or growth factor inhibitor. Preferred pan kinase inhibitors include Sutent™ (sunitinib), described in U.S. Patent No. 6,573,293 (Pfizer, Inc, NY, USA). Anti-angiogenesis agents, include but are not limited to the following agents, such as EGF inhibitors, EGFR inhibitors, VEGF inhibitors,. VEGFR inhibitors, TIE2 inhibitors, IGF1 R inhibitors, COX-II (cyclooxygenase II) inhibitors, MMP-2 (matrix-metalloprotienase 2) inhibitors, and MMP-9 (matrix- metalloprotienase 9) inhibitors.
Preferred VEGF inhibitors, include for example, Avastin (bevacizumab), an anti-VEGF monoclonal antibody of Genentech, Inc. of South San Francisco, California. Additional VEGF inhibitors include CP-547,632 (Pfizer Inc., NY, USA), AG13736 (Pfizer Inc.), ZD-6474 (AstraZeneca), AEE788
(Novartis), AZD-2171 , VEGF Trap (Regeneron/Aventis), Vatalanib (also known as PTK-787, ZK-222584:
Novartis & Schering AG), Macugen (pegaptanib octasodium, NX-1838, EYE-001 , Pfizer
Inc./Gilead/Eyetech), IM862 (Cytran Inc. of Kirkland, Washington, USA); and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colorado) and Chiron (Emeryville, California) and combinations thereof.
VEGF inhibitors useful in the practice of the present invention are described in US Patent No. 6,534,524 and 6,235,764, both of which are incorporated in their entirety for all purposes. Additional VEGF inhibitors are described in, for example in WO 99/24440, in WO 95/21613, WO 99/61422, U.S. Patent 5,834,504, WO 98/50356, U.S. Patent 5,883,113 U.S. Patent 5,886,020, U.S. Patent 5,792,783, U.S. Patent 6,653,308, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, all of which are herein incorporated by reference in their entirety.
Other anti-angiogenic compounds include acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain, Vitaxin and combinations thereof. Other antiproliferative agents that may be used in combination with the compounds of the present invention include inhibitors of the enzyme farnesyl protein transferase and inhibitors of the receptor tyrosine kinase PDGFr, including the compounds disclosed and claimed in the following: U.S. Patent 6,080,769; U.S. Patent 6,194,438; U.S. Patent 6,258,824; U.S. Patent 6,586447; U.S. Patent 6,071 ,935; U.S. Patent 6,495,564; and U.S. Patent 6,150,377; U.S. Patent 6,596,735; U.S. Patent 6,479,513; WO 01/40217; U.S. 2003-0166675. Each of the foregoing patents and patent applications is herein incorporated by reference in their entirety.
PDGRr inhibitors include but are not limited to those disclosed in international patent application publication numbers WO01/40217 and WO2004/020431 , the contents of which are incorporated in their entirety for all purposes. Preferred PDGFr inhibitors include Pfizer's CP-673,451 and CP-868,596 and its salts.
Preferred GARF inhibitors include Pfizer's AG-2037 (pelitrexol and its salts). GARF inhibitors useful in the practice of the present invention are disclosed in US Patent No. 5,608,082 which is incorporated in its entirety for all purposes.
Examples of useful COX-II inhibitors which can be used in conjunction with a compound of Formula (I) and pharmaceutical compositions disclosed herein include CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 (Lumiracoxib), BMS 347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD-8381 , 4-Methyl-2-(3,4-dimethylphenyl)-1- (4-sulfamoyl-phenyl)-1 H-pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1 H-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib). Additonally, COX-II inhibitors are disclosed in U.S. Patent Applications US 2005-0148627 and US 2005-0148777, the contents of which are incorporated in their entirety for all purposes.
In a particular embodiment the anti-tumor agent is celecoxib (U.S. Patent No. 5,466,823), valdecoxib (U.S. Patent No. 5,633,272), parecoxib (U.S. Patent No. 5,932,598), deracoxib (U.S. Patent No. 5,521,207), SD-8381 (U.S. Patent No. 6,034,256, Example 175), ABT-963 (WO 2002/24719), rofecoxib (CAS No. 162011-90-7), MK-663 (or etoricoxib) as disclosed in WO 1998/03484, COX-189 (Lumiracoxib) as disclosed in WO 1999/11605, BMS-347070 (U.S. Patent 6,180,651), NS-398 (CAS 123653-11-2), RS 57067 (CAS 17932-91-3), 4-Methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoyl-phenyl)-1 H- pyrrole, 2-(4-Ethoxyphenyl)-4-methyl-1-(4-sulfamoylphenyl)-1H-pyrrole, or meloxicam. Other useful inhibitors as anti-tumor agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include aspirin, and non-steroidal antiinflammatory drugs (NSAIDs) which inhibit the enzyme that makes prostaglandins (cyclooxygenase I and II), resulting in lower levels of prostaglandins, include but are not limited to the following, Salsalate (Amigesic), Diflunisal (Dolobid), lbuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), lndomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol), Oxaprozin (Daypro) and combinations thereof.
Preferred COX-I inhibitors include ibuprofen (Motrin), nuprin, naproxen (Aleve), indomethacin (Indocin), nabumetone (Relafen) and combinations thereof. Targeted agents used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein include EGFr inhibitors such as lressa (gefitinib, AstraZeneca), Tarceva (erlotinib or OSI-774, OSI Pharmaceuticals Inc.), Erbitux (cetuximab, lmclone Pharmaceuticals, Inc.), EMD-7200 (Merck AG), ABX-EGF (Amgen Inc. and Abgenix Inc.), HR3 (Cuban Government), IgA antibodies (University of Erlangen-Nuremberg), TP-38 (IVAX), EGFR fusion protein, EGF- vaccine, anti-EGFr immunoliposomes (Hermes Biosciences Inc.) and combinations thereof. Preferred EGFr inhibitors include lressa, Erbitux, Tarceva and combinations thereof.
Other anti-tumor agents include those selected from pan erb receptor inhibitors or ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), CI-1033 (canertinib, Pfizer, Inc.), Herceptin (trastuzumab, Genentech Inc.), Omitarg (2C4, pertuzumab, Genentech Inc.), TAK-165 (Takeda), GW-572016 (lonafarnib, GlaxoSmithKline), GW-282974 (GlaxoSmithKline), EKB-569 (Wyeth), PKM 66 (Novartis), dHER2 (HER2 Vaccine, Corixa and GlaxoSmithKline), APC8024 (HER2 Vaccine, Dendreon), anti- HER2/neu bispecific antibody (Decof Cancer Center), B7.her2.lgG3 (Agensys), AS HER2 (Research Institute for Rad Biology & Medicine), trifunctional bispecific antibodies (University of Munich) and mAB AR-209 (Aronex Pharmaceuticals Inc) and mAB 2B-1 (Chiron) and combinations thereof. Preferred erb selective anti-tumor agents include Herceptin, TAK-165, CP-724,714, ABX-EGF,
HER3 and combinations thereof. Preferred pan erbb receptor inhibitors include GW572016, CI-1033, EKB-569, and Omitarg and combinations thereof.
Additional erbB2 inhibitors include those disclosed in WO 98/02434, WO 99/35146, WO 99/35132, WO 98/02437, WO 97/13760, WO 95/19970, U.S. Patent 5,587,458, and U.S. Patent 5,877,305, each of which is herein incorporated by reference in its entirety. ErbB2 receptor inhibitors useful in the present invention are also disclosed in U.S. Patents 6,465,449, and 6,284,764, and in WO 2001/98277 each of which are herein incorporated by reference in their entirety.
Additionally, other anti-tumor agents may be selected from the following agents, BAY-43-9006 (Onyx Pharmaceuticals Inc.), Genasense (augmerosen, Genta), Panitumumab (Abgenix/Amgen), Zevalin (Schering), Bexxar (Corixa/GlaxoSmithKline), Abareiix, Alimta, EPO 906 (Novartis), discodermolide (XAA- 296), ABT-510 (Abbott), Neovastat (Aeterna), enzastaurin (EIi Lilly), Combrestatin A4P (Oxigene), ZD-6126 (AstraZeneca), flavopiridol (Aventis), CYC-202 (Cyclacei), AVE-8062 (Aventis), DMXAA (Roche/Antisoma), Thymitaq (Eximias), Temodar (temozolomide, Schering Plough) and Revilimd (Celegene) and combinations thereof. Other anti-tumor agents may be selected from the following agents, CyPat (cyproterone acetate),
Histerelin (histrelin acetate), Plenaixis (abareiix depot), Atrasentan (ABT-627), Satraplatin (JM-216), thalomid (Thalidomide), Theratope, Temilifene (DPPE), ABI-007 (paclitaxel), Evista (raloxifene), Atamestane (Biomed-777), Xyotax (polyglutamate paclitaxel), Targetin (bexarotine) and combinations thereof.
Additionally, other anti-tumor agents may be selected from the following agents, Trizaone (tirapazamine), Aposyn (exisulind), Nevastat (AE-941), Ceplene (histamine dihydrochloride), Orathecin (rubitecan), Virulizin, Gastrimmune (G17DT), DX-8951f (exatecan mesylate), Onconase (ranpirnase), BEC2 (mitumoab), Xcytrin (motexafin gadolinium) and combinations thereof.
Further anti-tumor agents may be selected from the following agents, CeaVac (CEA), NeuTrexin
(trimetresate glucuronate) and combinations thereof. Additional anti-tumor agents may be selected from the following agents, OvaRex (oregovomab), Osidem (IDM-1), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Advexin (ING 201), Tirazone (tirapazamine), and combinations thereof. Additional anti-tumor agents may be selected from the following agents, RSR13
(efaproxiral), Cotara (1311 chTNT 1/b), NBI-3001 (IL-4) and combinations thereof. Additional anti-tumor agents may be selected from the following agents, Canvaxin, GMK vaccine, PEG lnteron A, Taxoprexin (DHA/paciltaxel), and combinations thereof.
Other anti-tumor agents include Pfizer's MEK1/2 inhibitor PD325901, Array Biopharm's MEK inhibitor ARRY-142886, Bristol Myers' CDK2 inhibitor BMS-387,032, Pfizer's CDK inhibitor PD0332991 and AstraZeneca's AXD-5438, and combinations thereof.
Additionally, mTOR inhibitors may also be utilized such as CCI-779 (Wyeth) and rapamycin derivatives RAD001 (Novartis) and AP-23573 (Ariad), HDAC inhibitors, SAHA (Merck Inc./Aton Pharmaceuticals) and combinations thereof. Additional anti-tumor agents include aurora 2 inhibitor VX-680 (Vertex), and Chk1/2 inhibitor XL844 (Exilixis).
The following cytotoxic agents, e.g., one or more selected from the group consisting of epirubicin (Ellence), docetaxel (Taxotere), paclitaxel, Zinecard (dexrazoxane), rituximab (Rituxan) imatinib mesylate (Gleevec), and combinations thereof, may be used in combination with a compound of the present invention and pharmaceutical compositions disclosed herein.
The invention also contemplates the use of the compounds of the present invention together with hormonal therapy, including but not limited to, exemestane (Aromasin, Pfizer Inc.), leuprorelin (Lupron or Leuplin, TAP/Abbott/Takeda), anastrozole (Arimidex, Astrazeneca), gosrelin (Zoladex, AstraZeneca), doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen, Nolvadex, AstraZeneca), Casodex (AstraZeneca), Abarelix (Praecis), Trelstar, and combinations thereof.
The invention also relates to the use of the compounds of the present invention together with hormonal therapy agents such as anti-estrogens including, but not limited to fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole (Femara, Novartis), anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex™(4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-
(trifluoromethyl) propionanilide, bicalutamide) and combinations thereof.
Further, the invention provides a compound of the present invention alone or in combination with one or more supportive care products, e.g., a product selected from the group consisting of Filgrastim (Neupogen), ondansetron (Zofran), Fragmin, Procrit, Aloxi, Emend, or combinations thereof.
Particularly preferred cytotoxic agents include Camptosar, Erbitux, Iressa, Gleevec, Taxotere and combinations thereof.
The following topoisomerase I inhibitors may be utilized as anti-tumor agents: camptothecin; irinotecan HCI (Camptosar); edotecarin; orathecin (Supergen); exatecan (Daiichi); BN-80915 (Roche); and combinations thereof. Particularly preferred toposimerase Il inhibitors include epirubicin (Ellence).
Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitoi, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol; platinum- coordinated alkylating compounds include but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi) or satrplatin and combinations thereof. Particularly preferred alkylating agents include Eloxatin (oxaliplatin).
Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1 , Alimta (premetrexed disodium, LY231514,
MTA), Gemzar (gemcitabine, EIi Lilly), fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1 , melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine; or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6- ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid and combinations thereof.
Antibiotics include intercalating antibiotics and include, but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere), paclitaxel and combinations thereof.
Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicn, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, diflomotecan, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan, and combinations thereof.
Preferred cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan HCI (Camptosar), edotecarin, epirubicin (Ellence), etoposide, SN-38, topotecan, and combinations thereof.
Immunologicals include interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma-1a, interferon gamma-1b (Actimmune), or interferon gamma-n1 and combinations thereof. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y- muHMFGI), Provenge (Dendreon) and combinations thereof.
Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have antitumor activity. Such agents include krestin, lentinan, sizofiran, picibanil, ubenimex and combinations thereof.
Other anticancer agents that can be used in combination with a compound of the present invention include alitretinoin, ampligen, atrasentan bexarotene, bortezomib. Bosentan, calcitriol, exisulind, finasteride.fotemustine, ibandronic acid, miltefosine, mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, Telcyta (TLK-286, Telik Inc.),
Velcade (bortemazib, Millenium), tretinoin, and combinations thereof.
Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and combinations thereof. Camptothecin derivatives include but are not limited to camptothecin, 10-hydroxycamptothecin, 9- aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan and combinations thereof. Other antitumor agents include mitoxantrone, l-asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pentostatin, tretinoin and combinations thereof.
Anti-tumor agents capable of enhancing antitumor immune responses, such as CTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agents capable of blocking CTLA4 may also be utilized, such as MDX-010 (Medarex) and CTLA4 compounds disclosed in U.S. Patent 6,682,736; and anti-proliferative agents such as other farnesyl protein transferase inhibitors, for example the farnesyl protein transferase inhibitors. Additionally, specific CTLA4 antibodies that can be used in combination with compounds of the present invention include those disclosed in U.S. Patents 6,682,736 and 6,682,736 both of which are herein incorporated by reference in their entirety.
Specific IGF1 R antibodies that can be used in the combination methods of the present invention include those disclosed in WO 2002/053596, which is herein incorporated by reference in its entirety.
Specific CD40 antibodies that can be used in the present invention include those disclosed in WO 2003/040170 which is herein incorporated by reference in its entirety. Gene therapy agents may also be employed as anti-tumor agents such as TNFerade (GeneVec), which express TNFalpha in response to radiotherapy.
In one embodiment of the present invention statins may be used in combination with a compound of the present invention and pharmaceutical compositions thereof. Statins (HMG-CoA reducatase inhibitors) may be selected from the group consisting of Atorvastatin (Lipitor™, Pfizer Inc.), Provastatin (Pravachol™, Bristol-Myers Squibb), Lovastatin (Mevacor™, Merck Inc.), Simvastatin (Zocor™, Merck Inc.), Fluvastatin (Lescol™, Novartis), Cerivastatin (Baycol™, Bayer), Rosuvastatin (Crestor™, AstraZeneca), Lovostatin and Niacin (Advicor™, Kos Pharmaceuticals), derivatives and combinations thereof.
In a preferred embodiment the statin is selected from the group consisting of Atovorstatin and Lovastatin, derivatives and combinations thereof. Other agents useful as anti-tumor agents include Caduet. Methods of Preparation
Compounds of the present invention may be prepared using the reaction routes and synthetic schemes described below, employing the techniques available in the art using starting materials that are readily available. The preparation of certain embodiments of the present invention is described in detail in the following examples, but those of ordinary skill in the art will recognize that the preparations described may be readily adapted to prepare other embodiments of the present invention. For example, the synthesis of non-exemplified compounds according to the invention may be performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions. Alternatively, other reactions referred to herein or known in the art will be recognized as having adaptability for preparing other compounds of the invention.
In one general synthetic process, compounds of the general structure represented by 6 are prepared according to Method A.
Method A
R3X, base
X = N or C
Reaction of an aryl or heteroaryl ester (1) with the lithium anion of a methyl-substituted pyridine or pyrimidine (2) leads to formation of a ketone represented by formula 3. Ketone 3 can be further transformed to pyrazoles represented by formula 5 through a two step sequence involving enamine formation using N,N-dimethylformamide dimethyl acetal (DMF/DMA) followed by reaction with hydrazine. Introduction of the R3 group on the pyrazole nitrogen can be accomplished through N-alkylation of a suitable alkyl halide (R3X), using a suitable base such as K2CO3, NaOH, DBU, NaH, LiHMDS, or Cs2CO3. During the alkylation reaction, two regioisomeric pyrazoles are usually formed. Pyrazoles represented by 6 can be separated and purified by silica gel chromatography or preparative HPLC and identified using NMR experiments including nuclear Overhauser effect spectroscopy. In the cases where the R1 aryl ring bears a protected phenol, the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl. Various methods for phenol deprotection can be employed. These methods are known to those skilled in the art (e.g. see T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3rd Edition 1999, John Wiley & Sons).
In another general synthetic process, compounds of the general structure represented by 9 are prepared according to Method B.
Method B
Reactive intermediates represented by 8 are prepared using Method A where R2 = a suitable leaving group (LG) in the 2-position of the pyridine or pyrimidine ring. Suitable leaving groups include groups such as bromo, chloro, fluoro and methylsulfonyl. After the preparation of 8, displacement of the leaving group can be accomplished using primary or secondary amines in a suitable solvent such as THF, ethanol, 2-propanol, toluene or xylenes at elevated temperatures to afford 2-amino heterocycles represented by 9. In the cases where the R1 aryl ring bears a protected phenol, the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or methycyclopropane. Various methods for phenol deprotection can be employed and are known to those skilled in the art (e.g. see T. Greene and P. Wuts, "Protective Groups in Organic Synthesis", 3rd Edition 1999, John Wiley & Sons).
In another general synthetic process, compounds of the general structure represented by 16 and 17 are prepared according to Method C. Preparation of isoxazole 11 is accomplished via the Vilsmeier reaction on 4-methylpyrimidine or picoline followed by condensation with hydroxylamine. Ring-opening of the isoxazole with aqueous sodium hydroxide is followed by condensation with hydrazine to afford aminopyrazole 13. A Sandmeyer reaction converts the amino group to an iodopyrazole (14) and, prior to the Suzuki coupling reaction, the pyrazole NH is either alkylated with a preferred R3 group or protected with tetrahydropyranyl (THP) group to afford 15. A Suzuki coupling reaction of 15 with a boronic acid or boronic ester completes the synthesis of compounds represented by 16. In the case where the THP protecting group is used, it is removed under acidic conditions to afford 17. In the cases where the R1 ring bears a protected phenol, the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl. Various methods for phenol deprotection can be employed as discussed previously. Method C
In another general synthetic process, compounds of the general structure represented by 20 and 22 are prepared according to Method D. Reaction of ketone 3 with carbon disulfide and dibromomethane in the presence of a suitable base such as Na2CO3, K2CO3 or Cs2CO3 in a solvent such as DMF or acetone affords dithietane 18. Reaction of 18 with amines at elevated temperatures in a suitable solvent such as toluene or xylenes affords vinylogous amide 19. Reaction of the thiol with an alkyl halide such as methyl iodide under basic conditions is followed by pyrazole formation using either hydrazine or substituted hydrazines to afford 5-aminopyrazoles such as 20. Intermediate 18 can also be reacted with sodium or potassium alkoxides to afford vinylogous ester 21 and these intermediates undergo the same sequence to afford 5-alkoxypyrazoles such as 22. In the cases where the R1 aryl ring bears a protected phenol, the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl. Various methods for phenol deprotection can be employed as discussed previously.
Method D
1) CH3I, base
2) NH2NHR6
In another general synthetic process, compounds represented by 27 are prepared according to Method E. Reaction of a methyl or ethyl ester with the lithium anion of a methyl-substituted pyridine or pyrimidine (2) leads to formation of a ketone represented by formula 23. Ketone 23 can be transformed to 3,4,5-trisubstituted pyrazoles by tosylhydrazone formation followed by N-acylation of the tosylhydrazone with acid chlorides to form intermediates such as 25. The addition of 6 N HCI to 25 followed by gentle warming initiates a cyclization reaction and tosyl hydrazone elimination to form pyrazole 26. Introduction of the R4 group on the pyrazole nitrogen can be accomplished through N-alkylation of a suitable alkyl halide (R3X), using a suitable base such as K2CO3, NaOH, DBU, NaH or Cs2CO3. In the cases where the R1 aryl ring bears a protected phenol, the protecting group can be methyl, trityl, benzyl, p-methoxybenzyl, tetrahydropyranyl, or cyclopropylmethyl. Various methods for phenol deprotection can be employed as described previously.
Method E
Rt
TsNHNH,
Toluene, reflux Dean-Stark Trap 24 1) LHMDS, THF
2 2) R3COCI X = N or C
R3
R oiVγN s
27 26
25 Examples
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. Examples 1 to 25 provide detailed synthetic steps for preparing several specific compounds of the present invention. Table 1 shows additional compounds that were prepared as Examples 26 to 30, and 32 to 127 using the methods described herein. Table 2 shows the biochemical and cellular data for the compounds of Examples 1 30, and 32 to 127. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations. In the following examples molecules with a single chiral center, unless otherwise noted or indicated by the structural formula or chemical name, exist as a racemic mixture. Those molecules with two or more chiral centers, unless otherwise noted or indicated by the structural formula or chemical name, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers may be obtained by methods known to those skilled in the art.
Various starting materials and other reagents were purchased from commercial suppliers, such as Aldrich Chemical Company, and used without further purification, unless indicated otherwise. 1H-NMR spectra were recorded on a Bruker instrument operating either at 300 MHz, or 400 MHz and 13C-NMR spectra were recorded operating at 75 MHz. NMR spectra were obtained as CDCI3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or DMSO-D6 (2.50 ppm and 39.51 ppm) or CD3OD (3.4 ppm and 4.8 ppm and 49.3 ppm), or internal tetramethylsilane (0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are reported in Hertz (Hz). The following abbreviations may be used herein: Et2θ (diethyl ether); DMF (Λ/,Λ/-dimethylformamide); THF (tetrahydrofuran); DCM (dichloro-methane); DMA (dimethyl acetal); DBU (1 ,8- Diazabicyclo[5.4.0]undec-7-ene); LiHMDS or LHMDS (lithium hexamethyldisilazide); TBME (ferf-butyl methyl ether); LDA (Lithium Diisopropylamide); DMSO (dimethylsulfoxide); MeOH (methanol); EtOH (ethanol); EtOAc (ethyl acetate); THF (tetrahydrofuran); Ac (acetyl); Me (methyl); Et (ethyl); and Ph (phenyl).
Example 1 : 3-chloro-5-(4-pyridin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method A. To a mixture of 4-picoline
(5.55 mL, 57.0 mmol) and methyl 4-chloro-3-methylbenzoate (9.37 g, 50.9 mmol) in THF (20 mL) in a water bath at 20 0C was slowly added lithium bis(trimethylsilylamide) (100 mL of a 1M solution in THF, 100 mmol) to maintain the temperature at 20 0C. The reaction was stirred overnight. The reaction mixture was quenched with saturated aqueous NH4CI. Ethyl acetate was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine, dried with Na2SO4, and concentrated to furnish 1-(3-chloro-5- methoxyphenyl)-2-(pyridin-4-yl)ethanone (12.2 g, 98%). 1-(3-chloro-5-methoxyphenyl)-2-(pyridin-4- yl)ethanone (5.62 g, 22.9 mmol) was added to dimethylformamide dimethyl acetal (20 mL) and the mixture was stirred at room temperature for 18 hours. The resulting solution was concentrated to dryness to furnish 6.3 g of an oil which was used in the next step without any purification. To a portion of the oil from the previous step (0.137 g, 0.457 mmol) in ethanol (10 mL) was added hydrazine monohydrate (0.044 mL, 0.91 mmol) and the reaction was stirred overnight at ambient temperature. Water (20 mL) was added to the reaction mixture and the organics were extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give 4-(3-(3-chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl)pyridine (0.097 g, 74%). 4-(3-(3-chloro-5- methoxyphenyl)-1 H-pyrazol-4-yl)pyridine (0.097 g, 0.34 mmol) was taken up in CH2CI2 (5 mL) and cooled to -78 0C under nitrogen. Boron tribromide (0.5 mL of a 1M solution in CH2CI2, 0.50 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 48 hours. Additional boron tribromide (0.5 mL of a 1M solution in CH2CI2, 0.50 mmol) was added and the reaction stirred at ambient temperature for an additional 24 hours. Saturated aqueous NaHCO3 was added to quench the reaction. The precipitate that was formed was collected and dried to give a solid (65 mg, 70%). 1H NMR (400 MHz, DMSO-D6) δ ppm 6.58 - 7.06 (m, 3 H), 7.27 (m, 2 H), 7.91 (s, 0.45 H), 8.21 (s, 0.55 H), 8.36 - 8.70 (m, 2 H), 9.99 (s, 0.55 H), 10.20 (s, 0.45 H), 13.24 - 13.60 (m, 1 H). HRMS m/z Calcd for C14H10N3OCI [M+H]+ 272.05852 Found: 272.05794. Example 2: 3-chloro-5-(1-isopropyl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method A. To an 8% (v:v) solution of trifluoroacetic acid in dichloromethane (10 mL) was added 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl- 1H-pyrazol-4-yl]pyrimidine (242 mg, 0.43 mmol) and triethylsilane (80 μL, 58 mg, 0.5 mmol). The mixture was stirred at ambient temperature for 15 hours, then cautiously poured into saturated aqueous sodium hydrogen carbonate (40 mL). After stirring for an additional 45 minutes, the layers were separated and the aqueous phase extracted with dichloromethane (2 x 25 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to give a yellow solid. This residue was purified by silica gel chromatography using 30 to 80% ethyl acetate in hexanes to provide the title compound (104 mg, 76%). 1H NMR (300 MHz, DMSO-D6): δ 9.98 (1 H, s), 9.05 (1 H, s), 8.65 (1H, d, J = 4.9 Hz), 8.46 (1H, s), 7.35 (1H, d, J = 4.9 Hz), 6.96 (1 H, s), 6.85 (1H, s), 6.81 (1H, s), 4.58 (1H, septet, J = 6.8 Hz), 1.48 (6H, d, J = 6.8 Hz). Calcd for C16H15N4OCI-0.1 Et2O«0.1 EtOAc: C 60.96, H 5.12, N 16.93, Cl 10.71. Found: C 60.90, H 4.99, N 17.03, Cl 10.75. Prepration a-2-a 4-r-3-(3-chloro-5-trityloxyphenvh-1-isopropyl-1 H-pyrazol-4-yllpyrimidine
To a solution of 4-[-3-(3-chloro-5-trityloxyphenyl)-1H-pyrazol-4-yl]pyrimidine (400 mg, 0.80 mmol) and 2-iodopropane (0.15 ml_, 255 mg, 1.5 mmol) in Λ/,Λ/-dimethylformamide (5 mL) was added cesium carbonate (353 mg, 1.1 mmol). The resulting mixture was heated at 50 0C for 16 hours. After cooling to ambient temperature, the crude reaction mixture was poured into water (30 mL). The precipitate that formed was collected by filtration and washed with water (3 x 10 mL) to provide a brown solid. This residue was purified by silica gel chromatography using 0 to 50% ethyl acetate in hexanes to provide the title compound (177 mg, 41 %). 1H NMR (300 MHz, DMSO-D6): δ ppm 8.92 (1 H, d, J = 1.3 Hz), 8.57 (1 H, d, J = 5.5 Hz), 8.39 (1H, s), 7.39 - 7.21 (15H, m), 7.17 (1H, dd, J = 1.3, 5.5 Hz), 7.06 (1H, t, J = 1.9 Hz),
6.85 (1 H, t, J = 1.9 Hz), 6.64 (1 H, t, J = 1.9 Hz), 4.52 (1 H, septet, J = 6.6 Hz), 1.44 (6H, d, J = 6.6 Hz).
Preparation a-2-b 4-f-3-(3-chloro-5-trityloxyphenyl)-1 H-pyrazol-4-vnpyrimidine
To a solution of 1-(3-chloro-5-trityloxyphenyl)-2-(pyrimidin-4-yl)ethanone (1.51 g, 3.0 mmol) in tetrahydrofuran (25 mL) was added Λ/,Λ/-dimethylformamide dimethylacetal (1.2 mL, 1.08 g, 9.0 mmol). The resulting mixture was stirred at ambient temperature for 2 days. The solvent and any other volatiles were removed by concentration, in vacuo. The crude 1-(3-chloro-5-trityloxyphenyl)-3-(dimethylamino)-2- (pyrimidin-4-yl)propenone thus obtained was dissolved in ethanol (25 mL). Hydrazine hydrate (0.3 mL, 310 mg, 6.2 mmol) was added and the resulting solution was stirred overnight at ambient temperature. The solvent was removed by concentration, in vacuo, and the residue obtained was partitioned between water (50 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organics were dried (anhydrous sodium sulfate), filtered and concentrated to dryness. The residue obtained was purified by silica gel chromatography using 0 to 10% methanol in chloroform to provide the title compound (1.39g, 88%). 1H NMR (300 MHz DMSO-D6): δ ppm 8.91 (1H, s), 8.57 (1 H, d, J = 5.4 Hz), 8.36 (1 H, s), 7.39 - 7.11 (16H, m), 7.05 (1 H, s), 6.81 (1 H, s), 6.68 (1 H, s). Preparation a-2-c 1-(3-chloro-5-trityloxyphenyl)-2-(pvrimidin-4-vl)ethanone
A solution of methyl 3-chloro-5-trityloxybenzoate (1.73 g, 4 mmol) and 4-methylpyrimidine (0.4 mL, 412 mg, 4.4 mmol) in tetrahydrofuran (30 mL) was cooled to -5 0C under an argon atmosphere. To this mixture was added a 1.0 M solution of lithium bis(trimethylsilyl) amide in tetrahydrofuran (12 mL, 12 mmol). The cooling bath was removed and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction was quenched upon the cautious addition of saturated aqueous ammonium chloride
(50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organics were dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 20 to 80% ethyl acetate in hexane to provide the title compound (1.52 g, 77%). The 1H NMR spectrum obtained for this intermediate indicated that this material was a mixture of keto and enol tautomers.
Example 3: 3-chloro-5-(1-ethyl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 4-[-3-(3-chloro-5-trityloxyphenyl)-1-ethyl-1 H-pyrazol-4-yl]pyrimidine in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 53% yield. 1H NMR (300 MHz, DMSO-D6): δ ppm 9.98 (1H, s), 9.05 (1H, s), 8.65 (1H1 d, J = 5.1 Hz), 8.44 (1H, s), 7.32 (1H, d, J = 5.1 Hz), 6.96 (1H, s), 6.84 (1H, s), 6.81 (1H, s), 4.22 (2H1 q, J = 7.1 Hz), 1.44 (3H, t, J = 7.1 Hz). Calcd for C15H13N4OCLCI MeOH: C 59.67, H 4.44, N 18.43. Found: C 59.52, H 4.40, N 18.30.
Preparation a-3-a 4-r-3-(3-chloro-5-trityloxyphenyl)-1-ethyl-1 H-pyrazol-4-yllpyrimidine
Following the procedure described in Preparation a-2-a, using 2-iodoethane in place of iodopropane at 50 0C, the title compound was obtained in 43% yield. 1H NMR (300 MHz, DMSO-D6): δ ppm 8.92 (1 H, s), 8.57 (1 H, d, J = 4.9 Hz), 8.38 (1H, s), 7.39 - 7.20 (15H, m), 7.15 (1 H, d, J = 4.9 Hz), 7.05 (1 H, t, J = 1.5 Hz), 6.83 (1 H, t, J = 1.5 Hz), 6.66 (1 H, t, J = 1.5 Hz), 4.21 (1 H, q, J = 7.1 Hz), 1.44
(6H, t, J = 7.1 Hz).
Example 4: 3-chloro-2-methyl-5-(1-pyridin-2-yl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 4-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-1-(pyridin-2-yl)-1 H-pyrazol-4- yl)pyrimidine in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 58% yield. 1H NMR (300 MHz, DMSO-D6): δ ppm 10.04 (1H,s), 9.21 (1H, s), 9.14 (1 H, d, J = 1.32 Hz), 8.76 (1 H, d, J = 5.27 Hz), 8.56 (1 H, d, J = 4.71 Hz), 8.02-8.10 (2H, m), 7.60 (1 H, dd, J = 5.27 and 1.32 Hz), 7.48-7.44 (1 H, m), 7.15 (1 H, d, J = 1.51 Hz), 7.01 (1H, d, J = 1.51 Hz), 2.22 (3H, s); HRMS m/z Calcd for C19H14N5OCI [M+H]+ 364.09596 Found: 364.09572; Elemental Analysis: Calcd for C19H14N5OCI: C 62.73, H 3.88, N 19.25. Found: C 62.76, H 3.95, N 18.98. Preparation a-4-a
4-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-1-(pyridin-2-yl)-1H-pyrazol-4-vl)pvrimidine
To a solution of 4-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-1H-pyrazol-4-yl)pyrimidine (120 mg, 0.23 mmol) and 2-fluoropyridine (56 mg, 0.58 mmol) in Λ/,Λ/-dimethylformamide (3 mL) was added cesium carbonate (111 mg, 0.340 mmol). The resulting mixture was heated at 80 0C for 16 hours. After cooling to ambient temperature, the crude reaction mixture was concentrated under vacuum and the resulting residue was purified by silica gel chromatography using 0 to 50% ethyl acetate in CHCI3 to provide the title compound (122 mg, 89%). HRMS m/z Calcd for C38H28N5OCI [M+Hf 606.20551 Found: 606.20421.
Preparation a-4-b 4-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-1H-pyrazol-4-yl)pyrimidine
Following the procedure described in Preparation a-2-b using 1-(3-chloro-4-methyl-5- (trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone in place of 1-(3-chloro-5-trityloxyphenyl)-2-(pyrimidin-4- yl)ethanone provided the title compound in 86% yield. 1H NMR (300 MHz, DMSO-D6): δ ppm 8.88 (1 H, s), 8.52 (1 H, d, J = 5.27 Hz), 8.16 (1H, s), 7.46 - 7.17 (16H, m), 7.09 (1 H, s), 6.98 (1 H, dd, J = 5.27 and 1.32 Hz), 6.57 (1H, s), 2.30 (3H, s); HRMS m/z Calcd for C33H25N4OCI [M+H]+ 529.17897 Found: 529.17902.
Preparation a-4-c 1-(3-chloro-4-methyl-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone
Following the procedure described in Preparation a-2-c, using ethyl 3-chloro-4-methyl-5- (trityloxy)benzoate in place of methyl 3-chloro-5-trityloxybenzoate provided the title compound in quantitative yield. The 1H NMR spectrum obtained for this intermediate indicated that this material was a mixture of keto and enol tautomers. APCI m/z: 505 [M+H]+.
Example 5: 2-[3-(3-chloro-5-hydroxy-4-methylphenyl)-4-pyrimidin-4-yl-1H-pyrazol-1- yl]propanenitrile
The above compound was prepared as follows according to Method A. Following the procedure described in Example 2, using 2-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-4-(pyrimidin-4-yl)-1H-pyrazol-1- yl)propanenitrile in place of 4-[-3-(3-chloro-5-trityloxyphenyl)-1-isopropyl-1 H-pyrazol-4-yl]pyrimidine at ambient temperature, the title compound was obtained in 37% yield. 1H NMR (300 MHz, DMSO-D6): δ ppm 9.99 (1H, s), 9.12 (1 H, d, J = 1.32 Hz), 8.71 (1H, d, J = 5.27 Hz), 8.60 (1H, s), 7.37 (1H, dd, J = 5.37 and 1.41 Hz), 7.02 (1H, d, J = 1.32 Hz), 6.94 (1H, d, J = 132 Hz), 5.97 (1 H, q, J = 7.16 Hz), 2.20 (3H, s), 1.88 (3H, d, J = 7.16 Hz); HRMS m/z Calcd for C17H14N5OCI [M+H]+ 340.09596 Found: 340.09607.
Preparation a-5-a 2-(3-(3-chloro-4-methyl-5-(trityloxy)phenyl)-4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile
Following the procedure described in Preparation a-4-a using 2-bromopropionitrile instead of 2- fluoropyridine at 50 0C instead of 80 °C to give the title compound. This partially purified residue was used directly for the subsequent reaction. Example δ: 3-chloro-5-(1-piperidin-4-yl-4-pyrimidin-4-yl-1 H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method A. To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1H-pyrazol-4-yl]pyrimidine, (0.31 g, 1.1 mmol), prepared in the same way as in Example 1 except using 4-methylpyrimidine in place of picoline, and cesium carbonate (1.1 g, 3.2 mmol) in N,N-dimethylformamide (11 mL) was added tert-butyl 4-hydroxypiperidine-1-carboxylate (0.30 g, 1.1 mmol). The mixture was stirred at 70 0C for 16 hours then concentrated to dryness to furnish 0.50 grams of an oil which was used in the next step without any purification. A mixture of tert-butyl 4-[3-(3-chloro-5- methoxyphenyl)-4-pyrimidin-4-yl-1 H-pyrazol-1-yl]piperidine-1-carboxylate (0.50 g, 1.1 mmol) and a 48 % hydrobromic acid solution (25 mL) was stirred at 100 0C for 6 hours. After cooling to ambient temperature, the mixture was made neutral with solid sodium hydroxide and concentrated to dryness. The residue was treated with a 10% methanol in dichloromethane solution, solids filtered and rinsed with the 10% methanol in dichloromethane solution, and filtrate concentrated to dryness. The residue was purified by high performance liquid chromatography to provide the title compound (0.10 g, 27 %). 1H NMR (300 MHz, DMSO-D6) δ 2.35 - 2.49 (m, 2 H), 3.32 - 3.50 (m, 3 H), 3.63 - 3.69 (m, 1 H), 5.22 - 5.32.(m, 1 H), 6.85 - 6.90 (m, 2 H), 7.06 - 7.08 (m, 1 H), 7.37 (dd, J = 5.7, 1.4 Hz, 1 H), 8.61 (s, 1 H), 8.71 (d, J = 5.5 Hz, 1 H), 9.11 (d, J = 1.3 Hz, 1 H).
Example 7: S-chloro-S^I-P-fcyclopropylaminoJpropyy^-pyrimidin^-yl-IW-pyrazol-S-ylJphenol
The above compound was prepared as follows according to Method A. To a mixture of 4-[3-(3- chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl]pyrimidine (1.0 g, 3.5 mmol) in N,N-dimethylformamide (23 mL) was added lithium bis(trimethylsilyl)amide (3.8 mL, 3.8 mmol) (1 M solution in tetrahydrofuran) dropwise. After stirring for 20 minutes, 1-chloro-3-iodopropane (1.1 mL, 11 mmol) was added and the mixture was allowed to stir for 16 hours. The mixture was diluted with ethyl acetate (50 mL), washed with water (3 X 100 mL), dried (anhydrous magnesium sulfate), filtered, and concentrated to dryness to furnish 1.2 grams of an oil which was used in the next step without any purification. A mixture of 4-[3-(3-chloro-5- methoxyphenyl)-1-(3-chloropropyl)-1 H-pyrazol-4-yl]pyrimidine (0.21 g, 0.58 mmol), cyclopropanamine (0.41 mL, 5.8 mmol), and methanol (5 mL) were stirred at 120 0C for 30 minutes in a microwave reactor. The mixture was concentrated to dryness to furnish 0.22 grams of an oil which was used in the next step without any purification. A mixture of N-{3-[3-(3-chloro-5-methoxyphenyl)-4-pyrimidin-4-yl-1H-pyrazol-1- yl]propyl}cy.clopropanamine (0.22 g, 0.58 mmol) and a 48% aqueous HBr (6.0 mL) was stirred at 100 0C for 6 hours. After cooling to ambient temperature, the mixture was made neutral with solid sodium hydroxide and concentrated to dryness. The residue was treated with a 10% methanol in dichlororhethane solution, solids filtered and rinsed with the 10% methanol in dichloromethane solution, and filtrate concentrated to dryness. The residue was purified by high performance liquid chromatography to provide the title compound (0.010 g, 5%). 1H NMR (400 MHz, DMSO-D6) δ 0.62 - 0.70 (m, 4 H), 2.11 - 2.19 (m, 2 H), 2.60 - 2.67 (m, 1 H), 2.94 - 3.00 (m, 2 H), 4.27 - 4.34 (m, 2 H), 6.84 - 6.87 (m, 2 H), 6.98 - 7.00 (m, 1 H), 7.33 (dd, J = 5.7, 1.3 Hz, 1 H), 8.48 (s, 1 H), 6.86 (d, J = 5.3 Hz, 1 H), 9.09 (d, J = 1.0 Hz, 1 H), 10.03 (s, 1 H). Example 8: 3-[4-(2-anilinopyrimidin-4-yl)-1-methyl-1H-pyrazol-3-yl]-5-chlorophenol
The above compound was prepared as follows according to Method B. Boron tribromide (0.52 g. 2.1 mmol) was added to a solution of 4-[-3-(3-chloro-5-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl]-2-(N- phenylamino)pyrimidine (249 mg, 0.64 mmol) in dichloromethane (20 mL) at 0 0C. The cooling bath was removed and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction was quenched upon addition of an ice/water mixture (20 mL) and ethyl acetate (20 mL). Aqueous dimethylamine (40%, 2 mL) was added and the mixture was stirred for 40 minutes. The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 30 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to give an oil which was crystallized from dichloromethane to provide the title compound as a yellow solid (103 mg, 43%). 1H NMR (300 MHz, DMSO-D6): δ ppm 9.95 (1 H, s), 9.48 (1H, s), 8.36 (1H, d, J = 5.1 Hz), 8.26 (1H, s), 7.54 (2H, dd, J = 7.3, 7.6 Hz), 7.14 (2H, d, J = 7.6 Hz), 6.93 (1H, dd, J = 1.5, 1.7 Hz), 6.86 (1 H, t, J = 7.3 Hz), 6.82 (1H, dd, J = 1.5, 2.1 Hz), 6.78 (1H, dd, J = 1.7, 2.1 Hz), 6.70 (1 H, d, J = 5.1 Hz), 3.93 (3H, s).
Preparation b-1-a 4-f-3-(3-chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-yl1-2-(N-phenylamino)pvrimidine
A solution of 4-[-3-(3-chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-yl]-2-
(methanesulfonyl)pyrimidine (249 mg, 0.66 mmol) in aniline (1.5 mL) was heated at 180 0C for one hour. After cooling to ambient temperature, the crude mixture was purified by silica gel chromatography using 40 to 60% ethyl acetate in hexane to provide the title compound (154 mg, 56%). 1H NMR (400 MHz, CDCI3): δ ppm 8.25 (1H, d, J = 5.1 Hz), 7.96 (1H, s), 7.55 (2H, dd, J = 7.3, 7.6 Hz), 7.31 (2H1 d, J = 7.6 Hz), 7.17 (1H, dd, J = 1.5, 1.8 Hz), 7.02 (1H, t, J = 7.3 Hz), 6.97 (1 H, dd, J = 1.5, 2.1 Hz), 6.92 (1 H, dd, J = 1.8, 2.1 Hz), 6.60 (1H, d, J = 5.1 Hz), 3.99 (3H, s), 3.77 (3H,s).
Preparation b-1-b
4-f-3-(3-chloro-5-methoxyphenyl)-1-methyl-1H-pyrazol-4-vn-2-(methanesulfonyl)pvrimidine
To a solution of 4-[-3-(3-chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-yl]-2-
(methanesulfanyl)pyrimidine (1.00 g, 2.89 mmol) in dichloromethane (20 mL) was added meta- chloroperbenzoic acid at 0 0C. The mixture was stirred at 0 0C for one hour, then for an additional hour at room temperature. The mixture was, again, cooled to 0 0C prior to addition of dimethylsulfoxide (250 mg, 3.24 mmol). After 10 minutes the reaction was washed with aqueous saturated NaHCO3 (3 x 30 mL).
The organic layer was dried (anhydrous sodium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography using 25% heptane in ethyl acetate to provide the title compound
(1.09 g, 99%). 1H NMR (400 MHz, CDCI3): δ ppm 8.63 (1 H, d, J = 5.3 Hz), 8.24 (1 H, s), 7.27 (1 H, d, J =
5.3 Hz), 7.08 (1 H, t, J = 1.4 Hz), 6.98 (1 H, t, J = 1.4 Hz), 6.92 (1 H, t, J = 1.4 Hz), 4.01 (3H, s), 3.82 (3H,s), 3.30 (3H, s).
Preparation b-1-c 4-f-3-(3-chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-vn-2-(methanesulfanvl)pvrimidine
A solution of potassium fe/t-butoxide (354 mg, 3.16 mmol) in N-methylpyrrolidine (3 mL) was added to a solution of 4-[-3-(3-chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl]-2-(methanesulfanyl)pyrimidine
(1.00 g, 3.01 mmol) in N-methylpyrrolidine (5 mL) at 0 0C. This was followed by addition of iodomethane
(0.225 mL, 513 mg, 3.61 mmol) in a single portion as the neat liquid. After stirring at 0 0C for an additional hour, the cooling bath was removed and the reaction was left to stir overnight. The mixture was pored into ice water, then extracted with ether (2 x 20 mL) and ethyl acetate (10 mL). The combined organic layers were washed with brine (3 x 20 mL), dried (anhydrous sodium sulfate), filtered and concentrated.
The residue was purified by silica gel chromatography using te/f-butylmethylether to provide the title compound (509 mg, 49%). 1H NMR (400 MHz, CDCI3): δ ppm 8.31 (1 H, d, J = 5.3 Hz), 8.04 (1 H, s), 7.13 (1H, t, J = 1.5 Hz), 6.94 (2H, d, J = 1.5 Hz), 6.79 (1H, d, J = 5.3 Hz), 3.99 (3H, s), 3.79 (3H, s), 2.50 (3H, s).
Preparation b-1-d 4-f-3-(3-chloro-5-methoxyphenyl)-1 H-pyrazol-4-yll-2-(methanesulfanvl)pvrimidine
Following the procedure described in Preparation a-2-b, using 1-(3-chloro-5-methoxyphenyl)-2-[2- (methylthio)pyrimidin-4-yl]ethanone in place of 1-(3-chloro-5-trityloxyphenyl)-2-(pyrimidin-4-yl)ethanone, by sequential treatment with Λ/,Λ/-dimethylformamide dimethylacetal and hydrazine hydrate at ambient temperature, the title compound was obtained in 82% yield. 1H NMR (400 MHz, DMSO-D6): δ ppm 13.52 (1 H, s), 8.49 (1 H, d, J = 5.3 Hz), 8.44 (1 H, s), 7.23 (1H, d, J = 5.3 Hz), 7.18 (1 H, s), 7.08 (2H, s), 3.79 (3H, s), 2.26 (3H, s).
Preparation b-1-e 1-(3-chloro-5-trityloxyphenyl)-2-(pyrimidin-4-yl)ethanone
Following the procedure described in Preparation a-2-c, using methyl 3-chloro-5- methoxybenzoate in place of methyl 3-chloro-5-trityloxybenzoate and 4-methyl-2-(methylthio)pyrimidine in place of 4-methylpyrimidine, the title compound was obtained in 82% yield. 1H NMR (300 MHz, CDCI3): δ ppm 8.31 (1 H, d, J = 5.4 Hz), 7.38 (1 H, t, J = 1.6 Hz), 7.25 (1H, t, J = 1.6 Hz), 6.94 (1 H, t, J = 1.6 Hz), 6.64 (1 H, d, J = 5.4 Hz), 5.92 (2H, s), 3.84 (3H,s), 2.60 (3H, s). Example 9: 3-chloro-5-{1-methyl-4-[2-(methylamino)pyrimidin-4-yl]-1H-pyrazol-3-yl}phenol
The above compound was prepared as follows according to Method B. BBr3 (0.20 ml_, 0.52 g, 2.1 mmol) was added to a solution of {4-[3-(3-chloro-5-methoxy-phenyl)-1-methyl-1 H-pyrazol-4-yl]-pyrimidin-
2-yl}-methyl-amine (190 mg, 0.577 mmol) in CH2CI2 (5 mL) at 0 0C under an argon atmosphere, and the reaction mixture was stirred at room temperature for 5 hours. Ice (~10 mL), water (2 mL) and EtOAc (30 mL) were added to the reaction mixture. Aqueous dimethylamine (40%, ~1.5 mL) was added until a basic reaction on pH paper. The mixture was stirred for 1 hour, the layers were separated and the water layer was extracted with EtOAc (2 x 10 ml_). The combined organic layers were washed with brine (10 ml_) dried (Na2SO4) and concentrated in vacuo to give an oil (264 mg). The compound was crystallized from CH2CI2/Me0H (~1 mL, 95:5), to give 3-chloro-5-[1-methyl-4-(2-methylamino-pyrimidin-4-yl)-1 H-pyrazol-3- yl]-phenol (132 mg, 73%) as an off-white solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.90 (s, 1 H) 8.17 - 8.36 (m, 1 H) 8.13 (d, J=5.05 Hz, 1 H) 7.00 (s, 1 H) 6.82 - 6.96 (m, 2 H) 6.76 (t, J=2.02 Hz, 1 H) 6.45 (s, 1 H) 3.90 (s, 3 H) 2.69 (s, 3 H). MS (m/z) = 316.6
Preparation of b-2-a
4-(3-(3-chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-yl)-N-methylpyrimidin-2-amine
Aqueous methylamine (40% w/w, 0.57 mL, 6.6 mmol) was added to a solution of 4-[3-(3-chloro-5- methoxy-phenyl)-1-methyl-1 H-pyrazol-4-yl]-2-methanesulfonyl-pyrimidine (as obtained in Preparation b-1- b) (250 mg, 0.661 mmol) in dioxane (5 mL). The reaction mixture was stirred in a high pressure vessel at 85 0C overnight, allowed to cool to room temperature, and concentrated in vacuo. Flash column chromatography on silica (EtOAc) gave an oil, which was evaporated from Et2O (2 x 5 mL) to 4-(3-(3- chloro-5-methoxyphenyl)-1-methyl-1 H-pyrazol-4-yl)-N-methylpyrimidin-2-amine as a white foam (194 mg, 89%). 1H NMR (CDCI3, 300 MHz): δ ppm 8.31 (1 H, d, J = 5.0 Hz), 7.93 (1 H, s), 7.19 (1H, dd, J = 1.5, 1.9 Hz), 6.99 (1 H, dd, J = 1.5, 2.2 Hz), 6.91 (1H, dd, J = 1.9, 2.2 Hz), 6.42 (1 H, d, J = 5.0 Hz), 5.02 (1 H, d, J = 4.8 Hz), 3.98 (3H, s), 3.78 (3H, s), 2.98 (3H, d, J = 4.8 Hz). Example 10: 3-chloro-5-[4-(2-{[2-(dimethylamino)ethyl]amino}pyrimidin-4-yl)-1-ethyl-1 H-pyrazol-3- yl]phenol
The above compound was prepared as follows according to Method B. To a solution of 4-(3-(3- chloro-5-methoxyphenyl)-1-ethyl-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine (as prepared in Preparation b-1-b) (100 mg, 0.255 mmol) in THF (4 mL) was added N1,N1-dimethylethane-1 ,2-diamine (2.5 mmol). The reaction was heated at 95 0C for 3.5 hours. The reaction was concentrated under vacuum to an oily residue. The residue was dissolved in HBr (37% aq., 4 mL) and heated at 95 0C for 18 hours. The reaction volume was reduced to approximately 0.5 mL and then EtOAc (50 mL) was added. The organic layer was washed cautiously with saturated aqueous NaHCO3, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with TBME to give a foam (91 mg). 1H NMR (400 MHz, DMSO-D6) δ ppm 9.87 - 10.39 (m, 1 H) 8.28 (s, 1 H) 8.14 (d, J=5.05 Hz, 1 H) 6.85 - 7.04 (m, 2 H) 6.76 (t, J=2.02 Hz, 2 H) 6.30 - 6.62 (m, 1 H) 4.19 (q, J=7.24 Hz, 2 H) 3.18 - 3.31 (m, 2 H) 2.24 - 2.43 (m, J=11.37 Hz, 2 H) 2.13 (s, 6 H) 1.42 (t, J=7.20 Hz, 3 H). ). Elemental Analysis: Calcd for C19H23CIN6O 0.85 H2O- 0.25 TBME C 57.33, H 6.58, N 19.81. Found: C 57.19, H 6.32, N 19.80.
Preparation b-3-a 4-(3-(3-Chloro-5-methoxyphenyl)-1-ethyl-1/-/-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine
To a solution of 4-[-3-(3-chloro-5-methloxyphenyi)-1 H-pyrazol-4-yl]-2-(methylsulfonyl)pyrimidine,
(as prepared in Preparation b-1-b) (1.00 g, 2.75 mmol) in ty/V-dimethylformamide (10 ml_) was added iodoethane (2.20 mL, 27.5 mmol). The resulting mixture was heated at 60 0C for 27 hours. Another portion of iodoethane (2.20 mL, 27.5 mmol) was added and the mixture was heated at 60 0C for an additional 4 days. After cooling to ambient temperature, the crude reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 15% ethyl acetate in dichloromethane. The purified residue was dissolved in ethyl acetate (100 mL), washed with saturated aqueous sodium thiosulfate (1 x 50 mL), brine (1 x 50 mL), dried (anhydrous magnesium sulfate), and concentrated to dryness to provide the title compound (590 mg, 55%). 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 8.71 (d, J=5.56 Hz, 1 H), 8.32 (s, 1 H), 7.50 (d, J=5.56 Hz, 1 H), 7.14 (t, J=1.52 Hz, 1 H), 7.01 - 7.05 (m, 2 H), 4.25 (q, J=7.33 Hz, 2 H), 3.78 (s, 3 H), 3.11 (s, 3 H), 1.51 (t, J=7.33 Hz, 3 H) Example H: 2-(3-(3-chloro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H- pyrazol-1 -yl)acetonitrile
The above compound was prepared as follows according to Method B. A mixture of 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile (2.00 g, 5.14 mmol) and (S)-(+)-1-aminopropan-2-ol (3.86 g, 51.4 mmol) in anhydrous THF (50 mL) was heated to 80 0C in an oil bath for 1.5 hours. The reaction mixture was diluted with ethyl acetate and methanol until homogeneous and was washed with sodium citrate buffer (1M, pH 4.5), and saturated sodium chloride (2 x 50 mL). The combined aqueous phases were extracted with ethyl acetate (50 mL). The combined organic extracts were washed with brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 7% methanol in a (1 :1) mixture of ethyl acetate and dichloromethane to provide the title compound (1.4 g, 71%). 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 8.15 (d, J=5.31 Hz, 1 H), 8.13 (s, 1 H), 7.49 (br. s, 1 H), 7.09 (t, J=1.52 Hz, 1 H), 6.98 (s, 1 H), 6.88 (t, J=2.02 Hz, 1 H), 6.53 (br. d, J=4.55 Hz, 1 H), 5.78 (br. t, J=5.43 Hz, 1 H), 5.22 (br. s, 2 H), 3.80 (br. s, 1 H), 3.30 (s, 2 H), 3.15 (s, 1 H), 1.06 (d, J=6.06 Hz, 3 H) Calcd for C18H17N6O2CI«0.4 MTBE.0.2 H2O: C 56.69, H 5.28, N 19.84. Found: C 56.66, H 5.29, N 19.67.
Preparation b-4-a 2-(3-(3-Chloro-5-hvdroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile
To a solution of 2-(3-(3-chloro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol- 1-yl)acetonitrile (1.72 g, 4.26 mmol) in dichloromethane (120 mL) was added boron trifluoride-methyl sulfide complex (4.5 mL, 42.6 mmol) dropwise. The resulting suspension was stirred at room temperature for 21 hours. The mixture was concentrated and the residue was partitioned between ethyl acetate and brine. The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organics were dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 50% ethyl acetate in dichloromethane to provide the title compound. (1.27 g, 77%). 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 8.77 (d, J=5.31 Hz, 1 H), 8.41 (s, 1 H), 7.52 (d, J=5.31 Hz, 1 H), 7.41 (d, J=1.01 Hz, 1 H), 7.07 (t, J=1.52 Hz, 1 H), 6.83 - 6.99 (m, 2 H), 5.27 (s, 2 H), 3.15 (s, 3 H).
Preparation b-4-b
2-(3-(3-Chloro-5-methoxyprienyl)-4-(2-(metriylsulfonyl)pyrimidin-4-yl)-1/-/-pyrazol-1-yl)acetonitrile
To the solution of 4-(3-(3-chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfony!)pyrimidine (3.84 g, 10.5 mmol) in 50 mL DMF were added 2-bromoacetonitrile (7.00 mL, 105 mmol) and freshly ground potassium carbonate (1.88 g, 13.7 mmol). The reaction mixture was then heated to 50 0C in an oil bath for 16 hours, and then the crude reaction mixture was partitioned between saturated aqueous sodium chloride (500 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 150 mL). The combined organics were washed with water (150 mL), brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 25% methyl tert-butyl ether in dichloromethane to provide the title compound. (2.94 g, 69%). 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 8.76 (d, J=5.31 Hz, 1 H), 8.43 (s, 1 H), 7.51 (d, J=5.30 Hz, 1 H), 7.14 (d, J=1.77 Hz, 1 H), 7.07 (t, J=2.02 Hz, 1 H), 7.02 (dd, J=2.27, 1.52 Hz, 1 H), 5.27 (s, 2 H), 3.79 (s, 3 H), 3.12 (s, 3 H). Example 12: 2-(3-(3-Chloro-5-hydroxyphenyl-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1H-pyrazol- 1-yl)acetonitrile
The above compound was prepared as follows according to Method B. A mixture of 2-(3-(3- chloro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol-1-yl)acetonitrile (200 mg, 0.510 mmol) and 2-aminoethanol (0.31 mL, 5.1 mmol) were reacted at 80 0C according to Example 11. After a similar work up, the crude residue was purified by reverse phase HPLC to provide the title compound (91 mg, 48%). 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 8.02 - 8.21 (m, 2 H), 7.09 (t, J=1.64 Hz, 1 H), 6.98 (s, 1 H), 6.88 (t, J=2.02 Hz, 1 H), 6.52 (d, J=5.05 Hz, 1 H), 5.79 (br. s, 1 H), 5.22 (s, 2 H), 3.57 (t, J=5.18 Hz, 2 H)1 3.24 - 3.46 (m, 2 H) Calcd for C17H15N6O2CI.0.6 AcOH.0.5 H2O: C 52.57, H 4.46, N 20.21. Found: C 52.78, H 4.37, N 20.02.
Example 13: 3-[3-(3-hydroxy-5-methylphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)- 1 H-py razol-1 -yl]propanenitrile
The above compound was prepared as follows according to Method B. To a solution of 3-(3-(3- hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile (203 mg, 0.53 mmol) in tetrahydrofuran (8 mL) was added (S)-(+)-1-aminopropan-2-ol (0.416 mL, 5.30 mmol). The mixture was then heated at 80 0C for 2 hours and allowed to cool to ambient temperature. The solution was concentrated to dryness. The residue was purified by HPLC to give the title compound (70.5 mg,
35%). 1H NMR (400 MHz, MeOD) δ ppm 1.13 (d, J=6.29 Hz, 3 H), 2.28 (s, 3 H), 3.10 (t, J=6.42 Hz, 2 H),
3.14 - 3.24 (m, J=7.30 Hz, 1 H), 3.37 (dd, J=13.72, 3.90 Hz, 1 H), 3.82 - 3.93 (m, J=4.28 Hz, 1 H), 4.49 (t,
J=6.42 Hz, 2 H), 6.49 (d, J=5.04 Hz, 1 H), 6.67 (s, 1 H), 6.71 (s, 1 H), 6.79 (s, 1 H), 8.04 (d, J=5.29 Hz, 1
H), 8.28 (S, 1 H). HRMS m/z Calcd for C20H22N6O2 [M+H]+ 379.18770 Found: 379.18742. Preparation b-6-a
3-(3-(3-hvdroxy-5-methylphenvπ-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-vπpropanenitrile
To a solution of 3-(3-(3-methyl-5-(trityloxy)phenyl)-4-(2-(methylthio)pyrimidin-4-yl)-1 H-pyrazol-1- yl)propanenitrile (2.2 g, 3.7 mmol) in tetrahydrofuran (37 mL) was added water (27 mL) and Oxone (9.1 g, 15 mmol). The mixture was then heated at 60 0C for 5 hours and allowed to cool to ambient temperature. The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The crude product was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ ppm 2.32 (s, 3 H), 3.15 (t, J=6.42 Hz, 2 H), 3.22 (s, 3 H), 4.55 (t, J=6.55 Hz, 2 H), 6.72 (s, 2 H), 6.82 (s, 1 H), 7.51 (d, J=5.29 Hz, 1 H), 8.63 (s, 1 H), 8.72 (d, J=5.29 Hz, 1 H). Preparation b-6-b 3-(3-(3-methyl-5-(trityloxy)phenv[)-4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile
To a solution of 4-(3-(3-methyl-5-(trityloxy)phenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimiciine (2.0 g, 3.7 mmol) in Λ/,Λ/-dimethylformannide (25 mL) was added 3-bromopropanenitriie (0.46 mL, 5.5 mmol) and cesium carbonate (1.8 g, 5.5 mmol). The mixture was then heated at 70 0C for 18 hours and allowed to cool to ambient temperature. Water was introduced and the aqueous phase extracted with ethyl acetate (3 x 75 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated. The crude product was used in the next step without further purification. 1H NMR (400 MHz, MeOD) δ ppm 2.13 (s, 3 H), 2.38 (s, 3 H), 3.07 (t, J=6.55 Hz, 2 H), 4.45 (t, J=6.55 Hz, 2 H), 6.54 (s, 1 H), 6.58 - 6.64 (m, 2 H), 6.78 (s, 1 H), 7.14 - 7.25 (m, 9 H), 7.36 - 7.42 (m, J=7.55 Hz, 6 H), 8.18 (d, J=5.29 Hz, 1 H), 8.31 (s, 1 H). Preparation b-6-c
4-(3-(3-methyl-5-(trityloxy)phenyl)-1 H-pyrazol-4-yl)-2-(methvlthio)pvrimidine
To a solution of methyl 3-methyl-5-(trityloxy)benzoate (10.0 g, 24.5 mmol) and 4-methyl-2- (methylthio)pyrimidine (3.77 g, 26.9 mmol) in tetrahydrofuran (40 mL) was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (36.8 mL, 36.8 mmol) at 0 0C under nitrogen. The mixture was warmed to ambient temperature and stirred for 18 hours. Saturated aqueous ammonium chloride was introduced and the mixture extracted with ethyl acetate (3 x 150 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to provide 1-(3-methyl-5-(trityloxy)phenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone as a mixture of keto / enol tautomers. To a solution of 1-(3-methyl-5-(trityloxy)phenyl)-2-(2- (methylthio)pyrimidin-4-yl)ethanone (12.6 g, 24.5 mmol) in toluene (42 mL) was added N1N- dimethylformamide dimethyl acetal (33 mL, 245 mmol). The mixture was then heated at 90 0C overnight and allowed to cool to ambient temperature. The solution was concentrated to provide crude 3- (dimethylamino)-1-(3-methyl-5-(trityloxy)phenyl)-2-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one. To 3- (dimethylamino)-1-(3-methyl-5-(trityloxy)phenyl)-2-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one in absolute ethanol (122 mL) was added hydrazine monohydrate (2.4 mL, 49 mmol). The mixture was stirred at ambient temperature for 1 hour. The precipate that formed was filtered and the resulting solid was dried in vacuo to give the title compound (10.3 g, 81% after 3 steps). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.08 (s, 3 H), 2.27 (s, 3 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.73 - 6.80 (m, 2 H), 7.13 - 7.50 (m, 16 H), 8.32 (d, J=5.29 Hz, 1 H).
Example 14: 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-((R)-2-hydroxypropylamino)pyrimidin-4-yl)-1H- py razol-1 -y l)propanenitrile
The above compound was prepared as follows according to Method B. To a solution of 3-(3- hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-yl)propanenitrile (as obtained in Preparation b-6-a) (203 mg, 0.530 mmol) in tetrahydrofuran (8 mL) was added (f?)-(-)-1-aminopropan-2- ol (0.416 mL, 5.30 mmol). The mixture was then heated at 80 0C for 2 hours and allowed to cool to ambient temperature. The solution was concentrated to dryness. The residue was purified by HPLC to give the title compound (76.7 mg, 38%). 1H NMR (400 MHz, MeOD) δ ppm 1.13 (d, J=6.29 Hz, 3 H), 2.28 (s, 3 H), 3.10 (t, J=6.42 Hz, 2 H), 3.15 - 3.23 (m, J=7.55 Hz, 1 H), 3.37 (dd, J=13.72, 3.90 Hz, 1 H), 3.83 - 3.92 (m, J=4.28 Hz, 1 H), 4.49 (t, J=6.42 Hz, 2 H), 6.49 (d, J=4.78 Hz, 1 H), 6.67 (s, 1 H), 6.72 (s, 1 H), 6.79 (s, 1 H), 8.04 (d, J=5.29 Hz, 1 H), 8.28 (s, 1 H). HRMS m/z Calcd for C20H22N6O2 [M+H]+ 379.18770, Found: 379.18799. Example 15: 3-(1-(azetidin-3-yl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-3-yl)-5- methylphenol
The above compound was prepared as follows according to Method B. To a solution of tert-butyl 3-(3-(3-methoxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-yl)azetidine-1- carboxylate (535 mg, 1.07 mmol) in tetrahydrofuran (11 mL) was added (S)-1-aminopropan-2-ol (0.844 mL, 10.7 mmoi). The mixture was then heated at 80 0C for 2 hours and allowed to cool to ambient temperature. The solution was concentrated to provide terf-butyl 3-(4-(2-((S)-2- hydroxypropylamino)pyrimidin-4-yl)-3-(3-methoxy-5-methylphenyl)-1 H-pyrazol-1-yl)azetidine-1- carboxylate (267 mg, 50%). To a solution of terf-butyl 3-(4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)- 3-(3-methoxy-5-methylphenyl)-1 H-pyrazol-1-yl)azetidine-1-carboxylate (133 mg, 0.270 mmol) in dichloromethane (5 mL) was added a 1.0 M solution of boron tribromide in dichloromethane (1.5 mL, 1.5 mmol). The mixture was stirred at ambient temperature for 4 hours. Methanol was introduced at 0 0C and the mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound (26.9 mg, 26%). 1H NMR (400 MHz, MeOD) δ ppm 1.14 (d, J=6.29 Hz, 3 H), 2.31 (s, 3 H), 3.17 - 3.23 (m, 2 H), 3.86 - 3.92 (m, 1 H), 4.56 - 4.63 (m, 4 H), 5.46 - 5.53 (m, 1 H), 6.51 (d, 1 H), 6.70 (s, 1 H), 6.74 - 6.77 (m, 1 H), 6.86 (s, 1 H), 8.07 (d, J=5.29 Hz, 1 H), 8.26 (s, 1 H). HRMS m/z Calcd for C20H24N6O2 [M+H]+ 381.20335, Found: 381.20387.
Preparation b-8-a tert-butyl 3-(3-(3-methoxy-5-methylphenvπ-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-vπazetidine-
To a solution of tert-butyl 3-(3-(3-methoxy-5-methylphenyl)-4-(2-(methylthio)pyrimidin-4-yl)-1 H- pyrazol-1-yl)azetidine-1-carboxylate (2.04 g, 4.36 mmol) in dichloromethane (44 mL) was added 3- chloroperoxybenzoic acid (2.93 g, 13.1 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was diluted with dichloromethane (50 mL) and saturated aqueous sodium bisulfite was introduced at 0 0C. The organic phase was extracted with saturated aqueous sodium carbonate (3 x
20 mL). The combined aqueous washes were extracted with dichloromethane (2 x 20 mL). The combined organics were dried (anhydrous magnesium sulfate), filtered and concentrated to give the title compound
(2.06 g, 94%). 1H NMR (400 MHz, MeOD) δ ppm 1.48 (s, 9 H), 2.36 (s, 3 H), 3.18 (s, 3 H), 3.79 (s, 3 H), 4.38 - 4.47 (m, 4 H), 5.23 - 5.35 (m, J=18.88 Hz, 1 H), 6.87 (s, 2 H), 6.94 (s, 1 H), 7.51 (d, J=5.54 Hz, 1
H), 8.67 (s, 1 H), 8.72 (d, J=5.29 Hz, 1 H). Preparation b-8-b tert-butyl 3-(3-(3-metrιoxy-5-rnethylphenyl)-4-(2-(methyltriio)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1- carboxvlate
Following the procedure described in Preparation b-6-b, using 4-(3-(3-methoxy-5-methylphenyl)- 1H-pyrazol-4-yl)-2-(methylthio)pyrimidine in place of 4-(3-(3-methyl-5-(trityloxy)phenyl)-1H-pyrazol-4-yl)-2- (methylthio)pyrimidine, and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate in place of 3- bromopropanenitrile at 70 0C, the title compound was obtained in 68% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.48 (s, 9 H), 2.35 (s, 3 H), 2.37 (s, 3 H), 3.78 (s, 3 H), 4.35 - 4.46 (m, 4 H), 5.26 - 5.29 (m, 1 H), 6.83 (s, 1 H), 6.85 (S, 1 H), 6.92 (s, 1 H), 6.96 (d, J=5.29 Hz, 1 H), 8.30 (d, J=5.54 Hz, 1 H), 8.43 (s, 1 H).
Preparation b-8-c 4-(3-(3-methoxy-5-methylphenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine
Following the procedure described in Preparation b-6-c, using 3-(dimethylamino)-1-(3-methoxy-5- methylphenyl)-2-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one in place of 3-(dimethylamino)-1-(3-methyl- 5-(trityloxy)phenyi)-2-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one at ambient temperature, the title compound was obtained in 57% yield. 1H NMR (400 MHz, MeOD) δ ppm 2.34 (s, 3 H), 3.78 (s, 3 H), 3.78 (S, 3 H), 6.85 (s, 2 H), 6.90 (s, 1 H), 7.03 (s, 1 H), 8.14 - 8.28 (m, 1 H), 8.30 (d, J=5.29 Hz, 1 H).
Preparation b-8-d
3-(dimethylamino)-1-(3-methoxy-5-methylphenvπ-2-(2-(methylthio)pyrimidin-4-yl)prop-2-en-1-one
Following the procedure described in Preparation b-6-c, using 1-(3-methoxy-5-methylphenyl)-2- (2-(methylthio)pyrimidin-4-yl)ethanone in place of 1-(3-methyl-5-(trityloxy)phenyl)-2-(2- (methylthio)pyrimidin-4-yl)ethanone at 90 0C1 the title compound was obtained as a crude oil which was used in the next step without purification. 1H NMR (400 MHz, MeOD) δ ppm 2.31 (s, 3 H), 2.41 (s, 3 H), 2.54 (s, 1 H), 2.96 (s, 6 H), 3.75 (s, 3 H), 6.86 (d, 1 H), 6.91 (s, 1 H), 6.98 (s, 1 H), 7.73 (s, 1 H), 8.17 (d, J=5.54 Hz, 1 H).
Preparation b-8-e 1-(3-methoxy-5-methylphenvπ-2-(2-(methylthio)pyrimidin-4-vl)ethanone
Following the procedure described in Preparation b-6-c, using methyl methyl 3-methyl-5- methoxybenzoate in place of methyl 3-methyl-5-(trityloxy)benzoate at 0 0C, the title compound was obtained . as a crude product which was used in the next step without purification. 1H NMR (400 MHz, MeOD) δ ppm 2.36 (s, 3 H), 2.38 (s, 1 H), 2.49 (s, 1 H), 2.59 (s, 3 H), 3.82 (s, 3 H), 6.84 (d, J=5.04 Hz, 2 H), 7.19 (s, 1 H), 7.27 (s, 1 H), 8.29 (d, J=5.54 Hz, 1 H). Preparation b-8-f methyl 3-methoxy-5-methylbenzoate
To a solution of methyl 3-hydroxy-5-methylbenzoate (20.0 g, 120 mmol) in N, N- dimethylformamide (120 mL) was added iodomethane (11.2 mL, 180 mmol), cesium carbonate (4.65 g, 180 mmol) and catalytic amount of 4-dimethylaminopyridine. The mixture was stirred at ambient temperature overnight. Water (200 mL) was introduced and the mixture extracted with ethyl acetate (3 x
150 mL). The combined organics were washed with saturated aqueous sodium chloride, dried
(anhydrous magnesium sulfate), filtered and concentrated to give the title compound (19.9 g, 92%). 1H
NMR (400 MHz, CHLOROFORM-D) δ ppm 2.38 (s, 3 H), 3.84 (s, 3 H), 3.91 (s, 3 H), 6.93 (s, 1 H), 7.37 (s, 1 H), 7.48 (s, 1 H). Example 16: 3-chloro-5-{4-{2-[(4-fluorophenyl)amino]pyrimidin-4-yl}-1-t(2R)-pyrrolidin-2-ylmethyl]- 1 H-py razol-3-y l}phenol
The above compound was prepared as follows according to Method B. The protected title compound was obtained following the sequence described in Example 15, using tert-butyl (2R)-2-
{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate {Tetrahedron: Asymmetry 1997, 8(13), 2209) in place of tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate, and using 4-fluoroaniline in place of (S)-1- aminopropan-2-ol and using microwave heating (200 0C, dioxane, 1 hour) to displace the 2- methanesulfonyl group off the pyrimidine. Deprotection was carried out as in Example 7 using 48% aqueous HBr (100 0C, 6 hours) to obtain the title compound in 9.0 % yield. 1H NMR (300 MHz, DMSO-D6) δ 1.51 - 1.61 (m, 1 H), 1.70 - 1.86 (m, 2 H), 1.93 - 2.03 (m, 1 H), 2.94 - 3.09 (m, 2 H), 3.68 - 3.78 (m, 1
H), 4.21 - 4.40 (m, 2 H), 6.76 - 6.88 (m, 3 H), 6.91 - 7.03 (m, 3 H), 7.50 - 7.57 (m, 2 H), 8.36 (s, 1 H),
8.41 (d, J = 5.1 Hz, 1 H), 9.57 (s, 1 H).
Example 17: S-chloro-S^-p-OsobutylaminoJpyrimidin^-yll-i-ti-methylpiperidin^-ylJ-IH-pyrazol- 3-yl]phenol
The above compound was prepared as follows according to Method B. To a mixture of 3-chloro- 5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1 H-pyrazol-3-yl}phenol (0.15 g, 0.32 mmol) in acetonitrile (4 mL) was added a 51 % aqueous formaldehyde solution (75 mL, 0.95 mmol). The mixture was allowed to stir for 20 minutes then sodium cyanoborohydride (60 mg, 0.95 mmol) was added and the mixture was allowed to stir for 10 minutes. Acetic acid was added dropwise until neutral and the entire mixture was concentrated to dryness. The residue was purified by high performance liquid chromatography to provide the title compound (8.0 mg, 5.8 %). 1H NMR (300 MHz, DMSO-D6) δ 0.63 - 0.81 (m, 6 H), 1.96 - 2.06 (m, 3 H), 2.15 - 2.28 (m, 3 H), 2.72 - 2.97 (m, 3 H), 3.22 - 3.34 (m, 5 H), 4.13 - 1.25 (m, 1 H), 6.45 - 6.59 (m, 1 H), 6.70 - 6.72 (m, 1 H), 6.80 - 6.85 (m, 1 H), 6.86 - 6.97 (m, 2 H), 8.09 (d, J = 5.1 Hz, 1 H), 8.25 (s, 1 H), 9.83 (s, 1 H). Example 18: 3-chloro-5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1H-pyrazol-3-yl}phenol
The above compound was prepared as follows according to Method B. Following the procedure described in Example 16, the title compound was obtained in 9.1% yield. 1H NMR (300 MHz, DMSO-D6) δ 0.62 - 0.74 (m, 6 H), 1.50 - 1.62 (m, 1 H), 2.09 - 2.27 (m, 4 H), 2.77 - 2.84 (m, 2 H), 2.97 - 3.09 (m, 2 H)1 3.31 - 3.38 (m, 2 H), 4.50 - (m, 1 H), 6.77 - 6.80 (m, 1 H), 6.81 - 6.83 (m, 1 H), 6.88 - 6.91 (m, 1 H), 7.00 - 7.05 (m, 1 H), 8.25 (d, J = 5.5 Hz, 1 H), 8.30 - 8.37 (m, 1 H), 8.73 - 8.77 (m, 1 H), 9.13 - 9.20 (m, 1 H).
Example 19: 3-chloro-5-[4-{2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl}-1 -(1 - methylpiperidin-4-yl)-1H-pyrazol-3-yl]phenol
The above compound was prepared as follows according to Method B. Following the procedure described in Example 17, using 3-chloro-5-(4-{2-[(2-hydroxy-2-methylpropyl)amino]pyrimidin-4-yl}-1- piperidin-4-yl-1/-/-pyrazol-3-yl)phenol in place of 3-chloro-5-{4-[2-(isobutylamino)pyrimidin-4-yl]-1-piperidin- 4-yl-1 H-pyrazol-3-yl}phenol, the title compound was obtained in 57% yield. 1H NMR (300 MHz, DMSO- D6) δ 1.22 - 1.33 (m, 6 H), 2.14 (s, 3 H), 2.31 - 2.46 (m, 4 H), 2.79 - 2.93 (m, 2 H), 3.37 - 3.46 (m, 3 H), 4.51 - 4.64 (m, 1 H), 4.66 - 4.79 (m, 1 H), 6.71 - 6.83 (m, 2 H), 7.01 - 7.04 (m, 1 H), 7.10 - 7.14 (m, 1 H), 7.19 - 7.22 (m, 1 H), 8.40 (d, J = 5.1 Hz, 1 H), 8.59 (s, 1 H), 10.17 (s, 1 H). Preparation b-12-a
3-chloro-5-(4424(2-hvdroxy-2-methylpropyl)aminolpyrimidin-4-yl)-1-piperidin-4-yl-1H-pyrazol-3-vnphenol
To a mixture of terf-butyl 4-(3-(3-chloro-5-hydroxyphenyl)-4-{2-[(2-hydroxy-2- methylpropyl)amino]pyrimidin-4-yl}-1/-/-pyrazoi-1-yl)piperidine-1-carboxylate (0.40 g, 0.73 mmoi) in 1,4- dioxane (8 mL) was added a solution of 4 N HCI in 1 ,4-dioxane (1.2 mL) and the mixture was stirred at ambient temperature for 6 hours. The mixture was concentrated to dryness and purified by high performance liquid chromatography to provide the title compound (61 mg, 19%). 1H NMR (300 MHz, DMSO-D6) δ 0.96 - 1.11 (m, 6 H), 2.15 - 2.36 (m, 4 H), 2.96 - 3.19 (m, 4 H), 3.37 - 3.48 (m, 2 H), 4.56 - 4.67 (m, 1 H), 6.84 - 6.91 (m, 2 H), 6.93 - 7.01 (m, 1 H), 7.02 - 7.08 (m, 1 H), 7.71 - 7.87 (m, 1 H), 8.28 - 8.36 (m, 1 H), 8.76 - 8.82 (m, 1 H), 8.90 - 9.02 (m, 1 H), 9.19 - 9.27 (m, 1 H), 10.14 (s, 1 H).
Preparation b-12-b tert-butyl 4-(3-(3-chloro-5-hvdroxyphenylV4-f2-[(2-hvdroxy-2-methylpropyπaminolpyrimidin-4-yl}-1H- pyrazol-1-vnpiperidine-1-carboxylate
A mixture of tert-butyl 4-{3-(3-chloro-5-hydroxyphenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]-1H- pyrazol-1-yl}piperidine-1-carboxylate (0.18 g, 0.33 mmol), 1-amino-2-methylpropan-2-ol (88 mg, 0.98 mmol) and 1 ,4-dioxane (3 mL) was stirred at 90 0C for 1 hour in a microwave reactor. The mixture was concentrated to dryness to furnish 0.13 grams of an oil which was used in the next step without any purification. APCI m/z: 543.40. Preparation b-12-c teff-butyl 4-{3-(3-chloro-5-hvdroxyphenvπ-4-[2-(nnethylsulfonyl)pyrimiclin-4-yll-1/-/-pyrazol-1-yl)piperidine-1- carboxylate
To a mixture of te/t-butyl 4-{3-[3-chloro-5-(trityloxy)phenyl]-4-[2-(methylthio)pyrimidin-4-yl]-1/-/- pyrazol-1-yl}piperidine-1 -carboxylate (4.0 g, 5.3 mmol) in dichloromethane (120 mL) was added 3- chlorobenzenecarboperoxoic acid (2.8 g, 16 mmol). The mixture was stirred at room temperature for 22 hours then concentrated to dryness. The residue was purified by column chromatography using a hexane and ethyl acetate gradient to give the title compound as a white solid (2.6 g, 90.0%). 1H NMR (400 MHz, DMSO-D6) δ 1.43 (s, 9 H), 1.75 - 1.95 (m, 2 H), 2.05 - 2.2 (m, 2 H), 2.80 - 3.10 (m, 2 H), 3.19 (s, 3 H), 4.00 - 4.20 (m, 2 H), 4.40 - 4.60 (m, 1 H), 6.80 - 6.90 (m, 2 H), 6.95 - 7.05 (m, 1H), 7.70 (d, J = 5.3 Hz, 1 H), 8.75 (s, 1 H), 8.92 (d, J = 5.3 Hz, 1 H), 10.02 (s, 1 H).
Preparation b-12-d fert-butyl 4-(3-[3-chloro-5-(trityloxy)phenyl1-4-r2-(methylthio)pyrimidin-4-vn-1/-/-pyrazol-1-yl>piperidine-1- carboxylate
Following the procedure described in Preparation b-6-b, 4-methanesulfonyloxy-piperidine-1- carboxylic acid tert-butyl ester in place of 3-bromopropanenitrile, the title compound was obtained as a white foam after chromatographic separation of regioisomeric pyrazoles by silica gel chromatography. The major isomer had the regiochemistry depicted as shown above as confirmed by NOE spectroscopy. 1H NMR (400 MHz, DMSO-D6) δ 1.45 - 1.40 (m, 9 H), 1.65 - 1.56 (m, 2 H), 1.94 - 1.87 (m, 2 H), 1.86 - 1.76 (m, 2 H), 2.07 - 2.01 (m, 2 H), 2.24 (s, 3 H), 4.86 - 4.79 (m, 1 H), 6.62 - 6.60 (m, 1 H), 6.92 - 6.89 (m, 1 H), 7.05 - 7.02 (m, 2 H), 7.43 - 7.23 (m, 15 H), 8.45 (d, J = 5.3 Hz, 1 H), 8.50 (s, 1 H). Preparation b-12-e ΦO-fS-chloro-δ-^rityloxy^phenvn-IH-pyrazol-ΦvD^-dinethylthio^pyrimidine
To a mixture of 4-methyl-2-(methylthio)pyrimidine (1.4 g, 10 mmol) and methyl 3-chloro-5- (trityloxy)benzoate (4.3 g, 10 mmol) in tetrahydrofuran (50 ml_) was added a 1.0 M tetrahydrofuran solution of LiHMDS (20.0 mL, 20.0 mmol). The mixture was stirred at room temperature for 4 hours then a 4 molar dioxane solution of hydrochloric acid was added (50 mL). The mixture was diluted with ethyl acetate (100 mL) and water (100 mL) then the layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 50 mL). Combined organic layers were dried (MgSO4), filtered, and concentrated to dryness to furnish 5.3 grams of a solid, which was used in the next step without any purification. A mixture of 1-[3-chloro-5-(trityloxy)phenyl]-2-[2-(methylthio)pyrimidin-4-yl]ethanone (5.3 g, 10 mmol) and (dimethoxymethyl)dimethylamine 1,1-dimethoxy-Λ/,Λ/-dimethylmethanamine (3.6 g, 30 mmol) in toluene (100 mL) was stirred at reflux for 2 hours then concentrated to dryness. The residue was dissolved in ethanol (60 mL) then treated with hydrazine (3.20 g, 100 mmol). The mixture was stirred at room temperature for 2 hours. The resulting precipitate was filtered, washed with ethanol, and dried under vacuum to give the title compound as a solid (4.57 g, 82%). 1H NMR (400 MHz, DMSO-D6) δ 2.21 (s, 3 H), 6.56 - 6.67 (m, 1 H), 6.85 - 6.95 (m, 1 H), 6.98 - 7.10 (m, 2 H), 7.20 - 7.50 (m, 15 H), 8.34 (s, 1 H), 8.43 (d, J = 5.3 Hz, 1 H), 12.7 - 13.8 (broad, 1 H). Example 20: 3-[3-(3-hydroxy-2,5-dimethy!phenyl)-4-pyrimidin-4-yl-1H-pyrazol-1-yl]propanenitrile
The above compound was prepared as follows according to Method C. To a solution of 3-(3-(3- methoxy-2,5-dimethylphenyl)-4-(pyrimidin-4-yl)-1 H-pyrazol-1-yl)propanenitrile in dichloromethane (5 mL) at 0 0C was added BBr3 (1M in CH2CI2, 3.0 mL, 3.0 mmol). The mixture was stirred at ambient temperature for 2 hours at 0 0C then cautiously poured into saturated aqueous sodium hydrogen carbonate. The layers were separated and the aqueous phase extracted with chloroform. The combined organics were washed with saturated aqueous sodium chloride, and concentrated to dryness. The resulting residue was purified by silica gel chromatography using 0 to 20% methanol in chloroform to provide the title compound (16 mg, 15%). 1H NMR (300 MHz, DMSO-D6): δ 9.39 (1 H, s), 9.03 (1 H, d, J = 0.94 Hz), 8.64 (1H, s), 8.50 (1 H, d, J = 5.46 Hz), 6.76 (1 H, dd, J = 5.46 and 1.13 Hz), 6.73 (1 H, s), 6.53 (1H, S), 4.49 (2H, t, J = 6.31 Hz), 3.16 (2H, t, J = 6.31 Hz), 2.21 (3H, s), 1.77 (3H, s); HRMS m/z Calcd for Ci8H17N5O [M+H]+ 320.15059 Found: 320.15062.
Preparation c-1-a 3-(3-(3-methoxy-2,5-dimethylphenylM-(PVrimidin-4-yl)-1H-pyrazol-1-vQpropanenitrile
Following the procedure described in Preparation a-4-a, using 3-Bromopropionitrile instead of 2- fluoropyridine at 70 °C instead of 80 0C afforded the crude residue which was purified by silica gel chromatography using 0 to 10% methanol in chloroform to provide the title compound (115 mg, 100%).
1H NMR (300 MHz, DMSO-D6): δ 9.07 (1 H, s), 8.40 (1 H, d, J = 5.46 Hz), 8.37 (1 H, s), 6.81-6.76 (3H, m), 4.49 (2H, t, J = 6.69 Hz), 3.88 (3H, s), 3.08 (2H, t, J = 6.78 Hz), 2.37 (3H, s), 1.93 (3H, s).
Preparation c-1-b 4-(3-(3-methoxy-2,5-dimethylphenvfl-1 H-pyrazol-4-vπpyrimidine
To a solution of 4-(3-(3-methoxy-2,5-dimethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazol-4- yl)pyrimidine (328 mg, 0.925 mmol) in methanol (12 mL) was added polymer-bound p-toluenesulfonic acid, (2.0 mmol/g, 100 mg, 0.2 mmol). The resulting mixture was stirred at 50 °C for 3 hours, cooled to room temperature, and filtered to remove the polymer beads. The beads were then treated with saturated aq. NaHCO3 and washed thoroughly with a CHCI3//-PrOH solution. The organics were all combined and concentrated under vacuum to give the titled compound (192 mg, 76%). 1H NMR (300 MHz, CDCI3): δ 9.10 (1 H, d, J = 1.32 Hz), 8.41 (1 H, d, J = 5.46 Hz), 8.39 (1 H, s), 6.85 - 6.82 (2H, m), 6.77 (1 H, s), 3.89
(3H, s), 2.38 (3H, s), 1.93 (3H, s).
Preparation c-1-c 4-(3-(3-methoxy-2.5-dimethylphenyl)-1-(tetrahvdro-2H-pyran-2-vπ-1 H-pyrazol-4-vl)pvrimidine
To a degassed mixture of 4-(3-iodo-1-(tetrahydrofuran-2-yl)-1 H-pyrazol-4-yl)pyrimidine (564 mg,
1.58 mmol), 3-methoxy-2,5-dimethylphenylboronic acid, and 1M aq. K2CO3 (3.3 mL, 3.3 mmol) in DMF (10 mL) was added Pd(PPh3)4 (1.83 mg, 0.158 mmol). The resulting mixture was stirred at 100 0C for 10 hours. The reaction mixture was cooled to room temperature, diluted with chloroform, washed with H2O, concentrated under vacuum, and the residue obtained was purified by silica gel chromatography using 30 to 80% ethyl acetate in chloroform to provide the title compound (331 mg, 58%). APCI m/z: 365 [M+H]+.
Preparation c-1-d 3-methoxy-2,5-dimethylphenylboronic acid
To a solution of 1-bromo-3-methoxy-2,5-dimethylbenzene (297 mg, 1.38 mmol) in tetrahydrofuran (5 mL) at -78 0C was added /7-BuLi (2.5 M in hexanes, 0.650 mL, 1.63 mmol) dropwise. After 20 min, triisopropyl borate (408 mg, 2.17 mmol) was added, and the resulting mixture was allowed to warm to ambient temperature. After 16 h, the reaction was quenched with saturated aqueous NH4CI and the reaction mixture was partitioned with ethyl acetate. The layers were separated and the ethyl acetate was concentrated to dryness. The residue obtained was used without further purification.
Preparation c-1-e
1 -bromo-3-methoxv-2, ,5-dimethvlbenzene
To a solution of the crude 3-bromo-2,5-dimethylphenol (365 mg) in acetone (10 mL) was added K2CO3 (345 mg, 2.50 mmol) and methyl iodide (341 mg, 2.40 mmol). After 4 hours at ambient temperature, additional methyl iodide was added (685 mg, 4.80 mmol) and the reaction mixture stirred at ambient temperature for an additional 16 hours. The solvent and any other volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc, washed with H2O, concentrated and purified by silica gel chromatography using 0 to 30% CHCI3 in hexanes to provide the title compound (300 mg, 9% for the 3-steps). 1H NMR (CDCI3, 300 MHz): δ 7.00 (1 H, s), 6.60 (1 H, s), 3.81 (3H, s), 2.30 (3H, s), 2.27 (3H, s).
Preparation c-1-f 3-bromo-2,5-dimethylphenol
A suspension of the crude 2,4,5-tribromo-3,6-dimethylphenol (2.06 g) in hydroiodic acid (57% in H2O, 20 mL) was warmed to reflux. After 3 hours, the mixture was cooled to room temperature, diluted with H2O (25 mL), and extracted with chloroform (4 x 20 mL). The combined chloroform extracts were washed with 1 N Na2S2O3 (aq) and then H2O and concentrated under vacuum. The residue obtained was purified by silica gel chromatography using 50 to 100% chloroform in hexanes to provide the title compound (370 mg), contaminated with significant amounts of 3,6-dimethylphenol. This mixture was used without further purification. 1H NMR (300 MHz, CDCI3) δ 6.99 (1H, s), 6.55 (1H, s), 4.74 (1 H, S), 2.30 (3H, s), 2.25 (3H, s).
Preparation c-1-q 2,4,5-tribromo-3,6-dimethylphenol
To bromine (14 mL) at 0 0C was slowly added aluminum powder (200 Mesh, 300 mg, 11.1 mmol). After 20 minutes, the mixture was slowly warmed to room temperature and 2,5-dimethylphenol (3.00 g, 24.6 mmol) was added slowly. After complete addition, the bromine was evaporated under a stream of N2(g), and the resulting residue was triturated with equal volumes of chloroform and 1N HCI. The chloroform layer was concentrated to give the title compound (3.27 g) which was contaminated with significant amounts of 2,4-dibromo-3,6-dimethylphenol. This mixture was used without further purification. 1H NMR (300 MHz, CDCI3): δ 2.67 (3H, s), 2.48 (3H, s). Example 21 : 2,3-dimethyl-5-(4-pyrimidin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method C. Following the procedure described in Example 20, using 2,3-dimethyl-5-(4-(pyrimidin-4-yl)-1H-pyrazol-3-yl)phenol in place of 3-(3- (3-methoxy-2,5-dimethylphenyl)-4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile, the title compound was obtained in 46% yield. 1H NMR (300 MHz, DMSO-D6) δ 13.35 (0.6H, s), 13.31 (0.4H, s), 9.49 (0.6H, s), 9.25 (0.4H, s), 9.07 (1H, s), 8.60 (1 H, d, J = 5.46 Hz), 8.39 (0.4H, d, J = 1.51 Hz), 8.11 (0.6H, d, J = 1.88 Hz), 7.29 (0.6H, dd, J = 5.46 and1.32 Hz), 7.25 (0.4H, dd, J = 5.46 and 1.51 Hz), 6.80 (0.6H, s), 6.77 (1.4H, s), 2.23 (1.8H, s), 2.19 (1.2H, s), 2.10 (1.8H, s), 2.07 (1.2H, s); HRMS m/z Calcd for C15H14N4O [M+H]+ 267.12404 Found: 267.12363; Elemental Analysis: Calcd for C15H14N4O0.04 CHCI3.0.51 H2O: C 64.46, H 5.42, N 19.99. Found: C 64.57, H 5.30, N 19.70.
Preparation c-2-a 4-(3-(3-methoxy-4,5-dimethylphenyl)-1 H-pyrazol-4-vDpyrimidine
To a solution of the crude 4-(3-(3-methoxy-4,5-dimethylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1 H- pyrazol-4-yl)pyrimidine (1.84 mmol, theoretical yield from the previous reaction) in methanol (10 mL) was added a catalytic amount of p-toluenesulfonic acid. The resulting mixture was stirred at 60 0C for 16hours, cooled to room temperature, concentrated under vacuum, re-dissolved in chloroform, washed with saturated aqueous NaHCO3 and concentrated under vacuum. The resulting residue was purified by silica gel chromatography using 0 to 20% methanol in chloroform to provide the title compound (285 mg, 55%). APCI m/z: 281 [M+H]+.
Preparation c-2-b 4-(3-(3-methoxy-4,5-dimethylphenyl)-1-(tetrahvdro-2H-pyran-2-yl)-1H-pyrazol-4-vπpyrimidine
Following the procedure described in Preparation c-1-c, using 3-methoxy-4,5- dimethylphenylboronic acid (prepared as described in Preparation c-1-d from 2,3-dimethylphenol) in place of 3-methσxy-2,5-dimethy!phenylboronic acid, the title compound was obtained and used directly without further purification. APCI m/z: 365 [M+H]+. Example 22: 4-FIuoro-2-(1-methyl-4-(pyrimidin-4-yl)-1W-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method C. Boron tribromide (0.084 ml_ of 1.0 M solution in DCM, 0.84 mmol) was added to a solution of 4-(3-(5-fluoro-2-methoxyphenyl)-1- methyl-1W-pyrazol-4-yl)pyrimidine (80 mg, 0.28 mmol) in dichloromethane (2 mL) at 0 0C. The resulting suspension was stirred at 0 °C for 45 minutes. The reaction was diluted with dichloromethane (10 mL) and quenched by the slow addition of saturated aqueous sodium hydrogen carbonate (10 mL). The resulting mixture was stirred at ambient temperature until two phases were evident. The layers were separated and the aqueous phase extracted with dichloromethane (2 x 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 3% methanol in a (1 :1) mixture of ethyl acetate and dichloromethane to provide the title compound. (41 mg, 56%). 1H NMR (400 MHz, ACETONITRILE-cfe) δ ppm 9.38 (s, 1 H), 9.05 (d, J=1.52 Hz, 1 H), 8.63 (d, J=5.31 Hz, 1 H), 8.14 (s, 1 H), 7.39 (dd, J=5.31 , 1.52 Hz, 1 H), 7.20 (dd, J=9.73, 3.16 Hz, 1 H), 7.04 (td, J=8.59, 3.03 Hz, 1 H), 6.96 (dd, J=9.09, 5.05 Hz, 1 H), 3.98 (s, 3 H). Preparation c-3-a
4-(3-(5-fluoro-2-methoxyphenylH-rnethyl-1/-/-pyrazol-4-yl)pyrimidine
To a mixture of 4-(3-iodo-1-methyl-1H-pyrazol-4-yl)pyrimidine (0.2 g, 0.7 mmol) and 5-fluoro-2- methoxyphenylboronic acid (120 mg, 0.70 mmol) in DMF (5.6 ml_) was added a 2M solution of aqueous potassium carbonate (0.875 mL, 1.75 mmol). The resulting mixture was purged with nitrogen for 5 minutes before the addition of a solution of tetrakis(triphenylphosphine)palladium (40 mg, 0.035 mmol) in tetrahydrofuran (2.8 mL). The nitrogen bubbler was removed shortly after the addition and the mixture was sealed and placed in a Biotage Initiator™ Microwave Synthesizer and heated at 130 0C for 1 hour. After cooling to ambient temperature, the crude reaction mixture was partitioned between saturated aqueous sodium chloride (100 mL) and ethyl acetate (50 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (2x50 mL), brine (50 mL), dried (anhydrous magnesium sulfate), filtered and concentrated to dryness. This residue was purified by silica gel chromatography using 0 to 50% ethyl acetate in dichloromethane to provide the title compound (87 mg, 44%). 1H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 8.94 (d, J=I .26 Hz, 1 H), 8.44 (d, J=5.56 Hz, 1 H), 8.17 (s, 1 H), 7.13 - 7.22 (m, 2 H), 6.94 - 7.02 (m, 2 H), 3.94 (S, 3 H), 3.45 (s, 3 H).
Example 23: 3-chloro-5-(1-methyI-5-morpholin-4-yl-4-pyrimidin-4-yl-1H-pyrazol-3-yl)phenol
The above compound was prepared as follows according to Method D. (E/Z)-1-(3-chloro-5-
(trityloxy)phenyl)-3-(methylthio)-3-morphoIino-2-(pyrimidin-4-yl)prop-2-en-1-one (250 mg, 0.395 mmol) was dissolved in THF (4 mL) and methylhydrazine (42 μL, 0.79 mmol) was added in one portion. The reaction was allowed to stir at ambient temperature for 48 hours. The solvents were removed. The crude NMR taken in C6D6 indicated a 3:1 ratio of pyrazole regiosiomers. The mixture was purified by flash chromatography eluting with a gradient of 9:1 PetEther: EtOAc then 4:1 PetEther: EtOAc to afford 90 mg of the mixture. The pyrazole regiochemistry of the major regioisomer was confirmed as drawn above by running a nuclear Overhauser effect (NOE) spectroscopy experiment in C6D6 prior to trityl deprotection. The protected phenol (90.0 mg, 0.147 mmol) was dissolved in DCM (3 mL) and treated with Et3SiH (100 μL) followed by TFA (0.5 mL). After 30 minutes, LC/MS analysis indicated complete deprotection and showed the two regioisomers resolved by LCMS. After removing the solvents, the product was purified via silica gel chromatography, eluting with 60/40, 70/30 then 80/20 EtOAc / Pet Ether. The major isomer eluted first and was separated cleanly using this gradient system. The pure fractions were combined to obtain the product as a pale yellow solid (20 mg, 55%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 3.00 - 3.10 (m, 4 H), 3.72 - 3.81 (m, 4 H), 3.86 (s, 3 H), 6.59 (s, 3 H), 6.76 (m, 1 H), 6.78 (s, 1H), 7.25 (d, J=4.78 Hz, 1 H), 8.62 (d, J=4.78 Hz, 1 H), 9.22 (s, 1 H). HRMS m/z Calcd for C18H18N5O2CI [M+H]+ 372.12218 Found: 372.12148.
Preparation d-1 -a (E/Z)-1-(3-chloro-5-(trityloxy)phenvπ-3-(methylthio)-3-morpholino-2-(pyrimidin-4-yl)prop-2-en-1-one
1-(3-chloro-5-(trityloxy)phenyl)-2-(1,3-dithietan-2-ylidene)-2-(pyrimidin-4-yl)ethanone (850 mg,
1.47 mmol) was dissolved in toluene (15 ml_) and morpholine (385 uL, 4.41 mmol) was added. After fitting the reaction with a reflux condenser, the mixture was heated to 100 0C for 1 hour. The solvents were removed to obtain a red foam used as is in the next step. The red foam (715 mg, 1.15 mmol) was dissolved in DMF (6 mL). Cs2CO3 (415 mg, 1.27 mmol) and methyl iodide (80 uL, 1.3 mmol) were added. The mixture was allowed to stir at ambient temperature for 30 minutes. Water (15 mL) was added and the aqueous layer extracted with a 1 :1 mixture of isopropyl ether : EtOAc (4 x 15 mL). The combined organic extracts were washed with water (2X) and brine (1X) and dried over MgSO4. The product was a 1 :1 mixture of E and Z isomers as observed by 1H NMR. 1H NMR (400 MHz, CDCI3) δ ppm 2.89 (s, 1.5 H), 2.96 (s, 1.5 H)7 3.30 - 3.32 (m, 4 H), 3.65 - 3.67 (m, 4H), 6.79 - 6.80 (m, 1 H), 6.82 - 8.83 (m, 1 H), 6.89 - 6.90 (m, 1 H), 7.11 (dd, J = 5.54, 1.51 Hz, 1 H), 7.22 - 7.40 (m, 15 H), 8.38 (d, 5.54 Hz, 1 H), 8.95 (s, 1 H).
Preparation d-1-b
1-(3-chloro-5-(trityloxy^phenylV2-(1.3-dithietan-2-ylidene)-2-(pyrimidin-4-vπethanone
To a suspension of 1-(3-chloro-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone (as obtained in Preparation a-2-c) (7.3 g, 14.9 mmol) in DMF (75 mL) was added Cs2CO3 (9.70 g, 29.8 mmol) followed by carbon disulfide (2.69 g, 44.7 mmol) and dibromomethane (3.10 mL, 44.7 mmol). The reaction was allowed to stir at ambient temperature for 20 hours. The reaction was diluted with water (100 mL) and extracted with a 1 :1 mixture of Et2O / EtOAc (75 ml_). The aqueous layer was further extracted with a 1 :1 mixture of Et2O / EtOAc (3 x 75 mL). The combined organic extracts were washed with water (3 x 75 ml_) and brine (1 x 100 mL) then dried over MgSO4. The solvents were removed to afford an orange foam (7.3 g, 85%) used in the next step without further purification. 1H NMR (400 MHz, CDCI3) δ ppm 4.11 (s, 2 H), 6.15 (d, J = 5.54 Hz, 1 H), 6.75 (s, 1 H)1 6.88 (s, 2 H), 7.22 - 7.42 (m, 15 H), 8.24 (d, J = 5.54 Hz, 1 H), 9.00 (s, 1 H).
Example 24: 3-methyl-5-[1-methyl-5-(4-methylpiperazin-1-yl)-4-pyrimidin-4-yl-1H-pyrazol-3- yl]phenol
The above compound was prepared as follows according to Method D. To a solution of 1-(3- methyl-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone (8 g, 17.0 mmol) in Λ/,Λ/-dimethylformamide (86 mL) was added cesium carbonate (11.1 g, 2 equiv), followed by carbon disulfide (3.08 mL, 3 equiv) and dibromomethane (3.54 mL, 3 equiv). The mixture was stirred at ambient temperature for 6 hours. The solution was poured into ice water and extracted with a mixture of 50% ethyl acetate and 50% diethyl ether (4x). The combined organics were washed with water (3x) and saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to provide 2-(1 ,3-dithietan-2-ylidene)-1-(3- methyl-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone (7.4 g, 78%). To a solution of 2-(1 ,3-dithietan-2- ylidene)-1-(3-methyl-5-(trityloxy)phenyl)-2-(pyrimidin-4-yl)ethanone (1.00 g, 1.79 mmol) in toluene (9 mL) was added 1-methylpiperazine (0.805 mL, 5.55 mmol). The mixture was then heated at 100 0C for 4 hours and allowed to cool to ambient temperature. Water was introduced and the mixture extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous magnesium sulfate), filtered and concentrated to provide 3-mercapto-1-(3-methyl-5- (trityloxy)phenyl)-3-(4-methylpiperazin-1-yl)-2-(pyrimidin-4-yl)prop-2-en-1-one. To a solution of 3- mercapto-1-(3-methyl-5-(trityloxy)phenyl)-3-(4-methylpiperazin-1-yl)-2-(pyrimidin-4-yl)prop-2-en-1-one (1.15 g, 1.79 mmol) in Λ/,Λ/-dimethylformamide (10 mL) was added cesium carbonate (642 mg, 1.97 mmol) followed by iodomethane (0.123 mL, 1.97 mmol). The mixture was stirred at ambient temperature for 1 hour. Water was introduced and the mixture extracted with a mixture of 50% ethyl acetate and 50% isopropyl ether (3x75 mL). The combined organics were washed with saturated aqueous sodium chloride (2x), dried (anhydrous magnesium sulfate), filtered and concentrated to provide 1-(3-methyl-5- (trityloxy)phenyl)-3-(4-methylpiperazin-1-yl)-3-(methylthio)-2-(pyrimidin-4-yl)prop-2-en-1-one. To a solution of 1-(3-methyl-5-(trityloxy)phenyl)-3-(4-methylpiperazin-1-yl)-3-(methylthio)-2-(pyrimidin-4-yl)prop- 2-en-1-one (563 mg, 0.900 mmol) in tetrahydrofuran (5 mL) was added methyl hydrazine (95 μL, 1.80 mmol). The mixture was stirred at ambient temperature for 2 days. The solution was concentrated to dryness. The residue was purified by silica gel chromatography using 50% ethyl acetate in petroleum ether to provide 4-(1-methyl-3-(3-methyl-5-(trityloxy)phenyl)-5-(4-methylpiperazin-1-yl)-1 H-pyrazol-4- yl)pyrimidine (99.3 mg, 18%). To a solution of 4-(1-methyl-3-(3-methyl-5-(trityloxy)phenyl)-5-(4- methylpiperazin-1-yl)-1H-pyrazol-4-yl)pyrimidine (99 mg, 0.16 mmol) in dichloromethane (4 mL) was added triethylsilane (15 μL, 0.176 mmol), followed by trifluoroacetic acid (0.6 mL). The mixture was stirred at ambient temperature for 3 hours. The solution was concentrated to dryness. The residue was purified by HPLC to give the title compound (30.3 mg, 51%). 1H NMR (400 MHz, MeOD) δ ppm 2.24 (s, 3 H), 2.98 (s, 3 H), 3.20 - 3.28 (m, 2 H), 3.32 - 3.40 (m, 2 H), 3.47 - 3.57 (m, 2 H), 3.62 - 3.74 (m, 2 H), 3.89 (s, 3 H), 6.50 (s, 1 H), 6.62 (s, 1 H), 6.66 (s, 1 H), 7.06 - 7.16 (m, 1 H), 8.51 (d, J=5.54 Hz, 1 H), 9.21 (s, 1 H). HRMS m/z Calcd for C20H24N6O [M+H]+ 365.20844, Found: 365.20887.
Example 25: 3-(5-piperidin-4-y!-4-pyrimidin-4-yl-1H-pyrazo!-3-yl)phenol hydrochloride
The above compound was prepared as follows according to Method E. To a suspension of tert- butyl 4-(3-(3-methoxyphenyl)-4-(pyrimidin-4-yl)-1 H-pyrazol-5-yl)piperidine-1 -carboxylate prepared according to the method of Benson, et al., WO 2003/104223 (150 mg, 0.441 mmol) in DCM, was added BBr3 (2.2 mL of a 1.0 M solution in DCM, 2.2 mmol) dropwise. The suspension was stirred at ambient temperature for 24 hours. The mixture was then cooled to -78 0C and the excess BBr3 quenched with MeOH (4 mL). After allowing the reaction to slowly warm to ambient temperature, the solvents were removed to afford a brown solid. The product was partially purified via silica gel chromatography eluting with 30% MeOH in EtOAc and the resulting solid was dissolved in water (1 mL) and several drops of concentrated HCI was added. The resulting precipitate (HCI salt) was triturated with a mixture of toluene / IPA (1 :1) to afford the product (107 mg, 67%). 1H NMR (400 MHz, METHANOL-D4) δ ppm 2.15 (m, 2 H), 2.32 (m, 2 H) 2.35 (m, 1 H), 3.52 (m, 3.92, 2 H), 3.92 (qd, J=6.09, 5.92 Hz, 2 H) 6.89 (s, 1 H) 6.91 - 6.99 (m, 2 H) 7.36 (t, J=7.81 Hz, 1 H) 7.47 (s, 1 H) 8.64 (s, 1 H) 9.47 (s, 1 H). HRMS m/z Calcd for C18H19NO5 [M+H]+ 322.16624 Found: 322.16569. Example 129:
3-(4-(2-(isobutylamino)pyrimidin-4-yl)-1-(1-methylazetidin-3-yl)-1H-pyrazol-3-yl)-5-methylphenol
The title compound was prepared according to method B. 3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenol
To a solution of tert-butyl 3-(3-(3-methoxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-
1H-pyrazol-1-yi)azetidine-1-carboxylate (8.81 g, 17.6 mmol) in dichloromethane (1.2 L) at OC was added BF3S(CH3)2 (19 mL, 180.5 mmol). After stirring for19 hrs with warming to room temperature, the temp was increased to 35C and was stirred for 3hr. The mixture was reduced to minimum volume and the residue concentrated from toluene/IPA. The residue was then taken up in a 1 :1 mixture of isopropyl alchol and dichloroethane and treated with sodium triacetoxyborohydride (29.9g, 141 mmol, gas evolution was observed and slight exotherm) followed by fomaldehyde (37% aq solution, 10.5 mL, 141 mmol) at ambient temperature. After stirring for 1 hr, the mixture was concentrated onto silica gel and was purified on silica gel using a gradient of 0-25% (ethanol containing 10% triethylamine) in a 1:1 mixture of DCM/EtOAc. As the desired fractions were concentrated, the product began to ppt out and was filtered off in 2 crops to yield 3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-3-yl)phenol (3.65g , 52%). This material was ~90% pure and was carried on without further purification. 1 H NMR (400 MHz, ACETONITRILE-c/3) δ ppm 9.04 (br. s., 1 H), 8.69 (d, J=5.31 Hz, 1 H), 8.49 (s, 1 H), 7.48 (d, J=5.31 Hz, 1 H), 6.78 (s, 1 H), 6.71 (s, 1 H), 6.68 (s, 1 H), 4.85 - 5.07 (m, 1 H), 3.71 (t, J=7.33 Hz, 2 H), 3.39 - 3.56 (m, 2 H), 3.14 (s, 3 H), 2.34 (s, 3 H), 2.26 (s, 3 H)
Example 130:
3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(2-(pyrazin-2-yl)ethylamino)pyrimidin-4-yl)-1H-pyrazoI-3- yl)phenol
The title compound was prepared following the procedure described in Example 13 (see also general method B) except 3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1/-/- pyrazol-3-yl) phenol was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin- 4-yl)-1/-/-pyrazol-yl)propanenitrile and (2-pyrazin-2-ylethyl)amine was used in place of (S)-(+)-1- aminopropan-2-ol to give 3-methyl-5-(1-(1-methylazetidin-3-yl)-4-(2-(2-(pyrazin-2-yl)ethylamino)pyrimidin- 4-yl)-1H-pyrazol-3-yl)phenol in 11 % yield. 1 H NMR (400 MHz, ACETONITRILE-d3/DMSO-c(6) δ ppm 8.96 (s, 1 H), 8.47 (s, 1 H), 8.40 (br. s., 1 H), 8.37 (d, J=2.27 Hz, 1 H), 8.19 (br. s., 1 H), 8.04 (d, J=5.05 Hz, 1 H), 6.79 (S, 1 H), 6.73 (s, 1 H), 6.59 (s, 1 H), 6.42 (d, J=3.79 Hz, 1 H), 6.32 (br. t, J=5.56 Hz, 1 H), 4.91 - 5.04 (m, 1 H), 3.81 (br. t, J=6.44 Hz, 2 H), 3.52 - 3.68 (br. m, 4 H), 2.93 - 3.02 (br. m, 2 H), 2.42 (s, 3 H, partially obscured by DMSO), 2.23 (s, 3 H) Examples 134 and 135: 5-(1-(2-hydroxyethyl)-4-(2-(2-(1-methylpyrrolidin-2-yl)ethylamino)pyrimidin- 4-yl)-1H-pyrazol-3-yl)-2,3-dimethylphenol and 5-(1-(2-hydroxyethyl)-4-(2-((tetrahydrofuran-3- yl)methylamino)pyrimidin-4-yl)-1H-pyrazol-3-yl)-2,3-dimethylphenol
5-(1-(2-hydroxyethyl)-4-(2-(2-(1-methylpyrrolidin-2-yl)ethylamino)pyrimidin-4-yl)-1 H-pyrazol-3-yl)- 2,3-dimethylphenol (Example 134) and 5-(1-(2-hydroxyethyl)-4-(2-((tetrahydrofuran-3- yl)methylamino)pyrimidin-4-yl)-1H-pyrazol-3-yl)-2,3-dimethylphenol (Example 135) were prepared by Method A starting from the protected phenol, methyl 3,4-dimethyl-5-(tetrahydro-2H-pyran-2- yloxy)benzoate and 4-methyl-2-(methylthio)pyrimidine. The pyrazole formed after the two step sequence involving enamine formation using DMF/DMA followed by reaction with hydrazine was alkylated with (2- bromoethoxy)(tert-butyl)dimethylsilane. Both the tetrahyropyran and tertbutyl dimethyl silyl protecting groups are removed in the subsequent oxidation step. Displacement of the sulfone with amines according to Method B gave the final targets.
Example 136: 2-(3-(3-hydroxy-4,5-dimethylphenyl)-4-(2-((S)-2-hydroxypropylamino)-pyrimidin-4-yl)- 1 H-py razol-1 -yl)acetonitrile
Example 136 was prepared following the procedure described in Example 13 (see also general method B) except 2-(3-(3-hydroxy-4,5-dimethylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1 - yl)acetonitrile was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)-pyrimidin-4-yl)- 1H-pyrazol-yl)propanenitrile and the alkylating step was carried out with bromoacetonitrile. The preparation gave 2-(3-(3-hydroxy-4,5-dimethylphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H- pyrazol-1-yl)acetonitrile in 60% yield. 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 8.15 (s, 2 H), 6.95 (s, 1 H), 6.91 (S, 1 H), 6.84 (s, 1 H), 6.52 (s, 1 H), 5.81 (br. s., 1 H), 5.23 (s, 2 H), 3.77 - 3.90 (br. m, 1 H), 3.31 - 3.57 (br. m, 2 H), 3.22 (br. s., 1 H), 2.28 (s, 3 H), 2.17 (s, 3 H, coincident with water peak), 1.10 (d, J=6.32 Hz, 3 H) Example 139:
2-(3-(3-Flouro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1 H-pyrazol-1- yl)acetonitrile (Example 139) was prepared according to method C except starting with 4-methyl-2- (methylthio)pyrimidine gives 4-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazoi-4-yl)-2-
(methylthio)pyrimidine. Subsequent Suzuki reaction with 3-fluoro-5-methoxyphenylboronic acid, removal of the pyrazole tetrahydropyranyl protecting group, pyrazole alkylation with bromoacetonitrile, oxidation of the sulfide to the sulfone, and finally displacement of the sulfone with amines gave the final target.
2-(3-(3-Flouro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile
The title compound was prepared following the procedure described in Example 13 except 2-(3- (3-flouro-5-hydroxypheny])-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1 -yl)acetonitrile was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-yl)propanenitrile to give 2-(3-(3-Flouro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile in 62% yield. 1 H NMR (400 MHz1 ACETONITRILE-c/s) δ ppm 8.10 - 8.17 (m, 2 H), 7.58 (br. s, 1 H), 6.78 - 6.89 (m, 2 H), 6.61 (dt, JM 0.61, 2.27 Hz, 1 H), 6.52 (d, J=5.05 Hz, 1 H), 5.80 (br. s, 1 H), 5.22 (s, 2 H), 3.71 - 3.87 (br. m, 1 H), 3.06 - 3.48 (br. m, 3 H), 1.07 (d, J=6.06 Hz, 3 H)
2-(3-(3-fIouro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile
The title compound was prepared following the procedure described in Example b-4-a except 2- (3-(3-flouro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 /-/-pyrazol-1-yl)acetonitrile was used in place of 2-(3-(3-chloro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile to give 2-(3-(3-flouro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile in
63% yield. 1H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 8.76 (d, J=5.31 Hz, 1 H), 8.41 (s, 1 H), 7.51
(d, J=5.31 Hz, 1 H), 7.42 (s, 1 H), 6.79 - 6.90 (m, 2 H), 6.67 (dt, J=10.61 , 2.27 Hz, 1 H), 5.27 (s, 2 H), 3.16 (s, 3 H)
2-(3-(3-flouro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)acetonitrile
The title compound was prepared following the procedure described in Example b-4-b except 4- (3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine was used in place of 4-(3-(3- chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine to give 2-(3-(3-flouro-5- methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1W-pyrazol-1-yl)-acetonitrile in 53% yield. 1H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 8.75 (d, J=5.56 Hz, 1 H), 8.43 (s, 1 H), 7.50 (d, J=5.56 Hz, 1 H), 6.86 - 6.95 (m, 2 H), 6.81 (dt, J= 11.05, 2.31 Hz, 1 H)1 5.27 (s, 2 H)1 3.79 (S1 3 H)1 3.14 (s, 3 H) 4-(3-(3-fluoro-5-methoxyphenyl)-1W-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine
The title compound was prepared following the procedure described in Example b-8-a except 4- (3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of tert-butyl 3- (3-(3-methoxy-5-methylphenyl)- 4-(2-(methylthio)pyrimidin-4-yl)-1/-/-pyrazol-1-yl)azetidine-1 carboxylate to give 4-(3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine in quantitative yield. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 11.58 (br. s, 1 H), 8.73 (d, J=5.31 Hz, 1 H), 8.31 (s, 1 H), 7.57 (d, J=5.31 Hz, 1 H), 6.86 - 7.01 (m, 2 H), 6.81 (dt, J=10.93, 2.24 Hz, 1 H), 3.80 (s, 3 H), 3.11 (s, 3 H) 4-(3-(3-fluoro-5-methoxyphenyl)-1W-pyrazol-4-yl)-2-(methylthio)pyrimidine
he title compound was prepared following the procedure described in Example c-1-c except 3- fluoro-5-methoxyphenylboronic acid was used in place of 3-methoxy-2,5-dimethylphenylboronic acid and 4-(3-iodo-1-tetrahydro-2/-/-pyran-2-yl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of 4-(3- iodo-1-tetrahydro-2W-pyran-2-yl)-1H-pyrazol-4-yl)pyrimidine. The mixture was heated in a microwave at 13O0C for 1 hour rather than in an oil bath at 1000C for 10 hours. After the reaction had cooled to room temperature, the supernatant solution was decanted into a separate flask. The solids were rinsed with a small amount of DMF and the rinse combined with the supernatant solution. The solvent was removed en vacuo and the residue was taken up in methanol and treated with HCI (4N in dioxane, 4 eq). The mixture was stirred at ambient temperature for 15 minutes then reduced to minimum volume. The residue was triturated with dichloromethane/ te/t-methyl butyl ether (~1 :1) and the solids collected by filtration to yield clean product. Another crop of product was obtained by purifying the filtrate on silica gel using a gradient of 0%-3% methanol in dichloromethane/ethyl acetate (1 :1) as eluent to give 4-(3-(3-fluoro-5- methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine in 64% yield. 1 H NMR (400 MHz1 DMSO-Cf6) Mixture of tautomers, major tautomer reported δ ppm 13.51 (br. s, 1 H), 8.52 (d, J=1.26 Hz, 1 H), 8.48 (d, J=5.31 Hz, 1 H), 7.17 (d, J=5.05 Hz, 1 H), 6.79 - 7.03 (m, 3 H), 3.77 (s, 3 H), 2.28 (s, 3 H) Example 140:
3-(1-(cyanomethyl)-4-(2-(2-hydroxyethylamino)primidin-4-yl)-1H-pyrazole-3-yl)-5- hydroxybenzonitrile (Example 140) was prepared according to method B and subsequent conversion of the chloro to the cyano following the procedure of Leadbeater and Arvela; JOC 2003, 68, 9122-9125.
3-(1-(cyanomethyl)-4-(2-(2-hydroxyethylamino)primidin-4-yl)-1H-pyrazole-3-yl)-5- hydroxybenzonitrile
To a solution of 2-(3-(3-chloro-5-hydroxyphenyl)-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1H- pyrazol-1-yl)acetonitrile (135mg, 0.36 mmol) in N-methylpyrrόlidinone (1 mL) was added nickel bromide
(80 mg, 0.36 mmol) and sodium cyanide (35 mg, 0.72 mmol). The resulting suspension was sealed in a microwave vial with a stir bar and heated at 200 watts in a microwave at 100C for 10 minutes, then at
150C for 10 minutes, then at 200C for 20 minutes, than again at 200C for 10 minutes. After cooling, the mixture was dropped into brine and partitioned with ethyl acetate. Some insoluble inorganics were removed by filtration before the layers were separated. The filtrate was separated into layers and the aqueous phase extracted twice with ethyl acetate. The combined organics were washed with water 3 times, followed by a brine wash, dried over Mg SO4 and reduced to minimum volume. The residue was purified on silica gel using a gradient of 0% to 8% methanol in a 1 :1 mixture of ethyl acetate and dichoromethane as eluent. The product was then purified by HPLC and lyophyllized to give 19 mg (15%) of the title compound. 1 H NMR (400 MHz, ACETONITRILE-c/3) δ ppm 8.09 - 8.23 (m, 2 H), 7.44 (t, J=1.39
Hz, 1 H), 7.29 - 7.39 (m, 1 H), 7.07 - 7.23 (m, 1 H), 6.55 (d, J=4.55 Hz, 1 H), 5.80 (br. s, 1 H), 5.23 (s, 2
H), 3.55 (br. s, 2 H), 3.34 (br. s, 2 H) Example 141:
2-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-N- methylacetamide (Example 141)
The title compound was prepared following the procedure described in Example 13 (See also general Method B) except 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H- pyrazol-1-yl)acetonitrile was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2- (methylsulfonyl)pyrimidin-4-yl)-1/-/-pyrazol-yl)propanenitrile and methylamine was used in place of (S)-(+)- 1 -aminopropan-2-ol to give 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1 H- pyrazol-1-yl)-N-methylacetamide in 43% yield. 1H NMR (400 MHz, ACETONITRILE-d3 /DMSO-Cf6) δ ppm 9.06 (s, 1 H), 8.12 (br. s., 1 H), 8.03 (d, J=5.05 Hz, 1 H), 7.66 - 7.75 (br. m, 1 H), 6.76 (s, 1 H), 6.71 (s, 1 H), 6.59 (S, 1 H), 6.25 - 6.43 (m, 2 H), 4.77 (s, 2 H), 2.77 (d, J=4.55 Hz, 3 H), 2.65 (d, J=4.80 Hz, 3 H), 2.22 (s, 3 H).
Example 142:
2-(3-(3-chIoro-4-fluoro-5-hydroxyphenyl)-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile (Example 142)
The title compound was prepared following the procedure described in Example 13 (See also general Method B) except 2-(3-(3-chloro-4-fluoro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)- 1H-pyrazol-1-yl)acetonitrile was used in place of 3-(3-(3-hydroxy-5-methylphenyl)-4-(2- (methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-yl)propanenitrile and ethanolamine was used in place of (S)- (+)-1-aminopropan-2-ol to give 2-(3-(3-chloro-4-fluoro-5-methoxyphenyl)-4-(2-(2- hydroxyethylamino)pyrimidin-4-yl)-1/-/-pyrazol-1-yl)acetonitrile in 34% yield. 1H NMR (400 MHz, ACETONITRILE-ck) δ ppm 8.08 - 8.19 (m, 2 H), 7.79 (br. s., 1 H), 7.14 - 7.23 (m, 2 H), 6.55 (d, J=5.05 Hz, 1 H), 5.77 (br. m., 1 H), 5.21 (s, 2 H), 3.58 (t, J=4.67 Hz, 2 H), 3.33 - 3.42 (br. m, 4 H), 3.24 (br. s., 1 H)
2-(3-(3-chloro-4-fluoro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile
The title compound was prepared following the procedure described in Example b-4-a except 2- (3-(3-chloro-4-fluoro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1/-/-pyrazol-1-yl)acetonitrile was used in place of 2-(3-(3-chloro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile to give 2-(3-(3-chloro-4-fluoro-5-hydroxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H- pyrazol-1-yl)acetonitrile in 65% yield. 1 H NMR (400 MHz, ACETONITRILE-c/3) δ ppm 8.77 (d, J=5.31 Hz, 1 H), 8.40 (s, 1 H), 7.65 (br. s., 1 H), 7.52 (d, J=5.31 Hz, 1 H), 6.98 - 7.23 (m, 2 H), 5.26 (s, 2 H), 3.17 (s, 3 H)
2-(3-(3-chloro-4-fluoro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile
The title compound was prepared following the procedure described in Example b-4-b except 4- (3-(3-chloro-4-fluoro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine was used in place of 4-(3-(3-chloro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine to give 2-(3-(3-chloro-4- fluoro-5-methoxyphenyl)-4-(2-(methylsulfonyl)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile in 58% yield. 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 8.76 (d, J=5.30 Hz, 1 H), 8.44 (s, 1 H), 7.51 (d, J=5.31 Hz, 1 H), 7.13 - 7.28 (m, 2 H), 5.27 (s, 2 H), 3.85 (s, 3 H), 3.15 (s, 3 H) 4-(3-(3-chloro-4-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine
The title compound was prepared following the procedure described in Example b-6-a except 4- (3-(3-chloro-4-fluoro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylthio)pyrimidine was used in place of 3- (3-(3-methyl-5-(trityloxy)phenyl)-4-(2-(methylthio)pyrimidin-4-yl)-1/-/-pyrazol-yl)propanenitrile to give 4-(3- (3-chloro-4-fluoro-5-methoxyphenyl)-1 H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine in 73% yield. 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 11.60 (br. s., 1 H), 8.74 (d, J=5.31 Hz, 1 H), 8.33 (s, 1 H), 7.58 (d, J=5.31 Hz, 1 H), 7.17 - 7.27 (m, 2 H), 3.86 (s, 3 H), 3.12 (s, 3 H) 4-(3-(3-chloro-4-fluoro-5-methoxyphenyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine
The title compound was prepared following the procedure described in Example 1 (See also General Method A) for 4-(3-(3-chloro-5-methoxyphenyl)-1W-pyrazol-4-yl)pyridine except methyl 3-chloro- 4-fluoro-5-methoxybenzoate was used in place of methyl 3-chloro-5-methoxybenzoate and 4-methyl-2- (methylthio)pyrimidine was used in place of 4-picoline to give 4-(3-(3-chloro-4-fluoro-5-methoxyphenyl)- 1H-pyrazol-4-yl)-2-(methylthio)pyrimidine in 42% yield. 1 H NMR (400 MHz, ACETONITRILE-Cf3) δ ppm 11.47 (br. s., 1 H), 8.38 (d, J=5.30 Hz, 1 H), 8.20 (s, 1 H), 7.16 - 7.36 (m, 2 H), 7.07 (d, J=5.05 Hz, 1 H), 3.85 (s, 3 H), 2.34 (s, 3 H) Methyl 3-chloro-4-fluoro-5-methoxybenzoate
To a solution of the S-chloro^-fluoro-δ-hydroxybenzoic acid (2.33g, 12.2 mmol)in DMF (20 mL) was added freshly ground potassium bicarbonate (2.69g, 26.9 mmol). The resulting dark green slurry was stirred at ambient temperature for a few minutes then iodomethane (1.9 mL, 30.6 mmol) was added and the resulting mixture was stirred at 4OC. After 20 hr, more iodomethane (0.4mL, 6.4 mmol) and potassium bicarbonate (0.5g, 5 mmol) was added and stirring continued at 4OC. After another 24hr, solid NaOH (300mg, 7.5 mmol) was added and stirring continued at 4OC for 1 hr. The mixture was poured into aqueous sodium bicarbonate/brine mixture and the resulting tan solids were collected by filtration, rinsed with water and air dried to give methyl 3-chloro-4-fluoro-5-methoxybenzoate in 72% yield. 1H NMR (400 MHz, ACETONITRILE-da) δ ppm 7.68 (dd, J=6.32, 2.02 Hz, 1 H), 7.62 (dd, J=7.58, 2.02 Hz, 1 H), 3.94 (s, 3 H), 3.88 (S, 3 H) 3-chloro-4-fluoro-5-hydroxybenzoic acid
A solution of 3-chloro-2-fluoro-5-(trifluoromethyl)phenol (5g, 23 mmol) in cone H2SO4 (15ml_) was heated by microwave to 130C for lOminutes. (Caution: Reaction develops pressure. Vent carefully before opening.) The resulting dark mixture was dropped into water and the resulting purple solids collected by filtration, rinsed with water and air dried to give 3-chloro-4-fluoro-5-hydroxybenzoic acid in
73% yield. 1H NMR (400 MHz, DMSO-Cf6) δ ppm 13.25 (br. s., 1 H), 10.83 (s, 1 H), 7.29 - 7.69 (m, 2 H)
Example 143: 2-(3-(4-fluoro-3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1H- pyrazol-1-yl)acetonitrile
The title compound was made in a similar fashion to Example 13: 2-(3-(3-chloro-4-fluoro-5- hydroxyphenyl)-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile, starting from methyl 4-fluoro-3-methoxy-5-methylbenzoate and 4-methyl-2-(methylthio)pyrimidine. The final step was done following the procedure described in Example 13 except excess anhydrous methyl amine was used at -78C with warming to room temperature over 3 hours in place of (S)-(+)-1-aminopropan-2-ol at 8OC for 2 hours to give 2-(3-(4-fluoro-3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1 H-pyrazol-1- yl)acetonitrile in 74% yield. 1H NMR (400 MHz, ACETONITRILE-c/3) δ ppm 8.14 (s, 1 H), 8.1 1 (d, J=5.31 Hz, 1 H), 7.14 (s, 1 H), 6.85 - 6.99 (m, 2 H), 6.44 (d, J=5.05 Hz, 1 H), 5.54 (br. s., 1 H), 5.20 (s, 2 H), 2.82 (d, J=4.80 Hz, 3 H), 2.26 (d, J=2.27 Hz, 3 H) Methyl 4-fluoro-3-methoxy-5-methylbenzoate
A suspension of methyl S-chloro^-fluoro-δ-methoxybenzoate, methyl boronic acid, freshly ground K3PO4, phosphine ligand and water (8uL) in toluene/THF (1mL, 1:1) was degassed with N2 bubbler for a few minutes. Palladium acetate suspended in 0.1 mLTHF was added and the mixture was sealed and heated in microwave at 100C for 10 min. TLC shows complete conversion to new spot. The mixture was diluted with EtOAc and washed with aq. NaHCO3. The organics were dried over MgSO4, reduced to minimum volume and the residue purified on silica gel using dichloromethane as eluent to give methyl 4- fluoro-3-methoxy-5-methylbenzoate in 98% yield. 1H NMR (400 MHz, ACETONITRILE-da) δ ppm 7.46 - 7.54 (m, 2 H), 3.85 (s, 3 H), 2.29 (d, J=2.53 Hz, 3 H). See Buchwald et al; Angew. Chem. 2004,116,1907- 1912.
Example 144: (S)-1-(4-(1-(cyanomethyl)-3-(3-hydroxy-5-methylphenyl)-1H-pyrazol-4-yl)pyrimidin-2- ylamino)propan-2-yl 2,6-dimethoxybenzoate
To a suspension of 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4- yl)-1H-pyrazol-1-yl)acetonitrile (200 mg, 0.55 mmol) in dichloromethane (5 mL) was added Hunig's Base (0.15 mL, 0.86 mmol). The resulting mixture was cooled to -10C and 2,6-dimethoxybenzoyl chloride (120 mg, 0.6 mmol) was added. The mixture was allowed to warm slowly with stirring overnight. The mixture was cooled to -10C and more 2,6-dimethoxybenzoyl chloride (40m, 0.2 mmol) was added. The mixture was allowed to slowly warm to RT and was stirred at RT for 3 days. The mixture was loaded directly onto a silica gel column and purified using a gradient of 0% to 5% methanol in a 1:1 mixture of ethyl acetate and dichoromethane as eluent. The product was repurified on silica gel using a gradient of 0% to 50% ethyl acetate in dichloromethane to give (S)-1-(4-(1-(cyanomethyl)-3-(3-hydroxy-5-methylphenyl)-1 H- pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-yl 2,6-dimethoxybenzoate in 18% yield. 1H NMR (400 MHz, ACETONlTRILE-d3) δ ppm 8.17 (br. s., 1 H), 8.13 (d, J=5.31 Hz, 1 H), 7.36 (t, J=8.46 Hz, 1 H), 6.92 (br. s., 1 H), 6.86 (s, 1 H), 6.73 (s, 1 H), 6.65 - 6.70 (m, 3 H), 6.50 (br. d, J=4.04 Hz, 1 H), 5.79 (dd, J=6.95, 4.93 Hz, 1 H), 5.24 (br. s., 1 H), 5.21 (s, 2 H), 3.81 (s, 6 H), 3.68 (br. s., 1 H), 3.28 (br. s., 1 H), 2.29 (s, 3 H), 1.25 (br. d, J=5.05 Hz, 3 H)
Table 1
(s, (s,
(m,
(s,
1 1 H) 1 1 H)
(t,
Hz,
(s,
(s, 1 1 H) 1
δ
(s, (s, (s,
δ 1 1 H) (dd, - (m,
(m,
δ 1 1 H) (dd, - (m,
(m,
(m, H, H) δ (d, 1 1 -
δ 1 1H) J =
2
δ
1 - 2
δ
J =
2
δ (m, (m, 6.74 (m, (s,
δ (m, (s, 2H) 1H) δ (s, (m,
8.40
H, s) δ
H,
δ (s,
H,
δ
d, J J = = =
δ Hz)1 J =
m),
δ
d, J J =
δ (1 H, Hz),
1.7, (3H, δ (d, 6 2 1 2 H) Hz1
δ (s, - H) H) H) 1 1
ppm s, 1 1 1 1
ppm s, 1 1 1 1 2 4 3 3 δ 3 1 1 1 H) H)
δ 3 1 1 1 H)
1
Hz, 3.78 2 (t, 1 1 1 H)
3.74
- Hz, 1 1 1
3.74 1 -
1 1 1 H)
- - 2 2 - H)
(s,
1
- 2
Example 128: Raf Biochemical Assay
Compounds of the present invention were evaluated for potency against b-Raf using an in vitro kinase assay. Raf kinase activity is measured in vitro by determining transfer of radiolabeled 32-P phosphate from ATP to the specific Raf substrate Mek1. Full-length wild type b-Raf is expressed in recombinant form and purified from bacterial or insect cells. Recombinant Mek1 is purified from E. coli bacterial cells. In one assay format (designated G1), the full-length wild type Mek1 is used as the b-Raf substrate. In a second assay format (designated G2), the full-length K97R Mek1 mutant is used as the b- Raf substrate.
In vitro kinase assays are performed in solution containing the following; 50 mM Hepes (pH 7.4), 5 nM b-Raf, 0.8 μM Mek1 , 10 mM MgCI2, 25 μM ATP, 0.002% (v/v) Tween-20, 5 μg/mL leupeptin, 1.2 mM DTT, 2% (v/v) DMSO, 0.2-1.0 μCi [γ-32P]ATP per well.
The assays are performed in wells of a 96 well polypropylene round bottom plate, each well containing 43.5 μl_ assay mix and 1.5 μl_ inhibitor compound or DMSO vehicle. 15 μL of b-Raf mix is added and the plate is shaken on a plate shaker and preincubated for 10 minutes at ambient temperature.
The reaction is started by addition of 15 μL ATP mix and shaking. The reaction is terminated after 40 minutes by addition of 25 μL 0.5 M EDTA (pH 7.4).
60 μL of the stopped reaction is transferred to a well of a 96-well nylon 66 Biodyne A membrane Silent Screen filter plate (Nalge/Nunc: 256081). The wells are filtered and washed five times with 0.85% phosphoric acid. The filter is placed in a tray with about 50 mL 0.85% phosphoric acid and gently rotated for 10 minutes on an orbital shaker. The procedure is repeated once with fresh 0.85% phosphoric acid.
Five samples of 0.5 μL of ATP mix are also spotted onto filter paper for calculation of specific activity. The filters are air dried for one hour and sandwiched between cellophane wrap on an Amersham Biosciences Storage Phosphor Screen and developed at least over night. The image is read using a Molecular Dynamics Storm 840 phosphoimager. Volumes of spots are calculated using ImageQuantδ.l
Raf kinase activity is calculated from the specific activity of [32-P] ATP, 32-P incorporation into Mek1 , and the concentration of b-Raf.
Example 129: Raf Cellular Assay
Compounds of the present invention were evaluated for potency against b-Raf using a cellular assay as follows. The activity of Raf kinases in cells is determined by measuring the level of phosphorylation of Mek1/2 at serine 217/221 , the site phosphorylated by Raf kinases in vivo. Mek1/2 Ser phosphorylation is measured using anti-phospho-Mek1/2 antibodies (Cell Signaling #9121) in an ELISA format.
Healthy growing human melanoma A2058 cells (harboring a b-Raf mutation) are used for the assay. A2058 cells are grown in 10% FBS DMEM medium. When the cells are near 85%+ confluence, the cells are rinsed with PBS once and trypsinized with trypsin/EDTA for 3 minutes. The cells are resuspended in 10% FBS DMEM and are centrifuged down at 1000 rpm for 5 minutes. The cells are resuspended in 0.5% FBS DMEM and counted on a cell counter. The cells are seeded at 50,000 cells/well in a volume of 100 μL/well in 0.5% FBS DMEM in a 96 well flat-bottom plate. The negative control wells receive only 100 μl_ of 0.5% FBS DMEM medium without cells. The plate is incubated overnight in a cell culture incubator with 5% CO2 at 37 0C.
On day 2, testing compounds are prepared in 0.5% FBS DMEM medium and serially diluted at 1:3 for 11 test concentrations. Each concentration of the compounds is tested in duplicate. The compound solutions are added at 25 μL/well to the corresponding wells in the cell plate, and 25 μL/well of the vehicle (0.5% DMSO in 0.5% FBS DMEM) is added to the negative control wells (no cells) and the positive control wells (cells without compounds). The plate is incubated for 1 hour in a cell culture incubator with 5% CO2 at 37 °C. After 1 hour of incubation, the medium is removed, 100 μL/well of cell lysis buffer is added into the cell plate, and the plate is shaken for 15 minutes at room temperature. After 15 minutes, the cell lysates are transferred to an ELISA plate (pre-coated with anti-Mek1 anti-body, Cell Signaling #2352), and the plate is incubated with gentle shaking for 2 hours at room temperature. After 2 hours, the contents of the wells are aspirated and the wells are washed 4 times with wash buffer. 100 μL of phospho-Mek1/2 detection antibody (Cell Signaling #9121) is added into each well and the plate is incubated with gentle shaking for 1 hour at room temperature. After 1 hour, the wells are aspirated and washed 4 times with wash buffer. 100 μL of anti-rabbit IgG HRP-linked antibody (Cell Signaling #7074) is added to each well, and the plate is incubated with gentle shaking for 1 hour at room temperature. After 1 hour, the contents of the wells are aspirated and the wells are washed 4 times with wash buffer. 100 μL of TMB substrate solution (Sigma #T0440) is added into each well, and the plate is incubated with gentle shaking at room temperature for 20 minutes. After 20 minutes of color development, 100 μL of stop solution (1N hydrochloric acid) is added to each well to terminate color development. The plate is read at 450 nm on an ELISA plate reader. Example 130: B-Raf Biochemical and Cellular Activity Data

Claims

Claims We claim:
1. A compound of Formula (I)
(I) wherein:
R1 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b),
-C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group; each R2 is independently H, halogen, (Ci to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to
C8) alkoxy, or cyano; R3 is H, or -NR11(CH2)nR7;
R4 is -SR8, -OR8, H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, -N(R5aR5b),
-C(O)N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C3 to C8) cycloalkyl, (C6 to C14) aryl, (C2 to C9) cycloheteroalkyl, and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group; R5a and R5b are each independently H, (C-, to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to
C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C2 to C9) cycloheteroalkyl and (C3 to
C8) cycloalkyl is optionally substituted with at least one R6 group;
R6 is -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, cyano, (C3 to C8) cycloalkyl, (C2 to C9) cycloheteroalkyl, (C6 to C14) aryl, (C2 to C9) heteroaryl, -(CH2)πC(O)R9, or -N(R1OaR1ob); R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, (C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C1 to
C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen,
-OH, (C1 to C6) alkyl, -N(R5aR5b), -OC(O)R12, (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl;
R8 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -(CH2)n-cyano, -(CH2)n-(C3 to C8) cycloalkyl, -(CH2Jn-(C6 to C14) aryl, -(CH2)n-(C2 to C9) cycloheteroalkyl, or -(CH2)n-(C2 to C9) heteroaryl; R9 is H, -OH, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C1 to C8) alkoxy, or
_N(R10aR10b);
R1Oa and R10b are each independently H, (Ci to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl; R11 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C2 to
C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to C14) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloaikyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl; R12 is (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl,
(C2 to C9) heteroaryl, (C3 to C8) cycloalkyl, or (C6 to Ci4) aryl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) heteroaryl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) aikyl, -N(RSaR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, (C1 to C8) alkoxy, and (C2 to C9) cycloheteroalkyl; X is N or CH; m is O, 1 , 2, or 3; each n is independently 0, 1, 2, 3, or 4; p is O, 1 , 2, 3, or 4; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R7 is H, (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, -N(R5aR5b), (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C1 to C6) alkyl, (C2 to C8) alkenyl, (C2 to C8) alkynyl, (C2 to C9) cycloheteroalkyl, and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C6) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C2 to C9) heteroaryl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl.
3. The compound according to claim 1 , wherein p is 0, 1 , 2, or 3 and R1 is H, -N(R5aR5b), (C1 to C6) alkyl, cyano, (C2 to C9) cycloheteroalkyl, or (C2 to C9) heteroaryl, wherein each of said (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl and (C2 to C9) heteroaryl is optionally substituted with at least one R6 group.
4. The compound according to claim 3, wherein p is 1 or 2 and R1 is cyano or (C1 to C6) alkyl.
5. The compound according to claim 3, wherein p is 0 and R1 is H or (C1 to C6) alkyl.
6. The compound according to claim 3, wherein p is 0 or 1 and R1 is (C2 to C9) cycloheteroalkyl and is optionally substituted with at least one R6 group.
7. The compound according to claim 6, wherein the (C2 to Cg) cycloheteroalkyl is selected from the group consisting of:
, and wherein each of said (C2 to C9) cycloheteralkyl groups are optionally substituted with at least one R6 group.
8. The compound according to claim 1 , wherein m is 1 or 2 and the compound of Formula (I) has the following structure:
9. The compound according to claim 8, wherein each R2 is independently halogen, -OCH3, or (C1 to C6) alkyl.
10. The compound according to claim 9, wherein m is 1 and the compound of Formula (I) has the following structure:
wherein:
R2 is Cl or CH3.
11. The compound according to claim 1 , wherein X is N and R3 is -NH(CH2)nR7.
12. The compound according to claim 11, wherein R7 is H, (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, or (C3 to C8) cycloalkyl, wherein each of said (C1 to C6) alkyl, (C2 to C9) cycloheteroalkyl, and (C3 to C8) cycloalkyl are optionally substituted with at least one group selected from halogen, -OH, (C1 to C5) alkyl, -N(R5aR5b), (C3 to C8) cycloalkyl, (C6 to C14) aryl, and (C2 to C9) cycloheteroalkyl.
13. The compound according to claim 12, wherein R3 is -NH(CH2)nR7 where n is 1 or 2, and R7 is (Ci to C6) alkyl and is substituted with one -OH group.
14. The compound according to claim 1 , wherein X is N and R4 is H, (C2 to C9) cycloheteroalkyl, -OR8, or -N(R5aR5b), wherein said (C2 to C9) cycloheteroalkyl is optionally substituted with at least one R6 group.
15. The compound according to claim 1 , which is selected from the group consisting of: 3-chloro-5-(1- isopropyl-4-pyrimidin-4-yl-1 H-pyrazol-3-yl)phenol; 3-[4-(2-aniiinopyrimidin-4-yl)-1-methyl-1 H-pyrazol-3-yl]- 5-chlorophenol; 2-(3-(3-chloro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1/-/- pyrazol-1-yl)acetonitrile; 2-(3-(3-Chloro-5-hydroxyphenyl-4-(2-(2-hydroxyethylamino)pyrimidin-4-yl)-1/-/- pyrazol-1-yl)acetonitrile; 3-[3-(3-hydroxy-5-methylphenyl)-4-(2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4- yl)-1H-pyrazol-1-yl]propanenitrile; 3-(3-(3-hydroxy-5-methylphenyl)-4-(2-((R)-2- hydroxypropylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile; 3-chloro-5-[4-[2-
(isobutylamino)pyrimidin-4-yl]-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl]phenol; 3-chloro-5-{4-[2-
(isobutylamino)pyrimidin-4-yl]-1-piperidin-4-yl-1W-pyrazol-3-yl}phenol; 3-chloro-5-[4-{2-[(2-hydroxy-2- methylpropyl)amino]pyrimidin-4-yl}-1-(1-methylpiperidin-4-yl)-1H-pyrazol-3-yl]phenol; 3-chloro-5-{4-[2- (isobutylamino)pyrimidin-4-yl]-1-methyl-1 H-pyrazol-3-yl}phenol; {3-(3-chloro-5-hydroxyphenyl)-4-[2- (tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1H-pyrazol-1-yl}acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4-{2- [(2-hydroxy-1-methylethyl)amino]pyrimidin-4-yl}-1 H-pyrazol-1 -yl]acetonitrile; [4-(2-aminopyrimidin-4-yl)-3- (3-chloro-5-hydroxyphenyl)-1 H-pyrazol-1 -yl]acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2-{[2-(1 H- imidazol-4-yl)ethyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1-yl]acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2- {[(2R)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1 -yljacetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4- (2-{[(2S)-2-hydroxypropyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1 -yljacetonitrile; 3-[4-{2-[(2- hydroxyethyl)amino]pyrimidin-4-yl}-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol-1-yl]propanenitrile; 3-{3-(3- hydroxy-5-methylphenyl)-4-[2-(tetrahydrofuran-3-ylamino)pyrimidin-4-yl]-1 H-pyrazol-1 -yljpropanenitrile; [3- (3-chloro-5-hydroxyphenyl)-4-(2-{[(1S)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)-1 H-pyrazol-1 - yl]acetonitrile; [3-(3-chloro-5-hydroxyphenyl)-4-(2-{[(1R)-2-hydroxy-1-methylethyl]amino}pyrimidin-4-yl)- 1 H-pyrazol-1 -yl]acetonitrile; 2-(3-(3-fluoro-5-hydroxyphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4- yl)-1 H-pyrazol-1 -yl)acetonitrile; 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-((S)-2-hydroxypropylamino)- pyrimidin-4-yl)-1 H-pyrazol-1 -yl)-acetonitrile; 3-(1-(cyanomethyl)-4-(2-(2-hydroxyethylamino)-pyrimidin-4- yl)-1H-pyrazol-3-yl)-5-hydroxybenzonitrile; 3-(4-(2-((S)-2-hydroxypropylamino)-pyrimidin-4-yl)-1-((5- methylisoxazol-3-yl)methyl)-1 H-pyrazol-3-yl)-5-methylphenol; 5-(4-(2-(isopropylamino)pyrimidin-4-yl)-1-(1- methyl-azetidin-3-yl)-1 H-pyrazol-3-yl)-2,3-dimethylphenol; 5-(1-(2-hydroxyethyl)-4-(2-(2-(1-methyl- pyrrolidin-2-yl)-ethylamino)pyrimidin-4-yl)-1H-pyrazol-3-yl)-2,3-dimethylphenol; 5-(1-(2-hydroxy-ethyl)-4- (2-((tetrahydrofuran-3-yl)methylamino)-pyrimidin-4-yl)-1H-pyrazol-3-yl)-2,3-dimethyl-phenol; 3-(4-(2-
(isobutylamino)pyrimidin-4-yl)-1-(1-methylazetidin-3-yl)-1 H-pyrazol-3-yl)-5-methylphenol; 2-(3-(3-hydroxy- 4,5-dimethylphenyl)-4-(2-((S)-2-hydroxypropylamino)pyrimidin-4-yl)-1 H-pyrazol-1 -yl)acetonitrile; 3-methyl- 5-(1-(1-methylazetidin-3-yl)-4-(2-(2-(pyrazin-2-yl)-ethylamino)pyrimidin-4-yl)-1 H-pyrazol-3-yl)phenol; 2-(3- (3-hydroxy-5-methylphenyl)-4-(2-(methylamino)pyrimidin-4-yl)-1H-pyrazol-1-yl)-N-methyl-acetamide; 2-(3- (3-chloro-4-fluoro-5-hydroxyphenyl)-4-(2-(2-hydroxyethylamino)-pyrimidin-4-yl)-1H-pyrazol-1- yl)acetonitrile; 2-(3-(3-hydroxy-5-methylphenyl)-4-(2-((2-hydroxyethyl)(methyl)-amino)pyrimidin-4-yl)-1 H- pyrazol-1-yi)acetonitrile; 2-(4-(2-(dimethylamino)pyrimidin-4-yl)-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol- 1-yl)-acetonitrile; (S)-1-(4-(1-(cyanomethyl)-3-(3-hydroxy-5-methylphenyl)-1 H-pyrazol-4-yl)-pyrimidin-2- ylamino)propan-2-yl-2,6-dimethoxybenzoate; 2-(3-(4-fluoro-3-hydroxy-5-methylphenyl)-4-(2-
(methylamino)pyrimidin-4-yl)-1 H-pyrazol-1-yl)acetonitrile and (S)-1-(4-(1-(cyanomethyl)-3-(3-hydroxy-5- methylphenyl)-1 H-pyrazol-4-yl)pyrimidin-2-ylamino)propan-2-yl acetate, or a pharmaceutically acceptable salt thereof.
16. A pharmaceutical composition, comprising at least one compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
17. A method of treating abnormal cell growth in a mammal in need thereof, comprising the step of administering to said mammal a therapeutically effective amount of at least one compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
18. The method of claim 17, wherein the abnormal cell growth is cancerous.
19. A method of inhibiting Raf enzymatic activity, comprising contacting a Raf enzyme with a Raf- inhibiting amount of at least one compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.
20. Use of a compound according to any one of claims 1 to 15, or a salt or solvate thereof, in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal.
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Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103739595A (en) 2006-10-02 2014-04-23 Irm责任有限公司 Compounds and compositions as protein kinase inhibitors
JP5603770B2 (en) * 2007-05-31 2014-10-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング CCR2 receptor antagonist and use thereof
WO2009016460A2 (en) 2007-08-01 2009-02-05 Pfizer Inc. Pyrazole compounds and their use as raf inhibitors
UA104849C2 (en) 2007-11-16 2014-03-25 Інсайт Корпорейшн 4-pyrazolyl-n-arylpyrimidin-2-amines and 4-pyrazolyl-n-heteroarylpyrimidin-2-amines as inhibitors of janus kinases
EP2224932A4 (en) * 2007-11-28 2011-09-14 Tragara Pharmaceuticals Inc Cancer treatment using cox-2 inhibitor and antimetabolite combinations
PT2324008E (en) 2008-07-24 2012-06-25 Nerviano Medical Sciences Srl 3,4-diarylpyrazoles as protein kinase inhibitors
CN102256963B (en) 2008-12-19 2014-06-11 贝林格尔.英格海姆国际有限公司 Cyclic pyrimidine-4-carboxamides as CCR2 receptor antagonists for the treatment of inflammation, asthma and COPD
ES2422263T3 (en) * 2008-12-19 2013-09-10 Nerviano Medical Sciences Srl Bicyclic pyrazoles as protein kinase inhibitors
KR101111247B1 (en) * 2009-07-17 2012-06-12 한국과학기술연구원 Pyrazole compounds for Ros kinase inhibitors
AR077975A1 (en) 2009-08-28 2011-10-05 Irm Llc PIRAZOL PYRIMIDINE DERIVATIVES AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS
EP2308866A1 (en) 2009-10-09 2011-04-13 Bayer CropScience AG Phenylpyri(mi)dinylpyrazoles and their use as fungicides
KR101123071B1 (en) * 2009-10-23 2012-03-05 한국과학기술연구원 Novel imidazole derivatives or pharmaceutically acceptable salts thereof, preparation method thereof and pharmaceutical composition for the prevention and treatment of melanoma containing the same as an active ingredient
ES2674275T3 (en) 2009-12-17 2018-06-28 Centrexion Therapeutics Corporation CCR2 receptor antagonists and uses thereof
CN104958294A (en) * 2010-01-27 2015-10-07 内尔维安诺医学科学有限公司 Sulfonamido derivatives of 3, 4-diarylpyrazoles as protein kinase inhibitors
AR081810A1 (en) 2010-04-07 2012-10-24 Bayer Cropscience Ag BICYCLE PIRIDINYL PIRAZOLS
WO2011141474A1 (en) 2010-05-12 2011-11-17 Boehringer Ingelheim International Gmbh Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
JP5646736B2 (en) 2010-05-12 2014-12-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Novel CCR2 receptor antagonists, methods for their preparation, and their use as drugs
WO2011144501A1 (en) 2010-05-17 2011-11-24 Boehringer Ingelheim International Gmbh Ccr2 antagonists and uses thereof
WO2011147772A1 (en) 2010-05-25 2011-12-01 Boehringer Ingelheim International Gmbh Ccr2 receptor antagonists
US8962656B2 (en) 2010-06-01 2015-02-24 Boehringer Ingelheim International Gmbh CCR2 antagonists
EP2601185B1 (en) 2010-08-03 2015-10-07 Nerviano Medical Sciences S.r.l. Derivatives of pyrazolophenyl-benzenesulfonamide compounds and use thereof as antitumor agents
ES2541289T3 (en) * 2010-12-01 2015-07-17 Nissan Chemical Industries, Ltd. Pyrazole compounds that have a therapeutic effect on multiple myeloma
CN103402519B (en) 2011-04-18 2015-11-25 卫材R&D管理有限公司 Therapeutic agent for tumor
EP2731941B1 (en) 2011-07-15 2019-05-08 Boehringer Ingelheim International GmbH Novel and selective ccr2 antagonists
RU2622015C2 (en) 2011-11-11 2017-06-08 Новартис Аг Method for proliferative disease treatment
SI2782557T1 (en) 2011-11-23 2019-02-28 Array Biopharma, Inc., Pharmaceutical formulations
KR20160100975A (en) 2013-12-23 2016-08-24 노파르티스 아게 Pharmaceutical combinations
PT3317270T (en) 2015-07-02 2020-08-24 Centrexion Therapeutics Corp (4-((3r,4r)-3-methoxytetrahydro-pyran-4-ylamino)piperidin-1-yl)(5-methyl-6-(((2r,6s)-6-(p-tolyl)tetrahydro-2h-pyran-2-yl)methylamino)pyrimidin-4yl)methanone citrate
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
TW202100520A (en) 2019-03-05 2021-01-01 美商英塞特公司 Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2020205560A1 (en) 2019-03-29 2020-10-08 Incyte Corporation Sulfonylamide compounds as cdk2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2020223469A1 (en) 2019-05-01 2020-11-05 Incyte Corporation N-(1-(methylsulfonyl)piperidin-4-yl)-4,5-di hydro-1h-imidazo[4,5-h]quinazolin-8-amine derivatives and related compounds as cyclin-dependent kinase 2 (cdk2) inhibitors for treating cancer
CA3150681A1 (en) 2019-08-14 2021-02-18 Incyte Corporation Imidazolyl pyrimidinylamine compounds as cdk2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2021120890A1 (en) 2019-12-20 2021-06-24 Novartis Ag Pyrazolyl derivatives useful as anti-cancer agents
AU2021372796A1 (en) * 2020-10-30 2023-06-01 Novartis Ag New crystalline forms of a kras g12c inhibitor compound
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU754830C (en) * 1997-05-22 2004-02-12 G.D. Searle Llc Substituted pyrazoles as p38 kinase inhibitors
AU7922100A (en) * 1999-10-25 2001-05-08 Basf Aktiengesellschaft Agrochemical compositions containing pyrazoles as the active agents and use of said compositions as plant protection agents with a fungicidal action
ATE374753T1 (en) * 2001-12-21 2007-10-15 Vernalis Cambridge Ltd 3-(2,4)DIHYDROXYPHENYL-4-PHENYLPYRAZOLES AND THEIR MEDICAL USE
TW200400960A (en) * 2002-06-05 2004-01-16 Pharmacia Corp Novel pyrazoles and their use as P38 kinase inhibitors
GB0215844D0 (en) * 2002-07-09 2002-08-14 Novartis Ag Organic compounds
KR100896380B1 (en) * 2005-01-07 2009-05-08 화이자 프로덕츠 인코포레이티드 Heteroaromatic quinoline compounds and their use as pde10 inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007105058A2 *

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