WO2006001958A2 - Amino cyclopentyl heterocyclic and carbocyclic modulators of chemokine receptor activity - Google Patents

Amino cyclopentyl heterocyclic and carbocyclic modulators of chemokine receptor activity Download PDF

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WO2006001958A2
WO2006001958A2 PCT/US2005/017836 US2005017836W WO2006001958A2 WO 2006001958 A2 WO2006001958 A2 WO 2006001958A2 US 2005017836 W US2005017836 W US 2005017836W WO 2006001958 A2 WO2006001958 A2 WO 2006001958A2
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Prior art keywords
substituted
mmol
alkyl
unsubstituted
hydroxy
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PCT/US2005/017836
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French (fr)
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WO2006001958A3 (en
Inventor
Lihu Yang
Songnian Lin
Gregori Morriello
Liangqin Guo
Changyou Zhou
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Merck & Co., Inc.
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Priority to AU2005257859A priority Critical patent/AU2005257859A1/en
Priority to CA002567851A priority patent/CA2567851A1/en
Priority to US11/596,937 priority patent/US20100234409A1/en
Priority to JP2007527495A priority patent/JP2008502719A/en
Priority to EP05785401A priority patent/EP1753740A2/en
Publication of WO2006001958A2 publication Critical patent/WO2006001958A2/en
Publication of WO2006001958A3 publication Critical patent/WO2006001958A3/en

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Definitions

  • chemokines are a family of small (70-120 amino acids), proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). These molecules were originally defined by four conserved cysteines and divided into two subfamilies based on the arrangement of the first cysteine pair.
  • CXC- chemokine family which includes EL-8, GRO ⁇ , NAP-2 and IP-IO
  • these two cysteines are separated by a single amino acid
  • CC-chemokine family which includes RANTES, MCP-I, MCP-2, MCP- 3, MIP-Ia, MIP-IB and eotaxin, these two residues are adjacent.
  • the ⁇ -chemokmes such as interleukin-8 (EL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas ⁇ -chemokines, such as RANTES, MDMa, MEP-l ⁇ , monocyte chemotactic protein-1 (MCP-I), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)).
  • EL-8 interleukin-8
  • NAP-2 neutrophil-activating protein-2
  • MGSA melanoma growth stimulatory activity protein
  • the chemokines are secreted by a wide variety of cell types and bind to specific G- protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes. Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets.
  • GPCRs G- protein coupled receptors
  • chemokine receptors On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration.
  • CCR-I or "CKR-I” or "CC-CKR-I”
  • CKR-I or "CC-CKR-I”
  • CC-CKR-I chemokine receptors that bind or respond to ⁇ -chemokines with the following characteristic pattern: CCR-I (or "CKR-I” or "CC-CKR-I”) [MJP-Io, MBP-l ⁇ , MCP- 3, RANTES] (Ben-Barruch, et al., J. Biol.
  • the ⁇ -chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein”) and RANTES ("regulation-upon-activation, normal T expressed and secreted”) among other chemokines.
  • Chemokine receptors such as CCR-I, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR- 5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
  • Humans who are homozygous for the 32-basepair deletion in the CCR-5 gene appear to have less susceptibility to rheumatoid arthritis (Gomez, et al., Arthritis & Rheumatism, 42, 989-992 (1999)).
  • chemokines are potent chemoattractants for monocytes and macrophages. The best characterized of these is MCP-I (monocyte chemoattractant protein-1), whose primary receptor is CCR2.
  • MCP-I is produced in a variety of cell types in response to inflammatory stimuli in various species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes.
  • MCP-I production correlates with monocyte and macrophage infiltration at inflammatory sites.
  • Deletion of either MCP-I or CCR2 by homologous recombination in mice results in marked attenuation of monocyte recruitment in response to thioglycollate injection and Listeria monocytogenes infection (Lu et al., J. Exp. Med., 187, 601-608 (1998); Kurihara et al. J. Exp. Med.. 186, 1757-1762 (1997); Boring et al.
  • MCP-1-induced CCR2 activation plays a major role in monocyte recruitment to inflammatory sites, and that antagonism of this activity will produce a sufficient suppression of the immune response to produce therapeutic benefits in immunoinflammatory and autoimmune diseases. Accordingly, agents which modulate chemokine receptors such as the CCR-2 receptor would be useful in such disorders and diseases.
  • the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation.
  • MCP-I is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in
  • CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall.
  • the present invention is directed to compounds of the formulae I and II:
  • A is selected from: -O-, -NR12-, -S-, -SO-, -SO2-, -CR 12 R 12 -, -NSO 2 R 14 -, -NCOR 13 -, -CR 12 COR 1 I-, CR 12 OCOR 13 - and -CO-;
  • G 1 is selected from: -N(R 31 )-CO- N(R 30 )(R 29 ), -N(R 31 )-SO 2 R 32 , -N(R 31 )-COR 32 , -CON(R 29 )(R 30 ), -Q- 6 alkyl unsubstituted or substituted with 1-6 fluoro, and -Cs ⁇ cycloalkyl unsubstituted or substituted with 1- 6 fluoro,
  • R ⁇ 9 and R ⁇ O are independently selected from: hydrogen, Ci-6alkyl, C ⁇ -galkyl substituted with 1-6 fluoro, Ci- ⁇ cycloalkyl, aryl, aryl-Ci- ⁇ alkyl, heterocycle and heterocycle-Ci- ⁇ alkyl, or R29 and R ⁇ O join to form a C3-6 membered ring;
  • R ⁇ l and R ⁇ 2 are independently selected from: hydrogen, Cl-6alkyl, Ci- ⁇ cycloalkyl, Ci- galkyl substituted with 1-6 fluoro, aryl and heterocycle, or R ⁇ l and R ⁇ 2 join to form a C3-6 membered ring;
  • G 2 is selected from (where either end of the group is joined to X and the other end is joined to the aromatic ring): a single bond, -(CR 11 R 11 J M -, -N(R 12 )SO r , -N(R 12 )SO 2 N(R 12 )-, -N(R 12 )CO-, - C(R 11 XR 1 1)CO-, -C(R 11 XR 11 X)CO-, -CO-, -C(R 11 )(R 11 )SO 2 -, -OCO-, -SO 2 -, or G 2 is C R 11 or N and is joined to R 2 forming a fused carbocyclic or heterocyclic ring;
  • X is a 5-7 membered saturated, partially unsaturated or unsaturated carbocyclic or heterocyclic ring, wherein:
  • ring when said ring is heterocyclic it contains 1-4 heteroatoms independently selected from O, N and S,
  • R 28 is independently selected from: halo, hydroxy, -O-Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, -O-C3-5cycloalkyl unsubstituted or substituted with 1-6 fluoro, -CORI l, -SO2R14, -NR 12 COR 13 , -NR 12 SO 2 R 14 , - phenyl unsubstituted or substituted with 1-3 fluoro or trifluoromethyl, and -CN, and
  • said ring is optionally bonded to R 6 to form a fused or spiro ring system (as shown by the curving dashed line in formula II);
  • Y is C, N, O, S or SO 2 ;
  • Z is independently selected from C and N, where no more than two of Z are N;
  • Rl is selected from: hydrogen, -SO 2 R 14 , -C 0-3 alkyl-S(O)R 14 , -SO 2 NR 12 R 12 , -Chalky!, -Co-6alkyl-0-Cl- galkyl, -Co- ⁇ alkyl-S-Ci-galkyl, -(Co-6alkyl)-(C3_7cycloalkyl)-(C(>6alkyl), hydroxy, heterocycle, -CN, - NR 12 R 12 , -NR 12 COR 13 , -NR 12 SO 2 R 14 , -COR 11 , -CONR 12 R 12 , and phenyl,
  • alkyl and the cycloalkyl are imsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: halo, hydroxy, -O-Ci_3alkyl, trifluoromethyl, Ci-3alkyl, -O-Cs-scycloalkyl, -CORl 1, -SO2R 14 .
  • substituents are independently selected from: halo, hydroxy, -O-Ci_3alkyl, trifluoromethyl, Ci-3alkyl, -O-Cs-scycloalkyl, -CORl 1, -SO2R 14 .
  • phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Cl_3alkyl, Ci_3alkoxy and trifluoromethyl;
  • R 3 , R 4 , and R 5 are independently selected from B 1 when Z is C, and are independently selected from B 2 when Z is N;
  • R 2 is independently selected from B 1 when Z is C, and is independently selected from B 2 when Z is N, or R 2 is a link to G 2 wherein said link is a bond or is a chain 1-4 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
  • R 6 is independently selected from B 1 when Z is C, and is independently selected from B 2 when Z is N, or R 6 is a link to any atom on X, wherein said link is a bond or is a chain 1-3 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
  • B 1 is selected from: Ci_6alkyl unsubstituted or substituted with 1-6 fluoro, hydroxyl, or both, -O-Ci- ⁇ alkyl unsubstituted or substituted with 1-6 fluoro, -CO-Ci-galkyl unsubstituted or substituted with 1-6 fluoro, -S-Ci-galkyl unsubstituted or substituted with 1-6 fluoro, -pyridyl unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, Ci.
  • R7 is selected from: hydrogen, (C ⁇ -6alkyl)-phenyl, (Co-6alkyl)-heterocycle, (Co-6alkyl)-C 3-7 cycloalkyl , (C ⁇ -6alkyl)-(alkene)-COR 1 ! , (C ⁇ -6alkyl)-S0 3 H, (C ⁇ -6alkyl)-W-C ⁇ -4alkyl, (Q)- 6alkyl)-CONR 12 -pheny and (C ⁇ -6alkyl)-CONR 15 -V-COR ⁇ when Y is N or C, or R 7 is absent when Y is O, S or SO 2 , where
  • V is Ci. 6 alkyl or phenyl
  • W is a single bond, -O-, -S-, -SO-, -SO2-, -CO-, -CO 2 -, -CONR 12 - or-NRl2-,
  • R 13 is hydrogen or Ci- 4 alkyl, or R 15 is joined via a 1-5 carbon chain linked to one of the carbons of V, forming a ring,
  • said C ⁇ -6alkyl is unsubstituted or substituted with 1-5 substituents independently selected from halo, hydroxy, -C ⁇ -6 a lkyl, -O-Ci_3alkyl, trifiuoromethyl and -Co- 2 alkyl- ⁇ henyl,
  • said phenyl, heterocycle, cycloalkyl and C ⁇ -4alkyl are unsubstituted or substituted with 1-5 substituents independently selected from halo, trifiuoromethyl, hydroxy, Ci-galkyl, -O-C1- 3alkyl, -C 0 . 3 -CORll, -CN, -NR12R12, -CONR12R12 an d -Co- 3 -heterocycle, or said phenyl or heterocycle may be fused to another heterocycle where said another heterocycle is unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR 11 , and -Q- 4 alkyl, and
  • alkene is unsubstituted or substituted with 1-3 substituents independently selected from halo, trifiuoromethyl, C 1-3 alkyl, phenyl and heterocycle;
  • R ⁇ is selected from hydrogen, hydroxy, Ci-6alkyl, Cj-6alkyl-hydroxy, -O-Ci-3alkyl, -CORl 1, - CONR12R12 and -CN when Y is N or C, or R 8 is absent when Y is O, S, SO 2 or N or when a double bond joins the carbons to which R 7 and R 10 are attached;
  • R 7 and R ⁇ are joined to form a ring selected from: lH-indene, 2,3-dihydro-lH-indene, 2,3-dihydro- benzofuran, 1,3-dihydro-isobenzofuran, 2,3-dihydro-benzothiofuran, 1,3-dihydro-isobenzothiofuran, 6H- cyclopenta[ ⁇ ]isoxazol-3-ol, cyclopentane and cyclohexane, where said ring is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, Ci-3alkyl, -O-Ci-3alkyl, -C 0-3 -CORlI, -CN, -NR12R12, _ CONR.12R.12 and -Co- 3 -heterocycle;
  • R ⁇ and R ⁇ , or R 8 and R 10 together form a ring which is phenyl or heterocycle, wherein said ring is unsubstituted or substituted with 1-7 substituents independently selected from halo, trifluoromethyl, hydroxy, Ci-3alkyl, -O-Ci-3alkyl, -COR!!, -CN, -NR12R12 an d -CONR12R12 ;
  • R ⁇ is independently selected from: hydroxy, hydrogen, Ci_g alkyl, -O-Ci- ⁇ alkyl, benzyl, phenyl and C3- 6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1-6
  • R!2 is selected from: hydrogen, Ci-6 alkyl, benzyl, phenyl and C3-6 cycloalkyl, where said alkyl,
  • phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1-.6 alkyl, and trifluoromethyl;
  • R 13 is selected from: hydrogen, C ⁇ -(, alkyl, -O-C 1 . 6 alkyl, benzyl, phenyl and C3_6 cycloalkyl, where said
  • alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1.6 alkyl and trifluoromethyl;
  • R 14 is selected from: hydroxy, C ⁇ _6 alkyl, -O-C ⁇ alkyl, benzyl, phenyl and C3.6 cycloalkyl, where said
  • alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1.6 alkyl, and trifluoromethyl;
  • R 16 and R 18 are independently selected from: hydroxy, Ci_6alkyl, Ci_6alkyl-COR H , Ci_6alkyl- hydroxy, -O-Ci_3alkyl, halo and hydrogen, where said alkyl is unsubstituted or substituted with 1-6
  • R 16 and R 18 together are -C !-4 alkyl-, -C 0 . 2 alkyl-O-Ci-3alkyl- or-C )-3 alkyl-0-C ⁇ -2alkyl-, forming a
  • R 17 , R 19 , R 20 and R 21 are independently selected from: hydrogen, hydroxy, Ci-galkyl, Ci_6alkyl-COR ⁇ , Ci-6alkyl-hydroxy, -O-Ci-3alkyl, trifluoromethyl and halo;
  • R 22 is hydrogen or C 1 6 alkyl unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -CO 2 H, -CO 2 d.. 6 alkyl and -O-C ⁇ alkyl;
  • R 2 ⁇ is selected from: hydrogen, Ci- ⁇ alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, d, 3 alkoxy, hydroxyl and -COR* 1 , COR 1 ⁇ , hydroxyl and -O-Q.
  • 6 alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, Ci- 3 alkoxy, hydroxyl and -COR ⁇ , or R 23 and R 2 ⁇ together are Ci_4alkyl or C 0 , 3 alkyl-0-Co- 3 alkyl, forming a 3-6 membered ring;
  • R25 is selected from: hydrogen, Ci- ⁇ alkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C 3 , gcycloalkyl and -O-Ci -3 alkyl unsubstituted or substituted with 1-6 fluoro,
  • R 2 3 and R 2 ⁇ together are C2-3alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -CORH, Ci -3 alkyl, and Ci. 3 alkoxy,
  • alkyls are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR ⁇ , Ci -3 alkyl and Ci. 3 alkoxy,
  • R 23 and R 2 ⁇ together are -O-Q ⁇ alkyl-O-, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR ⁇ ⁇ , Ci. 3 alkyl and Ci. 3 alkoxy; R 26 is selected from: Cl- ⁇ alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C 1 .
  • R 27 is selected from: hydrogen, Cj-galkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C 3- gcycloalkyl, and -O-Ci -3 alkyl unsubstituted or substituted with 1-6 fluoro; m, i, and n are independently selected from 0, 1 and 2; the dashed line represents an optional bond; and pharmaceutically acceptable salts thereof and individual diastereomers thereof.
  • Embodiments of the invention include those of formula Ia
  • R ⁇ R ⁇ , R 28 , R 31 , R 32 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • R 1 , R ⁇ , R 29 , R 30 , R 3 *, R 32 , R 28 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 28 , G 2 , and Z are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Embodiments of the invention include those of formula lib
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 28 , and G 2 are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Embodiments of the invention include those of formula Hc:
  • R*, R ⁇ , R 9 , R 28 , G 2 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • M is selected from O, S and NR 12' '
  • R33 and R ⁇ 4 are independently selected from hydrogen, halo, trifluoromethyl, O- Ci- ⁇ alkyl and O-Ci- galkyl substituted with 1-6 fluoro, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Embodiments of the invention include those of formula He:
  • RA R ⁇ , R ⁇ 3 , R ⁇ , R 28 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • Additional embodiments of the present invention include those wherein R 2S is selected from H, F, Cl, Br, Me and CF 3 , and in particular those wherein R 28 is selected from H, Me and CF 3 .
  • Additional embodiments of the present invention include wherein Y is C.
  • Additional embodiments of the present invention include those wherein A is O.
  • Additional embodiments of the present invention include those X is phenyl.
  • R ⁇ is selected from hydrogen, -Ci-6alkyl unsubstituted or substituted with 1-6 substituents independently selected from halo, hydroxy, -O-C1 -3alkyl and trifluoromethyl, -C()-6alkyl-O-Ci-6alkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, -C()-6 a lkyl-S-Ci-6alkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, - (C3_5cycloalkyl)-(C ⁇ -6alkyl) unsubstituted or substituted with 1-7 substituents independently selected from halo, hydroxy, -O-Ci_3alkyl and trifluoromethyl.
  • R ⁇ is selected from hydrogen, Ci_6alkyl, Ci-6alkyl-hydroxy and Ci-galkyl substituted with 1-6 fluoro, specifically wherein R* is selected from hydrogen, methyl, hydroxymethyl and trifluoromethyl.
  • Additional embodiments of the present invention include those wherein when Z is N, R 2 is absent, and those wherein when Z is C, R 2 is hydrogen or is linked to G 2 .as described herein. Further embodiments of the present invention include those wherein if Z is N, R 3 is absent, and those wherein if Z is C, R 3 is hydrogen.
  • R ' is selected from phenyl, heterocycle, C 3-7 cycloalkyl, C 1-6 alkyl, -COR 11 and -CONH-V-COR 11 , where V is Ci -6 alkyl or phenyl, and where said phenyl, heterocycle, C 3-7 cycloalkyl and Q ⁇ alkyl is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, C]__3alkyl, -O-Ci- 3alkyl, -CORlI, _CN, -heterocycle and -CONR12R12.
  • R ⁇ is selected from: hydrogen, hydroxy, -CN and -F.
  • R 7 and R 8 are joined together to form a ring which is selected from: lH-indene and 2,3-dihydro-lH-indene, where said ring is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, Ci_3alkyl, -O-Ci_3alkyl, -CORl 1 and -heterocycle.
  • R i0 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 23 , R 24 , R 25 , R 26 and R 27 is hydrogen.
  • Representative compounds of the present invention include those described in the Examples, below, and pharmaceutically acceptable salts and individual diastereomers thereof.
  • the compounds of the instant invention where E is the cyclopentyl ring have at least two asymmetric centers at the 1- and 3-positions of the cycloalkyl ring. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention.
  • the carbon bearing the amine substituent is designated as being of the (R) absolute configuration and the carbon bearing the amide subunit can be designated as being of either the (S) or (R) absolute configuration depending on the priority for R 1 .
  • R is isopropyl
  • the absolute stereochemistry at the carbon bearing the amide subunit would be (S) since the amide and amine units are preferred to have the cis arrangement on the cyclopentyl ring.
  • the independent syntheses of diastereomers and enantiomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo.
  • alkyl is intended to mean linear, branched and cyclic carbon structures having no double or triple bonds.
  • C ⁇ -8 as in Ci-galkyl, is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that C ⁇ -8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. More broadly, C a -balkyl (where a and b represent whole numbers) is defined to identify the group as having a through b carbons in a linear or branched arrangement. Co, as in Coalkyl is defined to identify the presence of a direct covalent bond.
  • Cycloalkyl is an alkyl, part or all of which which forms a ring of three or more atoms.
  • the term “heterocycle” as used herein is intended to include the following groups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyr
  • ring is employed herein to refer to the formation or existence of a cyclic structure of any type, including free standing rings, fused rings, and bridges formed on existing rings. Rings may be non-aromatic or aromatic. Moreover, the existence or formation of a ring structure is at times herein disclosed wherein multiple substituents are defined “together”, as in “...R ⁇ and R ⁇ together are C 1-4 alkyl." In this case a ring is necessarily formed regardless of whether the term "ring” is employed.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are employed.
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are employed.
  • Suitable salts are found, e.g. in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418.
  • Specific compounds within the present invention include a compound which selected from the group consisting of those compounds described in the Examples, and pharmaceutically acceptable salts thereof and individual diastereomers and enantiomers thereof.
  • the subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound.
  • the present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity.
  • these compounds are useful as modulators of the chemokine receptors, in particular CCR-2.
  • the utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993) which may be readily adapted for measurement of CCR-2 binding.
  • Receptor affinity in a CCR-2 binding assay was determined by measuring inhibition of 1251-MCP-I to the endogenous CCR-2 receptor on various cell types including monocytes, THP-I cells, or after heterologous expression of the cloned receptor in eukaryotic cells.
  • the cells were suspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM MgCl2, 1 mM CaCl2, and 0.50% BSA or 0.5% human serum) and added to test compound or DMSO and 125]_MCP-1 at room temperature for 1 h to allow binding. The cells were then collected on GFB filters, washed with 25 mM HEPES buffer containing 500 mM NaCl and cell bound 125I-MCP-1 was quantified.
  • binding buffer 50 mM HEPES, pH 7.2, 5 mM MgCl2, 1 mM CaCl2, and 0.50% BSA or 0.5% human serum
  • chemotaxis assay was performed using T cell depleted PBMC isolated from venous whole or leukophoresed blood and purified by Ficoll-Hypaque centrifugation followed by rosetting with neuraminidase-treated sheep erythrocytes. Once isolated, the cells were washed with HBSS containing 0.1 mg/ml BSA and suspended at Ixl ⁇ 7 cells/ml. Cells were fluorescently labeled in the dark with 2 ⁇ M Calcien-AM (Molecular Probes), for 30 min at 37° C.
  • the filter was removed and the topside was washed with HBSS containing 0.1 mg/ml BSA to remove cells that had not migrated into the filter.
  • Spontaneous migration was determined in the absence of chemoattractant.
  • the compounds of the following examples had activity in binding to the CCR-2 receptor in the aforementioned assays, generally with an IC50 of less than about 1 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity.
  • Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or leukocyte function in a mammal, such as a human.
  • Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or leukocyte function for therapeutic purposes.
  • compounds which inhibit or promote chemokine receptor function would be useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and further, chronic obstructive pulmonary disease, and multiple schlerosis.
  • an instant compound which inhibits one or more functions of a mammalian chemokine receptor e.g., a human chemokine receptor
  • one or more inflammatory processes such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited.
  • mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated.
  • the method can also be practiced in other species, such as avian species (e.g., chickens).
  • the disease or condition is one in which the actions of leukocytes are to be inhibited or promoted, in order to modulate the inflammatory response.
  • Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren' s syndrome,
  • respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hyper
  • Inhibitors of chemokine receptor function may also be useful in the treatment and prevention of stroke (Hughes et al., Journal of Cerebral Blood Flow & Metabolism, 22:308-317, 2002, and Takami et al., Journal of Cerebral Blood Flow & Metabolism, 22:780-784, 2002), neurodegenerative conditions including but not limited to Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and Parkinson's disease, obesity, type II diabetes, neuropathic and inflammatory pain, and Guillain Barre syndrome.
  • ALS amyotrophic lateral sclerosis
  • Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis and chronic obstructive pulmonary disease.
  • reperfusion injury e.g., atherosclerosis
  • certain hematologic malignancies e.g., cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis and chronic obstructive pulmonary disease.
  • cytokine-induced toxicity e.g., septic shock, endotoxic shock
  • polymyositis e.g., septic shock, endotoxic shock
  • dermatomyositis e.g., chronic obstructive pulmonary disease.
  • Diseases or conditions of humans or other species, which can be treated with modulators of chemokine receptor function include or involve but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms), (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis), trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercos
  • treatment of the aforementioned inflammatory, allergic, infectious and autoimmune diseases can also be contemplated for agonists of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells.
  • the compounds of the present invention are accordingly useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies.
  • the present invention is directed to the use of the subject compounds for treating, preventing, ameliorating, controlling or reducing the risk of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis and multiple schlerosis.
  • the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-2.
  • the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors.
  • the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds.
  • the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition.
  • the compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-2.
  • CCR-2 putative specific modulators of the chemokine receptors
  • the present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent.
  • the present invention is further directed to the use of the present compounds in treating, preventing, ameliorating, controlling or reducing the risk of infection by a retrovirus, in particular, herpes virus or the human immunodeficiency virus (HTV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS.
  • a retrovirus in particular, herpes virus or the human immunodeficiency virus (HTV)
  • HTV human immunodeficiency virus
  • Treating AIDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (ADDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
  • the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
  • a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-2, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor.
  • a chemokine receptor such as CCR-2
  • the subject treated in the methods above is a mammal, for instance a human being, male or female, in whom modulation of chemokine receptor activity is desired.
  • Modulation as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In an aspect of the present invention, modulation refers to antagonism of chemokine receptor activity.
  • composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • administration of and or “administering a” compound should be understood to mean providing a compound of the invention to the individual in need of treatment.
  • treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
  • Combined therapy to modulate chemokine receptor activity for thereby treating, preventing, ameliorating, controlling or reducing the risk of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and multiple sclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis bf nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, biological TNF sequestrants, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic agent such as an opiate agonist, a lipoxygenase inhibitor,
  • the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
  • a pain reliever such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide
  • a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinep
  • compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may be used.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • Examples of other active ingredients that may be combined with CCR2 antagonists, such as the CCR2 antagonists compounds of the present invention, either administered separately or in the same pharmaceutical compositions include, but are not limited to: (a) VLA-4 antagonists such as those described in US 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin, EDG receptor agonists including FTY
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for
  • compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl ⁇ pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
  • dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known ait using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
  • topical application shall include mouthwashes and gargles.
  • the pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • an appropriate dosage level will generally be about 0.0001 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.0005 to about 400 mg/kg per day; or from about 0.005 to about 300 mg/kg per day; or from about 0.01 to about 250 mg/kg per day, or from about 0.05 to about 100 mg/kg per day, or from about 0.5 to about 50 mg/kg per day. Within this range the dosage may be 0.0001 to 0.005, 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day.
  • compositions may be provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, or 0.1 to 500, 1.0 to 400, or 2.0 to 300, or 3.0 to 200, particularly 0.01, 0.05, 0.1, 1, 4, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, or once or twice per day.
  • 3-oxocyclopentylbenzene (1-4) which is synthesized by treatment of cyclopentenone (1-1) with functionalized benzene boronic acid (1-2) in the catalysis of palladium acetate and antimony chloride or with substituted bromobenzene (1-3) in the catalysis of palladium acetate/triphenyl phosphine in neat triethyl amine (Ref. H. A. Dieck & R. F. Heck, J. Am. Chem. Soc. 1974, 99, 1133).
  • the cyclopentane core structures can also be prepared according to the Scheme 2. Treating a mixture of cis-l,4-dichloorobut-2-ene (2-1) and the substituted phenyl acetonitrile (2-2) in a mixture of DMF/DMPU gives the cyclopentene (2-3). Sequential reduction of the double bond with borane-THF and oxidation of the resulting intermediate (2-4) with PCC in one pot affords the corresponding cyclopentanone (2-5). The following reductive alkylation gives the aminocyclopentylbenzene (2-6) whose cyano group is further converted into the aldehyde (2-7).
  • the alcohol (2-8) is prepared from the aldehyde (2-7) by reduction with sodium borihydride.
  • the bromo atom in (2-8) can be converted into the ester (2-9) by heating it with palladium acetate in the atmosphere of carbon monoxide.
  • Standard saponification of (2-9) and the following coupling of the resulting amino acid (2-10) with the amine afford the final chemokine modulator (2-11).
  • cyclobutane modulator To prepare cyclobutane modulator, the double alkylation of substituted acetonitrile (2-2) with dimethyl-l,3-dibromo-acetal (3-1) is carried out using sodium hydride as a base. The following acidic hydrolysis of the resulting ketal (3-2) gives the corresponding cyclobutanone (3-3). After reduction amination, the aminocyclobutylbenzene (3-4) is obtained. Further derivatization of the bromobenzene (3-4) via a palladium chemistry results in the formation of the ester (3-5). After hydrolysis, EDC-initiated coupling of the acid (3-7) and acetic acid treatment of the coupling intermediate (3-8), the final imidazole modulator (3-9) is synthesized.
  • keto acid (4-1) is converted into the ketoamide (4-3) by EDC-initiated coupling with the amine (4-2).
  • the following reductive amination affords the modulator (4-4).
  • the second route starts from the keto ester which can be prepared by either procedure in Scheme 1 or by esterifying the keto acid.
  • the resulted keto ester (4-5) is then converted into the amino ester (4-6).
  • the amino acid (4-7) is obtained.
  • the standard EDC-initiated coupling gives the final modulator (4-4).
  • the (5-3) can be converted into various derivatives such as modulators (5-4), (5-5) and (5- 6) based on standard chemistry.
  • SCHEME 6 The chemokine modulators (6-5) is also prepared starting from the previously prepared amino ester (6-1).
  • the amino ester (6-2) is hydrolyzed into the amino acid (6-2) which undergoes the coupling and cyclization to give the chemokine modulators (6-4) and (6-5).
  • amine 8-1 is first reductively alkylated with a tetrahydropyranone in the presence of a suitable base such as triethylamine and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as DCM or methanol respectivly.
  • a suitable base such as triethylamine and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as DCM or methanol respectivly.
  • the resulting amine can then be further reductively alkylated with formaldehyde to give the amino-ester 8-2.
  • Saponification of the ester functionality can be achieved with a base such as sodium hydroxide in a suitable aqueous solvent mixture.
  • the chemokine modulator can be further modified to yield a new chemokine modulator such as 8-6, via a transition metal catalyzed cross coupling reaction. This route is shown in Scheme 9.
  • the diol prepared in Step A (11.8 g crude [-86% pure], ca. 83 mmol) was dissolved in DCM (150 mL) and treated with BoC 2 O (23.4 g, 107 mmol) in DCM (75 mL) over 15 min. The reaction mixture was stirred over the weekend, concentrated, and purified by MPLC, eluting with 5% MeOH/EtOAc to provide 14.8 g (81%) of product.
  • the aqueous layer was extracted again with DCM (200 mL), and the organic layers were combined and washed with IN HCl (250 mL), saturated NaHCO 3 solution (250 mL), and brine (250 mL). The organic layer was dried over MgSO 4 , filtered, and concentrated to give 22.8 g of crude bis-mesylate, which was used immediately. If not used immediately the bis-mesylate underwent decomposition.
  • Indene (7.03 mL, 7.00 g, 60.3 mmol) was added dropwise over 4 min to a 1.0 M THF solution of LHMDS (127 mL, 127 mmol) at 0 0 C. After stirring for an additional 30 min., this solution was transferred via cannula to a solution of bis-mesylate (22.6 g, 60.3 mmol), prepared as described in Step C above, in THF (75 mL) at 0 0 C. The mixture was stirred for 2 h, warmed to it and stirred overnight. The reaction mixture was partially concentrated and then partitioned between ethyl acetate and water. The organic layer was extracted again with ethyl acetate and the organic layers were combined.
  • the ketone from Step B of Example 6 (155 mg, 0.5 mmol) was combined in DCM (20 mL) with 4-fluorophenylpiperidine hydrochloride (220 mg, 1.0 mmol), triethylamine (260 mg, 2.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 1.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO 3 solution, then with brine, dried over anhydrous MgSO 4 , filtered, and concentrated.
  • the ketone from Step B of Example 6 (155 mg, 0.5 mmol) was combined in DCM (20 mL) with spiroindene hydrochloride (120 mg, 0.5 mmol), triethylamine (129 mg, 1.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 1.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO 3 solution, then with brine, dried over anhydrous MgSO 4 , filtered, and concentrated.
  • N-Boc-4-bromo-3-trifluoroaniline 7.06 g, 20.83 mmol
  • cyclopentenone 8.75 ml, 104.15 mmol
  • triethyl amine 4.355 ml, 32.7 mmol
  • palladium acetate 93.5 mg, 0.417 mmol
  • triphenyl phosphine 218.7 mg, 0.834

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Abstract

Compounds of the formulae (I) and (II): (wherein Q, X, E, G1, G2, R2, R3, R4, R5, R6 and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved.

Description

TITLE OF THE INVENTION
AMINO CYCLOPENTYL HETEROCYCLIC AND CARBOCYCLIC MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
BACKGROUND OF THE INVENTION The chemokines are a family of small (70-120 amino acids), proinflammatory cytokines, with potent chemotactic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation (reviewed in Schall, Cytokine, 3, 165-183 (1991) and Murphy, Rev. Immun., 12, 593-633 (1994)). These molecules were originally defined by four conserved cysteines and divided into two subfamilies based on the arrangement of the first cysteine pair. In the CXC- chemokine family, which includes EL-8, GROα, NAP-2 and IP-IO, these two cysteines are separated by a single amino acid, while in the CC-chemokine family, which includes RANTES, MCP-I, MCP-2, MCP- 3, MIP-Ia, MIP-IB and eotaxin, these two residues are adjacent. The α-chemokmes, such as interleukin-8 (EL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils, whereas β-chemokines, such as RANTES, MDMa, MEP-lβ, monocyte chemotactic protein-1 (MCP-I), MCP-2, MCP-3 and eotaxin are chemotactic for macrophages, monocytes, T-cells, eosinophils and basophils (Deng, et al., Nature, 381, 661-666 (1996)). The chemokines are secreted by a wide variety of cell types and bind to specific G- protein coupled receptors (GPCRs) (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) present on leukocytes and other cells. These chemokine receptors form a sub-family of GPCRs, which, at present, consists of fifteen characterized members and a number of orphans. Unlike receptors for promiscuous chemoattractants such as C5a, fMLP, PAF, and LTB4, chemokine receptors are more selectively expressed on subsets of leukocytes. Thus, generation of specific chemokines provides a mechanism for recruitment of particular leukocyte subsets. On binding their cognate ligands, chemokine receptors transduce an intracellular signal though the associated trimeric G protein, resulting in a rapid increase in intracellular calcium concentration. There are at least seven human chemokine receptors that bind or respond to β-chemokines with the following characteristic pattern: CCR-I (or "CKR-I" or "CC-CKR-I") [MJP-Io, MBP-lβ, MCP- 3, RANTES] (Ben-Barruch, et al., J. Biol. Chem, 270, 22123-22128 (1995); Beote, et al, Cell, 72, 415- 425 (1993)); CCR-2A and CCR-2B (or "CKR-2A"/"CKR-2A" or "CC-CKR-2A'7"CC-CKR-2A") [MCP-I, MCP-2, MCP-3, MCP-4]; CCR-3 (or "CKR-3" or "CC-CKR-3") [Eotaxin, Eotaxin 2, RANTES, MCP-2, MCP-3] (Rollins, et al., Blood, 90, 908-928 (1997)); CCR-4 (or "CKR-4" or "CC- CKR-4") [MIP-Iq RANTES, MCP-I] (Rollins, et al., Blood, 90, 908-928 (1997)); CCR-5 (or "CKR-5" or "CC-CKR-5") [MIP-Iq RANTES, MIP-I β] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); and the Duffy blood-group antigen [RANTES, MCP-I] (Chaudhun, et al., J. Biol. Chem.. 269, 7835-7838 (1994)). The β-chemokines include eotaxin, MIP ("macrophage inflammatory protein"), MCP ("monocyte chemoattractant protein") and RANTES ("regulation-upon-activation, normal T expressed and secreted") among other chemokines. Chemokine receptors, such as CCR-I, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR- 5, CXCR-3, CXCR-4, have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases, including asthma, rhinitis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Humans who are homozygous for the 32-basepair deletion in the CCR-5 gene appear to have less susceptibility to rheumatoid arthritis (Gomez, et al., Arthritis & Rheumatism, 42, 989-992 (1999)). A review of the role of eosinophils in allergic inflammation is provided by Kita, H., et al., J. Exp. Med. 183, 2421-2426 (1996). A general review of the role of chemokines in allergic inflammation is provided by Lustger, A.D., New England J. Med-, 338(7), 426-445 (1998). A subset of chemokines are potent chemoattractants for monocytes and macrophages. The best characterized of these is MCP-I (monocyte chemoattractant protein-1), whose primary receptor is CCR2. MCP-I is produced in a variety of cell types in response to inflammatory stimuli in various species, including rodents and humans, and stimulates chemotaxis in monocytes and a subset of lymphocytes. In particular, MCP-I production correlates with monocyte and macrophage infiltration at inflammatory sites. Deletion of either MCP-I or CCR2 by homologous recombination in mice results in marked attenuation of monocyte recruitment in response to thioglycollate injection and Listeria monocytogenes infection (Lu et al., J. Exp. Med., 187, 601-608 (1998); Kurihara et al. J. Exp. Med.. 186, 1757-1762 (1997); Boring et al. J. Clin. Invest., 100, 2552-2561 (1997); Kuziel et al. Proc. Natl. Acad. Sci., 94, 12053-12058 (1997)). Furthermore, these animals show reduced monocyte infiltration into granulomatous lesions induced by the injection of schistosomal or mycobacterial antigens (Boring et al. L Clin. Invest., 100, 2552-2561 (1997); Warmington et al. Am J. Path., 154, 1407-1416 (1999)). These data suggest that MCP-1-induced CCR2 activation plays a major role in monocyte recruitment to inflammatory sites, and that antagonism of this activity will produce a sufficient suppression of the immune response to produce therapeutic benefits in immunoinflammatory and autoimmune diseases. Accordingly, agents which modulate chemokine receptors such as the CCR-2 receptor would be useful in such disorders and diseases. In addition, the recruitment of monocytes to inflammatory lesions in the vascular wall is a major component of the pathogenesis of atherogenic plaque formation. MCP-I is produced and secreted by endothelial cells and intimal smooth muscle cells after injury to the vascular wall in
- ? - hypercholesterolemia conditions. Monocytes recruited to the site of injury infiltrate the vascular wall and differentiate to foam cells in response to the released MCP-I. Several groups have now demonstrated that aortic lesion size, macrophage content and necrosis are attenuated in MCP-I -/- or CCR2 -/- mice backcrossed to APO-E -/-, LDL-R -/- or Apo B transgenic mice maintained on high fat diets (Boring et al. Nature. 394, 894-897 (1998); Gosling et al. J. Clin. Invest.. 103, 773-778 (1999)). Thus, CCR2 antagonists may inhibit atherosclerotic lesion formation and pathological progression by impairing monocyte recruitment and differentiation in the arterial wall.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formulae I and II:
Q E — X-G1
Figure imgf000004_0001
(wherein Q, X, E, G1, G2, R2, R3, R4, R5, R6 and Z are as defined herein) which are modulators of chemokine receptor activity and are useful in the prevention or treatment of certain inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which chemokine receptors are involved. DETAILED DESCRIPTION OF THE INVENTION The present invention is rected to compounds of the formulae I and II: Q E — X-G1
Figure imgf000005_0001
wherein: Q is:
Figure imgf000005_0002
A is selected from: -O-, -NR12-, -S-, -SO-, -SO2-, -CR12R12-, -NSO2R14-, -NCOR13-, -CR12COR1I-, CR12OCOR13- and -CO-;
Figure imgf000005_0003
G1 is selected from: -N(R31)-CO- N(R30)(R29), -N(R31)-SO2R32, -N(R31)-COR32, -CON(R29)(R30), -Q- 6alkyl unsubstituted or substituted with 1-6 fluoro, and -Cs^cycloalkyl unsubstituted or substituted with 1- 6 fluoro,
where R^9 and R^O are independently selected from: hydrogen, Ci-6alkyl, C^-galkyl substituted with 1-6 fluoro, Ci-βcycloalkyl, aryl, aryl-Ci-^alkyl, heterocycle and heterocycle-Ci-όalkyl, or R29 and R^O join to form a C3-6 membered ring;
where R^l and R^2 are independently selected from: hydrogen, Cl-6alkyl, Ci-βcycloalkyl, Ci- galkyl substituted with 1-6 fluoro, aryl and heterocycle, or R^l and R^2 join to form a C3-6 membered ring;
G2 is selected from (where either end of the group is joined to X and the other end is joined to the aromatic ring): a single bond, -(CR11R11JM-, -N(R12)SOr, -N(R12)SO2N(R12)-, -N(R12)CO-, - C(R11XR11)CO-, -C(R11XR11X)CO-, -CO-, -C(R11)(R11)SO2-, -OCO-, -SO2-, or G2 is C R11 or N and is joined to R2 forming a fused carbocyclic or heterocyclic ring;
X is a 5-7 membered saturated, partially unsaturated or unsaturated carbocyclic or heterocyclic ring, wherein:
when said ring is heterocyclic it contains 1-4 heteroatoms independently selected from O, N and S,
said ring is unsubstituted or substituted with 1-4 R28, R28 is independently selected from: halo, hydroxy, -O-Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, -O-C3-5cycloalkyl unsubstituted or substituted with 1-6 fluoro, -CORI l, -SO2R14, -NR12COR13, -NR12SO2R14, - phenyl unsubstituted or substituted with 1-3 fluoro or trifluoromethyl, and -CN, and
said ring is optionally bonded to R6 to form a fused or spiro ring system (as shown by the curving dashed line in formula II);
Y is C, N, O, S or SO2;
Z is independently selected from C and N, where no more than two of Z are N; Rl is selected from: hydrogen, -SO2R14, -C0-3alkyl-S(O)R14, -SO2NR12R12, -Chalky!, -Co-6alkyl-0-Cl- galkyl, -Co-δalkyl-S-Ci-galkyl, -(Co-6alkyl)-(C3_7cycloalkyl)-(C(>6alkyl), hydroxy, heterocycle, -CN, - NR12R12, -NR12COR13, -NR12SO2R14, -COR11, -CONR12R12, and phenyl,
wherein said alkyl and the cycloalkyl are imsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: halo, hydroxy, -O-Ci_3alkyl, trifluoromethyl, Ci-3alkyl, -O-Cs-scycloalkyl, -CORl 1, -SO2R14. -NHCOCH3, -NHSO2CH3, -heterocycle, =0 and -CN, and
wherein said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Cl_3alkyl, Ci_3alkoxy and trifluoromethyl;
R3, R4, and R5 are independently selected from B1 when Z is C, and are independently selected from B2 when Z is N;
R2 is independently selected from B1 when Z is C, and is independently selected from B2 when Z is N, or R2 is a link to G2 wherein said link is a bond or is a chain 1-4 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
R6 is independently selected from B1 when Z is C, and is independently selected from B2 when Z is N, or R6 is a link to any atom on X, wherein said link is a bond or is a chain 1-3 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
B1 is selected from: Ci_6alkyl unsubstituted or substituted with 1-6 fluoro, hydroxyl, or both, -O-Ci- βalkyl unsubstituted or substituted with 1-6 fluoro, -CO-Ci-galkyl unsubstituted or substituted with 1-6 fluoro, -S-Ci-galkyl unsubstituted or substituted with 1-6 fluoro, -pyridyl unsubstituted or substituted with one or more substituents selected from the group consisting of: halo, trifluoromethyl, Ci.4alkyl and COR1 !, fluoro, chloro, bromo, -C-j-βcycloalkyl, -O-C-i-βcycloalkyl, phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, C^alkyl and COR11, -O-phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, C^alkyl and COR11, -C3.6cycloalkyl unsubstituted or substituted with 1-6 fluoro, -O-Cs^cycloalkyl unsubstituted or substituted with 1-6 fluoro, -heterocycle, -CN, -COR11 and hydrogen; B is absent or is O (to form an N-oxide);
R7 is selected from: hydrogen, (Cθ-6alkyl)-phenyl, (Co-6alkyl)-heterocycle, (Co-6alkyl)-C3-7cycloalkyl ,
Figure imgf000008_0001
(Cθ-6alkyl)-(alkene)-COR1 ! , (Cθ-6alkyl)-S03H, (Cθ-6alkyl)-W-Cθ-4alkyl, (Q)- 6alkyl)-CONR12-pheny and (Cθ-6alkyl)-CONR15-V-CORπ when Y is N or C, or R7 is absent when Y is O, S or SO2, where
V is Ci.6alkyl or phenyl,
W is a single bond, -O-, -S-, -SO-, -SO2-, -CO-, -CO2-, -CONR12- or-NRl2-,
R13 is hydrogen or Ci-4alkyl, or R15 is joined via a 1-5 carbon chain linked to one of the carbons of V, forming a ring,
said Cθ-6alkyl is unsubstituted or substituted with 1-5 substituents independently selected from halo, hydroxy, -Cθ-6alkyl, -O-Ci_3alkyl, trifiuoromethyl and -Co-2alkyl-ρhenyl,
said phenyl, heterocycle, cycloalkyl and Cθ-4alkyl are unsubstituted or substituted with 1-5 substituents independently selected from halo, trifiuoromethyl, hydroxy, Ci-galkyl, -O-C1- 3alkyl, -C0.3-CORll, -CN, -NR12R12, -CONR12R12 and -Co-3-heterocycle, or said phenyl or heterocycle may be fused to another heterocycle where said another heterocycle is unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR11, and -Q- 4alkyl, and
said alkene is unsubstituted or substituted with 1-3 substituents independently selected from halo, trifiuoromethyl, C1-3alkyl, phenyl and heterocycle;
R^ is selected from hydrogen, hydroxy, Ci-6alkyl, Cj-6alkyl-hydroxy, -O-Ci-3alkyl, -CORl 1, - CONR12R12 and -CN when Y is N or C, or R8 is absent when Y is O, S, SO2 or N or when a double bond joins the carbons to which R7 and R10 are attached;
or R7 and R^ are joined to form a ring selected from: lH-indene, 2,3-dihydro-lH-indene, 2,3-dihydro- benzofuran, 1,3-dihydro-isobenzofuran, 2,3-dihydro-benzothiofuran, 1,3-dihydro-isobenzothiofuran, 6H- cyclopenta[^]isoxazol-3-ol, cyclopentane and cyclohexane, where said ring is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, Ci-3alkyl, -O-Ci-3alkyl, -C0-3-CORlI, -CN, -NR12R12, _ CONR.12R.12 and -Co-3-heterocycle;
R^ and RIO are independently selected from: hydrogen, hydroxy, Ci-6alkyl, Ci_6alkyl-CORπ, Ci- galkyl-hydroxy, -O-Ci-3alkyl, halo and =O (connected to the ring via a double bond);
or R^ and R^, or R8 and R10, together form a ring which is phenyl or heterocycle, wherein said ring is unsubstituted or substituted with 1-7 substituents independently selected from halo, trifluoromethyl, hydroxy, Ci-3alkyl, -O-Ci-3alkyl, -COR!!, -CN, -NR12R12 and -CONR12R12;
R^ is independently selected from: hydroxy, hydrogen, Ci_g alkyl, -O-Ci-βalkyl, benzyl, phenyl and C3- 6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1-6
alkyl and trifluoromethyl;
R!2 is selected from: hydrogen, Ci-6 alkyl, benzyl, phenyl and C3-6 cycloalkyl, where said alkyl,
phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1-.6 alkyl, and trifluoromethyl;
R13 is selected from: hydrogen, C\-(, alkyl, -O-C1.6alkyl, benzyl, phenyl and C3_6 cycloalkyl, where said
alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1.6 alkyl and trifluoromethyl;
R14 is selected from: hydroxy, Cχ_6 alkyl, -O-C^alkyl, benzyl, phenyl and C3.6 cycloalkyl, where said
alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -CO2-C1.6 alkyl, and trifluoromethyl;
R16 and R18 are independently selected from: hydroxy, Ci_6alkyl, Ci_6alkyl-CORH, Ci_6alkyl- hydroxy, -O-Ci_3alkyl, halo and hydrogen, where said alkyl is unsubstituted or substituted with 1-6
substituents independantly chosen from fluoro and hydroxyl;
or R16 and R18 together are -C!-4alkyl-, -C0.2alkyl-O-Ci-3alkyl- or-C)-3alkyl-0-Cθ-2alkyl-, forming a
bridge, where said alkyl groups are unsubstituted or substituted with 1-2 substituents selecterd from oxy (where the oxygen is joined to the bridge via a double bond), fluoro, hydroxy, methoxy, methyl and trifluoromethyl-,
R17, R19, R20 and R21 are independently selected from: hydrogen, hydroxy, Ci-galkyl, Ci_6alkyl-CORπ, Ci-6alkyl-hydroxy, -O-Ci-3alkyl, trifluoromethyl and halo;
R22 is hydrogen or C1 6alkyl unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -CO2H, -CO2d..6alkyl and -O-C^alkyl;
R23 is selected from: Ci .galkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, Cualkoxy, hydroxyl and -COR^, fluoro, -O-Ci_3alkyl unsubstituted or substituted with 1-3 fluoro, C3.6 cycloalkyl, -O-Cs^cycloalkyl, hydroxy, -COR^, -OCOR^ and =0 (where the oxygen is connected to the ring via a double bond), or R22 and R23 together are C2.4alkyl or C0-2alkyl-O-C1-3alkyl, forming a 5-7 membered ring;
R2^ is selected from: hydrogen, Ci-βalkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, d,3alkoxy, hydroxyl and -COR*1, COR1 ^, hydroxyl and -O-Q.6alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, Ci-3alkoxy, hydroxyl and -COR^, or R23 and R2^ together are Ci_4alkyl or C0,3alkyl-0-Co-3alkyl, forming a 3-6 membered ring;
R25 is selected from: hydrogen, Ci-βalkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C3, gcycloalkyl and -O-Ci-3alkyl unsubstituted or substituted with 1-6 fluoro,
or R23 and R2^ together are C2-3alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -CORH, Ci-3alkyl, and Ci.3alkoxy,
or R23 and
Figure imgf000010_0001
forming a 6-8 membered ring, where said alkyls are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR^, Ci-3alkyl and Ci.3alkoxy,
or R23 and R2^ together are -O-Q^alkyl-O-, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR^ ^, Ci.3alkyl and Ci.3alkoxy; R26 is selected from: Cl-βalkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C1.3alk.oxy, hydroxyl and -COR* !, fluoro, -O-Cl_3alkyl unsubstituted or substituted with 1-3 fluoro, C3_6 cycloalkyl, -O-C^cycloalkyl, hydroxyl and -COR^, or R26 is absent if R23 is connected to the Q ring via double bond (as in the case where R23 is =0), or R26 and R23 together form a bridgeselected from -C2-5alkyl-, -O-C2.5alkyl-, -OC2-5alkyl-0-, and -Q- 3alkyl-O-Ci-3aIkyl-, where said alkyls are unsubstituted or substituted with 1-6 fluoro; R27 is selected from: hydrogen, Cj-galkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C3- gcycloalkyl, and -O-Ci-3alkyl unsubstituted or substituted with 1-6 fluoro; m, i, and n are independently selected from 0, 1 and 2; the dashed line represents an optional bond; and pharmaceutically acceptable salts thereof and individual diastereomers thereof. Embodiments of the invention include those of formula Ia
Figure imgf000011_0001
Ia wherein R*, R7, R8, R9, R10, R28, and G1 are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof. Embodiments of the invention include those of formula Ib:
Figure imgf000011_0002
Ib wherein R*, R^, R29, R30, and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
Embodiments of the invention include those of formula Ic:
Figure imgf000012_0001
Ic
wherein RΛ R^, R28, R31, R32 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
Embodiments of the invention include those of formula Id:
Figure imgf000012_0002
Id
wherein R1, R^, R29, R30, R3*, R32, R28 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
Embodiments of the invention include those of formula Ie:
Figure imgf000012_0003
Ie wherein R^, R? , R31 , R32? g28 ancj ^6 dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof. Embodiments of the invention include those of formula Ha:
Figure imgf000013_0001
Ha wherein R1, R3, R4, R5, R6, R7, R8, R9, R10, R28, G2, and Z are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof. Embodiments of the invention include those of formula lib
Figure imgf000013_0002
wherein R1, R3, R4, R5, R6, R28, and G2 are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof. Embodiments of the invention include those of formula Hc:
Figure imgf000014_0001
lie
wherein R*, R^, R9, R28, G2 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
Embodiments of the invention include those of formula Hd:
Figure imgf000014_0002
lid
wherein
R^, R9, R28 and the dashed line are defined herein,
M is selected from O, S and NR12''
R33 and R^4 are independently selected from hydrogen, halo, trifluoromethyl, O- Ci-βalkyl and O-Ci- galkyl substituted with 1-6 fluoro, and pharmaceutically acceptable salts and individual diastereomers thereof. Embodiments of the invention include those of formula He:
Figure imgf000015_0001
He
wherein RA R^ , R^3 , R^, R28 and the dashed line are defined herein, and pharmaceutically acceptable salts and individual diastereomers thereof.
Additional embodiments of the present invention include those wherein R2S is selected from H, F, Cl, Br, Me and CF3, and in particular those wherein R28 is selected from H, Me and CF3.
Additional embodiments of the present invention include wherein Y is C.
Additional embodiments of the present invention include those wherein A is O.
Additional embodiments of the present invention include those X is phenyl.
Additional embodiments of the present invention include those wherein R^ is selected from hydrogen, -Ci-6alkyl unsubstituted or substituted with 1-6 substituents independently selected from halo, hydroxy, -O-C1 -3alkyl and trifluoromethyl, -C()-6alkyl-O-Ci-6alkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, -C()-6alkyl-S-Ci-6alkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, - (C3_5cycloalkyl)-(Cθ-6alkyl) unsubstituted or substituted with 1-7 substituents independently selected from halo, hydroxy, -O-Ci_3alkyl and trifluoromethyl. In particular, embodiments incluse thoses wherein R^ is selected from hydrogen, Ci_6alkyl, Ci-6alkyl-hydroxy and Ci-galkyl substituted with 1-6 fluoro, specifically wherein R* is selected from hydrogen, methyl, hydroxymethyl and trifluoromethyl.
Additional embodiments of the present invention include those wherein when Z is N, R2 is absent, and those wherein when Z is C, R2 is hydrogen or is linked to G2.as described herein. Further embodiments of the present invention include those wherein if Z is N, R3 is absent, and those wherein if Z is C, R3 is hydrogen.
Further embodiments of the present invention include those wherein if the Z bonded to R4 is N, R4 is absent.
Further embodiments of the present invention include those wherein if the Z bonded to R4 is C, R4 is hydrogen.
Further embodiments of the present invention include those wherein, if the Z bonded to R3 is N, R5 is absent.
Further embodiments of the present invention include those wherein if the Z bonded to R6 is N, R6 is absent.
Further embodiments of the present invention include those wherein if the Z bonded to R6 is C, R6 is hydrogen.
Further embodiments of the present invention include those wherein R ' is selected from phenyl, heterocycle, C3-7cycloalkyl, C1-6alkyl, -COR11 and -CONH-V-COR11, where V is Ci-6alkyl or phenyl, and where said phenyl, heterocycle, C3-7cycloalkyl and Q^alkyl is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, C]__3alkyl, -O-Ci- 3alkyl, -CORlI, _CN, -heterocycle and -CONR12R12.
Further embodiments of the present invention include those wherein R^ is selected from: hydrogen, hydroxy, -CN and -F.
Further embodiments of the present invention include those wherein R7 and R8 are joined together to form a ring which is selected from: lH-indene and 2,3-dihydro-lH-indene, where said ring is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, Ci_3alkyl, -O-Ci_3alkyl, -CORl 1 and -heterocycle.
Further embodiments of the present invention include those wherein R^ and R^" are independently s ieelleecctteedd f frroomm:: 1 hydrogen, hydroxy, -CH3, -O-CH3 and =0 (where R9 and/or R10 are joined to the ring via a double bond). Further embodiments of the present invention include those wherein R9 is hydrogen or methyl.
Further embodiments of the present invention include those wherein one or more of Ri0, R16, R17, R18, R19, R20, R21, R23, R24, R25, R26 and R27 is hydrogen.
Further embodiments of the present invention include those wherein R22 is methyl.
Representative compounds of the present invention include those described in the Examples, below, and pharmaceutically acceptable salts and individual diastereomers thereof.
The compounds of the instant invention where E is the cyclopentyl ring have at least two asymmetric centers at the 1- and 3-positions of the cycloalkyl ring. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The absolute configurations of the more preferred compounds of this orientation where the substituents on the cycloalkyl ring (amide and amine units) are cis, as depicted:
Figure imgf000017_0001
The absolute configurations of the most preferred compounds of this invention are those of the orientation as depicted:
Figure imgf000017_0002
wherein the carbon bearing the amine substituent is designated as being of the (R) absolute configuration and the carbon bearing the amide subunit can be designated as being of either the (S) or (R) absolute configuration depending on the priority for R1. For example if R is isopropyl then the absolute stereochemistry at the carbon bearing the amide subunit would be (S) since the amide and amine units are preferred to have the cis arrangement on the cyclopentyl ring. The independent syntheses of diastereomers and enantiomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. As appreciated by those of skill in the art, halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo. As used herein, "alkyl" is intended to mean linear, branched and cyclic carbon structures having no double or triple bonds. Cχ-8, as in Ci-galkyl, is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a linear or branched arrangement, such that Cχ-8alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. More broadly, Ca-balkyl (where a and b represent whole numbers) is defined to identify the group as having a through b carbons in a linear or branched arrangement. Co, as in Coalkyl is defined to identify the presence of a direct covalent bond. "Cycloalkyl" is an alkyl, part or all of which which forms a ring of three or more atoms. The term "heterocycle" as used herein is intended to include the following groups: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof. The term "ring" is employed herein to refer to the formation or existence of a cyclic structure of any type, including free standing rings, fused rings, and bridges formed on existing rings. Rings may be non-aromatic or aromatic. Moreover, the existence or formation of a ring structure is at times herein disclosed wherein multiple substituents are defined "together", as in "...R^ and R^ together are C1-4alkyl...". In this case a ring is necessarily formed regardless of whether the term "ring" is employed. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts of the present invention can be prepared from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are employed. Suitable salts are found, e.g. in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418. Specific compounds within the present invention include a compound which selected from the group consisting of those compounds described in the Examples, and pharmaceutically acceptable salts thereof and individual diastereomers and enantiomers thereof. The subject compounds are useful in a method of modulating chemokine receptor activity in a patient in need of such modulation comprising the administration of an effective amount of the compound. The present invention is directed to the use of the foregoing compounds as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors, in particular CCR-2. The utility of the compounds in accordance with the present invention as modulators of chemokine receptor activity may be demonstrated by methodology known in the art, such as the assay for chemokine binding as disclosed by Van Riper, et al., J. Exp. Med., 177, 851-856 (1993) which may be readily adapted for measurement of CCR-2 binding. Receptor affinity in a CCR-2 binding assay was determined by measuring inhibition of 1251-MCP-I to the endogenous CCR-2 receptor on various cell types including monocytes, THP-I cells, or after heterologous expression of the cloned receptor in eukaryotic cells. The cells were suspended in binding buffer (50 mM HEPES, pH 7.2, 5 mM MgCl2, 1 mM CaCl2, and 0.50% BSA or 0.5% human serum) and added to test compound or DMSO and 125]_MCP-1 at room temperature for 1 h to allow binding. The cells were then collected on GFB filters, washed with 25 mM HEPES buffer containing 500 mM NaCl and cell bound 125I-MCP-1 was quantified. In a chemotaxis assay chemotaxis was performed using T cell depleted PBMC isolated from venous whole or leukophoresed blood and purified by Ficoll-Hypaque centrifugation followed by rosetting with neuraminidase-treated sheep erythrocytes. Once isolated, the cells were washed with HBSS containing 0.1 mg/ml BSA and suspended at Ixlθ7 cells/ml. Cells were fluorescently labeled in the dark with 2 μM Calcien-AM (Molecular Probes), for 30 min at 37° C. Labeled cells were washed twice and suspended at 5x10^ cells/ml in RPMI 1640 with L-glutamine (without phenol red) containing 0.1 mg/ml BSA. MCP-I (Peprotech) at 10 ng/ml diluted in same medium or medium alone were added to the bottom wells (27 μl). Monocytes (150,000 cells) were added to the topside of the filter (30 μl) following a 15 min preincubation with DMSO or with various concentrations of test compound. An equal concentration of test compound or DMSO was added to the bottom well to prevent dilution by diffusion. Following a 60 min incubation at 37° C, 5 % CO2, the filter was removed and the topside was washed with HBSS containing 0.1 mg/ml BSA to remove cells that had not migrated into the filter. Spontaneous migration (chemokinesis) was determined in the absence of chemoattractant. In particular, the compounds of the following examples had activity in binding to the CCR-2 receptor in the aforementioned assays, generally with an IC50 of less than about 1 μM. Such a result is indicative of the intrinsic activity of the compounds in use as modulators of chemokine receptor activity. Mammalian chemokine receptors provide a target for interfering with or promoting eosinophil and/or leukocyte function in a mammal, such as a human. Compounds which inhibit or promote chemokine receptor function, are particularly useful for modulating eosinophil and/or leukocyte function for therapeutic purposes. Accordingly, compounds which inhibit or promote chemokine receptor function would be useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic diseases, atopic conditions including allergic rhinitis, dermatitis, conjunctivitis, and asthma, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis, and further, chronic obstructive pulmonary disease, and multiple schlerosis. For example, an instant compound which inhibits one or more functions of a mammalian chemokine receptor (e.g., a human chemokine receptor) may be administered to inhibit (i.e., reduce or prevent) inflammation. As a result, one or more inflammatory processes, such as leukocyte emigration, chemotaxis, exocytosis (e.g., of enzymes, histamine) or inflammatory mediator release, is inhibited. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). Diseases and conditions associated with inflammation and infection can be treated using the compounds of the present invention. In a certain embodiment, the disease or condition is one in which the actions of leukocytes are to be inhibited or promoted, in order to modulate the inflammatory response. Diseases or conditions of humans or other species which can be treated with inhibitors of chemokine receptor function, include, but are not limited to: inflammatory or allergic diseases and conditions, including respiratory allergic diseases such as asthma, particularly bronchial asthma, allergic rhinitis, hypersensitivity lung diseases, hypersensitivity pneumonitis, eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilic pneumonia), delayed-type hypersentitivity, interstitial lung diseases (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic sclerosis, Sjogren' s syndrome, polymyositis or dermatomyositis); systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies; autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allograft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spondyloarthropathies; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory dermatoses such an dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis); eosinphilic myositis, eosinophilic fasciitis; and cancers, including cancers with leukocyte infiltration of the skin or organs and other cancers. Inhibitors of chemokine receptor function may also be useful in the treatment and prevention of stroke (Hughes et al., Journal of Cerebral Blood Flow & Metabolism, 22:308-317, 2002, and Takami et al., Journal of Cerebral Blood Flow & Metabolism, 22:780-784, 2002), neurodegenerative conditions including but not limited to Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and Parkinson's disease, obesity, type II diabetes, neuropathic and inflammatory pain, and Guillain Barre syndrome. Other diseases or conditions in which undesirable inflammatory responses are to be inhibited can be treated, including, but not limited to, reperfusion injury, atherosclerosis, certain hematologic malignancies, cytokine-induced toxicity (e.g., septic shock, endotoxic shock), polymyositis, dermatomyositis and chronic obstructive pulmonary disease. Diseases or conditions of humans or other species, which can be treated with modulators of chemokine receptor function, include or involve but are not limited to: immunosuppression, such as that in individuals with immunodeficiency syndromes such as AIDS or other viral infections, individuals undergoing radiation therapy, chemotherapy, therapy for autoimmune disease or drug therapy (e.g., corticosteroid therapy), which causes immunosuppression; immunosuppression due to congenital deficiency in receptor function or other causes; and infections diseases, such as parasitic diseases, including, but not limited to helminth infections, such as nematodes (round worms), (Trichuriasis, Enterobiasis, Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis), trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tape worms) (Echinococcosis, Taeniasis saginata, Cysticercosis), visceral worms, visceral larva migraines (e.g., Toxocara), eosinophilic gastroenteritis (e.g., Anisaki sp., Phocanema sp.), and cutaneous larva migraines (Ancylostona braziliense, Ancylostoma caninum). In addition, treatment of the aforementioned inflammatory, allergic, infectious and autoimmune diseases can also be contemplated for agonists of chemokine receptor function if one contemplates the delivery of sufficient compound to cause the loss of receptor expression on cells through the induction of chemokine receptor internalization or delivery of compound in a manner that results in the misdirection of the migration of cells. The compounds of the present invention are accordingly useful in treating, preventing, ameliorating, controlling or reducing the risk of a wide variety of inflammatory and immunoregulatory disorders and diseases, allergic conditions, atopic conditions, as well as autoimmune pathologies. In a specific embodiment, the present invention is directed to the use of the subject compounds for treating, preventing, ameliorating, controlling or reducing the risk of autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis and multiple schlerosis. In another aspect, the instant invention may be used to evaluate putative specific agonists or antagonists of chemokine receptors, including CCR-2. Accordingly, the present invention is directed to the use of these compounds in the preparation and execution of screening assays for compounds that modulate the activity of chemokine receptors. For example, the compounds of this invention are useful for isolating receptor mutants, which are excellent screening tools for more potent compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other compounds to chemokine receptors, e.g., by competitive inhibition. The compounds of the instant invention are also useful for the evaluation of putative specific modulators of the chemokine receptors, including CCR-2. As appreciated in the art, thorough evaluation of specific agonists and antagonists of the above chemokine receptors has been hampered by the lack of availability of non-peptidyl (metabolically resistant) compounds with high binding affinity for these receptors. Thus the compounds of this invention are commercial products to be sold for these purposes. The present invention is further directed to a method for the manufacture of a medicament for modulating chemokine receptor activity in humans and animals comprising combining a compound of the present invention with a pharmaceutical carrier or diluent. The present invention is further directed to the use of the present compounds in treating, preventing, ameliorating, controlling or reducing the risk of infection by a retrovirus, in particular, herpes virus or the human immunodeficiency virus (HTV) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HTV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (ADDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery. In a further aspect of the present invention, a subject compound may be used in a method of inhibiting the binding of a chemokine to a chemokine receptor, such as CCR-2, of a target cell, which comprises contacting the target cell with an amount of the compound which is effective at inhibiting the binding of the chemokine to the chemokine receptor. The subject treated in the methods above is a mammal, for instance a human being, male or female, in whom modulation of chemokine receptor activity is desired. "Modulation" as used herein is intended to encompass antagonism, agonism, partial antagonism, inverse agonism and/or partial agonism. In an aspect of the present invention, modulation refers to antagonism of chemokine receptor activity. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions. Combined therapy to modulate chemokine receptor activity for thereby treating, preventing, ameliorating, controlling or reducing the risk of inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and multiple sclerosis, and those pathologies noted above is illustrated by the combination of the compounds of this invention and other compounds which are known for such utilities. For example, in treating, preventing, ameliorating, controlling or reducing the risk of inflammation, the present compounds may be used in conjunction with an antiinflammatory or analgesic agent such as an opiate agonist, a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of the synthesis bf nitric oxide, a non-steroidal antiinflammatory agent, or a cytokine-suppressing antiinflammatory agent, for example with a compound such as acetaminophen, aspirin, codeine, biological TNF sequestrants, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, and the like. Similarly, the instant compounds may be administered with a pain reliever; a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antiitussive such as codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention may be used. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. Examples of other active ingredients that may be combined with CCR2 antagonists, such as the CCR2 antagonists compounds of the present invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) VLA-4 antagonists such as those described in US 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216, WO96/22966, WO96/31206, WO96/40781, WO97/03094, WO97/02289, WO 98/42656, WO98/53814, WO98/53817, WO98/53818, WO98/54207, and WO98/58902; (b) steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressants such as cyclosporin, tacrolimus, rapamycin, EDG receptor agonists including FTY- 720, and other FK-506 type immunosuppressants; (d) antihistamines (Hl-histamine antagonists) such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, desloratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and the like; (e) non-steroidal anti-asthmatics such as β2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, rnontelukast, pranlukast, iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); (T) non-steroidal antiinflammatory agents (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indorαethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone); (g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors of phosphodiesterase type IV (PDE-IV); (i) other antagonists of the cheniokine receptors, especially CCR-I, CCR-2, CCR-3, CXCR-3, CXCR-4 and CCR-5; (j) cholesterol lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin, rosuvastatin, and other statins), sequestrants (cholestyramine and colestipol), cholesterol absorption inhibitors (ezetimibe), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), and probucol; (k) anti-diabetic agents such as insulin, sulfonylureas, biguanides (metformin), α-glucosidase inhibitors (acarbose) and glitazones (troglitazone and pioglitazone); (1) preparations of interferon beta (interferon beta-lα, interferon beta-lβ); (m) preparations of glatiramer acetate; (n) preparations of CTLA4Ig; (o) preparations of hydroxychloroquine, (p) Copaxone® and (q) other compounds such as 5 -aminosalicylic acid and prodrugs thereof, antimetabolites such as azathioprine, 6-mercaptopurine and methotrexate, leflunomide, teriflunomide, and cytotoxic and other cancer chemotherapeutic agents. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with an NSAID the weight ratio of the compound of the present invention to the NSAID will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl¬ pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known ait using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles.) The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. In treating, preventing, ameliorating, controlling or reducing the risk of conditions which require chemokine receptor modulation an appropriate dosage level will generally be about 0.0001 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. In certain embodiments the dosage level will be about 0.0005 to about 400 mg/kg per day; or from about 0.005 to about 300 mg/kg per day; or from about 0.01 to about 250 mg/kg per day, or from about 0.05 to about 100 mg/kg per day, or from about 0.5 to about 50 mg/kg per day. Within this range the dosage may be 0.0001 to 0.005, 0.005 to 0.05, 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 0.01 to 1000 milligrams of the active ingredient, or 0.1 to 500, 1.0 to 400, or 2.0 to 300, or 3.0 to 200, particularly 0.01, 0.05, 0.1, 1, 4, 5, 10, 15, 20, 25, 30, 50, 75, 100, 125, 150, 175, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or once or twice per day. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made by known procedures or as illustrated. One of the principal routes used for preparation of compounds within the scope of the instant invention which bear a 1,1,3-trisubstituted cyclopentane framework is depicted in Scheme 1. SCHEME l
Figure imgf000030_0001
According to this route, 3-oxocyclopentylbenzene (1-4) which is synthesized by treatment of cyclopentenone (1-1) with functionalized benzene boronic acid (1-2) in the catalysis of palladium acetate and antimony chloride or with substituted bromobenzene (1-3) in the catalysis of palladium acetate/triphenyl phosphine in neat triethyl amine (Ref. H. A. Dieck & R. F. Heck, J. Am. Chem. Soc. 1974, 99, 1133). The resulting ketone then undergoes reductive amination in a presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride to give the aminocyclopentyl benzene (1-6) which can be further converted into other chemokine modulators according to the procedures depicted in the following schemes. SCHEME 2
Figure imgf000031_0001
2-6
Figure imgf000031_0002
The cyclopentane core structures can also be prepared according to the Scheme 2. Treating a mixture of cis-l,4-dichloorobut-2-ene (2-1) and the substituted phenyl acetonitrile (2-2) in a mixture of DMF/DMPU gives the cyclopentene (2-3). Sequential reduction of the double bond with borane-THF and oxidation of the resulting intermediate (2-4) with PCC in one pot affords the corresponding cyclopentanone (2-5). The following reductive alkylation gives the aminocyclopentylbenzene (2-6) whose cyano group is further converted into the aldehyde (2-7). The alcohol (2-8) is prepared from the aldehyde (2-7) by reduction with sodium borihydride. The bromo atom in (2-8) can be converted into the ester (2-9) by heating it with palladium acetate in the atmosphere of carbon monoxide. Standard saponification of (2-9) and the following coupling of the resulting amino acid (2-10) with the amine afford the final chemokine modulator (2-11). SCHEME 3
Figure imgf000033_0001
3-3 3-4
Figure imgf000033_0002
3-5 3-6
Figure imgf000033_0003
3-9
To prepare cyclobutane modulator, the double alkylation of substituted acetonitrile (2-2) with dimethyl-l,3-dibromo-acetal (3-1) is carried out using sodium hydride as a base. The following acidic hydrolysis of the resulting ketal (3-2) gives the corresponding cyclobutanone (3-3). After reduction amination, the aminocyclobutylbenzene (3-4) is obtained. Further derivatization of the bromobenzene (3-4) via a palladium chemistry results in the formation of the ester (3-5). After hydrolysis, EDC-initiated coupling of the acid (3-7) and acetic acid treatment of the coupling intermediate (3-8), the final imidazole modulator (3-9) is synthesized.
SCHEME 4
Figure imgf000034_0001
4-4
Two alternative routes can be used to prepare aminocyclopentyl benzene chemokine modulator. In the first route, the keto acid (4-1) is converted into the ketoamide (4-3) by EDC-initiated coupling with the amine (4-2). The following reductive amination affords the modulator (4-4). The second route starts from the keto ester which can be prepared by either procedure in Scheme 1 or by esterifying the keto acid. The resulted keto ester (4-5) is then converted into the amino ester (4-6). After hydrolysis, the amino acid (4-7) is obtained. The standard EDC-initiated coupling gives the final modulator (4-4). SCHEME 5
Figure imgf000035_0001
H+
Figure imgf000035_0002
The carbamate (5-1), which is prepared according to the Scheme 1, undergoes reductive amination to give the amine (5-2). After removal of the protecting group, the aminocyclopentylaniline (5- 3) is obtained. The (5-3) can be converted into various derivatives such as modulators (5-4), (5-5) and (5- 6) based on standard chemistry. SCHEME 6
Figure imgf000036_0001
The chemokine modulators (6-5) is also prepared starting from the previously prepared amino ester (6-1). The amino ester (6-2) is hydrolyzed into the amino acid (6-2) which undergoes the coupling and cyclization to give the chemokine modulators (6-4) and (6-5). SCHEME 7
Figure imgf000036_0002
An alternative route is also developed starting from the ketoaldehyde (7-1), which is prepared according to the procedure in the Scheme 1. Direct oxidative condensation of the aldehyde with diamino benzene gives the keto imidazole (7-2). Various chemokine modulators (7-3) can be readily prepared by reductive amination. Scheme 8 shows a route to non cylopentyl chemokine modulators. According to this route, amine 8-1 is first reductively alkylated with a tetrahydropyranone in the presence of a suitable base such as triethylamine and a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent such as DCM or methanol respectivly. The resulting amine can then be further reductively alkylated with formaldehyde to give the amino-ester 8-2. Saponification of the ester functionality can be achieved with a base such as sodium hydroxide in a suitable aqueous solvent mixture. Condensation of the resulting acid (8-3) with a diamine of the form 8-4, in the presence of EDC, DMAP, and a abse such as triethylamine in DCM, followed by prolonged heating with acetic acid give chemokine modulators of the formula 8-5.
SCHEME 8
Figure imgf000037_0001
In cases where Rm or Rn is a suitable electrophile, such as an aryl halide or triflate (X'), the chemokine modulator can be further modified to yield a new chemokine modulator such as 8-6, via a transition metal catalyzed cross coupling reaction. This route is shown in Scheme 9. SCHEME 9
Figure imgf000038_0001
An alternate method for the preparation of non-cyclopentyl chemokine modulators is shown in Scheme 10. According to this route, the condensation reaction between the diamine (8-4) and the boc protected amino acid (8-7) gives the imidazole 8-8. Removal of the Boc protecting group can be accomplished using HCl to give the amine 8-9. Successive reductive alkylations of the amine with the pyranone and formalydehyde then gives chemokine modulator 8-10.
SCHEME 10
Figure imgf000038_0002
7h; Et3N,
Figure imgf000038_0004
Figure imgf000038_0003
In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosed invention. Concentration of solutions was generally carried out on a rotary evaporator under reduced pressure. Flash chromatography was carried out on silica gel (230-400 mesh). NMR spectra were obtained in CDCI3 solution unless otherwise noted. Coupling constants (J) are in hertz (Hz). Abbreviations: diethyl ether (ether), triethylamine (TEA), N,N-diisopropylethylamine (DIEA) saturated aqueous (sat'd), room temperature (rt), hour(s) (h), minute(s) (min). The following are representative Procedures for the preparation of the compounds used in the following Examples or which can be substituted for the compounds used in the following Examples which may not be commercially available.
INTERMEDIATE 1
Figure imgf000039_0001
To a cooled (0 0C) solution of ethanolamine (41.8 g, 0.685 mol) in water (90 mL) was added neat (R)-propylene oxide (4.97 g, 85.6 mmol), dropwise. After 1 h at 0 0C the reaction was allowed to rise to rt and stirred overnight. The reaction mixture was concentrated at -80 0C in vacuo to remove the water and most of the ethanolamine, to give 11.79 g of crude product, containing some residual ethanolamine. This material was used without further purification in Step B.
Figure imgf000039_0002
The diol prepared in Step A (11.8 g crude [-86% pure], ca. 83 mmol) was dissolved in DCM (150 mL) and treated with BoC2O (23.4 g, 107 mmol) in DCM (75 mL) over 15 min. The reaction mixture was stirred over the weekend, concentrated, and purified by MPLC, eluting with 5% MeOH/EtOAc to provide 14.8 g (81%) of product.
Figure imgf000040_0001
To a solution of the Boc-protected diol prepared in Step B (13.2 g, 60.3 mmol) and triethylamine (21.0 mL, 15.3 g, 151 mmol) in DCM (150 mL) at 0 0C was added dropwise methanesulfonyl chloride (9.56 mL, 14.1 g, 125 mmol). The reaction mixture was then stirred for 1.5 h, diluted with more DCM (100 mL) and washed with 3N HCl (250 mL). The aqueous layer was extracted again with DCM (200 mL), and the organic layers were combined and washed with IN HCl (250 mL), saturated NaHCO3 solution (250 mL), and brine (250 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give 22.8 g of crude bis-mesylate, which was used immediately. If not used immediately the bis-mesylate underwent decomposition.
Figure imgf000040_0002
Indene (7.03 mL, 7.00 g, 60.3 mmol) was added dropwise over 4 min to a 1.0 M THF solution of LHMDS (127 mL, 127 mmol) at 0 0C. After stirring for an additional 30 min., this solution was transferred via cannula to a solution of bis-mesylate (22.6 g, 60.3 mmol), prepared as described in Step C above, in THF (75 mL) at 0 0C. The mixture was stirred for 2 h, warmed to it and stirred overnight. The reaction mixture was partially concentrated and then partitioned between ethyl acetate and water. The organic layer was extracted again with ethyl acetate and the organic layers were combined. The organic phase was then washed with brine, dried over MgSO4, filtered and concentrated to give 17.3 g of crude product. Purification by MPLC, eluting with 15% ethyl acetate/hexane, afforded 9.51 g (53%) of piperidine as a -3:1 mixture of trans to cis (determined by H NMR). The mixture was crystallized from hot hexane to give 6 g (33%) of pure trans isomer (>20: 1 by H NMR). H NMR (CDCl3, 400 MHz): δ 7.29 (dt, J = 6.4, 1.6 Hz, IH), 7.20 (m, 3H), 6.83 (d, J = 6.0 Hz, IH), 6.67 (d, J = 5.6 Hz, IH), 4.20 (br s, 2H), 2.97 (br t, J = 3.2 Hz, IH), 2.69 (br t, J = 2.4 Hz, IH), 2.16 (m, IH), 2.07 (dt, J = 4.4, 13.2 Hz, IH), 1.49 (s, 9H), 1.25 (m, IH), 0.31 (d, J = 6.8 Hz, 3H).
Figure imgf000041_0001
The Boc-piperidine prepared in Step D (4.35 g, 14.5 mmol) was dissolved in an anhydrous 4 N HCl solution in dioxane and stirred at rt for 1 h. The reaction mixture was then concentrated to afford 3.81 g of product. EI-MS calc. for C14H17N: 199; Found: 200 (M)+.
EXAMPLE 1
Figure imgf000041_0002
A mixture of cyclopentenone (6.5 g, 80 mmol), 4-carboxybenzene boric acid (15.0 g, 90 mmol), sodium acetate (16.4 g, 200 mmol), palladium acetate (2.30 g, 10 mmol), antimony trichloride (2.30 g, 10 mmol) in acetic acid (250 ml) was stirred over two days. The dark solid was removed by filtration and the filtrate was evaporated to remove acetic acid under reduced pressure. To the residue was added water (200 mL) and ethyl acetate (400 ml), stirred for 30 min. The organic phase was separated and washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to afford the title compound as a yellow solid (1.2 g). 1H-NMR (CDCl3, 300 MHz): δ 7.99 (d, J = 8.3 Hz, 2H), 7.41 (d, J = 8.2, 2H), 3.30 (m, IH), 2.60 (m, IH), 2.40 (m, 4H), 2.00 (m, IH).
Figure imgf000042_0001
The acid (1.02 g, 5 mmol) from Step A immediately above, iodomethane (0.62 ml, 10 mmol) and potassium carbonate (1.38 g, 10 mmol) in DMF (20 ml) was stirred at RT overnight. The reaction mixture was diluted with 50 ml of water, extracted with 20% ethyl acetate/hexane (2 x 50 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to afford a yellow solid (1.0 g). 1H-NMR (CDCl3, 300 MHz): δ 7.98 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4, 2H), 3.89 (s, 3H), 3.43 (m, IH), 2.62 (dd, IH), 2.40 (m, 4H), 2.00 (m, IH).
Figure imgf000042_0002
The cyclopentanone from Step B immediately above (220 mg, 1 mmol) was combined in DCM (20 mL) with 3-methylspiroindeneρiperidine Intermediate 1 (236 mg, 1 mmol), triethylamine (195 mg, 1.5 mmol), sodium tiacetoxyborohydride (633 mg, 3 mmol), and molecular sieves (4A, 2.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NHUOH/methanol/DCM) gave 280 mg of the title product. ESI-MS calc. for C27H31NO2: 401; Found: 402 (M+H).
Figure imgf000042_0003
The ester from Step C immediately above (280 mg, 0.7 mmol) was combined in a mixture of THF and water (20 ml, 2:1 v/v) with lithium hydroxide monohydrate (82 mg, 2 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was condensed and purified by preparative TLC (silica, 1:9 of methanol/DCM) to give 200 mg of the title product amino acid. ESI-MS calc. for C26H29N2O: 387; Found: 388 (M+H).
Figure imgf000043_0001
The amino acid from Step D immediately above (38.7 mg, 0.1 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (28 mg, 0.2 mmol), EDAC (38 mg, 0.2 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 25 mg of the title product aminoamide. ESI-MS calc. for C32H34C1N3O: 511; Found: 512 (M+H).
Figure imgf000043_0002
The aminoamide from Step E immediately above (20 mg) in 0.5 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NHUOH/methanol/DCM) to give 12 mg of the title product aminoimidazole as a mixture of 4 diastereomers. Four respective single enantiomers were obtained by chiral HPLC (OD column, 10% ethanol/hexane). ESI-MS calc. for C32H32C1N3: 493; Found: 494 (M+H). EXAMPLE 2
Figure imgf000044_0001
A mixture of 3-methyl-cyclopentenone (7.7 g, 80 mmol), 4-carboxybenzene boric acid (15.0 g, 90 mmol), sodium acetate (16.4 g, 200 mmol), palladium acetate (2.30 g, 10 mmol), antimony trichloride (2.30 g, 10 mmol) in acetic acid (250 ml) was stirred over two days. The dark solid was removed by filtration and the filtrate was evaporated to remove acetic acid under reduced pressure. To the residue was added water (200 mL) and ethyl acetate (400 ml), stirred for 30 min. The organic phase was separated and washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was mixed with potassium carbonate (40 g) and iodomethane (10 ml) in DMF (100 ml), stirred overnight, diluted with water, extracted with 20% ethyl acetate/hexane, dried over sodium sulfate, evaporated. Purification on FC (10% ethyl acetate/hexane) gave the title compound (0.42 g). 1H-NMR (CDCl3, 300 MHz): δ 7.92 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5, 2H), 3.88 (s, 2H), 3.83 (s, 3H), 3.42 (m, 4H), 1.35 (s, 2H).
Figure imgf000044_0002
The cyclopentanone from Step A immediately above (233 mg, 1 mmol) was combined in DCM (20 mL) with 3-methylspiroindenepiperidine Intermediate 1 (236 mg, 1 mmol), triethylamine (195 mg, 1.5 mmol), sodium tiacetoxyborohydride (633 mg, 3 mmol), and molecular sieves (4A, 2.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 120 mg of the title product. ESI-MS calc. for C28H33NO2: 415; Found: 416 (M+H).
Figure imgf000045_0001
The ester from Step B immediately above (120 mg) was combined in a mixture of THF and water (20 ml, 2:1 v/v) with lithium hydroxide monohydrate (41 mg, 1 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was condensed and purified by preparative TLC (silica, 1:9 of methanol/DCM) to give 120 mg of the title product amino acid as a white solid. ESI-MS calc. for C27H31N2O: 401; Found: 402 (M+H).
Figure imgf000045_0002
The amino acid from Step C immediately above (120 mg, 0.3 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (142 mg, 1.0 mmol), EDAC (191 mg, 1.0 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 110 mg of the corresponding amide. This material was heated with acetic acid (0.5 ml) at 600C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH^OH/methanol/DCM) to give 80 mg of the title compound as a brown solid. ESI-MS calc. for C33H34C1N3: 508; Found: 509 (M+H). EXAMPLE 3
Figure imgf000046_0001
A mixture of cyclopentenone (10.0 g, 120 mmol), 3-formylbenzene boric acid (15.0 g, 100 mmol), sodium acetate (16.4 g, 200 mmol), palladium acetate (2.30 g, 10 mmol), antimony trichloride (2.30 g, 10 mmol) in acetic acid (500 ml) was stirred over two days. The dark solid was removed by filtration and the filtrate was evaporated to remove acetic acid under reduced pressure. To the residue was added water (200 mL) and ethyl acetate (400 ml), stirred for 30 min. The organic phase was separated and washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluted with 25% ethyl acetate in hexane) to afford the title compound as a yellow oil (5.2 g). 1H-NMR (CDCl3, 300 MHz): δ 9.96 (s, IH), 7.75 (m, 3H), 7.49 (m, 3H), 3.44 (m, IH), 2.68 (m, IH), 2.42 (m, 2H), 2.30 (m, 2H), 2.00 (m, IH).
Figure imgf000046_0002
The aldehyde (150 mg, 0.8 mmol) from Step A immediately above was heated at 65 oC for 20 min with sodium bisulfite (200 mg) in methanol (10 ml), then 3-chloro-l,2-phenylenediamine (120 mg, 0.8 mmol) was added. The mixture was stirred at 65 oC for one hour, diluted with ethyl acetate (50 ml), washed with sat. aq. sodium bicarbonate, water and then brine, dried over anhydrous sodium sulfate, evaporated, purified on preparative TLC (50% ethyl acetate/hexane) to give 156 mg of the title compound as a yellow gummy solid. ESI-MS calc. for C18H15C1N2O: 310; Found: 311 (M+H).
Figure imgf000047_0001
The ketone from Step B immediately above (155 mg, 0.5 mmol) was combined in DCM (20 mL) with 3-methylspiroindenepiperidine Intermediate 1 (140 mg, 0.5 mmol), triethylamine (129 mg, 1.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 2.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 90 mg of the title product. ESI-MS calc. for C32H32C1N3: 494; Found: 495 (M+H).
Figure imgf000047_0002
To a thick wall pressure tube was added ethyl 2-bromobenzoate (5.0 g, 21.8 mmol), cyclopentenone (5.5 ml, 61.5 mmol), triethyl amine (4.56 ml, 32.7 mmol), palladium acetate (48.9 mg, 0.218 mmol) and triphenyl phosphine (114.4 mg, 0.436). The tube was capped and stirred in 100 0C oil bath for 30 h. TLC showed the reaction was almost complete. The entire mixture was loaded on silica gel column without any workup, eluted with 30% ethyl acetate in hexane to afford 1.101 g of the title compound (second major spot on TLC). 1H-NMR (CDCl3, 300 MHz): δ 7.85 (m, IH), 7.49 (m, IH), 7.38 (m, IH), 7.28 (m, IH), 4.35 (q, J = 7.14, 2H), 4.25 (m, IH), 2.70 (m, IH), 2.25-2.50 (m, 4H), 2.00 (m, IH), 1.40 (t, J = 7.14, 3H).
Figure imgf000048_0001
The cyclopentanone from Step A immediately above (900 mg, 3.873 mmol) was combined in DCM (50 mL) with 3-methylspiroindenepiperidine Intermediate 1 (1.096 g, 4.648 mmol), DEEA (0.816 ml, 4.684 mmol), sodium tiacetoxyborohydride (3.284 g, 15.49 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 10% in DCM) to give 1.517 g (66%) of the title product as an oil. ESI-MS calc. for C28H33NO2: 415; Found: 416 (M+H).
Figure imgf000048_0002
The ester from Step C immediately above (1.51 g, 3.64 mmol) was combined in a mixture of dioxane (10 ml), ethanol (5 ml) and water (5 ml) with lithium hydroxide monohydrate (0.917 g, 21.83 mmol). The resulting mixture was stirred at 700C for 15 h. The reaction mixture was condensed to dryness and purified on FC (silica, 20% methanol/DCM) to give two fractions (cis: faster isomer: 412.7 mg + trans: slower isomer : 391.1 mg) of the title product amino acid. Both fractions showed the same LC-MS data. ESI-MS calc. for C26H29NO2: 387; Found: 388 (M+H).
Figure imgf000049_0001
The cis amino acid from Step C immediately above (faster isomer, 50 mg, 0.129 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (55.2 mg, 0.387 mmol), EDAC (123.6 mg, 0.647 mmol) and DMAP (3.1 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give the title product aminoamide. ESI-MS calc. for C32H34C1N3O: 511; Found: 512 (M+H).
Figure imgf000049_0002
The entire aminoamide from Step E immediately above in 3 ml of acetic acid was heated at 100 0C for two days. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 100% ethyl acetate) to give 16.6 mg of the title product aminoimidazole as a mixture of 2 cis diastereomers. ESI-MS calc. for C32H32C1N3: 493; Found: 494 (M+H). The similar procedure starting from trans amino acid from Step C immediately above (slower isomer, 50 mg, 0.129 mmol) gave the title aminoimidazole as a mixture of 2 trans diastereomers. ESI-MS calc. for C32H32C1N3: 493; Found: 494 (M+H).
Figure imgf000050_0001
Figure imgf000050_0002
The cis amino acid from Step C of Example 4 (faster isomer, 48.8 mg, 0.129 mmol) was combined in DCM (2 ml) with 4-fluoro-l,2-phenylenediamine (55.2 mg, 0.387 mmol), EDAC (123.6 mg, 0.647 mmol) and DMAP (3.1 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give the title product amhioamide. ESI-MS calc. for C32H34FN3O: 495; Found: 496 (M+H).
Step B:
Figure imgf000050_0003
The entire aminoamide from Step A immediately above in 3 ml of acetic acid was heated at 100 0C for two days. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 100% ethyl acetate) to give 16.6 mg of the title product aminoimidazole as a mixture of 2 cis diastereomers. ESI-MS calc. for C32H32FN3: 477; Found: 478 (M+H). The similar procedure starting from trans amino acid from Step C of Example 4 (slower isomer, 50 mg, 0.129 mmol) gave the title aminoimidazole as a mixture of 2 trans diastereomers. ESI-MS calc. for C32H32FN3: 477; Found: 478 (M+H).
EXAMPLE 6
Figure imgf000051_0001
A mixture of cyclopentenone (10.0 g, 120 mmol), 4-formylbenzene boric acid (15.0 g, 100 mmol), sodium acetate (16.4 g, 200 mmol), palladium acetate (4.60 g, 20 mmol), antimony trichloride (4.60 g, 20 mmol) in acetic acid (500 ml) was stirred over two days. The dark solid was removed by filtration and the filtrate was evaporated to remove acetic acid under reduced pressure. To the residue was added water (200 mL) and ethyl acetate (400 ml), stirred for 30 min. The organic phase was separated and washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluted with 30% ethyl acetate in hexane) to afford the title compound as a yellow oil (8.7 g).
Figure imgf000051_0002
The aldehyde (3.0g, 16 mmol) from Step A immediately above was heated at 65 0C for 60 min with sodium bisulfite (4.0 g) in methanol (100 ml), then 3-chloro-l,2-phenylenediamine (2.4 mg, 16 mmol) was added. The mixture was stirred at 65 0C for one hour, diluted with ethyl acetate (50 ml), washed with sat. aq. sodium bicarbonate, water and then brine, dried over anhydrous sodium sulfate, evaporated give 5.3 g of the title compound as a yellow solid. ESI-MS calc. for C18H15C1N2O: 310; Found: 311 (M+H).
Figure imgf000052_0001
The ketone from Step B immediately above (155 mg, 0.5 mmol) was combined in DCM (20 mL) with 3-methylspiroindenepiperidine Intermediate 1 (140 mg, 0.5 mmol), triethylamine (129 mg, 1.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 2.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 74 mg of the title product. ESI-MS calc. for C29H30C1N3: 457; Found: 458 (M+H).
EXAMPLE 7
Figure imgf000052_0002
The ketone from Step B of Example 6 (155 mg, 0.5 mmol) was combined in DCM (20 mL) with 4-fluorophenylpiperidine hydrochloride (220 mg, 1.0 mmol), triethylamine (260 mg, 2.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 1.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 54 mg of the title product. ESI-MS calc. for C29H29C1FN3: 474; Found: 475 (M+H).
EXAMPLE 8
Figure imgf000053_0001
The ketone from Step B of Example 6 (155 mg, 0.5 mmol) was combined in DCM (20 mL) with spiroindene hydrochloride (120 mg, 0.5 mmol), triethylamine (129 mg, 1.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 1.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 77 mg of the title product. ESI-MS calc. for C31H30C1N3: 479; Found: 480 (M+H).
EXAMPLE 9
Figure imgf000053_0002
The amino acid from Step C of Example 1 (100 mg, 0.25 mmol) was combined in DCM (2 ml) with 4-trifluoromethyl-l,2-phenylenediamine (88 mg, 0.5 mmol), EDAC (191 mg, 1.0 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give the corresponding amide. This material was heated with acetic acid (0.5 ml) at 60 0C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 59 mg of the title compound arninoimidazole as a mixture of 4 diastereomers. Four respective single enantiomers were obtained by chiral HPLC (OD column, 10% ethanol/hexane). ESI-MS calc. for C33H32F3N3: 527; Found: 528 (M+H).
EXAMPLE 10
Figure imgf000054_0001
The amino acid from Step C of Example 1 (38.7 mg, 0.1 mmol) was combined in DCM (1 ml) with 4-tert-butyl -1,2-phenylenediamine (164 mg, 0.5 mmol), EDAC (95 mg, 0.5 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give the corresponding amide. This material was heated with acetic acid (0.5 ml) at 60 0C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 23 mg of the title compound aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C36H41N3: 515; Found: 516 (M+H).
EXAMPLE Il
Figure imgf000054_0002
The amino acid from Step C of Example 1 (100 mg, 0.25 mmol) was combined in DCM (2 ml) with 4-fluoro- 1,2-phenylenediamine (80 mg, 0.5 mmol), EDAC (191 mg, 1.0 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH7methanol/DCM to give the corresponding amide. This material was heated with acetic acid (0.5 ml) at 60 0C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 50 mg of the title compound aminoimidazole as a mixture of 4 diastereomers. Four respective single enantiomers were obtained by chiral HPLC (OD column, 10% ethanol/hexane). ESI-MS calc. for C32H32FN3: 477; Found: 478 (M+H).
EXAMPLE 12
Figure imgf000055_0001
The amino acid from Step C of Example 1 (100 mg, 0.25 mmol) was combined in DCM (2 ml) with 1,2-phenylenediamine (108 mg, 1.0 mmol), EDAC (191 mg, 1.0 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give the corresponding amide. This material was heated with acetic acid (0.5 ml) at 60 0C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 52 mg of the title compound aminoimidazole as a mixture of 4 diastereomers. Four respective single enantiomers were obtained by chiral HPLC (OD column, 10% ethanol/hexane). ESI-MS calc. for C32H33N3: 459; Found: 460 (M+H).
EXAMPLE 13
Figure imgf000055_0002
The amino acid from Step C of Example 1 (38.7 mg, 0.1 mmol) was combined in DCM (1 ml) with l-amino-2-methylaminobenzene dihydrochloride (195 mg, 1.0 mmol), triethylamine (260 mg, 2 mmol), EDAC (191 mg, mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NHtOH/methanol/DCM to give the corresponding amide. This material was heated with acetic acid (0.5 ml) at 60 0C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NH^H/methanol/DCM) to give 32 mg of the title compound aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C33H35N3: 473; Found: 474 (M+H).
EXAMPLE 14
Figure imgf000056_0001
The amino acid from Step C of Example 1 (100 mg, 0.258 mmol) was combined in DCM (3 ml) with 3,4-diaminopyridine (84.5 mg, 0.76 mmol), triethylamine (260 mg, 2 mmol), EDAC (99 mg, mmol) and DMAP (3 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 5 mg of the corresponding amide. This material was heated with acetic acid (0.5 ml) at 600C overnight, evaporated to remove acetic acid. The residue was purified on preparative TLC (silica, 1/9/90 of NHiOH/methanol/DCM) to give 2.5 mg of the title compound aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C31H32N4: 460; Found: 461 (M+H).
EXAMPLE 15
Figure imgf000056_0002
To a thick wall pressure tube was added methyl 4-bromo-3 -methyl benzoate (5.0 g, 21.8 mmol), cyclopentenone (5.479 ml, 61.5 mmol), triethyl amine (4.65 ml, 32.7 mmol), palladium acetate (48.9 mg, 0.218 mmol) and triphenyl phosphine (114.4 mg, 0.436). The tube was capped and stirred in 1000C oil bath for 30 h. TLC showed the reaction was almost complete. The entire mixture was loaded on silica gel column without any workup, eluted with 30% ethyl acetate in hexane to afford 2.16 g of the title compound (second major spot on TLC). 1H-NMR (CDCl3, 300 MHz): δ 7.85 (m, 2H), 7.26 (m, IH), 3.89 (s, 3H), 3.62 (m, IH), 2.65 (m, IH), 2.40 (s, 3H), 2.25-2.50 (m, 4H), 2.00 (m, IH).
Figure imgf000057_0001
The cyclopentanone from Step A immediately above (1.0 g, 4.3 mmol) was combined in DCM (50 mL) with 3-methylspiroindenepiperidine Intermediate 1 (1.217 g, 5.16 mmol), DIEA (0.899 ml, 5.16 mmol), sodium tiacetoxyborohydride (2.735 g, 12.9 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 100% ethyl acetate) to give 1.1846 g (66%) of the title product. ESI-MS calc. for C28H33NO2: 415; Found: 416 (M+H).
Figure imgf000057_0002
The ester from Step C immediately above (1.10 g, 2.647 mmol) was combined in a mixture of dioxane (20 ml), ethanol (5 ml) and water (10 ml) with lithium hydroxide monohydrate (0.667 g, 2 mmol). The resulting mixture was stirred at 60 0C for 4 h. The reaction mixture was condensed to dryness and purified on FC (silica, 50% methanol/DCM) to give 1.07 g (100%) of the title product amino acid. ESI-MS calc. for C27H31NO2: 401; Found: 402 (M+H).
Figure imgf000058_0001
The amino acid from Step C immediately above (100 mg, 0.249 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (106.5 mg, 0.747 mmol), EDAC (238.7 mg, 1.245 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of N^OH/methanol/DCM to give 153.2 mg of the title product aminoamide. ESI-MS calc. for C33H36C1N3O: 526; Found: 527 (M+H).
Figure imgf000058_0002
The aminoamide from Step E immediately above (130 mg, 0.249 mmol) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 64.2 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C33H34C1N3: 507; Found: 508 (M+H). EXAMPLE 16
Figure imgf000059_0001
Figure imgf000059_0002
The amino acid from Step C of Example 15 (100 mg, 0.249 mmol) was combined in DCM (2 ml) with 4-fluoro-l,2-phenylenediamine (94.2 mg, 0.747 mmol), EDAC (238.7 mg, 1.245 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 147.5 mg of the title product aminoamide. ESI-MS calc. for C33H36FN3O: 509; Found: 510 (M+H).
Figure imgf000059_0003
The aminoamide from Step A immediately above (127 mg, 0.249 mmol) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 55.9 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C33H34FN3: 491; Found: 492 (M+H).
EXAMPLE 17
Figure imgf000060_0001
Figure imgf000060_0002
The amino acid from Step C of Example 15 (100 mg, 0.249 iranol) was combined in DCM (2 ml) with 4-trifluoromethyl-l,2-phenylenediamine (131.6 mg, 0.747 mmol), EDAC (238.7 mg, 1.245 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 147.5 mg of the title product aminoamide. ESI-MS calc. for C34H36F3N3O: 559; Found: 560 (M+H).
Figure imgf000060_0003
: The aminoamide from Step A immediately above (139 mg, 0.249 mmol) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 63.9 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C34H34F3N3: 541; Found: 542 (M+H).
EXAMPLE 18
Figure imgf000061_0001
Figure imgf000061_0002
The cyclopentanone from Step A of Example 15 (1.0 g, 4.3 mmol) was combined in DCM (50 mL) with 4-phenylpiperidine hydrochloride (1.02 g, 5.16 mmol), DIEA (0.899 ml, 5.16 mmol), sodium triacetoxyborohydride (2.735 g, 12.9 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 100% ethyl acetate) to give 1.323 g (81%) of the title product. ESI-MS calc. for C25H31NO2: 377; Found: 378 (M+H).
Figure imgf000062_0001
The ester from Step A immediately above (1.30 g, 3.444 rπmol) was combined in a mixture of dioxane (15 ml), ethanol (5 ml) and water (5 ml) with lithium hydroxide monohydrate (0.579 g, 2 mmol). The resulting mixture was stirred at 60 0C for 4 h. The reaction mixture was condensed to dryness and purified on FC (silica, 50% methanol/DCM) to give 1.347 g (100%) of the title product amino acid. ESI-MS calc. for C24H29NO2: 363; Found: 364 (M+H).
Figure imgf000062_0002
The amino acid from Step B immediately above (100 mg, 0.275 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (117.6 mg, 0.825 mmol), EDAC (263.6 mg, 1.375 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 81.5 mg of the title product aminoamide. ESI-MS calc. for C30H34C1N3O: 487; Found: 488 (M+H).
Figure imgf000063_0001
The aminoarnide from Step C immediately above (81 mg) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NHtOH/methanol/DCM) to give 28.8 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C30H32C1N3: 469; Found: 470 (M+H).
EXAMPLE 19
Figure imgf000063_0002
The amino acid from Step B of Example 18 (100 mg, 0.275 mmol) was combined in DCM (2 ml) with 4-fluoro-l,2-phenylenediamine (104.1 mg, 0.825 mmol), EDAC (263.6 mg, 1.375 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH^H/methanol/DCM to give 77.3 mg of the title product aminoamide. ESI-MS calc. for C30H34FN3O: 471; Found: 472 (M+H).
Figure imgf000064_0001
The aminoamide from Step A immediately above (77 mg, 0.164) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NHUOH/methanol/DCM) to give 31.6 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C30H32FN3: 453; Found: 454 (M+H).
EXAMPLE 20
Figure imgf000064_0002
The amino acid from Step B of Example 18 (100 mg, 0.275 mmol) was combined in DCM (2 ml) with 4-fluoro-l,2-phenylenediamine (145.3 mg, 0.825 mmol), EDAC (263.6 mg, 1.375 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH^H/methanol/DCM to give 79.5 mg of the title product aminoamide. ESI-MS calc. for C31H34F3N3O: 521; Found: 522 (M+H).
Figure imgf000065_0001
The aminoamide from Step A immediately above (77 mg, 0.164) in 3 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NHUOH/methanol/DCM) to give 31.6 mg of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C31H32F3N3: 503; Found: 504 (M+H).
EXAMPLE 21
Figure imgf000065_0002
The example 16 (25 mg, 0.0443 mmol) was dissolved in EtOH (5 ml) and 10% Pd/C (5 mg) was added. Hydrogenation was carried out with a hydrogen balloon for 2 h, the catalyst was removed by filtration and the filtrate was concentrated in vacuum to give 21.5 mg of the title product. ESI-MS calc. for C33H36FN3: 493; Found: 494 (M+H). EXAMPLE 22
Figure imgf000066_0001
The ketone from Step B of Example 6 (155 mg, 0.5 mmol) was combined in DCM (20 mL) with 4-tetrahydropyranyl amine hydrochloride (136 mg, 1.0 mmol), triethylamine (129 mg, 1.0 mmol), sodium tiacetoxyborohydride (411 mg, 2.0 mmol), and molecular sieves (4A, 2.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated. Purification by preparative TLC (silica, 0.1/0.9/99 of NH4OH/methanol/DCM) gave 74 mg of the title product. ESI-MS calc. for C23H6C1N3O: 395; Found: 396 (M+H).
EXAMPLE 23
Figure imgf000066_0002
The amino acid from Step D of Example 1 (20 mg, 0.0514 mmol) was combined in DCM (0.5 ml) with aniline (70 mg, 0.753 mmol), EDAC (70 mg, 0.366 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 100% ethyl acetate to give 24 mg of the title product aminoamide. ESI-MS calc. for C32H34N2O: 462; Found: 463 (M+H).
EXAMPLE 24
Figure imgf000066_0003
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (0.5 ml) with 2,2,2-trifluoroethylamine hydrochloride (35.2 mg, 0.39 mmol), EDAC (74.2 mg, 0.366 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 28.7 mg of the title product. ESI-MS calc. for C28H31F3N2O: 468; Found: 469 (M+H).
EXAMPLE 25
Figure imgf000067_0001
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (0.5 ml) with ethylamine hydrochloride (21 mg, 0.39 mmol), EDAC (74.2 mg, 0.366 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 28.7 mg of the title product. ESI-MS calc. for C28H34N2O: 414; Found: 415 (M+H).
EXAMPLE 26
Figure imgf000067_0002
The amino acid from Step D of Example 1 (38.7 mg, 0.1 mmol) was combined in DCM (1.0 ml) with cyclohexylamine (20 mg, 0.2 mmol), EDAC (100 mg, 0.52 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 100% ethyl acetate to give 37 mg of the title product aminoamide. ESI-MS calc. for C32H40N2O: 468; Found'. 469 (M+H). EXAMPLE 27
Figure imgf000068_0001
The amino acid from Step D of Example 1 (38.7 mg, 0.1 mmol) was combined in DCM (1.0 ml) with tert-butylamine (36.5 mg, 0.5 mmol), EDAC (191 mg, 1.0 mmol) and 4N HCl in dioxane (0.1 ml). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 15 mg of the title product aminoamide. ESI-MS calc. for C30H38N2O: 442; Found: 443 (M+H).
EXAMPLE 28
Figure imgf000068_0002
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (1.0 ml) with benzylamine (28.4 mg, 0.26 mmol), EDAC (74.2 mg, 0.26 mmol) and 4N HCl in dioxane (0.065 ml, 0.26 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 32 mg of the title product. ESI-MS calc. for C33H36N2O: 476; Found: 477 (M+H).
EXAMPLE 29
Figure imgf000068_0003
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (1.0 ml) with phenylethylamine (32.0 mg, 0.26 mmol), EDAC (74.2 mg, 0.26 mmol) and 4N HCl in dioxane (0.065 ml, 0.26 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 29.8 mg of the title product. ESI-MS calc. for C34H38N2O: 490; Found: 491 (M+H).
EXAMPLE 30
Figure imgf000069_0001
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (1.0 ml) with phenylpropylamine (35.2 mg, 0.26 mmol), EDAC (74.2 mg, 0.26 mmol) and 4N HCl in dioxane (0.065 ml, 0.26 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 36.0 mg of the title product. ESI-MS calc. for C35H40N2O: 504; Found: 505 (M+H).
EXAMPLE 31
Figure imgf000069_0002
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (1.0 ml) with N-allylaniline (34.6 mg, 0.26 mmol), EDAC (74.2 mg, 0.26 mmol) and 4N HCl in dioxane (0.065 ml, 0.26 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 54.0 mg of the title product. ESI-MS calc. for C35H38N2O: 502; Found: 503 (M+H). EXAMPLE 32
Figure imgf000070_0001
The amino acid from Step D of Example 1 (50 mg, 0.13 mmol) was combined in DCM (1.0 ml) with piperidine (0.026 ml, 0.26 mmol), EDAC (74.2 mg, 0.26 mmol) and 4N HCl in dioxane (0.065 ml, 0.26 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 54.0 mg of the title product. ESI-MS calc. for C31H38N2O: 454; Found: 455 (M+H).
EXAMPLE 33
Figure imgf000070_0002
The amino acid from Step C of Example 15 (50 mg, 0.1245 mmol) was combined in DCM (1.0 ml) with 2,2,2-trifluoroethylamine hydrochloride (33.7 mg, 0.249 mmol), EDAC (119.3 mg, 0.623 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 7% MeOH in DCM to give 49.7 mg of the title product. ESI-MS calc. for C29H33F3N2O: 482; Found: 483 (M+H).
EXAMPLE 34
Figure imgf000070_0003
The example 33 (25 mg, 0.048 mmol) was dissolved in EtOH (5 ml) and 10% Pd/C (5 mg) was added. Hydrogenation was carried out with a hydrogen balloon for 2 h, the catalyst was removed by filtration and the Filtrate was concentrated in vacuum to give 26.9 mg of the title product. ESI-MS calc. for C29H35F3N2O: 484; Found: 485 (M+H).
EXAMPLE 35
Figure imgf000071_0001
The amino acid from Step C of Example 15 (50 mg, 0.1245 mmol) was combined in DCM (1.0 ml) with aniline (0.024 ml, 0.249 mmol), EDAC (119.3 mg, 0.623 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 7% MeOH in DCM to give 57.5 mg of the title product. ESI-MS calc. for C33H36N2O: 476; Found; 477 (M+H).
EXAMPLE 36
Figure imgf000071_0002
The amino acid from Step C of Example 15 (50 mg, 0.1245 mmol) was combined in DCM (1.0 ml) with benzyl amine (0.027 ml, 0.249 mmol), EDAC (119.3 mg, 0.623 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 52 mg of the title product. ESI-MS calc. for C34H38N2O: 490; Found: 491 (M+H). EXAMPLE 37
Figure imgf000072_0001
The amino acid from Step C of Example 15 (50 mg, 0.1245 mniol) was combined in DCM (1.0 ml) with c-hexyl methylamine (0.032 ml, 0.249 mmol), EDAC (119.3 mg, 0.623 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 57 mg of the title product. ESI-MS calc. for C34H44N2O: 496; Found: 497 (M+H).
EXAMPLE 38
Figure imgf000072_0002
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with tetrahydropyranyl amine hydrochloride (20.5 mg, 0.149 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 27 mg of the title product. ESI-MS calc. for C32H40N2O2: 484; Found: 485 (M+H). EXAMPLE 39
Figure imgf000073_0001
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 3-isopropylaniline (20.4 mg, 0.149 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 34 mg of the title product. ESI-MS calc. for C36H42N2O: 518; Found: 519 (M+H).
EXAMPLE 40
Figure imgf000073_0002
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 3-trifluoromethyl aniline (24 mg, 0.149 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 32 mg of the title product. ESI-MS calc. for C34H35F3N2O: 544; Found: 545 (M+H). EXAMPLE 41
Figure imgf000074_0001
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.022 ml, 0.22 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 22.5 mg of the title product. ESI-MS calc. for C33H35FN2O: 494; Found: 495 (M+H).
EXAMPLE 42
Figure imgf000074_0002
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.022 ml, 0.22 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 30.8 mg of the title product. ESI-MS calc. for C33H35FN2O: 494; Found: 495 (M+H).
EXAMPLE 43
Figure imgf000074_0003
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.022 ml, 0.22 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 33.7 mg of the title product. ESI-MS calc. for C33H35FN2O: 494; Found: 495 (M+H).
EXAMPLE 44
Figure imgf000075_0001
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.024 ml, 0.22 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 31 mg of the title product. ESI-MS calc. for C33H35C1N2O: 510; Found: 511 (M+H).
EXAMPLE 45
Figure imgf000075_0002
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.024 ml, 0.26 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 51 mg of the title product. ESLMS calc. for C34H38N2O2: 506; Found: 507 (M+H). EXAMPLE 46
Figure imgf000076_0001
The amino acid from Step C of Example 15 (30 mg, 0.0747 mmol) was combined in DCM (1.0 ml) with 2-fluoroaniline (0.026 ml, 0.26 mmol), EDAC (57 mg, 0.299 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 25.7 mg of the title product. ESI-MS calc. for C33H42N2O: 482; Found: 483 (M+H).
EXAMPLE 47
Figure imgf000076_0002
The amino acid from Step C of Example 15 (50 mg, 0.1245 mmol) was combined in DCM (1.0 ml) with (R)-(-)-2-phenylglycine methyl ester hydrochloride (37.7 mg, 0.1868 mmol), EDAC (119.7 mg, 0.299 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 58.5 mg of the title product. ESI-MS calc. for C36H40N2O3: 548; Found: 549 (M+H). EXAMPLE 48
Figure imgf000077_0001
The amino ester (Example 47, 40 mg) was combined in a mixture of ethanol (1 ml) and water (0.5 ml) with lithium hydroxide monohydrate (20 mg). The resulting mixture was stirred at room temperature for 4 h, evaporated to dryness. The residue was dissolved in methanol, filtered through silica gel plug, washed with methanol, concentrated to dryness to give a white solid (41 mg). ESI-MS calc. for C35H38N2O3: 534; Found: 535 (M+H).
EXAMPLE 49
Figure imgf000077_0002
The amino acid from Step C of Example 15 (50 mg, 0.1245 mmol) was combined in DCM (1.0 ml) with (S)-(+)-2-phenylglycine methyl ester hydrochloride (37.7 mg, 0.1868 mmol), EDAC (119.7 mg, 0.299 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 43.2 mg of the title product. ESI-MS calc. for C36H40N2O3: 548; Found: 549 (M+H). EXAMPLE 50
Figure imgf000078_0001
The amino ester (Example 47, 40 mg) was combined in a mixture of ethanol (1 ml) and water (0.5 ml) with lithium hydroxide monohydrate (20 mg). The resulting mixture was stirred at room temperature for 4 h, evaporated to dryness. The residue was dissolved in methanol, filtered through silica gel plug, washed with methanol, concentrated to dryness to give a white solid (42 mg). ESI-MS calc. for C35H38N2O3: 534; Found: 535 (M+H).
EXAMPLE 51
Figure imgf000078_0002
The cyclopentanone from Step A of Example 15 (100 mg, 0.43 mmol) was combined in DCM (5 mL) with 3-spiroindanepiperidine Intermediate hydrochloride (115.5 mg, 0.516 mmol), DIEA (0.090 ml, 0.516 mmol), sodium triacetoxyborohydride (364.6 mg, 1.72 mmol), and molecular sieves (4A, 500 mg). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 10% in DCM) to give 163.1 mg of the title product. ESI-MS calc. for C27H33NO2: 403; Found: 404 (M+H).
Figure imgf000079_0001
The amino ester from Step A immediately above (1.50 mg, 0.372 mmol) was combined in a mixture of ethanol (4 ml) and water (2 ml) with lithium hydroxide monohydrate (94 mg, 2.23 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness and purified on FC (silica, 20% methanol/DCM) to give 68.5 mg of the title product. ESI-MS calc. for C26H31NO2: 389; Found: 390 (M+H).
Figure imgf000079_0002
The amino acid from Step B immediately above (60 mg, 0.154 mmol) was combined in DCM (2 ml) with aniline (0.042 ml, 0.462 mmol), EDAC (148 mg, 0.77 mmol) and DMAP (4 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 63.2 mg of the title product. ESI-MS calc. for C32H36N2O: 464; Found: 465 (M+H). EXAMPLE 52
Figure imgf000080_0001
A mixture of 4-bromophenylacetonitrile (39.2 g, 0.2 mol), LiH (4.0 g, 0.5 mol), cis-1,4- dichloro-2-butene (23.6 g, 0.225 mol) in DME/DMU (9:1, 400 ml) was heated at 60 0C overnight, cooled at RT, poured into ice-water, extracted with 20% ethyl acetate/hexane. The organic phase was washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by FC (silica gel, 20% ethyl acetate/hexane) to afford 42 g of the title product as light yellow oil. 1H-NMR (CDCl3, 300 MHz): δ 7.49 (d, J = 1.93, 2H), 7.40 (d, J = 1.93, IH), 5.80 (s, 2H), 3.32 (d, J = 14.12, 2H), 2.87 (d, J = 14.12, 2H), IH).
Figure imgf000080_0002
To a stirred solution of cyclopentane from Step A immediately above in ether (70 ml) at 0 0C was added borane-THF (1.0 M, 35 ml, 35 mmol) slowly. The mixture was stirred at room temperature for 3 h, diluted with methylene dichloride (600 ml), then added magnesium sulfate (24 g) and PCC (74 g, 342 mmol). The mixture was stirred overnight, dumped the solution on a silica gel column, eluted with 30% ethyl acetate in hexane to give 4.65 g of the title compound. 1H-NMR (CDCl3, 300 MHz): δ 7.60 (m, 2H), 7.32 (d, J = 8.45 Hz, IH), 7.12 (d, J = 8.45 Hz, IH), 3.72 (m, IH), 3.10 (m, IH), 1.80-2.90 (m, 5H).
Figure imgf000081_0001
The cyclopentanone from Step B immediately above (2.83 g, 10.7 mmol) was combined in DCM (80 mL) with 3-methylspiroindenepiperidine Intermediate 1 (2.52 g, 10.7 mmol), DIEA (1.86 ml, 10.7 mmol), sodium tiacetoxyborohydride (4.537 g, 21.4 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 40% ethyl acetate in hexane) to give 1.5446 g (32%) of the title product. ESI-MS calc. for C26H27BrN2: 446; Found: 447 (M+H).
Figure imgf000081_0002
The phenylbromide from Step C immediately above (918 mg, 2.05 mmol) was combined in a mixture of triethylamine (249 mg, 2.46 mmol), palladium chloride (36.3 mg, 0.21 mmol), triphenylphosphine (107.5 mg, 0.41 mmol) in ethanol (20 ml). The mixture vacuum and then flushed with carbon monoxide. The procedure was repeated three times and the mixture was then stirred under atmosphere of carbon monoxide at 100 0C for 3 days. After filtered off the solid catalyst, the solution was evaporated to dryness. The residue was purified on preparative TLC (silica gel, 10% MeOH/DCM) to afford 389.7 mg (43%) of the title product. ESI-MS calc. for C29H32N2O2: 440; Found: 441 (M+H).
Figure imgf000082_0001
The ester from Step C immediately above (369 mg, 0.838 mmol) was combined in a mixture of dioxane (8 ml) and water (4 ml) with lithium hydroxide monohydrate (140.8 mg, 3.352 mmol). The resulting mixture was stirred at RT for 4 h. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 10% methanol/DCM) to give 278 mg (80%) of the title product amino acid. ESI-MS calc. for C27H28N2O2: 412; Found: 413 (M+H).
Figure imgf000082_0002
The amino acid from Step E immediately above (100 mg, 0.242 mmol) was combined in DCM (2 ml) with 4-chloro-l,2-phenylenediamine (103.5 mg, 0.726 mmol), EDAC (139.2 mg, 0.726 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 0.1/0.9/99 of NH4OH/methanol/DCM to give 105.0 mg (81%) of the title product. ESI-MS calc. for C33H33C1N4O. 536; Found: 537 (M+H).
Figure imgf000082_0003
The aminoamide from Step F immediately above (100 mg, 0.249 mmol) in 2 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol7DCM) to give 56.5 mg (51%) of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C33H31C1N4: 518; Found: 519 (M+H).
EXAMPLE 53
Figure imgf000083_0001
The amino acid from Step E of Example 52 (50 mg, 0.121 mmol) was combined in DCM (2.0 ml) with aniline (0.022 ml, 0.242 mmol), EDAC (69.6 mg, 0.363 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 7% MeOH in DCM to give 32.5 mg (51%) of the title product. ESI-MS calc. for C33H33N3O: 487; Found: 488 (M+H).
EXAMPLE 54
Figure imgf000083_0002
The amino acid from Step E of Example 52 (50 mg, 0.121 mmol) was combined in DCM (2.0 ml) with trifluoroethylamine hydrochloride (32.8 ml, 0.242 mmol), EDAC (69.6 mg, 0.363 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 7% MeOH in DCM to give 36.3 mg (57%) of the title product. ESI-MS calc. for C29H30F3N3O: 493; Found: 494 (M+H). EXAMPLE 55
Figure imgf000084_0001
To the stirred solution of the phenylbromide (1.185 g, 2.65 mmol) from Step C of Example 52 in ether (40 ml) at 0 0C was added a solution of DIBAL (1.0 M, 4 ml, 4 mmol) in toluene dropwise under nitrogen atmosphere. The mixture was stirred at 0 0C for 1 h. TLC showed a complete conversion. The reaction was quenched by adding MeOH (10 ml), filtered through silica gel in a frit funnel, washed with 20% MeOH in DCM, concentrated in vacuo to afford 0.971 g (81%) of the title product as white foam. ESI-MS calc. for C26H28BrNO: 449; Found: 450 (M+H).
Figure imgf000084_0002
The aldehyde (0.96 g, 2.13 mmol) from Step A immediately above was taken up in MeOH (30 ml), sodium borohydride (0.563 g, 15 mmol) was added at RT with stirring. The starting aldehyde was not completely soluble in MeOH, ~5 ml of THF was added. The resulting transparent solution was stirred for 1 h, TLC showed a complete conversion. The reaction was quenched by adding water (5 ml), evaporated to dryness. The residue was diluted with water (10 ml), extracted with DCM (4 x 20 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified on FC (silica gel, 10% MeOH in DCM) to give 469.8 mg of the title product. ESI-MS calc. for C26H30BrNO: 451; Found: 450 (M+H).
Figure imgf000085_0001
The phenylbromide from Step B immediately above (460 mg, 1.017 mmol) was combined in a mixture of triethylamine (124 mg, 1.22 mmol), palladium chloride (36 mg, 0.203 mmol), triphenylphosphine (107 mg, 0.406 mmol) in ethanol (15 ml). The mixture vacuum and then flushed with carbon monoxide before heating started. The procedure was repeated three times and the mixture was then stirred under atmosphere of carbon monoxide at 100 0C for 3 days. TLC showed the reaction was messy. After filtered off the solid catalyst, the solution was evaporated to dryness. The residue was purified on preparative TLC (silica gel, 10% MeOH/DCM) to afford 127.6 mg of the title product which was contaminated with de-bromated starting material. ESI-MS calc. for C29H35NO3: 445; Found: 446 (M+H).
Figure imgf000085_0002
The crude ester from Step C immediately above (127 mg, 0.28 mmol) was combined in a mixture of dioxane (4 ml) and water (2 ml) with lithium hydroxide monohydrate (42 mg, 1.0 mmol). The resulting mixture was stirred at RT for 4 h. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 25% methanol/DCM) to give the polar 12.5 mg of the title product.. ESI-MS calc. for C27H31NO3: 417; Found: 418 (M+H).
Figure imgf000086_0001
The amino acid from Step D immediately above (11 mg, 0.0263 mmol) was combined in DCM (1 ml) with trifluoroethylamine hydrochloride (10.7 mg, 0.0789 mmol), EDAC (20.2 mg, 0.1052 mmol) and triethylamine (0.013 ml, 0.0789 mmol). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10% methanol/DCM to give 7.8 mg (55%) of the title product. ESI-MS calc. for C29H33F3N2O2: 498; Found: 499 (M+H).
EXAMPLE 56
Figure imgf000086_0002
To a cool (0 oC) solution of 4-bromophenylacetonitrile (9.8 g, 50 mmol) in DMF (200 ml) was added sodium hydride (60% oil, 4.8 g, 120 mmol) in multiple portions under nitrogen protection. Stirring was continued until the cease of bubble formation, then l,3-dibromo-2,2-dimethoxypropane (13.0 g, 50 mmol) was added in one portion. The reaction was stirred at RT overnight, then at 65 oC for 3h, cooled at RT, quenched with ice-water (500 ml), extracted with ether (3 x 500 ml). The combined ether layers were washed with water (2 x 500 ml), dried over sodium sulfate, filtered, evaporated. The crude brown-dark residue was used for further hydrolysis without purification.
Figure imgf000087_0001
The entire crude product from Step A immediately above was stirred with a mixture of TFA (25 ml) and DCM (25 ml) at RT overnight, evaporated to dryness. The residue was purified on FC (silica gel, 10% ethyl acetate/hexane) to afford 4.2 g of the title product as light brown oil. 1H-NMR (CDCl3, 300 MHz): δ 7.58 (d, J = 8.76 Hz, 2H), 7.38 (d, J = 8.76 Hz, IH), 4.09 (d, J = 2.41 Hz, 2H), 3.70 (d, J = 2.41 Hz, 2H).
Figure imgf000087_0002
The cyclobutanone from Step B immediately above (3.152 g, 12.6 mmol) was combined in DCM (70 mL) with 3-methylspiroindenepiperidine Intermediate 1 (2.971 g, 12.6 mmol), DIEA (2.195 ml, 22.8 mmol), sodium triacetoxyborohydride (5.342 g, 25.2 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with 50%methanol in DCM. The filtrates were concentrated and purified on FC (silica, 40% ethyl acetate in hexane) to give 5.447 g of the title product. ESI-MS calc. for C25H25BrN2: 433; Found: 434 (M+H).
Figure imgf000087_0003
The phenylbromide from Step C immediately above (5.4 g, 12.5 mmol) was combined in a mixture of triethylamine (2.1 ml 15 mmol), palladium chloride (221 mg, 1.25 mmol), triphenylphosphine (656 mg, 2.5 mmol) in ethanol (50 ml). The mixture vacuum and then flushed with carbon monoxide. The procedure was repeated three times and the mixture was then stirred under atmosphere of carbon monoxide at 100 0C for 3 days. After filtered off the solid catalyst, the solution was evaporated to dryness. The residue was purified on preparative TLC (silica gel, 10% MeOH/DCM) to collect all the possible products as a mixture which was used in next step without further purification.
Figure imgf000088_0001
The entire material from Step D immediately above was combined in a mixture of dioxane (14 ml) and water (7 ml) with lithium hydroxide monohydrate (210 mg, 5 mmol). The resulting mixture was stirred at RT for 4 h. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 10% methanol/DCM) to give 1.28 g of the title product which was contaminated by other impurities. ESI-MS calc. for C26H26N2O2: 398; Found: 399 (M+H).
Figure imgf000088_0002
The amino acid from Step E immediately above (199 mg, 0.5 mmol) was combined in DCM (3 ml) with trifluoroethylamine hydrochloride (135.5 mg, 1.0 mmol), EDAC (383.4 mg, 2.0 mmol) and DMAP (5 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 40% ethyl acetate/hexane to give 9.0 mg of the title product. ESI-MS calc. for C28H28F3N3O: 479; Found: 480 (M+H). EXAMPLE 57
Figure imgf000089_0001
A mixture of cyclopentenone (10.0 g, 120 mmol), 4-cyanobenzene boric acid (14.6 g, 100 mmol), sodium acetate (16.4 g, 200 mmol), palladium acetate (4.60 g, 20 mmol), antimony trichloride (4.60 g, 20 mmol) in acetic acid (500 ml) was stirred over two days. The dark solid was removed by filtration and the filtrate was evaporated to remove acetic acid under reduced pressure. To the residue was added water (200 mL) and ethyl acetate (400 ml), stirred for 30 min. The organic phase was separated and washed with brine (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluted with 20% ethyl acetate in hexane) to afford 7.5 g of the title compound as a yellow oil. 1H-NMR (CDCl3, 300 MHz): δ 7.62 (d, J = 8.62 Hz, 2H), 7.38 (d, J = 8.62 Hz, IH), 3.35 (m, IH), 2.20-2.80 (m, 5H), 2.00 (m, IH).
Figure imgf000089_0002
The ketone from Step A immediately above (1.798 g, 9.7 mmol) was combined in DCM (50 mL) with 4-phenylpiperidine hydrochloride (2.303 g, 11.64 mmol), DIEA (2.03 ml, 11.64 mmol), sodium triacetoxyborohydride (6.17 g, 29.1 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with ethyl acetate. The filtrate was washed with saturated NaHCO3 solution, then with brine, dried over anhydrous MgSO4, filtered, and concentrated to give the crude product which was used in next step without purification. ESI-MS calc. for C23H26N2: 330; Found: 331 (M+H).
Figure imgf000090_0001
The entire material (-9.7 mmol) from Step B immediately above was combined in a mixture of ethanol (20 ml) and water (10 ml) with sodium hydroxide (1.94 g, 48.5 mmol). The resulting mixture was stirred at reflux for 4 h. TLC showed a complete conversion. The reaction was neutralized with 3N aq. HCl (-33 ml) until pH = 7-8. This aqueous mixture was extracted with DCM (5 x 100 ml). The combined organic phases were condensed to dryness. The resulting solid residue was dissolved in methanol/DCM (1:1) and loaded on a FC column (silica gel), eluted with 10% MeOH in DCM to give 3.24 g (96% in two steps) of the title product. ESI-MS calc. for C23H27NO2: 349; Found: 350 (M+H).
Figure imgf000090_0002
The amino acid from Step C immediately above (100 mg, 0.286 mmol) was combined in DCM (2 ml) with 4-trifluoromethyl-l,2-phenylenediamine (151.4 mg, 0.858 mmol), EDAC (219.3 mg, 1.144 mmol) and DMAP (7 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with ethyl acetate to give 123.4 mg (85%) of the title product. ESI-MS calc. for C30H32F3N3O: 507; Found: 508 (M+H).
Figure imgf000091_0001
The aminoamide from Step D immediately above (123 mg, 0.243) in 2 ml of acetic acid was heated at 60 0C overnight. The acetic acid was removed under reduced pressure and the residue was purified on preparative TLC (silica, 1/9/90 of NH4OH/methanol/DCM) to give 46 mg (34%) of the title product aminoimidazole as a mixture of 4 diastereomers. ESI-MS calc. for C30H30F3N3: 489; Found: 450 (M+H).
EXAMPLE 58
Figure imgf000091_0002
The cyclopentanone from Step A of Example 15 (100 mg , 0.430 mmol) was combined in DCM (5 mL) with 4-(para-fluorophenyl)piperidine hydrochloride (111.3 mg, 0.516 mmol), DIEA (0.090 ml, 0.516 mmol), sodium triacetoxyborohydride (364.6 mg, 1.72 mmol), and molecular sieves (4A, 0.50 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 124 mg (73%) of the title product. ESI-MS calc. for C25H30FNO2: 395; Found: 396 (M+H).
Figure imgf000092_0001
The ester from Step A immediately above (110 mg, 0.278 mmol) was combined in a mixture of ethanol (4 ml) and water (2 ml) with lithium hydroxide monohydrate (70.1 mg, 1.668 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 20% methanoVDCM) to give 92.1 mg (87%) of the title product amino acid. ESI-MS calc. for C24H28FNO2: 381; Found: 382 (M+H).
Figure imgf000092_0002
The amino acid from Step B immediately above (70 mg, 0.184 mmol) was combined in DCM (2 ml) with aniline (0.05 ml, 0.552 mmol), EDAC (176.4 mg, 0.920 mmol) and DMAP (4.5 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10%MeOH/DCM to give 63.2 mg (70%) of the title product. ESI-MS calc. for C30H33FN2O: 456; Found: 457 (M+H). EXAMPLE 59
Figure imgf000093_0001
The cyclopentanone from Step A of Example 15 (100 mg , 0.430 mmol) was combined in DCM (5 mL) with racemic ϊraπs-3-methyl-4-phenylpiperidme hydrochloride (109.2 mg, 0.516 mmol), DIEA (0.090 ml, 0.516 mmol), sodium triacetoxyborohydride (364.6 mg, 1.72 mmol), and molecular sieves (4A, 0.50 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 151.4 mg (90%) of the title product. ESI-MS calc. for C26H33NO2: 391 ; Found: 392 (M+H).
Figure imgf000093_0002
The ester from Step A immediately above (145 mg, 0.370 mmol) was combined in a mixture of ethanol (4 ml) and water (2 ml) with lithium hydroxide monohydrate (93.4 mg, 2.22 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 20% methanol/DCM) to give 52.4 mg (38%) of the title product amino acid. ESI-MS calc. for C25H31NO2: 377; Found: 378 (M+H).
Figure imgf000094_0001
The amino acid from Step B immediately above (45 mg, 0.119 mmol) was combined in DCM (2 ml) with aniline (0.033 ml, 0.357 mmol), EDAC (114.1 mg, 0.595 mmol) and DMAP (3.0 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10%MeOH7DCM to give 46.8 mg (80%) of the title product. ESI-MS calc. for C31H36N2O: 452; Found: 453 (M+H).
EXAMPLE 60
Figure imgf000094_0002
The cyclopentanone from Step A of Example 15 (100 mg , 0.430 mmol) was combined in DCM (5 mL) with racemic 3-spiroindanepiperidine hydrochloride (115.5 mg, 0.516 mmol), DIEA (0.090 ml, 0.516 mmol), sodium triacetoxyborohydride (364.6 mg, 1.72 mmol), and molecular sieves (4A, 0.50 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 163.1 mg (94%) of the title product. ESI-MS calc. for C27H33NO2: 403; Found: 404 (M+H).
Figure imgf000095_0001
The ester from Step A immediately above (150 mg, 0.372 mmol) was combined in a mixture of ethanol (4 ml) and water (2 ml) with lithium hydroxide monohydrate (94 mg, 2.22 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 20% methanol/DCM) to give 68.5 mg (47%) of the title product amino acid. ESI-MS calc. for C26H31NO2: 389; Found: 390 (M+H).
Figure imgf000095_0002
The amino acid from Step B immediately above (60 mg, 0.154 mmol) was combined in DCM (2 ml) with aniline (0.042 ml, 0.462 mmol), EDAC (148 mg, 0.770 mmol) and DMAP (4.0 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10%MeOH/DCM to give 63.2 mg (82%) of the title product. ESI-MS calc. for C32H36N2O: 464; Found: 465 (M+H).
EXAMPLE 61
Figure imgf000096_0001
The cyclopentanone from Step A of Example 15 (1.0 g , 4.3 mmol) was combined in DCM (50 mL) with tetrahydropyranylamine hydrochloride (887 mg, 6.45 mmol), DIEA (1.15 ml), sodium triacetoxyborohydride (5.47 g, 25.8 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 1.296 g (95%) of the title product. , ESI-MS calc. for C19H27NO3: 317; Found: 318 (M+H).
Figure imgf000096_0002
The free amino ester from Step A immediately above (150 mg, 0.473 mmol) was combined in DCM (5 mL) with 37% formaldehyde in water (382 mg, 4.73 mmol) and molecular sieves (4A, 1.0 g). The resulting mixture was stirred for 15 min, then sodium triacetoxyborohydride (1.0 g, 4.73 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 148.7 mg (95%) of the title product. ESI-MS calc. for C20H29NO3: 331; Found: 332 (M+H).
Figure imgf000097_0001
The amino ester from Step B immediately above (140 mg, 0.423 mmoi) was combined in a mixture of ethanol (3 ml) and water (1.5 ml) with lithium hydroxide monohydrate (106.5 mg, 2.538 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness and purified on preparative TLC (silica, 50% methanol/DCM) to give 103.1 mg (77%) of the title product amino acid.
ESI-MS calc. for C19H27NO3: 317; Found: 317 (M+H).
Figure imgf000097_0002
The amino acid from Step C immediately above (50 mg, 0.157 mmol) was combined in DCM (1 ml) with aniline (0.043 ml, 0.462 mmol), EDAC (150 mg, 0.785 mmol) and DMAP (4.0 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10%MeOH/DCM to give 47.8 mg (70%) of the title product. ESI-MS calc. for C25H32N2O2: 392; Found: 393 (M+H). EXAMPLE 62
Figure imgf000098_0001
Figure imgf000098_0002
To a thick wall pressure tube was added N-Boc-4-bromo-3-trifluoroaniline (7.06 g, 20.83 mmol), cyclopentenone (8.75 ml, 104.15 mmol), triethyl amine (4.355 ml, 32.7 mmol), palladium acetate (93.5 mg, 0.417 mmol) and triphenyl phosphine (218.7 mg, 0.834). The tube was capped and stirred in 100 0C oil bath for 3 days. TLC showed the reaction was still not complete. The entire mixture was loaded on silica gel column without any workup, eluted with 30% ethyl acetate in hexane to afford 1.32 g (18%) of the title compound (second major spot on TLC). 1H-NMR (CDCl3, 300 MHz): δ 7.68 (m, IH), 7.55 (m, IH), 7.35 (m, IH), 7.08 (ms, IH), 3.70 (m, IH), 2.20-2.70 (m, 5H), 2.00 (m, IH), 1.48 (m, 9H).
Figure imgf000098_0003
The cyclopentanone from Step A immediately above (0.82 g, 2.39 mmol) was combined in DCM (50 mL) with 3-methylspiroindenepiperidine Intermediate 1 (0.676 g, 2.868 mmol), DIEA (0.5 ml, 2.868 mmol), sodium tiacetoxyborohydride (2.027 g, 12.9 mmol), and molecular sieves (4A, 5.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on FC (silica, 80% ethyl acetate in hexane) to give 1.257 g (99%) of the title product. ESI-MS calc. for C31H37F3N2O2: 526; Found: 527 (M+H).
Figure imgf000099_0001
The carbamide from Step B immediately above (1.157 g, 2.20 mmol) was dissolved in a neat TFA (15 ml), stirred at RT for 30 min, evaporated to dryness. The residue was dissolved in DCM (50 ml), washed with aq. sodium bicarbonate (3 x 50 ml), dried over sodium sulfate, evaporated to dryness to give 0.77 g (82%) of the title product as white foam. ESI-MS calc. for C26H29F3N2: 426; Found: 427 (M+H).
Figure imgf000099_0002
The aniline from Step C immediately above (100 mg, 0.234 mmol) was combined in DCM (3 ml) with benzoic acid (57.2 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 121.7 mg (92%) of the title product. ESI-MS calc. for C33H33F3N2O: 530; Found: 531 (M+H). EXAMPLE 63
Figure imgf000100_0001
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with 4-trifluoromethylbenzoic acid (89 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 8% MeOH/DCM to give 78.6 mg (100%) of the title product. ESI-MS calc. for C34H32F6N2O: 598; Found: 599 (M+H).
EXAMPLE 64
Figure imgf000100_0002
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with 3-trifluoromethylbenzoic acid (89 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 8% MeOH/DCM to give 76.7 mg (99%) of the title product. ESI-MS calc. for C34H32F6N2O: 598; Found: 599 (M+H).
EXAMPLE 65
Figure imgf000100_0003
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with 2-trifluoromethylbenzoic acid (89 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 8% MeOH/DCM to give 73.3 mg (98%) of the title product. ESI-MS calc. for C34H32F6N2O: 598; Found: 599 (M+H).
EXAMPLE 66
Figure imgf000101_0001
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with cyclohexane carboxylic acid (60 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 8% MeOH/DCM to give 59 mg (88%) of the title product. ESI-MS calc. for C33H39F3N2O: 536; Found: 537 (M+H).
EXAMPLE 67
Figure imgf000101_0002
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with phenyl acetic acid (63.7 mg, 0.468 mmol), EDAC (179.4 mg, 0.936 mmol) and DMAP (6 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 70.1 mg (100%) of the title product. ESI-MS calc. for C34H35F3N2O: 544; Found: 545 (M+H). EXAMPLE 68
Figure imgf000102_0001
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with phenyl isocyante (0.0636 ml, 0.585 mmol). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 52.8 mg (78%) of the title product. ESI-MS calc. for C33H34F3N3O: 545; Found: 546 (M+H).
EXAMPLE 69
Figure imgf000102_0002
The aniline from Step C of Example 62 (50 mg, 0.117 mmol) was combined in DCM (2 ml) with benzene sulfonyl chloride (0.018 ml, 0.234 mmol). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 50.0 mg (71%) of the title product. ESI-MS calc. for C32H32F3N2O2S: 566; Found: 567 (M+H).
EXAMPLE 70
Figure imgf000102_0003
Figure imgf000103_0001
The amino acid from Step D of Example 1 (350 mg, 0.903 mmol) was combined in toluene (3 ml) with TEA ( 109.6 mg, 1.086 mmol) and diphenyl phosphoryl azide (0.214 ml, 1.0 mmol). The resulting mixture was stirred at 90 0C for 2 h, and then tert-butanol (4 ml) was added. The mixture was stirred at 90 0C overnight, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 82.8 mg of the title product. ESI-MS calc. for C30H38N2O2: 458; Found: 459 (M+H).
Figure imgf000103_0002
The carbamide from Step A immediately above (82.8 mg) was dissolved in TFA (2 ml). The resulting mixture was stirred at RT for 30 min, condensed and loaded on preparative TLC (silica), developed with l%:9%:90% of aq. NH4OH/MeOH/DCM to give 53.5 mg (91%) of the title product. ESI-MS calc. for C25H30N2: 358; Found: 359 (M+H).
Figure imgf000103_0003
The aniline from Step B immediately above (23 mg, 0.064 mmol) was combined in DCM (1 ml) with benzoic acid (15.7 mg, 0.128 mmol), EDAC (37 mg, 0.192 mmol) and DMAP (2 mg). The resulting mixture was stirred at room temperature for 2 days, condensed and loaded on preparative TLC (silica), developed with 10% MeOH/DCM to give 25.4 mg (77%) of the title product. ESI-MS calc. for C32H34N2O: 477; Found: 478 (M+H).
EXAMPLE 71
Figure imgf000104_0001
The cyclopentanone from Step A of Example 62 (150 mg , 0.437 mmol) was combined in DCM (5 mL) with tetrahydropyranylamine hydrochloride (90.1 mg, 0.655 mmol), DIEA (0.152 ml, 0.874 mmol), sodium triacetoxyborohydride (371 mg, 1.748 mmol), and molecular sieves (4A, 1.0 g). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 204.2 mg (100%) of the title product. ESI-MS calc. for C22H31F3N2O3: 428; Found: 428 (M+H).
Figure imgf000104_0002
The amine from Step A immediately above (150 mg, 0.350 mmol) was combined in DCM (5 mL) with 37% formaldehyde in water (283 mg, 3.5 mmol) and molecular sieves (4A, 2.0 g). The resulting mixture was stirred for 15 min, then sodium triacetoxyborohydride (742 mg, 3.5 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative TLC (silica, 10%MeOH in DCM) to give 125.3 mg of the title product. ESI-MS calc. for C23H33F3N2O3: 442; Found: 443 (M+H).
Figure imgf000105_0001
The amino ester from Step B immediately above (100 mg, 0.226 mmol) was dissolved in neat TFA (2 ml). The resulting mixture was stirred at RT for 30 min. The reaction mixture was condensed to dryness, dissolved in DCM (20 ml), washed with aq. sodium bicarbonate, dried over sodium sulfate and evaporated to dryness to give 75 mg (97%) of the title product. ESI-MS calc. for C18H25F3N2O: 342; Found: 343 (M+H).
Figure imgf000105_0002
The aniline from Step C immediately above (50 mg, 0.146 mmol) was combined in DCM (2 ml) with benzoic acid (71.3 mg, 0.584 mmol), EDAC (448 mg, 2.346 mmol) and DMAP (7.0 mg). The resulting mixture was stirred at room temperature for 16 h, condensed and loaded on preparative TLC (silica), developed with l:9:90%aq.NH4OH/MeOH/DCM to give 72 mg of the title product. ESI-MS calc. for C25H29F3N2O2: 446; Found: 447 (M+H).
EXAMPLE 72
Figure imgf000105_0003
Figure imgf000106_0001
The ester from Step A of Example 15 (1.0 g, 4.31 mmol) was combined in a mixture of ethanol (10 ml) and water (5 ml) with lithium hydroxide monohydrate (0.362 g, 8.62 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was condensed to dryness, the residue was partitioned between ethyl acetate (50 ml) and IN HCl aqueous solution (50 ml), separated. The aq. solution was extracted with ethyl acetate (2 x 50 ml). The combined organic layers were dried over sodium sulfate, evaporated to dryness to give 850 mg (90%) of the title product as brown foam. ESI-MS calc. for C13H14O3: 218; Found: 219 (M+H).
Figure imgf000106_0002
The acid from Step A immediately above (800 mg, 3.67 mmol) was combined in DCM (30 ml) with aniline (334.4 mg, 3.67 mmol), EDAC (1.41 g, 7.34 mmol) and DMAP (22 mg). The resulting mixture was stirred at room temperature for 2 days, diluted with DCM (150 ml) and washed with aq. IN HCl (3 x 50 ml). The organic layers were dried over sodium sulfate and evaporated to dryness to give 1.01 g of the title product with good purity. ESI-MS calc. for C19H19NO2: 293; Found: 294 (M+H).
Figure imgf000106_0003
The cyclopentanone from Step B immediately above (100 mg, 0.341 mmol) was combined in DCM (3 mL) with 4-hydroxy-4-phenylpiperidine (90.7 mg, 0.5115 mmol), sodium triacetoxyborohydride (289 mg, 1.364 mmol), and molecular sieves (4A, 500 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative (silica, 10%MeOH in DCM) to give 17 mg (11%) of the title product. ESI-MS calc. for C30H34N2O2: 454; Found: 455 (M+H).
EXAMPLE 73
Figure imgf000107_0001
The cyclopentanone from Step B of Example 72 (100 mg, 0.341 mmol) was combined in DCM (3 mL) with 4-cyano -4-phenylpiperidine hydrochloride (114 mg, 0.5115 mmol), DIEA (0.089 ml, 0.5115 mmol), sodium triacetoxyborohydride (289 mg, 1.364 mmol), and molecular sieves (4A, 500 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative (silica, 10%MeOH in DCM) to give 20.5 mg (12%) of the title product. ESI-MS calc. for C31H33N3O: 463; Found: 463 (M+H).
EXAMPLE 74
Figure imgf000107_0002
The cyclopentanone from Step B of Example 72 (100 mg, 0.341 mmol) was combined in DCM (3 mL) with piperidine (0.051, 0.5115 mmol), sodium triacetoxyborohydride (289 mg, 1.364 mmol), and molecular sieves (4A, 500 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative (silica, 10%MeOH in DCM) to give 26 mg (19%) of the title product. ESI-MS calc. for C24H30N2O: 362; Found: 363 (M+H).
EXAMPLE 75
Figure imgf000108_0001
The cyclopentanone from Step B of Example 72 (100 mg, 0.341 mmol) was combined in DCM (3 mL) with 3-methylpiperidine (0.060, 0.5115 mmol), sodium triacetoxyborohydride (289 mg, 1.364 mmol), and molecular sieves (4A, 500 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a celite plug, washing with methanol. The filtrates were concentrated and purified on preparative (silica, 10%MeOH in DCM) to give 19.8 mg (14%) of the title product. ESI-MS calc. for C25H32N2O: 376; Found: 377 (M+H).
EXAMPLE 76
Figure imgf000108_0002
The amino acid from Step D of Example 1 (387 mg, 1 mmol) was combined in DCM (5.0 ml) with N,O-dimethylhydroxylamine hydrochloride(200 mg, 2.0 mmol), EDAC (382 mg, 2.0 mmol). The resulting mixture was stirred at room temperature for 16 h, loaded on preparative TLC (silica) and developed with 10% MeOH in DCM to give 274 mg of the title product as a light brown solid. ESI-MS calc. for C28H34N2O2: 430; Found: 431 (M+H).
Step B
Figure imgf000109_0001
The aminoamide from Step A immediately above (96 mg, 0.2) in 2.0 ml of THF was treated with benzylmagnesium chloride in THF (2.0 M, 2.0 ml, 4.0 mmol) at RT for 2 h. The entire mixture was loaded on preparative TLC (silica gel) and developed with 5% MeOH in DCM to give 72 mg of the title product as a mixture of 4 diastereomers. ESI-MS calc. for C33H35NO: 461; Found: 462 (M+H).
EXAMPLE 77
Figure imgf000109_0002
The aminoamide from Step A of Example 75 (96 mg, 0.2) in 2.0 ml of THF was treated with 4-fluorophenylmagnesium bromide (1.0 M, 4.0 ml, 4.0 mmol) at RT for 2 h. The entire mixture was loaded on preparative TLC (silica gel) and developed with 5% MeOH in DCM to give 54 mg of the title product as a mixture of 4 diastereomers. ESI-MS calc. for C32H32FNO: 465; Found: 466 (M+H). EXAMPLE 78
Figure imgf000110_0001
To a solution of 4-methoxycarbonylbenzyl amine HCl salt (3.025 g, 15 mmol) in dichloroethane (34 mL) was added tetrahydro-4H-pyran-4-one (1.4 mL, 15.15 mmol), triethyl amine (2.1 mL, 15.15 mmol), and sodium triacetoxyboron hydride (4.45 g, 21 mmol) at 0 0C, and the mixture was warmed to room temperature and stirred for 2 hours at room temperature before re-cooled to 00C. An aqueous formaldehyde solution (1.23 mL, 37%, 16.5 mmol) and another portion of sodium triacetoxyboronhydride (4.45 g, 21 mmol) were added at 0 0C, and the mixture was warmed to room temperature and stirred for 16 hours at room temperature. The volatiles were removed and the mixture was neutralized with an aqueous saturated sodium bicarbonate solution, and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over magnesium sulfate and concentrated to offer the desired methyl ester as colorless oil (4.0 g). ESI-MS calc. for C15H21NO3: 263; Found: 264 (M+H).
Figure imgf000110_0002
To a solution of the methyl ester (3.5 g, 13.29 mmol) from Step A immediately above in THF/methanol (50/20 mL) was added a 2N aqueous sodium hydroxide solution (26.5 mL, 53 mmol) at room temperature, and the mixture was stirred for 5 hours at room temperature. The pH of the mixture was adjusted to ~7 with IN HCl, and the mixture was concentrated down before taken up by chloform/2- propanol (S5/15). The organic phase was dried over magnesium sulfate and concentrated to offer the desired acid as white solids (3.05 g). ESI-MS calc. for C14H19NO3: 249; Found: 250 (M+H).
Figure imgf000111_0001
The acid from Step B immediately above (50 mg, 0.2 mmol) was combined in DCM (2 mL) with 4-methylphenylenel,2-diamine (32 mg, 0.26 mmol), EDCI (50 mg, 0.13 mmol), 4- dimethylaminopyridine (2.5 mg, 0.02 mmol), and diisopropyl ethyl amine (0.105 mL, 0.6 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 33 mg of the title product as a thick oil. ESI-MS calc. for C21H27N3O2: 353; Found: 354 (M+H).
Figure imgf000111_0002
The amide from Step C immediately above (25 mg, 0.07 mmol) was dissolved in glacial acetic acid (1 mL) and the solution was heated to 70 0C for 16 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 24 mg of the title product as off-white solids. ESI-MS calc. for C21H25N3O: 335; Found: 336 (M+H). EXAMPLE 79
Figure imgf000112_0001
The acid from Step B of Example 1 (50 mg, 0.2 mmol) was combined in DCM (2 mL) with 4-chlorophenylenel,2-diamine (37 mg, 0.26 mmol), EDCI (50 mg, 0.13 mmol), 4- dimethylaminopyridine (2.5 mg, 0.02 mmol), and diisopropyl ethyl amine (0.105 mL, 0.6 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 36 mg of the title product as a thick oil. ESI-MS calc. for C20H24N3O2C1: 373; Found: 374 (M+H).
Figure imgf000112_0002
The amide from Step A immediately above (29 mg, 0.078 mmol) was dissolved in glacial acetic acid (1 mL) and the solution was heated to 700C for 16 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 27.5 mg of the title product as off-white solids. ESI-MS calc. for C20H22N3OC1: 355; Found: 356 (M+H). EXAMPLE 80
Figure imgf000113_0001
The acid from Step B of Example 1 (50 mg, 0.2 mmol) was combined in DCM (2 mL) with 4-bromophenylenel,2-diamine (49 mg, 0.26 mmol), EDCI (50 mg, 0.13 mmol), 4- dimethylaminopyridine (2.5 mg, 0.02 mmol), and diisopropyl ethyl amine (0.105 mL, 0.6 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 36 mg of the title product as a thick oil. ESI-MS calc. for C20H24N3O2Br: 417; Found: 418 (M+H).
Figure imgf000113_0002
The amide from Step A immediately above (26 mg, 0.062 mmol) was dissolved in glacial acetic acid (1 rnL) and the solution was heated to 700C for 16 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 25 mg of the title product as off-white solids. ESI-MS calc. for C20H22N3OBr: 399; Found: 400 (M+H). EXAMPLE 81
Figure imgf000114_0001
The acid from Step B of Example 1 (50 mg, 0.2 mmol) was combined in DCM (2 mL) with 4-trifluoromethylphenylenel,2-diamine (46 mg, 0.26 mmol), EDCI (50 mg, 0.13 mmol), 4- dimethylaminopyridine (2.5 mg, 0.02 mmol), and diisopropyl ethyl amine (0.105 mL, 0.6 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 36 mg of the title product as off- white solids. ESI-MS calc. for C21H24N3F3O2: 407; Found: 408 (M+H).
Figure imgf000114_0002
The amide from Step A immediately above (28 mg, 0.069 mmol) was dissolved in glacial acetic acid (1 mL) and the solution was heated to 70 0C for 16 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 26 mg of the title product as off-white solids. ESI-MS calc. for C21H22N3F3O: 389; Found: 390 (M+H). EXAMPLE 82
Figure imgf000115_0001
The acid from Step B of Example 1 (50 mg, 0.2 mmol) was combined in DCM (2 mL) with 3,5-bistrifluoromethylphenylenel,2-diamine (63.5 mg, 0.26 mmol), EDCI (50 mg, 0.13 mmol), 4- dimethylaminopyridine (2.5 mg, 0.02 mmol), and diisopropyl ethyl amine (0.105 mL, 0.6 mmol). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 24 mg of the title product as white solids. ESI-MS calc. for C22H23N3F6O2: 475; Found: 476 (M+H).
Figure imgf000115_0002
The amide from Step A immediately above (18 mg, 0.038 mmol) was dissolved in glacial acetic acid (1 mL) and the solution was heated to 700C for 16 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 11/1) to afford 16 mg of the title product as white solids. ESI-MS calc. for C22H21N3F6O: 457; Found: 458 (M+H).
EXAMPLE 83
Figure imgf000116_0001
The bromide from Step B of Example 13 (21 mg, 0.052 mmol) was combined in toluene/ethanol/water (0.9/0.3/0.3 mL) with p-tolyboronic acid (8.6 mg, 0.063 mmol), potassium carbonate (25 mg, 0.182 mmol), and tetrakistriphenylphosphine palladium (0) (11.6 mg, 0.01 mmol) under nitrogen. The resulting mixture was refluxed for 3.5 h and cooled down to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate (x3). The combined extracts were dried over magnesium sulfate and concentrated. The residue was purified by preparative TLC (silica, DCM/methanol = 10/1) to afford 7 mg of the title product as off-white solids. ESI-MS calc. for C27H29N3O: 411; Found: 412 (M+H).
EXAMPLE 84
Figure imgf000116_0002
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (151 mg, 0.6 mmol) was combined in DCM (2 mL) with 4-chloroρhenylenel,2-diamine (111.2 mg, 0.78 mmol), EDCI (149.5 mg, 0.78 mmol), and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/ethyl acetate = 5/1) to afford 157 mg of the title product as white solids. ESI-MS calc. for C19H22C1N3O3: 375; Found: 398 (M+Na).
Figure imgf000117_0001
The amide from Step A immediately above (157 mg, 0.418 mmol) was dissolved in glacial acetic acid (3 rnL) and the solution was heated to 700C for 6 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/ethyl acetate = 20/1) to afford 156 mg of the title product as light yellow solids. ESI-MS calc. for C19H20C1N3O2: 357; Found: 358 (M+H).
Figure imgf000117_0002
A 4 N solution of HCl in dioxane (1 mL) was added to the benzimidazole from Step B immediately above (78 mg, 0.22 mmol), and the mixture was stirred for 4 h at room temperature. All volatiles were removed to afford the title product. ESI-MS calc. for C14H12C1N3: 257; Found: 258 (M+H).
Figure imgf000117_0003
To a solution of amine HCl salt obtained in Step C immediately above (78 mg, 0.022 mmol) in dichloroethane (2 mL) was added tetrahydro-4H-pyran-4-one (0.02 mL, 0.022 mmol), triethyl amine (0.067 mL, 0.048 mmol), and sodium triacetoxyboron hydride (65 mg, 0.305 mmol) at 00C, and the mixture was warmed to room temperature and stirred for 15 hours at room temperature before re- cooled to 0 0C. An aqueous formaldehyde solution (0.018 mL, 37%, 0.24 mmol) and another portion of sodium triacetoxyboronhydride (65 mg, 0.035 mmol) were added at 00C, and the mixture was warmed to room temperature and stirred for 5 hours at room temperature. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 10/1) to afford 68 mg of the title product as white solids. ESI-MS calc. for C20Η22C1N3O: 355; Found: 356 (M+H).
EXAMPLE 85
Figure imgf000118_0001
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (151 mg, 0.6 mmol) was combined in DCM (2 mL) with 4-bromophenylenel,2-diamine (146 mg, 0.78 mmol), EDCI (149.5 mg, 0.78 mmol), and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/ethyl acetate = 5/1) to afford 221 mg of the title product as white solids. ESI-MS calc. for C19H22BrN3O3: 419; Found: 442 (M+Na).
Figure imgf000119_0001
The amide from Step A immediately above (221 mg, 0.526 mmol) was dissolved in glacial acetic acid (3 mL) and the solution was heated to 700C for 6 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/ethyl acetate = 20/1) to afford 188 mg of the title product as light yellow solids. ESI-MS calc. for C19H20BrN3O2: 401; Found: 402 (M+H).
Figure imgf000119_0002
A 4 N solution of HCl in dioxane (1 mL) was added to the benzimidazole from Step B immediately above (97 mg, 0.24 mmol), and the mixture was stirred for 4 h at room temperature. All volatiles were removed to afford the title product. ESI-MS calc. for C14H12BrN3: 301; Found: 302 (M+H).
Figure imgf000119_0003
To a solution of amine HCl salt obtained in Step C immediately above (97 mg, 0.024 mmol) in dichloroethane (2 mL) was added tetrahydro-4H-pyran-4-one (0.022 mL, 0.024 mmol), triethyl amine (0.074 mL, 0.053 mmol), and sodium triacetoxyboron hydride (71 mg, 0.336 mmol) at 00C, and the mixture was warmed to room temperature and stirred for 15 hours at room temperature before re- cooled to 00C. An aqueous formaldehyde solution (0.02 mL, 37%, 0.26 mmol) and another portion of sodium triacetoxyboronhydride (71 mg, 0.336 mmol) were added at 00C, and the mixture was warmed to room temperature and stirred for 5 hours at room temperature. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 10/1) to afford 62 mg of the title product as white solids. ESI-MS calc. for C20H22BrN3O: 399; Found: 400 (M+H).
EXAMPLE 86
Figure imgf000120_0001
3-(tert-Butoxycarbonylaminomethyl)benzoic acid (151 mg, 0.6 mmol) was combined in DCM (2 mL) with 4-trichloromethylphenylenel,2-diamine (137 mg, 0.78 mmol), EDCI (149.5 mg, 0.78 mmol), and 4-dimethylaminopyridine (7.3 mg, 0.06 mmol). The resulting mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and purified by preparative TLC (silica, DCM/ethyl acetate = 5/1) to afford 230 mg of the title product as white solids. ESI-MS calc. for C20H22F3N3O3: 409; Found: 432 (M+Na).
Figure imgf000120_0002
The amide from Step A immediately above (230 mg, 0.562 mmol) was dissolved in glacial acetic acid (3 mL) and the solution was heated to 700C for 6 h. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/ethyl acetate = 20/1) to afford 213 mg of the title product as light yellow solids. ESI-MS calc. for C20H20F3N3O2: 391; Found: 392 (M+H).
Figure imgf000121_0001
A 4 N solution of HCl in dioxane (1 mL) was added to the benzimidazole from Step B immediately above (108 mg, 0.22 mmol), and the mixture was stirred for 4 h at room temperature. AU volatiles were removed to afford the title product. ESI-MS calc. for C15H12F3N3: 291; Found: 292 (M+H).
Figure imgf000121_0002
To a solution of amine HCl salt obtained in Step C immediately above (108 mg, 0.026 mmol) in dichloroethane (2 mL) was added tetrahydro-4H-pyran-4-one (0.024 mL, 0.026 mmol), triethyl amine (0.08 mL, 0.057 mmol), and sodium triacetoxyboron hydride (77 mg, 0.364 mmol) at 00C, and the mixture was warmed to room temperature and stirred for 15 hours at room temperature before re-cooled to 0 0C. An aqueous formaldehyde solution (0.021 mL, 37%, 0.286 mmol) and another portion of sodium triacetoxyboronhydride (77 mg, 0.0364 mmol) were added at 0 0C, and the mixture was warmed to room temperature and stirred for 5 hours at room temperature. Volatiles were removed and the residue was purified by preparative TLC (silica, DCM/methanol = 10/1) to afford 77 mg of the title product as white solids. ESI-MS calc. for C21H22F3N3O: 389; Found: 390 (M+H). While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in the responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. Likewise, the specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I or formula II:
Q — E — X-G1
Figure imgf000123_0001
Il
wherein:
Q is:
Figure imgf000123_0002
A is selected from: -O-, -NR.12-, -S-, -SO-, -SO2-, -CR12R12-, -NSO2R14-, -NCOR13-, -CR12CORl 1-, CR12OCOR13- and -CO-;
E is:
Figure imgf000123_0003
G1 is selected from: -N(R31)-CO- N(R30)(R29), -N(R31)-SO2R32, -N(RM)-COR32, -CON(R29)(R30), -Q- 6alkyl unsubstituted or substituted with 1-6 fluoro, and -Cs^cycloalkyl unsubstituted or substituted with 1- 6 fluoro,
where R^9 and R^O are independently selected from: hydrogen, Ci-βalkyl, Ci-galkyl substituted with 1-6 fluoro, Ci_6cycloalkyl, aryl, aryl-Ci -βalkyl, heterocycle and heterocycle-Cl-όalkyl, or R29 and R^O join to form a C3-6 membered ring;
where R^l and R^2 are independently selected from: hydrogen, Ci-galkyl, Ci-βcycloalkyl, Ci- βalkyl substituted with 1-6 fluoro, aryl and heterocycle, or R^l and R^2 jom to form a C3.6 membered ring;
G2 is selected from: a single bond, -(CR11R1 \.A-, -N(R12)SO2-, -N(R12)SO2N(R12)-, -N(R12)CO-, - C(R11XR1 ^CO-, -C(Rn)(R11)OCO-, -CO-, -C(R11XR1 ^SO2-, -OCO-, -SO2-, or G2 is C R11 or N and is joined to R2 forming a fused carbocyclic or heterocyclic ring;
X is a 5-7 membered saturated, partially unsaturated or unsaturated carbocyclic or heterocyclic ring, wherein:
when said ring is heterocyclic it contains 1-4 heteroatoms independently selected from O, N and S,
said ring is unsubstituted or substituted with 1-4 R28, R28 is independently selected from: halo, hydroxy, -O-Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, Cl-3alkyl unsubstituted or substituted with 1-6 fluoro, -O-C3-5cycloalkyl unsubstituted or substituted with 1-6 fluoro, -CORIl, -SO2R14, -NR12COR13, -NR12SO2R14, - phenyl unsubstituted or substituted with 1-3 fluoro or trifluoromethyl, and -CN, and
said ring is optionally bonded to R6 to form a fused or spiro ring system;
Y is C, N, O, S or SO2;
Z is independently selected from C and N, where no more than two of Z are N; Rl is selected from: hydrogen, -SO2R14, -C0.3alkyl-S(O)R14, -SO2NR12R12, -Chalky!, -Q)_6alkyl-0-Ci- galkyl, -Co-όalkyl-S-Ci-galkyl, -(Co-6alkyl)-(C3_7cycloalkyl)-(C()-6alkyl), hydroxy, heterocycle, -CN, - NR12R12, -NR12COR13, -NR12SO2R14, -COR1 1, -CONR12R12, and phenyl, wherein said alkyl and the cycloalkyl are unsubstituted or substituted with 1-7 substituents where the substituents are independently selected from: halo, hydroxy, -O-Ci_3alkyl, trifluoromethyl, Ci-3alkyl, -O-C3_5cycloalkyl, -COR1*, -SO2R14' -NHCOCH3, -NHSO2CH3, -heterocycle, =0 and -CN, and
wherein said phenyl and heterocycle are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Cl-3alkyl, Ci-3alkoxy and trifluoromethyl;
R3, R4, and R5 are independently selected from B1 when Z is C, and are independently selected from B2 when Z is N;
R2 is independently selected from B1 when Z is C, and is independently selected from B2 when Z is N, or R2 is a link to G2 wherein said link is a bond or is a chain 1-4 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
R6 is independently selected from B! when Z is C, and is independently selected from B2 when Z is N, or R6 is a link to any atom on X, wherein said link is a bond or is a chain 1-3 atoms in length where said atoms are independantly selected from O, N, C and S and where said atoms are independantly joined by single or double bonds, said link forming a fused carbocyclic or heterocyclic ring;
B1 is selected from: Ci-βalkyl unsubstituted or substituted with 1-6 fluoro, hydroxyl, or both, -O-Ci- 6alkyl unsubstituted or substituted with 1-6 fluoro, -C0-Ci_6alkyl unsubstituted or substituted with 1-6 fluoro, -S-Ci-βalkyl unsubstituted or substituted with 1-6 fluoro, -pyridyl unsubstituted or substituted with one or more substituents selected from'the group consisting of: halo, trifluoromethyl, Q^alkyl and COR1 1, fluoro, chloro, bromo, -C4_6cycloalkyl, -O-C4-6cycIoalkyl, phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, Ci.4alkyl and COR11, -O-phenyl unsubstituted or substituted with one or more substituents selected from halo, trifluoromethyl, Ci_4alkyl and COR1 1, -C3-6Cycloalkyl unsubstituted or substituted with 1-6 fluoro, -O-C3.6cycloalkyl unsubstituted or substituted with 1-6 fluoro, -heterocycle, -CN, -COR11 and hydrogen;
B2 is absent or is O, forming an N-oxide; R7 is selected from: hydrogen, (CQ-6alkyl)-phenyl, (Cθ-6alkyl)-heterocycle, (Cθ-6alkyl)-C3-7cycloalkyl , (Cθ-6alkyl)-CORπ, (Cθ-6alkyl)-(alkene)-CORn, (Cθ-6alkyl)-S03H, (Cθ-6alkyl)-W-Cθ-4alkyl, (CQ. 6alkyl)-CONR12-pheny and (Cθ-6alkyl)-CONR15-V-CORn when Y is N or C, or R7 is absent when Y is O, S or SO2, where
V is C^alkyl or phenyl,
W is a single bond, -O-, -S-, -SO-, -SO2-, -CO-, -CO2-, -CONR12- or -NR.12-,
R15 is hydrogen or
Figure imgf000126_0001
or R15 is joined via a 1-5 carbon chain linked to one of the carbons of V, forming a ring,
said Co-βalkyl is unsubstituted or substituted with 1-5 substituents independently selected from halo, hydroxy, -Cθ-6alkyl, -O-C1 -3alkyl, trifluoromethyl and -C0.2alkyl-phenyl,
said phenyl, heterocycle, cycloalkyl and Cø-4alkyl are unsubstituted or substituted with 1-5 substituents independently selected from halo, trifluoromethyl, hydroxy, Cl_6alkyl, -O-Ci_ 3alkyl, -Cc3-CORlI, -CN, -NR12R12, -CONR12R12 and -Co-3-heterocycle, or said phenyl or heterocycle may be fused to another heterocycle where said another heterocycle is unsubstituted or substituted with 1-2 substituents independently selected from hydroxy, halo, -COR11, and -Cj- 4alkyl, and
said alkene is unsubstituted or substituted with 1-3 substituents independently selected from halo, trifluoromethyl, Ci_3alkyl, phenyl and heterocycle;
R8 is selected from hydrogen, hydroxy, Ci-βalkyl, Ci_6alkyl-hydroxy, -O-Ci_3alkyl, -COR11, - CONR12R12 and -CN when Y is N or C, or R8 is absent when Y is O, S, SO2 or N or when a double bond joins the carbons to which R7 and R10 are attached;
or R7 and R8 are joined to form a ring selected from: lH-indene, 2,3-dihydro-lH-indene, 2,3-dihydro- benzofuran, 1,3-dihydro-isobenzofuran, 2,3-dihydro-benzothiofuran, 1,3-dihydro-isobenzothiofuran, 6H- cyclopenta[cZ]isoxazol-3-ol, cyclopentane and cyclohexane, where said ring is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, Ci^alkyl, -O-Ci _3alkyl, -C0-3-COR1I, -CN, -NR12R12, - CONR12R12 and -Co-3-heterocycle;
R^ and R1^ are independently selected from: hydrogen, hydroxy, Cl-6alkyl, Ci_6alkyl-CORπ, Ci_ galkyl-hydroxy, -O-Cl_3alkyl, halo and =0;
or R^ and R^, or R^ and R10, together form a ring which is phenyl or heterocycle, wherein said ring is unsubstituted or substituted with 1-7 substituents independently selected from halo, trifluoromethyl, hydroxy, Ci-3alkyl, -O-Ci-3alkyl, -CORlI, -CN, -NR*2R12 and -CONR12R12;
RH is independently selected from: hydroxy, hydrogen, Ci_6 alkyl, -O-Ci-βalkyl, benzyl, phenyl and C3_ 5 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci_3alkoxy, -CO2H, -Cθ2-Ci_6 alkyl and trifluoromethyl;
R!2 is selected from: hydrogen, C\.β alkyl, benzyl, phenyl and C3-6 cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci-3alkyl, Ci-3alkoxy, -C02H, -CO2-C1-6 alkyl, and trifluoromethyl;
R13 is selected from: hydrogen, Ci-g alkyl, -O-C]-6alkyl, benzyl, phenyl and C3-6 cycloalkyl, where said alkyl, phenyl, benzyl and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci-3alkyl, Cχ-3alkoxy, -CO2H, -CO2-C1-6 alkyl and trifluoromethyl;
R14 is selected from: hydroxy, C\-β alkyl, -O-Ci_6alkyl, benzyl, phenyl and C3-6" cycloalkyl, where said alkyl, phenyl, benzyl, and cycloalkyl are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, Ci_3alkyl, Ci -3alkoxy, -CO2H, -Cθ2-Ci _(5 alkyl, and trifluoromethyl;
R*6 and R18 are independently selected from: hydroxy, Ci-galkyl, Cμgalkyl-COR11, Ci_6alkyl- hydroxy, -O-Ci-3alkyl, halo and hydrogen, where said alkyl is unsubstituted or substituted with 1-6 substituents independantly chosen from fluoro and hydroxyl;
or R16 and R18 together are -CMalkyl-, -C0.2alkyl-O-C 1.3 alkyl- or
Figure imgf000127_0001
forming a bridge, where said alkyl groups are unsubstituted or substituted with 1-2 substituents selected from oxy, fluoro, hydroxy, methoxy, methyl and trifluoromethyl; R17, R19, R20 and R21 are independently selected from: hydrogen, hydroxy, C] -6alkyl, Ci-βalkyl-COR11, Ci-6alkyl-hydroxy, -O-Ci_3alkyl, trifluoromethyl and halo;
R22 is hydrogen or Cj.6alkyl unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -CO2H, -CO2Ci-6alkyl and -O-C1-3alkyl;
R23 is selected from: Ci-βalkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, Ci-3alkoxy, hydroxyl and -COR11, fluoro, -O-Ci_3alkyl unsubstituted or substituted with 1-3 fluoro, C cycloalkyl, -O-C3-6cycloalkyl, hydroxy, -COR1 1, -OCOR13, and =0, or R22 and R23 together are C2- 4alkyl or C0.2alkyl-O-Ci.3alkyl, forming a 5-7 membered ring;
R24 is selected from: hydrogen, Ci-galkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C^alkoxy, hydroxyl and -COR11, COR11, hydroxyl and -O-Ci_6alkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, C1-3alkoxy, hydroxyl and -COR1 ^ or R23 and R2^ together are Ci-4alkyl or Co-salkyl-O-Co^alkyl, forming a 3-6 membered ring;
R2^ is selected from: hydrogen, Cj-galkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C3. 6cycloalkyl and -O-Ci-3alkyl unsubstituted or substituted with 1-6 fluoro,
or R23 and R2^ together are C2-3alkyl, forming a 5-6 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR11,
Figure imgf000128_0001
and Ci_3alkoxy,
or R23 and R2^ together are Ci.2alkyl-O-C1-2alkyl, forming a 6-8 membered ring, where said alkyls are unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR11, Ci-3alkyl and Ci-3alkoxy,
or R23 and R2^ together are -O-Ci_2alkyl-O-, forming a 6-7 membered ring, where said alkyl is unsubstituted or substituted with 1-3 substituents independently selected from halo, hydroxy, -COR11, Ci.3alkyl and C1-3alkoxy;
R26 is selected from: Ci-βalkyl unsubstituted or substituted with 1-6 substituents selected from fluoro, Q_3alkoxy, hydroxyl and -COR11, fluoro, -O-Ci-3alkyl unsubstituted or substituted with 1-3 fluoro, C3.6 cycloalkyl, -O-Cs.gcycloalkyl, hydroxyl and -COR , or R25 is absent if R23 is connected to the Q ring via double bond, or R26 and R23 together form a bridgeselected from -C2-salkyl-, -O-C^alkyl-, -0-C2_5alkyl-O, and -C1- 3alkyl-O-Ci-3alkyl-, where said alkyls are unsubstituted or substituted with 1-6 fluoro; R27 is selected from: hydrogen, Ci-βalkyl unsubstituted or substituted with 1-6 fluoro, fluoro, -0-C3- 6cycloalkyl, and -O-Ci.3alkyl unsubstituted or substituted with 1-6 fluoro; m, i, and n are independently selected from 0, 1 and 2; the dashed line represents an optional bond; and pharmaceutically acceptable salts thereof and individual diastereomers thereof. 2. The compound of claim 1 having the formula Ia:
Figure imgf000129_0001
Ia and pharmaceutically acceptable salts and individual diastereomers thereof. 3. The compound of claim 1 having the formula Ib:
Figure imgf000129_0002
Ib and pharmaceutically acceptable salts and individual diastereomers thereof. 4. The compound of claim 1 having the formula Ic:
Figure imgf000130_0001
Ic and pharmaceutically acceptable salts and individual diastereomers thereof. 5. The compound of claim 1 having the formula Id:
Figure imgf000130_0002
Id and pharmaceutically acceptable salts and individual diastereomers thereof. 6. The compound of claim 1 having the formula Ie:
Figure imgf000130_0003
Ie and pharmaceutically acceptable salts and individual diastereomers thereof. 17836
7. The compound of claim 1 having the formula Ha:
Figure imgf000131_0001
Ha
and pharmaceutically acceptable salts and individual diastereomers thereof.
The compound of claim 1 having the formula lib:
Figure imgf000131_0002
lib
and pharmaceutically acceptable salts and individual diastereomers thereof.
9. The compound of claim 1 having the formula Hc:
Figure imgf000131_0003
lie
and pharmaceutically acceptable salts and individual diastereomers thereof. 10. The compound of claim 1 having the formula Hd:
Figure imgf000132_0001
Hd wherein M is O, S or NR12"' R.33 and R^4 are independently selected from hydrogen, halo, trifluoromethyl, O-Cl-galkyl and 0-Ci- galkyl substituted with 1-6 fluoro, and pharmaceutically acceptable salts and individual diastereomers thereof. 11. The compound of claim 1 having the formula He:
Figure imgf000132_0002
and pharmaceutically acceptable salts and individual diastereomers thereof. 12. The compound of claim 1 wherein R is selected from H, F, Cl, Br, Me and CF3. 13. The compound of claim 1 wherein Y is C. 14. The compound of claim 1 wherein A is O. 15. The compound of claim 1 wherein X is phenyl.
16. The compound of claim 1 wherein R* is selected from: hydrogen, -Cl-βalkyl unsubstituted or substituted with 1-6 substituents independently selected from halo, hydroxy, -O-Ci- 3alkyl and trifluoromethyl, -Cθ-6alkyl-0-Ci_(5alkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, -Co-δalkyl-S-Ci-galkyl- unsubstituted or substituted with 1-6 substituents independently selected from halo and trifluoromethyl, -(C3_5cycloalkyl)- (Cθ-6alkyi) unsubstituted or substituted with 1-7 substituents independently selected from halo, hydroxy, -O-Ci_3alkyl and trifluoromethyl.
17. The compound of claim 16 wherein R* is selected from hydrogen, Cl-βalkyl, Cl-galkyl-hydroxy and Ci_6alkyl substituted with 1-6 fluoro, specifically wherein R* is selected from hydrogen, methyl, hydroxymethyl and trifluoromethyl.
18. The compound of claim 1 wherein when Z is N, R2 is absent.
19. The compound of claim 1 wherein when Z is C, R2 is hydrogen or is linked to G2.
20. The compound of claim 1 wherein if Z is N, R3 is absent.
21. The compound of claim 1 wherein if Z is C, R3 is hydrogen.
22. The compound of claim 1 wherein if the Z bonded to R4 is N, R4 is absent.
23. The compound of claim 1 wherein if the Z bonded to R4 is C, R4 is hydrogen.
24. The compound of claim 1 wherein if the Z bonded to R5 is N, R5 is absent.
25. The compound of claim 1 wherein if the Z bonded to R6 is N, R6 is absent.
26. The compound of claim 1 wherein if the Z bonded to R6 is C, R6 is hydrogen.
27. The compound of claim 1 wherein R^ is selected from phenyl, heterocycle, C3. 7cycloalkyl, d.6alkyl, -COR11 and -CONH-V-COR11, where V is Ci.6alkyl or phenyl, and where said phenyl, heterocycle, C3.7cycloalkyl and Ci_6alkyl is unsubstituted or substituted with 1-5 substituents independently selected from: halo, trifluoromethyl, hydroxy, Ci_3alkyl, -O-Ci_3alkyl, -CORl 1, -CN, - heterocycle and -CONR12Rl2.
28. The compound of claim 1 wherein R^ is selected from: hydrogen, hydroxy, -CN and -F.
29. The compound of claim 1 wherein R7 and R8 are joined together to form a ring selected from: lH-indene and 2,3-dihydro-lH-indene, where said ring is unsubstituted or substituted with 1-3 substituents independently selected from: halo, hydroxy, Ci-3alkyl, -O-Ci_3alkyl, -CORl 1 anj . heterocycle.
30. The compound of claim 1 wherein R^ and R^ are independently selected from: hydrogen, hydroxy, -CH3, -O-CH3 an(i =0-
Figure imgf000134_0001
Figure imgf000135_0001
-134-
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000141_0001
and pharmaceutically acceptable salts thereof and individual diastereomers and enantiomers thereof.
32. A pharmaceutical composition which comprises an inert carrier and the compound of Claim 1.
33. The use of the compound of Claim 1 for the preparation of a medicament useful in the treatment of an inflammatory and immunoregulatory disorder or disease.
34. The use according to claim 14 wherein said disorder or disease is rheumatoid arthritis'.
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