WO2006055184A2 - Novel heterocycle derivatives useful as selective androgen receptor modulators (sarms) - Google Patents

Novel heterocycle derivatives useful as selective androgen receptor modulators (sarms) Download PDF

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WO2006055184A2
WO2006055184A2 PCT/US2005/038292 US2005038292W WO2006055184A2 WO 2006055184 A2 WO2006055184 A2 WO 2006055184A2 US 2005038292 W US2005038292 W US 2005038292W WO 2006055184 A2 WO2006055184 A2 WO 2006055184A2
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alkyl
group
phenyl
hydrogen
methyl
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PCT/US2005/038292
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French (fr)
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WO2006055184A3 (en
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Xuqing Zhang
Xiaojie Li
Zhihua Sui
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Janssen Pharmaceutica N.V.
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Priority to EP05815801.5A priority Critical patent/EP1817292B1/en
Priority to AU2005307003A priority patent/AU2005307003B2/en
Priority to CA2587678A priority patent/CA2587678C/en
Priority to JP2007543066A priority patent/JP4969451B2/en
Publication of WO2006055184A2 publication Critical patent/WO2006055184A2/en
Publication of WO2006055184A3 publication Critical patent/WO2006055184A3/en

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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/18—Antivirals for RNA viruses for HIV
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    • 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
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more androgen receptors and processes for their preparation.
  • the compounds of the present invention are selective androgen receptor modulators (SARMs).
  • Androgens are the anabolic steroid hormones of animals, controlling muscle and skeletal mass, the maturation of the reproductive system, the development of secondary sexual characteristics and the maintenance of fertility in the male.
  • testosterone is converted to estrogen in most target tissues, but androgens themselves may play a role in normal female physiology, for example, in the brain.
  • the chief androgen found in serum is testosterone, and this is the effective compound in tissues such as the testes and pituitary.
  • testosterone is converted to dihydrotestosterone (DHT) by the action of 5 ⁇ -reductase.
  • DHT dihydrotestosterone
  • androgens Like all steroid hormones, androgens bind to a specific receptor inside the cells of target tissues, in this case the androgen receptor. This is a member of the nuclear receptor transcription factor family. Binding of androgen to the receptor activates it and causes it to bind to DNA binding sites adjacent to target genes. From there it interacts with co-activator proteins and basic transcription factors to regulate the expression of the gene. Thus, via its receptor, androgens cause changes in gene expression in cells. These changes ultimately have consequences on the metabolic output, differentiation or proliferation of the cell that are visible in the physiology of the target tissue.
  • Non-steroidal agonists and antagonists of the androgen receptor are useful in the treatment of a variety of disorders and diseases. More particularly, agonists of the androgen receptor could be employed in the treatment of prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne. Antagonists of the androgen receptor could be employed in male contraception, male performance enhancement, as well as in the treatment of cancer, AIDS, cachexia, and other disorders.
  • W is selected from the group consisting of O, S abd NR F ;
  • R F is selected from the group consisting of hydrogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy and -SO 2 -C 1 -4 alkyl;
  • R 1 is selected from the group consisting of C 1-4 alkyl and halogenated C 1- 4 alkyl
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogenated C 1-4 alkyl, -C(O)O-C 1 -4 alkyl, -C(O)-C 1-4 alkyl and -C(O)- (halogenated C 1-4 alkyl);
  • a is an integer from O to 1 ;
  • phenyl selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
  • R 3 is absent or selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(Ci- 4 alkyl)amino, -O-C 1-4 alkyl, -S(O)o- 2 -Ci. 4 alkyl, -NR A -C(O)-C 1-4 alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)o- 2 -phenyl; wherein R A is selected from hydrogen or C 1-4 alkyl;
  • R 4 absent or is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, Ci. 4 alkylamino, di(Ci- 4 alkyl)amino, -O-C 1-4 alkyl, -S(O) 0-2 -C 1 -4 alkyl, -NR B -C(O)-C 1-4 alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O) 0 - 2 -phenyl; wherein R B is selected from hydrogen or C 1-4 alkyl; provided that when js phenyl then at least one of R 3 or R 4 is other than hydrogen;
  • R 6 and R 7 are each independently absent or selected from the group consisting of hydrogen halogen, C 1-4 alkyl, C- 2 - 4 alkenyl, cyano, - C(O)O-C 1 -4 alkyl and -S(O)o- 2 -C 1-4 alkyl; provided further that R 3 is absent when a nitrogen atom is present at the
  • R 4 is absent when a nitrogen
  • R 7 is absent when a nitrogen atom is present at the 2-
  • R 5 is selected from the group consisting of halogen and Ci-
  • R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, benzyl Or -C(O)-CF 3 ;
  • R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C 1-4 alkyl), -C(O)O-C 1-4 alkyl, -C(O)O-aryl, -C 1-4 alkyl- S(O) 0- 2-C 1-4 alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C
  • the present invention is further directed to compounds of formula (II)
  • Z is selected from the group consisting of OR E , SR E and N(R F ) 2 ; wherein R E is selected from the group consisting of hydrogen and Ci- 4 alkyl; wherein each R F is independently selected from the group consisting of hydrogen, hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy and -SO 2 -C 1-4 alkyl; provided that when one R F group is hydroxy or cyano, then the other R F group is hydrogen; alternatively, the two R F groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure;
  • R 1 is selected from the group consisting of C 1-4 alkyl and halogenated Ci- 4 alkyl; a is an integer from 0 to 1 ;
  • phenyl is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
  • R 3 is absent or selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, CIi(C 1 - 4 alkyl)amino, -O-C 1-4 alkyl, -S(O) 0-2 -C 1-4 alkyl, -NR A -C(O)-Ci. 4 alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O) 0 - 2 -phenyl; wherein R A is selected from hydrogen or C 1-4 alkyl;
  • R 4 absent or is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(Ci- 4 alkyl)amino, -O-C 1-4 alkyl, -S(O) 0-2 -C 1-4 alkyl, -NR B -C(O)-C 1-4 alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O) 0 - 2 -phenyl; wherein R B is selected from hydrogen or
  • R 3 or R 4 are each independently absent or selected from the group consisting of hydrogen halogen, C 1-4 alkyl, C-2- 4 alkenyl, cyano, - C(O)O-C 1 -4 alkyl and -S(O) 0 - 2 -C 1-4 alkyl; provided further that R 3 is absent when a nitrogen atom is present at the
  • R 5 is selected from the group consisting of halogen and Ci-
  • R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, benzyl or -C(O)-CF 3 ;
  • R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C 1-4 alkyl), -C(O)O-C 1-4 alkyl, -C(O)O-aryl, -C 1-4 alkyl-
  • the present invention is further directed to a tautomeric mixture comprising
  • R F is selected from the group consisting of hydrogen, hydroxy, cyano, C- M alkyl, C 1-4 alkoxy and -SO 2 -C 1-4 alkyl;
  • R 1 is selected from the group consisting of Ci ⁇ alkyl and halogenated Ci-
  • R 3 is absent or selected from the group consisting of hydrogen, halogen,
  • Ci-4alkyl halogenated C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(Ci. 4 alkyl)amino, -O-C 1-4 alkyl, -S(0)o- 2 -Ci ⁇ alkyl, -NR B -C(O)-C 1-4 alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O) 0 - 2 -phenyl; wherein R B is selected from hydrogen or C 1-4 alkyl; provided that when phenyl then at least one of R a or R 4 is other than hydrogen;
  • R 6 and R 7 are each absent or independently selected from the group consisting of hydrogen halogen, C 1-4 alkyl, C 2-4 alkenyl, C 1-4 alkoxy, cyano, - C(O)O-C 1-4 alkyl and -S(O) 0 - 2 -C 1-4 alkyl; provided further that R 3 is absent when a nitrogen atom is present at the
  • ⁇ is selected from the group consisting of
  • R 5' is selected from the group consisting of halogen and Ci-
  • R 10 and R 11 are each independently selected from hydrogen, C 1-4 alkyl, benzyl Or -C(O)-CF 3 ;
  • R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C 1-4 alkyl), -C(O)O-C 1-4 alkyl, -C(O)O-aryl, -C 1-4 alkyl- S(O)o- 2 -C 1-4 alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy,
  • Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described herein.
  • An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described herein and a pharmaceutically acceptable carrier.
  • Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described herein and a pharmaceutically acceptable carrier.
  • Exemplifying the invention are methods of treating disorders and conditions modulated by the androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described herein.
  • An example of the invention is a method for treating an androgen receptor modulated disorder selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia, hirsutism, or for male contraception, comprising administering to a subject in need thereof an effective amount of any of the compounds or pharmaceutical compositions described herein.
  • Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, for (j) male contraception, or for (k) male performance enhancement, in a subject in need thereof.
  • DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of formula (I) and compounds of formula (II)
  • R 1 1 , D FT2 1 ⁇ R->3 ⁇ , r R-,4 4 , D R6 b , D R7', W, Z, a are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and / or as a male performance enhancer.
  • BPH benign prostatic hyperplasia
  • hirsutism hirsutism
  • alopecia anorexia nervosa
  • breast cancer acne
  • AIDS cachexia
  • cachexia as a male contraceptive
  • / or as a male performance enhancer as a male performance enhancer.
  • the present invention is further directed to tautomeric mixtures comprising a compound of formula (It) and a compound of formula (lit)
  • R 1 are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and / or as a male performance enhancer.
  • BPH benign prostatic hyperplasia
  • hirsutism hirsutism
  • alopecia anorexia nervosa
  • breast cancer acne
  • AIDS AIDS
  • cachexia cachexia
  • R 1 is selected from the group consisting of and halogenated Ci- 4 alkyl
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl and - C(O)O-C 1-4 alkyl; a is an integer from 0 to 1 ;
  • phenyl selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
  • R 3 is absent or selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, cyano, nitro, amino, C 1-4 alkylamino, di(C-
  • R A is selected from hydrogen or Ci ⁇ alkyl
  • R 4 absent or is selected from the group consisting of hydrogen, halogen,
  • ch independently selected from hydrogen, C 1-4 alkyl or benzyl
  • R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C 1-4 alkyl), -C(O)O-C 1-4 alkyl, -C(O)O-aryl, -C 1-4 alkyl- S(O)o- 2 -C 1-4 alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy,
  • W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, cyano and -SO 2 -C 1-4 alkyl.
  • W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, C 1-4 alkyl, Ci -2 alkoxy, cyano and -SO 2 -Ci -2 alkyl.
  • W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and -SO 2 -methyl.
  • W is selected from the group consisting of O, S and NR F ; wherein R F is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and -SO 2 -methyl.
  • W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy). In another embodiment of the present invention, W is selected from the group consisting of O and N(ethyl).
  • W is selected from the group consisting of O and S.
  • W is O.
  • W is selected from the group consisting of O and NR F .
  • W is NR F .
  • W is NR F and R F is selected form the group consisting of hydrogen, hydroxy, cyano, Ci- 4 alkyl and -SO 2 -C 1-4 alkyl. More preferably ,W is NR F and R F is selected form the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl and -SO 2 - methyl.
  • Z is selected from the group consisting of -O-methyl, -O-ethyl, -S-ethyl, -NH 2 , -NH(OH), -NH-ethyl, - N(ethyl) 2 and -NH(OCH 3 ).
  • R E is selected from the group consisting of hydrogen and In another embodiment of the present invention, R E is selected from the group consisting of C 1-4 alkyl. In another embodiment of the present invention, R E is selected from the group consisting of methyl and ethyl.
  • each R F is independently selected from the group consisting of hydrogen, hydroxy, cyano, C 1-4 alkyl, Ci- 4 alkoxy and -SO 2 -C 1-4 alkyl. In another embodiment of the present invention, each R F is independently selected from the group consisting of hydrogen, hydroxy, cyano, C- ⁇ alkyl, Ci -2 alkoxy and -SO 2 -Ci- 2 alkyl. In another embodiment of the present invention, R F is independently selected from the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl, methoxy and - SO 2 -methyl.
  • the two R F groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure. In another embodiment of the present invention, the two R F groups are taken together with the nitrogen atom to which they are bound to form 1 -pyrrolidinyl or 1-piperidinyl. In another embodiment of the present invention, the two R F groups are taken together with the nitrogen atom to which they are bound to form 1-pyrrolidinyl.
  • R 1 is selected from the group consisting of In another embodiment of the present invention, R 1 is selected from the group consisting of C 1-4 alkyl and halogenated Ci -2 alkyl. In another embodiment of the present invention, R 1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n- propyl and trifluoromethyl. In another embodiment of the present invention, R 1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl.
  • R 1 is selected from the group consisting of Ci -2 alkyl and halogenated In another embodiment of the present invention, R 1 is selected from the group consisting of Ci -2 alkyl. In another embodiment of the present invention, R 1 is selected from the group consisting of methyl, (R)-methyl and (S)-methyl. In another embodiment of the present invention, R 1 is selected from the group consisting of methyl and (S)- methyl.
  • R 1 is selected from the group consisting of C h alky! and halogenated In another embodiment of the present invention, R 1 is selected from the group consisting of C 1-4 alkyl. In another embodiment of the present invention, R 1 is selected from the group consisting of methyl, ethyl and n-propyl. Preferably, R 1 is selected from the group consisting of methyl, ethyl and n-propyl. More preferably, R 1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl and ethyl. More preferably still, R 1 is methyl.
  • R 2 is selected from the group consisting of hydrogen and C 1-4 alkyl. In another embodiment of the present invention, R 2 is selected from the group consisting of hydrogen and methyl. Preferably, R 2 is hydrogen.
  • R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, halogenated C-
  • a is 1. In another embodiment of the present invention, a is 0.
  • phenyl and pyridyl are selected from the group consisting of phenyl, 3-pyridyl and 4-pyridyl.
  • s phenyl Preferably s phenyl.
  • R 3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O) 0-2 -C 1-4 alkyl and -S(O) 0 -2-phenyl.
  • R 3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl and cyano.
  • R 3 is absent or selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano.
  • R 3 is selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl and cyano. In another embodiment of the present invention, R 3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano. Preferably, R 3 is selected from the group consisting of hydrogen and trifluoromethyl. More preferably, R 3 is trifluoromethyl.
  • R 3 is absent or hydrogen.
  • R 3 is absent or selected from the group consisting of hydrogen, halogen and halogenated Ci- 2 alkyl. In another embodiment of the present invention, R 3 is halogenated Ci- 2 alkyl. In another embodiment of the present invention, R 3 is trifluoromethyl.
  • R 4 is selected from the group consisting of hydrogen, halogen, halogenated C 1-4 alkyl, cyano, nitro, benzyl, - O-phenyl, -C(O)-phenyl, -S(O) 0 - 2 -C 1-4 alkyl and -S(O) 0 -2-phenyl.
  • R 4 is absent or selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)o-2- C- ⁇ - 4 alkyl and -S(O)o- 2 -phenyl.
  • R 4 is absent or selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, - C(O)-phenyl, -SO 2 -methyl and -SO 2 -phenyl.
  • R 4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, -C(O)- phenyl, -SO 2 -methyl and -SO 2 -phenyl.
  • R 4 is selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)o- 2 -C 1-4 alkyl and -S(O)o- 2 -phenyl.
  • R 4 is selected from the group consisting of bromo, cyano, nitro and -SO 2 -phenyl. More preferably, R 4 is selected from the group consisting of chloro, cyano and nitro.
  • R 4 is absent or selected from the group consisting of hydrogen, halogen, halogenated Ci -2 alkyl and cyano. In another embodiment of the present invention, R 4 is cyano.
  • R 6 and R 7 are each independently absent or selected from the group consisting of hydrogen, halogen, C-i -4 alkyl, cyano, -C(O)O-Ci -4 alkyl and -S(O)o-2-C 1-4 alkyl.
  • R 6 and R 7 are each independently absent or selected from the group consisting of hydrogen, halogen, Ci -2 alkyl, Ci- 2 alkoxy, cyano, -C(O)O-Ci -2 alkyl, -S-C 1-4 alkyl and -SO 2 - C 1-4 alkyl.
  • R 6 and R 7 are each independently absent or selected from the group consisting of hydrogen, halogen, C 1-4 alkyl and halogenated Ci -2 alkyl.
  • R 6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, -C(O)O-methyl, -S- ethyl, -S-t-butyl and -SO 2 -ethyl. In another embodiment of the present invention, R 6 is selected from the group consisting of hydrogen, iodo, chloro and -S-ethyl. In another embodiment of the present invention, R 6 is selected from the group consisting of hydrogen, chloro, ethyl and -SO 2 -ethyl. In another embodiment of the present invention, R 6 is hydrogen.
  • R 7 is selected from the group consisting of hydrogen, chloro and ethyl. In another embodiment of the present invention, R 7 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R 7 is hydrogen.
  • . is selected from the
  • y / i IsC selected from
  • ⁇ v -— / ⁇ is selected from the
  • ⁇ ⁇ S ⁇ is selected from the
  • R 5' is selected from the group consisting of halogen and Ci- 2 alkyl. In another embodiment of the present invention, R 5' is selected from the group consisting of halogen and C 1- 4 alkyl. In another embodiment of the present invention, R 5' is selected from the group consisting of halogen and C h alky!. In another embodiment, R 5' is selected from the group consisting of chloro, bromo, idoo, methyl and ethyl. Preferably, R 5 ' is chloro or methyl, more preferably, R 5 ' is chloro.
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, methyl and benzyl.
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen and methyl.
  • R 10 is selected from hydrogen, C 1-4 alkyl, benzyl Or -C(O)-CF 3 . In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen, Ci- 4 alkyl, benzyl and -C(O)-CF 3 . In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen, C 1-2 alkyl and benzyl. In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen, methyl and benzyl. In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen and C 1-4 alkyl.
  • R 10 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R 10 is selected from the group consisting of hydrogen and methyl. Preferably, R 10 is hydrogen.
  • R 5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, - C(O)-C 1-4 alkyl, -C(O)-(halogenated C 1-4 alkyl), -C(O)O-C 1-4 alkyl, -C(O)O-aryl, - C 1-4 alkyl-S(0)o- 2 -C 1-4 alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C- ⁇ .
  • R c and R D are each independently selected from hydrogen or C 1-4 alkyl.
  • R 5 is selected from the group consisting of hydrogen, carboxy, C 1-4 alkyl, halogenated C 1-4 alkyl, -Ci- 4 alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C 1-4 alkyl-S-Ci.
  • R 5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl,
  • 2,3,4,5,6-pentafluorophenyl 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3- fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4- methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t- butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4- methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2- thienyl, 3-pyridyl, 2-tetrahydrofuryl
  • R 5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy- phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4- ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fiuoro-3-hydroxy- phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl- phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phen
  • R 5 is selected from the group consisting of halogenated Ci- ⁇ alkyl. In another embodiment of the present invention, R 5 is trifluoromethyl. In another embodiment of the present invention, R 5 is selected from the group consisting of halogenated C- M alkyl and aryl; wherein the aryl is optionally substituted with one to two halogen. Preferably, R 5 is selected from the group consisting of trifluoromethyl and 4- fluorophenyl.
  • R 5 is selected from the group consisting of methyl, trifluoromethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, -C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl.
  • R 5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6- pentafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2- thienyl.
  • compounds of formula (I) selected from the group consisting of 3-Methyl-5-trifluoromethyl-3,4-dihydro- 2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 3- Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro- 2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4- Acetylamino-phenyO-S-methyl-S ⁇ -dihydro ⁇ H-pyrazole-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenyl)-amide; 3-Methyl-5-[4-(
  • the R 1 group on the compound of formula (I) or the compound of formula (II) is in the (R) stereo- configuration. In anotehr embodiment of the present invention, the R 1 group on the compound of formula (I) or the compound of formula (II) is in the (S) stereo- configuration.
  • substituent group further indicates the numbering of the atoms on the ring. More specifically, the "C" carbon atom is counted as 1 , with the other atoms numbered (counted off) in a clockwise fashion.
  • substituent group is other than phenyl, for example pyridyl, as in the following representative compound of formula (I)
  • the substituent group is 3-pyridyl, substituted with a cyano group at the 4-position.
  • halogen shall mean chlorine, bromine, fluorine and iodine.
  • C a - b wherein a and b are integers, is intended to denote the number of carbon atoms within the substituent group.
  • C 1-4 alkyl denotes alkyl chains containing one (1 ) to four (4) carbon atoms.
  • C 2-4 alkenyl denotes an alkenyl chain containing two (2) to four (4) carbon atoms.
  • alkyl whether used alone or as part of a substituent group, include straight and branched chains.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like.
  • halogenated Ci ⁇ alkyl shall mean any straight or branched alkyl chain comprising one to four carbon atoms wherein the alkyl chain is substituted with one or more, preferably one to five, more preferably one to three halogen atoms, and wherein the halogen atoms are independently selected from chloro, bromo, fluoro or iodo, preferably chloro or fluoro, more preferably fluoro. Suitable examples include, but are not limited to trifluoromethyl, 2,2,2-trilfuoroethyl, 1 ,1 ,2,2,2-pentafluoroethyl, and the like.
  • the halogenated C 1-4 alkyl is trifluoromethyl or 1 -(2,2,2- trifluoroethyl), more preferably, trifluoromethyl.
  • alkenyl shall include straight and branched chains comprising at least one unsaturated double bond. Suitable examples include, but are not limited to, vinyl, 1-propenyl, and the like. Preferably, the alkenyl group contains one unsaturated double bond.
  • alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
  • aryl shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
  • cycloalkyl shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • heteroaryl shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
  • heterocycloalkyl shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S.
  • the heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
  • heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3- dihydrobenzofuryl, and the like.
  • the term "5 or 6 membered, saturated, heterocyclic ring structure” shall mean any stable ring structure comprising 5 to 6 ring atoms independently selected from C, N, O and S, wherein the ring structure does not contain any unsaturated bonds.
  • the 5 to 6 membered, saturated heterocyclic ring structure contains one to two ring atoms selected from the group consisting of N, O and S (wherein the remaining ring atoms are C). More preferably, the 5 or 6 membered, saturated, heterocyclic ring structure contains one nitrogen ring atom and optionally contains an additional ring atom selected from the group consisting of O, N and S (wherein the remaining ring atoms are C).
  • Suitable examples include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, and the like; preferably pyrrolidinyl.
  • substituents e.g., alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl
  • that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
  • aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
  • leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
  • nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
  • phenylCr C ⁇ alkylaminocarbonylCi-Cealkyr substituent refers to a group of the formula
  • DIPEA or DIEA Diisopropylethylamine
  • TMSCHN 2 Trimethylsilyl diazomethane
  • Ts tosyl (-S ⁇ 2 -(p-toluene))
  • subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
  • the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
  • the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
  • crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
  • some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
  • the present invention includes within its scope prodrugs of the compounds of this invention.
  • prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound.
  • the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., quaternary ammonium salts.
  • representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edentate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate,
  • acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid,
  • a suitably substituted compound of formula (X), a known compound or compound prepared by known methods is reacted with a suitably substituted compound of formula (Xl), wherein Q 1 is a suitable leaving group such as hydroxy, halogen, and the like, a known compound or compound prepared by known methods, according to known methods (for example, where Q is a halogen, in an organic solvent such as THF, methylene chloride, and the like; where Q is hydroxy, in the presence of cyanochloride, oxalyl chloride, and the like, in an organic solvent such as DMA, DMF, and the like), to yield the corresponding compound of formula (XII).
  • Q is a halogen, in an organic solvent such as THF, methylene chloride, and the like
  • Q is hydroxy, in the presence of cyanochloride, oxalyl chloride, and the like, in an organic solvent such as DMA, DMF, and the like
  • the compound of formula (XII) is reacted with a suitably substituted and protected hydrazone, a compound of formula (XIII), wherein R 0 a group such as tolyl, and the like, (wherein -SO 2 -R 0 is a leaving group), a known compound or compound prepared by known methods, in the presence of a base such as NaH, potassium t-butoxide, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux temperature, preferably at a temperature in the range of from about 80 to about 100°C, to yield the corresponding compound of formula (Ib).
  • a base such as NaH, potassium t-butoxide, and the like
  • organic solvent such as THF, dioxane, and the like
  • the compound of formula (Ib) is further, optionally converted to the corresponding compound of formula (Ia) by treating the compound of formula (Ib) with a weak acid such as acetic acid, TFA, dilute HCI, and the like, or by passing the compound of formula (Ib) through silica gel, according to known methods.
  • a weak acid such as acetic acid, TFA, dilute HCI, and the like
  • the compound of formula (Ia) is further, optionally reacted with a suitably substituted alkylating agent, according to known methods, to yield the corresponding compound of formula (Ic).
  • R 5' is C 1-4 alkyl
  • R 5' is C 1-4 alkyl
  • a suitably substituted compound of formula (XII) is reacted with a suitably substituted hydrazine, a compound of formula (XIV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (Ic).
  • an organic amine base such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as THF, dioxane, and the like
  • a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 50 0 C, preferably at about room temperature, to yield the corresponding compound of formula (Id).
  • an organic amine base such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as THF, dioxane, and the like
  • a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by known methods, in an organic solvent such as toluene, xylene, chlorobenzene, and the like, at a temperature in the range of about room temperature to about 120°C, to yield the corresponding compound of formula (Ie).
  • a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by known methods, in an organic solvent such as toluene, xylene, chlorobenzene, and the like, at a temperature in the range of about room temperature to about 120°C, to yield the corresponding compound of formula (Ie).
  • a suitably substituted compound of formula (XII) is reacted with a suitable reducing agent such as mCPBA, hydrogen peroxide, and the like, at a temperature in the range of about 0 0 C to about room temperature, according to known methods, to yield the corresponding compound of formula (XVII).
  • a suitable reducing agent such as mCPBA, hydrogen peroxide, and the like
  • the compound of formula (XVII) is reacted with a suitably substituted amine, a compound of formula (XVIII), a known compound or compound prepared by known methods, in an organic solvent such as DMF, DMSO, and the like, at a temperature in the range of about O to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (XIX).
  • the compound of formula (XIX) is reacted with a suitably substituted compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, and the like or in an alcohol such as methanol, ethanol, and the like, at a temperature in the range of about 0 to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (If).
  • a suitably substituted compound of formula (XX) a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, and the like or in an alcohol such as methanol, ethanol, and the like, at a temperature in the range of about 0 to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (If).
  • a suitably substituted compound of formula (XVII) is reacted with a suitably substituted compound of formula (XXI), a known compound or compound prepared by known methods, in the presence of a Lewis acid such as BF 3 «Etherate, AICI 3 , and the like, in an organic solvent such as methylene chloride, chloroform, and the like, to yield the corresponding compound of formula (Ig).
  • a Lewis acid such as BF 3 «Etherate, AICI 3 , and the like
  • organic solvent such as methylene chloride, chloroform, and the like
  • a suitably substituted compound of formula (XXIII), wherein Q 2 is suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like is reacted with a suitably substituted aldehyde, a compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, benzene, and the like, at a temperature in the range of from about room temperature to about 5O 0 C, to yield the corresponding compound of formula (XXIV).
  • the compound of formula (XXIV) Q 2 is alkoxy and the like
  • the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH 3 )3AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ih).
  • a metallic agent such as (CH 3 )3AI, isopropyl-MgCI, and the like
  • organic solvent such as toluene, THF, and the like
  • the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50°C, to yield the corresponding compound of formula (Ih).
  • a coupling agent such as DCC, EDC, PyBroP, and the like
  • an organic amine such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as DCM, THF, and the like
  • a suitably substituted compound of formula (XXV), wherein Q 3 is a suitable leaving group such as hydroxy, halogen, alkoxy, and the like, is reacted with 1 ,1 'carbonyl-diimidazole (CDI), in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, to yield the corresponding compound of formula (XXVI).
  • CDI 1 ,1 'carbonyl-diimidazole
  • the compound of formula (XXVI) Q 3 is alkoxy and the like
  • the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH 3 ) 3 AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ij).
  • a metallic agent such as (CH 3 ) 3 AI, isopropyl-MgCI, and the like
  • organic solvent such as toluene, THF, and the like
  • the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50°C, to yield the corresponding compound of formula (Ij).
  • a coupling agent such as DCC, EDC, PyBroP, and the like
  • an organic amine such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as DCM, THF, and the like
  • the compound of formula (XXIX) Q 4 is alkoxy and the like
  • the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH 3 ) 3 AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ik).
  • a metallic agent such as (CH 3 ) 3 AI, isopropyl-MgCI, and the like
  • organic solvent such as toluene, THF, and the like
  • the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50 0 C, to yield the corresponding compound of formula (Ik).
  • a coupling agent such as DCC, EDC, PyBroP, and the like
  • an organic amine such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as DCM, THF, and the like
  • a suitably substituted compound of formula (Im), a compound of formula (Ic) wherein R 5 is hydrogen, is reacted with a reducing agent such as NaBH 4 , NaCNBH 3 , and the like, in an organic solvent such as AcOH, CF 3 CO 2 H, methanol, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (In).
  • a reducing agent such as NaBH 4 , NaCNBH 3 , and the like
  • organic solvent such as AcOH, CF 3 CO 2 H, methanol, and the like
  • the compound of formula (In) is reacted with a suitably substituted compound of formula (XXX), wherein Q 6 is a suitable leaving group such as halogen, alkyl-carbonyl-oxy-, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, DMF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ip)-
  • a suitably substituted compound of formula (Ix) is reacted with a source of sulfur such as Lawesson's reagent, P 2 S 5 , and the like, in an organic solvent such as toluene, xylene, p-oxlane, and the like, at a temperature in the range of from about 110 0 C to about 150°C, to yield the corresponding compound of formula (Iy).
  • a source of sulfur such as Lawesson's reagent, P 2 S 5 , and the like
  • organic solvent such as toluene, xylene, p-oxlane, and the like
  • a suitably substituted compound of formula (Ix) wherein R 2 is hydrogen is recated with a suitably substituted electrophile, a compound of formula (XXXI) wherein L v is a suitable leaving group such as Cl, Br, tosyl, triyl, mesyl, and the like, (for example where R E is ethyl, the compound of formula (XXIX) may be BF 4 etherate), in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, diethyl ether, and the like, at a temperature in the range of from about - 40 0 C to about room temperature, to yield a mixture of the corresponding compound of formula (Ha) and (Iz).
  • a suitably substituted electrophile a compound of formula (XXXI) wherein L v is a suitable leaving group such as Cl, Br, tosyl, triyl, mesy
  • a suitably substituted compound of formula (Iy) is reacted with a suitably substituted compound of formula (XXXI), wherein L v is a suitable leaving group such as Cl, Br, tosyl, trifyl, mesyl, and the like, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as acetone, THF, DMF, and the like, at a temperature in the range of from about 0°C to about 8O 0 C, to yield the corresponding compound of formula (lib).
  • an organic amine base such as TEA, DIPEA, pyridine, and the like
  • organic solvent such as acetone, THF, DMF, and the like
  • the compound of formula (lib) is reacted with a suitably substituted nitrogen containing nucleophile, a compound of formula (XXXII) (for example, NH 3 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2l NH(OC 1-4 alkyl), NH 2 (OH), NH(CN), NH(SO 2 - C 1-4 alkyl), pyrrolidine, and the like), in the presence of an inorganic base such as K 2 CO 3 , NaH, Na 2 CO 3 , and the like, in an organic solvent such as THF, DMF, dioxane, and the like, at a temperature in the range of from about room temperature to about 100°C, to yield the corresponding compound of formula (lie).
  • a compound of formula (XXXII) for example, NH 3 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2l NH(OC 1-4 alkyl), NH 2 (OH), NH
  • reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
  • the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
  • these isomers may be separated by conventional techniques such as preparative chromatography.
  • the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
  • the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base.
  • the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
  • any of the processes for preparation of the compounds of the present invention it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and/or (II) with a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 50-100 mg and may be given at a dosage of from about 0.5-5.0 mg/kg/day, preferably from about 1.0-3.0 mg/kg/day.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • a pharmaceutical carrier e.g.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
  • preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
  • the method of treating a disorder mediated by one or more androgen receptor(s) described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition may contain between about 0.1 mg and 500 mg, preferably about 50 to 100 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected.
  • Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
  • the compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
  • Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue.
  • the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by one or more androgen receptor(s) is required.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day.
  • the range is from about 0.5 to about 5.0 mg/kg of body weight per day, most preferably, from about 1.0 to about 3.0 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • the following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
  • synthesis products may be listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term “residue” does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
  • N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide 500 mg, 2.0 mmol
  • 4-fluoro-/V-(phenylmethyI)-benzenecarbohydrazonoyl chloride 520 mg, 2.0 mmol
  • Triethyl amine 300 mg, 3.0 mmol
  • Example 100 1 - ⁇ -Acetylamino-benzvO-S-methyl-pyrazolidine-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenvQ-amide

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Abstract

The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by the androgen receptor.

Description

NOVEL HETEROCYCLE DERIVATIVES USEFUL AS SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMS)
FIELD OF THE INVENTION
The present invention is directed to novel heterocycle derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more androgen receptors and processes for their preparation. The compounds of the present invention are selective androgen receptor modulators (SARMs).
BACKGROUND OF THE INVENTION
Androgens are the anabolic steroid hormones of animals, controlling muscle and skeletal mass, the maturation of the reproductive system, the development of secondary sexual characteristics and the maintenance of fertility in the male. In women, testosterone is converted to estrogen in most target tissues, but androgens themselves may play a role in normal female physiology, for example, in the brain. The chief androgen found in serum is testosterone, and this is the effective compound in tissues such as the testes and pituitary. In prostate and skin, testosterone is converted to dihydrotestosterone (DHT) by the action of 5α-reductase. DHT is a more potent androgen than testosterone because it binds more strongly to the androgen receptor.
Like all steroid hormones, androgens bind to a specific receptor inside the cells of target tissues, in this case the androgen receptor. This is a member of the nuclear receptor transcription factor family. Binding of androgen to the receptor activates it and causes it to bind to DNA binding sites adjacent to target genes. From there it interacts with co-activator proteins and basic transcription factors to regulate the expression of the gene. Thus, via its receptor, androgens cause changes in gene expression in cells. These changes ultimately have consequences on the metabolic output, differentiation or proliferation of the cell that are visible in the physiology of the target tissue.
Although modulators of androgen receptor function have been employed clinically for some time, both the steroidal (Basaria, S., Wahlstrom, J.T., Dobs, A.S., J. Clin Endocrinol MeXab (2001), 86, pp5108-5117; Shahidi, NT., Clin Therapeutics, (2001), 23, pp1355-1390), and non-steroidal (Newling, D.W., Br. J. Urol., 1996, 77 (6), pp 776-784) compounds have significant liabilities related to their pharmacological parameters, including gynecomastia, breast tenderness and hepatoxicity. In addition, drug-drug interactions have been observed in patients receiving anticoagulation therapy using coumarins. Finally, patients with aniline sensitivities could be compromised by the metabolites of non-steroidal antiandrogens.
Non-steroidal agonists and antagonists of the androgen receptor are useful in the treatment of a variety of disorders and diseases. More particularly, agonists of the androgen receptor could be employed in the treatment of prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne. Antagonists of the androgen receptor could be employed in male contraception, male performance enhancement, as well as in the treatment of cancer, AIDS, cachexia, and other disorders.
Nonetheless, there exists a need for small molecule, non-steroidal antagonists of the androgen receptor. We now describe a novel series of tri- substituted pyrazole derivatives as androgen receptor modulators. SUMMARY OF THE INVENTION The present invention is directed to compounds of formula (I)
Figure imgf000004_0001
wherein W is selected from the group consisting of O, S abd NRF;
RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -SO2-C1 -4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated C1- 4alkyl; R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl, -C(O)O-C1 -4alkyl, -C(O)-C1-4alkyl and -C(O)- (halogenated C1-4alkyl); a is an integer from O to 1 ;
Figure imgf000004_0002
selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)o-2-Ci.4alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)o-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, Ci.4alkylamino, di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1 -4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl; provided that when
Figure imgf000005_0001
js phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen halogen, C1-4alkyl, C-2-4alkenyl,
Figure imgf000005_0002
cyano, - C(O)O-C1 -4alkyl and -S(O)o-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position
Figure imgf000005_0003
provided further that R4 is absent when a nitrogen
atom is present at the 4-position
Figure imgf000005_0004
provided further that R is
absent when a nitrogen atom is present at the
Figure imgf000005_0005
provided further that R7 is absent when a nitrogen atom is present at the 2-
position
Figure imgf000005_0006
Figure imgf000006_0002
selected from the group consisting of
Figure imgf000006_0001
,
Figure imgf000006_0003
wherein R5 is selected from the group consisting of halogen and Ci-
4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl Or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)0-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-Ci -4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or C1-4alkyl; and pharmaceutically acceptable salts thereof.
The present invention is further directed to compounds of formula (II)
Figure imgf000007_0001
wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2; wherein RE is selected from the group consisting of hydrogen and Ci- 4alkyl; wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -SO2-C1-4alkyl; provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen; alternatively, the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 4alkyl; a is an integer from 0 to 1 ;
Figure imgf000007_0002
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, CIi(C1- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRA-C(O)-Ci.4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or
provid
Figure imgf000008_0001
ed that when js phenyl then at least one of R3 or R4 is other than hydrogen; R6 and R7 are each independently absent or selected from the group consisting of hydrogen halogen, C1-4alkyl, C-2-4alkenyl,
Figure imgf000008_0002
cyano, - C(O)O-C1 -4alkyl and -S(O)0-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position
Figure imgf000008_0003
; provided further that R is absent when a nitrogen
atom is present at the 4-position
Figure imgf000008_0004
provided further that R6 is
absent when a nitrogen atom is present at the 6-position
Figure imgf000008_0005
provided further that R7 is absent when a nitrogen atom is present at the 2-
Figure imgf000008_0006
Figure imgf000009_0002
is selected from the group consisting of
Figure imgf000009_0001
Figure imgf000009_0003
wherein R5 is selected from the group consisting of halogen and Ci-
4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl-
S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino,
Figure imgf000009_0004
di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl,
NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1 -4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or C1-4alkyl; and pharmaceutically acceptable salts thereof.
The present invention is further directed to a tautomeric mixture comprising
Figure imgf000010_0001
RF is selected from the group consisting of hydrogen, hydroxy, cyano, C-Malkyl, C1-4alkoxy and -SO2-C1-4alkyl; R1 is selected from the group consisting of Ci^alkyl and halogenated Ci-
4alkyl; a is an integer from 0 to 1 ;
Figure imgf000010_0002
selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; R3 is absent or selected from the group consisting of hydrogen, halogen,
C-Malkyl, halogenated C1-4alkyl, cyano, nitro, amino,
Figure imgf000010_0003
di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(0)o-2-Ci^alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(0)o-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl; R4 absent or is selected from the group consisting of hydrogen, halogen,
Ci-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci. 4alkyl)amino, -O-C1-4alkyl, -S(0)o-2-Ci^alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl; provided that when
Figure imgf000011_0001
phenyl then at least one of Ra or R4 is other than hydrogen;
R6 and R7 are each absent or independently selected from the group consisting of hydrogen halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, - C(O)O-C1-4alkyl and -S(O)0-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position
Figure imgf000011_0002
; provided further that R4 is absent when a nitrogen
atom is present at the 4-position
Figure imgf000011_0003
provided further that R is
absent when a nitrogen atom is present at the 6-position
Figure imgf000011_0004
provided further that R7 is absent when a nitrogen atom is present at the 2-
position
Figure imgf000011_0005
©, is selected from the group consisting of
Figure imgf000012_0001
Figure imgf000012_0002
wherein R5' is selected from the group consisting of halogen and Ci-
4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl Or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or C1-4alkyl; or a pharmaceutically acceptable salt thereof.
Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compounds described herein. An illustration of the invention is a pharmaceutical composition made by mixing any of the compounds described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the compounds described herein and a pharmaceutically acceptable carrier.
Exemplifying the invention are methods of treating disorders and conditions modulated by the androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described herein.
An example of the invention is a method for treating an androgen receptor modulated disorder selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia, hirsutism, or for male contraception, comprising administering to a subject in need thereof an effective amount of any of the compounds or pharmaceutical compositions described herein.
Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating: (a) prostate carcinoma, (b) benign prostatic hyperplasia, (c) hirsutism, (d) alopecia, (e) anorexia nervosa, (f) breast cancer, (g) acne, (h) AIDS, (i) cachexia, for (j) male contraception, or for (k) male performance enhancement, in a subject in need thereof. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to compounds of formula (I) and compounds of formula (II)
Figure imgf000014_0001
wherein R 11, D FT21 Γ R->3ό, r R-,44, D R6b, D R7', W, Z, a,
Figure imgf000014_0002
are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and / or as a male performance enhancer.
The present invention is further directed to tautomeric mixtures comprising a compound of formula (It) and a compound of formula (lit)
Figure imgf000014_0003
wherein R1,
Figure imgf000015_0001
are as herein defined, useful as selective androgen receptor modulators for the treatment of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, as a male contraceptive, and / or as a male performance enhancer.
One skilled in the art will recognize that some of the variables (e.g. R1, R2, R3, a, etc.) appear in compounds of formula (I) and compounds of formula (II). One skilled in the art will further recognize that wherein a particular substituent is selected for a given variable for a compound of formula (I), said selection is not intended to limit the scope of said variable for compounds of formula (II). Similarly, the selection of a particular substituent for a given variable for a compound of formula (II), is not intended to limit the scope of said variable for compounds of formula (I).
One skilled in the art will recognize that when in the compound of formula (I) R2 is hydrogen and W is NRF and in the compound of formula (II) Z is NHRF, then the corresponding compound of formula (I) and the corresponding compound formula (II) are tautomers. One skilled in the art will further recognize that in solution, the tautomers may exist as a mixture of varying ratios, depending on the nature of the solvent. Upon isolation as a solid, only one of the tautomers is isolated, although which tautomer was isolated was not determined for the compounds of the instant application. In an embodiment, the present invention is directed to compounds of formula (I)
Figure imgf000016_0001
wherein
R1 is selected from the group consisting of
Figure imgf000016_0002
and halogenated Ci- 4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl and - C(O)O-C1-4alkyl; a is an integer from 0 to 1 ;
Figure imgf000016_0003
selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(C-|.
4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)o-2-phenyl; wherein RA is selected from hydrogen or Ci^alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen,
C-Malkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci-
4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(0)o-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
Figure imgf000016_0004
is phenyl then at least one of R3 or R4 is other than hydrogen; provided further that R is absent when a nitrogen atom is present at the
3-position
Figure imgf000017_0001
provided further that R is absent when a nitrogen
atom is present at the 4-position
Figure imgf000017_0002
Figure imgf000017_0004
is selected from the group consisting of
Figure imgf000017_0003
Figure imgf000017_0005
ch independently selected from hydrogen, C1-4alkyl or benzyl;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, Ci.4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(Ci.4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -S(0)o-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or C1-4alkyl; and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-4alkoxy, cyano and -SO2-C1-4alkyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, Ci-2alkoxy, cyano and -SO2-Ci-2alkyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and -SO2-methyl. In another embodiment of the present invention, W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and -SO2-methyl.
In an embodiment of the present invention, W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy). In another embodiment of the present invention, W is selected from the group consisting of O and N(ethyl).
In an embodiment of the present invention W is selected from the group consisting of O and S. Preferably W is O. In another embodiment of the present invention W is selected from the group consisting of O and NRF. In another embodiment of the present invention W is NRF. Preferably, W is NRF and RF is selected form the group consisting of hydrogen, hydroxy, cyano, Ci- 4alkyl and -SO2-C1-4alkyl. More preferably ,W is NRF and RF is selected form the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl and -SO2- methyl. In an embodiment of the present invention, Z is selected from the group consisting of -O-methyl, -O-ethyl, -S-ethyl, -NH2, -NH(OH), -NH-ethyl, - N(ethyl)2 and -NH(OCH3).
In an embodiment of the present invention, RE is selected from the group consisting of hydrogen and
Figure imgf000019_0001
In another embodiment of the present invention, RE is selected from the group consisting of C1-4alkyl. In another embodiment of the present invention, RE is selected from the group consisting of methyl and ethyl.
In an embodiment of the present invention, each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, Ci- 4alkoxy and -SO2-C1-4alkyl. In another embodiment of the present invention, each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C-^alkyl, Ci-2alkoxy and -SO2-Ci-2alkyl. In another embodiment of the present invention, RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl, methoxy and - SO2-methyl.
In an embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure. In another embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form 1 -pyrrolidinyl or 1-piperidinyl. In another embodiment of the present invention, the two RF groups are taken together with the nitrogen atom to which they are bound to form 1-pyrrolidinyl.
In an embodiment of the present invention, R1 is selected from the group consisting of
Figure imgf000019_0002
In another embodiment of the present invention, R1 is selected from the group consisting of C1-4alkyl and halogenated Ci-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (S)-methyl, (R)-methyl, ethyl, n- propyl and trifluoromethyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl, ethyl and trifluoromethyl.
In an embodiment of the present invention, R1 is selected from the group consisting of Ci-2alkyl and halogenated
Figure imgf000020_0001
In another embodiment of the present invention, R1 is selected from the group consisting of Ci-2alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, (R)-methyl and (S)-methyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl and (S)- methyl.
In an embodiment of the present invention, R1 is selected from the group consisting of Chalky! and halogenated
Figure imgf000020_0002
In another embodiment of the present invention, R1 is selected from the group consisting of C1-4alkyl. In another embodiment of the present invention, R1 is selected from the group consisting of methyl, ethyl and n-propyl. Preferably, R1 is selected from the group consisting of methyl, ethyl and n-propyl. More preferably, R1 is selected from the group consisting of methyl, (R)-methyl, (S)-methyl and ethyl. More preferably still, R1 is methyl.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen and C1-4alkyl. In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen and methyl. Preferably, R2 is hydrogen.
In an embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C-|.4alkyl and -C(O)- (halogenated C1-4alkyl). In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated
Figure imgf000020_0003
and -C(O)-(halogenated
Figure imgf000020_0004
In another embodiment of the present invention, R2 is selected from the group consisting of hydrogen, methyl, trifluoroethyl and -C(O)-CF3.
In an embodiment of the present invention, a is 1. In another embodiment of the present invention, a is 0.
In an embodiment of the present invention,
Figure imgf000021_0001
is selected from
the group consisting of phenyl and pyridyl. In another embodiment,
Figure imgf000021_0002
is selected from the group consisting of phenyl, 3-pyridyl and 4-pyridyl.
Preferably s phenyl. In another embodiment of the present
invention, pyridyl. In yet another embodiment of the present
invention,
Figure imgf000021_0003
selected from the group consisting of 3-pyridyl and 4- pyridyl.
In an embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)0-2-C1-4alkyl and -S(O)0-2-phenyl. In another embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano. Preferably, R3 is absent or selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano.
In an embodiment of the present invention, R3 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano. In another embodiment of the present invention, R3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano. Preferably, R3 is selected from the group consisting of hydrogen and trifluoromethyl. More preferably, R3 is trifluoromethyl.
In an embodiment of the present invention, R3 is absent or hydrogen.
In an embodiment of the present invention, R3 is absent or selected from the group consisting of hydrogen, halogen and halogenated Ci-2alkyl. In another embodiment of the present invention, R3 is halogenated Ci-2alkyl. In another embodiment of the present invention, R3 is trifluoromethyl.
In an embodiment of the present invention, R4 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, - O-phenyl, -C(O)-phenyl, -S(O)0-2-C1-4alkyl and -S(O)0-2-phenyl. In another embodiment of the present invention, R4 is absent or selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)o-2- C-ι-4alkyl and -S(O)o-2-phenyl. Preferably, R4 is absent or selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, - C(O)-phenyl, -SO2-methyl and -SO2-phenyl.
In an embodiment of the present invention, R4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, -C(O)- phenyl, -SO2-methyl and -SO2-phenyl. In another embodiment of the present invention, R4 is selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)o-2-C1-4alkyl and -S(O)o-2-phenyl. Preferably, R4 is selected from the group consisting of bromo, cyano, nitro and -SO2-phenyl. More preferably, R4 is selected from the group consisting of chloro, cyano and nitro.
In an embodiment of the present invention, R4 absent or is selected from the group consisting of cyano and halogen. In another embodiment of the present invention, R4 absent or is selected from the group consisting of cyano and chloro.
In an embodiment of the present invention, R4 is absent or selected from the group consisting of hydrogen, halogen, halogenated Ci-2alkyl and cyano. In another embodiment of the present invention, R4 is cyano.
In an embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C-i-4alkyl,
Figure imgf000023_0001
cyano, -C(O)O-Ci -4alkyl and -S(O)o-2-C1-4alkyl. In another embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, Ci-2alkyl, Ci-2alkoxy, cyano, -C(O)O-Ci-2alkyl, -S-C1-4alkyl and -SO2- C1-4alkyl. In another embodiment of the present invention, R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl and halogenated Ci-2alkyl.
In an embodiment of the present invention, R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, -C(O)O-methyl, -S- ethyl, -S-t-butyl and -SO2-ethyl. In another embodiment of the present invention, R6 is selected from the group consisting of hydrogen, iodo, chloro and -S-ethyl. In another embodiment of the present invention, R6 is selected from the group consisting of hydrogen, chloro, ethyl and -SO2-ethyl. In another embodiment of the present invention, R6 is hydrogen.
In an embodiment of the present invention, R7 is selected from the group consisting of hydrogen, chloro and ethyl. In another embodiment of the present invention, R7 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R7 is hydrogen.
In an embodiment of the present invention,
Figure imgf000024_0003
. is selected from the
Figure imgf000024_0001
In another embodiment of the present invention,
Figure imgf000024_0004
y/ i IsC selected from
Figure imgf000024_0002
In another embodiment of the present invention,
Figure imgf000025_0001
i.s selected from
Figure imgf000025_0002
group consisting of M ,
Figure imgf000025_0003
In another embodiment of the present invention, i.s selected from
the group consisting of
Figure imgf000025_0004
, , and
In another embodiment of the present invention,
Figure imgf000026_0001
is selected from
the group consisting of
Figure imgf000026_0002
and . In another embodiment of the
present invention,
Figure imgf000026_0003
In an embodiment of the present invention, © v-—/■ is selected from the
group consisting of
Figure imgf000026_0004
Figure imgf000026_0005
, and I . In another embodiment of the
H
present invention,
Figure imgf000026_0006
and
Figure imgf000026_0007
- Pr-e-f'e-r-a ■b■ ■ly■ ,
Figure imgf000026_0008
In an embodiment of the present invention, © ^S ■ is selected from the
group consisting of
Figure imgf000027_0001
and
Figure imgf000027_0002
. In another embodiment of the present invention,
Figure imgf000027_0003
selected from the group consisting of
Figure imgf000027_0004
, ,
Figure imgf000027_0005
In yet another embodiment of
the present invention,
Figure imgf000027_0006
,
Figure imgf000027_0007
and . in yet another embodiment of the present invention,
Figure imgf000028_0001
is selected from the group consisting of
Figure imgf000028_0002
In an embodiment of the present invention, R5' is selected from the group consisting of halogen and Ci-2alkyl. In another embodiment of the present invention, R5' is selected from the group consisting of halogen and C1- 4alkyl. In another embodiment of the present invention, R5' is selected from the group consisting of halogen and Chalky!. In another embodiment, R5' is selected from the group consisting of chloro, bromo, idoo, methyl and ethyl. Preferably, R5' is chloro or methyl, more preferably, R5' is chloro.
In an embodiment of the present invention R10 and R11 are each independently selected from the group consisting of hydrogen, methyl and benzyl. Preferably, R10 and R11 are each independently selected from the group consisting of hydrogen and methyl.
In an embodiment of the present invention, R10 is selected from hydrogen, C1-4alkyl, benzyl Or -C(O)-CF3. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, Ci- 4alkyl, benzyl and -C(O)-CF3. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, C1-2alkyl and benzyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, methyl and benzyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and C1-4alkyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen, methyl and ethyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and ethyl. In another embodiment of the present invention, R10 is selected from the group consisting of hydrogen and methyl. Preferably, R10 is hydrogen.
In an embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, - C(O)-C1-4alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, - C1-4alkyl-S(0)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C-ι. 4alkyl, C1-4alkoxy, halogenated C1-4alkyl, cyano, nitro, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, trimethyl-silyl and t-butyl- dimethyl-silyloxy; wherein Rc and RD are each independently selected from hydrogen or C1-4alkyl.
In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, -Ci- 4alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C1-4alkyl-S-Ci. 4alkyl, -C(O)O-C1-4alkyl, -C(O)-(halogenated C1-4alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, -O-C1-4alkyl, -C(O)O-Ci -4alkyl, -NH-C(O)-Ci. 4alkyl, -NH-C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy.
In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl,
2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3- fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl-carbonyl-amino-phenyl, 4- methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl-carbonyl-amino)-phenyl, 2-(t- butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4- methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl-amino-phenyl, 2-furyl, 2- thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy- carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl.
Preferably, R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy- phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4- ethylphenyl, 4-methoxy-phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fiuoro-3-hydroxy- phenyl, 3-methyl-4-fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl- phenyl, 3-methyl-carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4- (trif luoromethyl-carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro- phenyl, t-butyl-dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 2- furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl.
In a embodiment of the present invention, R5 is selected from the group consisting of halogenated Ci-≥alkyl. In another embodiment of the present invention, R5 is trifluoromethyl. In another embodiment of the present invention, R5 is selected from the group consisting of halogenated C-Malkyl and aryl; wherein the aryl is optionally substituted with one to two halogen. Preferably, R5 is selected from the group consisting of trifluoromethyl and 4- fluorophenyl.
In an embodiment of the present invention, R5 is selected from the group consisting of methyl, trifluoromethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, -C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4-trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl. In another embodiment of the present invention, R5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6- pentafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2- thienyl.
In an embodiment of the present invention are compounds of formula (I) selected from the group consisting of 3-Methyl-5-trifluoromethyl-3,4-dihydro- 2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 3- Ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide; 5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro- 2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; 5-(4- Acetylamino-phenyO-S-methyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenyl)-amide; 3-Methyl-5-[4-(2,2,2-trifluoro- acetylamino)-phenyl]-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3- trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention, the R1 group on the compound of formula (I) or the compound of formula (II) is in the (R) stereo- configuration. In anotehr embodiment of the present invention, the R1 group on the compound of formula (I) or the compound of formula (II) is in the (S) stereo- configuration.
In another embodiment of the present invention is any single compound or subset of compounds selected from the representative compounds listed in Tables 1 -4 below.
Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (i.e.
Figure imgf000031_0001
selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein. Representative compounds of the present invention are as listed in Table 1 -9 below. Unless otherwise noted, wherein a stereogenic center is present in the listed compound, the compound was prepared as a mixture of stereo-configurations. Where a stereogenic center is present, the (S) and (R) designations are intended to indicate that the exact stereo-configuration of the center has been determined.
Table 1 : Representative Compounds of Formula (I)
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Table 2: Representative Compounds of Formula (0
Figure imgf000036_0002
Table 3: Representative Compounds of Formula (I)
Figure imgf000036_0001
Figure imgf000037_0001
Table 4: Representative Compounds of Formula (I)
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000041_0001
Table 6: Representative Compounds of Formula (Q
Figure imgf000041_0002
Table 7: Representative Compounds of Formula (I)
Figure imgf000041_0003
Figure imgf000042_0002
Table 8: Representative Compounds of Formula (I)
Figure imgf000043_0001
Representative compounds of formula (II) are as listed in Table 9 below. For convenience only one tautomeric form of the compounds listed below is specifically shown in Table 9.
Table 9: Representative Compounds of Formula (II)
Figure imgf000043_0002
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0006
One skilled in the art will recognize that in the recitation of the
substituent groups of
Figure imgf000046_0001
, the " * " symbol is intended to denote the point of
attachment of the
Figure imgf000046_0002
r riinnqg t too the rest of the molecule.
One skilled in the art will further recognize that in the drawing of the
substituent group
Figure imgf000046_0003
in the compounds of formula (I) and compounds of formula (II), the "C" within the ring structure is intended to indicate a carbon
atom. Thus when
Figure imgf000046_0004
is other than phenyl, the ring is attached to the -(CH2)a- portion of the compounds of formula (I) through a
carbon atom. One skilled in the art will further recognize that the
Figure imgf000046_0005
substituent group further indicates the numbering of the atoms on the ring. More specifically, the "C" carbon atom is counted as 1 , with the other atoms numbered (counted off) in a clockwise fashion. Thus for example, wherein the
Figure imgf000047_0001
substituent group is other than phenyl, for example pyridyl, as in the following representative compound of formula (I)
the
Figure imgf000047_0002
substituent group is 3-pyridyl, substituted with a cyano group at the 4-position.
As used herein, "halogen" shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, the abbreviation "Ca-b" wherein a and b are integers, is intended to denote the number of carbon atoms within the substituent group. For example, C1-4alkyl denotes alkyl chains containing one (1 ) to four (4) carbon atoms. Similarly, C2-4alkenyl, denotes an alkenyl chain containing two (2) to four (4) carbon atoms.
As used herein, the term "alkyl" whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like.
As used herein, unless then/vise noted, the term "halogenated Ci^alkyl" shall mean any straight or branched alkyl chain comprising one to four carbon atoms wherein the alkyl chain is substituted with one or more, preferably one to five, more preferably one to three halogen atoms, and wherein the halogen atoms are independently selected from chloro, bromo, fluoro or iodo, preferably chloro or fluoro, more preferably fluoro. Suitable examples include, but are not limited to trifluoromethyl, 2,2,2-trilfuoroethyl, 1 ,1 ,2,2,2-pentafluoroethyl, and the like. Preferably, the halogenated C1-4alkyl is trifluoromethyl or 1 -(2,2,2- trifluoroethyl), more preferably, trifluoromethyl.
As used herein, unless otherwise noted, the term "alkenyl" shall include straight and branched chains comprising at least one unsaturated double bond. Suitable examples include, but are not limited to, vinyl, 1-propenyl, and the like. Preferably, the alkenyl group contains one unsaturated double bond.
As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, unless otherwise noted, "aryl" shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.
As used herein, unless otherwise noted, the term "cycloalkyl" shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein, unless otherwise noted, "heteroaryl" shall denote any five or six membered monocyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine or ten membered bicyclic aromatic ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heteroaryl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the like.
As used herein, the term "heterocycloalkyl" shall denote any five to seven membered monocyclic, saturated or partially unsaturated ring structure containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to three additional heteroatoms independently selected from the group consisting of O, N and S; or a nine to ten membered saturated, partially unsaturated or partially aromatic bicyclic ring system containing at least one heteroatom selected from the group consisting of O, N and S, optionally containing one to four additional heteroatoms independently selected from the group consisting of O, N and S. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure.
Examples of suitable heterocycloalkyl groups include, but are not limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3- dihydrobenzofuryl, and the like.
As used herein, unless otherwise noted the term "5 or 6 membered, saturated, heterocyclic ring structure" shall mean any stable ring structure comprising 5 to 6 ring atoms independently selected from C, N, O and S, wherein the ring structure does not contain any unsaturated bonds. Preferably, the 5 to 6 membered, saturated heterocyclic ring structure contains one to two ring atoms selected from the group consisting of N, O and S (wherein the remaining ring atoms are C). More preferably, the 5 or 6 membered, saturated, heterocyclic ring structure contains one nitrogen ring atom and optionally contains an additional ring atom selected from the group consisting of O, N and S (wherein the remaining ring atoms are C). Suitable examples include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrazolidinyl, and the like; preferably pyrrolidinyl.
As used herein, the notation "*" shall denote the presence of a stereogenic center.
When a particular group is "substituted" (e.g., alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.
With reference to substituents, the term "independently" means that when more than one of such substituents is possible, such substituents may be the same or different from each other.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
As used herein, unless otherwise noted, the term "aprotic solvent" shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
As used herein, unless otherwise noted, the term "leaving group" shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
As used herein, unless otherwise noted, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(O)O-R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH- CH2-, and the like; amides - groups of the formula -C(O)-R' wherein R' is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO2-R" wherein R" is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4- methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenylCr CβalkylaminocarbonylCi-Cealkyr substituent refers to a group of the formula
Figure imgf000051_0001
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows: Ac Acetyl (i.e. -C(O)CH3)
AcOH Acetic acid
GDI N , N'-Carbonyl-Diimidazole
CSA Camphor sulfonic acid
DCC N,N'-Dicyclohexyl-carbodiimide
DCM Dichloromethane
DIPEA or DIEA = Diisopropylethylamine
DMA N , N-Dimethylacetamide
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
EDC 1 ,2-Dichloroethane
Et Ethyl
Et3N Triethylamine
Et2O Diethyl ether
EtOAc Ethyl acetate
LiHMDS Lithium Hexamethyldisilazinamide
Me methyl
MeOH Methanol
NCS N-chlorosuccinimide
NMP 1 -Methyl-2-pyrrolidinone
OXONE® Potassium monopersulphate triple salt
Pd-C or Pd/C Palladium on Carbon Catalyst
PdCI2(PPhIa)2 Palladium Bis(triphenylphosphine) chloride
PTSA or pTSA = p-Toluene sulfonic acid
PyBroP Bromortri(pyrrolidino)phosphonium hexafluorophosphate
TBAF Tetra(/τ-butyl)ammonium fluoride
TEA Triethylamine
Tf Triflate
TFA Trifluoroacetic Acid
TFAA Trifluoroacetic acid anhydride
THF Tetrahydrofuran TMS = Trimethylsilyl
TMSCHN2 = Trimethylsilyl diazomethane
Ts = tosyl (-Sθ2-(p-toluene))
The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similalry, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edentate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5- disulfonic acid, 1 -hydroxy-2-naphthoic acid, nicotine acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid, L- pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.
Compounds of formula (I) wherei inn Θ. is selected from
Figure imgf000056_0001
or
Figure imgf000056_0002
may be prepared according to the process outlined in Scheme 1.
Figure imgf000056_0003
Figure imgf000057_0001
Scheme 1
Accordingly, a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (Xl), wherein Q1 is a suitable leaving group such as hydroxy, halogen, and the like, a known compound or compound prepared by known methods, according to known methods (for example, where Q is a halogen, in an organic solvent such as THF, methylene chloride, and the like; where Q is hydroxy, in the presence of cyanochloride, oxalyl chloride, and the like, in an organic solvent such as DMA, DMF, and the like), to yield the corresponding compound of formula (XII).
The compound of formula (XII) is reacted with a suitably substituted and protected hydrazone, a compound of formula (XIII), wherein R0 a group such as tolyl, and the like, (wherein -SO2-R0 is a leaving group), a known compound or compound prepared by known methods, in the presence of a base such as NaH, potassium t-butoxide, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of from about room temperature to about reflux temperature, preferably at a temperature in the range of from about 80 to about 100°C, to yield the corresponding compound of formula (Ib).
The compound of formula (Ib) is further, optionally converted to the corresponding compound of formula (Ia) by treating the compound of formula (Ib) with a weak acid such as acetic acid, TFA, dilute HCI, and the like, or by passing the compound of formula (Ib) through silica gel, according to known methods.
The compound of formula (Ia) is further, optionally reacted with a suitably substituted alkylating agent, according to known methods, to yield the corresponding compound of formula (Ic).
One skilled in the art will recognize that compounds of formula (I)
wherein
Figure imgf000058_0001
and wherein R5' is C1-4alkyl may be similarly prepared according to the processs described in Scheme 1 by selecting and substituting a suitably substituted compound of formula (XXXX)
Figure imgf000058_0002
°2 (XXXX) for the compound of formula (XIII) above.
Compounds of formula (I) where )iinn
Figure imgf000058_0003
i iss a anndd R R5 i ijs halogen may be prepared from the corresponding compound of formula (I)
where iiinn
Figure imgf000058_0004
R by reacting with a suitable source of the halogen (for example, wherein the halgen is chloro by reacting with PCI5 or POCI3) according to known methods. Compounds of formula (I) wherein
Figure imgf000059_0001
is may be similarly prepared according to the process outlined in Scheme 1 above, by selecting and substituting a suitably substituted compound of formula (XXXXI)
Figure imgf000059_0002
(XXXXI) for the compound of formula (XIII).
Compounds of formula (I) where iinn
Figure imgf000059_0003
may be similarly prepared according to the process outlined in Scheme 1 above, by selecting and substituting a suitably substituted compound of formula (XXXXII)
Figure imgf000059_0004
(XXXXII) for the compound of formula (XIII).
Compounds of formula (Ic) wherein R10 is other than hydrogen may alternatively be prepared according to the process outline in Scheme 2.
Figure imgf000059_0005
Figure imgf000060_0001
Scheme 2
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted hydrazine, a compound of formula (XIV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (Ic).
Compounds of formula (I) wherein
Figure imgf000060_0002
. I jSS R may be prepared according to the process outlined in Scheme 3.
Figure imgf000060_0003
Scheme 3
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XV), wherein X is Cl or Br, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as THF, dioxane, and the like, at a temperature in the range of about 0 to about 500C, preferably at about room temperature, to yield the corresponding compound of formula (Id).
Compounds of formula (I) where ■ iinn
Figure imgf000061_0001
prepared according to the process outlined in Scheme 4.
Figure imgf000061_0002
Scheme 4
Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitably substituted compound of formula (XVI), a known compound or compound prepared by known methods, in an organic solvent such as toluene, xylene, chlorobenzene, and the like, at a temperature in the range of about room temperature to about 120°C, to yield the corresponding compound of formula (Ie).
Compounds of formula (I) where ϊiinn
Figure imgf000061_0003
i iss may be prepared according to the process outlined in Scheme 5.
Figure imgf000062_0001
Scheme 5 Accordingly, a suitably substituted compound of formula (XII) is reacted with a suitable reducing agent such as mCPBA, hydrogen peroxide, and the like, at a temperature in the range of about 00C to about room temperature, according to known methods, to yield the corresponding compound of formula (XVII). The compound of formula (XVII) is reacted with a suitably substituted amine, a compound of formula (XVIII), a known compound or compound prepared by known methods, in an organic solvent such as DMF, DMSO, and the like, at a temperature in the range of about O to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (XIX).
The compound of formula (XIX) is reacted with a suitably substituted compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, and the like or in an alcohol such as methanol, ethanol, and the like, at a temperature in the range of about 0 to about 50°C, preferably at about room temperature, to yield the corresponding compound of formula (If).
Compounds of formula (I) wherein
Figure imgf000063_0001
may be prepared according to the process outlined in Scheme 6.
Figure imgf000063_0002
Scheme 6
Accordingly, a suitably substituted compound of formula (XVII) is reacted with a suitably substituted compound of formula (XXI), a known compound or compound prepared by known methods, in the presence of a Lewis acid such as BF3«Etherate, AICI3, and the like, in an organic solvent such as methylene chloride, chloroform, and the like, to yield the corresponding compound of formula (Ig).
Alternatively, a suitably substituted compound of formula (XIXa), a compound of formula (XIX) wherein R10 is hydrogen, is reacted with a suitably substituted compound of formula (XXII), wherein Q is a leaving group such as hydroxy, halogen, and the like, a known compound or compound prepared by known methods, according to known methods, at an elevated temperature in the range of from about 50 to about 1200C, preferably at an elevated temperature in the range of about 80 to about 120°C, to yield the corresponding compound of formula (Ig).
Compounds of formula (I) where iiinn x V —-/ ' i ιs«
Figure imgf000064_0001
may be prepared according to the process outlined in Scheme 7.
Figure imgf000064_0002
Scheme 7
Accordingly, a suitably substituted compound of formula (XXIII), wherein Q2 is suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, is reacted with a suitably substituted aldehyde, a compound of formula (XX), a known compound or compound prepared by known methods, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as toluene, benzene, and the like, at a temperature in the range of from about room temperature to about 5O0C, to yield the corresponding compound of formula (XXIV). Wherein the compound of formula (XXIV) Q2 is alkoxy and the like, the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ih).
Alternatively, wherein the compound of formula (XXIV) Q2 is hydroxy, the compound of formula (XXIV) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50°C, to yield the corresponding compound of formula (Ih).
Compounds of formula (I) wherein
Figure imgf000065_0003
■ is
Figure imgf000065_0001
may be prepared according to the process outlined in Scheme 8.
Figure imgf000065_0002
Figure imgf000066_0001
Scheme 8
Accordingly, a suitably substituted compound of formula (XXV), wherein Q3 is a suitable leaving group such as hydroxy, halogen, alkoxy, and the like, is reacted with 1 ,1 'carbonyl-diimidazole (CDI), in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, to yield the corresponding compound of formula (XXVI).
Wherein the compound of formula (XXVI) Q3 is alkoxy and the like, the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ij). Alternatively, wherein the compound of formula (XXVI) Q3 is hydroxy, the compound of formula (XXVI) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 50°C, to yield the corresponding compound of formula (Ij).
Compounds of formula (I) where iiinn
Figure imgf000066_0002
i iss may be prepared according to the process outlined in Scheme 9.
Figure imgf000067_0001
Figure imgf000067_0002
Scheme 9 Accordingly, a suitably substituted compound of formula (XXVII), wherein Q4 is a suitable leaving group such as OH, halogen, alkoxy, alkyl- carbonyl-oxy-, and the like, a known compound or compound prepared by known methods, is reacted with a suitably substituted compound of formula (XXVIII), wherein Q5 is a suitable leaving group such as OH, halogen, alkoxy, alkyl-carbonyl-oxy-, and the like, a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an acid such as PTSA, CSA, and the like, in an organic solvent such as THF, toluene, benzene, and the like, at a temperature in the range of from about 50 to about 80°C, to yield the corresponding compound of formula (XXIX).
Wherein the compound of formula (XXIX) Q4 is alkoxy and the like, the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a metallic agent such as (CH3)3AI, isopropyl-MgCI, and the like, in an organic solvent such as toluene, THF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ik).
Alternatively, wherein the compound of formula (XXIX) Q4 is hydroxy, the compound of formula (XXIX) is reacted with a suitably substituted compound of formula (X), a known compound or compound prepared by known methods, in the presence of a coupling agent such as DCC, EDC, PyBroP, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, and the like, at a temperature in the range of from about room temperature to about 500C, to yield the corresponding compound of formula (Ik).
Compounds of formula (I) wherein
Figure imgf000068_0001
may be prepared according to the process outlined in Scheme 10.
Figure imgf000068_0002
Scheme 10
Accordingly, a suitably substituted compound of formula (Im), a compound of formula (Ic) wherein R5 is hydrogen, is reacted with a reducing agent such as NaBH4, NaCNBH3, and the like, in an organic solvent such as AcOH, CF3CO2H, methanol, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (In).
The compound of formula (In) is reacted with a suitably substituted compound of formula (XXX), wherein Q6 is a suitable leaving group such as halogen, alkyl-carbonyl-oxy-, and the like, in the presence of an organic amine such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, DMF, and the like, at a temperature in the range of from about 0°C to about room temperature, to yield the corresponding compound of formula (Ip)-
Compounds of formula (I) wherein W is S, may be prepared according to the process outlined in Scheme 11.
Figure imgf000069_0001
(Ix) (Iy)
Scheme 11
Accordingly, a suitably substituted compound of formula (Ix) is reacted with a source of sulfur such as Lawesson's reagent, P2S5, and the like, in an organic solvent such as toluene, xylene, p-oxlane, and the like, at a temperature in the range of from about 1100C to about 150°C, to yield the corresponding compound of formula (Iy).
Compounds of formula (II) wherein Q is -ORE may be prepared according to the process outlined in Scheme 12.
Figure imgf000069_0002
(Ix) (Ha)
Scheme 12 Accordingly, a suitably substituted compound of formula (Ix) wherein R2 is hydrogen, is recated with a suitably substituted electrophile, a compound of formula (XXXI) wherein Lv is a suitable leaving group such as Cl, Br, tosyl, triyl, mesyl, and the like, (for example where RE is ethyl, the compound of formula (XXIX) may be BF4 etherate), in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DCM, THF, diethyl ether, and the like, at a temperature in the range of from about - 400C to about room temperature, to yield a mixture of the corresponding compound of formula (Ha) and (Iz).
Compounds of formula (II) wherein Q is -SRE or -N(RF)2 may be prepared according to the process outlined in Scheme 13.
Figure imgf000070_0001
(lie)
Scheme 13
Accordingly, a suitably substituted compound of formula (Iy) is reacted with a suitably substituted compound of formula (XXXI), wherein Lv is a suitable leaving group such as Cl, Br, tosyl, trifyl, mesyl, and the like, a known compound or compound prepared by known methods, in the presence of an organic amine base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as acetone, THF, DMF, and the like, at a temperature in the range of from about 0°C to about 8O0C, to yield the corresponding compound of formula (lib). The compound of formula (lib) is reacted with a suitably substituted nitrogen containing nucleophile, a compound of formula (XXXII) (for example, NH3, NH(C1-4alkyl), N(C1-4alkyl)2l NH(OC1-4alkyl), NH2(OH), NH(CN), NH(SO2- C1-4alkyl), pyrrolidine, and the like), in the presence of an inorganic base such as K2CO3, NaH, Na2CO3, and the like, in an organic solvent such as THF, DMF, dioxane, and the like, at a temperature in the range of from about room temperature to about 100°C, to yield the corresponding compound of formula (lie).
One skilled in the art will recognize that when in the compound of formula (lie) at least one RF group is hydrogen, then the corresponding compound of formula (I) wherein W is NHRF is its tautomer.
One skilled in the art will recognize that compound of formula (I) wherein
Figure imgf000071_0001
is other than phenyl, may be similarly prepared according to the processes outlined in Scheme 1 -9 above, by selecting and substituting suitably substituted compounds for the starting materials and reagents.
One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartaric acid and/or (+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The present invention further comprises pharmaceutical compositions containing one or more compounds of formula (I) and/or (II) with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 50-100 mg and may be given at a dosage of from about 0.5-5.0 mg/kg/day, preferably from about 1.0-3.0 mg/kg/day. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
The method of treating a disorder mediated by one or more androgen receptor(s) described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 500 mg, preferably about 50 to 100 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders mediated by one or more androgen receptor(s) is required.
The daily dosage of the products may be varied over a wide range from 0.01 to 1 ,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day. Preferably, the range is from about 0.5 to about 5.0 mg/kg of body weight per day, most preferably, from about 1.0 to about 3.0 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages. The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products may be listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term "residue" does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
One skilled in the art will recognize that in the Examples which follow and describe the preparation of compounds of formula (II) wherein Z is NHRF and their corresponding tautomers (compounds of formula (I) wherein W is NRF), the identity and ratio of the two tautomeric forms in the isolated product was not determined.
Example 1 2-Methyl-N-(4-cvano-3-trifluoromethyl-phenyl)-acrylamide
Figure imgf000078_0001
Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated with thionyl chloride (714 mg, 6 mmol) at 0°C. The mixture was stirred for 30 min then 4-cyano-3-trifluoromethyl-aniline (1.Og, 6.0 mmol) was added. The resulting suspension was stirred overnight and then quenched with NaHCO3. The reaction mixture was extracted with ethyl acetate, washed with brine and dried with Na2SO4. The resulting concentrated crude product was purified on column (Ethyl acetate: Hexane, 1 :2) to yield the title compound as a yellow solid.
1H NMR (CDCI3) δ 8.10 (s, 1 H), 7.95 (dd, J=1.5 Hz, 0.5 Hz, 1 H), 7.90 (br, 1 H), 7.75 (d, J=1.5 Hz), 5.85 (s, 1 H), 5.60 (s, 1 H), 2.10 (s, 3H). MS (m/z): M+Na (277).
Example 2 2-Methvl-N-(4-nitro-3-trifluoromethvl-phenyl)-acrvlamide
Figure imgf000079_0001
Following the procedure described in Example 1 , starting from 4-nitro-3- trifluoromethyl-aniline (2.06 g, 10.0 mmol), the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 8.00 (m, 3H), 7.95 (s, 1 H), 5.88 (s, 1 H), 5.60 (s, 1 H), 2.10 (s, 3H).
MS (m/z): M+Na (297)
Example 3 2-Methyl-N-(4-Chloro-3-trifIuoromethyl-phenyl)-acrylamide
Figure imgf000079_0002
Following the procedure described in Example 1 , starting from 4-chloro - 3-trifluoromethyl-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.90 (s, 1 H), 7.70 (dd, J=1.5 Hz, 0.5 Hz, 1 H), 7.40 (d, J=1.5 Hz), 5.80 (s, 1 H), 5.50 (s, 1 H), 2.00 (s, 3H).
MS (m/z): MH+ (263)
Example 4 2-Methyl-N-(4-bromo-3-trifluoromethyl-phenyl)-acrylamide
Figure imgf000079_0003
Following the procedure described in Example 1 , starting from 4-bromo -3-trifluoromethyl-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.90 (s, 1 H), 7.85 (s, br, 1 H), 7.69 (d, J = 7.5 Hz, 1 H), 7.61 (d, J = 7.5 Hz, 1 H), 5.85 (s, 1 H), 5.55 (s, 1 H), 2.08 (s, 3H)
Example 5 2-Methyl-N-(3,4-di-chloro-phenvD-acrvIamide
Figure imgf000080_0001
Following the procedure described in Example 1 , starting from 3,4-di- chloro-aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.85 (s, 1 H), 7.50 (s, br, 1 H), 7.36 (s, 2H), 5.78 (s, 1 H), 5.51 (s, 1 H), 2.08 (s, 3H). MS (m/z): MH+ (230).
Example 6
2-Methyl-N-(3,4-di-cyano-phenyl)-acrylamide
Figure imgf000080_0002
Following the procedure described in Example 1 , starting from 3,4-di- cyano-aniline the title compound was prepared as a yellow solid. 1H NMR (CDCI3) δ 8.25 (s, 1 H), 8.05 (s, br, 1 H), 7.95 (d, J = 7.5 Hz, 1 H),
7.74 (d, J = 7.5 Hz, 1 H), 5.88 (s, 1 H), 5.65 (s, 1 H), 2.11 (s, 3H)
MS (m/z): MNa+ (234)
Example 7 N-(4-Benzoyl-phenyl)-2-methyl-acrylamide
Figure imgf000081_0001
Following the procedure described in Example 1 , starting from (4-amino- phenyl)-phenyl-methanone, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.98 (s, br, 1 H), 7.88 ~ 7.72 (m, 6H), 7.60 (t, J = 8.5 Hz, 1 H), 7.52 (t, J = 7.8 Hz, 2H), 5.88 (s, 1 H), 5.55 (s, 1 H)
MS (m/z): MH+ (266), MNa+ (288)
Example 8 N-(4-Benzoyl-benzyl)-2-methyl-acrylamide
Following the procedure described in Example 1 , starting from (4- Aminomethyl-phenyl)-phenyl-methanone, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.38 ~ 7.22 (m, 4H), 7.10 (t, J = 7.5 Hz, 1 H), 7.00 (m, 4H), 6.15 (S1 br, 1 H), 5.71 (s, 1 H), 5.35 (s, 1 H), 4.52 (d, J = 4.5 Hz, 2H), 2.11 (s, 3H)
MS (m/z): MH+ (280), MNa+ (302)
Example 9 2-Methyl-N-(4-phenoxy-phenyl)-acrylamide
Figure imgf000081_0003
Following the procedure described in Example 1 , starting from A- phenoxy-phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.70 (s, 1 H), 7.50 (m, 2H), 7.30 (m, 2H), 7.00 (m, 5H), 5.80 (s, 1 H), 4.90 (s, 1 H), 2.00 (s, 3H). MS (m/z): M+1 (254). MS (m/z): MH+ (254), MNa+ (276)
Example 10 2-Methyl-N-(4-cvano-phenvO-acrylamide
Figure imgf000082_0001
Following the procedure described in Example 1 , starting from 4- cyano- aniline, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) 67.70 (m, 5H), 5.80 (s, 1 H), 5.05 (s, 1 H), 2.00 (s, 3H) MS (m/z): MH+ (187), MNa+ (209)
Example 11
2-Methyl-N-(4-phenylsulfanyl-phenyl)-acrylamide
Figure imgf000082_0002
Following the procedure described in Example 1 , starting from 4- phenylsulfanyl-phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.60 (s, 1 H), 7.55 (d, J = 9.0Hz, 2H), 7.35 (d, J = 9.0 Hz, 2H), 7.20 (m, 5H), 5.80 (s, 1 H), 5.00 (s, 1 H), 2.00 (s, 3H)
MS (m/z): MH+ (270), MNa+ (292) Example 12 N-(4-Benzvl-phenvO-2-methvl-acrvlamide
Figure imgf000083_0001
Following the procedure described in Example 1 , starting from 4-benzyl- phenylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 8.00 (d, J = 9.0 Hz, 1 H), 7.15-7.35 (m, 9H)1 5.35 (s, 1 H), 5.25 (s, 1 H), 1.75 (s, 3H)
MS (m/z): MH+ (252), MNa+ (274)
Example 13 N-(4-Methanesulfonyl-benzvO-2-methvl-acrylamide
Figure imgf000083_0002
Following the procedure described in Example 1 , starting from 4- methanesulfonyl-benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.75 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 6.92 (s, 1 H), 5.78 (s, 1 H), 5.38 (s, 1 H), 4.55 (d, J = 6.5 Hz, 2H), 3.02 (s, 3H), 2.05 (s, 3H)
MS (m/z): MH+ (254), MNa+ (276)
Example 14 N-(4-Chloro-benzyl)-2-methvl-acrylamide
Figure imgf000084_0001
Following the procedure described in Example 1 , starting from 4-chloro- benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) 6 7.20 (m, 4H), 6.15 (s, 1 H), 5.75 (s, 1 H), 4.85 (s, 1 H), 4.50 (d, J = 5.0 Hz, 2H), 2.00 (s, 3H).
MS (m/z): MH+ (210).
Example 15 N-(4-phenoxy-benzyl)-2-methyl-acrylamide
Figure imgf000084_0002
Following the procedure described in Example 1 , starting from 4- phenoxy-benzylamine, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 7.18 ~ 6.94 (m, 4H), 6.85 (t, J = 6.5 Hz, 1 H), 6.77 (m, 4H), 5.56 (s, br, 1 H), 5.65 (s, 1H), 5.30 (s, 1 H), 4.38 (d, J = 5.5 Hz, 2H), 2.06 (s, 3H)
MS (m/z): MH+ (268), MNa+ (290)
Example 16 N-(4-Cvano-3-trifluoromethyl-phenvO-2-ethyl-acrylamide
Figure imgf000084_0003
Following the procedure described in Example 1 , starting from 4-cyano- 3-trifluoromethyl-aniline and 2-ethyl-acrylic acid, the title compound was prepared as a yellow solid. 1H NMR (CDCI3) δ 8.70 (s, 1H), 8.18 (s, 1H), 8.06 (d, J = 12.0H, 1 H), 7.78 (d, J = 12.0 Hz, 1 H), 5.75 (s, 1 H), 5.05 (s, 1 H), 2.40 (q, J = 9.0 Hz, 2H), 1.11 (t, J = 9.0 Hz, 3H).
MS (m/z): MH+ (270), MNa+ (292)
Example 17 N-(4-Cvano-3-trifluoromethyl-phenyl)-2-propyl-acrylamide
Figure imgf000085_0001
Following the procedure described in Example 1 , starting from 4-cyano- 3-trif luoromethyl-aniline and 2-propyl-acrylic acid, the title compound was prepared as a yellow solid.
MS (m/z): MH+ (284), MNa+ (306).
1H NMR (CDCI3) 58.20 (s, 1 H), 8.12 (s, 1 H), 8.00 (d, J = 12.0 Hz, 1 H), 7.78 (d, J = 12.0 Hz, 1 H), 5.70 (s, 1 H), 5.00 (s, 1 H), 2.40 (t, J = 9.0 Hz, 2H), 1.50 (m, 2H), 0.95 (t, J = 9.0 Hz, 3H).
Example 18 N-Benzyl-N"-(4-fluoro-benzylidene)-hvdrazine
Figure imgf000085_0002
4-Fluorobenzenealdehyde (1.24 g, 10.0 mmol) in benzene (40 ml) was mixed with benzyl hydrazine hydrochloride (1.95 g, 10.0 mmol). The reaction was stirred at room temperature for 12 h. The solvent was then removed by vacuum evaporation to yield the title compound as a white solid.
1H NMR (CDCI3) δ 7.60 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 4.45 (s, 1 H).
MS (m/z): MH+ (227) Example 19 N-r4-(Methvl-hvdrazonomethvO-phenvπ-acetamide
Figure imgf000086_0001
Following the procedure described in Example 18, starting from N-(4- formyl-phenyl)-acetamide and methyl hydrazine, the title compound was prepared as a white solid.
Example 20 4-Fluoro-benzaldehvde oxime
Figure imgf000086_0002
Following the procedure described in Example 18, starting from N-(4- formyl-phenyl)-acetamide and N-hydroxyamine, the title compound was prepared as a white solid.
MS (m/z): MH+ (140).
Example 21 4-Fluoro-/V-(phenylmethyl)-benzenecarbohvdrazonoyl chloride
Figure imgf000086_0003
NCS (1.33 g, 10.0 mmol) was mixed with dimethyl sulfide (620 mg, 10.0 mmol) in CH2Cb (20 ml) at 0°C for 30 min. The mixture was then cooled to - 78°C and N-benzyl-N"-(4-fluoro-benzylidene)-hydrazine, prepared as in Example 19, (2.62 g, 10.0 mmol) was added into the mixture. The mixture was maintained at -78°C for 1 h, then slowly warmed up to room temperature over 2hrs. The reaction mixture was quenched by NaHCO3, then extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (100% CH2CI2, Rf= 0.5) yielded the title compound as a white solid.
1H NMR (CDCI3) δ 7.80 (m, 2H), 7.30 (m, 5H), 7.05 (m, 2H), 6.10 (br, 1 H).
MS (m/z): MH+ (260).
Example 22
4-acetamido-ΛHmethyl)-benzenecarbohvdrazonoyl chloride
Figure imgf000087_0001
Following the procedure described in Example 21 , starting from N-[4- (methyl-hydrazonomethyl)-phenyl]-acetamide, the title compound was prepared as a white solid.
MS (m/z): MH+ (226).
Example 23
2-Benzyl-5-(4-fluoro-phenyl)-3-methyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #5
Figure imgf000088_0001
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (500 mg, 2.0 mmol) was mixed with 4-fluoro-/V-(phenylmethyI)-benzenecarbohydrazonoyl chloride (520 mg, 2.0 mmol) in CH2Cb at room temperature. Triethyl amine (300 mg, 3.0 mmol) was then added to the reaction mixture. The reaction was refluxed overnight, then quenched with NaHCO3, and extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (Hexane: ethyl acetate, 5:1 , Rf= 0.5) yielded the title compound as a white solid.
1H NMR (CDCI3) δ 9.25 (s, 1 H), 7.80 (s, 1 H), 7.70 (s, 2H), 7.60 (m, 2H), 7.45 (m, 2H), 7.05 (m, 5H), 4.30 (dd, J=11.1 Hz, 1.0 Hz, 2H), 3.30 (dd, J=3.6 Hz, 1.2 Hz, 2 H), 1.65 (s, 3H).
MS (m/z): MH+ (481)
Example 24
S^^FIuoro-phenvD-S-methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid
(4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #1
Figure imgf000089_0001
2-Benzyl-5-(4-fluoro-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3- carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (150 mg, 0.33 mmol) in ethanol, was treated with Pd/C (100 mg, 10%) under H2 balloon for two days. Pd/C was removed by vacuum filtration and the solvent was removed by vacuum rotary evaporation to yield a crude product. Purification of the crude product by silica gel (Hex: ethyl acetate, 2:1 , Rf=0.4) yielded the title compound as a white solid.
1H NMR (CDCI3) 5 9.75 (s, 1 H), 8.10 (s, 1 H), 7.85 (dd, J=4.5 Hz, 0.2 Hz, 2H), 7.65 (m, 2H), 7.05 (m, 2H), 5.70 (br, 1 H), 3.30 (dd, J=3.6 Hz, 1.2 Hz, 2 H), 1.65 (s, 3H)
MS (m/z): MH+ (390)
Example 25
5-(4-Acetylamino-phenyl)-2,3-dimethyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #39
Figure imgf000089_0002
Following the procedure described in Example 23, starting from 2- methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide and 4-acetamido-Λ/- (methyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as a white solid.
1H NMR (CDCI3) 69.62 (s, 1 H), 8.18 (s, 1 H), 8.02 (d, J = 7.5 Hz, 1 H), 7.98 (d, J = 7.5 Hz, 1 H), 7.80 (s, 1 H), 7.50 (m, 4H), 3.38 (abq, J = 12.5 Hz, 2H), 2.98 (s, 3H), 2.20 (s, 3H), 1.50 (s, 3H).
MS (m/z): MH+ (444), MH- (442)
Example 26
5-(4-Acetylamino-phenyl)-2,3-dimethyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-nitro-3-trifluoromethyl-phenvD-amide
Compound #40
Figure imgf000090_0001
Following the procedure described in Example 23, starting from 2- methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and 4-acetamido-Λ/- (methyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as a white solid.
1H NMR (CDCI3) 69.52 (s, 1 H), 8.15 (s, 1 H), 8.06 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.61 (s, 1 H), 7.55 (m, 4H), 3.38 (abq, J = 12.5 Hz, 2H), 2.98 (s, 3H), 2.18 (s, 3H), 1.48 (s, 3H)
MS (m/z): MH+ (464), MNa+ (486)
Example 27
3-(4-Fluoro-phenyl)-5-methyl-4,5-dihvdro-isoxazole-5-carboxylic acid (4- cvano-3-trifluoromethyl-phenyl)-amide
Compound #95
Figure imgf000091_0001
4-Fluorobenzamidoxime (1.39 g, 10 mmol) was mixed with triethylamine (200 mg, 2.0 mmol) and NaOCI (4%, 15 ml, 1.48 g, 10 mmol) in CH2CI2 (25 ml). N-(4-(Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (508 mg, 2.0 mmol) was added into the mixture and the mixture was then stirred for 3 hrs at room temperature. The reaction mixture was quenched by NaHCO3, and then extracted with ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield a crude product. Purification of the crude product on column (Hexane: ethyl acetate, 2:1 , Rf= 0.45) yielded the title compound as a white solid.
1H NMR (CDCI3) δ 9.15 (s, 1 H), 8.15 (s, 1 H), 7.85 (dd, J=4.5 Hz, 0.2 Hz, 2H), 7.60 (m, 2H), 7.05 (m, 2H), 3.75 (dd, J=17.4Hz, 2.0 Hz, 2 H), 1.75 (s, 3H).
MS (m/z): MH+ (392)
Example 28 1-R-p-Toluenesulfonylhydrazone (General procedure)
Figure imgf000091_0002
p-Toluenesulfonylhydrazine (10.0 mmol) was mixed with a suitably selected compound of the formula R-CHO (10.0 mmoL) in methanol (40 ml) at room temperature for 4 h. The mixture was then concentrated to yield the title compound as a white solid (unless otherwise noted). Example 29 S-rø-Fluoro-phenvO-S-methYl-S^-dihydro-ΣH-pyrazole-S-carboxylic acid
M-cvano-S-trifluoromethyl-PhenvD-amide and
S-rø-Fluoro-phenvO-S-methvM.S-dihvdro-SH-pyrazole-S-carboxylic acid rø-cvano-S-trifluoromethyl-phenvQ-amide
Compound #1 and Compound #64
Figure imgf000092_0001
2-[(1 E)-(4fluorophenyl)methylidene] toluenesulfonylhydrazone, prepared according to the procedure described in Example 29 (600 mg, 2.1 mmol) in THF (20 ml) was treated by NaH (60%, 120 mg, 3 mmol) at 0°C for 20 min, followed by the addition of N-(4-cyano-3-trifluoromethyl-phenyl)-2-methyl- acrylamide (500 mg, 2.0 mmol). The reaction mixture was then heated to 55°C overnight, then quenched by NaHCO3, and extracted by ethyl acetate. The organic layer was combined, washed with brine, dried over Na2SO4 and concentrated to yield crude product as a mixture. Purification of the crude product on a column yielded the title compound as separate products, as a white solids.
5-(4-Fluoroφhenyl)-3-methyl-3,4-dϊhydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (Hexane: ethyl acetate, 2:1 , Rf= 0.45, 475 mg, 61 %)
5-(4-Fluoro-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide
(Hexane: ethyl acetate: 2:1 , Rf=0.6, 100 mg, 13%): MS (m/z): MH+ (391) 1H NMR (CDCI3) δ 8.50 (s, 1 H), 8.10 (s, 1 H), 7.90 (del, J=1.5 Hz, 0.2 Hz, 1 H), 7.75 (d, J=1.5 Hz, 1 H), 7.20 (m, 2H), 7.10 (m, 2H), 5.60 (t, J=0.9 Hz, 1 H), 3.00 (dd, J=1.0 Hz, 0.8 Hz, 1 H), 1.87 (s, 3H), 1.55 (t, J=1.1 Hz, 0.6 Hz, 1 H).
Example 30 δ-rø-Fluoro-phenvO-S-methyl^Adihvdro-ΣH-pyrazole-S-carboxylic acid
(4-nitro-3-tNfluoromethyl-phenvO-amide
Compound #7
Figure imgf000093_0001
Following the procedure described in Example 29, starting from 2- methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and 2-[(1 E)- (4fluorophenyl) methylidene] toluenesulfonylhydrazone, the title compound was prepared as a yellow solid.
1H NMR (MeOH) 66.45 (d, J=0.9 Hz, 1 H), 6.20 (m, 1 H), 6.00 (s, 1 H), 5.55 (m, 4H), 2.00 (dd, J=5.5 Hz, 1.8 Hz, 2 H), 1.70 (s, 3H). MS (m/z): MNa+ (410)
Example 31
S-Methyl-δ-trimethylsilanyl^^-dihvdro-SH-pyrazole-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenvO-amide and
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenvD-amide Compound #51 and Compound #47
Figure imgf000094_0001
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acrylamide (180 mg, 0.71 mmoL) in THF (5 ml_) was treated with TMSCHN2 (2.0 M in hexanes, 3.54 mmoL, 1.8 ml_) at -10°C. The reaction mixture was then warmed to room temperature slowly and stirred overnight. The solvent was removed and the residue was purified by column chromatography (silica gel, 1 :1 hexanes : EtOAc) to yield the title compound as a white solids (1 :1 diastereomers). 3-Methyl-54rimethylsilanyl-4,5-dihydro-3Hφyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide: 1H NMR (CDCI3) δ 8.58 (br, s, 1 H) for diastereomer 1 , 8.35 (br, s, 1 H) for diastereomer 2, 7.90 (m, 1), 7.70 (m, 1 H), 7.58 (m, 1 H), 4.35 (dd, J = 10.5, 5.0 Hz, 1 H) for diastereomer 1 , 4.30 (dd, J = 11.0, 6.0 Hz, 1 H) for diastereomer 2, 2.30 (m, 1 H) for diastereomer 1 , 2.05 (m, 1 H) for diastereomer 2, 1.66 (m, 1 H) for diastereomer 1 , 1.48 (s, 3H) for diastereomer 1 , 1.42 (s, 3H) for diastereomer 2, 1.29 (m, 1 H) for diastereomer 2), 0.10 (s, 9H) for diastereomer 1 ), 0.01 (s, 9H) for diastereomer 2
MS (m/z), 298 [M-TMS+H]+, 319 [M-TMS+Na]+ 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- tπfluoromethyl-phenyl)-amide: 1H NMR (CDCI3) 9.62 (s, 1 H), 8.10 (s, 1 H), 7.95 (d, J=6.5 Hz, 1 H), 7.77
(d, J=6.5 Hz, 1 H), 6.88 (s, 1 H), 5.52 (s, 1 H), 3.05 (abq, J=12.5 Hz, 2H),1.56 (s, 3H)
MS (m/z), MH+ (297).
Example 32
3-Methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-nitro-3- trifluoromethyl-phenvD-amide and S-Methyl-δ-trimethylsilanyl^δ-dihvdro-SH-pyrazole-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenvO-amide
Compound #6 and Compound #57
Figure imgf000095_0001
Following the procedure described in Example 31 , starting from 2- methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide and TMSCHN2 the title compounds were prepared, both as a white solids.
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3- trifluoromethyl-phenyl)-amide: 1H NMR (CDCI3) δ 9.62 (br, s, 1 H), 8.10 (s, 1 H), 7.98 (m, 2H), 6.88 (s,
1 H), 5.50 (s, 1 H), 3.10 (Abq, J= 12.5 Hz, 2H), 1.52 (s, 3H) MS (m/z), MH+, 317, MH", 315
S-Methyl-δ-trimethylsilanyMjδ-dihydro-SH-pyrazole-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenyl)-amide : 1H NMR (CDCI3) 58.78 (br, s, 1 H), 8.05 (s, 1 H), 7.88 (d, J = 7.0 Hz, 1 H),
7.74 (d, J = 7.0 Hz, 1 H), 4.48 (dd, J = 11.0, 4.5 Hz, 1 H), 2.10 (dd, J = 13.0, 11.0
Hz, 1H), 1.78 (dd, J = 13.0, 4.5 Hz, 1H), 1.55 (s, 3H)
Example 33
/V-r4-cvano-3-(trif luoromethv0phenvπ-3-r2-rr(1.1 - dimethylethyl)dimethylsilvπoxy1phenyll-4,5-dihvdro-5-methyl-1 H- pyrazole-5-carboxamide Compound #54
Figure imgf000096_0001
Following the procedure described in Example 29, 4-methyl-2-[(12)-[2- [[(1 ,1 -dimethylethyl)dimethylsilyl]oxy]phenyl]methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 59.25 (s, 1 H), 8.16 (s, 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.65 (d, J=0.6 Hz, 1 H), 7.10 (m, 1 H), 6.80 (m, 3H), 5.80 (m, 1 H), 2.30 (m, 1 H), 1.80 (m, 1 H), 1.51 (s, 3H), 0.89 (s, 9H), 0.21 (s, 6H)
MS (m/z): M+ (503)
Example 34 /V-r^cvano-S-Ctrifluoromethvπphenvn^^δ-dihvdro-S-fΣ-hvdroxyphenvD-S- methyl-1 H-pyrazole-5-carboxamide and
5-(2-hvdroxy-phenyl)-3-methyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #76 and Compound #55
Figure imgf000096_0002
Λ/-[4-cyano-3-(trifluoromethyl)phenyl]-3-[2-[[(1 ,1 - dimethylethyl)dimethylsilyl]oxy] phenyl]-4,5-dihydro-5-methyl-1 H-pyrazole-5- carboxamide, prepared as in Example 34 (80mg, 1.6 mmol) in THF (20 ml) was treated with TBAF (1M, 3.2 ml, 3.2 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 h, then quenched with H2O, extracted with ethyl acetate, dried over Na2SO4 and concentrated to yield a crude product. The crude product was purified by silica gel (Hexane: ethyl acetate, 2:1 , Rf=O.35) to yield the title compound as a white solid.
/V-[4-cyano-3-(trifluoromethyl)phenyl]-4,5-dihydro-3-(2-hydroxyphenyl)-5- methyl-1 H-pyrazole-5-carboxamide:
1H NMR (CDCI3) δ 10.78 (br, 1 H)1 9.75 (s, 1 H), 8.16 (s, 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.70 (d, J=0.6 Hz, 1 H), 7.25 (m, 1 H), 7.08 (d, J=0.6 Hz, 1 H), 6.85 (m, 1 H), 5.95 (s, 1 H), 3.40 (dd, J=5.1 Hz1 2.1 Hz, 1 H), 1.65 (s, 3H)
MS (m/z): MNa+ (401)
5-(2-hydroxyφhenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.80 (s, 1 H), 8.25 (s, 1 H), 7.90 (d, J=7.6 Hz, 1 H), 7.70 (d, J=7.6 Hz, 1 H), 7.65 (s, 1 H), 7.55 (d, J=6.6 Hz, 2H), 6.92 (d, J=6.6 Hz, 2H), 5.70 (br, 1 H)1 3.15 (abq, J= 12.5 Hz, 1 H), 1.55 (s, 3H)
MS (m/z): MNa+ (401)
Example 35
Λ/-r4-cyano-3-(trif luoromethyl)phenvn-3-r2-rr(1 ,1 - dimethylethyl)dimethylsilvnoxy1-3-fluorophenvn-4,5-dihvdro-5-methyl-1 tf- pyrazole-5-carboxamide Compound #96
Following the procedure described in Example 29, 4-methyl-2-[(1Z)-[2- [[(1 ,1 -dimethylethyl)dimethylsilyl]oxy]-3-f luorophenyl]methylidene] benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) δ 9.60 (s, 1 H), 8.00 (s, 1 H), 7.78 (d, J=0.6 Hz, 1 H), 7.65 (d, J=0.6 Hz, 1 H), 7.10 (m, 1 H), 6.95 (m, 1 H), 6.75 (m, 1 H)1 5.50 (br, 1 H), 3.25 (dd, J=5.1 Hz 1.2 Hz, 2H), 1.55 (s, 3H), 0.78 (s, 9H), 0.21 (d, J=4.8 Hz, 6H)
MS (m/z): M Na+ (544), M- (520)
Example 36
Λ/-r4-cvano-3-(trifluoromethyl)phenvn-3-(3-fluoro-2-hvdroxyphenyl)"4,5- dihvdro-5-methyl-1 H-pyrazole-5-carboxamide
Compound #97
Figure imgf000098_0001
Following the procedure described in Example 34, Λ/-[4-cyano-3- (trif luoromethyl)phenyl]-3-[2-[[(1 , 1 -dimethylethyl)dimethylsilyl]oxy]-3- fluorophenyl]-4,5-dihydro-5-methyl-1 H-pyrazole-5-carboxamide, prepared as in Example 36, was reacted to yield the title compound as a white solid.
MS (m/z): M+ (407)
1H NMR (CDCI3) δ 10.84 (s, 1 H), 9.63 (s, 1 H), 8.14 (s, 1 H)1 7.97 (d, J=0.6 Hz1 1 H)1 7.79 (d, J=0.6 Hz1 1 H)1 7.11 (m, 1 H)1 6.92 (m, 1 H)1 6.82 (m, 1 H)1 5.87 (s, 1 H)1 3.45 (dd, J=3.6 Hz1 1.2 Hz1 2H), 1.69 (s, 3H)
Example 37
3-Methyl-5-thiophen-2-yl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #49
Figure imgf000099_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 £)-2- thienylmethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 59.75 (s, 1H), 8.13 (s, 1 H), 7.92 (dd, J=1.1 Hz, 0.2 Hz, 1 H), 7.78 (d, J=0.8 Hz, 1 H), 7.37 (m, 1H), 7.11 (m, 1 H), 7.04 (m, 1 H), 5.55 (br, 1 H), 3.35 (dd, J=5.4 Hz, 1.7 Hz, 2 H), 1.65 (s, 3H)
MS (m/z): MH+ (379)
Example 38
5-Furan-2-yl-3-methyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyano-
3-trifluoromethyl-phenyl)-amide Compound #4
Figure imgf000099_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 £)-2- furanylmethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) δ 9.75 (s, 1 H), 8.13 (s, 1 H), 7.92 (dd, J=1.1 Hz, 0.2 Hz, 1 H), 7.78 (d, J=0.8 Hz, 1 H), 6.65-6.50 (m, 3H), 3.31 (dd, J=5.4 Hz, 1.7 Hz, 2 H), 1.65 (s, 3H)
MS (m/z): MH+ (363) Example 39
3-Methyl-5-(tetrahvdro-furan-2-ylV4.5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #52
Figure imgf000100_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- (tetrahydro-2-furanyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 59.09 (s, 1 H), 8.16 (m, 1 H), 7.95 (m, 1 H), 7.81 (d, J=0.6 Hz, 1 H), 4.49 (dd, J=1.0 Hz, 0.5 Hz, 1 H), 4.00-3.60 (m, 3H), 2.50-1.60 (m, 6 H), 1.56 (s, 3H)
MS (m/z): MH+ (366)
Example 40
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #8
Figure imgf000100_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- 2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) δ 9.30 (s, 1 H), 8.11 (s, 1 H), 7.98 (dd, J=1.1 Hz, 0.2 Hz, 1 H), 7.80 (d, J=0.8 Hz, 1 H), 6.18 (br, 1 H), 3.15 (dd, J=6.0 Hz, 1.8 Hz, 2 H), 1.62 (s, 3H)
MS (m/z): MNa+ (387)
Example 41 5-Cvclohexyl-3-methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4- cvano-3-tπfluoromethyl-phenyl)-amide and
5-Cvclohexyl-3-methyl-4,5-dihvdro-3H-pyrazoie-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #25 and Compound #68
Figure imgf000101_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- cyclohexylmethylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
5-Cyclohexyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.2, 210 mg, 19%)
1H NMR (CDCI3) 59.82 (s, 1 H), 8.10 (s, 1 H), 7.95 (dd, J=1.0 Hz, 0.2 Hz, 1 H), 7.78 (d, J=0.8 Hz, 1 H), 2.98 (dd, J=5.1 Hz, 1.7 Hz, 2 H), 1.77 (m, 6H), 1.50 (s, 3H), 1.27 (m, 4H).
MS (m/z): MH+ (379) 5-Cyclohexyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
(Hexane: ethyl acetate, 2:1 , Rf=0.8, 160 mg, 16%)
1H NMR (CDCI3) 5 9.20 (s, 1 H), 8.20 (s, 1 H), 8.05 (dd, J=1.0 Hz, 0.2 Hz, 1 H), 7.85 (d, J=0.9 Hz, 1 H), 4.36 (dd, J=1.5 Hz, 0.8 Hz, 1 H), 2.15 (d, J=1.0 Hz, 1 H), 1.70 (m, 6H), 1.55 (s, 3H), 1.20 (m, 5H)
MS (m/z): MNa+ (401)
Example 42
S^-Ethyl-phenvD-S-methyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cvano-3-tNfluoromethyl-phenvD-amide
Compound #3
Figure imgf000102_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-(4- ethylphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 69.80 (s, 1 H), 8.16 (m, 1H), 7.90 (d, J=0.6 Hz, 1 H), 7.78 (d, J=0.6 Hz, 1H), 7.50 (d, J=0.8 Hz, 2H), 7.15 (d, J=0.8 Hz, 2H), 5.83 (br, 1 H), 3.32 (dd, J=3.9 Hz, 1.3 Hz, 1 H), 2.65 (q, J=0.6 Hz, 2H), 1.62 (s, 3H), 1.20 (t, J=0.4 Hz, 3H)
MS (m/z): MH+ (401)
Example 43
5-(4-Fluoro-3-methyl-phenyl)-3-methyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide\
Compound #56
Figure imgf000103_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-(A- fluoro-3-methylphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 59.75 (s, 1 H), 8.16 (S1 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.78 (d, J=0.6 Hz, 1 H), 7.50-7.40 (m, 2H), 7.05 (m, 2H), 4.60 (br, 1 H), 3.30 (dd, J=3.9 Hz, 1.3 Hz, 1 H), 2.30 (s, 3H), 1.65 (s, 3H)
MS (m/z): MNa+ (427)
Example 44 S-lsopropyl-S-methyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4-cyano-
3-tπfluoromethyl-phenyl)-amide and 5-lsopropyl-3-methv[-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyano-
3-trifluoromethyl-phenyl)-amide Compound #42 and Compound #69
Figure imgf000103_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 £)-2- methylpropylidene]benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids. δ-lsopropyl-S-methyl-S^-dihydro^H-pyrazole-S-cai-boxylic acid (4-cyano- 3-trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.2, 350 mg, 35%)
1H NMR (CDCI3) 6 9.85 (s, 1 H), 8.10 (s, 1 H), 7.95 (dd, J=1.0 Hz, 0.2 Hz, 1 H), 7.78 (d, J=0.8 Hz, 1 H), 5.35 (br, 1 H), 2.98 (dd, J=5.4 Hz, 1.8 Hz, 2 H), 1.55 (s, 3H), 1.16 (s, 3H), 1.17 (s, 3H)
MS (m/z): MH+ (339) δ-lsopropyl-S-methyl-^δ-dihydro-SH-pyrazole-S-carboxylic acid (4-cyano- 3~trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.8, 560 mg, 55%)
1H NMR (CDCI3) 59.18 (s, 1 H), 8.20 (s, 1 H), 8.05 (dd, J=1.0 Hz, 0.2 Hz, 1 H), 7.85 (d, J=0.9 Hz, 1 H), 4.36 (dd, J=1.2 Hz, 0.6 Hz, 1 H), 2.16 (q, J=0.7 Hz, 1 H), 1.80 (m, 2H), 1.55 (s, 3H), 1.22 (d, J=0.7 Hz, 3H), 1.00 (d, J=0.7 Hz, 3H)
MS (m/z): M+ (338)
Example 45
5-(4-Methoxy-phenyl)-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid
(4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #10
Figure imgf000104_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-(4- methoxyphenyl)methylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid.
1H NMR (CDCI3) 59.85 (s, 1 H), 8.16 (s, 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.76 (d, J=0.6 Hz, 1 H), 7.58 (d, J=0.6 Hz, 2H), 6.90 (d, J=0.6 Hz, 2H), 5.68 (br, 1 H), 3.82 (s, 3H), 3.30 (dd, J=3.9 Hz, 1.3 Hz, 1 H), 1.65 (s, 3H)
MS (m/z): M+ (403) Example 46
S-Methyl-S-pentafluorophenyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #9
Figure imgf000105_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- (pentafluorophenyl)methylidene] benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid. 1H NMR (CDCI3) δ 9.53 (s, 1H), 8.16 (s, 1 H)1 8.00 (d, J=0.6 Hz, 1 H),
7.79 (d, J=0.6 Hz, 1 H), 6.27 (s, 1 H), 3.40 (dd, J=6.0 Hz, 1.8 Hz, 1H), 1.67 (s, 3H)
MS (m/z): M+ (463)
Example 47
3,5-Dimethyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyO-amide and S^-Dimethyl^Λ-dihvdro-ΣH-pyrazole-S-carboxylic acid (4-cvano-3- trifluoromethyl-phenvD-amide Compound #97 and Compound #60
Figure imgf000105_0002
Diazoethane (~ 0.5 M, 20 mL) in diethyl ether (which may be prepared by according to known methods) was added into 2-methyl-N-(4-cyano-3- trifluoromethyl-phenyl)-acrylamide (250 mg, 1 mmoL) in THF (2 mL) at room temperature. The solution was stirred at room temperature for 72 hours. The solvent was removed and the residue was purified by column chromatography to yield the title compounds as a white solids.
Sjδ-DimethyMjδ-dihydro-SH-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.06 (s, 1 H), 8.16 (s, 1 H)1 7.99 (d, J=0.6 Hz, 1 H), 7.82 (d, J=0.6 Hz, 1 H), 4.58 (m, 1 H), 2.06 (dd, J=1.3 Hz1 0.5 Hz1 1 H)1 1.59 (m, 1 H)1 1.56 (S1 3H)
MS (m/z): MNa+ (333)
3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.85 (s, br, 1 HO1 8.05 (s, 1 H), 7.95 (d, J = 7.5 Hz1 1 H), 7.75 (d, J = 7.5 Hz, 1 H)1 2.95 (abq, J = 12.5 Hz1 2H)1 1.98 (s, 3H)1 1.55 (s, 3H)
MS (m/z): MH+ (311), MH- (309).
Example 48 δ-Ethyl-S-methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4-cvano-3- trifluoromethyl-phenvO-amide and 5-Ethyl-3-methyl-4,,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenvO-amide Compound #15 and Compound #58
Figure imgf000106_0001
Following the procedure described in Example 29, the mixture of 4- methyl-2-[(1 £)-propylidene] benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids. δ-Ethyl-S-methyl^jδ-dihydro-SH-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1, Rf=0.30)
1H NMR (CDCI3) δ 9.09 (s, 1 H), 8.18 (s, 1 H), 8.00 (d, J=0.6 Hz, 1 H), 7.98 (d, J=0.6 Hz, 1 H), 4.48 (m, 1H), 2.10 (m, 2H), 2.00 (m, 1 H), 1.65 (m, 1 H), 1.56 (s, 3H), 1.01 (t, J=0.7Hz, 3H)
MS (m/z): MNa+ (347)
5-Ethyl-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1, Rf=0.10)
1H NMR (CDCI3) δ 9.89 (s, 1 H), 8.14 (s, 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.80 (d, J=0.6 Hz, 1 H), 5.33 (m, 1 H), 2.95 (dd, J=6.0 Hz, 1.4 Hz, 2H), 2.35 (q, J=0.6 Hz, 2H), 1.58 (s, 3H), 1.18 (t, J=0.6Hz, 3H)
MS (m/z): MNa+ (347)
Example 49 5-lsobutyl-3-methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenvD-amide and 5-lsobutyl-3-methyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyanc-3- trifluoromethyl-phenvD-amide Compound #11 and Compound #61
Figure imgf000107_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 £)-3- methylbutylidene] benzenesulfonyl hydrazone was reacted to yield the two title compounds as a white solids.
5-lsobutyl-3-methyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.80)
1H NMR (CDCI3) 59.10 (s, 1 H), 8.17 (s, 1 H), 8.00 (d, J=0.6 Hz, 1 H), 7.82 (d, J=0.6 Hz, 1 H), 4.55 (q, J=0.5 Hz, 1 H), 2.00 (m, 3H), 1.60 (m, 1 H), 1.57 (s, 3H), 1.39 (m, 1 H), 1.04 (t, J=0.5Hz, 3H)
MS (m/z): MNa+ (375) δ-Isobutyl-S-methyl-S^-dihydro-aH-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.20)
1H NMR (CDCI3) 59.86 (s, 1 H), 8.12 (s, 1 H), 7.93 (d, J=0.6 Hz, 1 H), 7.77 (d, J=0.6 Hz, 1 H), 5.39 (br, 1 H), 2.90 (dd, J=5.4 Hz, 1.3 Hz, 2H), 2.19 (d, J=0.5 Hz, 2H), 1.91 (m, 1 H), 1.57 (s, 3H), 0.93 (m, 6H)
MS (m/z): M+ (353)
Example 50
3-Methyl-5-(2-methylsulfanyl-ethyl)-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #59
Figure imgf000108_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)S- (methylthio)propylidene]benzenesulfonyl hydrazone was reacted to yield the title compound as a white solid. 1H NMR (CDCI3) 59.02 (s, 1 H), 8.15 (s, 1 H), 7.98 (d, J=0.6 Hz, 1 H)1 7.82 (d, J=0.6 Hz, 1 H), 4.71 (q, J=0.5 Hz, 1 H), 2.82 (m, 2H), 2.35 (m, 1 H), 2.11 (s, 3H), 2.08 (m, 1H), 1.95 (m, 1H), 1.60 (m, 1H), 1.57 (s, 3H)
MS (m/z): MNa+ (393).
Example 51 S-Methyl-S-propyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenvD-amide and 3-Methyl-5-propyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenvD-amide Compound #14 and Compound #62
Figure imgf000109_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- butylidene] benzenesulfonyl hydrazonewas reacted to yield the two title compounds as a white solids.
S-Methyl-δ-propyl^δ-dihydro-SH-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.70)
1H NMR (CDCI3) δ 9.11 (s, 1 H), 8.11 (s, 1 H), 7.93 (d, J=0.6 Hz, 1 H), 7.70 (d, J=0.6 Hz, 1 H), 4.42 (q, J=0.5 Hz, 1 H), 2.00 (m, 3H), 1.60 (m, 3H), 1.49 (S, 3H), 1.00 (t, J=0.5Hz, 3H)
MS (m/z): M+ (338)
3-Methyl-5-propyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide:
(Hexane: ethyl acetate, 2:1 , Rf=0.15) 1H NMR (CDCI3) δ 9.88 (s, 1H), 8.13 (s, 1 H), 7.95 (d, J=0.6 Hz, 1 H), 7.79 (d, J=0.6 Hz, 1 H), 5.39 (s, 1 H), 2.90 (dd, J=5.8, 1.2 Hz, 2H), 2.29 (t, J=0.6Hz, 2H), 1.57 (m, 2H), 1.56 (s, 3H), 0.95 (t, J=0.5Hz, 3H)
MS (m/z): M+ (338).
Example 52 δ-f^Acetylamino-phenvD-S-methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #33
Figure imgf000110_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-A- (acetamidophenyl)methylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide to yield the title compound as a white solid.
1H NMR (CDCI3) 6 9.70 (s, 1 H), 8.11 (s, 1 H), 7.93-7.79 (m, 2H), 7.55 (s, 4H), 5.65 (s, 1 H), 3.82 (dd, J=4.8, 2.4 Hz, 2 H), 2.20 (s, 3H), 2.00 (s, 3H).
MS (m/z): M+ (430)
Example 53 5-(4-Acetylamino-phenvπ-3-methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide Compound #34
Figure imgf000111_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-A- (acetamidophenyl)methylidene]benzenesulfonyl hydrazone was reacted with 2- methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCI3) δ 8.30 (s, 1 H), 8.15-8.01 (m, 2H), 7.58 (m, 4H), 3.82 (dd, J=7.5, 2.4 Hz, 2 H), 2.05 (s, 3H), 2.00 (s, 3H).
MS (m/z): M+ (450), M- (448)
Example 54
S-Methyl-δ-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4- cyano-phenvD-amide Compound #20
Figure imgf000111_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- 2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl- N-(4-cyano-phenyl)-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCI3) 59.05 (s, 1 H), 7.70-7.60 (m, 4H), 5.95 (s, 1 H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H). MS (m/z): M- (295)
Example 55
S-Methyl-δ-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4- chlorø-3-trifluoromethyl-phenvO-amide
Compound #23
Figure imgf000112_0001
Following the procedure described Example 29, 4-methyl-2-[(1 £)-2,2,2- trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl-N-(4- cyano-3- chloro-phenyl)-acry!amide to yield the title compound as a yellow solid.
1H NMR (CDCI3) 58.95 (s, 1 H), 7.95 (s, 1 H), 7.75 (m, 1 H), 7.50 (m, 1 H)1 6.00 (s, 1 H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (374)
Example 56
S-Methyl-δ-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (3,4- dichloro-phenvD-amide Compound #24
Figure imgf000112_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- 2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with 2-methyl- N-(3,4-dichlorophenyl)-acrylamide to yield the title compound as a yellow solid. 1H NMR (CDCI3) 58.85 (s, 1 H), 7.85 (s, 1H), 7.40 (m, 2H), 5.85 (s, 1 H), 3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.60 (s, 3H). MS (m/z): MH+ (341).
Example 57
S-Methvi-δ^rifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4- benzyl-phenvO-amide Compound #18
Figure imgf000113_0001
Following the procedure described in Example 29, 4-methyl-2-[(1 E)-
2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with N-(4- Benzyl-phenyl)-2-methyl-acrylamide to yield the title compound as a yellow solid.
1H NMR (CDCI3) 8 8.60 (s, 1 H), 8.00 (m, 1 H), 7.30-7.10 (m, 8H), 5.40 (s, 1 H), 4.00 (s, 2H), 2.70 (s, 2H), 1.38 (s, 3H). MS (m/z): MH+ (362)
Example 58
3-Methyl-5-trifluoromethyl-3,4"dihydro-2H-pyrazole-3-carboxylic acid (4- benzoyl-phenvD-amide
Compound #17
Figure imgf000113_0002
Following the procedure described in Example 29, 4-methyl-2-[(1 E)- 2,2,2-trifluoroethylidene]benzenesulfonyl hydrazone was reacted with N-(4- benzoyl-phenyl)-2-methyl-acrylamide to yield the title compound as a yellow solid. 1H NMR (CDCI3) δ 9.00 (s, 1 H)1 7.85 (m, 2H), 7.75 (m, 2H), 7.58 (m,
5H)1 5.90 (s, 1 H), 3.15 (dd, J=6.5, 2.1 Hz, 2 H), 1.60 (s, 3H).
MS (m/z): MH+ (376)
Example 59 S-Methvl-δ-trifluoromethvl-S^-dihvdro^H-pyrazole-S-carboxvlic acid (4- phenoxv-phenvO-amide
Compound #19
Figure imgf000114_0001
Following the procedure described in Example 29, the title compound was prepared as a white solid.
1H NMR (CDCI3) 58.75 (s, 1H), 7.55 (m, 2H), 7.30 (m, 2H), 7.10 (m, 5H), 5.75 (s, 1 H), 3.15 (dd, J=6.4, 2.1 Hz, 2 H), 1.55 (s, 3H). MS (m/z): MH+ (364).
Example 60
S-Ethyl-S-trifluoromethyl-S^-dihvdro^H-pyrazole-a-carboxylic acid (4- cvano-3-trifluoromethyl-phenvπ-amide
Compound #30
Figure imgf000115_0001
Following the procedure described Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 69.37 (s, 1 H), 8.11 (s, 1 H), 7.95-7.80 (m, 2H), 6.10 (s, 1 H), 3.22 (dd, J=6.0, 2.7 Hz, 2 H), 2.05 (m, 2H), 1.00 (t, J=1.5Hz, 3H).
MS (m/z): MH+ (379).
Example 61
3^ropyl-5-trifluoromethyl-3,4<lihvdro-2H-pyrazole-3-cai'Poxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #73
Figure imgf000115_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 59.30 (s, 1 H), 8.15 (s, 1 H), 7.95 (m, 1 H), 7.80 (m, 1 H), 6.25 (s, 1 H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 2.00 (m, 2H), 1.30 (m, 2H), 1.65 (t, J = 1.0Hz, 3H)
MS (m/z): MH+ (393). Example 62
3-Methyl-5-trifluoromethyl-3,4<lihvdro-2H-pyrazole-3-carboxylic acid 4- methanesulfonyl-benzylamide Compound #27
Figure imgf000116_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 7.90 (m, 2H), 7.45 (m, 2H), 6.75 (s, 1 H), 4.50 (m, 2H), 3.05 (s, 3H), 3.00 (dd, J=6.0, 2.7 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (364).
Example 63
S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- phenylsulfanyl-phenvD-amide Compound #28
Figure imgf000116_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 8.75 (s, 1 H), 7.55 (m, 2H), 7.35 (m, 2H), 7.23 (m,
5H), 5.70 (s, 1 H), 3.00 (dd, J=8.4, 2.4 Hz, 2H)1 1.60 (s, 3H). MS (m/z): MH+ (380)
Example 64 S-Methyl-S-trifluoromethyl-S^-dihYdro-ΣH-pyrazole-S-carboxylic acid (4- benzenesulfonyl-phenvO-amide Compound #32
Figure imgf000117_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- phenylsulfanyl-phenyl)-amide (100 mg, 0.264 mmoL) in EtOAc (2 ml_) at room temperature was treated with Oxone (1.0 g) in water (10 ml_). Sat. NaHCOβ was added to adjust pH 7 ~ 8. The reaction mixture was stirred for 2 hrs. The mixture was then partitioned between ethyl acetate and water. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using ethyl acetate as eluent to afford the title product.
1H NMR (CDCI3) δ 8.50 (s, 1 H), 7.55 (m, 4H), 7.45 (m, 5H), 2.90 (dd, J=6.4, 2.1 Hz, 2H), 1.80 (s, 3H). MS (m/z): MNa+ (432).
Example 65
S-Methyl-S-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid ^ chloro-benzylamide Compound #29
Figure imgf000117_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid. 1H NMR (CDCI3) 57.35 (m, 4H)1 5.70 (s, 1H), 4.50 (m, 2H), 3.00 (dd, J=6.0, 2.1 Hz, 2H), 1.50 (s, 3H). MS (m/z): MH+ (319).
Example 66
S-O^-Difluoro-phenvD-S-methyl-S^-dihydro^H-pyrazole-S-carboxylic acid ^-cyano-S-trifluoromethyl-phenvD-amide and 5-(3,4-Difluoro-phenyl)-
3-methyl-4,5-dihvdro-3H-pyrazole-3-carboxylic acid (4-cvano-3- trifluoromethyl-phenvD-amide Compound #2 and compound #53
Figure imgf000118_0001
Following the procedure described in Example 29, the title compounds were obtained as white solids. δ-β^-Difluoro-phenyO-S-methyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide: MS (m/z): M+1 (409). δ-(3,4-Difluoroφhenyl)-3-methyl-4,δ-dihydro-3Hφyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide: MS (m/z): M+1 (409)
Example 67
3-Methyl-5-(2,2,2-trifluoro-ethvπ-3,4-dihydro-2H-pyrazole-3-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #75
Figure imgf000119_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.60 (s, 1 H), 8.15 (s, 1 H), 7.95 (m, 1 H), 7.80 (m, 1 H), 5.65 (s, 1 H), 3.20 (m, 2H), 3.05 (dd, J=6.0, 2.4 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (379).
Example 68
5-CvclopentvI-3-methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4- cvano-3-trifluoromethyl-phenvO-amide
Compound #48
Figure imgf000119_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 5 9.85 (s, 1 H), 8.10 (s, 1 H), 7.95 (m, 1 H), 7.80 (m, 1 H), 5.20 (s, 1 H), 2.80 (dd, J=7.8, 2.4 Hz, 2H), 1.60 (m, 1 H), 1.55 (s, 3H). MS (m/z): MH+ (365).
Example 69 5-(2-Fluoro-3-hvdroxy-phenyl)-3-methyl-3,4-dihvdro-2H-pyra2ole-3- carboxylic acid (4-cvano-3-trifluoromethyl-phenvD-amide Compound #12
Figure imgf000120_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 8.00 (s, 1 H), 7.95 (m, 2H), 7.82 (s, 1 H), 7.60 (m, 2H), 7.35 (m, 2H), 7.15 (m, 2H), 3.60 (dd, J = 25.0 Hz, 12.0 Hz, 2H), 1.35 (s, 3H)
MS (m/z): M+1 (400).
Example 70 S-Methyl-S-pyridin-S-yl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cvano-3 -trifluoromethvl-phenvD-amide
Compound #77
Figure imgf000120_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.70 (s, 1 H), 8.80 (s, 1 H), 8.60 (m, 1 H), 8.10 (s, 1 H), 8.00 (m, 2H), 7.80 (m, 1 H), 7.35 (m, 1 H), 6.00 (s, 1 H), 3.35 (dd, J=5.7, 2.4 Hz, 2H), 1.65 (s, 3H). MS (m/z): MH+ (374). Example 71
S-^-Fluoro-phenvO-S-methyl-S^^Hhvdro-ΣH-pyrazole-S-carboxylic acid rø-chloro-S-trifluoromethyl-phenvO-amide
Compound #13
Figure imgf000121_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 7.80 (s, 1 H), 7.45 (d, J = 9.0 Hz, 1 H), 6.80 (d, J = 9.0 Hz, 1 H), 3.60 (dd, J = 30.0 Hz, 18.0 Hz, 2H), 1.50 (s, 3H), 1.20 (s, 3H).
MS (m/z): M+1 (288).
Example 72
5^-Acetylamino-phenyπ-S-methyl-S^-dihydro-ΣH-pyrazole-S-carboxylic acid (4-chloro-3-trifluoromethyl-phenyl)-amide
Compound #44
Figure imgf000121_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.50 (s, 1 H), 8.00 (S1 1 H), 7.90 (s, 1 H), 7.75 (m, 1 H), 7.50 (s, 4H), 7.45 (m, 1 H), 5.70 (s, 1 H), 3.25 (dd, J=5.4, 2.7 Hz, 2H), 2.15 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (439).
Example 73
3-Methyl-5-r4-(2,2,2-trifluoro-acetylaminoVphenvn-3,4-dihvdro-2H- pyrazole-3-carboxyIic acid (4-chloro-3-trlfluoromethyl-phenyl)-amJde
Compound #46
Figure imgf000122_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.50 (s, 1 H), 8.80 (s, 1 H), 8.00 (s, 1 H), 7.75 (m, 1 H), 7.65 (s, 4H), 7.45 (m, 1 H), 5.80 (s, 1 H), 3.20 (dd, J=5.4, 2.4 Hz1 2H), 1.60 (s, 3H). MS (m/z): MH+ (492).
Example 74 δ-rø-Acetvlamino-benzvO-S-methvl-S^MJihvdro^H-pyrazole-S-carboxvlic acid (4-cvano-3-trifluoromethvl- phenvD-amide
Comoound #43
Figure imgf000123_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 5 9.80 (s, 1 H), 8.10 (s, 1 H), 8.00 (s, 1 H), 7.95 (m, 1 H), 7.75 (s, 1 H), 7.55 (s, 4H), 5.75 (s, 1 H), 3.30 (dd, J=5.4, 2.4 Hz, 2H), 2.20 (s, 2H), 1.60 (s, 3H). MS (m/z): MNa+ (468).
Example 75
Acetic acid 4-r5-(4-cvano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-
4,5-dihvdro-1 H-pyrazol-3-vπ-phenyl ester
Compound #45
Figure imgf000124_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 59.80 (s, 1 H), 8.10 (s, 1 H), 7.95 (m, 1H), 7.80 (m, 1 H), 7.55 (d, J = 1.0Hz, 2H), 6.85 (d, J = 1.0 Hz, 2H), 5.60 (s, 1 H), 3.30 (dd, J=5.4, 2.4 Hz, 2H), 2.0 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (431).
Example 76 δ-O-Acetylamino-phenvD-S-methyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #41
Figure imgf000124_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 69.75 (s, 1 H), 8.15 (s, 1 H), 8.00-7.75 (m, 4H), 7.40 (m, 1 H), 7.25 (s, 1 H), 5.80 (s, 1 H), 3.25 (dd, J=5.4, 2.4 Hz, 2H), 2.20 (s, 3H), 1.60 (s, 3H). MS (m/z): MH+ (431). Example 77
S-Methyl-δ-trifluoromethyl-S^-dihvdro-∑H-pyrazole-S-carboxylic acid (4- nitro-3-tπfluoromethyl-PhenvO-amide
Compound #74
Figure imgf000125_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 59.30 (s, 1 H), 8.10 (s, 1 H), 8.00 (m, 2H), 6.10 (s, 1 H),
3.15 (dd, J=6.0, 2.4 Hz, 2H), 1.66 (s, 3H). MS (m/z): MH+ (385).
Example 78
5-tert-Butyl-3-methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-cvano-
3-trifluoromethyl-phenyl)-amide Compound #86
Figure imgf000125_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.78 (br, s, 1 H), 8.12 (s, 1 H), 7.92 (d, J = 7.5 Hz, 1 H)1 7.78 (d, J = 7.5 Hz, 1 H), 5.25 (br, s, 1 H), 2.95 (abq, J = 12.5 Hz, 2H), 1.58 (s, 3H), 1.15 (s, 9H).
MS (m/z): MH+ (353), MH- (351). Example 79
S-tert-Butyl-S-methyl-S^-dihydro-ΣH-pyrazole-S-carboxylic acid (4-nitro-3- trifluoromethyl-phenvD-amide Compound #89
Figure imgf000126_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1 H NMR (CDCI3) δ 8.01 (d, J = 7.0 Hz, 1 H), 7.62 (s, 1 H), 7.05 (d, J = 7.0 Hz, 1 H), 6.10 (s, 1 H), 5.48 (s, 1H), 3.25 (abq, J = 12.5 Hz, 2H), 1.52 (s, 3H), 1.25 (s, 9H).
MS (m/z): MH+ (373), MH- (371).
Example 80
S-^-Cyano-S-trifluoromethyl-phenylcarbamovO-S-methylAS^Hhydro-IH- pyrazole-3-carboxylic acid ethyl ester
Compound #84
Figure imgf000126_0002
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (CDCI3) 699.18 (s, br, 1H), 8.11 (s, 1H), 7.98 (d, J = 7.2 Hz,
1 H), 7.81 (d, J = 7.2 Hz, 1H), 6.25 (s, 1 H), 4.32 (q, J = 8.5 Hz, 2H), 3.25 (abq, J
= 12.5 Hz, 2H), 1.62 (s, 3H), 1.45 (t, J = 8.5 Hz, 3H). MS (m/z): MH+ (369), MH- (367). Example 81
5-(4-Nitro-3-trifluoromethyl-Dhenylcarbamoyl)-5-methyl-4,5-dihvdro-1 H- pyrazole-3-carboχylic acid ethyl ester
Compound #83
Figure imgf000127_0001
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.22 (s, br, 1 H), 8.11 (s, 1 H), 8.02 (d, J = 6.5 Hz, 1 H), 8.00 (d, J = 6.5 Hz, 1 H), 6.38 (s, 1 H), 4.32 (q, J = 8.5 Hz, 2H), 3.25 (abq, J = 12.5 Hz, 2H), 1.61 (s, 3H), 1.48 (t, J = 8.5 Hz, 3H). MS (m/z): MH+ (389), MNa+ (411 ).
Example 82 5-(4-Bromo-34rifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1H- pyrazole-3-carboxylic acid ethyl ester Compound #85
Figure imgf000127_0002
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 8.95 (s, br, 1 H), 7.98 (s, 1 H), 7.65 (m, 2H), 6.35 (s, br, 1 H)1 4.33 (q, J = 7.8 Hz, 2H), 3.15 (abq, J = 10.5 z, 2H), 1.58 (s, 3H), 1.48 (t, J = 7.8 Hz, 2H). MS (m/z): MH+ (423)
Example 83
3-Methyl-5-r4-f2.2,2-trifluoro-acetylamino)-phenvn-3,4-dihvdro-2H- pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenvO-amide
Compound #37
Figure imgf000128_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid. 1H NMR (C6D6) δ 8.95 (s, 1 H), 7.62 (s, 1 H), 7.50 (d, J = 7.8 Hz, 2H),
7.35 (d, J = 7.0 Hz, 1 H), 7.20 (d, J = 7.5 Hz, 2H), 7.18 (d, J = 7.0 Hz, 1 H), 4.95 (s, 1 H)1 2.80 (abq, J = 15.6 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MH+ (504), MH- (502)
Example 84
S^ΦAcetylamino-phenvπ-S-methYl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (3.4-dicvano-phenvD-amide Compound #38
Figure imgf000129_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.79 (s, br, 1 H), 8.25 (s, 1 H)1 7.88 (d, J = 6.8 Hz, 1 H), 7.72 (d, J = 6.8 Hz, 1 H), 7.55 (s, 4H), 5.68 (s, 1 H), 3.35 (abq, J = 12.5 z, 2H), 2.28 (s, 3H), 1.68 (s, 3H).
MS (m/z): MH+ (387).
Example 85 S-Methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (3,4-dichloro-phenyl)- amide Compound #48
Figure imgf000129_0002
Following the procedure described in Example 31 , the title compound was obtained as a white solid. 1H NMR (CDCI3) δ 9.20 (s, 1 H), 7.88 (s, 1 H), 7.45 (s, 2H), 6.82 (s, 1 H),
3.05 (abq, J=12.5 Hz, 2H), 1.58 (s, 3H). MS (m/z): MH+ (273). Example 86
S-EthylsulfanylmethvI-S-methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid rø-cvano-S-trifluoromethyl-phenvO-amide
Compound #87
Figure imgf000130_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) 59.15 (s, br, 1 H), 7.95 (s, 1 H), 7.75 (m, 2H), 7.55 (s, 1 H), 4.35 (abq, J = 10.5 Hz, 2H), 3.85 (abq, J = 12.5 Hz, 2H), 2.65 (m, J = 8.5 Hz, 2H), 1.42 (s, 3H), 1.32 (t, J = 8.5 Hz, 3H).
MS(CI) m/z MH+ (371).
Example 87
S-fΦCyano-S-trifluoromethyl-phenylcarbamovπ-S-methyl^^-dihvdro-I H- pyrazole-3-carboxylic acid tert-butyl ester
Compound #90
Figure imgf000130_0002
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.32 (s, br, 1 H), 8.12 (s, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 6.45 (s, 1 H), 3.15 (abq, J = 10.5 Hz1 2H), 1.61 (s, 3H), 1.52 (s, 9H). MS (m/z): MH+ (397).
Example 88 δ^-Cvano-S-trifluoromethyl-phenylcarbamovπ-S-methyl^.S-dihydro-IH-
Pyrazole-3-carboxylic acid Compound #91
Figure imgf000131_0001
5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihyclro-1 H- pyrazole-3-carboxylic acid tert-butyl ester (450 mg, 1.135 mmoL) in trifluoroacetic acid (2 ml_) and DCM (2 ml_) was stirred for 6 hrs at room temperature. The reaction mixture was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the title product as a colorless oil.
1H NMR (CDCI3) δ 12.5 (s, br, 1 H), 9.11 (s, 1 H), 8.09 (s, 1 H), 7.98 (d, J = 7.5 Hz, 1 H), 7.81 (d, J = 7.5 Hz, 1 H), 3.25 (abq, J = 12.5 Hz, 2H), 1.61 (s, 3H). MS (m/z): MH+ (341)
Example 89
S-Hydroxymethyl-S-methyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #92
Figure imgf000131_0002
5-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-5-methyl-4,5-dihydro-1 H- pyrazole-3-carboxylic acid (150 mg, 0.441 mmoL) in THF (2 ml_) was treated dropwise with borane-THF complex (882 μL, 0.882 mmoL) at -78°C over 10 min. The resulting solution was stirred for another 10 min. and then quenched with MeOH. The solvent was removed and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM (3X). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel using 2:1 hexanes: ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCI3) δ 9.65 (s, 1 H), 8.25 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 5.50 (s, 1 H), 4.25 (abq, J = 10.5 Hz, 2H), 2.95 (abq, J = 12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (327).
Example 90
S-Methyl-S-pentafluoroethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cvano-3-tπfluoromethyl-phenvO-amide
Compound #98
Figure imgf000132_0001
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (MeOD) 5 8.21 (s, 1 H), 8.10 (d, J = 6.5 Hz, 1 H), 7.88 (d, J = 6.5
Hz1 1 H), 3.30 (abq, J = 12.5 Hz, 2H), 1.68 (s, 3H). Example 91
S-Methyl-S-pentafluoroethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenvπ-amide
Compound #99
Figure imgf000133_0001
Following the procedure described in Example 31 , the title compound was obtained as a white solid.
1H NMR (CDCI3) 59.21 (s, br, 1 H), 8.12 (s, 1 H), 8.02 (s, 2H), 6.05 (s, br, 1 H), 3.18 (abq, J = 13.5 Hz1 2H), 1.62 (s, 3H) MS (m/z): MH- (413)
Example 92 3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxyHc acid (4-benzoyl-phenvD- amide and S-Methyl-δ-trimethylsilanyl-pyrazolidine-S-carboxylic acid (4-benzoyl- phenyp-amide
Compound #16 and Compound #63
Figure imgf000133_0002
Following the procedure described in Example 31 , the title compounds were obtained as white solids.
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-benzoyl-phenyl)- amide : 1H NMR (CDCI3) δ 9.42 (s, br, 1 H), 7.85 (d, J = 8.5 Hz, 2H), 7.76 (d, J = 7.8 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.65 (t, J = 7.8 Hz, 1 H), 7.60 (t, J = 8.5 Hz, 2H), 6.82 (s, 1 H), 5.45 (s, 1 H), 3.01 (abq, J = 13.5 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (308), MNa+ (330). S-methyl-δ-trimethylsilanyl-pyrazolidine-S-carboxylic acid (4-benzoyl- phenyl)-amide:
1H NMR (CDCI3) δ (1 :1 isomers) 8.45 (s, 1 H, isomeri), 8.25 (s, 1 H, isomer 2), 7.30 ~ 7.75 (m, 9H, both isomers), 4.40 (m, 1 H, isomer 1), 4.32 (m, 1 H, isomer 2), 2.48 (m, 1 H, isomer 1), 2.10 (m, 1 H, isomer 2), 1.72 (m, 1 H, isomer 1 ), 1.32 (m, 1 H, isomer 2), 1.55 (s, 3H, isomer 1 ), 1.50 (s, 3H, isomer 2), 0.15 (s, 9H, isomer 1), 0.10 (s, 9H, isomer 2).
Example 93
S-Methyl-S^-dihvdro-^H-pyrazole-S-carboxylic acid (4-cvano-phenvD- amide and
S-methyl-δ-trimethylsilanyl^.δ-dihvdro-SH-pyrazole-S-carboxylic acid (4- cvano-phenvD-amide Compound #21 and Compound #65
Figure imgf000134_0001
Following the procedure described in Example 31 , the title compounds were obtained as white solids.
S-Methyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4-cyano-phenyl)- amide :
1H NMR (CDCI3) δ 9.45 (s, br, 1 H), 7.75 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 6.85 (s, 1H), 5.45 (s, br, 1H), 3.01 (abq, J = 12.5 Hz, 2H), 1.55 (s, 3H).
MS (m/z): MH+ (229), MNa+ (251), MH- (227) S-Methyl-S-trimethylsilanyl^jδ-dihydro-SH-pyrazole-S-carboxylic acid t^ cyano-phenyl)-amide:
1H NMR (CDCI3) δ (2:1 isomers) 9.35 (s, 1 H, isomeri), 8.51 (s, 1 H, isomer 2), 7.51 - 7.70 (m, 4H, both isomers), 4.45 (m, 1 H, isomer 1), 4.40 (m, 1 H, isomer 2), 2.08 (m, 1 H, both isomers), 1.72 (m, 1H, both isomers), 1.58 (s, 3H, isomer 1), 1.45 (s, 3H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).
Example 94 3-Methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid 3-phenoxy- benzylamide and S-Methyl-S-trimethylsilanyl^^-dihydro-SH-pyrazole-S-carboxylic acid 3- phenoxy-benzylamide Compound #22 and Compound #66
Figure imgf000135_0001
Following the procedure described in Example 31 , the title compounds were obtained as white solids.
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid 3-phenoxy- benzylamide : 1H NMR (CDCI3) δ 7.55 (s, br, 1 H), 7.32 (m, 2H), 7.25 (m, 2H), 7.12 (t, J = 7.8 Hz, 1 H), 6.98 (m, 4H), 6.72 (s, 1 H), 5.25 (s, br, 1 H), 4.40 (d, J = 5.2 Hz, 2H), 2.88 (abq, J = 12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (310), MNa+ (332), MH- (308) S-Methyl-δ-trimethylsilanyl^jS-dihydro-SH-pyrazole-S-carboxylic acid S- phenoxy-benzylamide:
1H NMR (CDCI3) δ (1 :1 isomers) 6.85 ~ 7.36 (m, 9H, both isomers), 6.75 (s, 1 H1 isomer"!), 6.51 (s, 1 H, isomer 2), 4.51 (m, 2H, both isomers), 4.40 (m, 1 H, isomer 1 ), 4.35 (m, 1 H, isomer 2), 2.32 (m, 1 H, isomer 1 ), 2.00 (m, 1 H, isomer 2), 1.65 (m, 1 H, isomer 1), 1.58 (s, 3H, isomer 1), 1.50 (s, 3H1 isomer 2), 1.32 (m, 1 H, isomer 2), 0.15 (s, 9H, isomer 1 ), 0.05 (s, 9H, isomer 2).
Example 95 3-Methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid 3-methanesulfonyl- benzylamide and 3-Methyl-54rimethylsHanyl-4,5<lihvdrø-3H-pyrazole-3-carboxylic acid 3- methanesulfonyl-benzylamide Compound #26 and Compound #67
Figure imgf000136_0001
Following the procedure described in Example 31 , the title compounds were obtained as white solids.
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid 3-methanesulfonyl- benzylamide
1H NMR (CDCI3) δ 7.90 (d, J = 7.5 Hz, 2H), 7.72 (br, s, 1 H), 7.42 (d, J = 7.5 Hz, 2H), 6.78 (s, 1 H), 5.28 (s, 1 H), 4.50 (d, J = 4.8 Hz, 2H), 3.15 (s, 3H), 2.98 (abq, J = 12.5 Hz, 2H), 1.48 (s, 3H).
MS (m/z): MH+ (296), MNa+ (318), MH- (294)
3-Methyl-5-trimethylsHanyl-4,5<Hhydro-3H^yrazole-3-carboxylic acid 3- methanesulfonyl-benzylamide:
1H NMR (CDCI3) δ (1 :1 isomers) 7.82 (m, 2H, both isomers), 7.40 (m, 2H, both isomers), 7.15 (s, 1 H, isomeri), 6.90 (s, 1 H, isomer 2), 4.51 (m, 2H, both isomers), 4.40 (m, 1 H, isomer 1 ), 4.32 (m, 1 H, isomer 2), 2.32 (m, 1 H, isomer 1), 1.92 (m, 1 H, isomer 2), 1.62 (m, 1 H, isomer 1),1.58 (s, 3H, isomer 1), 1.50 (s, 3H, isomer 2), 1.28 (m, 1 H, isomer 2), 0.15 (s, 9H, isomer 1), 0.05 (s, 9H, isomer 2).
Example 96 (R)-3-Methyl-5-trifluoromethyl-3.4-dihvdro-2H-pyra2ole-3-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide and
(SVS-Methyl-δ-trifluoromethyl-S^-dihvdro-ΣH-pyrazole^-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #35 and Compound #36
Figure imgf000137_0001
A racemic mixture of 3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole- 3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto a ChiralPak AD chiral HPLC column (50 mm LD. x 500 mm L) and eluted with 10% ethanol in heptane at the 70 mL/min flow rate. Two peaks were collected separately and were removed under vacuum to yield: (RJ-S-Methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide as peak two.
MS(CI) m/z 365(M+H+) and (S)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide as peak one.
MS(CI) m/z 365(M+H+) Example 97 (RVS-Ethyl-S-trifluoromethyl^^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenyl)-amide and
(SVS-Ethyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid f^ cvano-3-trifluoromethyl-phenyl)-amide
Compound #81 and Compound #82
Figure imgf000138_0001
The racemic mixture of 3-ethyl-5-trifluoromethyl-3,4-dihydro-2H- pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (500 mg) was loaded onto a ChiralPak AD chiral HPLC column (50 mm I. D. x 500 mm L) and eluted with 10% ethanol in heptane at the 70 mL/min flow rate. Two peaks were collected separately and were removed under vacuum to yield: (RJ-S-ethyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cyano-3-trifluoromethyI-phenyl)-amide as peak two.
MS(CI) m/z 379(M+H+) and (S)-3-ethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide as peak one.
MS(CI) m/z 379(M+H+)
Example 98
3-Methyl-pyrazolidine-3-carboxylic acid ^-cyano-S-trifluoromethyl- phenvO-amide Compound #100
Figure imgf000138_0002
3-Methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide (1.5 g, 5.1 mmoL) in glacial acetic acid (5 ml_) was treated with powder NaCNBH3 (750 mg, 12.7 mmoL) at room temperature. The reaction mixture was stirred for 1 hr. The reaction mixture was then neutralized with saturated NaHCO3 and extracted with ethyl acetate (3X). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil.
1H NMR (CDCI3) 59.89 (s, br, 1H), 8.11 (s, 1 H), 8.02 (d, J = 7.5 Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 3.28 (t, J = 8.5 Hz, 2H), 2.65 m, 2H), 1.61 (s, 3H). MS(CI) m/z MH+ (299), MH- (297).
Example 99 3-Methyl-1 -(2,2,2-trif luoro-acetyQ-pyrazolidine-S-carboxylic acid (4-cyano-
3-trifluoromethyl-phenyl)-amide Compound #101
Figure imgf000139_0001
S-Methyl-pyrazolidine-S-carboxylic acid (4-cyano-3-trifluoromethyl- phenyl)-amide (350 mg, 0.84 mmoL) in DCM (2 ml_) was treated with Et3N (118 μl_, 0.84 mmoL) and TFAA (117 μl_, 0.84 mmoL) at O0C. The reaction mixture was stirred for 30 min and then partitioned between saturated NaHCO3 and DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil, which was then purified by silica gel column using hexanes : ethyl acetate 1 :1 as eluent to yield the title compound as a white solid. 1 H NMR (CDCI3) δ 9.22 (s, br, 1 H), 8.08 (s, 1 H), 7.82 (s, 2H), 3.72 (m,
2H), 3.10 (m, 1 HO, 2.05 (m, 1 H), 1.65 (s, 3H). MS(CI) m/z MNa+ (417), MH- (393).
Example 100 1 -^-Acetylamino-benzvO-S-methyl-pyrazolidine-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenvQ-amide
Compound #102
Figure imgf000140_0001
S-Mθthyl-pyrazolidine-S-carboxylic acid (4-cyano-3-trifluoromethyl- phenyl)-amide (410 mg, 1.38 mmoL) and (225 mg, 1.38 mmoL) in MeOH (5 ml_) at room temperature was treated with NaCNBH3 (216 mg, 3.44 mmoL). The reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (3X). The combined organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to yield the title compound as a colorless oil, which was then purified by silica gel column using hexanes : ethyl acetate 1 :1 as eluent to yield the title compound as a white solid. 1H NMR (CDCI3) δ 8.05 (s, 1 H), 7.85 (d, J = 6.5 Hz, 1 H), 7.62 (d, J = 6.5
Hz, 1 H), 7.52 (d, J = 7.0 Hz, 2H), 7.25 (d, J = 7.0 Hz, 2H), 3.75 (abq, J = 12.5 Hz, 2H), 3.18 (m, 1 H), 2.65 (m, 3H), 2.15 (s, 3H), 1.48 (s, 3H). MS (m/z): MNa+ (468)
Example 101
2-Methvl-N-pvridin-4-vl-acrvlamide
Figure imgf000140_0002
LiHMDS (1.0 N in THF, 23.6 mmoL, 24 ml_) was added dropwise into pyridine (11.8 mmoL, 1.11 g) in THF (10 ml_) at 0°C. After 10 min, 2-methyl- acryloyl chloride (11.8 mmoL, 1.43 ml_) was added into the reaction at 0°C. The reaction was then slowly warmed to room temperature. The solvent was removed and the residue was partitioned between Et2O and water. The Et2O layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, EtOAc as eluent) to yield the title compound as a reddish oil.
1H NMR (CDCI3) δ 8.45 (br, s, 1 H), 8.22 (d, J = 7.5 Hz, 2H), 7.45 (d, J = 7.5 Hz, 2H), 5.68 (s, 1 H), 5.26 (s, 1 H), 1.89 (s, 3H).
Example 102 N-Cβ-Chloro-pyridin-S-vD-Σ-methyl-acrylamide
Figure imgf000141_0001
Following the procedure described in Example 1 , the title compound was obtained as a grey solid.
1H NMR (CDCI3) δ 8.45 (s, 1 H), 8.20 (d, J = 7.5 Hz, 1 H), 7.61 (s, br, 1 H), 7.34 (d, J = 7.5 Hz, 1 H), 5.88 (s, 1 H), 5.55 (s, 1 H), 2.05 (s, 3H).
Example 103 N-(6-Cvano-pyridin-3-vO-2-methy[-acrylamide
Figure imgf000141_0002
Following the procedure described in Example 1 , the title compound was obtained as a grey solid.
1H NMR (CDCl3) δ 8.65 (s, 1 H), 8.48 (d, J = 8.5 Hz, 1 H), 7.88 (s, br, 1 H), 7.70 (d, J = 8.5 Hz, 1 H), 5.88 (s, 1 H), 5.62 (s, 1 H), 2.12 (s, 3H).
MS (m/z): MH+ (188). Example 104 δ-rø-Fluoro-phenvO-S-methyl^^-dihvdro-ΣH-pyrazole-S-carboxylic acid pyridin-4-ylamide Compound #93
Figure imgf000142_0001
Following the procedure described in Example 29, the title compound was obtained as a pale solid.
1H NMR (CDCI3) 69.45 (br, s, 1 H), 8.35 (d, J = 7.5 Hz, 2H), 7.38 (d, J = 7.5 Hz1 2H), 7.15 (d, J= 6.5 Hz, 2H), 7.04 (d, J = 6.5 Hz, 2H), 3.36-3.22 (Abq, J= 12.5 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MH+ (299)
Example 105 3-Methyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (6-chloro-pyridin-3-yl)- amide Compound #80
Figure imgf000142_0002
Following the procedure described in Example 31 , the title compound was obtained as a white solid in pure form.
1H NMR (CDCI3) δ 9.05 (s, br, 1 H), 8.25 (s, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 7.05 (s, 1 H), 5.55 (s, br, 1 H), 2.72 (abq, J = 12.5 Hz, 2H), 1.25 (s, 3H). MS (m/z): MH+ (239)
Example 106
S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (6- chloro-pyridin-3-yl)-amide Compound #88
Figure imgf000143_0001
Following the procedure described in Example 29, the title compound was obtained as a white solid. 1H NMR (CDCI3) δ 8.90 (s, 1 H), 8.55 (m, 1 H), 8.15 (m, 1 H), 7.30 (m,
1 H), 6.10 (s, 1 H), 3.15 (dd, J=6.0, 2.7 Hz, 2H), 1.60 (s, 3H).
MS (m/z): MH+ (307).
Example 107
3-Methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (6- cvano-pyridin-3-yl)-amide Compound #88
Figure imgf000143_0002
Following the procedure described in Example 29, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.21 (s, br, 1 H), 8.75 (s, 1 H), 8.38 (d, J = 7.5 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 6.05 (s, 1 H), 3.20 (abq, J = 11.5 Hz, 2H), 1.62 (s, 3H).
MS (m/z): MNa+ (320). Example 108
S^-Acetylamino-phenvD-Σ^-dimethyl-isoxazoIidine-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenyl)-amide (
Figure imgf000144_0001
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (193 mg, 0.76 mmoL) in xylene (5ml_) was treated with N-methyl-{4-(oxyimino- methyl)phenyl)acetamide (250 mg, 0.76 mmoL) (which may be prepared by known methods). The reaction mixture was then heated to 50°C and stirred for 6 hrs. The solvent was removed and the residue was purified by silica gel column using 1 :1 hexanes : ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCI3) 59.42 (s, 1 H), 8.12 (s, 1 H), 7.98 (d, J = 7.3 Hz, 1 H), 7.81 (d, J = 7.3 Hz, 1 H), 7.55 (s, 1 H), 7.49 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 3.62 (t, J = 6.4 Hz, 1 H), 2.75 (m, 1 H), 2.68 (s, 3H), 2.61 (m, 1 H), 2.18 (s, 3H), 1.62 (s, 3H).
MS (m/z): MH+ (447), MNa+ (469), MH- (445). Example 109
S^-Acetylamino-phenvπ-Σ.S-dimethyl-isoxazolidine-S-carboxylic acid (4- nitro-3-trifluoromethyl-phenvO-amide
Compound #70
Figure imgf000145_0001
Following the procedure described in Example 108, the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.45 (s, br, 1 H), 8.12 (s, 1 H), 8.01 (m, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.38 (s, 1 H), 7.18 (d, J = 7.8 Hz, 2H), 3.61 (t, J = 6.5 Hz, 1 H), 2.81 (m, 1 H), 2.68 (s, 3H)1 2.61 (m, 1 H), 2.18 (s, 3H), 1.62 (s, 3H).
MS (m/z): MH+ (467), MNa+ (489)
Example 110 2-Methyl-oxirane-2-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)- amide
Figure imgf000145_0002
2-Methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-acrylamide (1.35 g, 5.0 mmol) in CH2CI2 (15 ml) was treated by TFA (3.0 ml) at 00C. To the reaction mixture was then added H2O2 (30%, 1.0 ml, 10.0 mmol) dropwise. The reaction mixture was stirred overnight and quenched by NaHCO3, then extracted by ethyl acetate. The organic layers were combined and dried over Na2SO4, concentrated and purified by silica gel column using hexanes:ethyl acetate 4:1 as eluent to yield the title compound as a white solid.
1H NMR (CDCI3) 58.40 (br. 1 H), 8.10-7.80 (m, 3H), 5.85 (s, 1 H), 5.60 (s, 1 H), 2.00 (s, 3H).
MS (m/z): MNa+ (293).
Example 111
3-Amino-N-(4-cvano-3-trifluoromethyl-phenvπ-2-hvdroxy-2-methyl- propionamide
Figure imgf000146_0001
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)- amide (1.0 g, 3.48 mmoL) was dissolved in 7N NH3ZMeOH solution (10 ml_) at room temperature. The reaction mixture was stirred overnight and the solvent was removed to yield the title compound as pale yellow solid.
1H NMR (CDCI3) 69.58 (s, br, 1 H), 8.15 (s, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 3.42 (d, J = 9.8 Hz, 1 H), 2.65 (d, J=9.8 Hz, 1 H), 1.48 (S1 3H)
MS (m/z): MH+ (288)
Example 112
2,5-Dimethyl-4,5-dihvdro-oxazole-5-carboxylic acid (4-cvano-3- trifluoromethyl-phenvD-amide
Compound #103
Figure imgf000146_0002
BF3«Etherate(1.0 mmol) was added to a mixture of 2-methyl-oxirane — 2carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (135 mg, 0.5 mmol) in acetonitrile (2 ml_) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then quenched with NaHCO3, the organic layer was extracted with ethyl acetate, washed with brine and concentrated to yield a crude product. The crude product was purified on silica gel with ethyl acetate to yield the title compound as a solid.
1H NMR (CDCI3) 58.50 (s, 1 H), 8.10 (s, 1 H), 8.00 (d, J=9.0 Hz, 1 H), 7.80 (d, J=9.0 Hz), 1 H), 4.00 (dd, J = 105Ha, 15Ha, 2H), 2.10 (s, 3H), 1.70 (s, 3H)
MS (m/z): MH+ (312), MNa+ (334).
Example 113
2-(4-Acetylamino-phenyl)-5-methyl-oxazoHdine-5-carboxylic acid (4- cvano-3-trifluoromethyl-phenvO-amide
Compound #72
Figure imgf000147_0001
2-Methyl-oxirane-2-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)- amide (100 mg, 0.35 mmoL) and acetic acid 4-formyl-phenyl ester (57 mg, 0.35 mmoL) in MeOH (5 ml_) was stirred at room temperature for 2 hr. Then, a catalytic amount of pTSA (-10 mg) was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by silica gel column using hexanes : ethyl acetate 2:1 as eluent to yield the title compound as a white solid. 1H NMR (CDCI3) δ 9.60 (s, br, 1 H), 8.31 (s, br, 1 H), 8.08 (s, 1 H), 7.92 (d,
J = 6.8 Hz, 1 H), 7.70 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 7.5 Hz, 2H), 4.42 (br, s, 1 H), 4.02 (abq, J = 12.5 Hz, 2H), 2.18 (s, 3H), 1.55 (s, 3H). MS (m/z): MH+ (433) Example 114 2.5-Dimethyl-4,5-dihydro-oxazole-5-carboxylic acid (3.4-dichloro-phenvO- amide Compound #104
Figure imgf000148_0001
Following the procedure described in Example 112, the title compound was obtained as a white solid.
1H NMR (CDCI3) 57.80 (s, 1 H), 7.45 (d, J=9.0 Hz, 1 H), 6.80 (d, J=9.0 Hz, 1 H), 3.60 (dd, J=30.0 Hz, 18.0 Hz1 2H), 1.50 (s, 3H), 1.20 (s, 3H)
MS (m/z): MH+ (332), MNa+ (354)
Example 115 2,5-Dimethyl-4.5-dihvdro-oxazole-5-carboxylic acid (4-cvano-phenvO- amide Compound #105
Figure imgf000148_0002
Following the procedure described in Example 112, the title compound was obtained as a white solid.
1H NMR (CDCI3) 58.15 (s, 1 H), 7.80 (dd, J=52.0 Hz, 9.0 Hz, 4H), 3.50 (dd, J= 60.0 Hz, 21.0 Hz, 2H), 1.90 (s, 3H), 1.40 (s, 3H)
MS (m/z): M+H2O (262) Example 116 4-acetamido-ΛAΪethvO-benzenecarbohvdrazonoyl chloride
Figure imgf000149_0001
Following the procedure described in Example 21 , starting from N-[4- (ethyl-hydrazonomethyl)-phenyl]-acetamide, the title compound was prepared as a white solid.
MS (m/z): MH+ (240).
Example 117
5-(4-Acetylamino-phenyl)-2-ethyl-3-methyl-3,4-dihydro-2H-pyrazole-3- carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #135
Figure imgf000149_0002
Following the procedure described in Example 23, starting from 4- acetamido-Λ/-(ethyl)-benzenecarbohydrazonoyl chloride, the title compound was prepared as an off-white solid.
MS (m/z): MH+ (458). Example 118
2-Ethyl-3,5-dimethyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-cvano-
3-trifluoromethyl-phenyl)-amide Compound #146
Figure imgf000150_0001
3,5-Dimethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amidθ (1 mmoL) was reacted with a diazoethane/diethyl ether solution (10 mmoL) in dioxane for about 5 days. The reaction mixtrure was worked up by solvent evaporation and column chromatography separation. The title compound was isolated as a minor product, as a white solid.
1H NMR (CDCI3) δ 9.68 (s, 1 H)1 8.07 (s, 1 H), 7.85 (d, J = 8.0 Hz,1 H), 7.75 (d, J = 8.0 Hz, 1 H), 3.15 (m, 1 H), 3.05 (abq, J = 10.0 Hz, 1 H), 2.80 (m, 1 H), 2.71 (abq, J = 10.0 Hz, 1 H), 1.98 (s, 3H), 1.40 (s, 3H), 1.35 (t, J = 9.5 hz, 3H) MS (m/z): MH+ 339.
Example 119 N-(4-Cvano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide
Figure imgf000150_0002
2-Trifluoromethyl-acrylic acid (36.0 mmoL) in thionyl chloride (2.86 ml_) was refluxed for 30 min. Excess thionyl chloride was removed in vacuo to yield a residue. 4-Amino-2-trifluoromethyl-benzonitrile (36.0 mmoL) in diethyl ether (50 mL) was added dropwise to the residue at -40°C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The diethyl ether layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the brown oil) was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as yellow solid. 1H NMR (CDCI3) δ 8.25 (br, s, 1 H), 7.60 (d, J = 8.0 Hz,1 H), 6.95 (s, 1 H),
6.75 (d, J = 8.0 Hz, 1H), 6.25 (s, 1 H), 5.98 (s, 1H).
Example 120
S^-Bis-trifluoromethyl-S^-dihydro^H-pyrazole^carboxylic acid (4- cvano-3-trifluoromethyl-phenyl)-amide
Compound #112
Figure imgf000151_0001
Following the procedure described in Example 29, starting from N-(4- cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide and 4-methyl-2- [(1 £)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) 59.18 (s, 1H), 8.11 (s, 1 H), 8.05 (d, J = 8.0 Hz,1 H), 7.82 (D, J = 8.0 Hz, 1 H), 7.05 (s, 1 H), 3.62 (abq, J = 9.0 Hz, 1 H), 3.08 (abq, J = 9.0 Hz, 1 H) MS (m/z): MH+ 419.
Example 121
S-^-Cvano-S-trifluoromethyl-phenylcarbamovπ-S-trifluoromethyl^.δ- dihvdro-1H-pyrazole-3-carboxylic acid ethyl ester
Compound #113
Figure imgf000152_0001
Following the procedure described in Example 31 , starting from N-(4- cvano-3-trifluoromethvl-phenvl)-2-trifluoromethvl-acrylamide and ethyl diazoacetate, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 9.28 (s, 1 H), 8.10 (s, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.70 (s, 1 H), 4.32 (q, J = 6.8 Hz, 2H), 3.72 (abq, J = 8.5 Hz, 1 H), 3.60 (abq, J = 8.5 Hz, 1 H), 1.35 (t, J = 8.5 Hz, 3H)
MS (m/z): MH+ 423.
Example 122 δ-Methyl^-trifluorømethyl^^-dihvdro-SH-pyrazole-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenvO-amide
Compound #114
Figure imgf000152_0002
and 5-Methyl-3-trifluoromethyl-3,4-dihvdro-2H-pyra2ole-3-carboxylic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #116
Figure imgf000153_0001
Following the procedure described in Example 47, starting from N-(4- cyano-3-trifluoromethyl-phenyl)-2-trifluoromethyl-acrylamide, the title compounds were prepared as off-white solids.
5-Methyl-3-trifluoromethyl-4,5-dihydro-3H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ diastereomer 1 , 9.01 (s, 1H), 8.15 (s, 1H), 8.01 (d, J = 7.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 4.85 (m, 1 H), 3.15 (m, 1 H), 2.40 (m, 1 H), 1.55 (d, J = 9.5 Hz, 3H); diastereomer 2, 8.55 (s, 1 H), 8.05 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 4.70 (m, 1 H), 2.75 (m, 1 H), 1.80 (m, 1 H), 1.65 (d, J = 10.0 Hz, 3H).
5-Methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.75 (br, s, 1 H), 8.15 (s, 1 H), 7.98 (d, J = 6.5 Hz, 1 H), 7.80 (d, J = 7.5 Hz, 1 H), 6.25 (s, 1 H), 3.45 (abq, J = 8.5 Hz, 1 H), 3.25 (abq, J = 8.5 Hz, 1 H), 2.12 (s, 3H)
MS (m/z): MH+ 365.
Example 123 N-(4-Cvano-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-N-(2-methyl-acrylovπ- acetamide
Figure imgf000153_0002
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methyl-acryIamide (4.4 mmoL) in DCM (15 ml_) was reacted with pyridine (6 mL) followed by trifluoroacetic anhydride (4.4 mmoL) at 0°C. The reaction mixture was slowly warmed to room temperature. The reaction mixture was partitioned between DCM and water. The DCM layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil. The crude material (the yellow oil) was purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compound as a yellow solid.
1H NMR (CDCI3) δ 8.15 (s, 1 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.85 (d, J = 8.5 Hz, 1 H), 6.25 (s, 1 H), 5.81 (s, 1 H), 5.65 (s, 1 H), 2.05 (s, 3H). MS (m/z): MH+ 351.
Example 124 S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cvano-3-trifluoromethyl-phenylH2,2,2-trifluoro-acetyl)-amide Compound #115
Figure imgf000154_0001
Following the procedure described in Example 29, starting from N-(4- cyano-3-trifluoromethyl-phenyl)-2,2,2-trifluoro-N-(2-methyl-acryloyl)-acetamide and 4-methyl-2-[(1 £)-2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) δ 8.10 (s, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.60 (d, J = 7.5 Hz, 1 H), 3.75 (d, J = 10.5 Hz, 1 H), 3.21 (d, J = 10.5 Hz, 1 H), 1.85 (s, 3H) MS (m/z): MNa+ 483 Example 125
S-Methyl-δ-trifluoromethyl-SΛ-dihvdro^H-pyrazole-S-carboxylic acid (4- bromo-3-trifluoromethyl-phenvO-amide
Compound #119
Figure imgf000155_0001
Following the procedure described in Example 29, starting from N-(4- bromo-3-trifluoromethyl-phenyl)-2-methyl-acrylamide and 4-methyI-2-[(1 E)- 2,2,2-trifluoroethylidene]benznenesulfonyl hydrazone, the title compound was prepared as a yellow solid.
1H NMR (CDCI3) 58.95 (s, 1 H)1 7.96 (s, 1 H), 7.65 (s, 2H), 5.86 (s, 1 H), 3.28 (abq, J = 9.8 Hz, 1 H)1 3.10 (abq, J = 9.8 Hz, 1 H), 1.60 (s, 3H)
MS (m/z): MH+ 419.
Example 126
2-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #120
Figure imgf000155_0002
and N-(4-Cvano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-4,5- dihydro-3H-pyrazole-3-carboximidic acid ethyl ester
Compound #200
Figure imgf000156_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (400 mg, 1.1 mmol) and Na2HPO4 (1.0 g, 7 mmol) in CH2CI2 (IO ml) was treated with BF4.O(CH2CH3)3 (1 M in CH2CI2, 5.0 ml) at 0°C. The reaction mixture was warmed to room temperature, stirred overnight and then quenched with NaHCO3. CH2CI2 was added to extract the product and the organic layer was then washed with brine and dried over Na2SO4. Upon the purification on silica gel (CH2CI2: ethyl acetate: 10: 1), the title compounds were obtained as white solids. a-Ethyl-S-methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (Φcyano-S-trifluoromethyl-phenyO-amide:
1H NMR (CDCI3) δ 9.10 (br, 1 H), 8.10 (s, 1 H), 7.95 (m, 1 H), 7.80 (m, 1 H), 3.40-3.00 (m, 4H), 1.50 (s, 3H), 1.35 (m, 3H)
MS (m/z): MH+ 393 N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-4,5- dihydro-3H-pyrazole-3-carboximidic acid ethyl ester:
1H NMR (CDCI3) δ 7.85 (m, 1 H), 7.65 (s, 1 H), 7.50 (s, 1 H), 5.30 (m, 1 H), 4.40 (m, 1 H), 3.90 (m, 1 H), 2.95 (m, 1 H), 2.40 (m, 1 H), 1.55 (m, 3H), 1.50 (s, 3H) MS (m/z): MH+ 393
Example 127
2-Ethyl-3(R)-methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #125
Figure imgf000157_0001
and N-(4-Cvano-3-trifluoromethyl-phenyl)-3(R)-methyl-5-trifluoromethvi- 4,5-dihydro-3H-pyrazole-3-carboximidic acid ethyl ester
Compound #202
Figure imgf000157_0002
Following the procedure described in Example 126, starting from 3(R)- methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide, the title compounds were prepared as off-white solids.
NMR and MS data of the title compounds were the same as described in Example 126.
Example 128
2-Ethyl-3(S)-methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyrazole-3- carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #122
Figure imgf000158_0001
and N-CΦCvano^-trifluoromethyl-phenvO^fSVmethyl-S-trifluoromethyl- 4,5-dihvdro-3H-pyrazole-3-carboximidic acid ethyl ester
Compound #201
Figure imgf000158_0002
Following the procedure described in Example 126, starting from 3(S)- methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide, the title compounds were prepared as off-white solids.
NMR and MS data of the title compounds were the same as described in Example 126.
Example 129
2,3-Dimethyl-5-trifluoromethyl-3.4-dihvdro-2H-pyrazo[e-3-carboxylic acid
^-cyano-S-trifluoromethyl-phenvO-amide
Compound #123
Figure imgf000159_0001
and N-(4-Cvano-3-trifluoromethyl-phenvπ-2,3-dimethyl-5-trifluoromethyl- 3.4-dihvdro-2H-pyrazole-3-carboximidic acid methyl ester
Compound #203
Figure imgf000159_0002
3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (2.5 mmoL) in DCM (25 ml_) at O0C was treated with diethylpropyl amine (10 mmoL) followed by methyl triflate (2.5 mmoL). The reaction mixture was gradually warmed to room temperature and then stirred overnight. The reaction mixture was partitioned between DCM and water. The DCM layer was washed with saturated sodium bicarbonate, brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield a yellow oil, which was then purified by column chromatography (silica gel, using ethyl acetate as eluent) to yield the title compounds as off-white solids. 2,3-Dimethyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.02 (s, 1 H), 8.11 (s, 1 H), 7.98 (d, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 3.32 (abq, J = 9.5 Hz, 1 H), 3.02 (abq, J = 9.5 Hz, 1 H), 3.01 (s, 3H), 1.52 (s, 3H) MS (m/z): MH+ 379.
N-(4-Cyano-3-trifluoromethyl-phenyl)-2,3-dimethyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboximidic acid methyl ester:
1H NMR (CDCI3) δ 8.21 (s, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 4.36 (s, 3H), 3.52 (s, 3H), 3.36 (d, J = 12.5 Hz, 1 H), 3.10 (d, J = 12.5 Hz, 1 H), 1.52 (s, 3H)
MS (m/z): MH+ 393.
Example 130 δ-Chloro^-methyl-δ-trifluoromethyl^^-dihydro-SH-pyrazole-S-carboxylic acid (4-cvano- 3-trifluoromethvl-phenvπ-amide
Compound #124
Figure imgf000160_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in toluene (5 ml_) was treated with PCI5 (1.2 mmoL) at 100°C for 2 hrs. The solvent was removed and the residue was purified by column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid (3:2 diastereomers). Major diastereomer:
1H NMR (CDCI3) δ 8.32 (s, 1 H), 8.10 (s, 1 H), 7.95 (d, J = 7.5 Hz,1 H),
7.85 (d, J = 7.5 Hz, 1 H), 3.05 (abq, J = 9.8 Hz, 1 H), 2.25 (abq, J = 9.8 Hz, 1 H),
1.90 (s, 3H).
Minor diastereomer 1H NMR (CDCI3) δ 8.62 (s, 1 H), 8.11 (s, 1 H), 7.96 (d, J = 7.5 Hz11 H),
7.87 (d, J = 7.5 Hz, 1 H), 2.90 (abq, J = 9.8 Hz, 1 H), 2.32 (abq, J = 9.8 Hz, 1 H),
1.88 (s, 3H).
MS, MH+, 399. Example 131
N-(4-Cvano-2-iodo-5-trifluoromethyl-phenyl)-2-methyl-acrylamide
Figure imgf000161_0001
Following the procedure described in Example 1 , starting from 4-amino- 5-iodo-2-trifluoromethyl-benzonitrile (known compound), the title compound was prepared as off-white solid.
1H NMR (CDCI3) δ 9.00 (s, 1 H), 8.30 (br, 1 H), 8.20 (s, 1 H), 6.00 (s, 1 H), 5.65 (s, 1 H), 2.15 (s, 3H)
MS (m/z): MH" 379
Example 132
3-Methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyra2ole-3-carboxylic acicl (4- cvano-2-iodo-5-trifluoromethyl-phenvO-amide
Compound #126
Figure imgf000161_0002
Following the procedure described in Example 29, starting from_N-(4- cyano-2-iodo-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) 6 9.80 (s, 1 H), 9.10 (s, 1 H), 8.20 (s, 1 H), 6.00 (s, 1 H), 3.25 and 3.10 (abq, J= 14.5 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ 491. Example 133 N-f4-Cvano-2-ethvl-3-trifluoromethyl-phenvl)-2-methvl-acrvlamide
Figure imgf000162_0001
Following the procedure described in Example 1 , starting from 4-amino- 2-ethyl-2-trifluoromethyl-benzonitrile (known compound), the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 8.60 (d, J = 8.5 Hz, 1 H), 7.80 (s, 1 H), 7.72 (d, J = 8.5 Hz, H), 5.88 (s, 1 H), 5.63 (s, 1 H), 2.85 (q, J = 9.0 Hz, 2H), 2.12 (s, 3H), 1.40 (t, J = 9.0 Hz, 3H)
MS (m/z): MH+ 283.
Example 134
S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cvano-2-ethyl-3-trifluoromethyl-phenvO-amide
Compound #127
Figure imgf000162_0002
Following the procedure described in Example 29, starting from_N-(4- cyano-2-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1 H NMR (MeOD) δ 9.50 (s, 1 H), 8.60 (d, J = 1.8 Hz, 1 H), 7.70 (d, J = 1.8 Hz, 1 H), 5.90 (s, 1 H), 3.30 and 3.05 (abq, J= 12.0 Hz, 2H), 2.80 (m, 2H), 1.65 (s, 3H), 1.20 (m, 3H)
MS (m/z): MH+ 393 Example 135 4-Amino-5-ethyl-2-trifluoromethyl-benzonitrile
Figure imgf000163_0001
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (936 mg, 3.0 mmol), CuI (I) (57 mg, 0.3 mmol ), PdCI2(PPh3)2 (105.3 mg, 0.15 mmol), triethylamine (1.01 g, 10 mmol) and ethynyl-trimethyl-silane (450 mg, 4.5 mmol) were mixed in THF (30 ml). The reaction mixture was stirred at room temperature overnight. Tetrabutylammonium fluoride (1.0 M in THF1 3.0 ml, 3.0 mmol) was added to the reaction mixture, which was then stirred at room temperature for 20 mins. The reaction mixture was quenched by addition of H2O and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated to yield crude product 4-amino-5-ethynyl-2- trifluoromethyl-benzonitrile.
The crude product was mixed with Pd/C (0.3 g) in methanol (50 ml) with H2 (40 psi). The reaction was shaken on a Parr shaker at room temperature overnight. Upon separation on silica gel (100% CH2CI2), the tile compound was obtained in as a colorless liquid.
1H NMR (CDCI3) δ 7.50 (s, 1 H), 7.00 (s, 1 H)1 4.50 (br, 2H), 2.50 (m, 2H)1 1.30 (m, 3H) MS (m/z): MH+ 214
Example 136 N-(4-Cvano-2-ethvl-5-trifluoromethvl-phenvπ-2-methvl-acrvlamide
Figure imgf000164_0001
Following the procedure described in Example 1 , starting from 4-amino- 6-ethyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) 68.80 (s, 1 H), 7.70 (br, 1H), 7.65 (s, 1 H), 5.90 (s, 1 H), 5.60 (s, 1H), 3.70 (m, 2H), 2.10 (s, 3H), 1.30 (m, 3H)
MS (m/z): MH" 283
Example 137
S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cyano-2-ethyl-5-trifluoromethyl-phenyl)-amide
Compound #128
Figure imgf000164_0002
Following the procedure described in Example 29, starting from_N-(4- cyano-6-ethyl-3-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 9.30 (s, 1 H)1 8.80 (s, 1 H), 7.55 (s, 1 H), 5.90 (s, 1 H), 3.25 and 3.10 (abq, J= 14.0 Hz, 2H), 2.70 (m, 2H), 1.65 (s, 3H), 1.30 (m, 3H)
MS (m/z): MH+ 393 Example 138
4-Amino-6-trifluoromethyl-isophthalonitrile
Figure imgf000165_0001
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (1.5 mmoL), CuCN (1.7 mmoL) in NMP (10 ml_) was heated at 150°C for 4 hrs. The reaction mixture was passed through a pad of Celite. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water, then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield the title compound as a brown solid. 1H NMR (CDCI3) 67.82 (s, 1 H), 7.15 (s, 1 H), 5.45 (br, s, 2H)
MS (m/z): MH+ 212
Example 139 N-(2,4-Dicvano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide
Figure imgf000165_0002
Following the procedure described in Example 1 , starting from 4-amino-
6-trifluoromethyl-isophthalonitrile, the title compound was prepared as an off- white solid.
1H NMR (CDCI3) 69.15 (s, 1 H), 8.45 (br, s, 1H), 8.08 (s, 1 H)1 6.05 (s, 1 H), 5.75 (s, 1 H), 2.12 (s, 3H)
MS (m/z): MH+ 280 Example 140
S-Methyl-S-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (2.4- dicvano-5-trifluoromethyl-phenvO-amide
Compound #129
Figure imgf000166_0001
Following the procedure described in Example 29, starting from N-(2,4- dicyano-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 10.10 (s, 1 H), 9.10 (s, 1 H), 8.10 (s, 1 H), 6.45 (s, 1 H), 3.30 and 3.10 (abq, J= 14.0 Hz, 2H), 1.65 (s, 3H)
MS (m/z): MH+ 390
Example 141
4-Amino-5-ethylsulfanyl-2-trifluoromethyl-benzonitrile
Figure imgf000166_0002
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (6.24 g, 20.0 mmol), CuI (I) (380 mg, 2.0 mmol ), K2CO3 (6.52 g, 40.0 mmol) and ethylthiol (1.25 g, 20.0 mmol) were mixed in ethanol (50 ml). The reaction mixture was refluxed overnight and then the solvent was removed under vacuum. Upon separation on silica gel (100% DCM), the tile compound was obtained as a colorless liquid.
1H NMR (CDCI3) 57.70 (s, 1 H), 7.00 (s, 1 H), 5.10 (br, 2H), 2.85 (m, 2H), 1.25 (m, 3H)
MS (m/z): MH2O+ 264 Example 142 N-^-Cvano-∑-ethvlsulfanvl-S-trifluoromethyl-phenvπ-Σ-methvl-acrvlamide
Figure imgf000167_0001
Following the procedure described in Example 1 , starting from 4-amino- 5-ethylsulfanyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) 5 9.10 (br, s, 1 H), 9.05 (s, 1 H), 7.88 (s, 1 H), 5.98 (s, 1 H), 5.60 (s, 1 H), 2.95 (q, J = 9.5 Hz, 2H), 2.12 (s, 3H), 1.32 (t, J = 9.5 Hz, 3H)
MS (m/z): MH+ 315
Example 143
S-Methyl-S-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4- cvano-2-ethylsulfanyl-5-trifluoromethyl-phenvπ-amide
Compound #140
Figure imgf000167_0002
Following the procedure described in Example 29, starting from_N-(4- cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 8.30 (br, 1 H), 7.35 (m, 1 H), 7.10 (s, 1 H), 6.80 (m, 1 H), 5.10 (br, 1 H), 3.25 and 3.10 (abq, J = 11.0 Hz, 2H), 1.60 (s, 3H)
MS (m/z): MH+ 365 Example 144
S-Methyl-δ-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (4- cvano-2-ethanesulfonyl-5-trifluoromethyl-pheny[)-amide
Compound #142
Figure imgf000168_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-2-ethylsulfanyl-5-trifluoromethyl-phenyl)-amide (150 mg, 0.35 mmol) in ethyl acetate was treated with Oxone® (2.0 g, pH=7-8, adjusted with saturated NaHCO3 and tetrabuylammonium hydrogensulfate (30 mg). The reaction mixture was stirred at room temperature overnight and then quenched with saturated NaHCO3. The crude product was extracted with ethyl acetate twice, washed with brine and dried with Na2SO4. Upon purification on silica gel (CH2CI2: EtOAc: 3:1 ), the title compound was obtained as a white solid.
1H NMR (CDCI3) δ 9.20 (s, 1 H), 8.30 (s, 1 H), 6.05 (s, 1 H), 3.25 and 3.10 (abq, J= 12.0 Hz, 2H), 3.15 (m, 2H), 1.65 (s, 3H), 1.30 (m, 3H). MS (m/z) MH+ 457
Example 145 4-Amino-5-tert-butvlsulfanvl-2-trifluoromethvl-benzonitrile
Figure imgf000169_0001
Following the procedure described in Example 141 , starting from t-butyl thiol, the title compound was prepared as a brown solid.
1H NMR (CDCI3) 67.75 (s, 1 H), 7.00 (s, 1 H), 5.45 (br, 2H), 1.30 (s, 9H) MS (m/z): MH2O 292
Example 146
N-(2-tert-Butylsulfanyl-4-cvano-5-trifluoromethyl-phenyl)-2-methyl- acrylamide
Figure imgf000169_0002
Following the procedure described in Example 1 , starting from 4-amino- 5-tert-butylsulfanyl-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 9.65 (s, 1 H), 9.15 (s, 1 H), 7.95 (s, 1 H), 6.00 (s, 1 H), 5.65 (S, 1 H), 2.10 (s, 3H), 1.35 (s, 9H)
MS (m/z): MK 341 Example 147
S-Methyl-δ-trifluoromethyl-S.Φdihvdro^H-pyrazole-S-carboxylic acid (2- tert-butylsulfanyl-4-cvano-5-trifluoromethyl-phenyl)-amide
Compound #143
Figure imgf000170_0001
Following the procedure described in Example 29, starting from N-(2- tert-butylsulfanyl^-cyano-δ-trifluoromethyl-phenyO^-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) 6 10.75 (s, 1 H), 9.10 (s, 1 H), 7.95 (s, 1 H), 6.00 (s, 1 H), 3.20 and 3.05 (abq, J= 11.0 Hz, 2H), 1.65 (s, 3H), 1.30 (s, 9H)
MS (m/z): MH" 452
Example 148 4-Amino-5-methoxy-2-trifluoromethyl-benzonitrile
Figure imgf000170_0002
4-Amino-5-iodo-2-trifluoromethyl-benzonitrile (312 mg, 1.0 mmol), CuI (I) (20 mg, 0.1 mmol ), Cs2CO3 (652mg, 2.0 mmol) and 1 ,10-phenanthroline (36 mg, 0.2 mmol) were mixed in methanol (20 ml). The reaction mixture was refluxed overnight and then the solvent was removed under vacuum. Upon separation on silica gel (100% CH2CI2), the tile compound was obtained as a colorless liquid.
1H NMR (CDCI3) δ 7.05 (s, 1 H), 6.90 (s, 1 H), 4.50 (br, 2H), 3.90 (s, 3H)
MS (m/z): MH+ 216 Example 149 N-(4-Cvano-2-methoxv-5-trif[uoromethyl-phenvl)-2-methvl-acrvlamide
Figure imgf000171_0001
Following the procedure described in Example 1 , starting from 4-amino- 5-methoxy-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 9.00 (s, 1 H), 8.40 (s, 1 H), 7.26 (s, 1 H), 5.90 (s, 1 H), 5.60 (s, 1 H), 4.00 (s, 3H), 2.10 (s, 3H)
Example 150
S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid (4- cvano-2-methoxy-5-trifluoromethyl-phenyl)-amide
Compound #141
Figure imgf000171_0002
Following the procedure described in Example 29, starting from N-(4- cyano-2-methoxy-5-trifluoromethyl-phenyl)-2-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 9.65 (br, 1 H), 8.90 (s, 1 H), 7.25 (s, 1 H), 5.90 (s, 1 H), 4.00 (s, 3H), 3.25 and 3.05 (abq, J= 10.0 Hz, 2H), 1.60 (s, 3H)
MS (m/z): MH+ 395 Example 151 4-Amino-5-chloro-2-trifluoromethyl-benzonitrile
Figure imgf000172_0001
and 4-Amino-3.5-dichloro-2-trifluoromethyl-benzonitrile
Figure imgf000172_0002
4-Amino-2-trifluoromethyl-benzonitrile (10.5 mmoL) , NCS (15.5 mmoL) in MeOH (50 ml_) at O0C was stirred for 2 hrs. The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with sodium thiosulfate, water and brine, then dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compounds as brown solids. 4-Amino-5-chloro-2-trifluoromethyl-benzonitrile:
H NMR (CDCI3) δ 7.65 (s, 1 H), 7.02 (s, 1 H), 4.90 (br, s, 2H) MS (m/z): MH+ 221.
4-Amino-3,5-dichloro-2-trifluoromethyl-benzonitrile: 1H NMR (CDCI3) δ 7.61 (s, 1 H), 5.32 (br, s, 2H) MS (m/z): MH+ 256.
Example 152 N-fΣ-Chloro^-cvano-S-trifluoromethyl-phenvπ-Σ-methvl-acrvlamide
Figure imgf000173_0001
Following the procedure described in Example 1 , starting from 4-amino- 5-chloro-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.95 (s, 1 H), 7.52 (s, 1 H), 5.80 (br, s, 1 H), 5.65 (s, 1 H), 5.60 (s, 1 H)
MS (m/z): MH+ 289
Example 153
S-Methyl-S-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboxylic acid (2- chloro-4-cvano-5-trifluoromethyl-phenvO-amide
Compound #130
Figure imgf000173_0002
Following the procedure described in Example 29, starting from_N-(2- chloro^-cyano-δ-trifluoromethyl-phenyO^-methyl-acrylamide, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 9.88 (br, s, 1 H), 9.05 (s, 1 H), 7.90 (s, 1 H), 3.31 (abq, J = 10.5 Hz, 1 H), 3.15 (abq, J = 11.0 Hz, 1 H), 1.68 (s, 3H)
MS (m/z): MH+ 399 Example 154 N^.S-Dichloro^-cvano-S-trifluoromethyl-phenvπ-Σ-methvl-acrvlamide
Figure imgf000174_0001
Following the procedure described in Example 1 , starting from 4-amino- 3,5-dichloro-2-trifluoromethyl-benzonitrile, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.88 (s, 1 H), 7.50 (s, 1 H), 6.02 (s, 1 H), 5.68 (s, 1 H), 2.11 (s, 3H)
MS (m/z): MH+ 324
Example 155
S-Methyl-S-trifluoromethyl^^-dihydro-SH-pyrazole-S-carboxylic acid (2,6- dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #137
Figure imgf000174_0002
and S-Methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid
(2,6-dichloro-4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #139
Figure imgf000175_0001
and 3-Methyl-5-trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxylic acid (2,6-dichloro-4-cvano-3-trifluoromethyl-phenylH2.2.2-trifluoro-ethyl)- amide Compound #138
Figure imgf000175_0002
Following the procedure described in Example 29, starting from_N-(2,6- dichloro^-cyano-S-trifluoromethyl-phenyO^-methyl-acrylamide, the title compounds were prepared as off-white solids. 3-Methyl-5-trif luoromethyl-^δ-dihydro-SH-pyrazole-S-carboxylic acid (2,6- dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 8.82 (s, 1 H), 7.71 (s, 1 H), 3.70 (m, 1 H), 3.60 (m, 1 H), 2.85 (m, 1 H), 1.35 (s, 3H)
MS (m/z): MH+ 434. 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (2,6- dichloro-4-cyano-3-trifluoromethyl-phenyl)-amide:
1H NMR (CDCI3) δ 9.08 (s, 1 H), 7.50 (s, 1 H), 5.72 (s, 1 H), 3.25 (abq, J = 10.5 Hz, 1 H), 2.85 (abq, J = 10.5 Hz, 1 H), 1.58 (s, 3H)
MS (m/z): MH+ 434. 3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (2,6- dichloro-4-cyano-3-trifluoromethyl-phenyl)-(2,2,2-trifluoro-ethyl)-amide:
1H NMR (CDCI3) δ 7.88 (s, 1 H), 5.62 (m, 1 H), 3.75 (m, 2H), 3.58 (abq, J = 12.5 Hz, 1 H), 2.92 (abq, J = 12.5 Hz, 1 H), 1.68 (s, 3H) MS (m/z): MH+ 516
Example 156
3-Methyl-2-(2,2,2-trifluoro-acetyl)-5-trifluoromethyl-3,4-dihvdro-2H- pyrazole-3-carboxylic acid (4-cvano-3-trifluoromethyl-phenyl)-amide
Compound #131
Figure imgf000176_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (1.5 mmoL) in DCM (-20 ml_) was reacted with pyridine (2.0 mmoL) followed by trifluoroacetic anhydride (1.5 mmoL) which was added dropwise at 0°C. The reaction mixture was then stirred for 2 hrs. The solvent was removed and the residue was partitioned between DCM and water. The organic layer was washed with saturated sodium bicarbonate, water and then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compound as an off-white solid.
1H NMR (CDCI3) δ 9.72 (s, 1 H), 8.08 (s, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 4.35 (abq, J = 12.5 Hz, 1H), 3.10 (abq, J = 12.5 Hz, 1 H), 2.01 (s, 3H)
MS (m/z): MH+ 461 Example 157
Σ-Ethyl-S-methyl-S-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carboxylic acid rø-cvano-S-trifluoromethyl-phenvD-methyl-amide
Compound #123
Figure imgf000177_0001
2-Ethyl-3-methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (1.1 mmoL) in DMF (10 ml_) was treated with NaH (60%, 1.2 mmoL) follwed by CH3I (1.1 mmoL) at 0°C. The reaction mixture was stirred for 1 hr and then warmed to room temperature. The reaction mixture was then partitioned between diethyl ether and water. The organic layer was washed with saturated sodium bicarbonate, water and then brine, dried over anhydrous Na2SO4, filtered and concentrated to yield crude material, which was then purified by column chromatography using hexanes and ethyl acetate to yield the title compound as an off-white solid. 1H NMR (CDCI3) δ 7.80 (m, 1 H), 7.60 (s, 1 H), 7.45 (m, 1 H), 3.40 (s, 3H),
3.35 and 2.90 (abq, J= 14.0 Hz, 2H), 3.20 (m, 1 H), 3.00 (m, 1H), 1.50 (s, 3H), 1.15 (t, J = 3.0 Hz, 3H)
MS (m/z): MH+ 390
Example 158
S.S-DimethvM.S-dihvdro-isoxazole-S-carboxylic acid (4-cvano-3- trifluoromethyl-phenvO-amide
Compound #134
Figure imgf000178_0001
Following the procedure described in Example 27, starting from acetaldehyde oxime, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 8.65 (s, 1 H), 7.95 (s, 1 H), 7.40 (m, 2H), 3.40 and 2.95 (abq, J= 14.0 Hz, 2H), 2.00 (s, 3H), 1.70 (s, 3H)
MS (m/z): MH+ 390
Example 159
S-Methyl-δ-trifluoromethyl-S^-dihvdro-ΣH-pyrazole-S-carbothioic acid (4- cyano-3-trifluoromethyl-phenyl)-amide
Compound #118
Figure imgf000179_0001
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (15 mmoL) and Lawesson's agent (15 mmoL) in toluene (100 mL) was refluxed for 6 hrs until the solution turned clear. The reaction mixture was then cooled and some precipitate was observed. The solid was removed by filtration and the filtrate was concentrated to yield crude product as a green oil. The green oil was purified by silica gel column chromatography using DCM and ethyl acetate as eluent to yeild the title compound as a green solid.
1H NMR (CDCI3) δ 11.05 (s, 1 H), 8.45 (s, 1 H), 8.30 (d, J = 8.5 Hz,1 H), 7.82 (d, J = 8.5 Hz, 1 H), 5.95 (br, s, 1 H), 3.40 (abq, J = 9.5 Hz, 1 H), 3.21 (abq, J= 9.5 Hz, 1 H),1.85 (s, 3H) MS (m/z): MH+ 381
Example 160
N-(4-Cvano-3-trifluoromethyl-phenyl)-3-methvi-5-trifluoromethyl-3.4- dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester
Compound #204
Figure imgf000180_0001
3-Methyl-5-trifluoromethyl-3,4-dihyclro-2H-pyrazole-3-carbothioic acid (4- cyano-3-trifluoromethyl-phenyl)-amide (10 mmoL), K2CO3 (15 mmoL) in acetone was treated with CH3CH2I (10 mmoL) at room temperature. The reaction mixture was heated gently and then stirred at 50°C for 1 hr. The solid was filtrated and the filtrate was concentrated to yield crude product as a brown oil, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a colorless oil.
1H NMR (CDCI3) δ 7.80 (d, J = 7.8 Hz, 1 H), 7.28 (s, 1 H), 7.15 (d, J = 7.9 Hz, 1 H), 6.50 (s, 1 H), 3.51 (abq, J = 12.5 Hz, 1 H), 2.88 (abq, J = 12.5 Hz, 1 H), 2.35 (q, J = 8.5 Hz1 2H), 1.08 (t, J = 8.5 Hz, 3H)
MS (m/z): MH+ 409
Example 161
N-f^Cvano-S-trifluoromethyl-phenvπ-N'-ethyl-S-methyl-S-trifluoromethyl- 3,4-dihvdro-2H-pyrazole-3-carboxamidine or its tautomer N-(4-Cvano-3- trifluoromethyl-phenyl)-N'-ethyl-3-methyl-5-trifluoromethyl-3,4-dihvdro-
2H-pyrazole-3-carboxamidine Compound #205 or its Tautomer
Figure imgf000181_0001
N-(4-Cyano-3-trifluoromθthyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro~2H-pyrazole-3-carboximidothioic acid ethyl ester (2 mmoL) in dioxane (15 mL) was treated with ethyl amine /THF solution (~3 mmoL) and K2CO3 (2 mmoL) at 70°C. The reaction mixture was then stirred 4 hr. The solid was removed by filtration. The filtrate was concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid. 1H NMR (CDCI3) δ 7.62 (d, J = 7.5 Hz, 1 H), 7.10 (s, 1 H), 6.95 (d, J = 7.5
Hz, 1 H), 6.15 (s, 1 H), 5.78 (s, 1 H), 3.20 (abq, J = 9.5 Hz, 1 H), 2.95 (abq, J = 9.5 Hz, 1 H), 2.85 (q, J = 8.0 Hz, 2H), 1.48 (s, 3H), 1.30 (t, J = 8.0 Hz, 3H) MS (m/z): MH+ 392
Example 162
N-(4-Cvano-3-trifluoromethyl-phenyl)-N'-hvdroxy-3-methyl-5- trifluoromethyl-3,4-dihvdro-2H-Pyrazole-3-carboxamidine or its tautomer
N-(4-Cvano-3-trifluoromethyl-phenyl)-N'-hydroxy-3-methyl-5- trifluoromethyl-3.4-dihvdro-2H-pyra2ole-3-carboxamidine
Compound #206 or its Tautomer
Figure imgf000182_0001
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (1 mmoL) in DMF (5 ml_) was treated with N-hydroxamine hydrochloride salt (1 mmoL) and K2CO3 (2 mmoL) at room temperature. The reaction mixture was then stirred for 4 hr. The solid was removed by filtration. The filtrate was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCI3) δ 8.20 (s, 1 H), 7.62 (d, J = 7.5 Hz, 1 H), 7.05 (s, 1 H), 6.85 (d, J = 7.5 Hz, 1 H), 5.92 (s, 1 H), 3.25 (abq, J = 8.8 Hz, 1 H), 2.82 (abq, J = 8.8 Hz1 1 H), 1.50 (s, 3H) MS (m/z): MH+ 380
Example 163
N-(4-Cvano-3-trifluoromethyl-PhenvO-N'-methoxy-3-methyl-5- trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxamidine or its tautomer
N-(4-Cvano-3-trifluoromethyl-phenyl)-N'-methoxy-3-methyl-5- trifIuoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxamidine
Compound #210 or its Tautomer
Figure imgf000183_0001
Following the procedure described in Example 162, starting from O- methyl-hydroxylamine and N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5- trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.72 (d, J = 6.5 Hz, 1 H), 7.22 (s, 1 H), 7.11 (d, J = 6.5 Hz, 1 H), 6.12 (s, 1 H), 3.60 (s, 3H), 3.50 (abq, J = 8.5 Hz, 1 H), 2.95 (abq, J = 8.5 Hz, 1 H), 1.58 (s, 3H) MS (m/z): MH+ 394
Example 164
N-(4-Cvano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboxamidine or its tautomer N-(4-Cvano-3- trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4-dihvdro-2H- pyrazole-3-carboxamidine Compound #207 or its Tautomer
Figure imgf000183_0002
and N-(4-Cvano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3.4- dihydro-2H-pyrazole-3-carboximldic acid methyl ester
Compound #212
Figure imgf000184_0001
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester (1.2 mmoL) in dioxane (10 ml_) was treated with ammonia in MeOH (7N solution, -10 ml_) in a sealed tube. The reaction mixture was heated to 100°C for 4 hrs. The solvent was removed and the residue was purified by silica gel column chromatography using ethyl acetate and methanol as eluent to yield the title compounds as white solids.
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboxamidine:
1H NMR (CDCI3) δ 9.50 (br, s, 1 H), 8.11 (s, 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 5.63 (s, 1 H), 3.05 (abq, J = 10.5 Hz, 1 H), 2.95 (abq, J = 10.5 Hz, 1 H)1 1.58 (s, 3H) MS (m/z): MH+ 364.
N-(4-Cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro-2H-pyrazole-3-carboximidic acid methyl ester: MS (m/z): MH+ 379.
Example 165 N-f4-Cvano-3-trifluoromethyl-phenvn-3,N'-dimethyl-5-trifluoromethyl-3.4- dihvdro-2H-pyrazole-3-carboxamidine or its tautotner N-(4-Cvano-3- trifluoromethyl-phenvπ-3.N'-dimethyl-5-trifluoromethyl-3,4-dihvdro-2H- pyrazole-3-carboxamidine Compound #211 or its Tautomer
Figure imgf000185_0001
Following the procedure described in Example 164, starting from methyl amine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro^H-pyrazole-S-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.60 (d, J = 8.5 Hz, 1 H), 7.00 (s, 1 H), 6.90 (d, J = 8.5 Hz, 1 H), 6.05 (s, 1 H), 5.60 (s, 1 H), 3.15 (abq, J = 10.5 Hz, 1 H), 2.85 (abq, J = 10.5 Hz, 1 H), 2.90 (s, 3H), 1.45 (s, 3H) MS (m/z): MH+ 378
Example 166
N'-(4-Cvano-3-trifluoromethyl-phenyl)-N,N-diethyl-3-methyl-5- trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxamidine
Compound #208
Figure imgf000185_0002
Following the procedure described in Example 164, starting from diethyl amine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl-3,4- dihydro^H-pyrazole-S-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.72 (d, J = 7.5 Hz, 1 H), 7.21 (s, 1 H), 7.10 (d, J = 7.5 Hz, 1 H), 6.31 (s, 1 H), 3.70 (q, J = 5.5 Hz, 1 H), 3.55 (abq, J = 10.5 Hz, 1 H), 3.45 (q, J = 5.5 Hz, 1 H), 3.05 (abq, J = 10.5 Hz, 1 H), 1.55 (s, 3H), 1.20 (t, J = 8.5 Hz, 6H)
MS (m/z): MH+ 420
Example 167
^frO-Methyl-S-trifluoromethyl-S.Φdihvdro-ΣH-pyrazoi-S-vD-pyrrolidin-i-vi- methylenei-aminol-2-trifluoromethyl-benzonitrile
Compound #209
Figure imgf000186_0001
Following the procedure described in Example 164, starting from pyrrolidine and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5-trifluoromethyl- 3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.71 (d, J = 7.0 Hz, 1 H), 7.22 (s, 1 H), 7.08 (d, J = 7.0 Hz, 1 H), 3.77 (t, J = 6.0 Hz, 1 H), 3.62 (t, J = 6.0 Hz, 1 H), 3.60 (abq, J = 9.5 Hz, 1 H), 3.05 (abq, J = 9.5 Hz, 1 H), 1.95 ~ 1.70 (m, 4H),1.58 (s, 3H)
MS (m/z): MH+ 418
Example 169
N-^-Cvano-S-trifluoromethyl-phenyliminoHS-methyl-δ-trifluoromethyl- 3,4-dihvdro-2H-pyrazol-3-yl)-methvπ-methanesulfonamide or its tautomer N-rf4-Cvano-3-trifluoromethyl-phenylamino)-(3-methyl-5-trifluoromethyl- 3,4-dihvdro-2H-pyrazol-3-yl)-methylene1-methanesulfonamide Compound #214 or its Tautomer
Figure imgf000187_0001
Following the procedure described in Example 164, starting from methylsulfonamide and N-(4-cyano-3-trifluoromethyl-phenyl)-3-methyl-5- trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 7.85 (br, s, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.58 (s, 1 H), 7.20 (d, J = 7.5 Hz, 1 H), 7.05 (br, s, 1 H), 3.62 (abq, J = 10.5 Hz, 1 H), 3.32 (abq, J = 10.5 Hz, 1 H), 1.61 9s, 3H)
MS (m/z): MH+ 442
Example 169
5-Nitro-2-r(3-methyl-3,4-dihvdro-2H-pyrazole-3-carbonvn-amino1-benzoic acid methyl ester Compound #147
Figure imgf000187_0002
Following the procedure described in Example 29, starting from 5-nitro- 2-(2-methyl-acryloylamino)-benzoic acid methyl ester, the title compound was prepared as an off-white solid.
1H NMR (CDCI3) δ 8.95 (d, J = 7.5 Hz, 1 H), 8.90 (s, 1 H), 8.48 (d, J = 7.5 Hz, 1 H), 6.80 (s, 1 H)1 5.61 (s, 1 H), 4.01 (s, 3H), 3.10 (abq, J = 10.5 Hz, 1 H), 2.90 (abq, J = 10.5 Hz, 1 H), 1.55 (s, 3H)
MS (m/z): MH+ 307
Example 170 S-Methyl-S-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carbothioic acid
(3 ,4-dichloro-phenvD-amide
Compound #136
Figure imgf000188_0001
Following the procedure described in Example 159, starting from 3- methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (3,4- dichloro-phenyl)-amide, the title compound was prepared as a green oil.
1H NMR (CDCI3) δ 10.70 (s, 1 H), 8.10 (s, 1 H), 7.65 (m, 1 H), 7.45 (m, 1 H), 5.80 (s, 1 H), 3.30 and 3.15 (abq, J= 13.0 Hz, 2H), 1.80 (s, 3H)
MS (m/z): MH+ 357
Example 171
N-(3,4-Dichloro-phenyl)-3-methyl-5-trifluoromethy[-3,4-dihvdro-2H- pyrazole-3-carboximidothioic acid ethyl ester
Compound #213
Figure imgf000189_0001
Following the procedure described in Example 160, starting from 3- methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carbothioic acid (3,4- dichloro-phenyl)-amide, the title compound was prepared as a colorless oil.
1H NMR (CDCI3) 57.40 (m, 1 H), 7.00 (s, 1 H), 6.80 (m, 1 H), 6.60 (br, 1 H), 5.30 (s, 1 H), 3.50 and 2.80 (abq, J = 14.0 Hz, 2H), 2.30 (m, 2H), 1.60 (s, 3H), 1.00 (m, 3H)
MS (m/z): MH+ 385
Example 172
3(R)-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid
(4-cyano-3-trifluoromethyl-phenyl)-amide
Compound #144
Figure imgf000189_0002
Following the procedure described in Example 159, starting from 3(R)- methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (3- trifluoromethyl-4-cyano-phenyl)-amide, the title compound was prepared as a green oil.
NMR and MS data are the same as described in Example 159. Example 173
N-(4-Cvano-3-trifluoromethyl-phenvπ-3(R)-methyl-5-trifluoromethyl-3,4- dihvdro-2H-pyrazole-3-carboximidothioic acid ethyl ester
Compound #215
Figure imgf000190_0001
Following the procedure described in Example 160, starting from 3(R)- methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3- trifluoromethyl-phenyl)-amide, the title compound was prepared as a colorless oil.
NMR and MS data are the same as described in Example 160.
Example 174
SfSVMethyl-S-trifluoromethyl-S^-dihvdro^H-pyrazole-S-carbothioic acid (4-cvano-3-tπfluoromethyl-phenyl)-amide
Compound #145
Figure imgf000190_0002
Following the procedure described in Example 159, starting from 3(S)- methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (3- trifluoromethyl-4-cyano-phenyl)-amide, the title compound was prepared as a green oil.
NMR and MS data are the same as described in Example 159. Example 175
N-f4-Cvano-3-trifluoromethyl-phenyl)-3(S)-methyl-5-trifluoromethyl-3,4- dihvdro-2H-pyrazole-3-carboximidothioic acid ethyl ester
Compound #216
Figure imgf000191_0001
Following the procedure described in Example 160, starting from 3-(S)- methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carbothioic acid (4-cyano-3- trifluoromethyl-phenyl)-amide, the title compound was prepared as a colorless oil.
NMR and MS data are the same as described in Example 160.
Example 176
N-(4-Cvano-3-trifluoromethyl-phenyl)-2>ethyl-3(S)-methyl-5- trifluoromethyl-S^-dihvdro^H-pyrazole-S-carboximidothioic acid ethyl ester Compound #218
Figure imgf000192_0001
Following the procedure described in Example 126, starting from N-(4- cyano-S-trifluoromethyl-phenyO-SCSJ-methyl-δ-trifluoromethyl-S^-dihydro^H- pyrazole-3-carboximidothioic acid ethyl ester, the title compound was prepared as a colorless oil.
1H NMR (CDCI3) δ 7.75 (d, J = 7.5 Hz, 1 H), 7.20 (s, 1 H), 7.08 (D, j = 7.5 Hz, 1 H), 3.50 (m, 2H), 3,28 (abq, J = 12.5 Hz, 1 H), 2.85 (abq, J = 12.5 hz, 1 H), 2.48 (m, 2H), 1.50 (s, 3H), 1.35 (t, J = 9.5 Hz, 3H), 1.28 (t, J = 9.5 Hz, 3H)
MS (m/z): MH+ 437
Example 177
N-(4-Cvano-3-trifluoromethyl-phenv»-N'-cvano-2-ethyl-3(S)-methyl-5- trifluoromethyl-3,4-dihvdro-2H-pyrazole-3-carboxamidine or its tautomer
Λf-cvano-Λ^r^cvano-S-ftrifluoromethvDphenvn-i-ethyl^^-dihydro-SCS)- methyl-3-(trifluoromethvO-H-pyrazole-5-carboximidamide
Compound #217 or its Tautomer
Figure imgf000193_0001
N-(4-Cyano-3-trifluoromethyl-phenyl)-2-ethyl-3-(S)-methyl-5- trifluoromethyi-3,4-dihyclro-2H-pyrazole-3-carboximiclothioic acid ethyl ester (0.7 mmoL) in dioxane (5 ml_) was treated with K2CO3 (1.4 mmoL) and NH2CN (1.0 mmoL) at 80°C for 2 hr. The reaction mixture was then filtrated through a pad of Celite. The filtrate was concentrated and purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid. 1H NMR (CDCI3) δ 9.25 (br, s, 1 H), 8.05 (s, 1 H), 8.01 (d, J = 7.5 Hz, 1 H),
7.85 (d, J = 7.5 Hz, 1 H), 3.40 (abq, J = 11.5 Hz, 2H), 3.28 (m, 1 H), 3.05 (m, 1 H), 1.90 (S1 3H), 1.55 (t, J = 85 Hz, 3H) MS (m/z): MH+ 417
Example 178
4-Methyl-2-trifluoromethyl-4,5-dihvdro-oxazole-4-carboxylic acid (4- cvano-3-trifluoromethyl-phenvO-amide
Compound #110
Figure imgf000194_0001
3-Hydroxy-2-methyl-2-(2,2,2-trifluoro-acetylamino)-propionic acid (3.2 mmoL) in DMA (10 ml_) was treated dropwise with thionyl chloride (4.5 mmoL) at O0C for 30 min. To the resulting solution was added 4-amino-2- trifluoromethyl-benzonitrile (3.2 mmoL) in DMA (5 ml_) followed by TEA (5 mmoL). The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtrated and concentrated to yield crude product, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to yield the title compound as a white solid.
1H NMR (CDCI3) δ 8.62 (s, 1 H), 8.05 (s, 1 H), 8.13 (d, J = 6.8 Hz, 1 H), 7.32 (d, J = 6.8 Hz, 1 H), 4.65 (abq, J = 8.5 Hz, 1 H), 4.45 (abq, J = 8.5 Hz, 1 H), 1.55 (s, 3H)
Example 179
4-Methyl-2-oxo-oxazolidine-4-carboxylic acid (4-cyano-3-trifluoromethyl- phenvD-amide Compound #111
Figure imgf000195_0001
Following the procedure described in Example 178, starting from 2-tert- butoxycarbonylamino-3-hydroxy-2-methyl-propionic acid (prepared by literature known method), the title compound was prepared as a white solid.
1H NMR (CDCI3) δ 8.31 (br, s, 1 H), 8.05 (s, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 1 H), 6.01 (s, 1 H), 4.65 (d, J = 8.0 Hz, 1 H), 4.23 (d, J = 8.0 Hz, 1 H), 1.68 (s, 3H)
MS (m/z): MH+ 314
Example 180 Ventral Prostate and Levator ani Weight in vivo Assay
Mature (150 to 200 g) castrated male Sprague Dawley rats (Charles River) were treated once daily for 14 days with test compound (usually administered by oral gavage at up to the desired dosage, up to 30 mg/kg in a volume of 1 ml_, in 30% cyclodextrin or 0.5% methylcellulose vehicle), or with testosterone propionate (administered subcutaneously by injection at the nape of the neck at 5 mg/kg, in a volume of 0.1 ml_ in sesame oil), or with vehicle (1 mL of 30% cyclodextrin or 0.5% methylcellulose, given orally). On the fifteenth day, the rats were euthanized by asphyxiation in carbon dioxide. Ventral prostates and levator ani muscles were removed and their wet weights determined.
Test compound activity was determined as the percent stimulation of tissue weight, with the vehicle-treated control group set to zero percent and the testosterone alone-treated control group set to 100%. A compound was designated as agonist active if it produced greater than or equal to 20% stimulation of levator ani at 30 mg/kg.
Representative compounds of the present invention were tested according to the procedure described, with results as listed in Table 10 below. For the compounds listed in Table 10 as "inactive", one skilled in the art will recognize that said compounds may or may not have shown an effect on prostate and / or vesical weight, rather they are listed herein as "inactive" as they did not meet the specified criteria defined above. A designation of "toxic" indicates that the compound exhibited toxicity in the rats tested.
Table 10
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Example 181 Ventral Prostate and Seminal Vesicle Weight in vivo Assay
Immature (approximately 50 g) castrated male Sprague Dawley rats (Charles River) were treated once daily for five days with test compound (usually given orally at 40 mg/kg in a volume of 0.3 ml_, in 30% cyclodextrin or 0.5% methylcellulose vehicle) and with testosterone propionate (given subcutaneously by injection at the nape of the neck at 2 mg/kg, in a volume of 0.1 mL in sesame oil). On the sixth day, the rats were euthanized by asphyxiation in carbon dioxide. Ventral prosatates and seminal vesicles were removed and their wet weights determined. Test compound activity was determined as the percent inhibition of testosterone-enhanced tissue weights, with a vehicle-treated control group set to zero percent and a testosterone alone-treated control group set to 100%.
A test compound was said to be "active" if the non weight adjusted prostate weight was < 40 mg or the % Inhibition prostate weight, body weight adjusted was >60% @ 2mg/day dosage. ID50 1S, if determined, of <20 mg/day also indicated an active compound.
Representative compounds of the present invention were tested according to the procedure described, with results as listed in Table 11 below. For the compounds listed in Table 11 as "inactive", one skilled in the art will recognize that said compounds may or may not have shown an effect on prostate and / or vesical weight, rather they are listed herein as "inactive" as they did not meet the specified criteria defined above.
Table 11
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Example 182
As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 95 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

We Claim:
1. A compound of formula (I)
Figure imgf000202_0001
wherein W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -SO2-C1-4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl, -C(O)O-C1-4alkyl, -C(O)-C1-4alkyl and -C(O)- (halogenated C1-4alkyl); a is an integer from 0 to 1 ;
Figure imgf000202_0002
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)o-2-C1-4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
Figure imgf000203_0001
is phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, - C(O)-C1 -4alkyl and -S(O)0-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position of
Figure imgf000203_0002
; provided further that R is absent when a nitrogen
Figure imgf000203_0003
absent when a nitrogen atom is present at the 6-position of 2 provided further that R7 is absent when a nitrogen atom is present at the 2-
position of
Figure imgf000203_0004
Figure imgf000204_0003
, is selected from the group consisting o
Figure imgf000204_0001
Figure imgf000204_0002
w erein R5 is selected from the group consisting of halogen and Ci-
4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl Or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl, C1-4alkoxy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein Rc and RD are each independently selected from hydrogen or C1-4alkyl;
or a pharmaceutically acceptable salt thereof.
2. A compound as in Claim 1 , wherein
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, C1-4alkoxy, cyano and -SO2-C1-4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 4alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated C1-4alkyl and -C(O)-(halogenated C1-4alkyl); a is an integer from 0 to 1 ;
Figure imgf000205_0001
is selected from the group consisting of phenyl and pyridyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)0-2- C1-4alkyl and -S(0)o-2-phenyl; R4 is absent or selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)0-2- C1-4alkyl and -S(O)o-2-phenyl;
provided that when
Figure imgf000205_0002
js phenyl then at least one of R3 or R4 is other than hydrogen; R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, C1-4alkoxy, cyano, -C(O)O-Ci -4alkyl and -S(O)0-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position of
Figure imgf000206_0001
provided further that R is absent when a nitrogen
atom is present at the 4-position of
Figure imgf000206_0002
provided further that R6 is
absent when a nitrogen atom is present at the 6-position of
Figure imgf000206_0003
provided further that R7 is absent when a nitrogen atom is present at the 2-
position of
©
Figure imgf000206_0004
, is selected from the group consisting of ,
Figure imgf000206_0005
Figure imgf000206_0006
wherein R5' is selected from the group consisting of halogen and Ci. 2alkyl; and wherein R10 is selected from hydrogen, C1-4alkyl, benzyl or -C(O)- CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C(O)-C1-4alkyl, -C(O)-(halogenated C1-4alkyl), - C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl-S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, Ci- 4alkyl, C1-4alkoxy, halogenated C-|.4alkyl, cyano, nitro, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, trimethyl-silyl and t-butyl- dimethyl-silyloxy; wherein Rc and RD are each independently selected from hydrogen or C1-4alkyl; or a pharmaceutically acceptable salt thereof.
3. A compound as in Claim 2, wherein W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, C1-4alkyl, Ci-2alkoxy, cyano and -SO2-Ci -2alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 2alkyl;
R2 is selected from the group consisting of hydrogen, C1-4alkyl, halogenated Ci-2alkyl and -C(O)-(halogenated Chalky!); a is an integer from 0 to 1 ;
Figure imgf000207_0001
is selected from the group consisting of phenyl and pyridyl; R3 is absent or selected from the group consisting of hydrogen, halogen, halogenated
Figure imgf000208_0001
and cyano;
R4 is absent or selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(0)o-2-C1-4alkyl and -S(O)0-2-phenyl;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, d.2alkyl, Ci-2alkoxy, cyano, -C(O)O-Ci-2alkyl, -S-C1-4alkyl and -SO2-C1-4alkyi; provided that R3 is absent when a nitrogen atom is present at the 3-
Figure imgf000208_0002
provided further that R4 is absent when a nitrogen atom
is present at the 4-position of
Figure imgf000208_0003
provided further that R is absent
when a nitrogen atom is present at the 6-position of
Figure imgf000208_0004
; provided further that R7 is absent when a nitrogen atom is present at the 2-position of
Figure imgf000208_0005
Figure imgf000209_0002
is selected from the group consisting of
Figure imgf000209_0001
Figure imgf000209_0003
wherein R5 is halogen; and wherein R10 is selected from hydrogen, Ci- 4alkyl, benzyl or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, -C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C1-4alkyl-S-C1-4alkyl, -C(O)O-Ci.4alkyl, -C(O)-(halogenated C1-4alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, -O-C1-4alkyl, -C(O)O-C1-4alkyl, -NH-C(O)-C1- 4alkyl, -NH-C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy; or a pharmaceutically acceptable salt thereof.
4. A compound as in Claim 3, wherein
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, methoxy, cyano and -SO2-methyl;
R1 is selected from the group consisting of methyl, (S)-methyl, (R)- methyl, ethyl, n-propyl and trifluoromethyl; R2 is selected from the group consisting of hydrogen, methyl, trifluoroethyl and -C(O)-CF3; a is an integer from 0 to 1 ;
Figure imgf000210_0001
is selected from the group consisting of phenyl, 3-pyridyl and 4-pyridyl;
R3 is absent or selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano;
R4 is absent or selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, -C(O)-phenyl, -SO2-methyl and - ' SO2-phenyl;
R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, -C(O)O-methyl, -S-ethyl, -S-t-butyl and -SO2-ethyl;
R7 is selected from the group consisting of hydrogen, chloro and ethyl; provided that R3 is absent when a nitrogen atom is present at the 3-
Figure imgf000210_0002
position of 2 ; provided further that R4 is absent when a nitrogen atom
is present at the 4-position of
Figure imgf000210_0003
provided further that R6 is absent
when a nitrogen atom is present at the 6-position of
Figure imgf000210_0004
; provided further that R7 is absent when a nitrogen atom is present at the 2-position of
Figure imgf000210_0005
is selected from the group consisting of
Figure imgf000211_0001
Figure imgf000211_0002
Figure imgf000211_0003
Figure imgf000211_0004
wherein R5 is chloro; and wherein R10 is selected from hydrogen, methyl, ethyl, benzyl Or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy- phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4- fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl- carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl- carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl- dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl- amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl; or a pharmaceutically acceptable salt thereof.
5. A compound as in Claim 2, wherein W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, hydroxy, cyano,
Figure imgf000212_0001
Ci- 2alkoxy and -SO2-Ci-2alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 4alkyl;
R2 is selected from the group consisting of hydrogen, C^alkyl, halogenated Ci-2alkyl and -C(O)-(halogenated C1-2alkyl); a is an integer from 0 to 1 ;
Figure imgf000212_0002
is phenyl; R3 is selected from the group consisting of hydrogen, halogen, halogenated C1-4alkyl and cyano;
R4 is selected from the group consisting of halogen, cyano, nitro, benzyl, -O-phenyl, -C(O)-phenyl, -S(O)0-2-C1-4alkyl and -S(O)0-2-phenyl;
R6 and R7 are each independently selected from the group consisting of hydrogen, halogen, Ci-2alkyl, Ci-2alkoxy, cyano, -C(O)O-C1-2alkyl, -S-C1-4alkyl and -SO2-C1-4alkyl;
Figure imgf000212_0004
is selected from the group consisting of
Figure imgf000212_0003
Figure imgf000212_0005
wherein R5' is halogen; and wherein R10 is selected from the group consisting of hydrogen, C1-4alkyl, benzyl and -C(O)-CFs;
R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, -C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C1-4alkyl-S-C1-4alkyl, -C(O)O-C1-4alkyl, -C(O)-(halogenated C1-4alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, -O-C1-4alkyl, -C(O)O-Ci.4alkyl, -NH-C(O)-Ci- 4alkyl, -NH-C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy; or a pharmaceutically acceptable salt thereof.
6. A compound as in Claim 5, wherein
W is selected from the group consisting of O, S and NRF; wherein RF is selected from the group consisting of hydrogen, methyl, ethyl, methoxy, cyano and -SO2-methyl;
R1 is selected from the group consisting of methyl, (S)-methyl, (R)- methyl, ethyl, n-propyl and trifluoromethyl;
R2 is selected from the group consisting of hydrogen, methyl, trifluoromethyl and -C(O)-CF3; a is an integer from 0 to 1 ;
Figure imgf000213_0001
is phenyl;
R3 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and cyano; R4 is selected from the group consisting of chloro, bromo, cyano, nitro, benzyl, -O-phenyl, -S-phenyl, -C(O)-phenyl, -SO2-methyl and -SO2-phenyl;
R6 is selected from the group consisting of hydrogen, chloro, iodo, ethyl, methoxy, cyano, -C(O)O-methyl, -S-ethyl, -S-t-butyl and -SO2-ethyl;
R7 is selected from the group consisting of hydrogen, chloro and ethyl;
Figure imgf000214_0002
is selected from the group consisting of
Figure imgf000214_0001
Figure imgf000214_0003
wherein R5' is chloro; and wherein R10 is selected from hydrogen, methyl, ethyl, benzyl or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, trifluoromethyl, 2,2,2-trifluoro-ethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, hydroxy-methyl-, 2-hydroxy-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-ethylphenyl, 4-methoxy- phenyl, 2-hydroxy-3-fluoro-phenyl, 2-fluoro-3-hydroxy-phenyl, 3-methyl-4- fluoro-phenyl, cyclopentyl, cyclohexyl, 4-methoxy-carbonyl-phenyl, 3-methyl- carbonyl-amino-phenyl, 4-methyl-carbonyl-amino-phenyl, 4-(trifluoromethyl- carbonyl-amino)-phenyl, 2-(t-butyl-dimethyl-silyloxy)-3-fluoro-phenyl, t-butyl- dimethyl-silyloxy-phenyl, 4-methyl-carbonyl-amino-benzyl, 4-methyl-carbonyl- amino-phenyl, 2-furyl, 2-thienyl, 3-pyridyl, 2-tetrahydrofuryl, methyl-thio-ethyl-, ethyl-thio-ehyl-, ethoxy-carbonyl-, t-butoxy-carbonyl-, trifluoromethyl-carbonyl- and trimethylsilyl; or a pharmaceutically acceptable salt thereof.
7. A compound as in Claim 2, wherein W is O; R1 is C1-4alkyl;
R2 is hydrogen;
Figure imgf000215_0001
is pyridyl; R3 is absent or hydrogen;
R4 absent or is selected from the group consisting of cyano and halogen; provided that R3 is absent when a nitrogen atom is present at the 3-
position of
Figure imgf000215_0002
; provided further that R4 is absent when a nitrogen atom
is present at the 4-position of
Figure imgf000215_0003
Figure imgf000215_0004
R5 is selected from the group consisting of halogenated C1-4alkyl and aryl; wherein the aryl is optionally substituted with one to two halogen; or a pharmaceutically acceptable salt thereof.
8. A compound as in Claim 7, wherein
W is O; R1 is methyl;
R2 is hydrogen; a is O;
Figure imgf000216_0001
is selected from the group consisting of 3-pyridyl and 4- pyridyl;
R3 is absent or hydrogen;
R4 is absent or selected from the group consisting of cyano and chloro; provided that R3 is absent when a nitrogen atom is present at the 3-
position of
Figure imgf000216_0002
provided further that R4 is absent when a nitrogen atom
is present at the 4-position of
Figure imgf000216_0003
H
Figure imgf000216_0004
R5 is selected from the group consisting of trifluoromethyl and 4- fluorophenyl; or a pharmaceutically acceptable salt thereof.
9. A compound as in Claim 4, wherein
W is selected from the group consisting of O, NH, N(OH), N(ethyl) and N(methoxy);
R1 is selected from the group consisting of methyl, (R)-methyl, (S)- methyl, ethyl and trifluoromethyl;
R2 is selected from the group consisting of hydrogen and methyl; a is an integer from 0 to 1 ;
Figure imgf000217_0001
is phenyl;
R3 is selected from the group consisting of hydrogen and trifluoromethyl;
R4 is selected from the group consisting of bromo, cyano, nitro and - SO2-phenyl;
R6 is selected from the group consisting of hydrogen, iodo, chloro and - S-ethyl;
R7 is selected from the group consisting of hydrogen and ethyl;
Figure imgf000217_0002
is selected from the group consisting of ,
Figure imgf000217_0003
wherein R5' is chloro; and wherein R10 is selected from the group consisting of hydrogen, methyl and ethyl;
R5 is selected from the group consisting of methyl, trifluoromethyl, 1 ,1 ,2,2,2-pentafluoro-ethyl, -C(O)O-ethyl, 4-methyl-carbonyl-amino-phenyl, 4- trifluoromethyl-carbonyl-amino-phenyl and 4-methyl-carbonyl-amino-benzyl; or a pharmaceutically acceptable salt thereof.
10. A compound as in Claim 4, wherein
W is selected from the group consisting of O and N(ethyl); R1 is methyl; R2 is selected from the group consisting of hydrogen and methyl; a is an integer from 0 to 1 ;
Figure imgf000218_0001
is phenyl; R3 is trifluoromethyl;
R4 is selected from the group consisting of chloro, cyano and nitro; R6 is selected from the group consisting of hydrogen, chloro, ethyl and - SO2-ethyl;
R7 is selected from the group consisting of hydrogen, chloro and ethyl;
Figure imgf000218_0002
is ; wherein R10 is selected from the group consisting of hydrogen and ethyl;
R5 is selected from the group consisting of hydrogen, n-propyl, isopropyl, trifluoromethyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-methoxyphenyl, 4-ethylphenyl, cyclohexyl, 2-furyl and 2-thienyl; or a pharmaceutically acceptable salt thereof.
11. A compound as in Claim 4, selected from the group consisting of S-Methyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide;
S-Ethyl-δ-trifluoromethyl-S^-dihydro^H-pyrazole-S-carboxylic acid (4- cyano-3-trifluoromethyl-phenyl)-amide;
5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide;
5-(4-Acetylamino-phenyl)-3-methyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide;
3-Methyl-5-[4-(2,2,2-trifluoro-acetylamino)-phenyl]-3,4-dihydro-2H- pyrazole-3-carboxylic acid (4-nitro-3-trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
12. A compound as in Claim 11 selected from the group consisting of (R)-3- Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carboxylic acid (4-cyano-3- trifluoromethyl-phenyl)-amide; (S)-3-Methyl-5-trifluoromethyl-3,4-dihydro-2H- pyrazole-3-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide; and pharmaceutically acceptable salts thereof.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 1.
14. A method of treating a disorder mediated by an androgen receptor, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Claim 1.
15. A method as in Claim 14, wherein the disorder mediated by an androgen receptor is selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS and cachexia.
16. A method as in Claim 14, wherein the disorder mediated by an androgen receptor is male contraception or male performance.
17. A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Claim 1.
18. A method of treating a disorder mediated by an androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 13.
19. A compound of formula (II)
Figure imgf000220_0001
wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2; wherein RE is selected from the group consisting of hydrogen and C-i-
4alkyl; wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -SO2-C1-4alkyl; provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen; alternatively, the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci-
4alkyl; a is an integer from 0 to 1 ;
Figure imgf000220_0002
selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino,
Figure imgf000220_0003
di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl; R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino,
Figure imgf000221_0001
di(Ci- 4alkyl)amino, -O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
Figure imgf000221_0002
js phenyl then at least one of R3 or R4 is other than hydrogen;
R6 and R7 are each absent or independently selected from the group consisting of hydrogen halogen,
Figure imgf000221_0003
C2-4alkenyl, C1-4alkoxy, cyano, - C(O)O-C1-4alkyl and -S(O)0.2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position
Figure imgf000221_0004
; provided further that R4 is absent when a nitrogen
atom is present at the 4-position
Figure imgf000221_0005
; provided further that R6 is
absent when a nitrogen atom is present at the 6-position
Figure imgf000221_0006
; provided further that R7 is absent when a nitrogen atom is present at the 2-
position
Figure imgf000221_0007
Θ. is selected from the group consisting of
Figure imgf000222_0001
Figure imgf000222_0002
wherein R5' is selected from the group consisting of halogen and Ci-
4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl Or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated C1-4alkyl, hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1 -4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C-ι-4alkyl, C1^aIkOXy, halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or
Figure imgf000223_0001
or a pharmaceutically acceptable salt thereof.
20. A compound as in Claim 19, wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2; wherein RE is selected from the group consisting of hydrogen and Ci- 4alkyl; wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -SO2-C1-4alkyl; provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen; alternatively the two RF groups are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated heterocyclic ring structure;
R1 is selected from the group consisting of Ci-2alkyl and halogenated Ci- salkyl; a is an integer from 0 to 1 ;
Figure imgf000223_0002
is selected from the group consisting of phenyl and pyridyl;
R3 is absent or selected from the group consisting of hydrogen, halogen and halogenated Ci-2alkyl;
R4 is absent or selected from the group consisting of hydrogen, halogen, halogenated Ci-2alkyl and cyano;
R6 and R7 are each independently absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl and halogenated Ci.2alkyl; provided that R3 is absent when a nitrogen atom is present at the 3-
position
Figure imgf000224_0001
; provided further that R4 is absent when a nitrogen atom
is present at the 4-position
Figure imgf000224_0002
provided further that R is absent
when a nitrogen atom is present at the 6-position
Figure imgf000224_0003
; provided further that R7 is absent when a nitrogen atom is present at the 2-position
Figure imgf000224_0004
©■ is selected from the group consisting of
Figure imgf000224_0005
, ,
Figure imgf000224_0006
wherein R5' is selected from the group consisting of halogen and Ci- 4alkyl; and wherein R10 is selected from the group consisting of hydrogen, Ci- 4alkyl, benzyl and -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, C1-4alkyl, halogenated C1-4alkyl, -C1-4alkyl-OH, cycloalkyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, -C1-4alkyl-S-C1-4alkyl, -C(O)O-C1-4alkyl, -C(O)-(halogenated C1-4alkyl) and trimethylsilyl; wherein the aryl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from hydroxy, halogen, C1-4alkyl, -O-C1-4alkyl, -C(O)O-C1-4alkyl, -NH-C(O)-Ci- 4alkyl, -NH-C(O)-(halogenated C1-4alkyl) or t-butyl-dimethyl-silyloxy; or a pharmaceutically acceptable salt thereof.
21. A compound as in Claim 20, wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2; wherein RE is selected from the group consisting of C1-4alkyl; wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, Ci-2alkoxy and -SO2-Ci-2alkyl; provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen; alternatively the two RF groups are taken together with the nitrogen atom to which they are bound to form 1 -pyrrolidinyl or 1-piperidinyl;
R1 is selected from the group consisting of Ci-2alkyl; a is 0;
Figure imgf000225_0001
R4 is cyano; R6 is hydrogen; R7 is hydrogen;
Figure imgf000226_0001
is selected from the group consisting of and wherein R10 is selected from the group consisting of hydrogen and Ci- 4alkyl;
R5 is selected from the group consisting of halogenated Ci-2alkyl; or a pharmaceutically acceptable salt thereof.
22. A compound as in Claim 21 , wherein
Z is selected from the group consisting of ORE, SRE and N(RF)2; wherein RE is selected from the group consisting of methyl and ethyl wherein each RF is independently selected from the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl, methoxy and -SO2-methyl; provided that when one RF group is hydroxy or cyano, then the other RF group is hydrogen; alternatively the two RF groups are taken together with the nitrogen atom to which they are bound to form 1 -pyrrolidinyl;
R1 is selected from the group consisting of methyl, (R)-methyl and (S)- methyl; a is 0;
Figure imgf000226_0002
is phenyl; R3 is trifluoromethyl;
R4 is cyano; R6 is hydrogen; R7 is hydrogen;
Figure imgf000227_0002
selected from the group consisting of
Figure imgf000227_0001
and wherein R10 is selected from the group consisting of hydrogen, methyl and ethyl;
R5 is trifluoromethyl; or a pharmaceutically acceptable salt thereof.
23. A compound as in Claim 22, wherein
Z is selected from the group consisting of -O-methyl, -O-ethyl, -S-ethyl, -NH2, -NH(OH), -NH-ethyl, -N(ethyl)2 and -NH(OCH3); R1 is selected from the group consisting of methyl and (S)-methyl; a is 0;
Figure imgf000227_0003
R3 is trifluoromethyl; R4 is cyano; R6 is hydrogen;
R7 is hydrogen;
Figure imgf000227_0004
is selected from the group consisting of and wherein R10 is selected from the group consisting of hydrogen and ethyl; R5 is trifluoromethyl; or a pharmaceutically acceptable salt thereof.
24. A compound as in Claim 22, selected from the group consisting of N-(4- cyano-S-trifluoromethyl-phenyO-N'-ethyl-S-methyl-δ-trifluoromethyl-S^-dihydro- 2H-pyrazole-3-carboxamidine and pharmaceutically acceptable salts thereof.
25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Claim 19.
26. A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Claim 19.
27. A method as in Claim 26, wherein the disorder mediated by an androgen receptor is selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS and cachexia.
28. A method as in Claim 26, wherein the disorder mediated by an androgen receptor is male contraception or male performance.
29. A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of Claim 19.
30. A method of treating a disorder mediated by an androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 25.
31. A tautomeric mixture comprising
Figure imgf000229_0001
wherein
RF is selected from the group consisting of hydrogen, hydroxy, cyano, C1-4alkyl, C1-4alkoxy and -Sθ2-C1-4alkyl;
R1 is selected from the group consisting of C1-4alkyl and halogenated Ci- 4alkyl; a is an integer from 0 to 1 ;
Figure imgf000229_0002
is selected from the group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl;
R3 is absent or selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino, C1-4alkylamino, di(Ci_ 4alkyl)amino, -O-C1-4alkyl, -S(0)o-2-C1-4alkyl, -NRA-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RA is selected from hydrogen or C1-4alkyl;
R4 absent or is selected from the group consisting of hydrogen, halogen, C1-4alkyl, halogenated C1-4alkyl, cyano, nitro, amino,
Figure imgf000229_0003
4alkyl)amino, -0-C^.talkyl, -S(O)0-2-C1-4alkyl, -NRB-C(O)-C1-4alkyl, benzyl, -O- phenyl, -C(O)-phenyl and -S(O)0-2-phenyl; wherein RB is selected from hydrogen or C1-4alkyl;
provided that when
Figure imgf000229_0004
is phenyl then at least one of R3 or R4 is other than hydrogen; R6 and R7 are each absent or independently selected from the group consisting of hydrogen halogen, C1-4alkyl, C2-4alkenyl, C1-4alkoxy, cyano, - C(O)O-Ci -4alkyl and -S(O)o-2-C1-4alkyl; provided further that R3 is absent when a nitrogen atom is present at the
3-position
Figure imgf000230_0001
provided further that R4 is absent when a nitrogen
atom is present at the 4-position is
absent when a nitrogen atom is p
Figure imgf000230_0002
resent at the 6-position provided further that R7 is absent when a nitrogen atom is present at the 2-
position
0
Figure imgf000230_0003
, is selected from the group consisting of
Figure imgf000230_0004
Figure imgf000231_0001
wherein R5' is selected from the group consisting of halogen and Ci- 4alkyl; and wherein R10 and R11 are each independently selected from hydrogen, C1-4alkyl, benzyl or -C(O)-CF3;
R5 is selected from the group consisting of hydrogen, carboxy, alkyl, halogenated
Figure imgf000231_0002
hydroxy substituted C1-4alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl-, heterocycloalkyl, heterocycloalkyl-alkyl-, -C(O)- alkyl, -C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -C(O)O-aryl, -C1-4alkyl- S(O)o-2-C1-4alkyl, t-butyl-dimethyl-silyl and trimethylsilyl; wherein the aryl, cycloalkyl, heteroaryl or heterocycloalkyl, whether alone or as part of a substituent group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-4alkyl,
Figure imgf000231_0003
halogenated C1-4alkyl, halogenated C1-4alkoxy, cyano, nitro, amino, C1-4alkylamino, di(C1-4alkyl)amino, -NRc-C(O)-C1-4alkyl, NRc-C(O)-(halogenated C1-4alkyl), -C(O)O-C1-4alkyl, -S(O)0-2-C1-4alkyl, -SO2- NRCRD, trimethyl-silyl and t-butyl-dimethyl-silyloxy; wherein each Rc and RD are each independently selected from hydrogen or C1-4alkyl; or a pharmaceutically acceptable salt thereof.
32. A tautomeric mixture as in Claim 31 , wherein
RF is selected from the group consisting of hydrogen, hydroxy, cyano, Ci-2alkyl, Ci-2alkoxy and -SO2-Ci-2alkyl;
R1 is selected from the group consisting of Ci-2alkyl and halogenated Ci- 2alkyl; a is an integer from 0 to 1 ;
Figure imgf000232_0001
is phenyl;
R3 is selected from the group consisting of hydrogen, halogen and halogenated
Figure imgf000232_0002
R4 is selected from the group consisting of halogenated Ci-2alkyl and cyano;
R6 is hydrogen;
R7 is hydrogen;
Figure imgf000232_0003
wherein R10 is selected from the group consisting of hydrogen and Chalky!; R5 is selected from the group consisting of halogenated C-i-2alkyl; or a pharmaceutically acceptable salt thereof.
33. A tautomeric mixture as in Claim 31 , wherein
RF is selected from the group consisting of hydrogen, hydroxy, cyano, methyl, ethyl, methoxy, and -SO2-methyl;
R1 is selected from the group consisting of methyl and (S)-methyl; a is O;
Figure imgf000232_0004
is phenyl;
R3 is trifluoromethyl; R4 is cyano;
R6 is hydrogen; R7 is hydrogen;
Figure imgf000233_0001
wherein R10 is selected from the group consisting of hydrogen and ethyl;
R5 is trifluoromethyl; or a pharmaceutically acceptable salt thereof.
34. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a tautomeric mixture of Claim 31.
35. A method of treating a disorder mediated by an androgen receptor, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the tautomeric mixture of Claim 31.
36. A method as in Claim 35, wherein the disorder mediated by an androgen receptor is selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS and cachexia.
37. A method as in Claim 35, wherein the disorder mediated by an androgen receptor is male contraception or male performance.
38. A method of treating a condition selected from the group consisting of prostate carcinoma, benign prostatic hyperplasia (BPH), hirsitutism, alopecia, anorexia nervosa, breast cancer, acne, AIDS, cachexia, male contraception, and male performance, in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the tautomeric mixture of Claim 31.
39. A method of treating a disorder mediated by an androgen receptor comprising administering to a subject in need thereof a therapeutically effective amount of the composition of Claim 34.
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