WO2004017961A2 - Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer - Google Patents

Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer Download PDF

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WO2004017961A2
WO2004017961A2 PCT/GB2003/003633 GB0303633W WO2004017961A2 WO 2004017961 A2 WO2004017961 A2 WO 2004017961A2 GB 0303633 W GB0303633 W GB 0303633W WO 2004017961 A2 WO2004017961 A2 WO 2004017961A2
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optionally substituted
formula
group
alkyl
hydrogen
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PCT/GB2003/003633
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French (fr)
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WO2004017961A3 (en
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Thomas Geoffrey Colerick Bird
Matthias Ferdinand Herdemann
Mickael Louis Pierre Maudet
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to US10/524,977 priority Critical patent/US7514570B2/en
Priority to AU2003255820A priority patent/AU2003255820A1/en
Priority to DE60324431T priority patent/DE60324431D1/en
Priority to EP03792487A priority patent/EP1531811B1/en
Priority to JP2004530361A priority patent/JP2006505528A/en
Publication of WO2004017961A2 publication Critical patent/WO2004017961A2/en
Publication of WO2004017961A3 publication Critical patent/WO2004017961A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • 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
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to compounds which are antagonists of gonadotropin releasing hormone (GnRH) activity.
  • the invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.
  • Gonadotropin releasing hormone is a decapeptide that is secreted by the hypothalamus into the hypophyseal portal circulation in response to neural and/or chemical stimuli, causing the biosynthesis and release of luteinizing hormone (LH) and follicle- stimulating hormone (FSH) by the pituitary.
  • GnRH is also known by other names, including gonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSH RH) and LH/FSH releasing factor (LH/FSH RF).
  • GnRH plays an important role in regulating the action of LH and FSH (by regulation of their levels), and thus has a role in regulating the levels of gonadal steroids in both sexes, including the sex hormones progesterone, oestrogens and androgens. More discussion of GnRH can be found in WO 98/5519 and WO 97/14697, the disclosures of which are incorporated herein by reference.
  • sex hormone related conditions such as sex hormone dependent cancer, benign prostatic hypertrophy and myoma of the uterus.
  • sex hormone dependent cancers are prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.
  • R 1 is selected from: hydrogen, optionally-substituted - ⁇ alkyl, optionally substituted aryl or optionally-substituted arylC ⁇ . 6 alkyl;
  • R 2 is an optionally-substituted mono or bi-cyclic aromatic ring;
  • R 3 is selected from a group of Formula (Ila) to Formula (Ef):
  • R 6 and R 6a are independently selected from hydrogen, fluoro, optionally substituted Cj . - 6 alkyl, optionally-substituted aryl or optionally substituted arylCi- ⁇ alkyl, or R 6 and R 6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R and R 6a taken together and the carbon atom to which they are attached form a carbonyl group;
  • A is not a direct bond the group forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
  • R 7 is selected from: hydrogen, optionally-substituted Cj . . 6 alkyl, optionally-substituted arylC 1 . 6 alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylC ⁇ . 6 alkyl, R'O -ealkyl-, R 9 R 10 NCi. 6 alkyl-,
  • R 9 R 10 NC(O)C ⁇ . 6 alkyl, -C(NR 9 R 10 ) NH; or when R is a group of Formula (He) or (Lid) R is of the formula -J-K-R ; R is selected from:
  • heterocyclyl or heterocyclylCi- ⁇ alkyl each of which is optionally substituted by up to 4 substituents independently selected from R , R and R ;
  • R and R ° are independently selected from: hydrogen, hydroxy, optionally substituted C ⁇ .
  • R 9 and R 10 taken together can form an optionally substituted ring of 3-9 atoms or R 9 and R 10 taken together with the carbon atom to which they are attached form a carbonyl group;
  • R 11 is selected from: hydrogen, optionally substituted Ci ⁇ alkyl, or N(R 9 R 10 );
  • R 12 is selected from: hydrogen, hydroxy, R 17 R 18 N(CH 2 ) CC -, R 17 R 18 NC(O)(CH 2 ) cc -, optionally substituted C ⁇ alkyl- C(O)N(R 9 )(CH 2 ) cc -, optionally substituted C 1 . 6 alkyl-SO 2 N(R 9 )-, optionally substituted aryl-SO 2 N(R 9 )-,
  • R 13 and R 14 are independently selected from: hydrogen, hydroxy, oxo, optionally substituted C ⁇ _ 6 alkyl, optionally substituted C ⁇ alkanoyl, optionally substituted
  • R 16 is selected from: hydrogen, C 1 . 6 alkyl, Cj . . 3 perfluoroalkyl or optionally-substituted aryl;
  • R 17 is independently selected from: hydrogen, hydroxy, cyano or optionally substituted - ⁇ alkyl;
  • R 18 is a group of formula R 18a -C(R 9 R 10 ) 0 -i- wherein R 18a is selected from: R 1 OC(O)-,
  • R 21 and R 22 are independently selected from hydrogen, optionally substituted optionally substituted C 3 . cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylC ⁇ _ 6 alkyl, optionally substituted C 3 . 6 alkenyl, optionally substituted C 3 . 6 alkynyl, -(C 1 . 5 alkyl) aa -S(O n )-(C 1 . 5 alkyl) bb -; R 9 R 10 NC 2 . 6 alkyl, R 9 OC 2 - 6 alkyl or R 9 R 10 NC(O)C 2 .
  • R 9 and R 10 independently or taken together are not optionally substituted aryl or optionally substituted arylCi- ⁇ alkyl; or R 21 and R 22 taken together form an optionally substituted non-aromatic heterocyclic ring;
  • A is selected from: (i) a direct bond;
  • optionally-substituted C ⁇ salkylene wherein the optional substituents are independently selected from: optionally-substituted C h alky! optionally-substituted aryl or optionally substituted arylCi- ⁇ alkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group or -C(O)-C(R d R d )-, wherein R is independently selected from hydrogen and
  • R is a group o f Formula (Ha) or (H ), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • R 3 is a group of Formula (Ha), (lib), (Lie) or (Ltd), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • B is selected from:
  • Formula (IV) wherein: X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the
  • (CH 2 ) P group is attached to R 8 ; and (iii) a group independently selected from: optionally substituted -ealkylene, optionally substitute C 3 . 7 cycloalkyl, optionally substituted C 3 . 6 alkenylene, optionally substituted C 3 . 6 alkynyl, C ⁇ _ 6 alkoxy, (C ⁇ .5alkyl) a a-S(O n )-(C ⁇ .5alkyl)bb-, -(C 1 . 5 alkyl) aa -O-(C 1 . 5 alkyl)bb-, -(C 1 . 5 alkyl)aa-C(O)-(C 1 . 5 alkyl)bb- or
  • E is -O-, -S(O n ), -C(O)-, -NR 15 - or -C(R 9 R 10 ) q ;
  • F is -E(CH 2 ) r -;
  • G is selected from: hydrogen, halo, N, O, S(O n ), C(O), C(R R 10 ) t , optionally substituted
  • J is a group of the formula: -(CH 2 ) S -L-(CH 2 ) S - wherein when s is greater than 0, the alkylene group is optionally substituted,
  • K is selected from: a direct bond, -(CH 2 ) s ⁇ -, -(CH 2 ) s ⁇ -O-(CH 2 ) s2 -, -(CH 2 ) s ⁇ -C(O)-(CH 2 ) s2 - -(CH 2 ) sl -S(O n )-(CH 2 ) s2 -, -(CH 2 ) sl -N(R 18 )-(CH 2 ) s2 -, -(CH 2 ) s ⁇ -C(O)N(R 9 )-(CH 2 ) s2 -, -(CH 2 ) sl -N(R 9 )C(O)-(CH 2 ) s2 -, -(CH 2 ) sl -N(R 9 )C(O)-(CH 2 ) s2 -, -(CH 2 ) sl -N(R 9
  • L is selected from optionally substituted aryl or optionally substituted heterocyclyl; M is selected from -(CH 2 ) 0 - 2 -O- or -C(O)NH-; n is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 4; r is an integer from 0 to 4; s is an integer from 0 to 4; si and s2 are independently selected from an integer from 0 to 4, and sl+s2 is less than or equal to 4; t is an integer between 0 and 4; and aa and bb are independently 0 or 1; cc is an integer between 0 to 2; with the proviso that
  • R is a group of the formula N(R R ) and R , R and R 5 are as defined above then R cannot be hydrogen; and (iv) R 3 cannot be an unsubstituted or substituted aromatic heterocyclic ring, wherein the aromatic heterocyclic ring is attached directed to the pyrazole in Formula (I); or a salt, solvate or pro-drug thereof.
  • R >1 is selected from: hydrogen, optionally-substituted C h alky!, optionally substituted aryl or optionally-substituted
  • R ,3 is selected from a group of Formula (Ila) to Formula (Hf):
  • Formula (lie) Formula (Ilf) R s is a group of Formula (III):
  • R 6 and R 6a are independently selected from hydrogen, optionally substituted optionally-substituted aryl or optionally substituted arylC ⁇ _ 6 alkyl, or R 6 and R 6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R 6 and R a taken together and the carbon atom to which they are attached form a carbonyl group; or when A is not a direct bond the group forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
  • R 7 is selected from: hydrogen, optionally-substituted optionally-substituted arylCj .
  • R is a group of Formula (lie) or (Ed) R is of the formula -J-K-R ; o R is selected from:
  • R 9 and R 10 are independently selected from: hydrogen, hydroxy, optionally substituted Ci_ 6 alkyl, optionally substituted aryl, optionally substituted arylCi- ⁇ alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylCj .
  • R 9 and R 10 taken together can form an optionally substituted ring of 3-9 atoms or R 9 and R 10 taken together with the carbon atom to which they are attached form a carbonyl group;
  • R 11 is selected from: hydrogen, optionally substituted or N(R 9 R 10 );
  • R 12 is selected from: hydrogen, hydroxy, R 17 R 18 N-, optionally substituted Ci- 6 alkyl-SO 2 N(R 9 )-, optionally substituted aryl-SO 2 N(R 9 )-,
  • R 13 and R 14 are independently selected from: hydrogen, optionally substituted C ⁇ _ 6 alkyl, optionally substituted C 2 _ 6 alkenyl, cyano, nitro, C ⁇ _ 3 perfluoroalkyl-, Cj . - 3 perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC ⁇ . 6 alkyl,
  • R is selected from: hydrogen, optionally substituted Cj . _ 6 alkyl, R OC(O)-, R 9 R 10 NC(O)-, R 9 C(O)-, R 9 S(O n )-;
  • R 16 is selected from: hydrogen, C ⁇ alkyl, Ci-sperfluoroalkyl or optionally-substituted aryl;
  • R is independently selected from: hydrogen, hydroxy, cyano or optionally substituted
  • R 18 is a group of formula R 18a -C(R 9 R 10 )o - wherein R 18a is selected from: R 19 OC(O)-,
  • R 19 is selected from: hydrogen, optionally substituted C h alky, optionally substituted aryl, optionally substituted optionally substituted C 3 . cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylC 1 . 6 alkyl;
  • R 20 is selected from R 12 or R 13 ;
  • R 21 and R 22 are independently selected from hydrogen, optionally substituted Ci- ⁇ alkyl, optionally substituted C 3 . cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCj . - 6 alkyl, optionally substituted C 3 . 6 alkenyl, optionally substituted C 3 . 6 alkynyl, -(C 1 . 5 alkyl)aa-S(O n )-(C 1 . 5 alkyl) b b-; R 9 R 10 NC 2 .
  • A is selected from: (i) a direct bond;
  • optionally-substituted C ⁇ alkylene wherein the optional substituents are independently selected from: optionally-substituted Ci- ⁇ alkyl optionally-substituted aryl, optionally substituted arylCj . . 6 alkyl or substituted arylCj . - 6 alkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group;
  • R is a group of Formula (Ha) or (lib), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • R is a group of Formula ( ⁇ a), (lib), (He) or (Hd), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
  • B is selected from: (i) a direct bond; (ii) a group of Formula (IV)
  • X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the (CH 2 )p group is attached to R ;
  • (iii) a group independently selected from: optionally substituted C ⁇ . . 6 alkylene, optionally substitute C 3 . cycloalkyl, optionally substituted C 3 . 6 alkenylene, optionally substituted C 3 _ 6 alkynyl, (C ⁇ .5alkyl) aa -S(O n )-(C ⁇ . 5 alkyl) b b-, (C 1 . 5 alkyl) aa -O-(C 1 . 5 alkyl)bb- or (C 1 . 5 alkyl)a a -N(R 15 )- (C ⁇ . 5 alkyl) bb , wherein R 15 and the or ( .salkylJbb chain can be joined to form a ring; or the group -B-R 8 represents a group of Formula (V)
  • E is -O-, -S(O n ), -C(O)-, -NR 15 - or -C(R 9 R 10 ) q ;
  • F is -E(CH 2 ) r -;
  • G is selected from: hydrogen, halo, N, O, S(O n ), C(O), C(R 9 R 10 ) t , optionally substituted
  • J is a group of the formula: -(CH 2 ) S -L-(CH 2 ) S - wherein when s is greater than 0, the alkylene group is optionally substituted K is selected from: a direct bond, -O-(CH 2 ) s -, -C(O)-(CH 2 ) s - , -S(O n ) -(CH 2 ) S -, -N(R 18 )-(CH 2 ) S -, -OC(O)-(CH 2 ) s -, -C(O)O-(CH 2 ) s -, -OS(O n )-(CH 2 ) s -, or -S(O n )-O-(CH 2 ) s -;
  • L is selected from optionally substituted aryl or optionally substituted heterocyclyl; M is -(CH 2 )o- 2 -O-; n is an integer between 0 and 2; p is an integer between 0 and 4; q is an integer between 0 and 4; r is an integer between 0 and 4; s is an integer between 0 and 4; and t is an integer between 0 and 4; with the proviso that
  • a pharmaceutical formulation comprising a compound of Formula (I) or Formula (la), or salt, pro-drug or solvate thereof, and a pharmaceutically acceptable diluent or carrier.
  • a medicament for administration to a patient for therapeutically treating and/or preventing a sex hormone related condition in the patient, preferably a sex hormone related condition selected from prostate cancer and pre- menopausal breast cancer.
  • a method of antagonising gonadotropin releasing hormone activity in a patient comprising administering a compound of Formula (I) or Formula (la), or salt, pro-drug or solvate thereof, to a patient.
  • pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutic ally-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention.
  • the invention comprises compounds of the invention, and salts, pro-drugs or solvates thereof, in a further embodiment of the invention, the invention comprises compounds of the invention and salts thereof.
  • alkyl, alkylene, alkenyl or alkynyl moiety may be linear or branched.
  • alkylene refers to the group -CH2-.
  • C 8 alkylene for example is -(CH 2 )s--
  • C 0 alkyl within the group Cn-salkyl is a direct bond.
  • propylene' refers to trimethylene and the branched alkyl chains -CH(CH 3 )CH 2 - and -CH 2 -CH(CH 3 )-.
  • the straight chain propylene di-radical is preferred, i.e. -CH 2 CH 2 CH 2 -.
  • Specific propylene radicals refer to the particular structure, thus the term, propyl-2-ene refers to the group -CH 2 -CH(CH 3 )-. Similar notation is used for other divalent alkyl chains such as butylene.
  • aryl refers to phenyl or naphthyl.
  • carbamoyl refers to the group -C(O)NH 2 .
  • halo refers to fluoro, chloro, bromo or iodo.
  • heterocyclyl or “heterocyclic ring” refers to a 4-12 membered, preferably 5-10 membered aromatic mono or bicyclic ring or a 4-12 membered, preferably 5-10 membered saturated or partially saturated mono or bicyclic ring, said aromatic, saturated or partially unsaturated rings containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring.
  • 5- or 6-membered aromatic heterocyclic rings examples include pyrrolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl.
  • a 9 or 10 membered bicyclic aromatic heterocyclic ring is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring.
  • Examples of 5/6 and 6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl, benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl and naphthyridinyl.
  • saturated or partially saturated heterocyclic rings include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, benzodioxyl and dihydropyrimidinyl.
  • This definition further comprises sulphur-containing rings wherein the sulphur atom has been oxidised to an S(O) or S(O2) group.
  • aromatic ring refers to a 5-10 membered aromatic mono or bicyclic ring optionally containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur.
  • aromatic rings include: phenyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl.
  • Preferred aromatic rings include phenyl, thienyl and pyridyl.
  • the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms', then the groups shown cyclises to form a ring, i.e
  • C ⁇ . 3 perfluoroalkyl refers to a C ⁇ _ 3 alkyl chain in which all hydrogens have been replaced with a fluorine atom.
  • Examples of C ⁇ . 3 perfluoroalkyl include trifluoromethyl, pentafluoroethyl and l-trifluoromethyl-l,2,2,2-tetrafluoroethyl-.
  • Preferably C ⁇ - 3 perfluoroalkyl is trifluromethyl.
  • Examples of C ⁇ . 8 alkyl include: methyl, ethyl, propyl, isopropyl, butyl, wo-butyl, tert-butyl and 2-methyl-pentyl;
  • example of Ci-salkylene include: methylene, ethylene and 2-methyl-propylene;
  • examples of Ci- ⁇ alkenyl include allyl (2-propenyl) and 2 — butenyl, examples of Ci- ⁇ alkynyl 2-propynyl and 3-butynyl,
  • examples of haloCi- ⁇ alkyl include fluoroethyl, chloropropyl and bromobutyl,
  • examples of hydroxyCi- ⁇ alkyl include hydroxymethyl, hydroxyethyl and hydroxybutyl,
  • examples of Ci-salkoxy include methoxy, ethoxy and butyloxy; examples of C ⁇ .
  • alkoxyC ⁇ . 4 alkyl include methoxyethyl, propoxybutyl and propoxymethyl, examples of C ⁇ . 6 alkanoyl incude formyl, ethanoyl, propanoyl or pentanoyl, examples of N-C ⁇ . 4 alkylamino include N-methylamino and N-ethylamino; examples of N,N-di-C ⁇ - 4 alkylamino include N,N-dimethylaminoethyl,
  • examples of HO-C 2 - 4 alkyl-NH include hydroxymethylamino hydroxyethylamino and hydroxypropyamino
  • examples of HO-C 2 - 4 alkyl-N(C ⁇ . 4 alkyl) include N-methyl-hydroxymethylamino
  • N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropyamino examples of methylthio, methylsulphinyl, ethylsulphinyl, ethylsulphonyl and propylsulphonyl, include examples of arylCi- ⁇ alkyl include benzyl, phenethyl and phenylbutyl, examples of heterocyclylCi-galkyl include pyrrolidin-1-yl ethyl, imidazolylethyl, pyridylmethyl and pyrimidinylethyl.
  • the invention includes in its definition any such optically active or racemic form which possesses the property of antagonizing gonadotropin releasing hormone (GnRH) activity.
  • GnRH gonadotropin releasing hormone
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, activity of these compounds may be evaluated using the standard laboratory techniques referred to hereinafter.
  • the invention also relates to any and all tautomeric forms of the compounds of the different features of the invention that possess the property of antagonizing gonadotropin releasing hormone (GnRH) activity.
  • GnRH gonadotropin releasing hormone
  • R 1 is selected from hydrogen or optionally substituted Ci- ⁇ alkyl. More preferably R 1 represents hydrogen or unsubstituted C; ⁇ _ 6 alkyl. Yet more preferably R 1 represents hydrogen, methyl, ethyl or tert-butyl. Most preferably R 1 represents hydrogen.
  • optional substituents on R 1 are independently selected from: optionally substituted C ⁇ . 6 alkyl, optionally substituted C 2 .
  • optional substituents on R 2 are independently selected from: optionally substituted C ⁇ alkyl, optionally substituted C 2 - 6 alkenyl, cyano, nitro, C ⁇ . 3 perfluoroalkyl, C ⁇ .. 3 perfluoroalkoxy, optionally substituted aryl, optionally substituted arylC ⁇ .
  • the optional substituents on R are independently selected from cyano, R e R f N-, optionally substituted C ⁇ . . 6 alkyl (preferably, C ⁇ .
  • alkyl eg, methyl or ethyl
  • C ⁇ _ 4 alkoxy eg, methoxy, ethoxy or tert-butoxy
  • halo eg, F, Br or Cl
  • R e and R f are independently selected from hydrogen, - ⁇ alkyl or aryl.
  • optional substituents on R 2 are independently selected from methyl, ethyl, methoxy, ethoxy, tert-butoxy, F or Cl.
  • R 2 bears 1, 2 or 3 substituents.
  • R 2 represents
  • R 3 is selected from a group of Formula (Ha) Formula (lib), Formula (He) or Formula (Hd). Further preferably R 3 is selected from Formula (Ha) or Formula (lib). Most preferably R 3 is a group of Formula (lib).
  • R 3 is a group of Formula (lib).
  • Formula (HI) is selected from a group of Formula Ill-a; Ill-b; III-c; Ill-d; Ill-e; Ill-f, Ill- , Ill-h, Hl-i, or III-j, III-k or III-l;
  • Ml-k lll-l wherein: het represents an optionally substituted 3- to 8- membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S; R 23 and R 23a are independently selected from: (i) hydrogen or optionally substituted C ⁇ _ 8 alkyl; or
  • R 23 and R 23a together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring;
  • R 24 and R 25 are selected from:
  • R selected from hydrogen; optionally substituted C h alky!; optionally substituted aryl; -R d -Ar, where R d represents Ci-salkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; and R 25 is selected from hydrogen; optionally substituted C h alky! and optionally substituted aryl; (ii) wherein the group of Formula (HI) represents a group of Formula IH-a , Ill-b or
  • the group NR 24 (-R 25 ) represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or
  • group of Formula (IH) represents structure Ill-e, represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S; More preferably the group of Formula (HI) is selected from a group of Formula Ill-a , Ill-g, Ill-h, Ill-i, III-j, Ill-k or III-l:
  • R2 ⁇ a lll-j lll-k lll-l wherein R 23 , R 23a , R 24 and R 25 are as defined above.
  • group of Formula (HI) is selected from one of the following groups:
  • R 23 , R 23a , R 24 and R 25 are as defined above.
  • the group of Formula (HI) is selected from one of the following groups:
  • R 6 and R 6a are independently selected from hydrogen, fluoro, optionally substituted C ⁇ . 6 alkyl or R 6 and R 6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms More preferably R 6 and R 6a are independently selected from hydrogen, unsubstituted Ci- ⁇ alkyl or R 6 and R 6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms. Yet more preferably R 6 and R 6a are independently selected from hydrogen, methyl or R 6 and R 6a taken together and the carbon atom to which they are attached form cyclopropyl. Most preferably R 6 is hydrogen and R 6a is methyl.
  • R 7 is selected from: hydrogen or C ⁇ alkyl. More preferably R 7 is hydrogen or methyl. Most preferably R 7 is hydrogen.
  • R is heterocyclyl then R is preferably selected from one of the following groups:
  • Z is selected from: O, S or N(R 9 ), T R>20 . is selected form any group within the definitions of R 12 and R 13 , and R ,9, r 13 R.” and R .1 1 4" are as defined above
  • R is preferably selected from one of the following groups:
  • Z is selected from: O, S or N(R ) and R , R and R are as defined above.
  • R 8 is aryl or aryl-(C)-aryl optionally substituted by R 12 , R 13 and R 14 , R 8 is preferably selected one of the following groups:
  • D is selected from group E, group F or a direct bond
  • R 8 is selected from
  • R b and R c are independently selected from hydrogen and Ci- ⁇ alkyl, and n is 0, 1 or 2;
  • R is selected from (i) hydrogen, Ci. 6 alkyl, C 2 . 6 alkenyl, haloC ⁇ . 6 alkyl, hydroxy, cyano, C ⁇ . 6 alkylS(O n )-, -0-R b , C 1 . 4 alkoxyC 1 .
  • R b and R c are independently selected from hydrogen and - ⁇ alkyl, and n is 0, l or 2; preferably selected from: hydrogen, methyl, isopropyl, t-butyl, 1-methylethyl, allyl, fluoroethyl, hydroxy, cyano, ethylsulphonyl, methoxy, l-methyl-2-methoxyethyl, acetyl, t-butoxycarbonyl, acetylamino, dimethylamino, diethylamino, (l-methylethyl)amino, isopropylamino or aminosulphonyl; (ii) -(Q)-aryl
  • phenyl optionally substituted by up to 3 groups selected from R , R and R or naphthyl;
  • R 8 is 1,3 benzodioxolyl.
  • R 8 is selected from piperidinyl or piperazinyl, azetidinyl, imidazolyl and thiazolyl, each of which is optionally substituted by up to 3 groups selected from R 12 , R 13 and R 14 .
  • R is selected from hydrogen, cyano, C ⁇ _ 4 alkyl (more preferably methyl), C 2 . 6 alkynyl (more prefeably 2-propynyl), hydroxyCi. 6 alkyl (more preferably hydroxyethyl), C ⁇ _ 4 alkoxyC 1 . 4 alkyl (more preferably methoxyethyl), haloCi- ⁇ alkyl (more preferably fluoroethyl), C 1 . 4 alkanoyl (more preferably formyl), (more preferably N,N-dimethylaminoethyl and N,N-dimethylaminopropyl), C ⁇ .
  • R 9 and R 10 are preferably independently selected from hydrogen, optionally substituted -galkyl, optionally substituted aryl, optionally substituted arylCi_ 6 alkyl or R 9 and R 10 forms C 3 . 7 cycloalkyl or heterocyclyl. Further preferably hydrogen or ⁇ alkyl. Most preferably hydrogen or methyl. Most preferably both R 9 and R 10 are methyl.
  • R 9 and/or R 10 are preferably independently selected from hydrogen, optionally substituted Ci_ 6 alkyl, optionally substituted aryl, optionally substituted arylC ⁇ alkyl or R 9 and R 10 forms C 3 . cycloalkyl or heterocyclyl.
  • R 9 is preferably heterocyclyl. Most preferably pyrrolidinyl, 7-azabicyclo[2.2.1]hept-7-yl or. 3-azabicyclo[3.2.2]nonyl.
  • R is hydrogen, hydroxy, cyano or is absent. Most preferably R is absent.
  • R 18 is selected from hydrogen, R 9 N(R 10 )C(O)-, R 9 C(O)-, R 9 OC(O)- or R 18a -C(R 9 R 10 )- wherein R 18a is R 9 N(R 10 )C(O)-. Further preferably R 9 C(O)-. Most preferably R 9 C(O)- wherein R 9 is heterocyclyl.
  • A is selected from a direct bond, optionally substituted .salkylene, carbonyl or -C(O)-C(R d R d )-, wherein R d is independently selected from a direct bond hydrogen and C ⁇ _ 2 alkyl.
  • R d is independently selected from a direct bond hydrogen and C ⁇ _ 2 alkyl.
  • A is selected from .salkylene optionally substituted with ⁇ alkyl, carbonyl or carbonylmethyl.
  • A is a direct bond methylene. Most preferably methylene.
  • B is selected from optionally substituted C ⁇ _ 6 alkylene, optionally substituted C 3 . 6 alkenylene, -(C 1 .5alkyl) aa -O-(C ⁇ . 5 alkyl)bb, -(C ⁇ -5alkyl)aa-C(O)-(C 1 .5alkyl)bb-,
  • C 4 . heterocyclic ring wherein aa and bb are independently 0 to 1 and, wherein the combined length of (Ci-5alkyl) aa and ( .salky bb is less than or equal to Csalkyl.
  • B is C ⁇ _ 6 alkylene, C 3 . 6 alkenylene ,-(C 1 .5alkyl) aa -O-(C ⁇ -5alkyl)bb-,
  • heterocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl, l,5-dioxa-9- azaspiro[5.5]undecanyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from, cyano, hydroxy, ox
  • the optional substituents are selected from: cyano, hydroxy, oxo, Csalkyl, C ⁇ _ 4 alkoxy and ⁇ alkanoyl, aa and bb are independently 0 or 1, wherein the combined length of (Cj..5alkyl) aa and (C ⁇ .-5alkyl)bb is less than or equal to Csalkyl and wherein C ⁇ _ 6 alkylene is optionally substituted by hydroxy.
  • B is selected from: methylene, ethylene, propylene, propyl-2-ene, butylene, pentylene, 2-propenyl, propoxy, ethoxyethyl, methylcarbonyl or methylcarbonylamino.
  • B is selected from ethylene or butylene. In another embodiment of the invention preferably B is selected from optionally
  • substituted C 1 . 6 alkylene or the group forms a C 5 . 7 heterocyclic ring.
  • G is a direct bond, -O- or -C(R 9 R 10 )-. More preferably -C(R 9 R 10 )-. Most preferably -C(CH 3 ) 2 -.
  • M is -CH 2 -O-.
  • R 3 is selected from a group of Formula (He) or Formula (Hd) then the group
  • the group forms an optionally substituted saturated C 4 . 7 heteocyclic ring.
  • C 4 . 7 heteocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazoUdinyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from oxo.
  • C 4 . 7 heteocyclic ring selected from: pyrrolidinyl, piperidinyl or piperazinyl, wherein the optional substituents are selected from oxo.
  • K is selected from: -(CH 2 ) S -, -(CH 2 ) s -O-(CH 2 ) s -, -(CH 2 ) s -C(O)-(CH 2 ) s -,
  • K is selected from: -(CH 2 ) S -, -(CH 2 ) s -O-(CH 2 ) s -, -(CH 2 ) s -C(O)-,
  • R 18 is selected from hydrogen or Csalkyl (preferably hydrogen or methyl) and the -(CH 2 ) S - group is optionally substituted by hydroxy or C ⁇ . 4 alkyl.
  • K is selected from: methylene, ethylene, propylene, butylene, oxy,
  • N-methyl-methylcarbonylamino aminocarbonyl, methylaminocarbonyl, methylaminocarbonylmethyl, propylsulphonylamino or methylaminosulphonyl.
  • K is selected from: methylene, ethylene, propylene, butylene carbonyl, methylcarbonyl or N-methylmethylcarbonylamino. Most preferably K is selected from: methylcarbonyl and
  • optional substituents on heterocyclyl groups in R , R , R , R and R or on heterocyclyl groups formed when R 17 and R 18 together form a heterocyclic ring are selected from: optionally substituted C ⁇ _ 6 alkyl, Ci. 6 alkoxy, Ci_ 6 alkanoyl, optionally substituted C 2 . 6 alkenyl, cyano, nitro, Cj . - 3 perfluoroalkoxy, optionally substituted aryl, optionally substituted aryld.
  • R More preferably optional substituents on R are selected from: cyano, hydroxy, oxo, nitro, halo, trifluromethyl, C ⁇ _ 4 alkyl, Cj.. 4 alkoxy, ⁇ alkanoyl, R 9 OC(O)(CH 2 ) w -,
  • R 8 is selected from: cyano, hydroxy, oxo, amino, N ⁇ -diC ⁇ alkyamino, N,N-diC 1 . 4 alkyaminoC 1 . 4 alkyl, N'-C 1 . alkylureido,
  • substituents on R 8 are selected from: cyano, oxo, methyl, t-butyl, methoxy, acetyl, amino, N,N-dimethylamino, N'-isopropylureido, N'-cyclohexylureido, N-methylsulphonylamino, N,N-dimethylsulphonylamino, nitro, chloro, fluoro, trifluoromethyl, isopropoxycarbonylamino and cyclopentylcarbonylamino.
  • substituents on R 8 are selected from: methoxy, fluoro, methylsulphonylamino and isopropoxycarbonylamino.
  • substituents on R are selected from: Ci. 4 alkoxy, fluoro, C ⁇ alkylsulphonylamino, C ⁇ . 4 alkanoylamino, C ⁇ _ 4 alkylureido and
  • R is phenyl then R is preferably
  • R 8 8 substituted and when R is a heterocyclic ring R is preferably unsubstituted.
  • the optional substituents on alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups are independently selected from C h alky!, C ⁇ _ 6 alkoxy, C 3 . 7 cycloalkyl, optionally substituted aryl, optionally substituted arylCi- ⁇ alkyl, hydroxy, oxo, cyano, C ⁇ _ 6 alkoxy, halo (preferably fluoro), R 16 S(O n )(CH 2 ) w -, R 9 OC(O)-, optionally substituted arylC ⁇ alkoxy wherein R 9 is as defined above.
  • optional substituents on optionally substituted aryl and arylC ⁇ . 6 alkyl groups are selected from: optionally substituted C ⁇ - 6 alkyl, optionally substituted C 2 - 6 alkenyl, cyano, nitro, halo (preferably fluoro), C ⁇ . 3 perfluoroalkyl, optionally substituted aryl, optionally substituted R 9 O(CH 2 ) p -, R 9 C(O)O(CH 2 ) w -,
  • R 9 OC(O)(CH 2 ) w -, R 16 S(O n )(CH 2 ) w -, R 9 R 10 NC(O)(CH 2 ) W - or halo; wherein w is an integer between 0 and 4 and n, R 9 and R 10 are as defined above.
  • each substituent can be independently selected from -salkyl (eg, C 2 . 6 alkyl, and most preferably methyl, ethyl or tert-butyl); C 3 _ 8 cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy; - ⁇ alkoxy, preferably methoxy or C 2 . 4 alkoxy; halo, preferably Cl or F; Hal 3 C-, Hal 2 CH-, HalCH 2 -, Hal 3 CO-, Hal 2 CHO or Hal
  • Hal represents halo (preferably F); R CH 2 O-, R h C(O)N(R)-, R h SO 2 N(R)- or R -R h N-, wherein R and R h independently represent hydrogen or C ⁇ _ 8 alkyl (preferably methyl or Csalkyl or C 2 . 4 alkyl), or R -R h N- represents an optionally substituted C 3 . 8 , preferably C 3 .
  • heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; hydrogen; or R k C(O)O- or R k C(O)-, R k representing hydrogen, optionally substituted phenyl or - ⁇ alkyl (preferably methyl, ethyl, is ⁇ -propyl or tert-butyl).
  • R -R h N- at least one (eg, one, two or three) substituents may be provided independently selected from C ⁇ diligent 6 alkyl (eg, C 2 .
  • alkyl more preferably methyl); phenyl; CF 3 O-; F 2 CHO-; -salkoxy, preferably methoxy, ethoxy or C 3 . 6 alkoxy; Ci- 8 alkoxyC(O), preferably methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or C 3 . 6 alkoxyC(O) ⁇ ; phenoxycarbonyl; phenoxy;
  • C ⁇ _ 8 alkanoyl preferably acetyl, ethanoyl or C 3 . 6 alkyanoyl; carboxy; C 1 - 8 alkylS(O nn ) wherein nn is an integer between 0 and 2, preferably methylthio, ethylthio, C 3 _ 6 alkylthio, methylsulphinyl, ethylsulphinyl, C 3 _ 6 alkylsulphinyl, methylsulphonyl, ethylsulphonyl or C 3 .
  • R 1 represents hydrogen or unsubstituted C ⁇ . 6 alkyl
  • R represents optionally substituted phenyl
  • R is selected from a group of Formula (Ha) to Formula (Hd):
  • R 5 is selected from a one of a group of Formula Ill-a to III-l:
  • het represents an optionally substituted 3- to 8- membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S;
  • R 2 and R 3a are independently selected from:
  • R 24 and R 25 are selected from:
  • R 24 selected from hydrogen; optionally substituted Cj . . 8 alkyl; optionally substituted aryl; -R d -Ar, where R d represents C ⁇ _ 8 alkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; and R is selected from hydrogen; optionally substituted C h alky!
  • R is selected from: hydrogen or C ⁇ _ 4 alkyl; R 8 is selected from
  • R b and R c are independently selected from hydrogen and Csalkyl, and n is 0, 1 or 2;
  • R b and R c are independently selected from hydrogen and Csalkyl, and n is 0, 1 or 2;
  • -aryl optionally substituted by up to 4 substituents selected from R 12 , R 13 and R 14 ;
  • C 4 . heterocyclyl optionally substituted by up to 4 substituents selected from R 12 , R 13 and R 14 ; or
  • R 9 and R 10 are independently selected from: hydrogen, hydroxy, optionally substituted Csalkyl, optionally substituted aryl, optionally substituted arylCi.
  • 6 alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylCi- ⁇ alkyl or R 9 and R 10 taken together can form an optionally substituted ring of 3-9 atoms or R 9 and R 10 taken together with the carbon atom to which they are attached form a carbonyl group;
  • R 12 is selected from: hydrogen, hydroxy, R 17 R 18 N(CH 2 ) CC -, R 17 R 18 NC(O)(CH ) C c-, optionally substituted C ⁇ . 6 alkyl- C(O)N(R 9 )(CH 2 ) cc -, optionally substituted
  • Ci-sperfluoroalkoxy optionally substituted C ⁇ _ 6 alkoxy, carboxy, halo, nitro or cyano
  • R 13 and R 14 are independently selected from: hydrogen, hydroxy, oxo, optionally substituted - ⁇ alkyl, optionally substituted C ⁇ . 6 alkanoyl, optionally substituted
  • R is independently selected from: hydrogen, hydroxy, cyano or optionally substituted
  • R 18 is a group of formula R 18a -C(R 9 R 10 ) 0 . 1 - wherein R 18a is selected from: R 19 OC(O)-, R 9 R 10 NC(O)-, R 9 R 10 N-, R 9 C(O)-, R 9 C(O)N(R 10 )-, R 9 R 10 NC(O)-, R 9 R 10 NC(O)N(R 10 )-,
  • R 19 is selected from: hydrogen, optionally substituted C h alky, optionally substituted aryl, optionally substituted aryl -ealkyl, optionally substituted C 3 . 7 cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl - ⁇ alkyl;
  • B is selected from optionally substituted or the group forms an optionally substituted C 4 . 7 heterocyclic ring, wherein the optional substituents are selected from R 12 , R 13 and R 14 ;
  • group preferably forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms, wherein the optional substituents are selected from R 12 ,
  • K is selected from: a direct bond, -(CH 2 ) s ⁇ -, -(CH 2 ) s2 -O-(CH 2 ) s -, -(CH 2 ) s ⁇ -C(O)-(CH 2 ) S 2-,
  • Formula (Ha) Formula (Hb) and R 1 , R 2 , R 5 , R 6 , R 6a , R 7 , R 8 , A, B and M are as defined above; or salt, solvate or pro-drug thereof.
  • a further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:
  • A is optionally substituted Ci-salkylene
  • B is selected from optionally substituted Ci_ 6 alkylene or the group forms a ring containing Cs. 7 heterocyclic ring;
  • M is -CH 2 -O-;
  • R 1 is hydrogen or C ⁇ _ 4 alkyl
  • R 6 and R 6a are independently selected from hydrogen and optionally substituted Ci_ 6 alkyl
  • R 7 is selected from: hydrogen or Csalkyl
  • R 8 is selected from hydrogen, cyano, C ⁇ . 6 alkyl, haloCi_ 6 alkyl, C 2 - 6 alkynyl, C ⁇ _ 6 alkanoyl,
  • R and R are as defined above or salt, solvate or pro-drag thereof.
  • a further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:
  • A is optionally substituted Ci-salkylene
  • B is selected from optionally substituted - ⁇ alkylene or the group forms a ring containing Cs- heterocyclic ring;
  • R 1 is hydrogen or C ⁇ . 4 alkyl, preferably hydrogen;
  • R 2 is an optionally substituted monocyclic aromatic ring structure, preferably optionally substituted phenyl, most preferably 3,5-dimethylphen-l-yl;
  • R 5 is a group of Formula ( ⁇ i) wherein the group of Formula (HI) is selected from a group of Formula Ill-a; Ill-b; III-c; Ill-d; Ill-e; III-f, Ill-g , Ill-h, III-I, III-j, lll-k and
  • R 23 , R 23a , R 24 and R 25 are as defined above, preferably the group of Formula (IH) is selected from (IH-a), (Hl-g) and (Hl-h); R 6 and R 6a , are independently selected from hydrogen and optionally substituted Ci- ⁇ alkyl; R is selected from: hydrogen or C ⁇ _ 4 alkyl;
  • R is selected from hydrogen, cyano, Ci_ 6 alkyl, halo - ⁇ alkyl, C 2 . 6 alkynyl, Ci. 6 alkoxycarbonyl, aryl, arylCi- 6 alkyl, C 3 . cycloalkyl, heterocyclyl, heterocyclyl -ealkyl, or heterocyclylcarbonylC ⁇ - 4 alkyl wherein aryl and heterocyclyl rings are optionally substituted by cyano and C 1 . alkyl; and ; are as defined above or salt, solvate or pro-drug thereof.
  • a further preferred group of compounds of the invention comprises a compound of Formula (Id):
  • R 1 , R 2 , R 5 ; R 7 , R 8 , A, B and M are as defined above or salt, solvate or pro-drag thereof.
  • a yet further preferred group of compounds of the invention comprises a compound of Formula (lb), (Ic) or (Id) wherein:
  • R 5 is a group of Formula (HI) wherein the group of Formula (HI) is a group of formula Ilia:
  • R 23 , R 3a , R 24 and R 25 are as defined above; or a salt, pro-drug or solvate thereof.
  • R is selected from a group of Formula (He) or Formula ( ⁇ d) and R 1 , R 2 and R 5 are as defined above.
  • R is selected from a group of Formula (He) or Formula (Hf) and R 1 , R 2 and R 5 are as defined above.
  • a compound of Formula (I) or Formula (la), or salt, solvate or pro-drag thereof wherein R 3 is selected from a group of Formula ( ⁇ a), Formula ( ⁇ c) or Formula Qtte) and R , R and R are as defined above.
  • a compound of Formula (I) or Formula (la), or salt, solvate or pro-drag thereof wherein R 3 is selected from a group of Formula (Hb), Formula (Hd) or Formula (Hf) and R 1 , R 2 and R 5 are as defined above.
  • Particularly preferred compounds according to the present invention are wherein the compound is selected from: -[3-(2,2-dimethyl-3-oxo-3- ⁇ azabicyclo[2.2.1]heptan-7-yl ⁇ propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5- yl)ethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3- ⁇ azabicyclo[2.2.1]heptan-7-yl ⁇ propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3- ⁇ azabicyclo[2.2.1]heptan-7-yl ⁇ propoxy)-5-(3,5- di
  • the compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I).
  • pro-drugs include in- vivo hydrolysable esters of a compound of the Formula (I).
  • pro-drags Various forms of pro-drags are known in the art.
  • pro-drag derivatives see: a) Design of Prodrags, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
  • An in- vivo hydrolysable ester of a compound of the Formula (I) containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ _ 6 alkoxymethyl esters for example methoxymethyl, -ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 . 8 cycloalkoxycarbonyloxyC ⁇ . 6 alkyl esters for example
  • An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • the compounds of Formula (I) can be prepared by a process comprising a step selected from (a) to (h) as follows, these processes are provided as a further feature of the invention:- (a) Reaction of a compound of formula XXXII with a compound of formula L 2 -R 5 ' to form a compound of Formula (I),
  • X 1 is selected from: ; L 1 is a displaceable group; and
  • H-R is selected from: ;
  • X is selected from: ; L is a displaceable group and R 7a is selected from the definition of R 7 or R 22 above, and 2 c» I ? p D 8
  • L -R is selected from: L— J-K-R 8 and L 2 — R 21
  • R ,22a is as defined above for R ,22 , with the exclusion of hydrogen and L is a displaceable group;
  • Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate; Process b) Compounds of XXXIII and L 2 -R 5 " can be coupled together in the presence of an organic base(such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature from room temperature to 120°C.
  • Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate, alternatively if ;can be reacted with a compound of formula XXXIII under Mitsunobu reaction conditions;
  • alkylation reaction conditions or (ii) acylation reaction conditions: Examples of said conditions include: (i) alkylation reaction conditions - the presence of an organic base(such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMF, DMA, DCM, at a temperature from room temperature to 120°C.
  • suitable displaceable groups include: a halide, such as chloro, methane sulphonate or toluene sulphonate;
  • acylation reaction conditions presence of organic base, such as triethylamine, temperature 0°C to 50-60°C in a suitable solvent such as DCM.
  • organic base such as triethylamine
  • suitable solvent such as DCM.
  • Suitable displaceable groups include an acylchloride or an acid anhydride,
  • This reaction can be performed in the presence of an organic base(such as DIP ⁇ A) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature from room temperature to 120°C.
  • Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate.
  • Compounds can also be prepared by reacting a compound wherein K' is -(CH 2 ) s i-N(R 9 )H with a compound of formula L 11 -(CH 2 ) s2 -R 8 , under identical conditions.
  • (viii.)E ⁇ r compounds of Formula (I) where K is - CH2) s ⁇ -0 - CH 2 ) s2 - these can be prepared by reacting a compound where K' is -(C ⁇ 2 ) s ⁇ -O ⁇ with a 8 I 1 ? compound of formula L -(CH2) S 2-R , wherein L is a displaceable group.
  • This reaction can be performed in the presence of an organic base (such as potassium t-butoxide) or an inorganic base (such as sodium hydride), in a suitable solvent such as DMA or DMF, at a temperature from room temperature and 120°C.
  • Suitable displaceable groups include: a halide, such as bromo, or a methane sulphonate or toluene sulphonate.
  • Compounds can also be prepared by reacting a compound wherein K' is -(CH 2 ) s ⁇ -L 1 with a compound of formula HO-(CH 2 ) S2 -R 8 , under identical conditions, (ix.)
  • K is -(CH2) s ⁇ C(0) - CH ) S 2-
  • K' is -(C ⁇ 2 ) s ⁇ -C(O)-L
  • a Grignard reagent of formula BrMg(CH 2 ) s2 -R 8 wherein L 13 is a displaceable group.
  • Suitable displaceable groups include: a halide, such as bromo, or a methane sulphonate or toluene sulphonate.
  • Compounds can also be prepared by reacting a compound wherein K' is -(CH 2 ) s ⁇ -MgBr with a compound of formula
  • Process h) reaction of a compound of Formula XXXVI with a compound of the formula L 8 -R **• can be performed under Friedel Craft conditions, for example in the presence of diethylaluminium chloride in a suitable solvent, such as DCM, in an inert atmosphere such as nitrogen, at a temperature between room temperature and the boiling point of the solvent or under Mannich conditions, for example, formaldehyde and a primary or secondary amine in acetic acid, in an inert atmosphere such as nitrogen at a temperature between room temperature and 100°C.It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of Formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the de- protection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the de-protection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the amine 6 can be prepared from a compound of formula 5 and phfhalimide using a Mitsunobu reaction with an activating agent such as diethyldiazocarboxylate (DEAD), diisopropyldiazocarboxylate or the like with triphenylphosphine, tri-butylphosphine and the like, in an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof, followec by deprotection with hydrazine to give the (Scheme b).
  • DEAD diethyldiazocarboxylate
  • diisopropyldiazocarboxylate or the like with triphenylphosphine, tri-butylphosphine and the like
  • an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof, followec by deprotection with hydrazine to give the (
  • a suitable pyrazole 6 can be converted to a compound of formula 10 by incorporation of a suitable protecting group (P)to form a compound of formula 7 , followed by a Mitsunobu reaction with a suitable alcohol 8 to form a compound of formula 9, followed by deprotection.
  • P protecting group
  • NMR nuclear magnetic resonance
  • mass spectral techniques proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet;
  • isoluteTM refers to silica (SiO 2 ) based columns with irregular particles with an average size of 50 ⁇ m with nominal 60 A porosity [Source: Jones Chromatography, Ltd.,
  • Example 1 as a beige solid (83 mg).
  • the starting material AR1 was prepared as follows:
  • the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 1 given above:-
  • Examples 1.3 - 1.5 were prepared by a robot. The last two steps were carried out sequentially without isolation of the intermediates AR4, AR5 or AR6.
  • Example 2 Dry, gaseous HCl was bubbled through a solution of Ab6 (180 mg ; 0.29 mmol) in CH 2 C1 2 (30 ml) until no Ab6 remained. The mixture was treated with iced sat. aq. NaHCO 3 , extracted with CH 2 CI 2 and the organic phase was washed with water, brine and dried over MgSO 4 . The residue was purified by flash chromatography eluting with increasingly polar mixtures of ammonia in MeOH(7N)/CH 2 Cl 2 (0 to 10% ammonia in MeOH) to give Example 2 (114 mg). Yield : 76%
  • the starting material Ab6 was prepared as follows:
  • Example 3 As a white solid (219 mg).
  • the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 3 given above: -
  • Example 4 A solution of partially purified* Cgl7 (4.2 g ; from 2.3 mmol of Cf) in CH 2 C1 2 (30 ml) under nitrogen was treated dropwise with n-propylamine (1.36 ml ; 23 mmol) at room temperature. The mixture was stirred at room temperature for 2h, the solvents evaporated and the residue purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc and then MeOH/CH 2 Cl 2 (0 to 15%) MeOH) to give Example 4 as a beige solid (768 mg). * Contains some Ph 3 PO
  • the table shows the R group relating to the above structure, the reaction conditions and characteristics of each example, corresponding to the description of the preparation of Example 4 given above: -
  • Example 4.34 was prepared by a different methodology (opening of epoxide by Ce) : see below.
  • Example C45 was prepared by a different methodology (reductive animation of Ce) : see below.
  • Example 4.53 was prepared by a different methodology (alkylation of Ce) : see below
  • Example 4.34 A solution of Ce (106 mg ; 0.25 mmol) in acetonitrile (3 ml) was treated with styrene oxide and the mixture was heated at 60°C overnight. The solvent was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH 2 Cl 2 hexanes (0 to 10% MeOH) to give Example 4.34 as a white foam (40 mg). Yield : 30%.
  • Example 4.44 as a white foam (88 mg).
  • This intermediate was prepared using a method analogous to the preparation of CR47.
  • This intermediate was prepared using a method analogous to the preparation of CR47.
  • This intermediate was prepared using a method analogous to the preparation of CR47.
  • Example 5 ⁇ solution of DR1 (350 mg ; 0.53 mmol) in pyrrolidine (2 ml) was heated at 45°C overnight. The pyrrolidine was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH 2 Cl 2 (0 to 7% MeOH) to give Example 5 as a colourless foam (288 mg). Yield : 97%
  • the starting material DR1 was prepared as follows :-
  • Example 5.1 was prepared in a similar manner to Example 5 and Example 5.2 was prepared in a manner similar to Example 2.

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Abstract

The invention relates to a group of novel pyrazole compounds of Formula (I): wherein: R1, R2, R3, M and R5 are as defined in the specification, which are useful as gonadotrophin releasing hormone antagonists. The invention also relates to pharmaceutical formulations of said compounds, methods of treatment using said compounds and to processes for the preparation of said compounds.

Description

CHEMICAL COMPOUNDS
The present invention relates to compounds which are antagonists of gonadotropin releasing hormone (GnRH) activity. The invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.
Gonadotropin releasing hormone (GnRH) is a decapeptide that is secreted by the hypothalamus into the hypophyseal portal circulation in response to neural and/or chemical stimuli, causing the biosynthesis and release of luteinizing hormone (LH) and follicle- stimulating hormone (FSH) by the pituitary. GnRH is also known by other names, including gonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSH RH) and LH/FSH releasing factor (LH/FSH RF).
GnRH plays an important role in regulating the action of LH and FSH (by regulation of their levels), and thus has a role in regulating the levels of gonadal steroids in both sexes, including the sex hormones progesterone, oestrogens and androgens. More discussion of GnRH can be found in WO 98/5519 and WO 97/14697, the disclosures of which are incorporated herein by reference.
It is believed that several diseases would benefit from the regulation of GnRH activity, in particular by antagonising such activity. These include sex hormone related conditions such as sex hormone dependent cancer, benign prostatic hypertrophy and myoma of the uterus. Examples of sex hormone dependent cancers are prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.
The following disclose compounds purported to act as GnRH antagonists: WO 97/21435, WO 97/21703, WO 97/21704, WO 97/21707, WO 55116, WO 98/55119, WO 98/55123, WO 98/55470, WO 98/55479, WO 99/21553, WO 99/21557, WO 99/41251, WO 99/41252, WO 00/04013, WO 00/69433, WO 99/51231, WO 99/51232, WO 99/51233, WO 99/51234, WO 99/51595, WO 99/51596, WO 00/53178, WO 00/53180, WO 00/53179, WO 00/53181, WO 00/53185, WO 00/53602, WO 02/066477, WO 02/066478, WO 02/06645 and WO 02/092565. It would be desirable to provide further compounds, such compounds being
GnRH antagonists. Thus, according to the first aspect of the invention there is provided a compound of Formula (I),
Figure imgf000003_0001
wherein:
R1 is selected from: hydrogen, optionally-substituted -βalkyl, optionally substituted aryl or optionally-substituted arylCι.6alkyl; R2 is an optionally-substituted mono or bi-cyclic aromatic ring; R3 is selected from a group of Formula (Ila) to Formula (Ef):
Figure imgf000003_0002
Formula (Ila) Formula (lib)
Figure imgf000003_0003
•ηfa,
Formula (lie) Formula (Lid)
Figure imgf000003_0004
Formula (He) Formula (Ef) R5 is a group of Formula (HI):
Figure imgf000004_0001
Formula (HI) R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted Cj.-6alkyl, optionally-substituted aryl or optionally substituted arylCi-βalkyl, or R6 and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R and R6a taken together and the carbon atom to which they are attached form a carbonyl group;
or when A is not a direct bond the group
Figure imgf000004_0002
forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
or the group
Figure imgf000004_0003
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; R7 is selected from: hydrogen, optionally-substituted Cj..6alkyl, optionally-substituted arylC1.6alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylCι.6alkyl, R'O -ealkyl-, R9R10NCi.6alkyl-,
R9R10NC(O)Cι.6alkyl, -C(NR9R10)=NH; or when R is a group of Formula (He) or (Lid) R is of the formula -J-K-R ; R is selected from:
(i) hydrogen, Chalky!, C2_6alkenyl, C2.6alkynyl,
Figure imgf000004_0004
hydroxy, hydroxyCι.6alkyl, cyano, N-C^alkylamino, N,N-di-C1. alkylamino,
C1.6alkyl-S(O„)-, -O-Rb, -NRbRc, -C(O)-Rb, -C(O)O-Rb, -CONRbRc, NH-C(O)-Rb or -S(On)NRbRc, where Rb and Rc are independently selected from hydrogen and Cj..4alkyl optionally substituted with hydroxy, amino, N-C^alkylamino, N,N-di-d.4alkylamino, HO-C2.4alkyl-NH- or HO-C2.4alkyl-N(Cι.4alkyl)-;
(ii) nitro when B is a group of Formula (IV) and X is CH and p is 0; (iii) C3.7cycloalkyl, aryl or arylCι_6alkyl each of which is optionally substituted by R12,
R13 and R14; (iv) -(Q)-aryl , -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of which is optionally substituted by R12, R13 and R14 wherein -(Q)- is selected from E, F or a direct bond;
(v) heterocyclyl or heterocyclylCi-βalkyl each of which is optionally substituted by up to 4 substituents independently selected from R , R and R ; (vi) a group selected from R12, R13 and R14; R and R ° are independently selected from: hydrogen, hydroxy, optionally substituted Cι.6alkyl, optionally substituted aryl, optionally substituted arylC1„6alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclyl -ealkyl or R9 and R10 taken together can form an optionally substituted ring of 3-9 atoms or R9 and R10 taken together with the carbon atom to which they are attached form a carbonyl group; R11 is selected from: hydrogen, optionally substituted Ci^alkyl, or N(R9R10);
R12 is selected from: hydrogen, hydroxy, R17R18N(CH2)CC-, R17R18NC(O)(CH2)cc-, optionally substituted C βalkyl- C(O)N(R9)(CH2)cc-, optionally substituted C1.6alkyl-SO2N(R9)-, optionally substituted aryl-SO2N(R9)-,
C1.3ρerfluoroalkyl-SO2N(R9)-; optionally substituted C1.6alkyl-N(R9)SO2-, optionally substituted aryl-N(R9)SO2-, C1.3ρerfluoroalkyl-N(R9)SO2- optionally substituted
C1.6alkanoyl-N(R9)SO2-; optionally substituted aryl-C(O)N(R9)SO2-, optionally substituted -galkyl-S On) -, optionally substituted aryl-S(On) - , Cj.-3perfluoroalkyl-, Ci-sperfluoroalkoxy, optionally substituted C^alkoxy, carboxy, halo, nitro or cyano; R13 and R14 are independently selected from: hydrogen, hydroxy, oxo, optionally substituted Cι_6alkyl, optionally substituted C^alkanoyl, optionally substituted
C2.6alkenyl, cyano, nitro, Ci-3perfluoroalkyl-,
Figure imgf000005_0001
optionally substituted aryl, optionally substituted arylCwal l, R9O(CH2)s-, R9(O)O(CH2)s-, R9OC(O)(CH2)s-, R16S(On)(CH2)s-, R9R10NC(O)(CH2)S- or halo; R15 is selected from: hydrogen, optionally substituted Cj..6alkyl, R19OC(O)-, R9R10NC(O)-, R9C(O)-, R9S(O„)-;
R16 is selected from: hydrogen, C1.6alkyl, Cj..3perfluoroalkyl or optionally-substituted aryl; R17 is independently selected from: hydrogen, hydroxy, cyano or optionally substituted -βalkyl; R18 is a group of formula R18a-C(R9R10)0-i- wherein R18a is selected from: R1 OC(O)-,
R9R10NC(O)-, R9R10N-, R9C(O)-, R9C(O)N(R10)-, R9R10NC(O)-, R9R10NC(O)N(R10)-, R9SO2N(R10)-, R9R10NSO2N(R10)-, R9C(O)O-, R9OC(O)-, R R10NC(O)O-, R9O-, R9S(On)-, R9R10NS(On) -, hydrogen, optionally substituted Cι_6alkyl, optionally substituted heterocyclyl; or R17 and R18 when taken together form an optionally substituted carbocyclic ring of 3-7 atoms or optionally substituted heterocyclyl; R19 is selected from: hydrogen, optionally substituted Chalky, optionally substituted aryl, optionally substituted arylCi.6alkyl, optionally substituted C3. cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylCι_6alkyl;
R21 and R22 are independently selected from hydrogen, optionally substituted
Figure imgf000006_0001
optionally substituted C3. cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCι_6alkyl, optionally substituted C3.6alkenyl, optionally substituted C3.6alkynyl, -(C1.5alkyl)aa-S(On)-(C1.5alkyl)bb-; R9R10NC2.6alkyl, R9OC2-6alkyl or R9R10NC(O)C2.6alkyl, with the proviso that R9 and R10 independently or taken together are not optionally substituted aryl or optionally substituted arylCi-όalkyl; or R21 and R22 taken together form an optionally substituted non-aromatic heterocyclic ring; A is selected from: (i) a direct bond;
(ii) optionally-substituted C^salkylene wherein the optional substituents are independently selected from: optionally-substituted Chalky! optionally-substituted aryl or optionally substituted arylCi-βalkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group or -C(O)-C(RdRd)-, wherein R is independently selected from hydrogen and
or when R is a group o
Figure imgf000006_0002
f Formula (Ha) or (H ), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; R7
or when R3 is a group of Formula (Ha), (lib), (Lie) or (Ltd), the group forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; B is selected from:
(i) a direct bond;
(ii) a group of Formula (IV)
Figure imgf000007_0001
Formula (IV) wherein: X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the
(CH2)P group is attached to R8; and (iii) a group independently selected from: optionally substituted -ealkylene, optionally substitute C3.7cycloalkyl, optionally substituted C3.6alkenylene, optionally substituted C3.6alkynyl, Cι_6alkoxy, (Cι.5alkyl)aa-S(On)-(Cι.5alkyl)bb-, -(C1.5alkyl)aa-O-(C1.5alkyl)bb-, -(C1.5alkyl)aa-C(O)-(C1.5alkyl)bb- or
(C1.5alkyl)aa-N(R15)- (C1_5alkyl)bb, wherein R15 and the (Cι.5alkyl)aa or (C salkyl b chain can be joined to form a ring, wherein the combined length of ( .salkyl a and
Figure imgf000007_0002
is less than or equal to Cjalkyl; or the group -B-R8 represents a group of Formula (V)
Figure imgf000007_0003
Formula (V); R7
or the group together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms; or the group
Figure imgf000008_0001
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; E is -O-, -S(On), -C(O)-, -NR15- or -C(R9R10)q; F is -E(CH2)r-; G is selected from: hydrogen, halo, N, O, S(On), C(O), C(R R10)t, optionally substituted
C2.6alkenylene, optionally substituted C .6alkynylene or a direct bond to R18, J is a group of the formula: -(CH2)S-L-(CH2)S- wherein when s is greater than 0, the alkylene group is optionally substituted,
or the group
Figure imgf000008_0002
together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms;
K is selected from: a direct bond, -(CH2)sι-, -(CH2)sι-O-(CH2)s2-, -(CH2)sι-C(O)-(CH2)s2- -(CH2)sl-S(On)-(CH2)s2-, -(CH2)sl-N(R18)-(CH2)s2-, -(CH2)sι-C(O)N(R9)-(CH2)s2-, -(CH2)sl-N(R9)C(O)-(CH2)s2-, -(CH2)sl-N(R9)C(O)N(R9)-(CH2)s2-, -(CH2)sl-OC(O)-(CH2)s2-, -(CH2)sl-C(O)O-(CH2)s2-, -(CH2)sl-N(R )C(O)O-(CH2)s2-, -(CH2)sl-OC(O)N(R9)-(CH2)s2-, -(CH2)sl-OS(O„)-(CH2)s2-, or
-(CH2)sl-S(On)-O-(CH2)s2-, -(CH2)sι-S(O)2N(R9)-(CH2)s2-or -(CH2)sl-N(R9)S(O)2-(CH2)s2-; wherein the -(CH2)sι- and -(CH2)s2- groups are independently optionally substituted by hydroxy or
Figure imgf000008_0003
L is selected from optionally substituted aryl or optionally substituted heterocyclyl; M is selected from -(CH2)0-2-O- or -C(O)NH-; n is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 4; r is an integer from 0 to 4; s is an integer from 0 to 4; si and s2 are independently selected from an integer from 0 to 4, and sl+s2 is less than or equal to 4; t is an integer between 0 and 4; and aa and bb are independently 0 or 1; cc is an integer between 0 to 2; with the proviso that
17 18
(i) when G is hydrogen or halo, then R and R are both absent; (ii) when G is O, S(On), C(O) or C(RuR12)t then G is substituted by a single group independently selected from the definition of R17 or R18 and when G is a direct bond to R18 then G is substituted by a single group selected from R18; (iii) when R3 is a group of Formula (lib), B is a group of Formula (IV), R8 is selected from group (i) or (ii) above, R11 is a group of the formula N(R10R11) and R1, R2 and R5 are as defined above then R4 cannot be hydrogen; (iv) R3 cannot be unsubstituted pyridyl or unsubstituted pyrimidinyl; and
(v) when R3 is pyrazolyl substituted by phenyl or pyrazolyl substituted by phenyl and acetyl, R5-M is hydroxyl or acetyloxy, R2 is unsubstituted phenyl, then R1 cannot be hydrogen or acetyl; or a salt, solvate or pro-drug thereof. According to the further feature of the first aspect of the invention there is provided a compound of Formula (I)with the proviso that
(i) when G is hydrogen or halo, then R17 and R18 are both absent;
(ii) when G is O, S(On), C(O) or C(RnR12)t then G is substituted by a single group
17 IS independently selected from the definition of R or R and when G is a direct bond to R then G is substituted by a single group selected from R ;
(iii) when R3 is a group of Formula (lib), B is a group of Formula (IV), R8 is selected
11 in 11 ' from group (i) or (ii) above, R is a group of the formula N(R R ) and R , R and R5 are as defined above then R cannot be hydrogen; and (iv) R3 cannot be an unsubstituted or substituted aromatic heterocyclic ring, wherein the aromatic heterocyclic ring is attached directed to the pyrazole in Formula (I); or a salt, solvate or pro-drug thereof.
According to the further feature of the first aspect of the invention there is provided a compound of Formula (la),
Figure imgf000009_0001
wherein
R >1 ; is selected from: hydrogen, optionally-substituted Chalky!, optionally substituted aryl or optionally-substituted
Figure imgf000010_0001
R • 2 i •s an optionally-substituted mono or bi-cyclic aromatic ring;
R ,3 ; is selected from a group of Formula (Ila) to Formula (Hf):
Figure imgf000010_0002
Formula (Ha) Formula (lib)
Figure imgf000010_0003
Formula (lie) Formula (Lid)
Figure imgf000010_0004
Formula (lie) Formula (Ilf) Rs is a group of Formula (III):
17
R" \
,18/ *-
R"
Formula (HI) R6 and R6a are independently selected from hydrogen, optionally substituted
Figure imgf000010_0005
optionally-substituted aryl or optionally substituted arylCι_6alkyl, or R6 and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R6 and R a taken together and the carbon atom to which they are attached form a carbonyl group; or when A is not a direct bond the group
Figure imgf000011_0001
forms a carbocyclic ring of 3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
or the group
Figure imgf000011_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; R7 is selected from: hydrogen, optionally-substituted
Figure imgf000011_0003
optionally-substituted arylCj.„6alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylCwalkyl, R9OCi.6alkyl-, R9R10NCi.6alkyl-, R9R10NC(O)Cι_6alkyl, -C(NR9R10)=NH;
•a 7 8 or when R is a group of Formula (lie) or (Ed) R is of the formula -J-K-R ; o R is selected from:
(i) hydrogen, Ci-βalkyl, C2.6alkenyl, C .6alkynyl,
Figure imgf000011_0004
hydroxy, hydroxyCi-βalkyl, cyano, N-Cι.4alkylamino, N,N-di-Cj..4alkylamino, C1.6alkyl-S(On)-, -O-Rb, -NR Rc, -C(O)-Rb, -C(O)O-Rb, -CONRbRc or NH-C(O)-Rb, where Rb and Rc are independently selected from hydrogen and Cι.4alkyl optionally substituted with hydroxy, amino, N-Cι.4alkylamino, N,N-di-Ci.4alkylamino, HO-C2.4alkyl-NH- or HO-C2.4alkyl-N(Cι.4alkyl)-; (ii) nitro when B is a group of Formula (TV) and X is CH and p is 0; (iii) C3.7cycloalkyl, aryl or arylCj.-6alkyl each of which is optionally substituted by R , R13 and R14;
(iv) -(Q)-aryl , -(Q)-heterocyclyl, -aryl~(Q)-aryl, each of which is optionally substituted by R12, R13 and R14 wherein -(Q)- is selected from E, F or a direct bond; (v) heterocyclyl or heterocyclylC1.6alkyl each of which is optionally substituted by R12, R13 and R14;
(vi) a group selected from R12, R13 and R14;
R9 and R10 are independently selected from: hydrogen, hydroxy, optionally substituted Ci_6alkyl, optionally substituted aryl, optionally substituted arylCi-όalkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylCj._6alkyl or R9 and R10 taken together can form an optionally substituted ring of 3-9 atoms or R9 and R10 taken together with the carbon atom to which they are attached form a carbonyl group; R11 is selected from: hydrogen, optionally substituted
Figure imgf000012_0001
or N(R9R10); R12 is selected from: hydrogen, hydroxy, R17R18N-, optionally substituted Ci-6alkyl-SO2N(R9)-, optionally substituted aryl-SO2N(R9)-,
C1.3perfluoroalkyl-SO2N(R9)-; optionally substituted Ci_6alkyl-N(R )S02-, optionally substituted aryl-N(R9)SO2-, C1_3perfluoroalkyl-N(R9)SO2- optionally substituted C1.6alkanoyl-N(R9)SO2-; optionally substituted aryl-C(O)N(R9)SO2-, optionally substituted C1.6alkyl-S(On) -, optionally substituted aryl-S(On) - , Cj..3perfluoroalkyl-,
Figure imgf000012_0002
carboxy, halo, nitro or cyano; R13 and R14 are independently selected from: hydrogen, optionally substituted Cι_6alkyl, optionally substituted C2_6alkenyl, cyano, nitro, Cι_3perfluoroalkyl-, Cj.-3perfluoroalkoxy, optionally substituted aryl, optionally substituted arylCι.6alkyl,
R9O(CH2)s-, R9(O)O(CH2)s-, R9OC(O)(CH2)s-, R16S(On)(CH2)s-, R9R10NC(O)(CH2)S- or halo; R is selected from: hydrogen, optionally substituted Cj._6alkyl, R OC(O)-, R9R10NC(O)-, R9C(O)-, R9S(On)-; R16 is selected from: hydrogen, C δalkyl, Ci-sperfluoroalkyl or optionally-substituted aryl;
17
R is independently selected from: hydrogen, hydroxy, cyano or optionally substituted
Ci-δalkyl; R18 is a group of formula R18a-C(R9R10)o - wherein R18a is selected from: R19OC(O)-,
R9R10NC(O)-, R9R10N-, R9C(O)-, R9C(O)N(R10)-, R9R10NC(O)-, R9R10NC(O)N(R10)-, R9SO2N(R10)-, R9R10NSO2N(R10)-, R9C(O)O-, R9OC(O)-, R9R10NC(O)O-, R9O-,
R9S(On)-, R9R10NS(On) -, optionally substituted Cι.6alkyl, optionally substituted heterocyclyl;
17 18 or R and R when taken together form an optionally substituted carbocyclic ring of 3-7 atoms or optionally substituted heterocyclyl; R19 is selected from: hydrogen, optionally substituted Chalky, optionally substituted aryl, optionally substituted
Figure imgf000012_0003
optionally substituted C3. cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylC1.6alkyl;
R20 is selected from R12 or R13; R21 and R22 are independently selected from hydrogen, optionally substituted Ci-βalkyl, optionally substituted C3. cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCj.-6alkyl, optionally substituted C3.6alkenyl, optionally substituted C3.6alkynyl, -(C1.5alkyl)aa-S(On)-(C1.5alkyl)bb-; R9R10NC2.6alkyl, R9OC2-6alkyl or R9R10NC(O)C2-6alkyl, with the proviso that R9 and R10 independently or taken together are not optionally substituted aryl or optionally substituted
Figure imgf000013_0001
R and R taken together form an optionally substituted non-aromatic heterocyclic ring; A is selected from: (i) a direct bond;
(ii) optionally-substituted C^alkylene wherein the optional substituents are independently selected from: optionally-substituted Ci-βalkyl optionally-substituted aryl, optionally substituted arylCj..6alkyl or substituted arylCj.-6alkyl; (iii) a carbocyclic ring of 3-7 atoms; (iv) a carbonyl group;
or when R is a group of Formula (Ha) or (lib), the group
Figure imgf000013_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
or when R is a group of Formula (πa), (lib), (He) or (Hd), the group
Figure imgf000013_0003
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
B is selected from: (i) a direct bond; (ii) a group of Formula (IV)
Figure imgf000013_0004
Formula (IV) wherein:
X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the (CH2)p group is attached to R ; and
(iii) a group independently selected from: optionally substituted Cι..6alkylene, optionally substitute C3. cycloalkyl, optionally substituted C3.6alkenylene, optionally substituted C3_6alkynyl,
Figure imgf000014_0001
(Cι.5alkyl)aa-S(On)-(Cι.5alkyl)bb-, (C1.5alkyl)aa-O-(C1.5alkyl)bb- or (C1.5alkyl)aa-N(R15)- (Cι.5alkyl)bb, wherein R15 and the
Figure imgf000014_0002
or ( .salkylJbb chain can be joined to form a ring; or the group -B-R8 represents a group of Formula (V)
Figure imgf000014_0003
Formula (V);
R'
or the group together forms a heterocyclic ring containing 5-7 carbons atoms;
or the group
Figure imgf000014_0004
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; E is -O-, -S(On), -C(O)-, -NR15- or -C(R9R10)q; F is -E(CH2)r-; G is selected from: hydrogen, halo, N, O, S(On), C(O), C(R9R10)t, optionally substituted
18 C .6alkenylene, optionally substituted C2.6alkynylene or a direct bond to R ,
J is a group of the formula: -(CH2)S-L-(CH2)S- wherein when s is greater than 0, the alkylene group is optionally substituted K is selected from: a direct bond, -O-(CH2)s-, -C(O)-(CH2)s- , -S(On) -(CH2)S-, -N(R18)-(CH2)S-, -OC(O)-(CH2)s-, -C(O)O-(CH2)s-, -OS(On)-(CH2)s-, or -S(On)-O-(CH2)s-;
L is selected from optionally substituted aryl or optionally substituted heterocyclyl; M is -(CH2)o-2-O-; n is an integer between 0 and 2; p is an integer between 0 and 4; q is an integer between 0 and 4; r is an integer between 0 and 4; s is an integer between 0 and 4; and t is an integer between 0 and 4; with the proviso that
17 18
(i) when G is hydrogen or halo, then R and R are both absent;
(ii) when G is O, S(On), C(O) or C(R R12)t then G is substituted by a single group
17 18 independently selected from the definition of R or R and when G is a direct bond to R18 then G is substituted by a single group selected from R18; and or a salt, solvate or pro-drug thereof.
According to a further feature of the first aspect of the invention there is provided a pharmaceutical formulation comprising a compound of Formula (I) or Formula (la), or salt, pro-drug or solvate thereof, and a pharmaceutically acceptable diluent or carrier.
According to a further feature of the first aspect of the invention there is provided the following uses of a compound of Formula (I) or Formula (la), or salt, pro-drug or solvate thereof:
(a) the use in the manufacture of a medicament for antagonising gonadotropin releasing hormone activity;
(b) the use in the manufacture of a medicament for administration to a patient, for reducing the secretion of luteinizing hormone by the pituitary gland of the patient; and
(c) the use in the manufacture of a medicament for administration to a patient, for therapeutically treating and/or preventing a sex hormone related condition in the patient, preferably a sex hormone related condition selected from prostate cancer and pre- menopausal breast cancer.
According to a further aspect of the invention there is provided a method of antagonising gonadotropin releasing hormone activity in a patient, comprising administering a compound of Formula (I) or Formula (la), or salt, pro-drug or solvate thereof, to a patient. Whilst pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutic ally-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention. Whilst the invention comprises compounds of the invention, and salts, pro-drugs or solvates thereof, in a further embodiment of the invention, the invention comprises compounds of the invention and salts thereof.
In the present specification, unless otherwise indicated, an alkyl, alkylene, alkenyl or alkynyl moiety may be linear or branched. The term "alkylene" refers to the group -CH2-.
Thus, C8 alkylene for example is -(CH2)s-- For avoidance of doubt the term C0alkyl within the group Cn-salkyl is a direct bond.
The term 'propylene' refers to trimethylene and the branched alkyl chains -CH(CH3)CH2- and -CH2-CH(CH3)-. The straight chain propylene di-radical is preferred, i.e. -CH2CH2CH2-. Specific propylene radicals refer to the particular structure, thus the term, propyl-2-ene refers to the group -CH2-CH(CH3)-. Similar notation is used for other divalent alkyl chains such as butylene.
The term '2-propenyl' refers to the group -CH2-CH=CH-. The term "aryl" refers to phenyl or naphthyl. The term "carbamoyl" refers to the group -C(O)NH2.
The term "halo" refers to fluoro, chloro, bromo or iodo.
The term "heterocyclyl" or "heterocyclic ring" refers to a 4-12 membered, preferably 5-10 membered aromatic mono or bicyclic ring or a 4-12 membered, preferably 5-10 membered saturated or partially saturated mono or bicyclic ring, said aromatic, saturated or partially unsaturated rings containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur, linked via ring carbon atoms or ring nitrogen atoms where a bond from a nitrogen is allowed, for example no bond is possible to the nitrogen of a pyridine ring, but a bond is possible through the 1 -nitrogen of a pyrazole ring. Examples of 5- or 6-membered aromatic heterocyclic rings include pyrrolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. A 9 or 10 membered bicyclic aromatic heterocyclic ring is an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5 membered ring or another 6 membered ring. Examples of 5/6 and 6/6 bicyclic ring systems include benzofuranyl, benzimidazolyl, benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, indolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl and naphthyridinyl. Examples of saturated or partially saturated heterocyclic rings include pyrrolinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, benzodioxyl and dihydropyrimidinyl. This definition further comprises sulphur-containing rings wherein the sulphur atom has been oxidised to an S(O) or S(O2) group.
The term "aromatic ring" refers to a 5-10 membered aromatic mono or bicyclic ring optionally containing up to 5 heteroatoms independently selected from nitrogen, oxygen or sulphur. Examples of such "aromatic rings" include: phenyl, pyrrolyl, pyrazolyl, furanyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridinyl, isoxazolyl, oxazolyl, 1,2,4 oxadiazolyl, isothiazolyl, thiazolyl and thienyl. Preferred aromatic rings include phenyl, thienyl and pyridyl.
The symbol
Figure imgf000017_0001
denotes where the respective group is linked to the remainder of the molecule.
For the avoidance of doubt where two groups or integers appear within the same definition, for example, -(CH2)S-L-(CH2)S- or R9R10NSO2N(R10)-, then these can be the same of different.
For the avoidance of doubt, where several groups together form a ring, for example:
'the group
Figure imgf000017_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms', then the groups shown cyclises to form a ring, i.e
Figure imgf000017_0003
the component of which are defined by the definitions of the groups which form the ring, thus in the above example the ring would include a nitrogen atom. For example in Example 5 this group forms a piperazine ring. The term Cι.3perfluoroalkyl refers to a Cι_3alkyl chain in which all hydrogens have been replaced with a fluorine atom. Examples of Cι.3perfluoroalkyl include trifluoromethyl, pentafluoroethyl and l-trifluoromethyl-l,2,2,2-tetrafluoroethyl-. Preferably Cι-3perfluoroalkyl is trifluromethyl.
Examples of Cι.8alkyl include: methyl, ethyl, propyl, isopropyl, butyl, wo-butyl, tert-butyl and 2-methyl-pentyl; example of Ci-salkylene include: methylene, ethylene and 2-methyl-propylene; examples of Ci-βalkenyl include allyl (2-propenyl) and 2 — butenyl, examples of Ci-βalkynyl 2-propynyl and 3-butynyl, examples of haloCi-βalkyl include fluoroethyl, chloropropyl and bromobutyl, examples of hydroxyCi-βalkyl include hydroxymethyl, hydroxyethyl and hydroxybutyl, examples of Ci-salkoxy include methoxy, ethoxy and butyloxy; examples of Cι. alkoxyCχ.4alkyl include methoxyethyl, propoxybutyl and propoxymethyl, examples of Cι.6alkanoyl incude formyl, ethanoyl, propanoyl or pentanoyl, examples of N-Cι.4alkylamino include N-methylamino and N-ethylamino; examples of N,N-di-Cι-4alkylamino include N,N-dimethylaminoethyl,
N,N-di-methylaminopropyl and N,N-dipropylaminoethyl, examples of HO-C2-4alkyl-NH include hydroxymethylamino hydroxyethylamino and hydroxypropyamino, examples of HO-C2-4alkyl-N(Cι.4alkyl) include N-methyl-hydroxymethylamino,
N-ethyl-hydroxyethylamino, and N-propyl-hydroxypropyamino, examples of
Figure imgf000018_0001
methylthio, methylsulphinyl, ethylsulphinyl, ethylsulphonyl and propylsulphonyl, include examples of arylCi-βalkyl include benzyl, phenethyl and phenylbutyl, examples of heterocyclylCi-galkyl include pyrrolidin-1-yl ethyl, imidazolylethyl, pyridylmethyl and pyrimidinylethyl.
It is to be understood that, insofar as certain of the compounds of the invention may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of antagonizing gonadotropin releasing hormone (GnRH) activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, activity of these compounds may be evaluated using the standard laboratory techniques referred to hereinafter.
The invention also relates to any and all tautomeric forms of the compounds of the different features of the invention that possess the property of antagonizing gonadotropin releasing hormone (GnRH) activity.
It will also be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms which possess the property of antagonizing gonadotropin releasing hormone (GnRH) activity.
Preferred compounds of Formula (I), Formula (la) and Formula (lb) are those wherein any one of the following apply. Preferably R1 is selected from hydrogen or optionally substituted Ci-βalkyl. More preferably R1 represents hydrogen or unsubstituted C;ι_6alkyl. Yet more preferably R1 represents hydrogen, methyl, ethyl or tert-butyl. Most preferably R1 represents hydrogen. Preferably optional substituents on R1 are independently selected from: optionally substituted Cι.6alkyl, optionally substituted C2.6alkenyl, cyano, nitro,
Figure imgf000019_0001
Cι_3ρerfIuoroalkoxy, optionally substituted aryl, optionally substituted arylCi-όalkyl, R9O(CH2)v-; R9C(O)O(CH2)v-, R9OC(O)(CH2)v-, R16S(On)(CH2)v-, R9R10NC(O)(CH2)V-, or halo wherein v is an integer between 0 and 4, and where 2 optional substituents are present together they can optionally form a C3. carbocyclic ring or a heterocyclic ring. Preferably R2 is an optionally substituted monocyclic aromatic ring structure. Most preferably R represents optionally substituted phenyl.
Preferably optional substituents on R2 are independently selected from: optionally substituted C^alkyl, optionally substituted C2-6alkenyl, cyano, nitro, Cι.3perfluoroalkyl, Cι..3perfluoroalkoxy, optionally substituted aryl, optionally substituted arylCι.6alkyl, R9O(CH2)p-, R9C(O)O(CH2)w-, R9OC(O)(CH2)w-, R16S(On)(CH2)w-, R9R10NC(O)(CH2)W-, R9R10N- or halo; wherein w is an integer between 0 and 4 and R9 and R10 are as defined above. Further preferably the optional substituents on R are independently selected from cyano, ReRfN-, optionally substituted Cι..6alkyl (preferably, Cι. alkyl, eg, methyl or ethyl), optionally substituted Cι„6alkoxy (preferably, Cι_4alkoxy, eg, methoxy, ethoxy or tert-butoxy) or halo (eg, F, Br or Cl) wherein Re and Rf are independently selected from hydrogen, -όalkyl or aryl. Yet further preferably optional substituents on R2 are independently selected from methyl, ethyl, methoxy, ethoxy, tert-butoxy, F or Cl. Most preferably optional substituents on R2 are independently selected from methyl, F or Cl. Preferably R2 bears 1, 2 or 3 substituents. Most preferably R2 represents
Figure imgf000019_0002
Preferably R3 is selected from a group of Formula (Ha) Formula (lib), Formula (He) or Formula (Hd). Further preferably R3 is selected from Formula (Ha) or Formula (lib). Most preferably R3 is a group of Formula (lib). Preferably the group of Formula (HI):
Figure imgf000020_0001
Formula (HI) is selected from a group of Formula Ill-a; Ill-b; III-c; Ill-d; Ill-e; Ill-f, Ill- , Ill-h, Hl-i, or III-j, III-k or III-l;
Figure imgf000020_0002
lll-a Ill-b III-c Ill-d Ill-e
Figure imgf000020_0003
lll-f Ill-g Ill-h lll-j
Figure imgf000020_0004
Ml-k lll-l wherein: het represents an optionally substituted 3- to 8- membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S; R23 and R23a are independently selected from: (i) hydrogen or optionally substituted Cι_8alkyl; or
(ii) R23 and R23a together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring; R24 and R25 are selected from:
(i) R selected from hydrogen; optionally substituted Chalky!; optionally substituted aryl; -Rd-Ar, where Rd represents Ci-salkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; and R25 is selected from hydrogen; optionally substituted Chalky! and optionally substituted aryl; (ii) wherein the group of Formula (HI) represents a group of Formula IH-a , Ill-b or
Ill-i, then the group NR24(-R25) represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or
(iii) wherein the group of Formula (IH) represents structure Ill-e,
Figure imgf000021_0001
represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S; More preferably the group of Formula (HI) is selected from a group of Formula Ill-a , Ill-g, Ill-h, Ill-i, III-j, Ill-k or III-l:
Figure imgf000021_0002
Ill-a |||-g |||-h Ill-i
R2\ a
Figure imgf000021_0003
Figure imgf000021_0004
lll-j lll-k lll-l wherein R23, R23a, R24 and R25 are as defined above.
Further preferably the group of Formula (HI) is selected from one of the following groups:
Figure imgf000021_0005
lll-a lll-g Ill-h
Figure imgf000021_0006
lll-k iii- wherein R23, R23a, R24 and R25 are as defined above. Yet further preferably the group of Formula (HI) is selected from one of the following groups:
Figure imgf000022_0001
wherein Me represents methyl. Yet further preferably the group of Formula (IH) is selected from one of the following groups:
Figure imgf000022_0002
Most preferably the group of Formula (III) is:
Figure imgf000022_0003
Preferably R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted Cι.6alkyl or R6 and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms More preferably R6 and R6a are independently selected from hydrogen, unsubstituted Ci-βalkyl or R6 and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms. Yet more preferably R6 and R6a are independently selected from hydrogen, methyl or R6 and R6a taken together and the carbon atom to which they are attached form cyclopropyl. Most preferably R6 is hydrogen and R6a is methyl.
Preferably R7 is selected from: hydrogen or C^alkyl. More preferably R7 is hydrogen or methyl. Most preferably R7 is hydrogen.
8 8 When R is heterocyclyl then R is preferably selected from one of the following groups:
Figure imgf000023_0001
Figure imgf000023_0003
Figure imgf000023_0002
Figure imgf000023_0005
Figure imgf000023_0004
Figure imgf000023_0006
wherein Z is selected from: O, S or N(R 9 ), T R>20 . is selected form any group within the definitions of R12 and R13, and R ,9, r 13
Figure imgf000023_0007
R." and R .114" are as defined above
8 8 I Inn aa ffuurrtthheerr eemmbbooddiimmeenntt ooff tthhee iinnvveenntion when R is heterocyclyl then R is preferably selected from one of the following groups:
Figure imgf000024_0001
Figure imgf000025_0001
wherein Z is selected from: O, S or N(R ) and R , R and R are as defined above.
When R8 is aryl or aryl-(C)-aryl optionally substituted by R12, R13 and R14, R8 is preferably selected one of the following groups:
Figure imgf000025_0002
wherein D is selected from group E, group F or a direct bond;
Preferably R8 is selected from
(i) hydrogen, C^alkyl, C2-6alkenyl, haloCj.-6alkyl, hydroxy, cyano, Cι.6alkylS(On)-,
-O-Rb,
Figure imgf000025_0003
-C(O)-Rb, C(O)O-Rb, -NH-C(O)-Rb, N,N-di-Cι.4alkylamino, -S(O„)NRbRc where Rb and Rc are independently selected from hydrogen and Ci-βalkyl, and n is 0, 1 or 2;
(ϋ) -(Q)-aryl, optionally substituted by up to 3 groups selected from R12, R13 and R14;
(iii) C4.7heterocyclyl, optionally substituted by up to 3 groups selected from R12, R13 and R14, more preferably selected from: azirinyl, azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, tetrahydrofuranyl, dioxolanyl, tetrahydropyranyl, dioxanyl, trioxanyl, tetrahydrothienyl, 1-oxotetrahydrothienyl, 1,1-dioxotetrahydrothienyl tetrahydrothiopyran, l-oxotetrahydrothiopyran, 1,1-dioxotetrahydrothiopyran, dithianyl, trithianyl, morpholinyl, oxathiolanyl, oxathianyl, thiomorpholinyl, thiazinanyl,
1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, thiazolidinyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thiadiazolyl, thiadiazinyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, octahydropyrrolopyrrolyl, octahydropyrrolopyrrolyl,benzotriazolyl, dihydrobenzotriazolyl, indolyl, indolinyl, benzimidazolyl, 2,3-dihydrobenzimidazoly, benzotriazolyl 2,3-dihydro benzotriazolyl quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinozalinyl, naphthyridinyl, pteridinyl, benzodioxolyl, tetrahydrodioxolopyrrolyl, l,5-dioxa-9- azaspiro[5.5]undecanyl or 8-oxa-3-azabicyclooctanyl; each of which is optionally substituted by up to 3 groups selected from R12, R13 and R14 or
(iv) C3.7carbocyclyl; optionally substituted by up to 3 groups selected from R ,12 , τ R.13 and R14;
Further preferably R is selected from (i) hydrogen, Ci.6alkyl, C2.6alkenyl, haloCι.6alkyl, hydroxy, cyano, Cι.6alkylS(On)-, -0-Rb, C1.4alkoxyC1.4alkyl, -C(O)-Rb, C(O)O-Rb, -NH-C(O)-Rb, N.N-di-C^alkylamino, -S(O„)NRbRc where Rb and Rc are independently selected from hydrogen and -βalkyl, and n is 0, l or 2; preferably selected from: hydrogen, methyl, isopropyl, t-butyl, 1-methylethyl, allyl, fluoroethyl, hydroxy, cyano, ethylsulphonyl, methoxy, l-methyl-2-methoxyethyl, acetyl, t-butoxycarbonyl, acetylamino, dimethylamino, diethylamino, (l-methylethyl)amino, isopropylamino or aminosulphonyl; (ii) -(Q)-aryl, wherein aryl is optionally substituted by up to 3 groups selected from R12, R13 and R14;
(iii) azetidinyl, furanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, tetrahydrothienyl, 1,1-dioxotetrahydrothienyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, imidazolyl, triazolyl, thienyl, thiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrahydro-3aH-[l,3]dioxolo[4,5-c]pyrrolyl, 1,5- dioxa-9-azaspiro[5.5]undecanyl, 8-oxa-3-azabicyclo[3.2. ljoctanyl, benzodioxolyl, 2,3-dihydrobenzotriazolyl, 1,2-dihydroquinolinyl or octahydropyrrolo[3,4-c]pyrrolyl; each of which is optionally substituted by up to 3 groups selected from R12, R13 and
R14; or
I 1? T
(iv) C3. carbocyclyl, optionally substituted by up to 3 groups selected from R , R and R14; Yet further preferably R is selected from
(i) phenyl optionally substituted by up to 3 groups selected from R , R and R or naphthyl; (ii) furanyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, morpholinyl,
1,1-dioxo-thiomorpholinyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, tetrahydro-3aH-[l,3]dioxolo[4,5-c]pyrrolyl, benzodioxolyl, 1,2-dihydroquinolinyl or
2,3-dihydrobenzotriazolyl; each of which is optionally substituted by up to 3 groups selected from R12, R13 and R14;or
(iii) C3. carbocyclyl (preferably cyclohexyl or cylopentyl, more preferably cyclohexyl) optionally substituted by up to 3 groups selected from R , R and R ;; Further preferably R is selected from: phenyl, thienyl, pyridyl and benzodioxlyl
1? 1*^ 1.1 optionally substituted by up to 3 groups selected from R , R and R .
Most preferably R8 is 1,3 benzodioxolyl.
In another embodiment of the invention R8 is selected from piperidinyl or piperazinyl, azetidinyl, imidazolyl and thiazolyl, each of which is optionally substituted by up to 3 groups selected from R12, R13 and R14.
In a further embodiment of the invention preferably R is selected from hydrogen, cyano, Cι_4alkyl (more preferably methyl), C2.6alkynyl (more prefeably 2-propynyl), hydroxyCi.6alkyl (more preferably hydroxyethyl), Cι_4alkoxyC1.4alkyl (more preferably methoxyethyl), haloCi-όalkyl (more preferably fluoroethyl), C1.4alkanoyl (more preferably formyl),
Figure imgf000027_0001
(more preferably N,N-dimethylaminoethyl and N,N-dimethylaminopropyl), Cι.6alkyl-S(On)- (more preferably ethylsulphonyl), cyclopentyl, phenyl, benzyl, cyanophenyl, pyrrolidinyl, pyrrolidinylethyl, imidazolyl, imidazolyCi-ealkyl (more preferably imidazolylethyl), thiazolyl, pyridyl, pyridylCι_6alkyl (more preferably pyridylmethyl) or pyrimidyl wherein a phenyl or heterocyclyl ring is optionally substituted by Cι_4alkyl or halo.
When R9 and or R10 is a component of group G, R9 and R10 are preferably independently selected from hydrogen, optionally substituted -galkyl, optionally substituted aryl, optionally substituted arylCi_6alkyl or R9 and R10 forms C3.7cycloalkyl or heterocyclyl. Further preferably hydrogen or ^alkyl. Most preferably hydrogen or methyl. Most preferably both R9 and R10 are methyl.
When R9 and/or R10 is a component of group R18, R9 and R10 are preferably independently selected from hydrogen, optionally substituted Ci_6alkyl, optionally substituted aryl, optionally substituted arylC όalkyl or R9 and R10 forms C3. cycloalkyl or heterocyclyl.
Further preferably when R9 is a component of group R18, R9 is preferably heterocyclyl. Most preferably pyrrolidinyl, 7-azabicyclo[2.2.1]hept-7-yl or. 3-azabicyclo[3.2.2]nonyl.
17 17
Preferably R is hydrogen, hydroxy, cyano or is absent. Most preferably R is absent. Preferably R18 is selected from hydrogen, R9N(R10)C(O)-, R9C(O)-, R9OC(O)- or R18a-C(R9R10)- wherein R18a is R9N(R10)C(O)-. Further preferably R9C(O)-. Most preferably R9C(O)- wherein R9 is heterocyclyl.
Preferably A is selected from a direct bond, optionally substituted .salkylene, carbonyl or -C(O)-C(RdRd)-, wherein Rd is independently selected from a direct bond hydrogen and Cι_2alkyl. Further preferably A is selected from .salkylene optionally substituted with ^alkyl, carbonyl or carbonylmethyl. Yet further preferably A is a direct bond methylene. Most preferably methylene.
Preferably B is selected from optionally substituted Cι_6alkylene, optionally substituted C3.6alkenylene, -(C1.5alkyl)aa-O-(Cι.5alkyl)bb, -(Cι-5alkyl)aa-C(O)-(C1.5alkyl)bb-,
or the group
Figure imgf000028_0001
Figure imgf000028_0002
forms an optionally substituted C4. heterocyclic ring, wherein aa and bb are independently 0 to 1 and, wherein the combined length of (Ci-5alkyl)aa and ( .salky bb is less than or equal to Csalkyl.
More preferably B is Cι_6alkylene, C3.6alkenylene ,-(C1.5alkyl)aa-O-(Cι-5alkyl)bb-,
-(C1.5alkyl)aa-C(O)-(Cι_5alkyl)bb-, -(CH2)sι-C(O)N(R9)-, or the group
Figure imgf000028_0003
forms an optionally substituted saturated C4.7heterocyclic ring, wherein aa and bb are independently 0 or 1 and wherein the combined length of (Cι_5alkyl)aa, (Cι-5alkyl)bb is less than or equal to C5alkyl and wherein Cι.6alkylene is optionally substituted by hydroxy. Further preferably B is unsubstituted Cj.-6alkylene, C3.6alkenylene
R7
Figure imgf000029_0001
-(Cι-salkyl)aa-C(O)- or the group forms an optionally substituted saturated C . heterocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazolidinyl, l,5-dioxa-9- azaspiro[5.5]undecanyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from, cyano, hydroxy, oxo, Csalkyl, ^alkoxy, ^alkanoyl, R9OC(O)(CH2)w-, R9R10NC(O)(CH2)W- or halo, wherein w is an integer between 0 and 4 and R9 and R10 are as defined above. Further preferably the optional substituents are selected from: cyano, hydroxy, oxo, Csalkyl, Cι_4alkoxy and ^alkanoyl, aa and bb are independently 0 or 1, wherein the combined length of (Cj..5alkyl)aa and (Cι.-5alkyl)bb is less than or equal to Csalkyl and wherein Cι_6alkylene is optionally substituted by hydroxy.
Yet further preferably B is selected from: methylene, ethylene, propylene, propyl-2-ene, butylene, pentylene, 2-propenyl, propoxy, ethoxyethyl, methylcarbonyl or methylcarbonylamino.
R7
or the group forms an C4.7heterocyclic ring selected from:pyrrolidinyl, piperidinyl, or piperazinyl, wherein the optional substituents are selected from oxo. Most preferably B is selected from ethylene or butylene. In another embodiment of the invention preferably B is selected from optionally
R7
substituted C1.6alkylene or the group forms a C5.7heterocyclic ring. Preferably unsubstituted C.6alkylene or a Cs. heterocyclic saturated ring. Most preferably methylene, ethylene, propylene, butylene or piperazinyl.
Peferably G is a direct bond, -O- or -C(R9R10)-. More preferably -C(R9R10)-. Most preferably -C(CH3)2-.
Preferably M is -CH2-O-. When R3 is selected from a group of Formula (He) or Formula (Hd) then the group
7
R7
preferably forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms
R7
More preferably the group forms an optionally substituted saturated C4.7heteocyclic ring.
R7
Further preferably the group forms an optionally substituted saturated
C4.7heteocyclic ring selected from: azetidinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, hexahydropyridazinyl, hexahydrotriazinyl, tetraydrotriazinyl, dihydrotriazinyl, morpholinyl, thiomorpholinyl, thiazinanyl, thiazoUdinyl or octahydropyrrolopyrrolyl, wherein the optional substituents are selected from oxo.
R7
Further preferably the group forms an optionally substituted saturated
C4.7heteocyclic ring selected from: pyrrolidinyl, piperidinyl or piperazinyl, wherein the optional substituents are selected from oxo.
R7
Most preferably the group forms an optionally substituted saturated
C .7heteocyclic ring selected from: piperazinyl.
Preferably K is selected from: -(CH2)S-, -(CH2)s-O-(CH2)s-, -(CH2)s-C(O)-(CH2)s-,
-(CH2)s-N(R18)-(CH2)s-, -(CH2)s-C(O)N(R18)-(CH2)s-, -(CH2)s-N(R18)C(O)-(CH2)s-,
-(CH2)s-S(O)2N(R18)-(CH2)s-, or -(CH2)s-NHS(O)2-(CH2)s-, wherein s is independently selected from 0,1,2,3 or 4, R18 is selected from hydrogen or
Cι.. alkyl (preferably hydrogen) and the -(CH2)S- group is optionally substituted by hydroxy or
Csalkyl. More preferably K is selected from: -(CH2)S-, -(CH2)s-O-(CH2)s-, -(CH2)s-C(O)-,
-C(O)-(CH2)s-, -(CH2)S-N(R18)-, -(CH2)s-C(O)N(R18)-, -(CH2)s-N(R18)C(O)-(CH2)s-,
-(CH2)s-S(O)2N(R18)- or -(CH2)s-NHS(O)2-, wherein s is independently selected from 0,1,2,3 or 4, R18 is selected from hydrogen or Csalkyl (preferably hydrogen or methyl) and the -(CH2)S- group is optionally substituted by hydroxy or Cι.4alkyl.
More preferably K is selected from: methylene, ethylene, propylene, butylene, oxy,
2-hydroxypropylene, carbonyl, methylcarbonyl, ethylcarbonyl, (methyl)methylcarbonyl,
(ethyl)methylcarbonyl, carbonylmethylene, carbonylethylene, ethoxyethylene, amino, 2-hydroxypropylamino, carbonylamino, methylcarbonylamino,
N-methyl-methylcarbonylamino, aminocarbonyl, methylaminocarbonyl, methylaminocarbonylmethyl, propylsulphonylamino or methylaminosulphonyl.
Further preferably K is selected from: methylene, ethylene, propylene, butylene carbonyl, methylcarbonyl or N-methylmethylcarbonylamino. Most preferably K is selected from: methylcarbonyl and
N-methylmehtylcarbonylamino.
8 1Ω 18 10
Preferably optional substituents on heterocyclyl groups in R , R , R , R and R or on heterocyclyl groups formed when R 17 and R 18 together form a heterocyclic ring are selected from: optionally substituted Cι_6alkyl, Ci.6alkoxy, Ci_6alkanoyl, optionally substituted C2.6alkenyl, cyano, nitro,
Figure imgf000031_0001
Cj.-3perfluoroalkoxy, optionally substituted aryl, optionally substituted aryld.6alkyl, R9O(CH2)p-, R9C(O)O(CH2)w-, R9OC(O)(CH2)w-, R16S(On)(CH2)w-, R9R10NC(O)(CH2)W- or halo; wherein w is an integer between 0 and 4 and p, R9, R10 and R16 are as defined above.
More preferably optional substituents on R are selected from: cyano, hydroxy, oxo, nitro, halo, trifluromethyl, Cι_4alkyl, Cj..4alkoxy, ^alkanoyl, R9OC(O)(CH2)w-,
R9R10N(CH2)W-, R9R10NC(O)(CH2)W-, R9R10NC(O)(CH2)W-, R9R10NC(O)N(R9)(CH2)W-, R9OC(O)N(R9)(CH2)w-, or halo, wherein w is an integer between 0 and 4 and R9 and R10 are selected from: hydrogen, Csalkyl, Cι_4alkylsulphonyl and C3.7carbocyclyl.
Further preferably optional substituents on R8 are selected from: cyano, hydroxy, oxo, amino, N^-diC^alkyamino, N,N-diC1.4alkyaminoC1.4alkyl, N'-C1. alkylureido,
N-C1. alkylsulphonylamino, N.N-di-Ci^alkylsulphonylamino, nitro, halo, trifluoromethyl, C1.4alkyl, C^alkoxy, Ci.4alkanoyl, Cl-4alkoxycarbonylamino and C3. carbocyclylcarbonylamino. More preferably optional substituents on R8 are selected from: cyano, oxo, methyl, t-butyl, methoxy, acetyl, amino, N,N-dimethylamino, N'-isopropylureido, N'-cyclohexylureido, N-methylsulphonylamino, N,N-dimethylsulphonylamino, nitro, chloro, fluoro, trifluoromethyl, isopropoxycarbonylamino and cyclopentylcarbonylamino. Most preferably op tional substituents on R8 are selected from: methoxy, fluoro, methylsulphonylamino and isopropoxycarbonylamino.
In a further embodiment of the invention optional substituents on R are selected from: Ci.4alkoxy, fluoro, C^alkylsulphonylamino, Cι.4alkanoylamino, Cι_4alkylureido and
Figure imgf000032_0001
8 8 In a further embodiment of the invention when R is phenyl then R is preferably
8 8 substituted and when R is a heterocyclic ring R is preferably unsubstituted.
Preferably the optional substituents on alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups are independently selected from Chalky!, Cι_6alkoxy, C3.7cycloalkyl, optionally substituted aryl, optionally substituted arylCi-βalkyl, hydroxy, oxo, cyano, Cι_6alkoxy, halo (preferably fluoro), R16S(On)(CH2)w-, R9OC(O)-, optionally substituted arylC^alkoxy wherein R9 is as defined above.
Preferably the optional substituents on optionally substituted aryl and arylCι.6alkyl groups are selected from: optionally substituted Cι-6alkyl, optionally substituted C2-6alkenyl, cyano, nitro, halo (preferably fluoro), Cι.3perfluoroalkyl,
Figure imgf000032_0002
optionally substituted aryl, optionally substituted
Figure imgf000032_0003
R9O(CH2)p-, R9C(O)O(CH2)w-,
R9OC(O)(CH2)w-, R16S(On)(CH2)w-, R9R10NC(O)(CH2)W- or halo; wherein w is an integer between 0 and 4 and n, R9 and R10 are as defined above.
In preferences for heterocyclyl in R the nitrogen atoms contained in R heteroaromatic rings exist either as drawn or, where chemically allowed, in their oxidised (N— O, N-OH) state.
Where optional substitution is mentioned at various places the optional substituents also comprise the following definition which refers to one, two, three or more optional substituents. Unless otherwise indicated above (i.e., where a list of optional substituents is specifically listed within a definition), each substituent can be independently selected from -salkyl (eg, C2.6alkyl, and most preferably methyl, ethyl or tert-butyl); C3_8cycloalkoxy, preferably cyclopropoxy, cyclobutoxy or cyclopentoxy; -βalkoxy, preferably methoxy or C2.4alkoxy; halo, preferably Cl or F; Hal3C-, Hal2CH-, HalCH2-, Hal3CO-, Hal2CHO or Hal
CH2O, wherein Hal represents halo (preferably F); R CH2O-, RhC(O)N(R)-, RhSO2N(R)- or R -RhN-, wherein R and Rh independently represent hydrogen or Cι_8alkyl (preferably methyl or Csalkyl or C2.4alkyl), or R -RhN- represents an optionally substituted C3.8, preferably C3.6, heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; hydrogen; or RkC(O)O- or RkC(O)-, Rk representing hydrogen, optionally substituted phenyl or -όalkyl (preferably methyl, ethyl, isσ-propyl or tert-butyl). For optional substitution of the heterocyclic ring represented by R -RhN-, at least one (eg, one, two or three) substituents may be provided independently selected from Cι„6alkyl (eg, C2. alkyl, more preferably methyl); phenyl; CF3O-; F2CHO-; -salkoxy, preferably methoxy, ethoxy or C3.6alkoxy; Ci-8alkoxyC(O), preferably methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or C3.6alkoxyC(O)~; phenoxycarbonyl; phenoxy;
Cι_8alkanoyl, preferably acetyl, ethanoyl or C3.6alkyanoyl; carboxy; C1-8alkylS(Onn) wherein nn is an integer between 0 and 2, preferably methylthio, ethylthio, C3_6alkylthio, methylsulphinyl, ethylsulphinyl, C3_6alkylsulphinyl, methylsulphonyl, ethylsulphonyl or C3.6alkylsulphonyl; hydroxy; halo (eg, F, Cl or Br); RmRnN- where R and Rn are independently hydrogen or Cι_6alkyl (preferably C2.4alkyl, more preferably methyl, most preferably Rm=Rn=methyl); and nitro.
According to a further aspect of the invention there is provided a compound of Formula (lb)
Figure imgf000033_0001
Formula (lb)
\f Yf .'1n11*.
R1 represents hydrogen or unsubstituted Cι.6alkyl;
R represents optionally substituted phenyl;
R is selected from a group of Formula (Ha) to Formula (Hd):
Figure imgf000033_0002
Formula (Ha) Formula (lib)
Figure imgf000034_0001
Formula (He) Formula (Hd)
R5 is selected from a one of a group of Formula Ill-a to III-l:
Figure imgf000034_0002
Ill-a Ill-b III-c Ill-d Ill-e
R
Figure imgf000034_0003
Ill-f Ill-g Ill-h Ill-i Ml-j
Figure imgf000034_0004
lll-k lll-l
wherein: het represents an optionally substituted 3- to 8- membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S; R2 and R 3a are independently selected from:
(i) hydrogen or optionally substituted Cι_8alkyl; or (ii) R and R together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring; R24 and R25 are selected from:
(i) R24 selected from hydrogen; optionally substituted Cj..8alkyl; optionally substituted aryl; -Rd-Ar, where Rd represents Cι_8alkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; and R is selected from hydrogen; optionally substituted Chalky! and optionally substituted aryl; (ii) wherein the group of Formula (HI) represents a group of Formula Ill-a , Ill-b or Ill-i, then the group NR24(-R25) represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or
(iii) wherein the group of Formula (HI) represents structure Ill-e,
Figure imgf000035_0001
represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S; R6 and R6a are independently selected from hydrogen, fluoro or optionally substituted d-ealkyl.
R is selected from: hydrogen or Cι_4alkyl; R8 is selected from
(i) hydrogen, Cj..6alkyl, C2.6alkenyl, haloCι.6alkyl, hydroxy, cyano, Cι_6alkylS(On)-, -O-Rb, Cι.4alkoxyd.4alkyl, -C(O)-Rb, C(O)O-Rb, -NH-C(O)-Rb, N^-di-Cwalkylamino or -S(On)NRbRc where Rb and Rc are independently selected from hydrogen and Csalkyl, and n is 0, 1 or 2; (ii)-aryl, , optionally substituted by up to 4 substituents selected from R12, R13 and R14; (iii) C4. heterocyclyl, optionally substituted by up to 4 substituents selected from R12, R13 and R14; or
(iv) C3-7carbocyclyl, , optionally substituted by up to 4 substituents selected from R12, R13 and R14; R9 and R10 are independently selected from: hydrogen, hydroxy, optionally substituted Csalkyl, optionally substituted aryl, optionally substituted arylCi.6alkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylCi-βalkyl or R9 and R10 taken together can form an optionally substituted ring of 3-9 atoms or R9 and R10 taken together with the carbon atom to which they are attached form a carbonyl group; R12 is selected from: hydrogen, hydroxy, R17R18N(CH2)CC-, R17R18NC(O)(CH )Cc-, optionally substituted Cι.6alkyl- C(O)N(R9)(CH2)cc-, optionally substituted
C1.6alkyl-S02N(R9)-, optionally substituted aryl-SO2N(R9)-, C1.3perfluoroalkyl-SO2N(R9)-; optionally substituted C1.6alkyl-N(R9)SO2-, optionally substituted aryl-N(R9)SO2-, C1.3perfluoroalkyl-N(R9)SO2- optionally substituted
Cι.6alkanoyl-N(R9)SO2-; optionally substituted aryl-C(O)N(R9)SO2-, optionally substituted C1.6alkyl-S(On) -, optionally substituted aryl-S(On) - , Ci-sperfluoroalkyl-,
Ci-sperfluoroalkoxy, optionally substituted Cι_6alkoxy, carboxy, halo, nitro or cyano; R13 and R14 are independently selected from: hydrogen, hydroxy, oxo, optionally substituted -βalkyl, optionally substituted Cι.6alkanoyl, optionally substituted
C2.6alkenyl, cyano, nitro, Cι-3perfluoroalkyl-, Ci-sperfluoroalkoxy, optionally substituted aryl, optionally substituted arylCι_6alkyl, R9O(CH2)s-, R9(O)O(CH2)s-,
R OC(O)(CH2)s-, R1<5S(O„XCH2)s-, R9R10NC(O)(CH2)S- or halo;A is selected from optionally substituted Ci-salkylene, carbonyl or -C(O)-C(RdRd)-, wherein Rd is independently selected from hydrogen and Cι.2alkyl.;
17
R is independently selected from: hydrogen, hydroxy, cyano or optionally substituted
Ci.6alkyl; R18 is a group of formula R18a-C(R9R10)0.1- wherein R18a is selected from: R19OC(O)-, R9R10NC(O)-, R9R10N-, R9C(O)-, R9C(O)N(R10)-, R9R10NC(O)-, R9R10NC(O)N(R10)-,
R9SO2N(R10)-, R9R10NSO2N(R10)-, R C(O)O-, R9OC(O)-, R9R10NC(O)O-, R O-, R9S(On)-, R9R10NS(On) -, hydrogen, optionally substituted Ci.6alkyl, optionally substituted heterocyclyl; or R17 and R18 when taken together form an optionally substituted carbocyclic ring of 3- 7 atoms or optionally substituted heterocyclyl;
R19 is selected from: hydrogen, optionally substituted Chalky, optionally substituted aryl, optionally substituted aryl -ealkyl, optionally substituted C3.7cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl -όalkyl;
R7
B is selected from optionally substituted
Figure imgf000036_0001
or the group forms an optionally substituted C4.7heterocyclic ring, wherein the optional substituents are selected from R12, R13 and R14;
R7
N-J+
: group preferably forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms, wherein the optional substituents are selected from R12,
R • 1"3 and R 14. K is selected from: a direct bond, -(CH2)sι-, -(CH2)s2-O-(CH2)s-, -(CH2)sι-C(O)-(CH2)S2-,
-(CH2)si-S(On)-(CH2)S2-, -(CH2)sl-N(R18)-(CH2)S2-, -(CH2)sl-C(O)N(R9)-(CH2)S2-, -(CH2)si-N(R9)C(O)-(CH2)s2-, -(CH2)sl-N(R9)C(O)N(R9)-(CH2)s2-, -(CH2)sl-OC(O)-(CH2)S2-, -(CH2)sl-C(O)O-(CH2)s2-, -(CH2)sl-N(R9)C(O)O-(CH2)s2-, -(CH2)sl-OC(O)N(R9)-(CH2)s2-, -(CH2)sι-OS(On)-(CH2)s2-, or
-(CH2)sl-S(On)-O-(CH2)S2-, -(CH2)sι-S(O)2N(R9)-(CH2)S2-, -(CH2)sι-N(R9)S(O)2-(CH2)s2-; wherein the -(CH2)sι- and -(CH2)s2- groups are independently optionally substituted by hydroxy, fluoro, cyano, carbamoyl, Csalkyl and Cι_4alkoxy, n is an integer from 0 to 2; si and s2 are independently selected from an integer from 0 to 4, and sl+s2 is less than or equal to 4; or a salt, pro-drug or solvate thereof.
According to a further aspect of the invention there is provided a compound of Formula (Ic)
Figure imgf000037_0001
Formula (Ic) wherein R3 is selected from a group of Formula (Ha) or Formula (Hb):
Figure imgf000037_0002
Formula (Ha) Formula (Hb) and R1, R2, R5, R6, R6a, R7, R8, A, B and M are as defined above; or salt, solvate or pro-drug thereof.
A further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:
A is optionally substituted Ci-salkylene; B is selected from optionally substituted Ci_6alkylene or the group
Figure imgf000038_0001
forms a ring containing Cs.7heterocyclic ring;
M is -CH2-O-;
R1 is hydrogen or Cι_4alkyl; R6 and R6a, are independently selected from hydrogen and optionally substituted Ci_6alkyl;
R7 is selected from: hydrogen or Csalkyl;
R8 is selected from hydrogen, cyano, Cι.6alkyl, haloCi_6alkyl, C2-6alkynyl, Cι_6alkanoyl,
C1.4alkoxyC1-4alkyl, Q-όalkoxycarbonyl, N,N-di-Cι-4alkylamino, aryl, arylCi.6alkyl, C3.
7cycloalkyl, C3-7cycloalkylC!-6alkyl, heterocyclyl, heterocyclylCi-όalkyl, or heterocyclylcarbonylC1.4alkyl wherein aryl and heterocyclyl rings are optionally substituted by cyano and Ci_4alkyl; and
R and R ; are as defined above or salt, solvate or pro-drag thereof.
A further preferred group of compounds of the invention comprises a compound of Formula (Ic), wherein:
A is optionally substituted Ci-salkylene;
B is selected from optionally substituted -βalkylene or the group
Figure imgf000038_0002
forms a ring containing Cs- heterocyclic ring; R1 is hydrogen or Cι.4alkyl, preferably hydrogen; R2 is an optionally substituted monocyclic aromatic ring structure, preferably optionally substituted phenyl, most preferably 3,5-dimethylphen-l-yl; R5 is a group of Formula (πi) wherein the group of Formula (HI) is selected from a group of Formula Ill-a; Ill-b; III-c; Ill-d; Ill-e; III-f, Ill-g , Ill-h, III-I, III-j, lll-k and
III-l;
Figure imgf000039_0001
Ill-b III-c Ill-d Ill-e
Figure imgf000039_0002
Ill-f Ill-g Ill-h Ill-i lll-j
Figure imgf000039_0003
lll-k lll-l wherein R23, R23a, R24 and R25 are as defined above, preferably the group of Formula (IH) is selected from (IH-a), (Hl-g) and (Hl-h); R6and R6a, are independently selected from hydrogen and optionally substituted Ci-βalkyl; R is selected from: hydrogen or Cι_4alkyl;
R is selected from hydrogen, cyano, Ci_6alkyl, halo -βalkyl, C2.6alkynyl,
Figure imgf000039_0004
Figure imgf000039_0006
Ci.6alkoxycarbonyl,
Figure imgf000039_0005
aryl, arylCi-6alkyl, C3. cycloalkyl,
Figure imgf000039_0007
heterocyclyl, heterocyclyl -ealkyl, or heterocyclylcarbonylCι-4alkyl wherein aryl and heterocyclyl rings are optionally substituted by cyano and C1. alkyl; and
Figure imgf000039_0008
; are as defined above or salt, solvate or pro-drug thereof.
A further preferred group of compounds of the invention comprises a compound of Formula (Id):
Figure imgf000039_0009
Formula (Id)
Wherein R1, R2, R5; R7, R8, A, B and M are as defined above or salt, solvate or pro-drag thereof.
A yet further preferred group of compounds of the invention comprises a compound of Formula (lb), (Ic) or (Id) wherein:
R5 is a group of Formula (HI) wherein the group of Formula (HI) is a group of formula Ilia:
Figure imgf000040_0001
Ilia wherein R23, R 3a, R24 and R25 are as defined above; or a salt, pro-drug or solvate thereof.
According to a further aspect of the invention there is provided a compound of Formula
(I) or Formula (la), or salt, solvate or pro-drag thereof, wherein R is selected from a group of Formula (He) or Formula (πd) and R1, R2 and R5 are as defined above.
According to a further aspect of the invention there is provided a compound of Formula
-a (I) or Formula (la), or salt, solvate or pro-drug thereof, wherein R is selected from a group of Formula (He) or Formula (Hf) and R1, R2 and R5 are as defined above.
According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (la), or salt, solvate or pro-drag thereof, wherein R3 is selected from a group of Formula (ϋa), Formula (πc) or Formula Qtte) and R , R and R are as defined above.
According to a further aspect of the invention there is provided a compound of Formula (I) or Formula (la), or salt, solvate or pro-drag thereof, wherein R3 is selected from a group of Formula (Hb), Formula (Hd) or Formula (Hf) and R1, R2 and R5 are as defined above. Particularly preferred compounds according to the present invention are wherein the compound is selected from: -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5- yl)ethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[4-(4-methoxyphenyl)butyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{ azabicyclo[2.2.1 ]heρtan-7-yl }propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-phenylethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine; -[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heρtan-7-yl}proρoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(3-fluorophenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heρtan-7-yl}proρoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}proρoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(3 ,4-difluorophenyl)ethyl] -(2S)-propylamine ;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(4-isopropylureidophenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-2-[3-(2,2-dimethyl-3-oxo-3-
{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-lH-pyrazol-4-yl]-
N-[2-(4-{cyclopentylcarbonylamino}phenyl)ethyl]-(2S)-propylamine; [2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(4-{isopropoxycarbonylamino}phenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}ρropoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(4-{cyclohexylureido}phenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l-methyl-2-oxo-l,2- dihydroquinolin-6-yl)ethyl]-(2S)-propylamine; 3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.2]oct-2-yl)propoxy]-5-(3,5-dimethylphenyl)-lH- pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine; and 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)- lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; or a salt, pro-drug or solvate thereof. More particularly preferred compounds according to the present invention are wherein the compound is selected from:
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)- lH-pyrazol-4-yl] -N- [2-( 1 ,3 -benzodioxol-5- yl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heρtan-7-yl}ρroρoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[4-(4-methoxyphenyl)butyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(3-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine; and
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)- lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; or a salt, pro-drag or solvate thereof.
Most preferred compounds according to the present invention are wherein the compound is selected from:
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)- 1 H-pyrazol-4-yl] -N- [2-( 1 ,3 -benzodioxol-5 - yl)ethyl]-(2S)-propylamine; and 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylρhenyl)- lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine; or a salt, pro-drag or solvate thereof.
In another embodiment of the invention preferred compounds according to the present invention are wherein the compound is selected from:
2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-l-ylpropoxy)-5-(3,5-dimethylphenyl)-lH- pyrazol-4-yl]-N-(2-pyridin-4-ylethyl)ethanamine;
2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-l-ylpropoxy)-5-(3,5-dimethylphenyl)-lH- pyrazol-4-yl]-N-(2-pyridin-4-ylbutyl)ethanamine; 2-[3-(2,2-dimethyl-3-oxo-3-(7-azabicyclo[2.2.1]hept-7-yl)propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-(2-pyridin-4-ylethyl)ethanamine; and 2-[3-(2,2-dimethyl-3-oxo-3-(7-azabicyclo[2.2.1]hept-7-yl)propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-(2-pyridin-4-ylbutyl)ethanamine; or a salt, pro-drag or solvate thereof. The compounds of Formula (I) may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of pro-drugs include in- vivo hydrolysable esters of a compound of the Formula (I).
Various forms of pro-drags are known in the art. For examples of such pro-drag derivatives, see: a) Design of Prodrags, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by . Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrags", by H. Bundgaard p. 113-
191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). An in- vivo hydrolysable ester of a compound of the Formula (I) containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include Cι_6alkoxymethyl esters for example methoxymethyl, -ealkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3.8cycloalkoxycarbonyloxyCι.6alkyl esters for example
1-cyclohexylcarbonyloxyethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-methyl-l,3- dioxolen-2-onylmethyl; and Cι.6alkoxycarbonyloxyethyl esters.
An in- vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and -acyloxyalkyl ethers and related compounds which as a result of the in- vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in- vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
The compounds of Formula (I) can be prepared by a process comprising a step selected from (a) to (h) as follows, these processes are provided as a further feature of the invention:- (a) Reaction of a compound of formula XXXII with a compound of formula L2-R5' to form a compound of Formula (I),
Figure imgf000045_0001
XXXII Formula (I)
wherein X1 is selected from:
Figure imgf000045_0002
; L1 is a displaceable group; and
H-R is selected from:
Figure imgf000045_0003
;
(b) Reaction of a compound of formula XXXIII with a compound of formula H-R5" to form a compound of Formula (I),
Figure imgf000045_0004
XXXIII Formula (I)
wherein X is selected from:
Figure imgf000045_0005
; L is a displaceable group and R7a is selected from the definition of R7 or R22 above, and 2 c» I ? p D8
L -R is selected from: L— J-K-R8 and L2— R21
(c) For compounds of Formula (I) wherein R is a group of Formula (Ha), (Hb), (He) or (Hd) and R7 is other than part of a heterocyclic ring or hydrogen, reaction of a compound of Formula (I) wherein R3 is a group of Formula (Ha), (Hb), (He) or (Hd) and R7 is hydrogen with a group of formula L3-R7a, wherein R7a is as defined above for R7 with the exclusion of hydrogen and L3 is a displaceable group;
(d) For compounds of Formula (I) wherein R is a group of Formula (He) or (Hf) and R is other than hydrogen, reaction of a compound of Formula (I) wherein R is a group of Formula (He) or (Hf) and R21 is hydrogen with a group of formula L4-R21a, wherein R21a is as defined above for R21 with the exclusion of hydrogen and L4 is a displaceable group;
-a f \
(e) For compounds of Formula (I) wherein R is a group of Formula (He) or (Hf) and R is
•a other than hydrogen, reaction of a compound of Formula (I) wherein R is a group of Formula (He) or (Hf) and R is hydrogen with a group of formula L -R , wherein
R ,22a is as defined above for R ,22 , with the exclusion of hydrogen and L is a displaceable group;
( ) For compounds of Formula (I) wherein R3 is a group of Formula (He) or (Hd) and
R7
the group together forms an optionally substituted nitrogen-containing heterocyclic ring containing 4-7 carbons atoms, reaction of a compound of Formula X XXXXXIIVVaa oorr XXXXXXrIVb, with a compound of Formula L6-K-R8, wherein L6 is a displaceable group
Figure imgf000046_0001
XXXIVa XXXIVb
(g) For compounds of Formula (I) wherein R3 is a group of Formula (He) or (Hd), reaction of a compound of Formula XXXVa or XXXVb, with a compound of Formula L7-K"-R8, wherein L is a displaceable group, and wherein the groups K' and K" comprise groups which when reacted together form K,
Figure imgf000047_0001
XXXVa
XXXVb
(h) reaction of a compound of Formula XXXVI with an electrophillic compound of the
8 *»• 8 formula L -R , wherein L is a displaceable group
Figure imgf000047_0002
XXXVI and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt, pro-drug or solvate.
Specific reaction conditions for the above reations are as follows: Process a) Compounds of formula XXXII and H-R5' can be coupled together in the presence of an organic base (such as DIPEA [di-isopropylethylamine]) or an inorganic base (such as potassium carbonate) base, in a suitable solvent such as DMA or DMF, at a temperature from room temperature and 120°C. Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate; Process b) Compounds of XXXIII and L2-R5" can be coupled together in the presence of an organic base(such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature from room temperature to 120°C. Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate, alternatively if
Figure imgf000047_0003
;can be reacted with a compound of formula XXXIII under Mitsunobu reaction conditions;
Process c, d, e andf) Reaction conditions to facilitate these reactions can be using
(i) alkylation reaction conditions or (ii) acylation reaction conditions: Examples of said conditions include: (i) alkylation reaction conditions - the presence of an organic base(such as DIPEA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMF, DMA, DCM, at a temperature from room temperature to 120°C. Suitable displaceable groups include: a halide, such as chloro, methane sulphonate or toluene sulphonate;
(ii) acylation reaction conditions - presence of organic base, such as triethylamine, temperature 0°C to 50-60°C in a suitable solvent such as DCM. Suitable displaceable groups include an acylchloride or an acid anhydride,
Process g) The skilled man would be familiar with a variety of reaction conditions and values for K' and K", which when reacted together would form the group K, examples of said conditions and values for K' and K" include:
(i.) For compounds of Formula (I) where K is -(CH2)sι-N(R9 )C(0)-(CH2)S2- these can be prepared by reacting a compound where K' is -(CH2)sι-N(R9)H with a carboxylic acid for formula HOOC-(CH2)S2-R8 to form the amide. Coupling of amino groups with carboxylic acids are well known in the art and can be facilitated by a number of chemical reactions using an appropriate coupling reagent. For example a carbodiimide coupling reaction can be performed with EDC1 in the presence of DMAP in a suitable solvent such as DCM, chloroform or DMF at room temperature;
(ii.) For compounds of Formula (I) where K is - CH2)si- C(0)N(R ) -(CH2)S2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-COOΗ with an amine of the HN(R9)-(CH2)S2-R8 to form the amide. Methodology is identical to processes described in (i) above in this section;
(iii.) For compounds of Formula (I) where K is -(CH sι- N(R9)C(0)0 -(CH2 2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-N(R9)Η with a chloroformate of formula ClC(O)O~(CH2)S2-R8 in a suitable solvent, such as DCM or chloroform, in the presence of a base, such as N-methylmorpholine, pyridine or triethylamine, at a temperature between -10°C and 0°C;
(iv.) For compounds of Formula (I) where K is -(CH2_)sr OC(0)N(R9 -( H2JS2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-OC(O)Cl with a compound of formula HΝ(R9)-(CH2)S2-R8. Methodology is identical to processes described in (iii) above in this section; (v.) For compounds of Formula (I) where K is - CH2)Si-N(R )S(O2)-(CH2 S2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-N(R9)Η with a sulphonyl chloride of formula ClS(O2)-(CH2)S2-R in the presence of a base, such as triethylamine or pyridine, in a suitable solvent such as chloroform or DCM at a temperature between 0°C and room temperature; (vi.) Eor compounds of Formula (I) where K is -(CH2)si-S(O )N(R ) -(CH2js2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-S(O2)Cl with a compound of HΝ(R9)-(CH2)S2-R8. Methodology is identical to processes described in (v) above in this section (vii.) For compounds of Formula (I) where K is -(CH2)s - N(R9) -(CH2 2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-L11 with a
0 8 11 compound of formula HN(R )-(CH2)S2-R , wherein L is a displaceable group. This reaction can be performed in the presence of an organic base(such as DIPΕA) or an inorganic base (such as potassium carbonate), in a suitable solvent such as DMA or DMF, at a temperature from room temperature to 120°C. Suitable displaceable groups include: a halide, such as chloro, or a methane sulphonate or toluene sulphonate. Compounds can also be prepared by reacting a compound wherein K' is -(CH2)si-N(R9)H with a compound of formula L11-(CH2)s2-R8, under identical conditions. (viii.)Eør compounds of Formula (I) where K is - CH2)sι-0 - CH2)s2- these can be prepared by reacting a compound where K' is -(CΗ2)sι-OΗ with a 8 I1? compound of formula L -(CH2)S2-R , wherein L is a displaceable group. This reaction can be performed in the presence of an organic base (such as potassium t-butoxide) or an inorganic base (such as sodium hydride), in a suitable solvent such as DMA or DMF, at a temperature from room temperature and 120°C. Suitable displaceable groups include: a halide, such as bromo, or a methane sulphonate or toluene sulphonate. Compounds can also be prepared by reacting a compound wherein K' is -(CH2)sι-L1 with a compound of formula HO-(CH2)S2-R8, under identical conditions, (ix.) For compounds of Formula (I) where K is -(CH2)sι~C(0) - CH )S2- these can be prepared by reacting a compound where K' is -(CΗ2)sχ-C(O)-L with a Grignard reagent of formula BrMg(CH2)s2-R8, wherein L13 is a displaceable group. This reaction can be performed in a non-polar solvent such as THF or diethylether at a temperature between room temperature and the boiling point of the solvent. Suitable displaceable groups include: a halide, such as bromo, or a methane sulphonate or toluene sulphonate. Compounds can also be prepared by reacting a compound wherein K' is -(CH2)sι-MgBr with a compound of formula
L13-C(O)-(CH2)s2-R8, under identical conditions. Process h) reaction of a compound of Formula XXXVI with a compound of the formula L 8 -R **• , can be performed under Friedel Craft conditions, for example in the presence of diethylaluminium chloride in a suitable solvent, such as DCM, in an inert atmosphere such as nitrogen, at a temperature between room temperature and the boiling point of the solvent or under Mannich conditions, for example, formaldehyde and a primary or secondary amine in acetic acid, in an inert atmosphere such as nitrogen at a temperature between room temperature and 100°C.It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of Formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.
The protection and de-protection of functional groups is described in Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and Protective
Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The de- protection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine. A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The de-protection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
EXPERIMENTAL
GENERAL REACTION SCHEMES
Figure imgf000051_0001
2 3
Scheme a Pyrazoles, such as 3 can be synthesised in two steps (Scheme a):
(1) by the reaction of a lactone with the appropriate ester using a Claisen condensation to form a compound of formula 2, under conditions of an inert atmosphere, such as argon, at a temperature of about 0°C in a suitable solvent such as THF.
(2) followed by cyclization of a compound of formula 2 with hydrazine to form the pyrazole 3, at a room temperature in a suitable solvent such as ethanol.
Figure imgf000051_0002
Scheme b The pyrazole 3 can undergo a selective alkylation reaction with a compound of formula 4, under conditions of an inert atmosphere, such as argon, in the presence of a suitable base, such as potassium carbonate in the a suitable solvent such as DMA at a temperature of about 90°C, to form a compound of formula 5. Then the amine 6 can be prepared from a compound of formula 5 and phfhalimide using a Mitsunobu reaction with an activating agent such as diethyldiazocarboxylate (DEAD), diisopropyldiazocarboxylate or the like with triphenylphosphine, tri-butylphosphine and the like, in an inert solvent such as benzene, toluene, tetrahydrofuran or mixtures thereof, followec by deprotection with hydrazine to give the (Scheme b).
Figure imgf000052_0001
Figure imgf000052_0002
10
Scheme c. A suitable pyrazole 6 can be converted to a compound of formula 10 by incorporation of a suitable protecting group (P)to form a compound of formula 7 , followed by a Mitsunobu reaction with a suitable alcohol 8 to form a compound of formula 9, followed by deprotection.
EXAMPLES
The invention will now be illustrated with the following non-limiting Examples in which, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration;
(ii) operations were carried out at room temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon or nitrogen;
(iii) yields are given for illustration only and are not necessarily the maximum attainable;
(iv) the structures of the end-products of the Formula (I) were confirmed by nuclear
(generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet;
(v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or NMR analysis;
(vi) chromatography was performed on silica (Merck Keiselgel: Art.9385);
(vii) isolute™ refers to silica (SiO2) based columns with irregular particles with an average size of 50μm with nominal 60 A porosity [Source: Jones Chromatography, Ltd.,
Glamorgan, Wales, United Kingdom].
Abbreviations boc t-butoxycarbonyl
DCC 1,3-dicyclohexylcarbodiimide
DEAD diethylazodicarboxylate DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMSO dimethyl sulphoxide
DMF dimethylformamide
DNS 2,4-dinitrobenzenesulphonyl EDC l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOBt 1-hydroxybenzotriazole
LHMDS lithium bis(trimethylsilyl)amide THF tetrahydrofuran
Example 1
2-[3-(2,2-dimethyl-3-oxo-3-pyrrolidin-l-ylpropoxy)-5-(3,5-dimethylphenyl)-lH-pyrazol- 4-yl] -N- (2-pyridin-4-ylethyl)ethanamine
Figure imgf000054_0001
Example 1
AR1
A solution of AR1 (123 mg ; 0.17 mmol) in CH2C12 (3 ml) was treated dropwise with propylamine (140 ul ; 1.7 mmol). The mixture was stirred at room temperature for lh and then purified directly by flash chromatography eluting with increasingly polar mixtures of
EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH CH2Cl2 (0 to 10% MeOH) to give
Example 1 as a beige solid (83 mg).
Yield : 100%
1H NMR spectrum (DMSO d6) : 1.27 (s, 6H) ; 1.75 (m, 4H) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 8H) ; 3.5 (m, 4H) ; 4.18 (s, 2H) ; 7.03 (s, IH) ; 7.10 (s, 2H) ; 7.2 (d, 2H) ; 8.44 (d, 2H), 11.9 (s br,
IH).
MS-ESI : 490 [M+H]+
The starting material AR1 was prepared as follows:
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
AR1
A solution of methyl 3,5-dimethylbenzoate (25 g ; 152 mmol) and butyrolactone (40 ml ; 520 mmol) in THF (300 ml) under argon was cooled to 0°C and treated dropwise with LHMDS (200 ml ; 200 mmol ; IM in hexanes). The mixture was stirred and allowed to warm to room temperature overnight. The THF was evaporated. The residue was taken up in Et2O and the organic phase was washed with sat. aq. NaHCO3, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (20 to 40% EtOAc) to give an oil which slowly crystallised to give 2 as a white solid (9.2 g). During the chromatography, the starting material methyl 3,5- dimethylbenzoate (12.4g) was recovered. Yield : 55% based on recovered methyl 3,5-dimethylbenzoate.
1H NMR spectrum (CDCL) : 2.39 (s, 6H) ; 2.5 (m, IH) ; 2.82 (m, IH) ; 4.41 (m, IH) ; 4.51 (m, 2H) ; 7.25 (s, IH) ; 7.65 (s, 2H). MS-ESI : 219 [M+Hf
Compound 2 (7.43 g ; 34 mmol) was dissolved in EtOH (200 ml) and hydrazine hydrate (17.2 ml ; 354 mmol) was added. The mixture was stirred for 30 min. The solvent was evaporated and the residue was triturated with pentane to give 3 as a white solid (7.05 g). Yield : 90%
1H NMR spectrum (DMSO d6) : 2.32 (s, 6H) ; 2.58 (t, 2H) ; 3.50 (t, 2H) ; 4.8 (br s, IH) ; 7.01 (s, IH) ; 7.14 (s, 2H) ; 9.5 (br s, IH). MS-ESI : 233 [M+H]+
A mixture of 3 (4.26 g ; 18.4 mmol) and 4 (4.51 g ; 19.3 mmol) in DMA (40 ml) under argon was treated with K2CO3 (5.07 g ; 36.7 mmol). The mixture was stirred and heated at 90°C for 2h. The mixture was poured into sat. aq. NaHCO3, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 100% EtOAc) to give the alcohol 5 as a pale yellow oil (6.56 g). Yield : 93%
1H NMR spectrum (DMSO d6) : 1.30 (s, 6H) ; 1.8 (m, 4H) ; 2.33 (s, 6H) ; 2.55 (m, 2H) ; 3.32 (m, 2H) ; 3.5 (m, 4H) ; 4.17 (s, 2H) ; 4.62 (t, IH) ; 7.04 (s, IH) ; 7.16 (s, 2H) ; 11.9 (br s, IH). MS-ESI : 386 [M+H]+
A mixture of 5 (3.85 g ; 10 mmol), phthalimide (1.62 g ; 11 mmol) and triphenylphosphine (10.5 g ; 40 mmol) in THF (100 ml) at 0°C under argon was treated with DEAD (6.33 ml ; 40 mmol). The mixture was stirred at this temperature for lh when water was added. The mixture was extracted with Et2O and the organic phase was washed with water, brine and dried over MgSO4.
Evaporation gave a crude solid which, without further purification, was immediately taken up in EtOH (50 ml) and treated with hydrazine hydrate (5 ml ; 100 mmol). The mixture was stirred for 1.5h and then the EtOH was partially evaporated. Addition of CH2C12 caused precipitation of phthalhydrazide which was filtered and rinsed with CH2C12. The filtrate was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 100%o EtOAc) and then MeOH/CH2Cl2 (0 to 8% MeOH) to give 6 as a beige solid (2.34 g). Yield : 61% 1H NMR spectrum (DMSO d6) : 1.30 (s, 6H) ; 1.79 (m, 4H) ; 2.33 (s, 6H) ; 2.52 (m, 2H) ; 2.67 (t, 2H) ; 3.5 (m, 4H) ; 4.18 (s, 2H) ; 7.03 (s, IH) ; 7.14 (s, 2H) ; 8.95 (br s, IH). MS-ESI : 385 [M+H]+ A solution of 6 (200 mg ; 0.52 mmol) in CH2C12 (5 ml) was treated with diisopropylethylamine (135 ul ; 0.78 mmol) and cooled to 0°C. A solution of 2,4- dinitrobenzenesulphonyl chloride (153 mg ; 0.57 mmol) in CH2C12 (1 ml) was added dropwise and the mixture was allowed to warm to room temperature for 30 min. The mixture was purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 50% EtOAc) to give 7 as a cream solid (224 mg). Yield : 70%
1H NMR spectrum (DMSO d6) : 1.24 (s, 6H) ; 1.75 (m, 4H) ; 2.29 (s, 6H) ; 2.57 (m, 2H) ; 3.11 (m, 2H) ; 3.5 (m, 4H) ; 4.15 (s, 2H) ; 7.0 (s, IH) ; 7.03 (s, 2H) ; 8.14 (d, IH) ; 8.56 (q, IH) ; 8.6 (br s, IH) ; 8.83 (d, IH). MS-ESI : 615 [M+H]+
A mixture of 7 (170 mg ; 0.27 mmol), 4-(2-hydroxyethyl)-pyridine (38 mg ; 0.3 mmol) and triphenylphosphine (283 mg ; 1.08 mmol) in THF (10 ml) at 0°C under argon was treated with DEAD (170 ul ; 1.08 mmol). The mixture was allowed to warm to room temperature for 30 min. when water was added. The mixture was extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 100% EtOAc) AR1 as a white solid (123 mg).
Yield : 63%
1H NMR spectrum (DMSO d6) : 1.27 (s, 6H) ; 1.7 (m, 4H) ; 2.28 (s, 6H) ; 2.69 (t, 2H) ; 2.83 (t, 2H) ; 3.4 (m, 4H) ; 3.48 (t, 2H) ; 3.56 (t, 2H) ; 4.21 (s, 2H) ; 7.01 (s, IH) ; 7.08 (s, 2H) ; 7.19 (d, 2H) ; 8.15 (d, IH) ; 8.41 (d, 2H) ; 8.42 (q, IH) ; 8.89 (d, IH). MS-ESI : 720 [M+H]+
Starting material 4 was prepared as follows:-
Figure imgf000057_0001
8 9 4
A mixture of 8 (14.48 g ; 80 mmol) and oxalyl bromide (43.2 g ; 200 mmol) containing one drop of DMF was heated at 50°C for 2h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up directly in CH2C12 (25 ml) and cooled to 0°C. Diisopropylethylamine (14 ml ; 80 mmol) was added followed by a solution of pyrrolidine (3.3 ml ; 40 mmol) in CH2C12 (30 ml). The mixture was allowed to warm to room temperature overnight and was diluted with CH2C12, washed with aq. HCl (2N), aq. NaOH (IN), water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of
EtOAc/CH2Cl2 (5 to 10% EtOAc) to give 4 as a white solid (6.5 g).
Yield : 70%
1H NMR spectrum (DMSO d6) : 1.39 (s, 6H) ; 1.9 (m, 4H) ; 3.57 (m, 4H) ; 3.62 (s, 2H)
MS-ESI : 235 [M+H]+
Examples 1.1-1.5
The following examples were prepared in a similar manner to Example 1,
Figure imgf000058_0001
the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 1 given above:-
Example 1.1
R AR2 mg ; CH2C12 Propylamine μl ; Prod. Mass mg MS- mmol ml mmol Form ; Yield ESI r^O 210 ; 0.28 5 235 ; 2.86 White 111 ; 504 solid 77% [M+H
] +
Chromato. - 1 ϊtOAc and th ;n MeOH/ CH2C12 (0 to 10% MeO H) 1H NMR spectram (DMSO d6) : 1.27 (s, 6H) ; 1.75 (m, 4H) ; 2.31 (s, 6H) ; 2.57-2.63 (m, 6H) ; 2.75 (m, 2H) ; 3.3-3.7 (m, 4H) ; 4.18 (s, 2H) ; 7.03 (s, IH) ; 7.11 (s, 2H) ; 7.2 (d, 2H) ; 8.44 (d, 2H); 11.9 (s br, IH). Example 1.2
Figure imgf000059_0001
1H NMR spectrum (DMSO d6) : 1.27 (s, 6H) ; 1.6-1.9 (m, 6H) ; 2.3 (s, 6H) ; 2.55-2.64 (m, 6H) ; 2.7 (m, 2H) ; 3.3-3.6 (m, 4H) ; 4.17 (s, 2H) ; 7.02 (s, IH) ; 7.12 (s, 2H) ; 7.29 (dd, IH) ; 7.58 (d, IH) ; 8.39 (d, IH) ; 11.9 (s br, IH).
Examples 1.3 - 1.5 were prepared by a robot. The last two steps were carried out sequentially without isolation of the intermediates AR4, AR5 or AR6.
Example 1.3
Figure imgf000059_0002
Chromato. - LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100%) H2O)
1H NMR spectrum (DMSO d6) : 1.26 (s, 6H) ; 1.74 (m, 4H) ; 2.3 (s, 6H) ; 2.55-2.8 (m, 8H) ; 3.4 (m, 4H) ; 4.16 (s, 2H) ; 7.02 (s, IH) ; 7.10 (s, 2H) ; 7.36 (d, 2H) ; 7.71 (d, 2H) ; 11.9 (s br, IH).
Example 1.4
Figure imgf000059_0003
Chromato. - LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100%)
H2O)
1H NMR spectram (DMSO d6) : 1.27 (s, 6H) ; 1.74 (m, 4H) ; 2.30 (s, 6H) ; 2.5-2.75 (m, 8H) ; 3.5 (m, 4H) ; 3.71 (s, 3H) ; 4.16 (s, 2H) ; 6.81 (d, 2H) ; 7.02 (s, IH) ; 7.05 (d, 2H) ; 7.11 (s, 2H) ; 11.9 (s br, IH).
Example 1.5
Figure imgf000060_0002
*nd = not determined
Chromato. - LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H20)
1H NMR spectram (DMSO d6) : 1.27 (s, 6H) ; 1.77 (m, 4H) ; 2.3 (s, 6H) ; 2.55-2.7 (m, 8H) ; 3.5 (m, 4H) ; 3.68 (s, 3H) ; 3.9 (t, 2H) ; 4.16 (s, 2H) ; 6.81 (m, 4H) ; 7.01 (s, IH) ; 7.12 (s, 2H) ; 11.9 (s br, IH).
Intermediates for Examples 1-1 - 1.5, AR2 - AR6 respectively
Starting materials AR2-AR6 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of AR1 given above:-
Figure imgf000060_0001
AR2
Figure imgf000061_0002
1H NMR spectrum (DMSO d6) : 1.22 (s, 6H) ; 1.6-1.8 (m, 4H) ; 1.84 (m, 2H) ; 2.28 (s, 6H) ; 2.55 (m, 2H) ; 2.69 (m, 2H) ; 3.3-3.5 (m, 8H) ; 4.18 (s, 2H) ; 7.00 (s, IH) ; 7.07 (s, 2H) ; 7.19 (d, 2H) ; 8.17 (d, IH) ; 8.43 (d, 2H) ; 8.47 (dd, IH) ; 8.92 (d, IH) ; 11.9 (s br, IH).
AR3
Figure imgf000061_0001
1H NMR spectrum (DMSO d6) : 1.22 (s, 6H) ; 1.5-1.9 (m, 4H) ; 1.84 (m, 2H) ; 2.28 (s, 6H) ; 2.55 (m, 2H) ; 2.68 (m, 2H) ; 3.3-3.5 (m, 8H) ; 4.18 (s, 2H) ; 7.00 (s, IH) ; 7.07 (s, 2H) ; 7.28 (dd, IH) ; 7.58 (d, IH) ; 8.17 (d, IH) ; 8.40 (m, 2H) ; 8.47 (dd, IH) ; 8.92 (d, IH) ; 11.9 (s br, IH).
AR4
Figure imgf000061_0003
*not determined: Intermediate used directly in last step of robot run without isolation or purification. AR5
Figure imgf000062_0003
AR6
Figure imgf000062_0001
Example 2
2-[3-(2,2-dimethyl-3-oxo-3-{pyrrolidin-l-yl}propoxy)-5-(3,5-dimethylphenyl)-lH- pyrazol-4-yl]-N-(4-pyridin-4-ylbutyl)ethanamine
Figure imgf000062_0002
Ab6
Example 2 Dry, gaseous HCl was bubbled through a solution of Ab6 (180 mg ; 0.29 mmol) in CH2C12 (30 ml) until no Ab6 remained. The mixture was treated with iced sat. aq. NaHCO3, extracted with CH2CI2 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ammonia in MeOH(7N)/CH2Cl2 (0 to 10% ammonia in MeOH) to give Example 2 (114 mg). Yield : 76%
1H NMR spectrum (CDC13) : 1.38 (s, 6H) ; 1.45 (m, 2H) ; 1.6 (m, 2H) ; 1.84 (m, 4H) ; 2.33 (s, 6H) ; 2.59 (m, 4H) ; 2.65 (t, 2H) ; 2.77 (t, 2H) ; 3.57 ; (m, 4H) ; 4.32 (s, 2H) ; 7.01 (s, IH) ; 7.04 (s, 2H) ; 7.08 (d, 2H) ; 8.47 (d, 2H) ; 11.9 (s br, IH). MS-ESI : 518 [M+H]+
The starting material Ab6 was prepared as follows:
Figure imgf000063_0001
Figure imgf000063_0002
Ab3 Ab4
Figure imgf000063_0003
Ab5 Ab6
A solution of methyl 3,5-dimethylbenzoate (50 g ; 300 mmol) in DME (80 ml) was added to a suspension of NaH (26.8 g ; 60% in oil ; 670 mmol) in DME (80 ml) under argon. The mixture was heated to reflux and a solution of methyl acetate (45 g ; 610 mmol) in DME (40 ml) added dropwise. The mixture was heated for a further 4 h under reflux. The mixture was cooled and the excess of NaH destroyed by the dropwise addition of MeOH (40 ml). The mixture was poured into dilute HCl (2N), extracted with E 2θ and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with Et2O /hexanes (10% Et2θ) to give methyl 4-(3',5'- dimethylphenyl) acetoacetate as a yellow oil (31 g). Yield : 50%
1H NMR spectrum (CDC13) : This compound exists as a 4/1 mixture of keto (k) and enol (e) forms : 2.36 (s, 6H)(e) ; 2.38 (s, 6H)(k) ; 3.76 (s, 3H)(k) ; 3.81 (s, 3H)(e) ; 4.03 (s, 2H)(k) ; 5.65 (s, lH)(e) ; 7.11 (s, lH)(e) ; 7.27 (s, lH)(k) ; 7.4 (s, 2H)(e) ; 7.56 (s, 2H)(k) ; 12.48 (s, lH)(e). MS-ESI : 207 [M+H]+
NaH (2.44 g ; 60% in oil ; 61 mmol) was added in small portions to a solution of methyl 4- (3',5'-dimethylphenyl) acetoacetate (9.66 g ; 46.9 mmol) in DMF (50 ml) at 0°C under argon. The mixture was stirred and allowed to warm to room temperature for 30 min. A solution of allyl bromide (4.05 ml ; 46.9 mmol) in DMF (5 ml) was added dropwise and the mixture stirred for a further 2 h. The mixture was poured into H2O, extracted with Et2O and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with Et2θ /hexanes (0 to 15% Et2θ) to give Abl as a pale yellow oil (8.3 g). Yield : 72%
1H NMR spectrum (CDC13) : 2.39 (s, 6H) ; 2.76 (m, 2H) ; 3.70 (s, 3H) ; 4.43 (t, IH) ; 5.08 (m, IH) ; 5.15 (m, IH) ; 5.82 (m, IH) ; 7.24 (s, IH) ; 7.60 (s, 2H). MS-ESI : 247 [M+H]+
A solution of Abl (3.4 g ; 13 mmol) in EtOH (30 ml) was treated with hydrazine hydrate (3.9 ml ; 78 mmol) and heated under reflux for 3 h. The EtOH was evaporated and the residue triturated with Et2O. The precipitate was filtered, washed with H2O and dried to give Ab2 as a white powder (2.8 g). Yield : 95%
1H NMR spectram (CDC13 + TFAD) : 2.42 (s, 6H) ; 3.32 (d, 2H) ; 5.11 (d, IH) ; 5.19 (d, IH); 5.97 (m, IH) ; 7.16 (s, 2H) ; 7.24 (s, IH) ; 10.95 (s br IH). MS-ESI : 229 [M+H]+
A mixture of Ab2 (2.1 g ; 9.2 mmol) and 4 (2.15 g ; 9.2 mmol) in DMA (30 ml) under argon was treated with K2CO3 (2.54 g ; 18.4 mmol). The mixture was stirred and heated at 80°C for 2h. The mixture was poured into sat. aq. NaHCO3, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (50 to 100% EtOAc) to give Ab3 as a pale yellow solid (2.8 g). Yield : 80% 1H NMR spectram (CDC13) : 1.35 (s, 6H) ; 1.8 (m, 4H) ; 2.32 (s, 6H) ; 3.14 (m, 2H) ; 3.55 (m,
4H) ; 4.18 (s, 2H) ; 4.97 (m, 2H) ; 5.89 (m, IH) ; 7.02 (s, IH) ; 7.03 (s, 2H) ; 8.9 (br s, IH). MS-ESI : 382 [M+H]+
5 A mixture of Ab3 (2.59 g ; 6.8 mmol) and (BOC)2O (7.4 g ; 34 mmol) in CH3CN (80 ml) was treated with Et3N (1.9 ml ; 13.6 mmol). The mixture was heated at 80°C for 3h. The solvent was evaporated, the mixture was poured into sat. aq. NaHCO3, extracted with Et2θ and the organic phase was washed with water, brine and dried over MgSO . The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtO AC/CH2CI2 (0 to
10 25%) EtOAc) to give Ab4 as a white solid (2.51 g). Yield : 76%
1H NMR spectrum (CDC13) : 1.18 (s, 9H) ; 1.34 (s, 6H) ; 1.8 (m, 4H) ; 2.3 (s, 6H) ; 2.85 (m, 2H) ; 3.54 (m, 4H) ; 4.43 (s, 2H) ; 4.87 (m, 2H) ; 5.73 (m, IH) ; 6.8 (s, 2H) ; 6.98 (s, IH). MS-ESI : 482 [M+H]+
15
4-Methyl-morphololine-N-oxide (1.6 ml ; 60% solution in H2O) was added to a solution of Ab4 (2.21 g ; 4.6 mmol) in THF (100 ml) and H2O (30 ml). The mixture was cooled to 0°C and a solution of OsO4 (92 mg ; 0.36 mmol) in t-BuOH (1.8 ml) was added dropwise. The mixture was allowed to warm to room temperature for 6 h. The reaction was quenched by the
20 addition of aq. Na2S2O5 (1.75g) in H2O (50 ml). The THF was evaporated and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO4. The residue (2.21 g) was taken up in THF (100 ml) and H2O (30 ml) and treated with NaIO . The mixture was stirred overnight. The THF was evaporated and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO4. The
25 residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 50% EtOAc) to give Ab5 as a buff solid (1.63 g). Yield : 73%
1H NMR spectram (CDC13) : 1.21 (s, 9H) ; 1.34 (s, 6H) ; 1.9 (m, 4H) ; 2.32 (s, 6H) ; 3.23 (d, 2H) ; 3.55 (m, 4H) ; 4.47 (s, 2H) ; 6.8 (s, 2H) ; 7.01 (s, IH) ; 9.56 (d, IH). 30 MS-ESI : 484 [M+H]+
A solution of Ab5 (360 mg ; 0.74 mmol) and 4-(4-aminobutyl)-pyridine (123 mg ; 0.82 mmol) in MeOH (6 ml) was treated with NaBH3CN (52 mg ; 0.82 mmol). The mixture was cooled to 0°C and acetic acid (45 μl ; 0.82 mmol) was added. The mixture was allowed to warm to room temperature for 2 h and evaporated. The residue was treated with aq. K2CO3 (10%) and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with EtOAc and then increasingly polar mixtures of MeOH CH2Cl2 (0 to 5% MeOH) to give Ab6 as an oil (180 mg). Yield : 40%
1H NMR spectrum (CDC13) : 1.20 (s, 9H) ; 1.37 (s, 6H) ; 1.61 (m, 2H) ; 1.87 (m, 6H) ; 2.31 (s, 6H) ; 2.48 (m, 2H) ; 2.62 (m, 4H) ; 2.76 (m, 2H) ; 3.57 (m, 4H) ; 4.45 (s, 2H) ; 6.8 (s, 2H) ; 7.0 (s, IH) ; 7.08 (d, 2H) ; 8.47 (d, 2H). MS-ESI : 618 [M+Hf
Example 3
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-(4-pyridin-4-ylbutyl)-ethanamine
Figure imgf000066_0001
Example 3
BR1
A solution of BR1 (322 mg ; 0.41 mmol) in CH2C12 (5 ml) was treated dropwise with propylamine (340 μl ; 4.1 mmol). The mixture was stirred at room temperature for lh and then purified directly by flash chromatography eluting with increasingly polar mixtures of
MeOH/CH2Cl2 (0 to 10% MeOH) to give Example 3 as a white solid (219 mg).
Yield : 98 %
1HΝMR spectrum (DMSO d6) : 1.25 (s, 6H) ; 1.43 (m, 6H) ; 1.61 (m, 6H) ; 2.3 (s, 6H) ; 2.59
(m, 4H) ; 2.65 (m, 2H) ; 2.75 (m, 2H) ; 4.16 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.11 (s, 2H) ; 7.21 (d, 2H) ; 8.44 (m, 2H) ; 11.8 (s br IH).
MS-ESI : 544 [M+H]+ Starting material BR1 was prepared as follows:-
Figure imgf000067_0001
Bd BR1
A mixture of 3 (4.64 g ; 20 mmol) and Ba (5.72 g ; 22 mmol) in DMA (50 ml) under argon was treated with K2CO3 (5.52 g ; 40 mmol). The mixture was stirred and heated at 70°C for 6h. The mixture was poured into sat. aq. NaHCO3, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtO Ac/CH2C12 (0 to 50% EtOAc) to give the alcohol Bb as a pale yellow oil (7.58 g). Yield : 92%
1H NMR spectrum (DMSO dβ) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.31 (s, 6H) ; 2.53 (m, 2H) ; 3.46 (m, 2H) ; 4.14 (s, 2H) ; 4.58 (s, 2H) ; 4.61 (t, IH) ; 7.02 (s, IH) ; 7.14 (s, 2H) ; 11.9 (br s, IH). MS-ESI : 412 [M+H]+
A mixture of Bb (3.29 g ; 8 mmol), phthalimide (2.35 g ; 16 mmol) and triphenylphosphine (12.5 g ; 48 mmol) in THF (50 ml) was cooled to -20°C under argon and treated dropwise with DEAD (7.6 ml ; 48 mmol). The mixture was allowed to warm to 10°C for lh when water was added and the THF evaporated. The mixture was extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. Evaporation gave a crude solid which, without further purification, was immediately taken up in EtOH (200 ml) and treated with hydrazine hydrate (16 ml ; 320 mmol). The mixture was stirred for 2h and then the EtOH was partially evaporated. Addition of CH2CI2 caused precipitation of phthalhydrazide which was filtered and rinsed with CH2C12. The filtrate was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH) to give Be as a pale beige solid (2.53 g). Yield : 77%
1H NMR spectram (DMSO d6) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.31 (s, 6H) ; 2.46 (m, 2H) ; 2.65 (t, 2H) ; 4.15 (s, 2H) ; 4.58 (m, 2H) ; 7.01 (s, IH) ; 7.12 (s, 2H) ; 11.8 (s br IH). MS-ESI : 411 [M+H]+
A solution of Be (1.43 g ; 3.48 mmol) in CH2C12 (30 ml) was treated with diisopropylethylamine (910 μl ; 5.22 mmol) and cooled to 0°C. A solution of 2,4- dinitrobenzenesulphonyl chloride (1.02 g ; 3.84 mmol) in CH2C12 (10 ml) was added dropwise and the mixture was allowed to warm to room temperature for 30 min. The mixture was poured into sat. aq. NaHCO3, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO . The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 20% EtOAc) to give Bd as a cream solid (1.1 g). Yield : 50%
1H NMR spectram (DMSO d6) : 1.22 (s, 6H) ; 1.41 (m, 4H) ; 1.59 (s, 4H) ; 2. 3 (s, 6H) ; 2.57 (m, 2H) ; 3.11 (m, 2H) ; 4.12 (s, 2H) ; 4.55 (s, 2H) ; 7.0 (s, IH) ; 7.03 (s, 2H) ; 8.17 (d, IH) ; 8.59 (m, 2H) ; 8.83 (d, IH) ; 11.8 (s br IH). MS-ESI : 641 [M+H]+
A mixture of Bd (300 mg ; 0.43 mmol), 4-(4-hydroxybutyl)-pyridine (84 mg ; 0.56 mmol) and triphenylphosphine (495 mg ; 1.87 mmol) in THF (10 ml) at 0°C under argon was treated dropwise with DEAD (300 μl ; 1.87 mmol). The mixture was allowed to warm to room temperature for 30 min. when water was added. The THF was evaporated, the mixture extracted with EtOAc and the organic phase washed with water, brine and dried over MgSO . The residue was purified by flash chromatography eluting with increasingly polar mixtures of
EtOAc/CH2Cl2 (0 to 100% EtOAc) BR1 as a white solid (322 mg). Yield : 89%
1H NMR spectram (DMSO dβ) : 1.24 (s, 6H) ; 1.38 (m, 4H) ; 1.54 (m, 8H) ; 2.29 (s, 6H) ; 2.57 (m, 2H) ; 2.64 (m, 2H) ; 3.36 (m, 4H) ; 4.18 (s, 2H) ; 4.52 (m, 2H) ; 7.02 (s, IH) ; 7.08 (s, 2H) ; 7.16 (d, 2H) ; 8.20 (d, IH) ; 8.41 (d, 2H) ; 8.47 (dd, IH) ; 8.91 (d, IH) ; 11.8 (s br IH). MS-ESI : 774 [M+H]+
Starting material Ba was prepared as follows: -
Figure imgf000069_0001
8 9 Ba
A mixture of 8 (14.48 g ; 80 mmol) and oxalyl bromide (43.2 g ; 200 mmol) containing one drop of DMF was heated at 50°C for 2h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up in CH2C12 (25 ml) and cooled to 0°C. Diisopropylethylamine (14 ml ; 80 mmol) was added followed by 2.2.1-azabicycloheptane hydrochloride (5.34 g ; 40 mmol). The mixture was allowed to warm to room temperature overnight and was diluted with CH2CI2, washed with aq. HCl (2N), aq. NaOH (IN), water, brine and dried over MgSO4.The residue was purified by flash chromatography eluting with CH2C12 to give Ba as a white solid (7.4 g). Yield : 71%
1H NMR spectram (CDCI3) : 1.36 (s, 6H) ; 1.49 (m, 4H) ; 1.82 (m, 4H) ; 3.59 (s, 2H) ; 4.61 (s, 2H).
Examples 3.1-3.5 The following examples were prepared in a similar manner to Example 3,
Figure imgf000069_0002
the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 3 given above: -
Example 3.1
Figure imgf000070_0002
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.55 (m, 2H) ; 2.71 (m, 4H) ; 2.81 (m, 2H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.02 (s, IH) ; 7.10 (s, 2H) ; 7.2 (d, 2H) ; 8.43 (dd, 2H) ; 11.7 (s br IH).
Example 3.2
Figure imgf000070_0003
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
!H NMR spectrum (DMSO d6) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.3 (s, 6H) ; 2.46 (m, 2H) ; 2.64 (m, 2H) ; 2.88 (m, 2H) ; 4.15 (s, 2H) ; 4.19 (t, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.09 (s, 2H) ; 7.92 (s, IH) ; 8.42 (s, IH) ; 11.9 (s br, IH).
Example 3.3
Figure imgf000070_0001
1H NMR spectrum (DMSO de) : 1.26 (s, 6H) ; 1.44 (m, 4H) ; 1.61 (m, 6H) ; 1.97 (s, 3H) 2.25 (s, 2H) ; 2.32 (s, 6H) ; 2.4-2.85 (m, 14H) ; 4.16 (s, 2H) ; 4.58 (s, 2H) ; 7.04 (s, IH) ; 7.11 (s, 2H) ; 11.8 (s, IH).
Example 3.4
Figure imgf000071_0001
1H NMR spectrum (DMSO d6) : 1.26 (s, 6H) ; 1.44 (m, 4H) ; 1.57 (m, 2H) ; 1.62 (m, 4H) ; 2.27 (m, 6H) ; 2.32 (s, 6H) ; 2.5-2.85 (m, 6H) ; 3.52 (s, 4H) ; 4.16 (s, 2H) ; 4.58 (s, 2H) ; 7.03 (s, IH) ; 7.12 (s, 2H) ; 11.8 (s, lH).
Example 3.5
Figure imgf000071_0002
1H NMR spectrum (DMSO d6) : 1.26 (s, 6H) ; 1.44 (m, 4H) ; 1.55 (m, 2H) ; 1.61 (m, 4H) ; 2.32 (s, 6H) ; 2.4-2.85 (m, 8H) ; 2.82 (s, 4H) ; 3.04 (m, 4H) ; 4.16 (s, 2H) ; 4.58 (s, 2H) ; 7.03 (s, IH) ; 7.12 (s, 2H) ; 11.8 (s, IH).
Intermediates for Examples 3.1-3.5. BR2 - BR6 respectively
Starting materials BR2-6 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of Example 3 given above:-
Figure imgf000071_0003
BR2
Figure imgf000072_0003
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc)
Figure imgf000072_0004
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc)
Figure imgf000072_0001
Figure imgf000072_0002
Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH)
Figure imgf000073_0001
Chromato. - EtOAc and then MeOHCH2Cl2 (0 to 10% MeOH).
Example 4
2-[3-(2,2-dimethyl-3-oxo-3-azabicycIo[2.2.1]heptan-7-ylpropoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine
Figure imgf000073_0002
CR1 Example 4 A solution of partially purified* Cgl7 (4.2 g ; from 2.3 mmol of Cf) in CH2C12 (30 ml) under nitrogen was treated dropwise with n-propylamine (1.36 ml ; 23 mmol) at room temperature. The mixture was stirred at room temperature for 2h, the solvents evaporated and the residue purified directly by flash chromatography eluting with increasingly polar mixtures of EtOAc and then MeOH/CH2Cl2 (0 to 15%) MeOH) to give Example 4 as a beige solid (768 mg). * Contains some Ph3PO
Yield : 59% for last two steps.
1H ΝMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 5.94 (s, 2H) ; 6.55 (d, IH) ; 6.69 (s, IH) ; 6.76 (d, IH) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 11.8 (s br IH). MS-ESI : 573 [M+H]+ Starting materials Ce, Cf and CR17 were prepared as follows:
Figure imgf000074_0001
Co
Cd Ce
Figure imgf000074_0002
CR17
Cf
A solution of methyl 3,5-dimethylbenzoate (148 g ; 0.9 mol) and 3S-methylbutyrolactone (90 g ; 0.9 mol) in THF (2.4 1) under argon was cooled to 0°C and treated dropwise rapidly with LHMDS (1.35 1 ; 1.35 mol ; IM in hexanes). The mixture was stirred for 2h while the temperature was maintained below 10°C. The mixture was poured into dilute HCl (2N, 800ml) at 0°C. Further dilute HCl (2N) was added until the pH reached 1.6. The THF was evaporated and the residual aqueous phase was extracted with EtOAc. The organic phase was washed with sat. aq. NaHCO3, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/hexanes (10 to 15% EtOAc) to give Ca as a colourless oil (127.7 g). Yield : 61%.
1H NMR spectrum (DMSO d6) : 1.09 (td, 3H) ; 2.36 (s, 6H) ; 3.05 (m, IH) ; 3.93 (t, IH) ; 4.50 (t, IH) ; 4.78 (d, IH) ; 7.36 (s, IH) ; 7.67 (s, 2H). MS-ESI : 233 [M+H]+
Compound Ca (127.5 g ; 0.55 mol) was dissolved in EtOH (2.0 1) and hydrazine hydrate (27 ml ; 0.55 mol) was added. The mixture was stirred overnight at room temperature. Dilute HCl (12N ; 12 ml) was added and the mixture stirred for a further lh. The precipitate was filtered to give Cb as a white solid (63 g). Crystallisation from the mother liquors yielded further batches of Cb (29 g). Yield : 68%
1H NMR spectrum (DMSO de) : 1.15 (d, 3H) ; 2.23 (s, 6H) ; 2.77 (m, IH) ; 3.53 (d, 2H) ; 4.77 (br s, IH) ; 7.01 (s, IH) ; 7.04 (s, 2H) ; 9.5 (br s, IH). MS-ESI : 247 [M+H]+
A mixture of Cb (50 g ; 0.20 mol) and Ba (60 g ; 0.23 mol) in DMA (350 ml) under argon was treated with K2CO3 (56 g ; 0.41 mol). The mixture was stirred and heated at 80°C overnight. The mixture was cooled and poured into a stirred mixture of sat. aq. NaHCO3/H2O
(1:2.5). The precipitate was filtered, washed abundantly with water and dried, to give the alcohol Ce as a pale beige solid. (84.5 g).
Yield : 99%
1H NMR spectrum (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.31 (s, 6H) ; 2.75 (m, IH) ; 3.46 (m, 2H) ; 4.14 (m, 2H) ; 4.51 (br s, IH) ; 4.58 (m, 2H) ; 7.03
(s, IH) ; 7.06 (s, 2H) ; 11.9 (br s, IH).
MS-ESI : 426 [M+H]+
A solution of Cc (42 g ; 0.1 mol) in CH2C12 (800 ml) under argon was treated with acetonitrile (3 1) and DMAP (250 mg ; cat.). The mixture was stirred and cooled to 0°C and a solution of BOCOBOC (24 g ; 0.11 mol) in acetonitrile (100 ML) was added slowly, dropwise. The mixture was allowed to warm to room temperature until no Cc remained (~1 day) and was poured into water (21) and stirred for 4 h. The organic solvents were evaporated. The mixture was extracted with CH2C12 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/ CH2C12 (20 to 50% EtOAc) to give Cd as a colourless foam (25.5 g).
Yield : 50%
1H NMR spectram (DMSO d6) : 1.02 (d, 3H) ; 1.16 (s, 9H) ; 1.270 (s, 6H) ; 1.44 (m, 4H) ; 1.62 (m, 4H) ; 2.29 (s, 6H) ; 2.33 (m, IH) ; 3.38 (m, 2H) ; 4.23 (m, 2H) ; 4.54 (m, IH) ; 4.59
(s, 2H) ; 6.89 (s, IH) ; 7.05 (s, 2H).
MS-ESI : 526 [M+H]+ A solution of Cd (50.9 g ; 97 mmol), phthalimide (17 g ; 116 mmol) and triphenyl phosphine
(38 g ; 145 mmol) in THF (1 1) under argon was cooled to 0°C and treated rapidly, portionwise with DTAD (33.3 g ; 145 mmol). The mixture was allowed to warm to room temperature for 2 h 30 min. Water (500 ml) was added to the mixture and the organic solvent evaporated. The mixture was extracted with CH2C12 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 15% EtOAc) to give a cream foam
(48.4 g) which was dissolved in EtOH (1.5 1). The mixture was treated with hydrazine hydrate
(143 ml ; 2.95 mol) at room temperature and was stirred for a further 26 h. The precipitate was filtered and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (5 to 15%) MeOH) to give Ce as a white solid (31.4 g). Yield : 77%
1H NMR spectrum (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.31 (s, 6H) ; 2.63 (m, 2H) ; 2.72 (m, IH) ; 4.15 (m, 2H) ; 4.57 (m, 2H) ; 7.02 (s, IH) ; 7.06 (s, 2H) ; 8.9 (br s, IH). MS-ESI : 425 [M+H]+
A solution of Ce (1.5g ; 3.58 mmol) in THF (70 ml) was cooled to 0°C under argon. DIEA (810 μl ; 4.65 mmol) was added followed by a solution of DNOSC1 (1.04 g ; 3.9 mmol) in THF (20 ml). The mixture was allowed to warm to room temperature for 2 h and was treated with aq. HCl (IN)- The mixture was extracted with CH2C12 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 100% EtOAc) to give Cf as a cream foam (2.07 g). Yield : 88%
1H NMR spectram (DMSO d6) : 1.10 (d, 3H) ; 1.23 (s, 6H) ; 1.41 (m, 4H) ; 1.58 (m, 4H) ; 2.29 (s, 6H) ; 2.83 (m, IH) ; 3.19 (m, 2H) ; 4.13 (m, 2H) ; 4.55 (m, 2H) ; 6.95 (s, 2H) ; 6.98 (s, IH) ; 8.12 (d, IH) ; 8.49 (br s, IH) ; 8.52 (q, IH) ; 8.79 (d, IH). MS-ESI : 655 [M+H]+
A mixture of Cf (1.5 g ; 2.3 mmol), the corresponding alcohol (575 mg ; 3.45 mmol) and triphenylphosphine (3.67 g ; 14 mmol) in THF (50 ml) at 0°C under argon was treated with DTAD (2.12 g ; 9.2 mmol). The mixture was allowed to warm to room temperature for 1 h when water was added. The mixture was extracted with CH2C12 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtO Ac/hexanes (0 to 50%) and then EtOAc/CH2Cl2 (0 to 100% EtOAc) to give CR17 as a beige solid (4.2 g). This partially purified intermediate (containing some Ph3PO) was used directly in the final step.
Example 4.1-4.54
The following examples were prepared using the same methodology as Example 4,
Figure imgf000077_0001
The table shows the R group relating to the above structure, the reaction conditions and characteristics of each example, corresponding to the description of the preparation of Example 4 given above: -
Example 4.1
Figure imgf000077_0002
Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ;
2.28 (s, 6H) ; 2.6-2.9 (m, 7H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.03 (s, 3H) ; 7.12 (d, 2H) ; 8.39
(d, 2H) ; 11.8 (s br lH). Example 4.2
Figure imgf000078_0001
Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.35 (m, 2H) ; 1.42 (m, 4H) ; 1.53 (m, 2H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.5-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.03 (s, IH) ; 7.05 (s, 2H) ; 7.17 (d, 2H) ; 8.42 (d, 2H) 11.8 (s br IH).
Example 4.3
Figure imgf000078_0002
Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6- TFAd) : 1.25 (m, 9H) ; 1.43 (m, 4H) ; 1.60 (m, 4H) ; 1.97 (m, 2H) ; 2.32 (s, 6H) ; 2.8-3.15 (m, 7H) ; 4.20 (s, 2H) ; 4.55 (s, 2H) ; 7.03 (s, 2H) ; 7.07 (s, IH) 7.96 (d, 2H) ; 8.89 (d, 2H) ; 11.8 (s br IH).
Example 4.4
Figure imgf000078_0003
Chromato. - EtOAc 1H NMR spectrum (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.32 (m, 2H) ; 1.42 (m, 4H) ; 1.50 ; (m,2H) ; 1.61 (m, 4H) ; 2.28 (s, 6H) ; 2.35-2.85 (m, 7H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.06 (s, 2H) ; 7.15 (m, 3H) ; 7.24 (m, 2H) ; 11.8 (s br IH). Example 4.5
Figure imgf000079_0003
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.35 (m, 2H) ; 1.44(m, 4H) ; 1.47 ; (m,2H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.4-2.9 (m, 7H) ; 3.70 (s, 3H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 6.81 (d, 2H) ; 7.04 (m, 5H) ; 11.8 (s br IH).
Example 4.6
Figure imgf000079_0001
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.37 (m, 2H) ; 1.42 (m, 4H) ; 1.54 (m, 2H) ; 1.59 (m, 4H) ; 2.28 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 7.44 (d, 2H) ; 8.14 (d,2H) ; 11.8 (s br IH)..
Example 4.7
Figure imgf000079_0002
1H NMR spectrum (DMSO de) : 1.17 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.48 (m, 2H) ; 1.61 (m, 4H) ; 1.71 (m, 2H) ; 2.3 (s, 6H) ; 2.55-3.0 (m, 7H) ; 4.17 (s, 2H) ; 4.58 (s, 2H) ; 7.04 (m, 3H) ; 7.32 (t, IH) ; 8.71 (d, 2H) ; 11.8 (s br IH). Example 4.8
Figure imgf000080_0001
1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 6H) ; 1.63 (m, 6H) ; 2.29 (s, 6H) ; 2.55-2.9 (m, 7H) ; 4.16 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 8.45 (d, IH) ; 8.52 (m, 2H) ; 11.8 (s br IH)..
Example 4.9
R CR9 mg ; CH2CI2 Propylamine ml ; Mass mg; MS-ESI mmol Cf ml mmol Yield nd* ; 0.38 10 0.31 ; 3.8 94 ; 45% 554
CN [M+H]+
Chromato. - MeO H/CH2C12 (0 to 1 0% MeO] H)
1H NMR spectrum pMSO d6) : 1.12 (d, 3H) ; 1.24 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.6-2.9 (m, 7H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.02 (s, 3H) ; 7.31 (d, 2H) ; 7.68 (d, 2H) ; 11.8 (s br lH).
Example 4.10
Figure imgf000080_0002
1H NMR spectrum (DMSO d6) : 1.16 (d, 3H) ; 1.25 (s, 6H) ; 1.40 (m, 4H) ; 1.59 (m, 4H) ; 2.27 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.16 (m, 2H) ; 4.56 (s, 2H) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 7.3 (d, IH) ; 7.46 (m, 2H) ; 7.62 (s, IH) ; 7.8 (m, 2H) ; 7.86 (d,lH) ; 11.8 (s br IH). Example 4.11
Figure imgf000081_0001
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.6-2.95 (m, 5H) ; 3.45 (s, 2H) ; 4.16 (s,2H) ; 4.41 (s, 2H) ; 4.56 (s, 2H) ; 7.03 (s, IH) ; 7.06 (s, 2H) ; 7.2-7.35 (m, 5H) ; 11.8 (s br IH).
Example 4.12
Figure imgf000081_0002
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.45-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.03 (s, IH) ; 7.04 (s, 2H), 7.10 (d, 2H) ; 7.16 (t, IH) ; 7.24 (t, 2H) ; 11.8 (s br IH).
Example 4.13
Figure imgf000081_0003
Chromato. - MeOH/CH2Cl2 (0 to 7% MeOH) IH NMR spectram (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.6 (m, 4H) ; 2.27 (s, 6H) ; 2.6-2.9 (m, 7H) ; 4.14 (m, 2H) ; 4.56 (s, 2H) ; 7.02 (s, IH) ; 7.03 (s, 2H) ; 7.45 (m, 4H) ; 11.8 (s br lH). Example 4.14
Figure imgf000082_0001
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectram (DMSO d«) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.6-2.9 (m, 7H) ; 3.68 (s, 3H) ; 3.70 (s, 3H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 6.60 (q, IH) ; 6.72 (d, IH) ; 6.79 (d, IH) ; 7.03 (s, IH) ; 7.05 (s, IH) ; 11.8 (s br IH).
Example 4.15
Figure imgf000082_0002
1H NMR spectram (DMSO d6) : 1.16 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.30 (s, 6H) ; 2.6-2.9 (m, 7H) ; 2.83 (s, 6H) ; 4.16 (s, 2H) ; 4.57 (s, 2H) ; 6.61 (d, 2H) ; 6.92 (d, 2H) ; 7.04 (s, 3H) ; 11.8 (s br IH).
Example 4.16
Figure imgf000082_0003
1H NMR spectram (DMSO de) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.03 (m, 5H) ; 7.12 (m, 2H) ; 11.8 (s br lH). Example 4.17
Figure imgf000083_0001
1H NMR spectram (CDC13) : 1.21 (d, 3H) ; 1.35 (d, 6H) ; 1.44 (m, 4H) ; 1.75 (m, 4H) ; 2.33 (s, 6H) ; 2.6-3.1 (m, 7H) ; 4.26 (m, 2H) ; 4.63 (s, 2H) ; 6.61 (m, 3H) ; 7.01 (s, 3H) ; 9.1 (s br, IH).
Example 4.18
Figure imgf000083_0002
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 15H) ; 1.41 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.02 (d, 2H) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 7.25 (d, 2H) ; 11.8 (s br IH).
Example 4.19
R CR20 mg ; CH2CI2 Propylamine ml ; Mass mg; MS-ESI mmol Cf ml mmol Yield κ nd* ; 0.25 5 0.27 ; 4.5 40 ; 29% 557 [M+H]+
Chromato. - Me( DH CH2C12 (0 to 1 0% MeOl . 1H NMR spectrum (DMSO d6) : 1.18 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.16 (s, 3H) ; 2.20 (s, 3H) ; 2.30 (s, 6H) ; 2.5-2.95 (m, 7H) ; 4.17 (s, 2H) ; 4.56 (s, 2H) ; 6.84 (s, IH) ; 6.88 (d, IH) ; 6.99 (s, IH) ; 7.05 (s, 3H) ; 11.8 (s br IH). Example 4.20
Figure imgf000084_0001
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.9 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.04 (s, 2H) ; 7.15 (m, IH) ; 7.27 (m, 2H) ; 11.8 (s br IH).
Example 4.21
Figure imgf000084_0002
Chromato. - MeOH CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.02 (s, IH) ; 7.04 (s, 2H) ; 7.10 (m, IH) ; 7.26 (m, IH) ; 7.35 (m, IH) ; 11.8 (s br IH).
Example 4.22
R CR23 mg ; CH2CI2 Propylamine ml ; Mass mg; MS-ESI mmol Cf ml mmol Yield nd* ; 0.25 5 0.27 ; 4.5 50 ; 34% 597 [M+H]+
Cl
Chromato. - MeC >H7CH2C12 (0 to 11 3% MeOF 0 1H NMR spectram (DMSO dβ) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.28 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.16 (m, 2H) ; 4.56 (s, 2H) ; 7.03 (s, 3H) ; 7.11 (d, IH) ; 7.41 (s, IH) 7.48 (d, IH) ; 11.8 (s br IH). Example 4.23
Figure imgf000085_0001
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 7.25 (t, IH) ; 7.4 (d, 2H) ; 11.8 (s br IH).
Example 4.24
Figure imgf000085_0002
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.31 (s, 6H) ; 2.55-2.95 (m, 3H) ; 3.1-3.75 (m, 4H) ; 3.67 (m, 2H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 4.62 (m, IH) ; 4.68 (m, IH) ; 4.76 (s, IH) ; 4.93 (s, IH) ; 7.03 (s, IH) ; 7.06 (s, 2H) ; 11.8 (s br IH).
Example 4.25
Figure imgf000085_0003
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.26 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.03 (m, 2H) ; 2.31 (s, 6H) ; 2.33 (m, 3H) ; 2.55-2.95 (m, 6H) ; 4.14 (s, 2H) ; 4.49 (m, 2) ; 4.58 (s, 2H) ; 4.71 (s, IH) ; 4.8 (s, IH) ; 7.03 (s, IH) ; 7.06 (s, 2H) ; 11.8 (s br IH). Example 4.26
Figure imgf000086_0001
1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 6.97 (m, 3H) ; 7.03 (s, 3H) ; 7.27 (m, lH) ; 11.8 (s br lH).
Example 4.27
Figure imgf000086_0002
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (m, 2H) ; 4.57 (s, 2H) ; 7.03 (s, 3H) ; 7.09 (m, IH) ; 7.25 (m, 3H) ; 11.8 (s br lH).
Example 4.28
Figure imgf000086_0003
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO d6) : 1.16 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.71 (s, 3H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 6.7 (m, 3H) ; 7.04 (s, 3H) ; 7.16 (m, IH) ; 11.8 (s br IH). Example 4.29
Figure imgf000087_0001
1H NMR spectram (DMSO de) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.24 (s, 3H) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.16 (s, 2H) ; 4.57 (s, 2H) ; 6.90 (m, 2H) ; 6.98 (d, IH) ; 7.04 (s, 3H) ; 7.12 (t, IH) ; 11.8 (s br IH).
Example 4.30
Figure imgf000087_0002
1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (m, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.5-2.9 (m, 7H) ; 4.16 (s, 2H) ; 4.56 (m, 2H) ; 7.03 (s, 3H) ; 7.14 (d, 2H) ; 7.29 (d, 2H) ; 11.8 (s br lH).
Example 4.31
Figure imgf000087_0003
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (m, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.24 (s, 3H) ; 2.29 (s, 6H) ; 2.5-2.95 (m, 7H) ; 4.15 (s, 2H) ; 4.56 (m, 2H) ; 6.98 (d, 2H) ; 7.04 (m, 5H) ; 11.8 (s br lH). Example 4.32
Figure imgf000088_0001
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (m, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.5-2.95 (m, 7H) ; 3.70 (s, 3H) ; 4.15 (s, 2H) ; 4.56 (m, 2H) ; 6.79 (d, 2H) ; 7.01 ; (d, 2H) ; 7.04 (s, 3H) ; 11.8 (s br IH).
Example 4.33
R CR34 mg CH2CI2 Propylamine Mass mg; MS-ESI ; mmol Cf ml ml ; mmol Yield po nd* ; 0.26 5 0.27 ; 3.3 51 ; 35% 547 [M+H]+
Chromato. - M eOH/CH2Cl2 (0 to 10% ] MeOH)
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.25 (m, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 4H) ; 2.29 (s, 6H) ; 2.5-2.95 (m, 7H) ; 3.70 (s, 3H) ; 4.16 (m, 2H) ; 4.56 (s, 2H) ; 7.04 (s, 3H) ; 7.09 (m, 2H) ; 7.21 ; (m, 2H) ; 11.8 (s br IH).
Example 4.34
Example 4.34 was prepared by a different methodology (opening of epoxide by Ce) : see below.
Example 4.35
Figure imgf000088_0002
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.14 (m, 2H) ; 4.57 (s, 2H) ; 6.94 (m, IH) ; 7.03 (s, 3H) ; 7.15 (m, IH) ; 7.26 (m, IH) ; 11.8 (s br IH). Example 4.36
Figure imgf000089_0002
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.68 (s, 6H) ; 4.15 (m, 2H) ; 4.57 (s, 2H) ; 6.3 (m, 3H) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 11.8 (s br IH).
Example 4.37
Figure imgf000089_0003
Figure imgf000089_0001
1H NMR spectram (DMSO dg) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.60 (s, 3H) ; 3.69 (s, 6H) ; 4.14 (s, 2H) ; 4.56 (s, 2H) ; 6.42 (s, 2H) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 11.8 (s br IH) .
Example 4.38
Figure imgf000089_0004
Chromato. - EtOAc/CH2C12 (50 to 100% EtOAc) and then MeOH/CH2C12 (0 to 10%
MeOH)
IH NMR spectram (DMSO d6) : 1.15 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ;
1.78 (m,2H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 5H) ; 3.68 (s, 3H) ; 3.88 (t, 2H) ; 4.15 (s, 2H) ; 4.56
(s, 2H) ; 6.80 (m, 4H) ; 7.02 (s, IH) ; 7.06 (s, 2H) ; 11.8 (s br IH). Example 4.39
R CR40 mg ; CH2CI2 Propylamine ml ; Mass mg; MS-ESI mmol Cf ml mmol Yield nd* ; 0.25 5 0.27 ; 4.5 85 ; 61% 562
}\AO N— [M+H]+
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH CH2Cl2 (0 to 10% MeOH). 1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.08 (s, 6H) ; 2.30 (s, 6H) ; 2.55-2.95 (m, 3H) ; 3.35 (s, 2H) ; 3.53 (s, 2H) ; 4.14 (m, 2H) ; 4.57 (s, 2H) ; 6.01 (d, IH) ; 6.10 (d, IH) ; 7.03 (s, IH) ; 7.05 (s, 2H) , 11.8 (s br IH).
Example 4.40
R CR41 mg CH2CI2 Propylamine Mass mg; MS-ESI ; mmol Cf ml ml ; mmol Yield nd* ; 0.25 0.27 ; 4.5 40 ; 29% 544 [M+H]+
Figure imgf000090_0001
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO d6) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.61 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 5H) ; 3.01 ; (m, 2H) ; 4.14 (s, 2H) ; 4.56 (s, 2H) ; 5.37 (s, IH) ; 6.50 (m, 3H) ; 7.04 (m, 5H) ; 11.8 (s br IH).
Figure imgf000090_0002
Chromato. - EtOAc/CH2Cl2 (50 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO d6) : 1.16 (d, 3H) ; 1.20 (m, 6H) ; 1.41 (m, 4H) ; 1.61 (m, 4H) ; 2.30 (s, 6H) ; 2.55-2.95 (m, 3H) ; 3.27 (m, 2) ; 4.13 (s, 2H) ; 4.53 (s, 2H) ; 6.23 (m, IH) ; 6.42 (d, IH) ; 7.04 (s, IH) ; 7.07 (s, 2H) ; 7.21 (t, IH) ; 7.30 (t, 2H) ; 7.35 (d, 2H) ; 11.8 (s br IH). Example 4.42
Figure imgf000091_0001
1H NMR spectram (DMSO d6) : 1.14 (d, 3H) ; 1.20 (m, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.31 (s, 6H) ; 2.61 (m, IH) ; 2.68 (m, IH) ; 2.85 (m, IH) ; 3.53 (s, 2H) ; 3.70 (s, 3H) ; 4.12 (m, 2H) ; 4.56 (s, 2H) ; 6.81 (d, 2H) ; 7.03 (s, IH) ; 7.07 (s, 2H) ; 7.12 (d, 2H) ; 11.8 (s br IH).
Example 4.43
Figure imgf000091_0002
1H NMR spectram (DMSO d6) : 1.08 (d, 6H) ; 1.18 (d, 3H) ; 1.26 (s, 6H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.31 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.73 (m, IH) ; 4.18 (m, 2H) ; 4.56 (s, 2H) ; 5.95 (s, IH) ; 6.96 (d, 2H) ; 7.04 (s, 3H) ; 7.25 (d, 2H) ; 8.22 (s, IH) ; 11.8 (s br IH).
Example 4.44
Example C45 was prepared by a different methodology (reductive animation of Ce) : see below.
Example 4.45
R CR46 mg CH2CI2 Propylamine ml ; Mass mg; MS-ESI mmol Cf ml mmol Yield
108 ; 0.14 0.17 ; 2.0 71 ; 93% 544
^ NH, [M+H]+ Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 15% MeOH) 1H NMR spectrum (DMSO da) : 1.14 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.3
(s, 6H) ; 2.55-2.95 (m, 7H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 4.83 (s, 2H) ; 6.44 (d, 2H) ; 6.74 (d, 2H) ; 7.04 (s, IH) ; 7.05 (s, 2H) ; 11.8 (s br, IH).
Example 4.46
Figure imgf000092_0002
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectram (DMSO d6) : 1.18 (d, 3H) ; 1.25 (m, 6H) ; 1.42 (m, 4H) ; 1.5-1.9 (m, 12H) ; 2.31 (s, 6H) ; 2.55-2.95 (m, 8H) ; 4.16 (m, 2H) ; 4.56 (s, 2H) ; 7.03 (m, 5H) ; 7.51 (d, 2H) ; 9.81 ; (s, lH) ; 11.8 (s br, IH).
Example 4.47
Figure imgf000092_0001
1H NMR spectram (DMSO d6-TFAd) : 1.28 (m, 9H) ; 1.43 (m, 4H) ; 1.62 (m, 4H) ; 2.33 (s, 6H) ; 2.8-3.25 (m, 7H) ; 3.51 (s, 6H) ; 4.23 (m, 2H) ; 4.57 (s, 2H) ; 7.05 (s, 2H) ; 7.08 (s, IH) ; 7.31 (d, 2H) ; 7.47 (d, 2H) ; 11.8 (s br, IH).
Example 4.48
Figure imgf000092_0003
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc) and then MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO de) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ;
2.30 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.15 (m, 2H) ; 4.57 (s, 2H) ; 6.76 (d, IH) ; 6.90 (dd, IH) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 7.27 (d, IH) ; 11.76 (s br, IH).
Example 4.49
Figure imgf000093_0001
1H NMR spectrum (DMSO d6) : 1.12 (d, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.85 (m, 7H) ; 2.92 (s, 3H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.06 (m, 7H) ; 11.74 (s br, IH).
Example 4.50
Figure imgf000093_0002
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectrum (DMSO d6) : 1.16 (d, 3H) ; 1.25 (m, 12H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.30 (s, 6H) ; 2.55-2.95 (m, 7H) ; 4.16 (m, 2H) ; 4.5 (s, 2H) ; 4.87 ; (m, IH) ; 7.0 (d, 2H) ; 7.04 (s, 3H) ; 7.34 (s, 2H) ; 9.44 (s, IH) ; 11.8 (s br, IH).
Example 4.51
R CR52 mg ; CH2CI2 Propylamine ml Mass mg; MS- mmol Cf ml ; mmol Yield ESI nd* ; 0.11 2 0.065 ; 1.1 42 ; 57% 669
H H [M+H]+
Chromato. - MeOH/CH2Cl2 (0 to 15% MeOH) 1H NMR spectram (DMSO de) : 1.16 (d, 3H) ; 1.25 (s, 6H) ; 1.25-1.8 (m, 18H) ; 2.31 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.43 (m, IH) ; 4.16 (m, 2H) ; 4.56 (s, 2H) ; 6.04 (s, IH) ; 6.96 (d, 2H) ; 7.04 (s, 3H) ; 7.25 (d, 2H) ; 8.25 (s, IH) ; 11.86 (s br, IH).
Example 4.52
Figure imgf000094_0001
Chromato. - EtOAc
1H NMR spectram (DMSO d6) : 1.13 (d, 3H) ; 1.25 (s, 6H) ; 1.1-1.7 (m, 21H) ; 2.3 (s, 6H) ;
2.35-2.85 (m, 5H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.03 (s, IH) ; 7.06 (s, 2H) 11.8 (s br, IH).
Example 4.53
Example 4.53 was prepared by a different methodology (alkylation of Ce) : see below
Example 4.54
Figure imgf000094_0002
Chromato. - EtOAc and then MeOH/CH2Cl2 (0 to 10% MeOH)
1H NMR spectram (DMSO d6) : 1.16 (m, 3H) ; 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.59 (m, 4H) ;
2.28 (s, 6H) ; 2.55-3.0 (m, 7H) ; 3.60 (s, 3H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 6.6 (d, IH) ; 7.02
(s, 3H) ; 7.42 (m, 3H) ; 7.81 (d, IH) ; 11.8 (s br, IH).
* nd = not determined, partially purified CR used directly from previous step. Example 4.34
2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-hydroxy-2-phenylethyl]-(2S)-propylamine
Figure imgf000095_0001
Ce Example 4.34 A solution of Ce (106 mg ; 0.25 mmol) in acetonitrile (3 ml) was treated with styrene oxide and the mixture was heated at 60°C overnight. The solvent was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 hexanes (0 to 10% MeOH) to give Example 4.34 as a white foam (40 mg). Yield : 30%. 1H ΝMR spectram (DMSO d6) : 1.15 (m, 3H) ; 1.26 (m, 6H) ; 1.42 (m,4H) ; 1.61 ; (m, 4H) ; 2.29 (s, 6H) ; 2.55-2.95 (m, 5H) ; 4.16 (m, 2H) ; 4.57 (m, 3H) ; 7.06 (m, 3H) ; 7.26 (m, 5H) ; 11.6 (s br, IH).
MS-ESI : 545 [M+H]+
Example 4.44
2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-methyl-2-phenylethyl]-(2S)-propylamine
Figure imgf000096_0001
(-'e Example 4.44 A solution of Ce (126 mg ; 0.3 mmol) and 2-phenyl propionaldehyde (45 μl ; 0.3 mmol) in methanol (6 ml) under argon was cooled to 0°C. Sodium cyanoborohydride (39 mg ; 0.6 mmol) was added portionwise and the mixture was stirred for 3 h. The methanol was evaporated and the residue taken up in CH2Cl2.The organic phase was washed with sat. aq.
ΝaHCO3, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 100% EtOAc) and then
MeOH/CH2Cl2 (0 to 10% MeOH) to give Example 4.44 as a white foam (88 mg).
Yield : 54%.
1H NMR spectrum (DMSO d6) : 1.10 (m, 6H) ; 1.24 (s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ;
2.28 (m, 6H) ; 2.55-2.95 (m, 6H) ; 4.14 (s, 2H) ; 4.56 (s, 2H) ; 7.03 (s, 3H) ; 7.09 (t, 2H) ; 7.16 (d, IH) ; 7.23 (t, 2H) ; 11.8 (s br IH).
MS-ESI : 543 [M+H]+ Example 4.53 2-[3-(2,2-dimethyl-3-oxo-3-azabicyclo[2.2.1]heptan-7-ylpropoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[lH-l,2,3- benzotriazol-5-ylaminocarbonylmethyl] - (2S)-propylamine
Figure imgf000097_0001
Ce Example 4.53
To a solution of Ce (200 mg ; 0.47 mmol) in DMA (1 ml) at 140°C was added solid N-1H- l,2,3-benzotriazole-5-yl-2-chloroacetamide (98 mg ; 0.47 mmol) over 5 min. The reaction mixture was heated at 140°C for a further 5 min. The resulting orange solution was allowed to cool to room temperature and purified by flash chromatography on silica gel eluting with CΗ2C12/ΝΗ3 in MeOH (0 to 5% NH3 in MeOH) to give Example 4.53 (110 mg). Yield : 37%
1H NMR spectram (CDC13) : 1.20 (d, 3H) ; 1.22 (s, 6H) ; 1.40 (m, 4H) ; 1.70 (m, 4H) ; 2.31 (s, 6H) ; 2.77 (m, IH) ; 2.99 (m, 2H) ; 3.34 (s, 2H), 4.28 (m, 2H) ; 4.57 (s, 2H) ; 5.37 (s, IH) ; 6.95 (s, 2H) ; 7.02 (s, IH) ; 7.17 (br d, IH) ; 7.84 (br d, IH) ; 8.26 (s, IH) ; 9.50 (br s, IH) ; 9.67 (s, lH).
MS-ESI : 599 [M+H]+
Figure imgf000097_0002
To a stirred solution of 5-aminobenzotriazole (1.00 g ; 7.50 mmol) in THF (20 ml) at -10°C, were added triethylamine (0.987 g ; 9.75 mmol) and chloroacetyl chloride (0.841 g; 7.50 mmol) dropwise over 5 min. The reaction mixture was allowed to warm to room temperature and stirred overnight.
The resulting precipitate was collected by filtration, washed with CH2C12 and dried to afford N-lH-l,2,3-benzotriazole-5-yl-2-chloroacetamide (1.32 g) as a beige solid. Yield : 83.5%
1H ΝMR spectram (DMSO d6) : 4.33 (s, 2Η) ; 7.42 (br d, IH) ; 7.91 (br d, IH) ; 8.35 (s, IH) . MS-ESI : 211 [M+H]+
Intermediates for Examples 4.1-4.55, CR1-CR55 respectively Starting materials CR1-CR55 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of Example 4 given above :-
CR1
Figure imgf000098_0001
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc).
CR2
Figure imgf000098_0002
Chromato. - EtOAc/CH2Cl2 (50 to 100%) EtOAc). CR3
Figure imgf000099_0002
CR4
Figure imgf000099_0003
Chromato. - EtOAc/CH2Cl2 (0 to 40% EtOAc)
CR5
R Cf mg ; Alcohol mg ; Ph3P mg ; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
327 ; 0.5 100 ; 0.6 786 ; 3 460 ; 2 nd* nd*
Figure imgf000099_0001
Chromato. - EtOAc/CH; .Cl2 (0 to 50 % EtOAc).
CR6
Figure imgf000099_0004
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc). CR7
Figure imgf000100_0001
Chromato. - EtOAc
CR8
Figure imgf000100_0002
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc)
CR9
Figure imgf000100_0003
Chromato. - EtOAc
CR10
Figure imgf000100_0004
Chromato. - EtOAc/CH2Cl2 (0 to 70% EtOAc). CR11
Figure imgf000101_0001
Chromato. - EtOAc/CH2Cl2 (0 to 70% EtOAc).
CR12
Figure imgf000101_0002
Chromato. - EtOAc/CH2Cl2 (0 to 30% EtOAc).
CR13
Figure imgf000101_0003
Chromato. - EtOAc/CH2Cl2 (0 to 40% EtOAc).
CR14
Figure imgf000101_0004
Chromato. - EtOAc/CH2Cl2 (0 to 70% EtOAc) CR15
Figure imgf000102_0002
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc)
CR16
Figure imgf000102_0001
CR18
Cgx Cf mg ; Alcohol mg ; Ph3P mg ; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
150 ; 0.23 50 ; 0.3 367 ; 1.4 212 ; 0.92 40 nd*
F
Chromato. - EtO Ac/CH2C12 ( 3 to 20% EtOAc)
CR19
Figure imgf000102_0003
Chromato. - EtOAc/CH2Cl2 (0 to 20% EtOAc) CR20
R Cfmg; Alcohol mg ; Ph3Pmg; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
"σ 163 ; 0.25 48 ; 0.32 393 ; 1.5 230 ; 1.0 nd* nd*
Chromato. - EtOAc/CH2Cl2 (0 to 20% EtOAc)
CR21
Figure imgf000103_0003
Figure imgf000103_0001
CR22
Figure imgf000103_0002
CR23
R Cfmg; Alcohol mg ; Ph3Pmg; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
163 ; 0.25 61 ; 0.32 393 ; 1.5 230 ; 1.0 nd* nd*
Cl
Chromato. - EtOj \c/CH2Cl2 (0 to 20% EtOAc) CR24
Figure imgf000104_0003
Chromato. - EtOAc/CH2Cl2 (0 to 20% EtOAc)
CR25 The intermediate CR25 was prepared as follows:-
Figure imgf000104_0001
Cf CR25
A solution of Cf (150 mg ; 0.23 mmol) in DMF (3 ml) was cooled to 0°C and treated with potassium t-butoxide (40 mg). The bromomethyl amide (82 mg ; 0.35 mmol) was added and the mixture allowed to warm to room temperature for 1 h. The mixture was treated with sat. aq. NaHCO3 and extracted with CH2C12. The organic phase was washed with water, brine and dried over MgSO4. The crude product was used directly in the final step.
CR26
R Cf mg ; Alcohol mg ; Ph3P mg ; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
150 ; 0.23 48 ; 0.3 367 ; 1.4 212 ; 0.92 nd* nd*
Figure imgf000104_0002
Chromato. - EtOj \c/CH2Cl2 (C > to 20 EtOAc). CR27
Figure imgf000105_0001
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc).
CR28
R Cfmg; Alcohol mg ; Ph3Pmg; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
—9 173 ; 0.26 50 ; 0.32 415 ; 1.58 243 ; 1.06 nd* nd*
Cl
Chromato. - El Ac/CH2Cl2 (0 to 20 EtOAc).
CR29
R Cfmg; Alcohol mg ; Ph3Pmg; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
—9 173 ; 0.26 49 ; 0.32 415 ; 1.58 243 ; 1.06 nd* nd*
0^
Chromato. - Et OAc/CH2Cl2 (0 to 20 EtOAc).
CR30
Figure imgf000105_0002
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc). CR31
R Cf mg ; Alcohol mg ; Ph3P mg ; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
173 ; 0.26 50 ; 0.32 415 ; 1.58 243 ; 1.06 nd* nd*
""X
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc).
CR32
Figure imgf000106_0001
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc).
CR33
Figure imgf000106_0002
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc).
CR34
Figure imgf000106_0003
Chromato. - EtOAc/CH2Cl2 (0 to 20 EtOAc).
CR36
Figure imgf000106_0004
Chromato. - EtOAc/CH2Cl2 (10 to 50 EtOAc).
CR37
R Cf mg ; Alcohol mg ; Ph3P mg ; DTAD mg ; Mass MS- mmol mmol mmol mmol mg ESI
164 ; 0.25 60 ; 0.33 393 ; 1.5 230 ; 1 nd* nd*
o-.
Chromato. - EtO A c/CH2Cl2 (IC ) to 50 EtOAc).
CR38
Figure imgf000107_0001
CR39
Figure imgf000107_0002
CR40
Figure imgf000107_0003
Chromato. - EtOAc/CH2Cl2 (10 to 50 EtOAc). CR41
Figure imgf000108_0001
Chromato. - EtOAc/CH2Cl2 (10 to 50 EtOAc).
CR42
Figure imgf000108_0002
Chromato. - EtOAc/CH2Cl2 (10 to 50 EtOAc).
CR43
Figure imgf000108_0003
Chromato. - EtOAc/CH2Cl2 (10 to 50 EtOAc).
CR44
R Cfmg; Alcohol mg Ph3Pmg DTADmg Mass MS- mmol ; mmol ;mmol ;mmol mg ESI
164; 75 ; 0.33 393 ; 1.5 230 ;1 nd* 859
H H 0.25 [M+H]+
Chromato. - EtOAc/CH2( :ι2 (0 to 10 0% EtOAc) CR45
Figure imgf000109_0002
Chromato. - EtOAc/CH2Cl2 (0 to 100% EtOAc)
1H NMR spectrum (DMSO d6) : 1.16 (d, 3H) ; 1.28 (s, 6H) ; 1.42 (m, 4H) ; 1.60 (m, 4H) ; 2.28 (s, 6H) ; 2.40 (m, 2H) ; 3.06 (m, IH) ; 3.18 (m, 2H) ; 3.45-3.75 (m, 2H) ; 4.17 (dd, 2H) ; 4.56 (s, 2H) ; 4.86 (s, 2H) ; 6.37 (d, 2H) ; 6.61 (d, 2H) ; 7.01 (s, 3H) ; 8.08 (d, IH) ; 8.43 (dd, IH) ; 8.86 (d, IH) ; 11.8 (s br, IH).
CR47
Figure imgf000109_0001
solution of CR46 (108 mg ; 0.14 mmol) in CH2C12 (2 ml)was cooled to 0°C and treated with DIEA (27 μl ; 0.154 mmol). A solution of the acid chloride (14 μl ; 0.11 mmol) in CH2C12 (1 ml) was added and the mixture allowed to warm to room temperature. The crude mixture was deprotected as described for C47 above.
CR48
This intermediate was prepared using a method analogous to the preparation of CR47.
Figure imgf000109_0003
Chromato. - EtOAc CR49
Figure imgf000110_0002
Chromato. - EtOAc/CH2Cl2 (0 to 50% EtOAc)
CR50 This intermediate was prepared using a method analogous to the preparation of CR47.
R CR46 mg ; DIEA μl ; Acid chloride CH2C12 Mass MS- mmol mmol μl ; mmol mg ESI
630 ; 0.6 315 ; 1.8 95 ; 1.2 50 nd* nd*
Figure imgf000110_0001
Chromato. - EtOAc/CE [2C12 (0 to 100 % EtOAc)
CR51
This intermediate was prepared using a method analogous to the preparation of CR47.
Figure imgf000110_0003
Chromato. - EtOAc/CH2Cl2 (0 to 50% EtOAc)
CR52
This intermediate was prepared using a method analogous to the preparation of CR47.
R CR46 DIEA μl Acid CH2C12 Mass MS- mg ; ; mmol chloride** μl ; mg ESI mmol mmol
88 ; 0.11 100 ; 0.6 50 ; 0.4 10 nd* nd*
H H
Chromato. - EtOAc/CH2C] 2 (0 to 50% EtOAc)
** Cyclohexyl isocyanate was used in place of the corresponding acid chloride.
CR53
Figure imgf000111_0001
Chromato. - EtOAc/CH2Cl2 (0 to 20% EtOAc)
CR55
Figure imgf000111_0002
Chromato. - EtOAc/CH2Cl2 (0 to 20% EtOAc)
* nd = not determined, partially purified Cgx used directly for final step. Example 5
3-[2,2-dimethyl-3-oxo-3-(pyrrolidin-l-yl)propoxy]-
4-[4-(2-pyrroIidin-l-yl-2-oxo-ethyl)piperzin-l-ylethyl]-5-(3,5-dimethylphenyl)-lH- pyrazole
Figure imgf000112_0001
DR1 Example 5 ^ solution of DR1 (350 mg ; 0.53 mmol) in pyrrolidine (2 ml) was heated at 45°C overnight. The pyrrolidine was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (0 to 7% MeOH) to give Example 5 as a colourless foam (288 mg). Yield : 97%
1H NMR spectrum (CDC13) : 1.38 (s, 6H) ; 1.78 (m, 4H) ; 1.84 (m, 2H) ; 1.94 (m, 2H); 2.35 (s, 6H) ; 2.5-2.7 (m, 12H) ; 3.10 (s, 2H) ; 3.47 (t, 4H) ; 3.58 (m, 4H) ; 4.32 (s, 2H) ; 7.03 (s, IH) ; 7.27 (s, 2H) ; 8.8 (s br, IH). MS-ESI : 565 [M+H]+
The starting material DR1 was prepared as follows :-
Figure imgf000112_0002
Ab5 DR1
A solution of Ab5 (242 mg ; 0.5 mmol) and 4-(4-aminobutyl)-pyridine (125 mg ; 0.65 mmol) in DCE (5 ml) was treated with NaBH(OAc)3 (425 mg ; 2.0 mmol). The mixture was stirred for 20 h and evaporated. The residue was treated with aq. K2CO3 (10%) and the mixture extracted with EtOAc. The organic phase was washed with water, brine and dried over
MgSO . The solution was evaporated to give pure DR1 as an white solid (350 mg).
Yield : 100%
1H NMR spectram (CDC13) : 1.20 (s, 9H) ; 1.36 (s, 6H) ; 1.74 (s, 4H) ; 1.84 (m, 2H) ; 1.92 (m, 2H) ; 2.31 (s, 6H) ; 2.4-2.6 (m, 12H) ; 3.07 (s, 2H) ; 3.46 (t, 4H) ; 3.57 (m, 4H) ; 4.45 (s,
2H) ; 6.81 (s, 2H) ; 6.98 (s, IH).
MS-ESI : 665 [M+H]+
Examples 5.1-5.2 The following Example 5.1 was prepared in a similar manner to Example 5 and Example 5.2 was prepared in a manner similar to Example 2.
Figure imgf000113_0001
the table shows the NRR' group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 5 given above:-
Figure imgf000113_0002
Chromato. -MeOH/CH2Cl2 (7 to 10% MeOH)
1H NMR spectram (CDC13) : 1.39 (s, 6H) ; 1.70 (s, 4H) ; 1.83(m, 2H) ; 2.35 (s, 6H) ; 2.5-2.9 (m, 7H) ; 3.0 (m, IH) ; 3.3 (m, IH) ; 3.58 (m, 4H) ; 4.34 (dd, 2H) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 7.17 (d, 2H) ; 8.48 (d, 2H) ; 8.9 (s br IH). Example 5.2
-NRR' DR3 mg CH2C12 Prod. Mass mg MS-ESI ; mmol Form ; Yield
194 ; 0.3 White 86 ; 52% 551 rγ ,o solid [M+H] +
Chromato. - LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (0 to 100% H2O)
1H NMR spectram (CDCI3) : 1.36 (s, 6H) ; 1.74 (m, 4H) ; 1.83(m, 4H) ; 2.32 (s, 6H) ; 2.4-2.7 (m, 20H) ; 3.56 (m, 4H) ; 4.30 (s, 2H) ; 7.01 (s, IH) ; 7.02 (s, 2H) ; 8.8 (s br IH).
Intermediates for Examples 5.1-5.2, DR2 - DR3 respectively
Starting materials DR2-3 were prepared as follows, the table showing the reaction conditions and characteristics for each example, corresponding to the description of DR1 given above:-
Figure imgf000114_0001
Ab5 DR
DR2
Figure imgf000114_0002
Chromato. -EtOAc then MeOH/CH2Cl2 (5% MeOH)
1H NMR spectram (CDCI3) : 1.20 (s, 9H) ; 1.37 (s, 6H) ; 1.70 (s, 4H) ; 1.90 (m, 2H) ; 2.30 (s, 6H) ; 2.4-2.7 (m, 7H) ; 2.9 (m, IH) ; 3.3 (m, IH) ; 3.56 (m, 4H) ; 4.47 (dd, 2H) ; 6.80 (s, 2H) ; 6.99 (s, IH) ; 7.15 (d, 2H) ; 8.48 (d, 2H). DR3
Figure imgf000115_0002
Example 6 3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-
4-[4-(2-pyrrolidin-l-yl-2-oxo-ethyl)piperzin-l-ylethyl]-5-(3,5-dimethylphenyl)-lJST- pyrazole
Figure imgf000115_0001
ER1 Example 6
A solution of ERl (160 mg ; 0.23 mmol) in pyrrolidine (1 ml) was heated at 45°C overnight. The pyrrolidine was evaporated and the residue purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (5 to 10% MeOH) to give Example 6 as a white solid (141 mg).
Yield : 100%
1H NMR spectram (CDC13) : 1.36 (s, 6H) ; 1.46 (m, 4H) ; 1.77 (m, 4H) ; 1.83 (m, 2H) ; 1.93 (m, 2H) ; 2.35 (s, 6H) ; 2.45-2.65 (m, 12H) ; 3.11 (s, 2H) ; 3.47 (m, 4H) ; 4.28 (s, 2H) ; 4.65
(s, 2H) ; 7.03 (s, 2H) ; 7.26 (s, IH) ; 8.8 (s br, IH).
MS-ESI : 591 [M+H]+ Starting material ERl was prepared as follows:-
Figure imgf000116_0001
Bb Ea
Figure imgf000116_0002
ER1
Eb
DMAP (100 mg ; cat.) was added to a solution of Bb (4.0 g ; 9.72 mmol) in a mixture of acetonitrile (175 ml) and CH2C12 (40 ml). The mixture was cooled to -10 °C and a solution of (BOC)2O (2.54 g ; 11.66 mmol) in CH2C12 (50 ml) added dropwise during 1.5 h. The mixture was stirred for a further 2.5 h at -10°C to -5°C. Water was added and the mixture stirred overnight at room temperature. The mixture was extracted with CH2C12 and the organic phase washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl (20 to 80% EtOAc) to give the alcohol Ea as colourless crystals (2.4 g). Yield : 48%
1H NMR spectram (CDC13) : 1.20 (s, 9H) ; 1.34 (s, 6H) ; 1.45 (m, 4H) ; 1.77 (m, 4H) ; 2.32 (s, 6H) ; 2.42 (t, 2H) ; 3.63 (m, 2H) ; 4.42 (s, 2H) ; 4.65 (s, 2H) ; 6.83 (s, 2H) ; 7.00 (s, IH) MS-ESI : 512 [M+H]+
A solution of Ea (3.7 g ; 7.23 mmol) and CBr (3.12 g ; 9.4 mmol) in CH2C12 (150 ml) was cooled to 0°C under argon. Solid PPh3 (2.84 g ; 10.85 mmol) was added portionwise and the mixture allowed to warm to room temperature overnight. The mixture was directly purified by flash chromatography eluting with increasingly polar mixtures of EtOAc/CH2Cl2 (0 to 30% EtOAc) to give the bromide Eb as colourless crystals (3.01 g). Yield : 73% 1H NMR spectram (DMSO d6) : 1.51 (s, 9H) ; 1.27 (s, 6H) ; 1.45 (m, 4H) ; 1.63 (m, 4H) ;
2.30 (s, 6H) ; 2.63 (t, 2H) ; 3.51 (t, 2H) ; 4.27 (s, 2H) ; 4.59 (s, 2H) ; 6.93 (s, 2H) ; 7.08 (s,
IH).
MS-ESI : 575 [M+Hf
A mixture of Eb (150 mg ; 0.26 mmol) and l-(pyrrolidinocarbonylmethyl)piperazine (108 mg
; 0.548 mmol) in acetonitrile (5 ml) under argon was heated at 80°C for 16 h.
The solvent was evaporated and the residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH CH2θ2 (0 to 7% MeOH) to give ERl as a beige powder (161 mg).
Yield : 89%
1H NMR spectrum (CDC13) : 1.20 (s, 9H) ; 1.34 (s, 6H) ; 1.46 (m, 4H) ; 1.77 (m, 4H) ; 1.85
(m, 2H) ; 1.94 (m, 2H) ; 2.32 (s, 6H) ; 2.35-2.6 (m, 12H) ; 3.01 (s, 2H) ; 3.46 (m, 4H) ; 4.42
(s, 2H) ; 4.65 (s, 2H) ; 6.82 (s, 2H) ; 7.00 (s, IH). MS-ESI : 691 [M+H]+
Examples 6.1-6.10
The following examples were prepared in a similar manner to Example 6,
Figure imgf000117_0001
the table shows the NRR' group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 6 given above. The final two steps were carried out without purification or characterisation of the intermediates ER:- Example 6.1
-NRR' Eb mg ; Piperazine Pyrrolidine Mass mg ; MS-ESI mmol mg ; mmol ml Yield
172 ; 116 ; 0.66 4 146 ; 85% 570 N-A K 0.3 [M+H] +
Chromato. - Prep. LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H2O)
1H NMR spectram (DMSO d6) : 1.24 (s, 6H) ; 1.41 (m, 4H) ; 1.61 (m, 4H) ; 2.30 (s, 6H) ; 2.3- 2.6 (m, 12H) ; 3.43 (s, 2H) ; 4.14 (s, 2H) ; 4.56 (s, 2H) ; 7.01 (s, IH) ; 7.10 (s, 2H) ; 7.3 (m, 5H) ; 11.7 (s br lH).
Example 6.2
Figure imgf000118_0001
Chromato. - Prep. LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H2O)
1H NMR spectram (DMSO d6) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.31 (s, 6H) ; 2.3- 2.6 (m, 12H) ; 3.10 (s, 2H) ; 3.35-3.6 (m, 8H) ; 4.15 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.10 (s, 2H) ; 11.7 (s br lH).
Example 6.3
Figure imgf000118_0002
Chromato. - Prep. LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H2O)
1H NMR spectrum (DMSO de) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.61 (m, 4H) ; 2.30 (s, 6H) ; 2.3- 2.6 (m, 12H) ; 2.85 (s br, 2H) ; 3.15 (s br, 3H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.09 (s, 2H) ; 7.32 (m, 3H) ; 7.41 (m, 2H) ; 11.7 (s br IH). Example 6.4
-NRR' Eb mg ; Piperazine Pyrrolidine Mass mg ; MS-ESI mmol mg ; mmol ml Yield
O 115 ; 84 ; 0.44 3 27 ; 25% 584 0.2 [M+H] +
Chromato. - Prep. 1 LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (6C
H2O) 1H NMR spectram (DMSO dβ) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.31 (s, 6H) ; 2.3- 2.6 (m, 14H) ; 2.70 (t, 2H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.02 (s, IH) ; 7.11 (s, 2H) ; 7.17 (t, IH) 7.21 (d, 2H) ; 7.26 (t, 2H) ; 11.7 (s br IH).
Example 6.5
Figure imgf000119_0001
romato. - rep. 2 e u ere w t ammon um car onate at p . %
H2O)
1H NMR spectram (DMSO d6) : 1.25 (s, 6H) ; 1.41 (m, 4H) ; 1.61 (m, 4H) ; 2.30 (s, 6H) ; 2.3-
2.6 (m, 12H) ; 3.48 (s, 2H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.10 (s, 2H) ; 7.30 (d,
2H) ; 8.49 (dd, 2H) ; 11.7 (s br IH).
Example 6.6
Figure imgf000119_0002
Chromato. - Prep. LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H2O) 1H NMR spectram (DMSO d6) : 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 1.69 (m, 2H) ;
2.23 (t, 2H) ; 2.30 (s, 6H) ; 2.3-2.7 (m, 14H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.10 (s, 2H) ; 7.17 (m, 3H) ; 7.27 (t, 2H) ; 11.7 (s br IH).
Example 6.7
Figure imgf000120_0001
Chromato. - Prep. LC MS H2O/MeCN buffered with ammonium carbonate at pH 8. 0% H2O)
1H NMR spectram (DMSO d6) : 1.25 (s, 6U) ; 1.42 (m, 6H) ; 1.54 (m, 2H) ; 1.62 (m, 4H) ; 2.23 (t, 2H) ; 2.30 (s, 6H) ; 2.3-2.6 (m, 14H) ; 4.14 (s, 2H) ; 4.57 (s, 2H) ; 7.01 (s, IH) ; 7.10 (s, 2H) ; 7.17 (m, 3H) ; 7.27 (t, 2H) ; 11.7 (s br IH).
Example 6.8
Figure imgf000120_0002
Chromato. - Prep. LC/MS H2O/MeCN buffered with ammonium carbonate at pH 8.9 80% H2O) 1H NMR spectram (DMSO d6) : 0.99 (m, IH) ; 1.15 (m, 3H) ; 1.27 (s, 6H) ; 1.45 (m, 4H) ; 1.55-1.65 (m, 8H) ; 1.85 (t, 2H) ; 2.32 (s, 6H) ; 2.3-2.6 (m, 6H) ; 2.88 (d 2H) ; 3.25 (t, 2H) ; 3.86 (m, 2H) ; 4.16 (s, 2H) ; 4.59 (s, 2H) ; 7.03 (s, IH) ; 7.12 (s, 2H) ; 11.86 (s br IH). Example 6.9
1H NMR spectrum (CDC13) + CD3OD) : 1.26 (m, 6H) ; 1.37 (m, 4H) ; 1.60 (m, 4H) ; 1.71 (m, IH) ; 1.97 (m, 2H) ; 2.1 (m, IH) ; 2.27 (s, 6H) ; 2.8-3.0 (m, 4H) ; 3.15 (m, 2H) ; 3.31 m, IH) ; 3.61 (m, 2H) ; 4.14 (dd, 2H) ; 4.47 (s, 2H) ; 6.96 (s, 3H) ; 7.36 (d, 2H) ; 7.52 (d, 2H) ; 8.9 (s br, IH).
Example 6.10
-NRR' Eb mg Piperazine Pyrrolidine Mass mg ; MS-ESI mmol mg ; mmol ml Yield
230 113 ; 0.84 10 166 ; 79% 529 0.4 [M+H]
Chromato. - MeOH CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (CDC13) : 1.36 (s, 6H) ; 1.43 (m, 4H) ; 1.75 (m, 4H) ; 2.33 (s, 6H) ; 2.39 (s, 3H) ; 2.6-2.8 (m, 8H) ; 4.29 (s, 2H) ; 4.64 (s, 2H) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 7.17 (m, 3H) ; 7.26 (m, 2H) ; 8.9 (s br IH).
Example 7 3-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5-dimethylphenyl)- lH-pyrazol-4-yl]-N-[2-(3-methoxyphenyI)ethyl]-(2S)-propylamine
Figure imgf000121_0001
FR Example 7 A mixture of FR (167 mg ; 0.25 mmol), 3-(2-hydroxyethyl)-methoxybenzene (50 mg ; 0.325 mmol) and triphenylphosphine (393 mg ; 1.5 mmol) in THF (5 ml) at 0°C under argon was treated with DTAD (230 mgl ; 1.0 mmol). The mixture was allowed to warm to room temperature for 1 h when water was added. The mixture was extracted with CH2CI2 and the organic phase was washed with water, brine and dried over MgSO4. The residue was taken up directly in CH2C12 (3 ml) and treated dropwise with n-propylamine (150 μl ; 2.5 mmol). The mixture was stirred at room temperature for lh and then purified directly by flash chromatography eluting with increasingly polar mixtures of CH2C12 and then MeOH/CH2Cl2 (0 to 10% MeOH) to give Example 7 as a white foam (100 mg). Yield : 70%
1H NMR spectram (DMSO dβ) : 1.15 (d, 3H) ; 1.27 (s, 6H) ; 1.54 (m, 4H) ; 1.67 (m, 4H) ; 1.85 (s, IH) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.24 (m, 2H) ; 3.7 (s, 3H) ; 4.16 (m, 3H) ; 6.7 (m, 3H) ; 7.03 (s, IH) ; 7.05 (s, 2H) ; 7.15 (t, IH) ; 11.8 (s br, IH). MS-ESI : 573 [M+H]+
The starting material FR was prepared as follows:
Figure imgf000122_0001
FR
This preparation was exactly analogous to that of Examples 4 and 8 Yields and data are given in the following table: -
Figure imgf000123_0001
A solution of Fd (1.12g ; 2.55 mmol) in CH2C12 (50 ml) was cooled to 0°C under argon.
DIEA (580 μl ; 3.3 mmol) was added followed by a solution of DNOSC1 (0.72 g ; 2.68 mmol) in CH2CI2 (10 ml). The mixture was allowed to warm to room temperature for 2 h and was treated with aq. HCl (IN). The mixture was extracted with CH2CI2 and the organic phase was washed with water, brine and dried over MgSO4. The residue was purified by flash chromatography eluting with increasingly polar mixtures of EtO Ac/CH2Cl2 (0 to 40% EtOAc) to give FR as a yellow foam (1.14 g). Yield : 67%
1H NMR spectram (DMSO d6) : 1.10 (d, 3H) ; 1.25 (s, 6H) ; 1.52 (m, 4H) ; 1.67 (m, 4H) ; 1.83 (s, IH) ; 2.29 (s, 6H) ; 2.83 (m, IH) ; 3.19 (m, 2H) ; 4.13 (m, 3H) ; 6.96 (s, 2H) ; 6.98 (s, IH) ; 8.12 (d, IH) ; 8.51 (br s, IH) ; 8.52 (q, IH) ; 8.79 (d, IH) ; 11.9 (s br IH). MS-ESI : 669 [M+H]+
Starting material Fa was prepared as follows :-
Figure imgf000124_0001
a Fa
A mixture of 8 (4.0 g ; 22 mmol) and oxalyl bromide (9.5 g ; 44 mmol) containing one drop of DMF was heated at 50°C for 2h and then cooled. The excess of oxalyl bromide was evaporated and the residue azeotroped with toluene to give crude 9 which was taken up directly in CH2C12 (30 ml) and cooled to 0°C. Diisopropylethylamine (40 ml ; 200 mmol) was added followed by 2.2.2-azabicyclooctane (2.95 g ; 20 mmol) in CH2C12 (20 ml). The mixture was allowed to warm to room temperature overnight and was diluted with CH2C12, washed with aq. HCl (2N), aq. NaOH (IN), water, brine and dried over MgSO4.The residue was evaporated to give Fa as a beige solid (3.75 g). Yield : 68% 1H NMR spectram (CDC13) : 1.38 (s, 6H) ; 1.67 (m, 6H) ; 1.89 (m, 2H) ; 1.95 (s, IH) ; 3.40 (m, 2H) ; 3.63 (s, 2H) 4.02 (s, IH). Example 7.1
The following example was prepared in a similar manner to Example 6,
Figure imgf000125_0001
The following example was prepared in a similar manner, the table shows the NRR' group relating to the above stracture, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 7 given above: -
Example 7.1
Figure imgf000125_0002
Chromato. - EtOAc
1H NMR spectrum (DMSO d6) : 1.13 (d, 3H) ; 1.27 (s, 6H) ; 1.55 (m, 4H) ; 1.68 (m, 4H) ;
1.86 (s, IH) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.31 (m, 2H) ; 4.14 (m, 3H) ; 5.93 (s, 2H) ;
6.53 (dd, IH) ; 6.67 (d, IH) ; 6.74 (d, IH) ; 7.02 (s, IH) ; 7.05 (s, 2H) ; 7.15 (t, IH) ; 11.74 (s br, IH). MS-ESI : 587 [M+H]+
Example 8
3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-
4-[l-(3-methoxyphenethylaminomethyl)cycloprop-l-yl]-5-(3,5-dimethylphenyl)-lH- pyrazole
Figure imgf000126_0001
Q I Example 8
Example 8 was prepared in a similar manner to Example 7, the table shows the reaction conditions and characteristics corresponding to the description of the preparation of Example 7 given above:-
Figure imgf000126_0002
Chromato. - MeOH/CH2Cl2 (0 to 10% MeOH) 1H NMR spectrum (DMSO d6) : 0.42 (m, 2H) ; 0.70 (m, 2H) ; 1.25 (s, 6H) ; 1.42 (m, 4H) ; 1.62 (m, 4H) ; 2.3 (s, 6H) ; 2.6-2.85 (m, 7H) ; 3.69 (s, 3H) ; 4.14 (s, 3H) ; 4.57 (s, 2H) ; 6.71 (m, 3H) ; 7.03 (s, IH) ; 7.15 (t, IH) ; 7.33 (s, 2H) ; 11.74 (s br, IH). MS-ESI : 571 [M+H]+
Starting material GR was prepared as follows:
Figure imgf000127_0001
Ga Gb
Figure imgf000127_0002
Gc
Gd Ge
Figure imgf000127_0003
GR
This preparation was exactly analogous to that of examples 4 and 7
Yields and data are given in the following table:
Figure imgf000127_0004
Figure imgf000128_0002
Example 9
3-[2,2-dimethyl-3-oxo-3-(azabicyclo[2.2.1]heptan-7-yl)propoxy]-
4-(4-phenylpiperidin-l-ylmethyl)-5-(3,5-dimethylphenyl)-lH-pyrazole
Figure imgf000128_0001
Example 9
HR A mixture of 4-phenyl piperidine (98 mg ; 0.6 mmol) and formaldehyde (0.32 ml ; 4.0 mmol ; 37wt% aqueous solution) in water (0.2 ml) and acetic acid (0.2 ml) was stirred for 5 min and treated with HR (74 mg ; 0.2 mmol). The mixture was heated at 75°C for 2 h. The solvents were evaporated, MeOH (0.5 ml),water (0.5 ml) and ammonia in MeOH(7N) (0.6 ml) were added and the mixture stirred for a further 3 h. The solvents were evaporated and the residue was purified by preparative LC/MS chromatography with H2θ/MeCN buffered with ammonium carbonate at pH 8.9 (80% H2O) to give Example 9 as a white solid (75 mg). Yield : 69% 1H NMR spectrum (DMSO d6) : 1.27 (s, 6H) ; 1.42 (m, 4H) ; 1.6 (m, 6H) ; 1.75 (m, 2H) ; 2.07 (m, 2H) ; 2.32 (s, 6H) ; 2.52 (m, IH) ; 2.97 (m, 2H) ; 3.16 (s, 2H) ; 4.17 (s, 2H) ; 4.57 (s, 2H) ; 7.02 (s, IH) ; 7.17 (t, IH) ; 7.23 (d, 2H) ; 7.28 (t, 2H) 12.1 (s, IH). MS-ESI : 541 [M+H]+
The starting material HR was prepared as follows:
Figure imgf000129_0001
Ha
Figure imgf000129_0002
A solution of 4-(3',5'-dimethylphenyl) acetoacetate (12.36 g ; 60 mmol) in EtOH (300 ml) was treated with hydrazine hydrate (5.82 ml ; 120 mmol) and heated under reflux for 3 h. The
EtOH was evaporated and the residue triturated with Et2θ. The precipitate was collected, washed and dried to give Ha as a white powder (9.54 g).
Yield : 85%
1H NMR spectrum (DMSO de) : 2.28 (s, 6H) ; 5.83 (s, IH) ; 6.93 (s, IH) ; 7.27 (s, 2H) ; 9.5 (s br, IH).
MS-ESI : 189 [M+H]+ A mixture of Ha (3.1 g ; 16.5 mmol) and Ba (5.15 g ; 19.8 mmol) in DMA (40 ml) under argon was treated with K2CO3 (4.56 g ; 33.0 mmol). The mixture was stirred and heated at 70°C for 5h. The mixture was poured into sat. aq. NaHCO3, extracted with EtOAc and the organic phase was washed with water, brine and dried over MgSO4. The solid residue was recrystallised from toluene to give HR as a pale yellow solid (2.96 g). Yield : 49%
1H NMR spectrum (DMSO d6) : 1.24 (s, 6H) ; 1.41 (m, 4H) ; 1.63 (m, 4H) ; 2.29 (s, 6U) ; 4.09 (s, 2H) ; 4.57 (s, 2H) ; 6.08 (s, IH) 6.97 (s, IH) ; 7.31 (s, 2H). MS-ESI : 368 [M+H]+
Examples 9.1-9.12
The following examples were prepared in a similar manner to Example 9,
Figure imgf000130_0001
H2-13
the table shows the R group relating to the above structure, the reaction conditions and characteristics for each example, corresponding to the description of the preparation of Example 9 given above:-
Figure imgf000130_0002
Chromato. - Preparative LC/MS chromatography with H2θ/MeCN buffered with ammonium carbonate at pH 8.9 (60%) H2O).
1H NMR spectrum (DMSO de) : 1.25 (s, 6H) ; 1.41 (m, 6H) ; 1.53 (m, 2H) ; 1.58 (m, 4H) ; 2.29 (s, 6H) ; 2.3-2.65 (m, 12H) ; 3.01 (s, 2H) ; 4.15 (s, 2H) ; 4.56 (s, 2H) ; 7.00 (s, IH) ; 7.17 (m, 3H) ; 7.25 (m, 2H) ; 7.44 (s, 2H) ; 11.9 (s br, IH).
Figure imgf000131_0002
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H2O). 1H NMR spectram (DMSO d6) : 1.23(s, 6H) ; 1.41 (m, 4H) ; 1.60 (m, 4H) ; 1.73 (m, 2H) ; 2.1 (s, 3H) ; 2.27 (s, 6H) ; 2.35 (m, 2H) 2.5-2.7 (m, 2H) ; 3.14 (s, 2H) ; 4.14 (s, 2H) ; 4.56 (s, 2H) ; 6.99 (s, IH) ; 7.12 (m, 3H) ; 7.23 (m, 2H) ; 7.44 (s, 2H) ; 11.9 (s br, IH).
Example 9.3
R HR mg ; Formaldehyde Amine mg ; Prod. Mass mg ; MS- mmol mmol Form Yield ESI ml ; mmol
^ 80 ; 0.20 0.25 ; 3.0 82 ; 0.6 White 27 ; 26% 516 solid [M+H]
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H2O).
Example 9.4
Figure imgf000131_0001
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H2O). Example 9.5
R HR mg ; Formaldehyde Amine mg ; Prod. Mass mg MS- mmol mmol Form ; Yield ESI ml ; mmol
80 ; 0.20 0.25 ; 3.0 97 ; 0.6 White 37 ; 34% 542
Figure imgf000132_0001
solid [M+H]
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (100 to 0% H2O).
Example 9.6
Figure imgf000132_0003
carbonate at pH 8.9 (100 to 0% H2O).
Example 9.7
R HR mg ; Formaldehyde Amine mg Prod. Mass mg MS- mmol ; mmol Form ; Yield ESI ml ; mmol
148 ; 0.16 ; 2.0 298 ; 2.0 White nd* ; nd* 543
Figure imgf000132_0002
0.40 solid [M+H]
+
Chromato. - Prep, arative LC/1N AS chromatograp hy with H2O/i\ tfeCN buff sred with an αmonium carbonate at pH 8.9 (60% H2O).
1H NMR spectrum (DMSO dg) : 1.24 (s, 6H) ; 1.42 (m, 6H) ; 1.54 (m, 2H) ; 1.61 (m, 4H) ; 2.06 (s, 3H) ; 2.25 (s, 6H) ; 2.31 (m, 2H) ; 2.5-2.65 (m, 2H) ; 3. 12 (s, 2H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 6.98 (s, IH) ; 7.13 (m, 3H) ; 7.22 (m, 2H) ; 7.42 (s, 2H) ; 11.9 (s br, IH). Example 9.8
R HR mg ; Formaldehyde Amine mg Prod. Mass mg MS- mmol ; mmol Form ; Yield ESI ml ; mmol
148 ; 0.16 ; 2.0 298 ; 2.0 gum nd* ; nd* 529
} 0.40 [M+H]
+
Chromato. - Prep arative LC/MS chromatograp ly with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H2O). 1H NMR spectrum (DMSO d6) : 1.24 (s, 6H) ; 1.42 (m, 6H) ; 1.57 (m, 6H) ; 2.28 (s, 6H) ; 2.5- 2.6 (m, 4H) ; 3. 45 (s, 2H) ; 4.16 (s, 2H) ; 4.55 (s, 2H) ; 6.99 (s, IH) ; 7.14 (m, 3H) ; 7.25 (m, 2H) ; 7.30 (s, 2H) ; 11.9 (s br, IH).
Example 9.9
Figure imgf000133_0001
romato. - reparat ve c romatograp y w t 2 e u ere w t ammon um carbonate at pH 8.9 (80% H2O).
1H NMR spectram (DMSO d6) : 1.24 (s, 6H) ; 1.29 (m, 2H) ; 1.42 (m, 6H) ; 1.53 (m, 2H) ;
1.57 (m, 4H) ; 2.29 (s, 6H) ; 2.5-2.6 (m, 4H) ; 3. 46 (s, 2H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 7.01
(s, IH) ; 7.15 (m, 3H) ; 7.25 (m, 2H) ; 7.30 (s, 2H) ; 11.9 (s br, IH). Example 9.10
R HR mg ; Formaldehyde Amine mg Prod. Mass mg MS- mmol ; mmol Form ; Yield ESI ml ; mmol
74 ; 0.20 0.08 ; 1.0 162 ; 1.2 White 42 ; 20% 529
)-N' solid [M+H]
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (80% H2O).
1H NMR spectrum (DMSO d6) : 1.24 (s, 6H) ; 1.41 (m, 4H) ; 1.59 (m, 4H) ; 1.69 (m, 2H) ; 2.29 (s, 6H) ; 2.3-2.65 (m, 4H) ; 3.45 (s, 2H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 7.01 (s, IH) ; 7.157 (m, 3H) ; 7.23 (m, 2H) ; 7.31 (s, 2H) ; 11.9 (s br, IH).
Example 9.11
Figure imgf000134_0001
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60% H2O).
1H NMR spectram (DMSO d6) : 1.24 (s, 6H) ; 1.28 (m, 2H) ; 1.41 (m, 6H) ; 1.49 (m, 2H) ; 1.60 (m, 4H) ; 2.30 (s, 6H) ; 2.3-2.65 (m, xH) ; 3.44 (s, 2H) ; 3.70 (s, 3H) ; 4.16 (s, 2H) ; 4.56 (s, 2H) ; 6.81 (d, 2H) ; 7.01 (s, IH) ; 7.04 (d, 2H) ; 7.30 (m, 2H) ; 11.9 (s br, IH).
Example 9.12
Figure imgf000134_0002
Chromato. - Preparative LC/MS chromatography with H2O/MeCN buffered with ammonium carbonate at pH 8.9 (60%) H2O).
1H NMR spectram (CDC13) : 1.34 (m, 6H) ; 1.45 (m, 5H) ; 1.75 (m, 4H) ; 1.9 (m, IH) ; 2.31 (m, IH) ; 2.35 (s, 6H) ; 2.5 (m, IH) ; 2.59 ( , 2H) ; 2.68 (m, 3H) ; 3.39 (dd, 2H) ; 4.28 (s, 2H) ; 4.65 (s, 2H) ; 7.02 (s, IH) ; 7.16 (m, 3H) ; 7.25 (m, 2H) ; 7.34 (s, 2H) ; 8.9 (s br, IH).
Example 10
2-[3-(2,2-dimethyl-3-{azabicycIo[2.2.1]heptan-7-yl}propoxy)-5-(3,5-dimethylphenyl)-lHr- pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine
Figure imgf000135_0001
C1 Example 10
A solution of Example 4 (123 mg ; 0.21 mmol) in THF (3 ml) under argon was treated with a solution of LiAlELt (420 μl ; 0.42 mmol ; IM solution in THF). The mixture was heated at 60°C for lh. The mixture was treated with an excess of Glaubers' Salt (Νa2SO4.10H2O), filtered and evaporated. The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (5 to 15% MeOH) to give Example 10 as a white solid (80 mg). Yield : 68%
1H NMR spectrum (DMSO d6) : 0.93 (s, 6H) ; 1.18 (d, 3H) ; 1.2 (m, 4H) ; 1.59 (m, 4H) ; 2.19 (s, 2H) ; 2.3 (s, 6H) ; 2.55-2.95 (m, 7H) ; 3.07 (s, 2H) ; 3.86 (s, 2H) ; 5.94 (s, 2H) ; 6.53 (d, IH) ; 6.66 (s, IH) ; 6.74 (d, IH) ; 7.04 (s, IH) ; 7.05 (s, 2H) ; 11.7 (s br IH). MS-ESI : 559 [M+H]+ Example 11
2-[3-(2,2-dimethyl-3-hydroxypropoxy)-5-(3,5-dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine
Figure imgf000136_0001
A solution of JR (109 mg ; 0.17 mmol) in THF (2 ml) under argon was treated with a solution of UAIU4 (350 μl ; 0.35 mmol ; IM solution in THF). The mixture was heated at 60°C for lh. The mixture was treated with an excess of Glaubers Salt (Na2SO .10H2θ), filtered and evaporated. The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (0 tol5% MeOH) to give Example 11 as a white solid (68 mg). Yield : 84%
1H NMR spectram (DMSO d6) : 0.92 (s, 6H) ; 1.17 (d, 3H) ; 2.3 (s, 6H) ; 2.5-2.9 (m, 7H) ; 3.27 (s, 2H) ; 3.86 (s, 2H) ; 4.61 (t br, IH) ; 5.94 (s, 2H) ; 6.53 (d, IH) ; 6.67 (s, IH) ; 6.74 (d, IH) ; 7.03 (s, IH) ; 7.04 (s, 2H) ; 11.7 (s br IH). MS-ESI : 480 [M+H]+
Starting material JR was prepared as follows: -
Figure imgf000136_0002
C17 JR
A solution of Example 4 (205 mg ; 0.35 mmol) in acetonitrile (2 ml) was treated with c.HCl (1 ml) and the mixture was stirred at room temperature for 2h. The mixture was concentrated, extrated with CH2CI2 and the organic phase was washed with water, brine and dried over MgSO4. The residue JJR. was obtained as a yellow solid (218 mg). It was used directly in the final step of the synthesis of Example 11 . Yield : 80% 1H NMR spectram (DMSO de) : 1.24 (m, 9H) ; 2.33 (s, 6H) ; 2.78 (m, 2H) ; 2.95 (m, 2H) ;
3.14 (m, 3H) ; 4.13 (m, 2H) ; 5.98 (s, 2H) ; 6.62 (d, IH) ; 6.76 (s, IH) ; 6.84 (d, IH) ; 7.05 (s, 2H) ; 7.07 (s, 2H) ; 8.6 (s br, IH) ; 11.7 (s br IH). MS-ESI : 494 [M+H]+
Example 12
2-[3-(2,2-dimethyl-3-oxo3-isopropoxy-propoxy)-5-(3,5-dimethylphenyl)-lH-pyrazol-4- yl]-N-[2-(l,3-benzodioxol-5-yl)ethyl]-(2S)-propylamine
Figure imgf000137_0001
JR Example 12 A solution of JR (109 mg ; 0.17 mmol) in CH2C12 (1 ml) was added to a solution of EDCI (37 mg ; 0.19 mmol) and DMAP (5 mg ; cat.) in iPrOH (5 ml). H2SO4 (5 drops ; cat.) was added and the mixture was heated under reflux overnight over molecular sieves. The mixture was concentrated and extracted with CH2Cl2/water and the organic phase was washed with water, brine and dried over MgSO . The residue was purified by flash chromatography eluting with increasingly polar mixtures of MeOH/CH2Cl2 (0 to 10% MeOH) to give Example 12 as a yellow gum (59 mg). Yield : 65%
1H ΝMR spectram (DMSO d6) : 1.16 (m, 6H) ; 1.24 (m, 9H) ; 2.32 (s, 6H) ; 2.8 (m, 2H) ; 2.95 (m, 2H) ; 3.15 (m, 3H) ; 4.16 (dd, 2H) ; 4.88 (m, IH) ; 5.98 (s, 2H) ; 6.62 (d, IH) ; 6.74 (s, IH) ; 6.83 (d, IH) ; 7.04 (s, 2H) ; 7.07 (s, 2H) ; 11.7 (s br IH). MS-ESI : 536 [M+H]+
THERAPEUTIC USES
Compounds of Formula (I) are provided as medicaments for antagonising gonadotropin releasing hormone (GnRH) activity in a patient, eg, in men and/or women. To this end, a compound of Formula (I) can be provided as part of a pharmaceutical formulation which also includes a pharmaceutically acceptable diluent or carrier (eg, water). The formulation may be in the form of tablets, capsules, granules, powders, syrups, emulsions (eg, lipid emulsions), suppositories, ointments, creams, drops, suspensions (eg, aqueous or oily suspensions) or solutions (eg, aqueous or oily solutions). If desired, the formulation may include one or more additional substances independently selected from stabilising agents, wetting agents, emulsifying agents, buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol.
The compound is preferably orally administered to a patient, but other routes of administration are possible, such as parenteral or rectal administration. For intravenous, subcutaneous or intramuscular administration, the patient may receive a daily dose of O.lmgkg"1 to 30mgkg_1 (preferably, 5mgkg_1 to 20mgkg_1) of the compound, the compound being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, the patient may receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. A suitable pharmaceutical formulation is one suitable for oral administration in unit dosage form, for example as a tablet or capsule, which contains between lOmg and lg (preferably, 100 mg and lg) of the compound of the invention.
Buffers, pharmaceutically acceptable co-solvents (eg, polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.
One aspect of the invention relates to the use of compounds according to the invention for reducing the secretion of LH and/or FSH by the pituitary gland of a patient. In this respect, the reduction may be by way of a reduction in biosynthesis of the LH and FSH and/or a reduction in the release of LH and FSH by the pituitary gland. Thus, compounds according to the invention can be used for therapeutically treating and/or preventing a sex hormone related condition in the patient. By "preventing" we mean reducing the patient's risk of contracting the condition. By "treating" we mean eradicating the condition or reducing its severity in the patient. Examples of sex hormone related conditions are: a sex hormone dependent cancer, benign prostatic hypertrophy, myoma of the uterus, endometriosis, polycystic ovarian disease, uterine fibroids, prostatauxe, myoma uteri, hirsutism and precocious puberty. Examples of sex hormone dependent cancers are: prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma. The compounds of the invention may be used in combination with other drags and therapies used to treat / prevent sex-hormone related conditions.
If formulated as a fixed dose such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically-active agent within its approved dosage range. Sequential use is contemplated when a combination formulation is inappropriate.
In the field of medical oncology examples of such combinations include combinations with the following categories of therapeutic agent: i) anti-angiogenic agents (for example linomide, inhibitors of integrin vβ3 function, angiostatin, endostatin, razoxin, thalidomide) and including vascular endothelial growth factor (NEGF) receptor tyrosine kinase inhibitors (RTKIs) (for example those described in international patent applications publication nos. WO-97/22596, WO-97/30035, WO-97/32856 and WO-98/13354, the entire disclosure of which documents is incorporated herein by reference); ii) cytostatic agents such as anti-oestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrozole, vorazole, exemestane), anti- progestogens, anti-androgens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), inhibitors of testosterone 5oc-dihydroreductase (for example finasteride), anti- invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function) and inhibitors of growth factor function, (such growth factors include for example epidermal growth factor (EGF), platelet derived growth factor and hepatocyte growth factor such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine/threonine kinase inhibitors); iii) biological response modifiers (for example interferon); iv) antibodies (for example edrecolomab); and v) anti-proliferative/anti-neoplastic drags and combinations thereof, as used in medical oncology, such as anti-metabolites (for example anti-folates like methotrexate, fluoropyrimidines like 5-fluorouracil, purine and adenosine analogues, cytosine arabinoside); anti-tumour antibiotics (for example anthracyclines like doxorabicin, daunomycin, epirubicin and idarabicin, mitomycin-C, dactinomycin, mithramycin); platinum derivatives (for example cisplatin, carboplatin); alkylating agents (for example nitrogen mustard, melphalan, chlorambucil, busulphan, cyclophosphamide, ifosfamide, nitrosoureas, thiotepa); anti-mitotic agents (for example vinca alkaloids like vincristine and taxoids like taxol, taxotere); enzymes (for example asparaginase); thymidylate synthase inhibitors (for example raltitrexed); topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, irinotecan).
The compounds of the invention may also be used in combination with surgery or radiotherapy.
ASSAYS The ability of compounds according to the invention to act as antagonists of GnRH can be determined using the following in vitro assays. Binding Assay Using Rat pituitary GnRH Receptor The assay is performed as follows :-
1. Incubate crude plasma membranes prepared from rat pituitary tissues in a Tris.HCl buffer (pH. 7.5, 50 mM) containing bovine serum albumin (0.1%), [I-125]D-t-Bu-Ser6-Pro9- ethyl amide-GnRH, and the test compound. Incubation is at 4 C for 90 minutes to 2 hours.
2. Rapidly filter and repeatedly wash through a glass fibre filter.
3. Determine the radioactivity of membrane bound radio-ligands using a gamma counter. From this data, the IC50 of the test compound can be determined as the concentration of the compound required to inhibit radio-ligand binding to GnRH receptors by 50%. Compounds according to the present invention have activity at a concentration from InM to 5 μM.
Binding Assay Using Human GnRH Receptor
Crude membranes prepared from CHO cells expressing human GnRH receptors are sources for the GnRH receptor. The binding activity of compounds according to the invention can be determined as an IC50 which is the compound concentration required to inhibit the specific binding of [125I]buserelin to GnRH receptors by 50%. [125I]Buserelin (a peptide GnRH analogue) is used here as a radiolabelled ligand of the receptor. Assay to Determine Inhibition of LH release
The LH release assay can be used to demonstrate antagonist activity of compounds, as demonstrated by a reduction in GnRH-induced LH release.
Preparation of Pituitary Glands
Pituitary glands obtained from rats are prepared as follows. Suitable rats are Wistar male rats (150-200g) which have been maintained at a constant temperature (eg, 25°C) on a 12 hour light/12 hour dark cycle. The rats are sacrificed by decapitation before the pituitary glands are aseptically removed to tube containing Hank's Balanced Salt Solution (HBSS). The glands are further processed by:-
1. Centrifugation at 250 x g for 5 minutes;
2. Aspiration of the HBSS solution;
3. Transfer of the glands to a petri dish before mincing with a scalpel; 4. Transfer of the minced tissue to a centrifuge tube by suspending the tissue three successive times in 10 ml aliquots of HBSS containing 0.2% collagenase and 0.2% hyaluronidase; 5. Cell dispersion by gentle stirring of the tissue suspension while the tube is kept in a water bath at 37°C; 6. Aspiration 20 to 30 times using a pipette, undigested pituitary fragments being allowed to settle for 3 to 5 minutes;
7. Aspiration of the suspended cells followed by centrifugation at 1200 x g for 5 minutes;
8. Re-suspension of the cells in culture medium of DMEM containing 0.37% NaHCO3, 10% horse serum, 2.5% foetal bovine serum, 1% non essential amino acids, 1% glutamine and 0.1% gentamycin;
9. Treatment of the undigested pituitary fragments 3 times with 30 ml aliquots of the collagenase and hyaluronidase;
10. Pooling of the cell suspensions and dilution to a concentration of 3 x 10 cells/ml;
11. Placing of 1.0ml of this suspension in each of a 24 well tray, with the cells being maintained in a humidified 5% CO /95% air atmosphere at 37°C for 3 to 4 days Testing of Compounds
The test compound is dissolved in DMSO to a final concentration of 0.5% in the incubation medium.
1.5 hours prior to the assay, the cells are washed three times with DMEM containing 0.37% NaHCOβ, 10% horse serum, 2.5% foetal bovine serum, 1% non essential amino acids
(100X), 1% glutamine (100X), 1% penicillin/streptomycin (10,000 units of each per ml) and
25 mM HEPES at pH 7.4. Immediately prior to the assay, the cells are again washed twice in this medium .
Following this, 1ml of fresh medium containing the test compound and 2nM GnRH is added to two wells. For other test compounds (where it is desired to test more than one compound), these are added to other respective duplicate wells. Incubation is then carried out at 37 °C for three hours.
Following incubation, each well is analysed by removing the medium from the well and centrifuging the medium at 2000 x g for 15 minutes to remove any cellular material. The supernatant is removed and assayed for LH content using a double antibody radio-immuno assay. Comparison with a suitable control (no test compound) is used to determine whether the test compound reduces LH release. Compounds according to the present invention have activity at a concentration from InM to 5 μM.

Claims

CLAIMS:
A compound of Formula (I),
Figure imgf000143_0001
Formula (I) wherein
R1 is selected from: hydrogen, optionally-substituted ^alkyl, optionally substituted aryl or optionally-substituted arylCι_6alkyl; R2 is an optionally-substituted mono or bi-cyclic aromatic ring; R3 is selected from a group of Formula (Ila) to Formula (Hf):
Figure imgf000143_0002
Formula (Ila) Formula (Eb)
Figure imgf000143_0003
Formula (Be) Formula (lid)
Figure imgf000143_0004
Formula (He) Formula (Hf) R5 is a group of Formula (IH):
Figure imgf000143_0005
Formula (HI)
R6 and R6a are independently selected from hydrogen, fluoro, optionally substituted Cj..6alkyl, optionally-substituted aryl or optionally substituted arylCι_6alkyl, or R and R6a taken together and the carbon atom to which they are attached form a carbocyclic ring of 3-7 atoms, or R and R a taken together and the carbon atom to which they are attached form a carbonyl group;
or when A is not a direct bond the group
Figure imgf000144_0001
forms a carbocyclic ring of
3-7 carbon atoms or a heterocyclic ring containing one or more heteroatoms;
or the group
Figure imgf000144_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms;
R7 is selected from: hydrogen, optionally-substituted Cι_6alkyl, optionally-substituted arylCi_6alkyl, optionally-substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylCι_6alkyl, R'O -βalkyl-, R9R10NCi.6alkyl-, R9R10NC(O)Cι.6alkyl, -C(NR9R10)=NH; or when R3 is a group of Formula (lie) or (lid) R7 is of the formula -J-K-R8;
R is selected from: (i) hydrogen, Cι.6alkyl, C2.6alkenyl, C2.6alkynyl, haloCi-isalkyl,
Figure imgf000144_0003
N,N-di-Cwalkylamino, C1.6alkyl-S(On)-, -O-Rb, -NRbRc, -C(O)-Rb, - C(O)O-Rb, -CONRbRc, NH-C(O)-Rb or -S(On)NRbRc, where Rb and Rc are independently selected from hydrogen and Ci.4alkyl optionally substituted with hydroxy, amino, N-Cι.4alkylamino, N,N-di-C1.4alkylamino, HO-C2.4alkyl-NH- or HO-C2.4alkyl-N(Cι..4alkyl)-; (ii) nitro when B is a group of Formula (IN) and X is CH and p is 0; (iii) C .7cycloalkyl, aryl or arylCj.. alkyl each of which is optionally substituted by
R12, R13 and R14; (iv) -(Q)-aryl , -(Q)-heterocyclyl, -aryl-(Q)-aryl, each of which is optionally substituted by R12, R13 and R14 wherein -(Q)- is selected from E, F or a direct bond; (v) heterocyclyl or heterocyclylCι_6alkyl each of which is optionally substituted by up to 4 substituents independently selected from R , R and R ;
(vi) a group selected from R12, R13 and R14;
R9 and R10 are independently selected from: hydrogen, hydroxy, optionally substituted Cι.6alkyl, optionally substituted aryl, optionally substituted arylCi-galkyl, an optionally substituted carbocyclic ring of 3-7 atoms, optionally substituted heterocyclyl, optionally substituted heterocyclylCι.6alkyl or R9 and
R10 taken together can form an optionally substituted ring of 3-9 atoms or R9 and R10 taken together with the carbon atom to which they are attached form a carbonyl group; R11 is selected from: hydrogen, optionally substituted Cι_6alkyl, or N(R9R10); R12 is selected from: hydrogen, hydroxy, R17R18N(CH2)CC-, R17R18NC(O)(CH2)cc-, optionally substituted Cι.6alkyl- C(O)N(R )(CH2)Cc-, optionally substituted Cι.6alkyl-SO2N(R9)-, optionally substituted aryl-SO2N(R9)-, C1.3perfluoroalkyl-SO2N(R9)-; optionally substituted C1.6alkyl-N(R9)SO2-, optionally substituted aryl-N(R9)SO2-, Cι- perfluoroalkyl-N(R9)SO2- optionally substituted Cι-6alkanoyl-N(R9)SO2-; optionally substituted aryl-C(O)N(R9)SO2-, optionally substituted Cι_6alkyl-S(On) -, optionally substituted aryl-S(On) - , Cι_3perfluoroalkyl-, Cι_3perfluoroalkoxy, optionally substituted Cι_6alkoxy, carboxy, halo, nitro or cyano; R 3 and R14 are independently selected from: hydrogen, hydroxy, oxo, optionally substituted Chalky!, optionally substituted Cι_6alkanoyl, optionally substituted
C2.6alkenyl, cyano, nitro, Cι. perfluoroalkyl-, Cι_3perfluoroalkoxy, optionally substituted aryl, optionally substituted arylCι_6alkyl, R9O(CH2)s-, R9(O)O(CH2)s-, R9OC(O)(CH2)s-, R16S(On)(CH2)s-, R9R10NC(O)(CH2)S- or halo; R15 is selected from: hydrogen, optionally substituted Cι.6alkyl, R19OC(O)-, R9R10NC(O)-, R9C(O)-, R9S(O„)-;
1 ή
R is selected from: hydrogen, Ci-6alkyl, Cι_3perfluoroalkyl or optionally-substituted aryl; 17
R is independently selected from: hydrogen, hydroxy, cyano or optionally substituted Cι.6alkyl; R18 is a group of formula R18a-C(R9R10)0-ι- wherein R18a is selected from:
R19OC(O)-, R9R10NC(O)-, R9R10N-, R9C(O)-, R9C(O)N(R10)-, R9R10NC(O)-, R R10NC(O)N(R10)-, R9SO2N(R10)-, R9R10NSO2N(R10)-, R9C(O)O-, R9OC(O)-,
R9R10NC(O)O-, R9O-, R9S(On)-, R9R10NS(On) -, hydrogen .optionally substituted
Ci-βalkyl, optionally substituted heterocyclyl;
17 18 or R and R when taken together form an optionally substituted carbocyclic ring of 3-7 atoms or optionally substituted heterocyclyl; R19 is selected from: hydrogen, optionally substituted Cι_6alky, optionally substituted aryl, optionally substituted arylCι_6alkyl, optionally substituted C3.7cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclyl -βalkyl; R and R are independently selected from hydrogen, optionally substituted Cι_6alkyl, optionally substituted C3. cycloalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylCι_6alkyl, optionally substituted
C3.6alkenyl, optionally substituted C3.6alkynyl, -(Cι.5alkyl)aa-S(On)-(Cι.5alkyl)bbS R9R10NC2.6alkyl, R9OC2.6alkyl or R9R10NC(O)C2.6alkyl, with the proviso that R9 and R10 independently or taken together are not optionally substituted aryl or optionally substituted arylCι.6alkyl; or
21 R and R taken together form an optionally substituted non-aromatic heterocyclic ring; A is selected from: (i) a direct bond;
(ii) optionally-substituted Ci-salkylene wherein the optional substituents are independently selected from: optionally-substituted Cι_6alkyl optionally-substituted aryl or optionally substituted arylCι.6alkyl; (iii) a carbocyclic ring of 3-7 atoms;
(iv) a carbonyl group or -C(O)-C(RdRd)-, wherein Rd is independently selected from hydrogen and Csalkyl; or when R is a group of Formula (Ha) or (Hb), the group
Figure imgf000147_0001
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; or when R is a group of Formula (Ha), (Hb), (He) or (Hd), the group
Figure imgf000147_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; B is selected from: (i) a direct bond; (ii) a group of Formula (IV)
Figure imgf000147_0003
Formula (IV)
I L pCirpeii tlll •.
X is selected from N or CH, wherein at position (a) Formula (IV) is attached to the nitrogen atom and the
(CH2)p group is attached to R ; and (iii) a group independently selected from: optionally substituted Cι_6alkylene, optionally substitute C3. cycloalkyl, optionally substituted C3.6alkenylene, optionally substituted C3.6alkynyl, Cι-6alkoxy, (C1.5alkyl)aa-S(On)-(C1.5alkyl)bb-, (Cι.5alkyl)aa-O-(C1.5alkyl)bb-, -(C1.5alkyl)aa-C(O)-(C1.5alkyl)bb- or (C1.5alkyl)aa-N(R15)- ( .salkylW wherein R15 and the (Cι_5alkyl)aa or (Cι-salkyl)bb chain can be joined to form a ring , wherein the combined length of (Cι.5alkyl)aa and (Cι.salkyl)bb is less than or equal to C5alkyl; or the group -B-R8 represents a group of Formula (V)
Figure imgf000148_0001
Formula (V); R7
or the group together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms;
or the group
Figure imgf000148_0002
forms a heterocyclic ring containing 3-7 carbon atoms and one or more heteroatoms; E is -O-, -S(On), -C(O)-, -NR15- or -C(R9R10)q; F is -E(CH2)r-; G is selected from: hydrogen, halo, N, O, S(On), C(O), C(R9R10)t, optionally substituted C2-6alkenylene, optionally substituted C2-6alkynylene or a direct bond to R18, J is a group of the formula: -(CH2)S-L-(CH2)S- wherein when s is greater than 0, the alkylene group is optionally substituted,
R7
or the group together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms; K is selected from: a direct bond, -(CEΪ2)si-, -(CH2)sι-O-(CH2)S2-,
-(CH2)siC(O)-(CH2)s2- , -(CH2)siS(On)-(CH2)S2-, -(CH2)sιN(R18)-(CH2)S2-, -(CH2)sι-C(O)N(R9)-(CH2)S2-, -(CH2)sι-N(R9)C(O)-(CH2)s2-, -(CH2)si-N(R9)C(O)N(R9)-(CH2)S2-, -(CH2)sι-OC(O)-(CH2)S2-,
-(CH2)sl-C(O)O-(CH2)s2-, -(CH2)sl-N(R9)C(O)O-(CH2)s2-, -(CH2)si-OC(O)N(R9)-(CH2)s2-, -(CH2)sι-OS(On)-(CH2)s2-, or -(CH2)si-S(On)-O-(CH2)S2-(CH2)si-S(O)2N(R9)-(CH2)s2-, -(CH2)si-N(R9)S(O)2-(CH2)S2-; wherein the -(CH2)sι- and -(CH2)s2- groups are independently optionally substituted by hydroxy or Cι. alkyl; L is selected from optionally substituted aryl or optionally substituted heterocyclyl;
M is selected from -(CH2)o-2-O- or -C(O)NH-; n is an integer from 0 to 2; p is an integer from 0 to 4; q is an integer from 0 to 4; r is an integer from 0 to 4; s is an integer from 0 to 4; si and s2 are independently selected from an integer from 0 to 4, and sl+s2 is less than or equal to 4; t is an integer from 0 to 4; aa and bb are independently 0 or 1; and cc is an integer between 0 to 2; with the proviso that
17 18
(i) when G is hydrogen or halo, then R and R are both absent; (ii) when G is O, S(On), C(O) or C(RπR12)t then G is substituted by a single group independently selected from the definition of R17 or R18 and when G is a direct bond to R18 then G is substituted by a single group selected from R18; (iii) when R is a group of Formula (lib), B is a group of Formula (TV), R is selected from group (i) or (ii) above, R11 is a group of the formula N(R10R11) and R1, R2 and R5 are as defined above then R4 cannot be hydrogen;
(iv) R3 cannot be unsubstituted pyridyl or unsubstituted pyrimidinyl; and (v) when R3 is pyrazolyl substituted by phenyl or pyrazolyl substituted by phenyl and acetyl, R5-M is hydroxyl or acetyloxy, R2 is unsubstituted phenyl, then R1 cannot be hydrogen or acetyl; or a salt, pro-drug or solvate thereof.
2. A compound according to Claim 1 wherein R1 is hydrogen.
3. A compound according to Claim 1 or Claim 2 wherein R is selected from a group of Formula (Ea) or Formula (Eb).
4. A compound according to Claim 3 wherein B is optionally substituted Cι_6alkylene.
5. A compound according to Claim 1 or Claim 2 wherein R3 is selected from a group of
Formula (Ec) or Formula (Ed).
R7
6. A compound according to Claim 5 wherein the group together forms an optionally substituted heterocyclic ring containing 4-7 carbons atoms
7. A compound according to Claim 6 wherein K is selected from: -(CH2)S-, -(CH2)s-O-(CH2)s-, -(CH2)s-C(O)-(CH2)s-, -(CH2)S-N(R18)-(CH2)S-, -(CH2)s-C(O)N(R18)-(CH2)s-, -(CH2)s-N(R18)C(O)-(CH2)s-, -(CH2)s-S(O)2N(R18)-(CH2)s-, or -(CH2)s-NHS(O)2-(CH2)s-.
8
8. A compound according to any one of Claims 3, 4, 5, 6 or 7 wherein R is selected from: (i) hydrogen, Ci-βalkyl, C2.6alkenyl, haloCι„6alkyl, hydroxy, cyano, Cι.6alkylS(On)-, -O-R , Cι.4alkoxyC!.4alkyl, -C(O)-Rb, C(O)O-Rb, -NH-C(O)-Rb, N,N-di-Cι.4alkylamino, -S(On)NRbRc where R and Rc are independently selected from hydrogen and Cι.6alkyl, and n is 0, 1 or 2;
12 1^ ΛΛ,
(ii)-(Q)-aryl, optionally substituted by up to 3 groups selected from R , R and R ;
12 1^
(iii) C4.7heterocyclyl, optionally substituted by up to 3 groups selected from R , R and R14, or
(iv) C3. carbocyclyl, optionally substituted by up to 3 groups selected from R , R and R14;
A compound according to any one of the preceding claims wherein R is a group of
Formula (IE) wherein the group of Formula (IE) is selected from any one of IH-a to III-l;
Figure imgf000151_0001
Ill-a Ill-b III-c Ill-d Ill-e
Figure imgf000151_0002
Ill-f lll-g Ill-h Ill-i lll-j
Figure imgf000151_0003
lll-k lll-l wherein: het represents an optionally substituted 3- to 8- membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S; R23 and R23a are independently selected from hydrogen, fluoro or optionally substituted Cι_8alkyl; or R and R together with the carbon to which they are attached form an optionally substituted 3 to 7-membered cycloalkyl ring
R24 is selected from hydrogen, optionally substituted Cι_8alkyl, optionally substituted aryl, -Rd-Ar, where Rd represents Cι_8alkylene and Ar represents optionally substituted aryl, and optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S;
R25 is selected from hydrogen; optionally substituted Cι_8alkyl and optionally substituted aryl; or where the group of Formula (IE) represents a group of Formula Ill-a , Ill-b or Ill-i, then the group NR 4(-R2S) represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or where the group of Formula (IE) represents structure IH-e, R24 and R25 together with the carbon to which they are attached represents an optionally substituted 3- to 8- membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S;
10. A compound according to any one of the preceding claims wherein R is selected from an optionally substituted monocyclic aromatic ring stracture wherein the optional substituents are selected from cyano, NReRf, optionally substituted Cι.8alkyl, optionally substituted Cι„8alkoxy or halo wherein Re and Rf are independently selected from hydrogen, Cι_6alkyl or aryl.
11. A compound selected from: 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5- yl)ethyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-pyrid-4-ylbutyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heρtan-7-yl}proρoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[4-(4-methoxyphenyl)butyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(43-trifluoromethylphenyl)ethyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(4-fluorophenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N- [2-(3-methoxyphenyl)ethyl]-(2S)-propylamine;
2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(4-methoxyphenyl)ethyl]-(2S)-propylamine; 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.1]heptan-7-yl}propoxy)-5-(3,5- dimethylphenyl)-lH-pyrazol-4-yl]-N-
[2-(4-methylsulphonylaminophenyl)ethyl]-(2S)-propylamine; and 2-[3-(2,2-dimethyl-3-oxo-3-{azabicyclo[2.2.2]oct-2-yl}propoxy)-5-(3,5- 5 dimethylphenyl)-lH-pyrazol-4-yl]-N-[2-(l,3-benzodioxol-5- yl)ethyl]-(2S)-proρylamine; or a salt, pro-drag or solvate thereof.
12. A compound, or salt, pro-drag or solvate thereof, according to any one of Claims 10 1 to 11 for use as a medicament.
13. A pharmaceutical formulation comprising a compound, or salt, pro-drag or solvate thereof, according to any one of Claims 1 to 11 and a pharmaceutically acceptable diluent or carrier.
15
14. Use of a compound, or salt, pro-drag or solvate thereof, according to any one of Claims 1 to 11, in the manufacture of a medicament for antagonising gonadotropin releasing hormone activity.
20 15. Use of a compound, or salt, pro-drag or solvate thereof, according to any one of Claims 1 to 11, in the manufacture of a medicament for administration to a patient, for therapeutically treating and/or preventing a sex hormone related condition in the patient.
16. A process for the preparation of a compound of Formula (I) as defined in Claim 1, 25 comprising a process selected from (a) to (h) as follows:
(a) Reaction of a compound of formula XXXII with a compound of formula Η-R5' to form a compound of Formula (I),
Figure imgf000153_0001
XXXII Formula (I) wherein X is selected from:
Figure imgf000154_0001
; L 1 is a displaceable group; and
H-R5' is selected from:
Figure imgf000154_0002
(b) Reaction of a compound of formula XXXIII with a compound of formula H-R5" to form a compound of Formula (I),
Figure imgf000154_0003
XXXIII Formula (I)
wherein X 2 is selected from:
Figure imgf000154_0004
; L 2 is a displaceable group and R7a is selected from the definition of R7 or R22 above, and L2-R5" is selected from:
L— B-R8 , L— J— K-R8 and L2— R21
(c) For compounds of Formula (I) wherein R is a group of Formula (Ea), (Eb), (Ec) or (Ed) and R7 is other than part of a heterocyclic ring or hydrogen, reaction of a compound of Formula (I) wherein R is a group of Formula (Ea), (Eb), (Ec) or (Ed) and R7 is hydrogen with a group of formula L3-R7a, wherein R7 is as
7 " defined above for R with the exclusion of hydrogen and L is a displaceable group;
(d) For compounds of Formula (I) wherein R is a group of Formula (Ee) or (Ef) and
21
R is other than hydrogen, reaction of a compound of Formula (I) wherein R is a
21 group of Formula (Ee) or (Ef) and R is hydrogen with a group of formula L4-R21a, wherein R21a is as defined above for R21 with the exclusion of hydrogen and L4 is a displaceable group; (e) For compounds of Formula (I) wherein R3 is a group of Formula (Ee) or (Ef) and
22 ^
R is other than hydrogen, reaction of a compound of Formula (I) wherein R is a group of Formula (Ee) or (Ef) and R22 is hydrogen with a group of formula L5-R22a, wherein R22a is as defined above for R22 with the exclusion of hydrogen and L5 is a displaceable group;
(f) For compounds of Formula (I) wherein R3 is a group of Formula (Ec) or (Ed) and
R7
the group together forms an optionally substituted nitrogen-containing heterocyclic ring containing 4-7 carbons atoms, reaction of a compound of Formula XXXIVa or XXXIVb, with a compound of Formula L -K-R , wherein L is a displaceable group
Figure imgf000155_0001
XXXIVa XXXIVb
(g) For compounds of Formula (I) wherein R3 is a group of Formula (Ec) or (Ed), reaction of a compound of Formula XXXVa or XXXVb, with a compound of
Formula L 7 -K"-R 8 , wherein L 7 is a displaceable group, and wherein the groups K' and K" comprise groups which when reacted together form K,
Figure imgf000155_0002
XXXVa
XXXVb
(h) reaction of a compound of Formula XXXVI with a compound of the formula L -R , wherein L8 is a displaceable group
Figure imgf000155_0003
XXXVI and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt, pro-drug or solvate.
PCT/GB2003/003633 2002-08-21 2003-08-19 Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer WO2004017961A2 (en)

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AU2003255820A AU2003255820A1 (en) 2002-08-21 2003-08-19 Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
DE60324431T DE60324431D1 (en) 2002-08-21 2003-08-19 DERIVATIVES OF 3-HYDROXY-4- (CYCLYL-ALKYLAMINOALKYL) -5-PHENYL-1H-PYRAZOLE AS ANTAGONISTS OF GONADOTROPINE RELEASING HORMONE (GNRH) FOR THE USE OF THE TREATMENT OF HEALTH HORMONAL DISEASES SUCH AS PROSTATE OR CANCER CANCER
EP03792487A EP1531811B1 (en) 2002-08-21 2003-08-19 Derivatives of 3-hydroxy-4-(cyclyl-alkylaminoalkyl)-5-phenyl-1h-pyrazole as antagonists of the gonadotropin releasing hormone (gnrh) for use in the treatment of sex hormone related conditions, such as prostatic of uterine cancer
JP2004530361A JP2006505528A (en) 2002-08-21 2003-08-19 3-Hydroxy-4- (cyclyl-alkylaminoalkyl) -5 as an antagonist of gonadotropin releasing hormone (gonadotropin releasing hormone: GNRH) for use in the treatment of sex hormone related conditions such as prostate and uterine cancer -Derivatives of phenyl-1H-pyrazole

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WO2005079805A1 (en) * 2004-02-20 2005-09-01 Astrazeneca Ab Pyrrole derivatives as gonadotropin releasing hormone (gnrh) antagonists
EP1829875A1 (en) 2006-03-01 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptor inhibitors
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EP1829866A1 (en) 2006-03-02 2007-09-05 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
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US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
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US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
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US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
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US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
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US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
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