Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases

Abstract

Disclosed are compounds active towards nuclear receptors, pharmaceutical compositions containing the compounds and use of the compounds in therapy.

Claims

1. A compound of Formula (I) ##STR00755## or a pharmaceutically acceptable salt, or stereoisomer thereof, wherein: Y is NR; R is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl; or or R and R2 in combination with the pyrimidine ring of formula (I) form a ring system selected from pyrrolo[2,3-d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine; or R.sub.3a is selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-4 alkylene-C.sub.3-6 heteroalicyclyl, C.sub.3-6 cycloalkyl, and C.sub.3-5 heteroalicyclyl, any of which may be substituted or unsubstituted; or R.sub.2 and R.sub.3a in combination with the pyrimidine ring of formula (I) form a ring system selected from pyrrolo[2,3-d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine; R.sub.1 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-4 alkyl, and substituted or unsubstituted C.sub.1-4 alkoxy; R.sub.4a is selected from the group consisting of —CF.sub.3, —CHF.sub.2, —OCF.sub.3, and —OCHF.sub.2; R.sub.4b is selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 hydroxyalkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.1-4 haloalkoxy; R.sub.5 is selected from the group consisting of —(CR.sub.8R.sub.9)pOR.sub.12, —(CR.sub.8R.sub.9)p-CR.sub.13R.sub.14R.sub.15, —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, and —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9; n and p are integers independently selected from the group consisting of 0, 1, 2, 3 and 4; R.sub.6a is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkoxy, and substituted or unsubstituted aryl; R.sub.6b is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkoxy, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted C.sub.2-9 heteroalicyclyl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted aryl; R.sub.7, R.sub.8, R.sub.9, and R.sub.12, are independently selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted aryl-C.sub.1-6 alkyl, substituted or unsubstituted heteroaryl-C.sub.1-6 alkyl and substituted or unsubstituted aryl; R.sub.13 is absent, or selected from the group consisting of hydrogen, —CN, —CH.sub.3, fluorine, —OH, —CH.sub.2OH, —OCH.sub.3, —CH.sub.2CH.sub.2OH, —CO.sub.2H, —CO.sub.2—C.sub.1-4-alkyl, and —CH.sub.2—SO.sub.2R.sub.20, and R.sub.20 is selected from C.sub.1-6 alkyl; R.sub.14 and R.sub.15 are independently selected from the group consisting of hydrogen, and substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-9 heteroalicyclyl; or R.sub.14 and R.sub.15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C.sub.3-7 cycloalkyl, substituted or unsubstituted C.sub.3-7 cycloalkenyl, substituted or unsubstituted C.sub.2-6 heteroalicyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; B is aryl or heteroaryl; R.sub.3b is selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-4 alkyl, C.sub.1-4 alkylene-C.sub.3-6 cycloalkyl, C.sub.1-4 alkylene-C.sub.3-6 heteroalicyclyl, C.sub.3-6 cycloalkyl, and C.sub.3-6 heteroalicyclyl; and R.sub.3c is selected from the group consisting of hydrogen, C.sub.1-4 alkyl, and C.sub.3-6 cycloalkyl.

2. The compound according to claim 1, wherein R and R.sub.2 in combination with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine, or 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine.

3. The compound according to claim 1, wherein R and R.sub.2 in combination with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine.

4. The compound according to claim 1, wherein R.sub.2 and R.sub.3a in combination with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine or a 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine.

5. The compound according to claim 1, wherein R.sub.2 and R.sub.3a in combination with the pyrimidine ring of formula (I) form a pyrrolo[2,3-d]pyrimidine.

6. The compound according to claim 1, wherein R.sub.3a is selected from the group consisting of methyl, ethyl, cyclopropyl, and cyclobutyl.

7. The compound according to claim 1, wherein R.sub.3a is cyclopropyl.

8. The compound according to claim 1, wherein R.sub.3b is hydrogen.

9. The compound according to claim 1, wherein R.sub.3c is hydrogen.

10. The compound according to claim 1, wherein R.sub.3b is hydrogen, and R.sub.3c is selected from the group consisting of hydrogen, methyl, cyclopropyl and cyclobutyl.

11. The compound according to claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9)p-C(═O)OR.sub.7, or —(CR.sub.8R.sub.9)p-C(═O)NR.sub.8R.sub.9.

12. The compound according to claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9).sub.pOR.sub.12.

13. The compound according to claim 1, wherein R.sub.5 is —(CR.sub.8R.sub.9)p-CR.sub.13R.sub.14R.sub.15.

14. The compound according to claim 13, wherein R.sub.14 and R.sub.15 are combined to form a ring system selected from the group consisting of substituted or unsubstituted C.sub.4-7 cycloalkyl, substituted or unsubstituted C.sub.6-12 membered aryl, substituted or unsubstituted 4-membered heteroalicyclyl, substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 5-membered heteroalicyclyl, substituted or unsubstituted 6-membered heteroaryl, a substituted or unsubstituted 6-membered heteroalicyclyl, and a substituted or unsubstituted 7-membered heteroaryl.

15. The compound according to claim 1, wherein R.sub.14 and R.sub.15 are combined to form a ring system selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, azetidinyl, thietanyl, pyrrolyl, pyrazolyl, imidazolyl, pyrrolidinyl, imidazolinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathianyl, 1,4-oxathianyl 4,4-dioxide, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxolanyl, dioxanyl, furyl, dihydrofuranyl, furazanyl, tetrahydrofuryl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, dithiolanyl, dithianyl, thiopyranyl, thianyl, thianyl-1,1-dioxide, thienyl, oxetanyl, quinolyl, isoquinolyl, indolyl, iso-indolyl, and tetrahydrothienyl, any of which may be substituted or unsubstituted.

16. The compounds according to claim 15, wherein the ring system is selected from the group consisting of cycloheptyl, cyclohexyl, cyclopentyl, dioxanyl, furyl, imidazolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, oxetanyl, oxathianyl, phenyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolyl, tetrahydrofuryl, tetrahydropyranyl, tetrazolyl, thianyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, and triazolyl, any of which may be substituted or unsubstituted.

17. The compound according to claim 16, wherein the ring system is selected from the group consisting of phenyl and oxetanyl, either of which may be substituted or unsubstituted.

18. The compound according to claim 17, wherein the ring system is a substituted or unsubstituted phenyl.

19. The compound according to claim 17, wherein the ring system is a substituted or unsubstituted oxetanyl.

20. The compound according to claim 13, wherein R.sub.14 and R.sub.15 join to form a ring system and the ring system formed by the combination of R.sub.14 and R.sub.15 is substituted with one or more —(CH.sub.2)q(R.sub.5a), wherein R.sub.5a is independently selected from the group consisting of —CH.sub.2COOR.sub.20, —CH.sub.2CONR.sub.21R.sub.22, —CN, —CH.sub.2—CN, C.sub.1-6 alkyl, —CH.sub.2-imidazolyl, —CH.sub.2—SO.sub.2R.sub.20, −CH.sub.2C(CH.sub.3).sub.2(OR.sub.20), —OR.sub.20, —CH.sub.2-triazolyl, —CF.sub.3, dimethyl substituted-imidazolyl-2,4-dione, —CH.sub.2—SO.sub.2NR.sub.21R.sub.22, morpholinyl, —C(═O)-morpholinyl, piperidyl-CH.sub.2OR.sub.20, —OCH.sub.2-tetrahydrofuryl, piperazinonyl, piperidinyl-CONR.sub.21R.sub.22, —OH, —COR.sub.20, —CONR.sub.21R.sub.22, —CH(OR.sub.20)CH.sub.3, —COOR.sub.20, —CH.sub.2-pyrrolidyl, C.sub.1-6 alkylene-OH, cyclopentyl, pyrrolidonyl, tetrazolyl, —CH.sub.2-tetrazolyl, —CH.sub.2OR.sub.20, acyl, —SO.sub.2R.sub.20, —SO.sub.2R.sub.20, —SO.sub.2NR.sub.21R.sub.22, —NR.sub.21SO.sub.2R.sub.20, and halogen; R.sub.21 and R.sub.22 are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, —CN, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heteroalicyclyl, or R.sub.21 and R.sub.22 are combined to form a C.sub.3-6 cycloalkyl; and q is an integer selected from 0, 1 or 2.

21. The compound according to claim 13, wherein R.sub.14 and R.sub.15 join to form a ring system and the ring system formed by the combination of R.sub.14 and R.sub.15 is substituted with one —CH.sub.2CONH.sub.2.

22. The compound according to claim 13, wherein R.sub.13 is absent or —CH.sub.2OH.

23. The compound according to claim 22, wherein R.sub.13 is absent.

24. The compound according to claim 22, wherein Ria is —CH.sub.2OH.

25. The compound according to claim 1, wherein R is hydrogen.

26. The compound according to claim 1, wherein R.sub.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

27. The compound according to claim 1, wherein R.sub.1 is hydrogen or —CF.sub.3.

28. The compound according to claim 1, wherein R.sub.1 is hydrogen.

29. The compound according to claim 1, wherein R.sub.4a is —CF.sub.3.

30. The compound according to claim 1, wherein R.sub.4b is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, tert-butyl, chlorine, fluorine, methoxy, ethoxy, C.sub.1-2 haloalkyl, and C.sub.1-2 haloalkoxy.

31. The compound according to claim 1, wherein R.sub.4b is selected from the group consisting of —CF.sub.3, —CF.sub.2CF.sub.3, —CHF.sub.2, —OCF.sub.2CF.sub.3, and —OCHF.sub.2.

32. The compound according to claim 1, wherein R.sub.4b is —CF.sub.3.

33. The compound according to claim 1, wherein R.sub.6a is selected from the group consisting of hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, and aryl.

34. The compound according to claim 1, wherein R.sub.6a is hydrogen.

35. The compound according to claim 1, wherein R.sub.6b is selected from the group consisting of hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-6 haloalkoxy, and C.sub.1-6-alkoxy-C.sub.1-6-alkyl, or R.sub.6b is selected from the group consisting of —(CH.sub.2).sub.q-aryl, and —(CH.sub.2).sub.q—C.sub.2-9 heteroalicyclyl, which may be substituted by one or more substituent selected from the group consisting of halogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, C.sub.3-5 cycloalkyl, —(CH.sub.2).sub.q—CONR.sub.23R.sub.24, —(CH.sub.2).sub.q—SO.sub.2R.sub.23, and —(CH.sub.2).sub.q—NR.sub.23SO.sub.2R.sub.24, and R.sub.23 and R.sub.24 are independently of each other selected from the group consisting of hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, —CN, substituted or unsubstituted C.sub.3-6 cycloalkyl, and substituted or unsubstituted C.sub.2-6 heteroalicyclyl; and q is an integer selected from 0, or 1.

36. The compound according to claim 1, wherein R.sub.6b is selected from the group consisting of hydrogen, —(CH.sub.2)C(CH.sub.3).sub.3, phenyl, phenyl substituted with 1 to 3 halogens, —CH(CH.sub.3)OC(CH.sub.3).sub.3, —CH.sub.2-phenyl-OCH.sub.3, -phenyl-OCH.sub.3, —CH.sub.2-phenyl-CH.sub.2CONH.sub.2, —CH.sub.2-phenyl-CONH.sub.2, —CH.sub.2-phenyl-SO.sub.2NH-cyclopropyl, —CH.sub.2-phenyl-SO.sub.2CH.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CF.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CH.sub.3, —CH.sub.2-phenyl-NHSO.sub.2CHF.sub.2, —CH.sub.2-pyridyl-CH.sub.3, —CH.sub.2-pyridyl-SO.sub.2CH.sub.3, —CH.sub.2-pyridyl-CH.sub.2CONH.sub.2, —CH.sub.2-pyrimidyl-NHSO.sub.2CH.sub.3, —CH.sub.2-piperidyl-SO.sub.2CH.sub.3, —CH.sub.2-piperidyl-SO.sub.2CF.sub.3, —CH.sub.2-tetrahydrofuranyl, —CH.sub.2-tetrahydropyranyl, and —CH.sub.2-oxetanyl.

37. The compound according to claim 1, wherein R.sub.6b is hydrogen.

38. The compound according to claim 1, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from hydrogen, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxyalkyl, and aryl.

39. The compound according to claim 1, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, and C.sub.1-4 hydroxyalkyl.

40. The compound according to claim 1, wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.12 are independently selected from hydrogen, methyl, ethyl and tert-butyl.

41. The compound according to claim 1, wherein ring system B is aryl.

42. The compound according to claim 1, wherein ring system B is selected from a 6-membered aryl having R.sub.4a in the para-position or meta-position, a 6-membered heteroaryl having R.sub.4a in the para-position or meta-position, or 5-membered heteroaryl having R.sub.4a in the 2- or 3-position.

43. The compound according to claim 1, wherein ring system B is a 6-membered aryl ring having R.sub.4a in the para-position or meta-position.

44. The compound according to claim 1, wherein ring system B is selected from the group consisting of phenyl, pyridyl, pyrazolyl, pyridazinyl, pyrimidinyl, naphthyl and furanyl.

45. The compound according to claim 1, wherein ring system B is a phenyl.

46. The compound according to claim 1, wherein n is an integer selected from the group consisting of 1, 2, 3 and 4.

47. The compound according to claim 1, wherein n is 0.

48. The compound according to claim 1, wherein p is an integer selected from 0, 1 or 2.

49. The compound according to claim 48, wherein p is 0.

50. The compound according to claim 1, wherein the compound of formula (I) has the formula (IIa) ##STR00756##

51. The compound according to claim 1, wherein the compound of formula (I) has the formula (IIab) ##STR00757##

52. A compound, or a pharmaceutically acceptable salt or stereoisomer thereof, selected from the group consisting of: ##STR00758##

53. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutical acceptable excipient.

54. A method for treating a disease or disorder selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic rhinitis, allergic conjunctivitis, uveitis, sprue and food allergy, atopic dermatitis, cystic fibrosis, lung allograph rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimotos disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögrens syndrome, optic neuritis, type I diabetes, neuromyelitis optica, Myasthenia Gravis, Guillain-Barre syndrome, Graves disease, scleritis, obesity, obesity-induced insulin resistance, and type II diabetes, comprising administering a therapeutically effective amount of a compound of claim 1 to a patient in need thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates the TAMRA-labelled probe.

(2) FIG. 2 illustrates the characterisation of the Fluorescence Polarization (FP) assay with the TAMRA-labelled probe used in the FP assay

GENERAL REMARKS

(3) As described above with reference to specific illustrative embodiments, it is not intended to be limited to the specific form set forth herein. Any combination of the above mentioned embodiments should be appreciated as being within the scope of the invention. Rather, the invention is limited only by the accompanying claims and other embodiments than the specific above are equally possible within the scope of these appended claims.

(4) In the claims, the term “comprises/comprising” does not exclude the presence of other species or steps. Additionally, although individual features may be included in different claims, these may possibly advantageously be combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. In addition, singular references do not exclude a plurality. The terms “a”, “an”, “first”, “second” etc. do not preclude a plurality. The phrases “at least one” or “one or more” refer to 1 or a number greater than 1, such as to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

(5) Whenever a chemical name or structure has been given it has been generated by conventional means or by means of a suitable software such as ChemDraw Ultra 8.0.7 or Accelrys Draw 4.0.NET.

(6) Experimental

(7) The following examples are mere examples and should by no mean be interpreted to limit the scope of the invention. Rather, the invention is limited only by the accompanying claims.

(8) General Chemical Procedures

(9) Unless otherwise stated, starting materials were obtained from commercial suppliers, such as (but not limited to); ABchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astatech, Bachem, Chem-Impex, ChemCollect, Chembridge, Combi-Blocks, Enamine, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech, Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific and Ukrorgsyn. N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dichloromethane (DCM) were dried over molecular sieves. Analytical HPLC was performed on a Waters Acquity systemusing a C18 reverse phase column (Merck Chromolith Speedrod RP-18E) with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 3.0 mL/min and UV detection at 254 nm at ambient temperature, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization, or on a Shimadzu Nexera X2 system using a C18 reverse phase column (Acquity UPLC BEH C18 1.7 μm, 2.1×50 mm), with a linear gradient of the binary solvent system water/methanol/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 0.78 mL/min and UV detection at 254 nm, combined with MS detecting on a Shimadzu LCMS-2020 Spectrometer instrument using electron spray ionization. Preparative HPLC was performed on a Waters Acquity system using a C18 reverse phase column (Supelco ASCENTIS C18 581358-U, 15 cm×21.2 mm), with a linear gradient of the binary solvent system water/acetonitrile/formic acid (A: 100/0/0.1% and B: 0/100/0.1%) with a flow rate of 15 mL/min and UV detection at 254 nm, combined with MS detection on a Waters Micromass QZ Quadrupole Mass Spectrometer instrument using electron spray ionization. Chiral resolution was performed on a Lux Cellulose2 (250×21 mm) column using a mobile phase of 0.2% diethyamine in hexane/ethanol, with a flow of 20 mL/min and UV detection at 290 nm. .sup.1H NMR spectra were recorded on a Bruker Avance 300 spectrometer (at 300 MHz), using CD.sub.3OD, CDCl.sub.3 or DMSO-d6 solvents. Chemical shifts are reported in ppm (δ) using residual solvent as an internal standard; CDCl.sub.3: 7.26 ppm; CD.sub.3OD: 3.31; DMSO-d.sub.6: 2.50 ppm. Coupling constants (J) are given in Hz.

(10) Synthetic Methods

(11) The compounds disclosed herein may be made by one of the following four general methods. Further, additional guidance for preparing building blocks to be used in providing compounds disclosed herein is present in the co-pending international application also claiming priority from SE 1450920-2 and SE 1451406-1.

(12) ##STR00190##

(13) A compound containing a free amino group 1a, e.g. N-[[4-(trifluoromethyl)phenyl]methyl]cyclopropanamine, was coupled to a fluorinated aromatic compound 1b, e.g. 4,5,6-trifluoro-pyrimidine, upon treatment with a suitable base in an appropriate solvent, e.g. N,N-Diisopropylethylamine (DIPEA) or cesium carbonate in dry DMSO or dioxane. Conversion to 1c was typically achieved after stirring at room temperature (i.e. 20-25° C.) overnight. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Subsequent nucleophilic aromatic substitution of 1e with a building block containing a free amino group was achieved upon treatment with a suitable base in an appropriate solvent. An example of treatment conditions is cesium carbonate in dry DMSO under microwave irradiation during a period of time, e.g. at 80-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The desired compound 1d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

(14) Use of General Method 1 to Prepare Example No. A5:

(15) ##STR00191##

(16) 4,5,6-Trifluoro-pyrimidine (0.27 g, 2.0 mmol) and N-[[4-(trifluoromethyl)phenyl]methyl]cyclopropanamine (0.43 g, 2.0 mmol) were dissolved in dry DMSO (4 mL) and DIPEA (0.7 mL, 4.0 mmol) was added. The reaction was stirred at room temperature overnight, poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel) yielding N-cyclopropyl-5,6-difluoro-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine (0.50 g, 76% yield). 4,5-difluoro-6-[2-[4-(trifluoromethyl)phenyl]pyrrolidin-1-yl]pyrimidine (0.33 g, 1.0 mmol) and 3-(aminomethyl)tetrahydrofuran-3-ol (0.12 g, 1.0 mmol) were dissolved in dry DMSO (2 mL) and cesium carbonate (0.65 g, 2.0 mmol) was added. The reaction was heated in a microwave reactor for 1 hour at 100° C., poured into 3M aq. calcium chloride, extracted with EtOAc, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: DCM/MeOH, on silica gel), yielding 3-[[[6-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-5-fluoro-pyrimidin-4-yl]amino]methyl]tetrahydrofuran-3-ol A5 (290 mg, 68% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (d, J=1.5 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.25 (s, 1H), 4.87 (s, 2H), 4.07-3.99 (m, 1H), 3.98-3.89 (m, 1H), 3.79 (d, J=9.2 Hz, 1H), 3.70-3.61 (m, 3H), 3.18-2.49 (m, 1H), 2.03-1.99 (m, 2H), 0.80 (d, J=6.6 Hz, 2H), 0.76-0.68 (m, 2H). m/z 427 (M+H).

(17) General method 1 was used to prepare the following example numbers using the shown starting materials:

(18) TABLE-US-00002 Fluorinated Ex. aromatic No. Free amine (1) Free amine (2) compound T1 X A1 00 A2 01 02 03 A3 04 05 06 A4 07 08 09 A5 0 A6 A7 A8 0 A9 A11 A12 0 A13 A14 A15 A16 0 A17 A18 A19 0 A20 A21 A22 0 A23 A24 A25 A26 0 A27 A28 A29 0 A30 A31 A32 0 A33 A34 A35 A36 00 01 02 A37 03 04 05 A38 06 07 08 A39 09 0 A40 A41 A42 0 A43 A44 A45 A47 0 A49 A52 A53 0 A54 A55 A57 0 A58 A59 A60 A61 0 A62 A63 A64 0 A65 A66 A67 0 A68 A69 A72 A73 0 A74 A75 A76 00 01 A77 02 03 04 A78 05 06 07 A79 08 09 0 A82 A83 A85 A88 0 A89 A90 A91 0 A92 A93 A97 0 A98 A99 A101 A102 0 A103 A104 A105 0 A106 A107 A108 0 A109 A110 A111 A112 0 A113 A114 A115 0 A118 A119 A120 00 A121 01 02 03 A122 04 05 06 A123 07 08 09 A124 0 A125 A126 A127 0 A128 A129 A130 0 A131 A132 A133 A134 0 A135 A136 A137 0 A138 A139 A140 0 A141 A142 A143 A144 0 A145 A147 A148 0 A149 A150 A156 0 A157 A158 A159 A160 00 01 02 A161 03 04 05 A162 06 07 08 A163 09 0 A165 A166 A167 0 A168 A169 A170 A171 0 A172 A173 A174 0 A175 A176 A177 0 A178 A179 A180 A181 0 A182 A183 A184 0 A185

(19) Synthesis of Selected Free Amines:

(20) Dialkyl Amines were Synthesized Using the Following General Method 2:

(21) ##STR00675##

(22) A primary amine 2a, e.g. cyclopropanamine, was coupled to a carbonyl compound 2b, e.g. 4-(trifluoromethyl)benzaldehyde, upon treatment with a suitable reducing agent, e.g. NaBH.sub.3CN or NaBH(OAc).sub.3, in an appropriate solvent, e.g. DCM or tetrahydrofuran (THF), with addition of an appropriate acid, e.g. AcOH. Conversion to 2c was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

Example of Use of Method 2 to Prepare N-[[4-(trifluoromethyl)phenyl]methyl]cyclopropanamine

(23) ##STR00676##

(24) Cyclopropanamine (202 mg, 2.0 mmol) and 4-(trifluoromethyl)benzaldehyde (348 mg, 2.0 mmol) were dissolved in 5 mL DCM and 2 drops of AcOH was added. The mixture was stirred for 15 min at rt, and sodium triacetoxyborohydride (424 mg, 4.0 mmol) was added. The mixture was stirred at room temperature for 4 hours. The mixture was poured into 1M HCl, washed with EtOAc, basicified with 4M NaOH, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: Heptane/EtOAc, on silica gel), yielding N-[[4-(trifluoromethyl)phenyl]methyl]cyclopropanamine (316 mg, 73%).

(25) General method 2 was used to prepare the following dialkyl amines using the shown starting materials:

(26) TABLE-US-00003 Primary amine Carbonyl 0 0 00 01 02 03 04 05 06 07 08 09 0

N-((2-(trifluoromethyl) pyrimidin-5-yl) methyl) cyclopropanamine

(27) To a solution of 2-(trifluoromethyl) pyrimidine-5-carboxylic acid (700 mg, 3.64 mmol, 1 eq) in dry THF (10 mL) at 0° C. was added borane dimethyl sulfide in THF (828 mg, 10.92 mmol, 3 eq), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was quenched with MeOH and stirred for another 3 hours at room temperature. The solvent was evaporated and the residue was poured into ice water and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with water (2×40 mL), brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (eluent: EtOAc/Pet ether, on silica gel) to afford (2-(trifluoromethyl) pyrimidin-5-yl) methanol (Compound-2) (260 mg, 40%) as yellow liquid.

(28) To a solution of (2-(trifluoromethyl) pyrimidin-5-yl) methanol (0.26 g, 1.46 mmol, 1 eq) in CH.sub.2Cl.sub.2 (10 mL) at 0° C. was added pyridinium chlorochromate (PCC, 0.53 g, 2.48 mmol, 1.0 eq), and the mixture was stirred at room temperature for 4 hours. After completion, the reaction mixture was diluted with CH.sub.2Cl.sub.2 (30 mL) and filtered through a pad of celite using CH.sub.2Cl.sub.2 (50 mL). The filtrate was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to afford 2-(trifluoromethyl) pyrimidine-5-carbaldehyde (100 mg, 39%) as yellow liquid. The crude product was used as such without further purification.

(29) To a solution of 2-(trifluoromethyl)pyrimidine-5-carbaldehyde (100 mg, 0.568 mmol, 1 eq) in CH.sub.2Cl.sub.2 (2 ml) was added cyclopropanamine (38 mg, 0.68 mmol, 1.2 eq), AcOH (0.5 ml), 4 Å molecular sieves powder (50 mg), and the mixture was stirred at room temperature for 30 min. Then Na(OAc).sub.3BH (240 mg, 1.36 mmol, 2 eq) was added and stirring was continued at room temperature for 4 hours. After completion, the reaction mixture was diluted with CH.sub.2Cl.sub.2 (50 mL) and filtered through a pad of celite. The filtrate was washed with saturated aq. NaHCO.sub.3 (25 mL), water (25 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (eluent: EtOAc/Pet ether, on silica gel) to afford N-((2-(trifluoromethyl) pyrimidin-5-yl) methyl) cyclopropanamine (100 mg, 81%) as pale yellow liquid.

[4-(1H-Tetrazol-5-ylmethyl)cyclohexyl]methanamine

(30) To 4-[(tert-butoxycarbonylamino)methyl]cyclohexanecarboxylic acid (0.84 g, 3.2 mmol) a BH.sub.3-THF solution in THF (16 mL, 1M) was slowly added. The reaction was allowed to stir for 2.5 hours, concentrated in vacuo and the residue was stirred with an aq. sodium hydroxide solution (1M, 30 mL) for 20 min. Ethyl acetate was added and the mixture was allowed to stir for another 10 min. The phases were separated, the EtOAc phase was concentrated in vacuo and the crude product thereof was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4 (hydroxymethyl)cyclohexyl]methyl]carbamate (0.76 g, quant yield).

(31) Tert-butyl N-[[4-(hydroxymethyl)cyclohexyl]methyl]carbamate (0.60 g, 2.5 mmol) was dissolved in DCM (20 mL), Et.sub.3N (1 mL) and methanesulfonyl chloride was the added to the solution, and the reaction was stirred over night at room temperature. Concentration under reduced pressure yielded a solid that was mixed with water and EtOAc. The EtOAc phase was separated and washed with brine and dried over sodium sulfate. Filtration and concentration in vacuo of the EtOAC phase gave a solid that was dissolved dry DMSO (10 mL). Potassium cyanide (0.36 g, 5.5 mmol) was added and the reaction was heated to 90° C. for 4 hours. The crude reaction was poured onto water and the resulting mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (0.57 g, 88% yield).

(32) To a solution of tert-butyl N-[[4-(cyanomethyl)cyclohexyl]methyl]carbamate (160 mg, 0.60 mmol) in nitrobenzene were added triethylammonium chloride (160 mg, 1.2 mmol) and sodium azide (91 mg, 1.4 mmol). The resulting mixture was heated to 105° C. for 11 hours using microwave irradiation. Some more sodium azide (40 mg, 0.7 mmol) was added and the reaction was heated for another 45 min at 105° C. with microwave irradiation. The reaction was extracted with water and the water phase was washed with ether, made acidic with 1M HCl and extracted with EtOAc. The EtOAc phase was dried using sodium sulfate, filtered and concentrated in vacuo and finally purified by flash CC (eluent: EtOAc/heptane, on silica gel) yielding tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 18% yield).

(33) Tert-butyl N-[[4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methyl]carbamate (33 mg, 0.11 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (TFA, 1 mL) was added, and the reaction was stirred for 2 hours. Concentration of the reaction mixture yielded [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methylammonium 2,2,2-trifluoroacetate that was used without further purification. Using an extra equivalent of the base in the General Method 1 gave [4-(1H-tetrazol-5-ylmethyl)cyclohexyl]methanamine in situ during the reaction.

N-((4-cyanotetrahydro-2H-pyran-4-yl)methyl)methanesulfonamide

(34) To a solution of 4-(aminomethyl) tetrahydro-2H-pyran-4-carbonitrile (0.5 g, 3.57 mmol) in pyridine (5 mL) was added methane sulfonyl chloride (0.4 g, 3.57 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL) and washed with saturated aq. citric acid (30 mL), water (30 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (Eluent: EtOAc/Pet ether, on silica gel) to afford N-((4-cyanotetrahydro-2H-pyran-4-yl) methyl) methanesulfonamide (370 mg, 48%) as yellow liquid. A suspension of N-((4-cyanotetrahydro-2H-pyran-4-yl) methyl) methanesulfonamide (0.32 g, 1.46 mmol), Raney Ni (0.82 g, 9.54 mmol), NH.sub.4OH (0.1 mL) in MeOH (6.5 mL) was stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was diluted with EtOAc (30 mL) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford N-((4-(aminomethyl) tetrahydro-2H-pyran-4-yl) methyl) methanesulfonamide (200 mg, 62%). The crude product was used as such without further purification.

4-(aminomethyl)-1-(methylsulfonyl) piperidin-4-ol

(35) To a solution of 1-(methylsulfonyl) piperidin-4-one (1 g, 5.64 mmol) in AcOH (10 mL) was added KCN (0.55 g, 8.57 mmol), and the mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was diluted with EtOAc (75 mL) and washed with saturated aq. NaHCO.sub.3 (40 mL), water (50 mL), brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (Eluent: EtOAc/Pet ether, on silica gel) to afford 4-hydroxy-1-(methylsulfonyl) piperidine-4-carbonitrile (500 mg, 43%) as yellow liquid.

(36) A suspension of 4-hydroxy-1-(methylsulfonyl) piperidine-4-carbonitrile (500 mg, 2.45 mmol), Raney Ni (1.35 g, 15.92 mmol), NH.sub.4OH (0.12 mL) in MeOH (10 mL) was stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was diluted with EtOAc (30 mL) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude product was triturated with diethyl ether to afford 4-(aminomethyl)-1-(methylsulfonyl) piperidin-4-ol (200 mg, 39%) as a pale yellow syrup.

2-(5-(aminomethyl)pyridin-2-yl)acetamide

(37) To a solution of 5-cyanopicolinic acid (1 g, 6.75 mmol) in dry THF (10 mL) at −15° C. was added Et.sub.3N (0.68 g, 6.75 mmol), ethyl chloro formate (0.73 g, 6.75 mmol), and the mixture was stirred for 16 hours at −15° C. Ether (15 mL), TMSCHN.sub.2 (1.54 g, 13.5 mmol) was added, and the mixture was stirred overnight while returning to room temperature. After completion, the reaction mixture was diluted with EtOAc (75 mL), washed with water (50 mL), brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The diazaketone was dissolved in dioxane:H.sub.2O (1:1) (10 mL), added AgCOOPh (cat), and the mixture was stirred at 100° C. for 16 hours. After completion, the reaction mixture was diluted with EtOAc (50 mL), acidified using 1N HCl and extracted using EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by triturating with ether (10 mL) and pentane (50 mL) to afford 2-(5-cyanopyridin-2-yl) acetic acid (350 mg, 32%) as yellow solid.

(38) To a solution of 2-(5-cyanopyridin-2-yl)acetic acid (0.35 g, 2.16 mmol) in DMF (3 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 0.82 g, 4.32 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 0.58 g, 4.32 mmol), DIPEA (1.16 mL, 6.48 mmol), NH.sub.4Cl (0.17 g, 3.24 mmol) and stirred at room temperature for 3 hours. After completion, the reaction mixture was poured into ice water and extracted with EtOAc (2×50 mL). The combined extracts were washed with water (40 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by flash CC (Eluent: MeOH/DCM) to afford 2-(5-cyanopyridin-2-yl) acetamide (190 mg, 55%) as yellow solid.

(39) A solution of 2-(5-cyanopyridin-2-yl) acetamide (190 mg, 1.18 mmol), Raney Ni (0.65 g, 7.67 mmol), NH.sub.4OH (0.05 vol) in MeOH (2 mL) was and stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was diluted with EtOAc (20 mL) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford 2-(5-(aminomethyl) pyridin-2-yl) acetamide (80 mg, 41%) as yellow solid.

(6-(methylsulfonyl) pyridin-3-yl) methanamine

(40) A suspension of 6-(methylsulfonyl) nicotinonitrile (500 mg, 2.74 mmol), Raney Ni (1.51 g, 17.85 mmol), NH.sub.4OH (0.12 mL) in MeOH (10 mL) was stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was diluted with EtOAc (30 mL) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford (6-(methylsulfonyl)pyridin-3-yl)methanamine (450 mg) as yellow solid. The crude product was used as such without further purification.

N-[4-(aminomethyl)phenyl]-1,1-difluoro-methanesulfonamide

(41) Tert-butyl N-[(4-aminophenyl)methyl]carbamate (222 mg, 1.0 mmol) was dissolved in 5 mL dry DCM, and the solution was cooled to −78° C. Pyridine (0.24 μL, 3.0 mmol) was added, followed by slow addition of a solution of difluoromethanesulfonyl chloride (150 mg, 1.0 mmol) in 5 mL DCM. The mixture was stirred overnight while returning to rt, poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and purified by flash CC (eluent: Heptane/EtOAc, on silica gel), yielding tert-butyl N-[[4-(difluoromethylsulfonylamino)phenyl]methyl]carbamate. The product was dissolved in 2 mL DCM and a solution of 4M HCl in dioxane (2 mL) was added. The mixture was stirred overnight at room temperature, then concentrated in vacuo, and the crude N-[4-(aminomethyl)phenyl]-1,1-difluoro-methanesulfonamide hydrochloride was used in the next step without further purification (55 mg, 23%).

(42) Using the same protocol the following compounds were prepared: 1-(1-methylsulfonyl-4-piperidyl)cyclopropanamine, 6-methylsulfonyl-6-azaspiro[2.5]octan-2-amine, [(1S,5R)-8-methylsulfonyl-8-azabicyclo[3.2.1]octan-3-yl]methanamine, 6-methylsulfonyl-6-azaspiro[2.4]heptan-2-amine, (3-methylsulfonyl-3-azabicyclo[3.1.0]hexan-5-yl)methanamine and 2-methylsulfonyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-4-amine.

N-(5-(aminomethyl)-3-fluoropyridin-2-yl)methanesulfonamide

(43) A suspension of 5-bromo-3-fluoropyridin-2-amine (2 g, 10.58 mmol), K.sub.4FeCN.sub.6 (1.78 g, 4.23 mmol) and 1,8-diazabicycloundec-7-ene (DBU, 399 mg, 2.64 mmol) in tBuOH:H.sub.2O (1:1) (20 mL) was degassed for 15 min. Then added Pd(PPh.sub.3).sub.4 (0.61 g, 0.529 mmol) and the mixture was stirred at 85° C. for 16 hours. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL), brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude compound was purified by flash CC (Eluent: MeOH/DCM, on silica gel) to afford 6-amino-5-fluoronicotinonitrile (600 mg, 42%) as a pale yellow solid.

(44) To a solution of 6-amino-5-fluoronicotinonitrile (600 mg, 4.37 mmol) in pyridine (6 mL) at 0° C. was added methane sulfonyl chloride (0.5 g, 4.37 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was diluted with EtOAc (75 mL), washed with water (50 mL), brine (40 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The crude compound was purified by flash CC (Eluent: MeOH/DCM, on silica gel) to afford N-(5-cyano-3-fluoropyridin-2-yl) methanesulfonamide (350 mg, 37%) as pale yellow solid.

(45) A suspension of N-(5-cyano-3-fluoropyridin-2-yl) methanesulfonamide (350 mg, 1.627 mmol), Raney Ni (0.9 g, 10.58 mmol), NH.sub.4OH (0.1 mL) in MeOH (6.5 mL) was stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was filtered through a pad of celite, the filtrate was dried over anhydrous Na.sub.2SO.sub.4 and evaporated. The crude product was triturated with DCM:pentane (1:5) to afford N-(5-(aminomethyl)-3-fluoropyridin-2-yl) methanesulfonamide (130 mg, 36%) as an off white solid.

5-(aminomethyl) pyrimidin-2-amine

(46) A suspension of 2-aminopyrimidine-5-carbonitrile (0.4 g, 3.33 mmol), Raney Ni (1.8 g, 21.7 mmol), NH.sub.4OH (0.2 mL) in MeOH (4 mL) was stirred at room temperature for 16 hours under hydrogen atmosphere. After completion, the reaction mixture was diluted with EtOAc (30 mL) and filtered through a pad of celite. The filtrate was dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated to afford 5-(amino methyl) pyrimidin-2-amine (300 mg, 72%) as pale yellow solid.

(47) Synthesis of Example No. A81

(48) ##STR00713##

(49) 5,6-Difluoro-N-[1-[4-(trifluoromethyl)phenyl]cyclopropyl]pyrimidin-4-amine (100 mg, 0.32 mmol), prepared using Method 1, was dissolved in 1 mL dry DMF and sodium hydride (60% in mineral olie, 13 mg, 0.34 mg) was added. The mixture was stirred at room temperature until gas formation had ceased (30 min). Methyl iodide (45 mg, 0.34 mmol) was added, and the mixture was stirred for 2 hours at room temperature. The mixture was poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was dissolved in 2 mL dry DMSO and 2-[4-(aminomethyl)phenyl]acetamide (56 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.7 mmol) were added. The mixture was heated at 100° C. in the microwave oven for 30 min, poured into H.sub.2O, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH). .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.33-7.21 (m, 6H), 4.57 (s, 2H), 3.49 (s, 2H), 3.21 (s, 3H), 1.61-1.42 (m, 4H). m/z 474 (M+H).

(50) Synthesis of Example No. A100

(51) ##STR00714##

(52) N-Cyclopropyl-5,6-difluoro-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine (100 mg, 0.3 mmol), prepared using Method 1, was dissolved in 1 mL DMSO. Ammonium chloride (22 mg, 0.4 mmol) and DIPEA (0.14 mL, 0.08 mmol) were added, and the mixture was heated at 100° C. for 2 hours. The mixture was poured into saturated aqueous NaHCO.sub.3, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, yielding N4-cyclopropyl-5-fluoro-N4-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4,6-diamine (40 mg, 41%). The crude product was used in the next step without further purification.

(53) N-Cyclopropyl-5-fluoro-4-[[4-(trifluoromethyl)phenyl]methyl]pyrimidine-4,6-diamine (33 mg, 0.1 mmol), 1-methylsulfonylpiperidine-4-carboxylic acid (21 mg, 0.1 mmol), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium hexafluorophosphate (HATU, 38 mg, 0.1 mmol) and DIPEA (40 μL, 0.2 mmol) were dissolved in dry DMSO (1 mL), and the mixture was stirred at 70° C. for 3 days. The mixture was poured into saturated aqueous NaHCO.sub.3, extracted with EtOAc, washed with brine, driven over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH). .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.16 (s, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 5.01 (s, 2H), 3.11-3.00 (m, 1H), 2.86 (s, 3H), 2.86-2.80 (m, 4H), 2.76-2.62 (m, 1H), 2.10-1.97 (m, 2H), 1.93-1.76 (m, 3H), 0.94-0.84 (m, 2H), 0.84-0.76 (m, 2H). m/z 516 (M+H).

(54) General Method 3

(55) ##STR00715##

(56) A halogenated pyrrolopyrimidine 3b, e.g. 6-chloro-7-deazapurine, was N-alkylated by addition of an alkyl halide 3a, e.g. [3-(bromomethyl)oxetan-3-yl]methanol, and an appropriate base in a suitable solvent, e.g. cesium carbonate in dry dioxane or sodium hydride in dry tetrahydrofuran. The mixture was stirred at room temperature until completion of reaction, typically overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Nucleophilic aromatic substitution of the halogen on intermediate 3c was achieved upon addition of a building block containing a free amino group, e.g. 2-(4-trifluoromethyl-phenyl)-pyrrolidine, and a suitable base in an appropriate solvent, e.g. cesium carbonate in dry DMSO. The reaction was achieved by microwave irradiation at elevated temperatures for a period of time, e.g. at 100-150° C. for 1-4 hours. The reaction may for example be monitored by thin layer chromatography. The desired compound 3d was obtained upon work-up, for example by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane.

(57) Use of General Method 3 to Prepare Example No. I1:

(58) ##STR00716##

(59) A suspension of 2-(4-(chloromethyl) phenyl) acetamide (1.2 g, 6.54 mmol) 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 6.54 mmol), Cs.sub.2CO.sub.3 (4.26 g, 13.08 mmol) in DMF (12 mL) was stirred at room temperature for 3 hours. After completion, the reaction mixture was poured into ice water, the solid filtered off and washed with diethyl ether (50 mL) to afford 2-(4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)acetamide (1.1 g, 56%) as a pale yellow solid.

(60) A solution of 2-(4-((4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)acetamide (Gemma-Pyrrolopyrimidine) (500 mg, 1.66 mmol), N-(4-(trifluoromethyl)benzyl)cyclopropanamine (358 mg, 1.66 mmol) and DIPEA (0.89 mL, 4.98 mmol) in DMSO (5 mL) was stirred at 150° C. for 4 hours under microwave conditions. After completion, the reaction mixture was poured into ice water and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (2×20 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and evaporated. The crude compound was purified by reverse phase chromatography (0.01 M ammonium acetate in water:ACN) to afford 2-(4-((4-(cyclopropyl (4-(trifluoromethyl) benzyl) amino)-7H-pyrrolo [2,3-d] pyrimidin-7-yl)methyl) phenyl)acetamide (75 mg) as an off white solid. .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.36 (s, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.40-7.33 (m, 2H), 7.24 (s, 4H), 6.92 (d, J=3.7 Hz, 1H), 6.83 (d, J=3.7 Hz, 1H), 5.41 (s, 2H), 5.31 (br s, 2H), 5.15 (s, 2H), 3.56 (s, 2H), 3.08 (dt, J=3.5, 6.9 Hz, 1H), 1.02-0.86 (m, 4H). m/z 480 (M+H).

(61) General method 3 was used to prepare the following example numbers using the shown starting materials:

(62) TABLE-US-00004 Ex. Halogenated No. pyrroloporimidine Alkyl halide Free amine I1 A56 0 A164

Synthesis of 2-[4-(chloromethyl)phenyl]acetamide

(63) To a solution of 2-(4-(hydroxymethyl) phenyl) acetic acid (20 g, 120.48 mmol) in MeOH:toluene (1:1)(200 mL) at 0° C. was added (trimethylsilyl)diazomethane (TMSCHN.sub.2, 27.51 g, 240 mmol), and the mixture was stirred at room temperature for 16 hours. After completion, the solvent was evaporated and the crude compound was purified by flash CC (eluent: EtOAc/Pet ether, on silica gel) to afford methyl 2-(4-(hydroxymethyl) phenyl) acetate (18 g, 830%) as an off white solid.

(64) To a solution of methyl 2-(4-(hydroxymethyl) phenyl) acetate (3.4 g, 1.87 mmol) in MeOH (10 vol) was added aqueous NH.sub.3 (34 ml), and the mixture was heated at 90° C. for 16 hours in a sealed tube. After completion, the reaction mixture was allowed to room temperature and filtered to afford 2-(4-(hydroxymethyl) phenyl) acetamide (1.1 g, 35%) as an off white solid.

(65) To a solution of 2-(4-(hydroxymethyl) phenyl) acetamide (2 g, 12.12 mmol), Et.sub.3N (5.1 mL, 36.36 mmol) in DMF (20 mL) was added methane sulfonyl chloride (1.5 mL, 18.18 mmol), and the mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was poured into ice water and filtered the solid to afford 2-(4-(chloromethyl) phenyl) acetamide (1.2 g, 54%) as an off white solid.

(66) General Method 4

(67) ##STR00726##

(68) A halogenated pyrimidine 4a, e.g. N-cyclopropyl-5,6-difluoro-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine, was coupled to an amino acid 4b, e.g. 3-(aminomethyl)cyclobutanecarboxylic acid, upon treatment with a suitable base in an appropriate solvent, e.g. DIPEA or cesium carbonate in dry DMSO or DMF, under microwave irradiation during a period of time, e.g. at 80-150° C. for 1 hour. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. The free carboxylic acid 4c can be converted to 4d upon acylation with a free amine containing compound, e.g. ammonium chloride, upon treatment with an appropriate coupling reagent or mixture of coupling reagents, e.g. HATU or EDC/HOAt, and a suitable base, e.g. DIPEA, in an appropriate solvent, e.g. DMF or DMSO. Conversion to 4d was typically achieved after stirring at room temperature overnight. The reaction may for example be monitored by thin layer chromatography. The reaction may for example be monitored by thin layer chromatography. The desired product was obtained upon work-up, e.g. by extraction with EtOAc, washing with water at a suitable pH and brine, drying over an appropriate drying agent, e.g. Na.sub.2SO.sub.4, and purification by flash column chromatography (CC) using an appropriate eluent combination on a suitable column material, e.g. heptane/EtOAc or DCM/MeOH on silica gel, or recrystallization from a suitable solvent or solvent mixture, e.g. toluene/heptane. Compounds in which 4d contain a tert-butyl protected acid, e.g. tert-butyl 2-[[2-[4-[[[6-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-5-fluoro-pyrimidin-4-yl]amino]methyl]tetrahydropyran-4-yl]acetyl]amino]acetate, can be hydrolyzed upon treatment with a suitable acid, e.g. HCl in dioxane, prior to purification.

(69) Use of General Method 4 to Prepare Example No. 96:

(70) ##STR00727##

(71) N-Cyclopropyl-5,6-difluoro-N-[[4-(trifluoromethyl)phenyl]methyl]pyrimidin-4-amine (100 mg, 0.3 mmol), prepared using Method 1, was dissolved in 2 mL dry DMSO. 3-(Aminomethyl)cyclobutanecarboxylic acid (39 mg, 0.3 mmol) and DIPEA (0.11 mL, 0.6 mmol) were added, and the mixture was heated at 90° C. for 4 hours. The reaction mixture was poured into 10% aqueous KHSO.sub.4, extracted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, yielding 3-[[[6-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-5-fluoro-pyrimidin-4-yl]amino]methyl]cyclobutanecarboxylic acid (68 mg, 52%).

(72) The crude 3-[[[6-[cyclopropyl-[[4-(trifluoromethyl)phenyl]methyl]amino]-5-fluoro-pyrimidin-4-yl]amino]methyl]cyclobutanecarboxylic acid (66 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (60 μL, 0.3 mmol) were dissolved in dry DMF (1 mL), and the mixture was stirred at room temperature overnight. The mixture was poured into saturated aqueous NaHCO.sub.3, extracted with EtOAc, washed with brine, driven over Na.sub.2SO.sub.4, concentrated in vacuo and purified by flash CC (eluent: DCM/MeOH). .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ7.82 (d, J=1.8 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.17-7.00 (n, 2H), 6.66 (s, 1H), 4.83 (s, 2H), 3.43-3.38 (i, 1H), 3.31-3.24 (i, 2H), 2.97-2.83 (m, 1H), 2.46-2.31 (n, 1H), 2.16-1.97 (i, 2H), 1.90-1.74 (i, 2H), 0.78-0.61 (in, 4H). m/z 438 (M+H).

(73) General method 4 was used to prepare the following example numbers using the shown starting materials:

(74) TABLE-US-00005 Ex. No. Amino acid Amine Fluorinated aromatic compound A80 0 A84 A95 A96 A151 0 A152 A153 A154 0 A155

(75) TABLE-US-00006 Table of .sup.1H NMR and MS Data for example compounds. Ex. No. .sup.1H NMR or MS Data T1 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.62 (d, J = 7.7 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.39-7.31 (m, 2H), 7.29- 7.21 (m, 2H), 4.89 (s, 2H), 4.63 (s, 2H), 4.31 (s, 2H), 3.01- 2.85 (m, 1H), 0.88-0.66 (m, 4H). I1 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.36 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.40-7.33 (m, 2H), 7.24 (s, 4H), 6.92 (d, J = 3.7 Hz, 1H), 6.83 (d, J = 3.7 Hz, 1H), 5.41 (s, 2H), 5.31 (br s, 2H), 5.15 (s, 2H), 3.56 (s, 2H), 3.08 (dt, J = 3.5, 6.9 Hz, 1H), 1.02-0.86 (m, 4H). X .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.98 (d, J = 1.5 Hz, 1H), 7.59- 7.52 (m, 2H), 7.35 (d, J = 7.9 Hz, 2H), 4.9 (s, 1H), 4.85 (s, 2H), 4.52 (d, J = 8.0 Hz, 1H), 3.80 (q, J = 8.9 Hz, 2H), 3.44-3.22 (m, 3H), 2.97-2.81 (m, 1H), 2.23-2.06 (m, 2H), 1.99-1.85 (m, 2H), 1.71-1.52 (m, 1H), 1.40-1.23 (m, 2H), 1.21-1.00 (m, 2H), 0.83- 0.65 (m, 4H). A1 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.39 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 1.8 Hz, 1H), 7.70-7.57 (m, 4H), 7.42 (d, J = 7.8 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 4.84 (s, 2H), 4.50 (d, J = 6.1 Hz, 2H), 2.95-2.86 (m, 1H), 2.42 (s, 3H), 0.77-0.64 (m, 4H). A2 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.02 (d, J = 1.6 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 7.6 Hz, 4H), 7.28 (d, J = 7.8 Hz, 2H), 5.35 (s, 2H), 5.05 (d, J = 6.7 Hz, 1H), 4.87 (s, 2H), 4.68 (d, J = 5.7 Hz, 2H), 3.59 (s, 2H), 2.90-2.87 (m, 1H), 0.80-0.75 (m, 2H), 0.75-0.70 (m, 2H). A3 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.05 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 1.9 Hz, 2H), 5.64 (q, J = 7.2 Hz, 1H), 5.34 (s, 2H), 5.07 (s, 1H), 4.69 (d, J = 5.8 Hz, 2H), 3.59 (s, 2H), 2.77- 2.63 (m, 1H), 1.79 (d, J = 7.1 Hz, 3H), 0.69-0.50 (m, 3H), 0.33- 0.19 (m, 1H). A4 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.01 (d, J = 1.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.36-7.29 (m, 4H), 7.24 (s, 2H), 5.24 (s, 3H), 4.95 (s, 1H), 4.80 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 4.04-3.93 (m, 1H), 3.86-3.74 (m, 2H), 3.68 (q, J = 8.3 Hz, 1H), 3.57 (s, 2H), 2.33-2.20 (m, 1H), 1.98-1.85 (m, 1H). A5 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 7.94 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.25 (s, 1H), 4.87 (s, 2H), 4.07-3.99 (m, 1H), 3.98-3.89 (m, 1H), 3.79 (d, J = 9.2 Hz, 1H), 3.70-3.61 (m, 3H), 3.18-2.49 (m, 1H), 2.03-1.99 (m, 2H), 0.80 (d, J = 6.6 Hz, 2H), 0.76-0.68 (m, 2H). A6 .sup.1H NMR (400 MHz, CDCl.sub.3) δ 8.03 (d, J = 1.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.33-7.26 (m, 4H), 7.14 (d, J = 8.1 Hz, 2H), 5.33 (s, 2H), 5.04 (s, 1H), 4.81 (s, 2H), 4.68 (d, J = 5.7 Hz, 2H), 3.59 (s, 2H), 2.86 (m, 1H), 0.82-0.66 (m, 4H). A7 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.83 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.21-7.12 (m, 1H), 4.83 (s, 2H), 3.60-3.49 (m, 2H), 3.23 (t, J = 6.1 Hz, 2H), 2.96- 2.85 (m, 1H), 2.83 (s, 3H), 2.71-2.57 (m, 2H), 1.81-1.65 (m, 3H), 1.28-1.07 (m, 2H), 0.77-0.63 (m, 4H). A8 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.87 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 4.90 (s, 2H), 3.54 (s, 2H), 3.42-3.34 (m, 2H), 3.01-2.87 (m, 3H), 2.22-2.04 (m, 4H), 0.89-0.67 (m, 4H). A9 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.87-7.81 (m, 3H), 7.62 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 4.90 (s, 2H), 4.74 (s, 2H), 2.98-2.89 (m, 1H), 2.20-2.09 (m, 1H), 0.86-0.77 (m, 2H), 0.77-0.69 (m, 2H), 0.59-0.44 (m, 4H). A11 m/z 466 (M + H) A12 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.88 (s, 2H), 4.02-3.88 (m, 2H), 3.44-3.27 (m, 4H), 2.95-2.83 (m, 1H), 1.99-1.78 (m, 1H), 1.75-1.63 (m, 2H), 1.40-1.19 (m, 2H), 0.87-0.62 (m, 4H). A13 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.00 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.29 (s, 2H), 5.33 (s, 2H), 5.07 (s, 1H), 4.70-4.68 (m, 3H), 3.59 (s, 2H), 3.49 (s, 1H), 2.98 (m, 1H), 1.82-1.64 (m, 1H), 1.36-1.17 (m, 1H), 1.05-0.81 (m, 2H), 0.74-0.68 (m, 3H), 0.54-0.45 (m, 3H), 0.30 (s, 1H). A14 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.04 (d, J = 1.6 Hz, 1H), 7.61- 7.54 (m, 2H), 7.44-7.30 (m, 6H), 5.14 (s, 1H), 4.89 (s, 2H), 4.74-4.67 (m, 2H), 3.76 (s, 2H), 3.03-2.83 (m, 1H), 0.87-0.63 (m, 4H). A15 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.00 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.38-7.29 (m, 4H), 7.23 (d, J = 1.8 Hz, 2H), 5.34 (s, 2H), 4.95 (s, 1H), 4.83 (d, J = 12.8 Hz, 3H), 4.64 (d, J = 5.8 Hz, 2H), 3.57 (s, 2H), 2.28-1.95 (m, 4H), 1.64 (dq, J = 10.4, 5.9, 5.5 Hz, 2H). A16 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.06 (s, 1H), 7.61-7.44 (m, 4H), 7.37 (d, J = 7.9 Hz, 2H), 7.29 (s, 2H), 5.92 (t, J = 7.7 Hz, 1H), 5.34 (s, 2H), 5.07 (s, 1H), 4.68 (d, J = 5.8 Hz, 2H), 3.64 (s, 3H), 3.59 (s, 2H), 3.32 (qd, J = 15.6, 7.7 Hz, 2H), 2.72 (d, J = 6.5 Hz, 1H), 0.76-0.49 (m, 3H), 0.29 (s, 1H). A17 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.11 (d, J = 1.5 Hz, 1H), 7.50 (q, J = 8.5 Hz, 4H), 7.38 (d, J = 7.9 Hz, 2H), 7.29 (s, 2H), 5.56 (d, J = 11.3 Hz, 1H), 5.34 (s, 2H), 5.06 (s, 1H), 4.69 (d, J = 5.8 Hz, 2H), 3.59 (s, 2H), 3.46 (m, 1H), 2.66-2.52 (m, 1H), 2.34-2.08 (m, 2H), 2.09-1.85 (m, 3H), 1.74 (d, J = 9.7 Hz, 1H), 0.62 (d, J = 6.2 Hz, 1H), 0.53-0.38 (m, 2H), 0.05 (d, J = 10.2 Hz, 1H). A18 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.59 (d, J = 1.5 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.12-7.00 (m, 4H), 4.76 (s, 2H), 4.38 (s, 2H), 3.28 (s, 2H), 2.62 (s, 2H), 0.98-0.84 (m, 1H), 0.35-0.22 (m, 2H), 0.05-0.01 (m, 2H). A19 m/z 448 (M + H) A20 m/z 464 (M + H) A21 m/z 423 (M + H) A22 m/z 469 (M + H) A23 m/z 485 (M + H) A24 m/z 462 (M + H) A25 m/z 448 (M + H) A26 m/z 427 (M + H) A27 m/z 480 (M + H) A28 m/z 427 (M + H) A29 m/z 455 (M + H) A30 m/z 457 (M + H) A31 m/z 517 (M + H) A32 m/z 437 (M + H) A33 m/z 465 (M + H) A34 m/z 473 (M + H) A35 m/z 475 (M + H) A36 m/z 481 (M + H) A37 m/z 509 (M + H) A38 m/z 448 (M + H) A39 m/z 442 (M + H) A40 m/z 417 (M + H) A41 m/z 418 (M + H) A42 m/z 406 (M + H) A43 m/z 453 (M + H) A44 m/z 475 (M + H) A45 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.91 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 5.73 (m, 1H), 5.27-5.16 (m, 1H), 4.85 (s, 2H), 4.79 (t, J = 7.1 Hz, 2H), 4.64 (t, J = 6.8 Hz, 2H), 4.00 (d, J = 6.9 Hz, 2H), 3.93-3.85 (m, 2H), 3.75-3.66 (m, 2H), 3.11 (s, 2H), 2.98 (s, 3H), 1.85-1.75 (m, 2H), 1.74-1.63 (m, 2H). A47 .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 7.83 (s, 1H), 7.71-7.53 (m, 5H), 7.41 (br s, 1H), 7.29-7.13 (m, 4H), 7.08 (m, 1H), 6.83 (br s, 1H), 5.53 (m, 1H), 4.57-4.44 (m, 2H), 3.79 (m, 2H), 3.00- 2.84 (m, 2H), 2.42 (m, 1H), 1.29 (s, 9H), 0.94 (d, J = 6.2 Hz, 3H), 0.62 (m, 1H), 0.49 (m, 2H), 0.07 (m, 1H). A49 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.94 (d, J = 1.5 Hz, 1H), 7.55 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 5.73 (m, 1H), 4.85 (s, 2H), 4.02 (d, J = 6.8 Hz, 2H), 3.91 (ddd, J = 2.9, 9.0, 12.0 Hz, 2H), 3.72 (td, J = 4.5, 12.1 Hz, 2H), 3.15 (s, 2H), 3.01 (s, 3H), 2.88 (dt, J = 2.9, 6.6 Hz, 1H), 1.87-1.79 (m, 2H), 1.76- 1.67 (m, 2H), 0.82-0.69 (m, 4H). A52 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.21 (dd, J = 2.6, 0.6 Hz, 1H), 7.85 (d, J = 1.7 Hz, 1H), 7.78-7.68 (m, 3H), 7.47-7.38 (m, 2H), 7.36-7.23 (m, 4H), 6.54 (dd, J = 2.5, 1.8 Hz, 1H), 4.83 (s, 2H), 4.65 (s, 3H), 4.62 (s, 2H), 3.51 (s, 2H), 3.16 (s, 1.5H), 3.15 (s, 1.5H). NB: peaks at 3.16 ppm and 3.15 ppm are from conformational isomers A53 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.04 (d, J = 1.0 Hz, 1H), 7.40- 7.34 (m, 2H), 7.28 (s, 2H), 7.16 (d, J = 2.4 Hz, 4H), 5.33 (br s, 2H), 5.01 (s, 1H), 4.79 (s, 2H), 4.67 (d, J = 5.9 Hz, 2H), 3.59 (s, 2H), 2.93-2.81 (m, 2H), 1.23 (d, J = 6.8 Hz, 6H), 0.81-0.66 (m, 4H). A54 .sup.1H NMR (300 MHz, DMSO-d6): δ 7.83 (d, J = 1.8 Hz, 1H), 7.59-7.49 (m, 1H), 7.40 (br s, 1H), 7.26-7.09 (m, 6H), 6.84 (d, J = 8.8 Hz, 3H), 4.66 (s, 2H), 4.50 (br d, J = 6.2 Hz, 2H), 3.97 (q, J = 7.0 Hz, 2H), 2.77 (m, 1H), 1.30 (t, J = 7.0 Hz, 3H), 0.78- 0.59 (m, 4H). A55 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.03 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.28 (s, 2H), 7.22 (t, J = 7.8 Hz, 1H), 6.86- 6.77 (m, 3H), 5.39-5.28 (br s, 2H), 5.01 (s, 1H), 4.79 (s, 2H), 4.67 (d, J = 5.4 Hz, 2H), 3.78 (s, 3H), 3.59 (s, 2H), 2.92-2.86 (m, 1H), 0.79-0.70 (m, 4H). A56 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.27 (s, 1H), 7.54 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 3.3 Hz, 1H), 6.82 (d, J = 3.7 Hz, 1H), 5.95 (br s, 1H), 5.14 (s, 2H), 4.63-4.54 (m, 4H), 4.46 (d, J = 6.2 Hz, 2H), 3.59 (s, 2H), 3.07 (dt, J = 3.1, 6.9 Hz, 1H), 1.00-0.85 (m, 4H). A57 m/z 570 (M + H) A58 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.47 (d, J = 2.5 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.77-7.67 (m, 3H), 7.54-7.39 (m, 3H), 7.25- 7.12 (m, 5H), 6.84 (s, 1H), 6.53 (t, J = 2.1 Hz, 1H), 4.80 (s, 2H), 4.51 (d, J = 6.1 Hz, 2H), 3.32 (s, 2H), 3.11 (s, 1.5H), 3.10 (s, 1.5H). NB: Peaks at 3.10 ppm and 3.11 ppm are from conformational isomers A59 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 4.88 (s, 2H), 4.60 (s, 2H), 2.97-2.86 (m, 4H), 0.88-0.65 (m, 4H). A60 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.86 (s, 2H), 4.63 (s, 2H), 2.98-2.87 (m, 1H), 0.87-0.75 (m, 2H), 0.75-0.64 (m, 2H). A61 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.81 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.09-7.01 (m, 1H), 4.82 (s, 2H), 3.18-3.11 (m, 3H), 2.93-2.83 (m, 1H), 2.79-2.72 (m, 2H), 1.76-1.58 (m, 5H), 1.58-1.43 (m, 1H), 1.03-0.78 (m, 4H), 0.78-0.56 (m, 4H). A62 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.81 (d, J = 1.7 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.11-7.02 (m, 1H), 4.83 (s, 2H), 3.21-3.11 (m, 2H), 2.96-2.83 (m, 1H), 2.42 (d, J = 6.4 Hz, 2H), 1.85-1.65 (m, 4H), 1.62-1.43 (m, 2H), 1.08-0.84 (m, 5H), 0.77-0.62 (m, 4H). A63 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.95 (s, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 7.20 (t, J = 6.6 Hz, 1H), 4.98 (br s, 1H), 4.87 (s, 2H), 3.86-3.74 (m, 2H), 3.74-3.62 (m, 2H), 3.42 (d, J = 6.8 Hz, 2H), 3.05 (d, J = 6.8 Hz, 2H), 2.96-2.83 (m, 4H), 1.70-1.59 (m, 2H), 1.53-1.47 (m, 2H), 0.86-0.77 (m, 2H), 0.73 (br s, 2H). A64 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.82 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.34-7.23 (m, 4H), 4.88 (s, 2H), 4.61 (s, 2H), 3.50 (s, 2H), 2.99-2.89 (m, 1H), 0.88-0.66 (m, 4H). A65 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.84 (d, J = 1.7 Hz, 1H), 7.60-7.52 (m, 1H), 7.45-7.30 (m, 3H), 7.27-7.14 (m, 5H), 6.85 (s, 1H), 4.86 (s, 2H), 4.51 (d, J = 6.2 Hz, 2H), 3.32 (s, 2H), 2.48-2.41 (m, 1H), 0.70-0.59 (m, 4H). A66 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.82 (d, J = 1.5 Hz, 1H), 7.44- 7.36 (m, 1H), 7.36-7.19 (m, 7H), 4.88 (s, 2H), 4.62 (s, 2H), 3.50 (s, 2H), 2.95-2.83 (m, 1H), 0.84-0.67 (m, 4H). A67 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.88 (d, J = 1.4 Hz, 1H), 7.35- 7.25 (m, 5H), 7.21-7.13 (m, 2H), 4.93 (s, 2H), 4.63 (s, 2H), 3.51 (s, 2H), 2.42-2.34 (m, 1H), 2.33 (s, 3H), 0.73-0.60 (m, 5H). A68 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.03 (d, J = 1.7 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 5.94 (s, 1H), 5.41 (s, 1H), 5.14 (s, 1H), 4.79 (s, 2H), 4.75-4.65 (m, 2H), 4.00 (t, J = 7.4 Hz, 2H), 3.60 (s, 1.5H), 3.15 (s, 1.5H), 3.13 (s, 1H), 2.27 (s, 3H), 1.82 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H). NB: Peaks at 3.15 ppm and 3.13 ppm are from conformational isomers. A69 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.91 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 7.8 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 5.92 (s, 1H), 5.15 (d, J = 2.9 Hz, 1H), 4.87 (s, 2H), 3.66 (d, J = 11.2 Hz, 2H), 3.49 (d, J = 5.9 Hz, 2H), 3.07 (dt, J = 2.4, 12.0 Hz, 2H), 2.96- 2.88 (m, 1H), 2.79 (s, 3H), 1.80 (d, J = 11.7 Hz, 2H), 1.62 (dt, J = 4.9, 12.7 Hz, 2H), 0.85-0.71 (m, 4H). A72 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.77 (d, J = 1.4 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 3.57 (s, 2H), 3.25 (s, 2H), 3.18-3.08 (m, 2H), 3.08-2.94 (m, 2H), 2.89-2.77 (m, 1H), 2.37 (s, 2H), 2.10-1.91 (m, 4H), 0.84-0.75 (m, 1H), 0.75- 0.56 (m, 4H). A73 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.02 (s, 1H), 7.59-7.53 (m, 2H), 7.50-7.43 (m, 2H), 5.62 (q, J = 7.3 Hz, 2H), 4.87 (s, 1H), 3.84 (d, J = 11.7 Hz, 2H), 3.43 (t, J = 6.4 Hz, 2H), 2.78 (s, 3H), 2.73- 2.60 (m, 3H), 1.90 (d, J = 11.7 Hz, 2H), 1.78 (d, J = 6.8 Hz, 3H), 1.47-1.32 (m, 2H), 0.75-0.64 (m, 1H), 0.63-0.48 (m, 2H), 0.25 (m, 1H). A74 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.04 (s, 1H), 7.59-7.52 (m, 2H), 7.50-7.43 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.25-7.20 (m, 2H), 5.64 (m, 1H), 4.70 (s, 2H), 2.71 (m, 1H), 1.79 (d, J = 7.0 Hz, 3H), 0.69 (m, 1H), 0.60 (m, 2H), 0.27 (m, 1H). A75 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.98 (s, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 5.00 (br s, 1H), 4.86 (s, 2H), 4.49 (s, 1H), 4.33 (s, 1H), 3.88-3.76 (m, 2H), 3.76-3.64 (m, 4H), 2.88 (m, 1H), 1.59 (m, 4H), 0.85-0.67 (m, 4H). A76 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.84 (d, J = 1.6 Hz, 1H), 7.72- 7.55 (m, 6H), 7.45 (d, J = 8.1 Hz, 2H), 4.90 (s, 2H), 4.72 (s, 2H), 2.99-2.89 (m, 1H), 2.80 (s, 3H), 0.86-0.67 (m, 4H). A77 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.85 (d, J = 1.7 Hz, 1H), 7.59-7.52 (m, 1H), 7.52-7.47 (m, 2H), 7.42 (s, 1H), 7.35 (dd, J = 8.8, 7.2 Hz, 1H), 7.25-7.15 (m, 4H), 6.85 (s, 1H), 4.94 (s, 2H), 4.51 (d, J = 6.1 Hz, 2H), 3.31 (s, 2H), 2.42-2.31 (m, 1H), 0.71-0.63 (m, 2H), 0.63-0.53 (m, 2H). A78 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.58 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 1.5 Hz, 1H), 7.69 (dd, J = 2.2, 8.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 7.24-7.23 (m, 1H), 7.24 (br s, 1H), 7.17 (br s, 1H), 5.33 (br s, 1H), 5.10 (s, 1H), 4.87 (s, 2H), 4.71 (d, J = 6.4 Hz, 2H), 3.74 (s, 2H), 2.90 (dt, J = 2.9, 6.8 Hz, 1H), 0.83-0.75 (m, 2H), 0.71 (d, J = 2.9 Hz, 2H). A79 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 7.93 (s, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 5.14 (m, 1H), 4.90 (s, 2H), 3.89-3.68 (m, 4H), 3.50 (d, J = 7.0 Hz, 2H), 2.94 (tt, J = 3.5, 6.7 Hz, 1H), 2.54 (s, 2H), 1.66-1.48 (m, 4H), 0.89-0.72 (m, 4H). A80 .sup.1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J = 4.4 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.44 (br d, J = 7.8 Hz, 2H), 7.15 (s, 1H), 4.84 (s, 2H), 3.66-3.53 (m, 4H), 3.50 (d, J = 6.4 Hz, 2H), 2.97-2.86 (m, 1H), 2.59 (d, J = 4.9 Hz, 3H), 2.24 (s, 2H), 1.41 (m, 4H), 0.78-0.64 (m, 4H). A81 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.33-7.21 (m, 6H), 4.57 (s, 2H), 3.49 (s, 2H), 3.21 (s, 3H), 1.61-1.42 (m, 4H). A82 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.83 (d, J = 1.5 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.51-7.42 (m, 4H), 7.38 (d, J = 8.4 Hz, 2H), 4.89 (s, 2H), 4.64 (s, 2H), 2.98-2.87 (m, 1H), 1.77 (s, 3H), 0.87-0.67 (m, 4H). A83 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.66 (s, 1H), 8.00 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.40- 7.33 (m, 2H), 7.28 (s, 2H), 5.43-5.29 (br s, 2H), 5.08 (d, J = 2.9 Hz, 1H), 4.89 (s, 2H), 4.68 (d, J = 5.9 Hz, 2H), 3.59 (s, 2H), 2.90 (tdd, J = 3.5, 6.8, 10.1 Hz, 1H), 0.86-0.78 (m, 2H), 0.72 (br s, 2H). A84 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.91-7.83 (m, 3H), 7.63 (d, J = 8.1 Hz, 2H), 7.53-7.41 (m, 4H), 4.88 (s, 2H), 4.72 (s, 2H), 2.99-2.87 (m, 1H), 0.88-0.69 (m, 4H). A85 .sup.1H NMR (300 MHz, DMSO-d6): δ 8.89 (s, 1H), 8.16-8.06 (m, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.59 (m, 1H), 7.50-7.33 (m, 1H), 7.50-7.33 (m, 1H), 7.20 (q, J = 8.1 Hz, 4H), 6.82 (s, 1H), 4.92 (s, 2H), 4.50 (d, J = 5.9 Hz, 2H), 3.05 (m, 2H), 0.72 (m, 4H). A88 m/z 497 (M + H) A89 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.74 (d, J = 2.0 Hz, 1H), 8.11- 8.02 (m, 1H), 8.00-7.94 (m, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 7.8 Hz, 2H), 5.23 (br s, 1H), 4.88 (s, 2H), 4.81 (d, J = 6.4 Hz, 2H), 3.22 (s, 3H), 2.91 (dt, J = 2.9, 6.8 Hz, 1H), 0.84- 0.70 (m, 4H). A90 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.86 (s, 1H), 7.35-7.22 (m, 4H), 5.74 (s, 1H), 4.77 (s, 2H), 4.62 (s, 3H), 4.54-4.40 (m, 1H), 3.50 (s, 2H), 2.85-2.73 (m, 1H), 1.95-1.82 (m, 1H), 1.38 (s, 3H), 1.36 (s, 3H), 0.94-0.76 (m, 4H), 0.76-0.66 (m, 2H), 0.66- 0.56 (m, 2H). A91 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.62 (t, J = 53.1 Hz, 1H), 4.87 (s, 2H), 4.61 (s, 2H), 2.97-2.86 (m, 1H), 0.86-0.66 (m, 4H). A92 m/z 453 (M + H) A93 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.64 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 1.5 Hz, 1H), 7.73 (dd, J = 2.2, 8.1 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.41-7.31 (m, 2H), 7.28 (s, 2H), 5.39 (br s, 2H), 5.10 (d, J = 2.4 Hz, 1H), 4.88 (s, 2H), 4.67 (d, J = 5.9 Hz, 2H), 3.58 (s, 2H), 2.92 (qt, J = 3.5, 6.8 Hz, 1H), 0.87-0.78 (m, 2H), 0.71 (br d, J = 1.5 Hz, 2H). A95 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.82 (s, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.22-6.96 (m, 2H), 6.64 (s, 1H), 4.83 (s, 2H), 3.44-3.35 (m, 1H), 3.31-3.23 (m, 2H), 2.94- 2.82 (m, 1H), 2.36 (h, J = 8.4 Hz, 1H), 2.22-2.00 (m, 3H), 1.91- 1.64 (m, 2H), 1.47-1.27 (m, 1H), 0.78-0.61 (m, 4H). A96 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.82 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 7.17-7.00 (m, 2H), 6.66 (s, 1H), 4.83 (s, 2H), 3.43-3.38 (m, 1H), 3.31-3.24 (m, 2H), 2.97-2.83 (m, 1H), 2.46-2.31 (m, 1H), 2.16-1.97 (m, 2H), 1.90-1.74 (m, 2H), 0.78-0.61 (m, 4H). A97 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.46 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 1.5 Hz, 1H), 7.51 (dd, J = 2.2, 8.0 Hz, 1H), 7.42-7.33 (m, 2H), 7.28 (s, 2H), 7.10 (d, J = 8.0 Hz, 1H), 5.33 (br s, 2H), 5.03 (m, 1H), 4.79 (s, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.59 (s, 2H), 3.04 (td, J = 6.9, 13.9 Hz, 1H), 2.84 (dt, J = 3.1, 6.7 Hz, 1H), 1.29 (d, J = 6.9 Hz, 6H), 0.85-0.69 (m, 4H). A98 .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 8.88 (s, 2H), 7.74 (s, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.17-7.07 (m, 4H), 6.77 (s, 1H), 4.79 (s, 2H), 4.44 (d, J = 6.1 Hz, 2H), 3.25 (s, 2H), 3.00-2.90 (m, 1H), 0.72-0.65 (m, 4H). A99 .sup.1H NMR (300 MHz, DMSO-d6): δ 8.23-8.09 (m, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H), 7.67 (br s, 1H), 7.42 (br s, 1H), 7.20 (q, J = 8.1 Hz, 4H), 6.85 (s, 1H), 5.13 (s, 2H), 4.51 (d, J = 5.9 Hz, 2H), 3.32 (s, 2H), 3.11 (d, J = 2.6 Hz, 1H), 0.75 (d, J = 5.1 Hz, 4H). A100 .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.16 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 5.01 (s, 2H), 3.11-3.00 (m, 1H), 2.86 (s, 3H), 2.86-2.80 (m, 4H), 2.76-2.62 (m, 1H), 2.10- 1.97 (m, 2H), 1.93-1.76 (m, 3H), 0.94-0.84 (m, 2H), 0.84-0.76 (m, 2H). A101 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.05 (d, J = 1.6 Hz, 1H), 7.64- 7.20 (m, 8H), 5.42 (s, 1H), 5.14 (s, 1H), 4.88 (s, 2H), 4.70 (d, J = 5.7 Hz, 2H), 3.60 (s, 2H), 2.98-2.82 (m, 1H), 0.91-0.64 (m, 4H). A102 .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.05 (d, J = 1.6 Hz, 1H), 7.42- 7.35 (m, 2H), 7.35-7.25 (m, 3H), 7.23-7.17 (m, 1H), 7.16-7.08 (m, 2H), 5.42 (s, 2H), 5.16 (s, 1H), 4.84 (s, 2H), 4.70 (d, J = 5.7 Hz, 2H), 3.60 (s, 2H), 2.96-2.82 (m, 1H), 0.88-0.66 (m, 4H). A103 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.70 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.85-7.80 (m, 2H), 7.70-7.62 (m, 1H), 7.42 (s, 1H), 7.20 (q, J = 8.2 Hz, 4H), 6.84 (s, 1H), 5.48 (q, J = 7.0 Hz, 1H), 4.55-4.47 (m, 2H), 3.30 (s, 2H), 2.87-2.77 (m, 1H), 1.78 (d, J = 7.1 Hz, 3H), 0.74-0.55 (m, 3H), 0.24-0.11 (m, 1H). A104 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.90 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.70-7.36 (m, 3H), 7.20 (q, J = 8.2 Hz, 4H), 6.84 (s, 1H), 5.46 (q, J = 7.0 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.30 (s, 2H), 2.95-2.81 (m, 1H), 1.78 (d, J = 7.1 Hz, 3H), 0.76-0.55 (m, 3H), 0.27 (d, J = 8.8 Hz, 1H). A105 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.66 (s, 1H), 8.00 (s, 1H), 7.77 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.24 (s, 2H), 6.85 (s, 1H), 6.46-6.09 (m, 1H), 5.12 (s, 1H), 4.90 (s, 2H), 4.68 (d, J = 5.9 Hz, 2H), 2.91 (d, J = 2.9 Hz, 1H), 0.88-0.68 (m, 4H). A106 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.81 (s, 1H), 7.97 (d, J = 1.5 Hz, 1H), 7.84 (dd, J = 2.0, 8.3 Hz, 1H), 7.39-7.29 (m, 3H), 7.24 (s, 2H), 6.68 (br s, 1H), 6.44-6.11 (m, 1H), 5.08 (s, 1H), 4.99 (s, 2H), 4.68 (d, J = 5.9 Hz, 2H), 3.07 (dt, J = 2.9, 6.8 Hz, 1H), 0.85-0.71 (m, 4H). A107 .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.99 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.47-7.30 (m, 4H), 7.22 (q, J = 8.2 Hz, 4H), 6.83 (s, 1H), 5.98 (s, 1H), 4.86 (s, 2H), 4.41 (d, J = 6.0 Hz, 2H), 3.30 (s, 2H), 2.44-2.34 (m, 1H), 0.82-0.71 (m, 2H), 0.63-0.52 (m, 2H). A108 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.81 (s, 1H), 8.73 (s, 1H), 8.08- 8.03 (m, 1H), 7.99-7.92 (m, 2H), 7.84 (dd, J = 2.0, 8.3 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 5.25 (br s, 1H), 5.00 (s, 2H), 4.81 (d, J = 6.4 Hz, 2H), 3.22 (s, 3H), 3.13-3.03 (m, 1H), 0.85-0.71 (m, 4H). A109 .sup.1H NMR (300 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.13 (s, 1H), 7.85 (s, 1H), 7.73-7.54 (m, 4H), 7.43 (d, J = 8.1 Hz, 2H), 4.85 (s, 2H), 4.52 (d, J = 5.9 Hz, 2H), 3.35 (s, 3H), 2.91 (m, 1H), 0.76-0.65 (m, 4H). A110 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.73 (s, 1H), 8.66 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.99-7.92 (m, 2H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 5.35-5.25 (m, 1H), 4.90 (s, 2H), 4.81 (d, J = 6.4 Hz, 2H), 3.22 (s, 3H), 2.98-2.89 (m, 1H), 0.89-0.82 (m, 2H), 0.77-0.71 (m, 2H). A111 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 9.16 (s, 1H), 8.66 (s, 2H), 7.99 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.14 (m, 1H), 4.87 (s, 2H), 4.64 (d, J = 5.8 Hz, 2H), 3.45 (s, 3H), 2.89 (m, 1H), 0.83-0.67 (m, 4H). A112 .sup.1H NMR (300 MHz, CDCl.sub.3): δ 8.66 (s, 1H), 8.57 (s, 1H), 7.99 (d, J = 1.5 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 2.2, 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.24 (s, 1H), 7.20-7.11 (m, 1H), 5.45-5.28 (m, 1H), 5.17-5.08 (m, 1H), 4.90 (s, 2H), 4.70 (d, J = 6.2 Hz, 3H), 3.74 (s, 2H), 2.96-2.86 (m, 1H), 0.88- 0.80 (m, 2H), 0.76-0.69 (m, 2H). A113 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.81 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.69 (dd, J = 2.4, 7.8 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.24 (s, 1H), 7.19-7.12 (m, 1H), 5.34 (br s, 1H), 5.16-5.06 (m, 1H), 4.99 (s, 2H), 4.70 (d, J = 5.9 Hz, 2H), 3.74 (s, 2H), 3.12-3.02 (m, 1H), 0.85-0.70 (m, 4H). A114 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.11 (d, J = 2.0 Hz, 1H), 8.66 (s, 1H), 8.20 (dd, J = 2.4, 8.3 Hz, 1H), 7.97 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 5.91 (br s, 1H), 4.94-4.85 (m, 4H), 3.11 (s, 3H), 2.98-2.90 (m, 1H), 0.91-0.81 (m, 2H), 0.78-0.71 (m, 2H). A115 .sup.1H NMR (400 MHz, CDCl.sub.3): δ 9.11 (s, 1H), 8.81 (s, 1H), 8.19 (dd, J = 2.4, 8.3 Hz, 1H), 7.95 (s, 1H), 7.84 (dd, J = 2.2, 8.1 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 5.89 (br s, 1H), 5 A118 m/z 430 (M + H) A119 m/z 410 (M + H) A120 m/z 460 (M + H) A121 m/z 430 (M + H) A122 m/z 464 (M + H) A123 m/z 438 (M + H) A124 m/z 446 (M + H) A125 m/z 464 (M + H) A126 m/z 448 (M + H) A127 m/z 483 (M + H) A128 m/z 444 (M + H) A129 m/z 441 (M + H) A130 m/z 489 (M + H) A131 m/z 457 (M + H) A132 m/z 468 (M + H) A133 m/z 526 (M + H) A134 m/z 469 (M + H) A135 m/z 426 (M + H) A136 m/z 426 (M + H) A137 m/z 429 (M + H) A138 m/z 408 (M + H) A139 m/z 440 (M + H) A140 m/z 461 (M + H) A141 m/z 397 (M + H) A142 m/z 542 (M + H) A143 m/z 474 (M + H) A144 m/z 481 (M + H) A145 m/z 452 (M + H) A147 m/z 509 (M + H) A148 m/z 454 (M + H) A149 m/z 490 (M + H) A150 m/z 427 (M + H) A151 m/z 553 (M + H) A152 m/z 565 (M + H) A153 m/z 567 (M + H) A154 m/z 540 (M + H) A155 m/z 554 (M + H) A156 m/z 470 (M + H) A157 m/z 433 (M + H) A158 m/z 488 (M + H) A159 m/z 433 (M + H) A160 m/z 474 (M + H) A161 m/z 473 (M + H) A162 m/z 477 (M + H) A163 m/z 431 (M + H) A164 .sup.1H NMR (300 MHz, CDCl3) δ = 8.42 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.1 Hz, 2H), 7.32-7.27 (m, 4H), 6.91 (d, J = 3.3 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), 5.46 (s, 2H), 5.41- 5.20 (m, 3H), 4.86 (d, J = 5.5 Hz, 2H), 3.59 (s, 2H) A165 m/z 528 (M + H) A166 m/z 489 (M + H) A167 m/z 492 (M + H) A168 m/z 490 (M + H) A169 m/z 514 (M + H) A170 m/z 475 (M + H) A171 m/z 528 (M + H) A172 m/z 500 (M + H) A173 m/z 475 (M + H) A174 m/z 500 (M + H) A175 m/z 514 (M + H) A176 m/z 475 (M + H) A177 m/z 475 (M + H) A178 m/z 475 (M + H) A179 m/z 457 (M + H) A180 m/z 494 (M + H) A181 m/z 503 (M + H) A182 m/z 475 (M + H) A183 m/z 469 (M + H) A184 m/z 483 (M + H) A185 m/z 497 (M + H)

(76) Biological Evaluation

(77) The activity of the compounds was evaluated using a Fluorescence Polarization (FP) Assay and, RORγ Reporter assay (also referred to as Gal4 assay). The FP assay is an in vitro assay monitoring binding within the ligand binding pocket. The RORγ and the Th17 assays (another suitable assay) are both cell-based assays monitoring functional activity of the compound assayed.

(78) Compounds disclosed herein have also been evaluated in two different mouse in vivo disease models: Experimental Autoimmune Encephalomyelitis (EAE) model (an animal model for multiple sclerosis), and Collagen-induced Arthritis (CIA) model (an animal model for rheumatoid arthritis).

(79) Fluorescence Polarization (FP) Assay

(80) A buffer containing 10 mM Hepes, 150 mM NaCl, 1 mM DTT, 0.05% Pluronic F-127 detergent (all from Sigma), and 100 nM human RORγt (Ligand Binding Domain obtained from Crelux (Planegg, Germany), batch no PC5032-1) was complemented with 1 μl test compounds diluted in 100% DMSO. The total volume was 25 μl, in a black Perkin Elmer OptiPlate. As negative control, 1 μl DMSO was used. Samples were incubated at room temperature for 30 min, followed by addition 5 μl of probe diluted in assay buffer to a concentration of 125 nM (final concentration of probe is 25 nM). The probe is a fluorescently labeled (TAMRA) RORγt ligand identified by Nuevolution with a total molecular weight of 910 g/mole as shown in Graph A in FIG. 1. Graph (B) in FIG. 2 shows the polarization signal rises with increasing concentration of human RORγt (LBD), using 50 nM TAMRA-labelled probe concentration. Graph (C) of FIG. 2 shows the RORγt inhibitor SR2211 (1,1,1,3,3,3-hexafluoro-2-(2-fluoro-4′-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)propan-2-ol; see Kumar et al, ACS Chem. Biol., 2012, 7 (4), pp 672-677) inhibits the probe from binding RORγt with an IC50 of 0.36 μM, which is close to the value reported in the literature. The plate was incubated for 10 min at room temperature and fluorescence polarization was read using an Envision 2102 plate reader (Perkin Elmer) with the TAMRA FP optical module installed.

(81) Th17 Assay (Another Suitable Assay)

(82) Human peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of healthy human volunteers using the Ficoll paque PLUS kit (GE Healthcare, cat no 17-1440-02), as instructed by the manufacturer. Naive CD4+ T cells were isolated with Naive CD4+ T cell kit, human (Milteny Biotec, cat no 130-094-131). The following modifications were made to the manufacturer's protocol: 1) Incubation with Biotin-Antibody Cocktail and Anti-Biotin MicroBeads was prolonged to 30 minutes, and 2) Cells were washed with 40 mL of Miltenyi buffer. Differentiation of Th17 cells in anti-CD3 (BD Pharmingen, 5 μg/ml) coated 96-well plates (400,000 cells/well, 160 μl RPMI 1640+10% Fetal Bovine Serum) containing 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2.5 ng/ml TGFβ-1 (R&D Systems), 20 ng/ml IL-10 (R&D Systems), 20 ng/ml IL-6 (R&D Systems), 30 ng/ml IL-23 (R&D Systems), 2.5 μg/ml anti-IL-4 (R&D Systems) and 1 μg/ml anti-IFNγ (R&D Systems) and with test compound during the entire differentiation (or vehicle, 0.1% DMSO for control). Test compounds were tested in triplicates, diluted 1000-fold in medium (final DMSO concentration is 0.1%). Incubated for seven days at 37° C., 5% CO.sub.2, 95% humidity, and 2-fluoro-4′-[[4-(4-pyridinylmethyl)-1-piperazinyl]methyl]-α,α-bis(trifluoromethyl)-[1,1′-biphenyl]-4-methanol (SR2211 Calbiochem, Cat. No. 557353) was used as positive control. As negative control, cells were differentiated into Th0 using 5 μg/ml anti-CD28 (BD Pharmingen), 10 ng/ml IL-2 (R&D Systems), 2 μg/ml anti-IL4 (R&D Systems) and 2 μg/ml anti-IFNγ (R&D Systems) are negative control. IL-17 levels in supernatants were measured with ELISA (R&D Systems).

(83) RORγ Reporter Assay (Gal4)

(84) Cell-based RORγ functional assays were performed using a commercially available assay product (INDIGO Biosciences, State College, Pa., USA; product #IB04001). The RORγ reporter cells are HEK293t cells transfected with one vector that provides high level constitutive expression of a hybrid protein comprised of the yeast Gal4-DNA binding domain fused to the ligand binding domain of human RORγ, and a second vector comprising the firefly luciferase cDNA functionally linked to the upstream activation sequence (UAS) of yeast Gal4. A suspension of RORγ Reporter Cells was prepared using the protocol and culture medium provided in the kit product, and 100 μl of the Reporter Cell suspension was then dispensed into wells of a white, collagen-treated, 96-well assay plate. Concentrated stocks of test compounds were prepared in DMSO, then further diluted using media provided in the kit to generate ‘2×-concentration’ treatment media. 100 μl of medium for each respective treatment concentration dispensed into triplicate assay wells, thereby combining with the reporter cells. All media formulations contained 10% charcoal stripped Fetal Bovine Serum, but are otherwise proprietary to INDIGO Biosciences. Final treatment concentrations for each test compound were 1,000 nM and 100 nM, each with 0.1% residual DMSO. Separate control treatments were media supplemented with vehicle only (0.1% DMSO) to determine the constitutive level of RORγ activity in the reporter cells, and the reference inverse-agonist ursolic acid (f.c. 6,000 nM to 8.2 nM in 3-fold decrements) to establish a positive control inverse-agonist dose response. Assay plates were placed in a 37° C., 5% CO.sub.2, 85% humidity incubator for 24 hour. Treatment media were then discarded, 100 μl of luciferase detection reagent was added to each well, and relative light units (RLUs) were quantified from each assay well using a plate reading luminometer. Values of average RLU+/−standard deviation were computed for all treatment sets, followed by the calculations of fold-reduction: [Average RLU.sub.Vehicle/Average RLU.sub.Test Cmpd]. Percent-reduction of RORγ activity in response to respective test compound treatments was calculated: [100*(1−[Ave RLU.sub.Test Cmpd/Ave RLU.sub.Vehicle)] where the theoretical minimum reduction (0% reduction) derives from Vehicle treatment only, no treatment compound. In some aspects it may be of interest to provide compounds with selective modulation of RORγ for example compounds that are selective to RORγ over RORα, compounds that are selective for RORγ versus RORβ, and compounds that are selective for RORγ versus BOTH RORα and RORβ. It may also be of interest to provide compounds that are selective for RORγ versus further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that selectivity against other nuclear receptors may also be of interest. It may for example be of interest to provide compounds that modulate RORγ and one or more further nuclear hormone receptors, as well as compounds that modulate both RORγ and RORα, or RORγ and RORβ. It may also be of interest to provide compounds that modulate RORγ and BOTH RORα and RORβ, as well as compounds that modulate both RORγ and one or more further nuclear hormone receptors such as CAR1, FXR, GR, LXRα, LXRβ, PPARα, PXR, RARα, RXRα, TRα, VDR. It is apparent to those skilled in the art that these nuclear hormone receptors are merely examples, and that modulation of even other nuclear receptors may also be of interest. By substituting the ligand binding domain of another nuclear hormone receptor for the ligand binding domain of RORγ, the reporter assay (Gal4) may be modified to provide activity data for compounds against said other nuclear hormone receptor. Those skilled in the art know how to accomplish such modification. By comparing activity against RORγ to activity against another nuclear hormone receptor in this assay, the selectivity of a compound towards RORγ versus said other nuclear hormone receptor can be established. A compound may be said to be selective for RORγ versus another nuclear hormone receptor if the activity of the compound against RORγ is greater than 5, 10, 20, or 100 fold higher for RORγ than for said other nuclear receptor. The compound(s) or pharmaceutical composition(s) described herein may modulate the activity of an RORγ receptor to a larger extent than it modulates the activity of RORα and/or RORP receptors.

(85) The results of the Fluorescence Polarization (FP) Assay, and RORγ Reporter (Gal4) Assay are shown in Tables 2-4 below.

(86) TABLE-US-00007 TABLE 2 Activity Data of Example Compounds obtained from the Fluorescence Polarization (FP) Assay. Example. No. FP activity range (nM) T1 <500 x <500 I1 <500 A1 <1000 A2 <500 A3 <500 A4 <2000 A5 <1000 A6 <500 A7 <500 A8 <500 A9 <500 A11 <500 A12 <1000 A13 <500 A14 <500 A15 <500 A16 <500 A17 <2000 A18 <500 A19 <500 A20 <2000 A21 <1000 A22 <500 A23 <500 A24 <500 A25 <500 A26 <500 A27 <1000 A28 <1000 A29 <500 A30 <500 A31 <500 A32 <500 A33 <500 A34 <500 A35 <500 A36 <500 A37 <500 A38 <500 A39 <500 A40 <1000 A41 <500 A42 <500 A43 <1000 A44 <500 A45 <2000 A47 <10000 A49 <500 A52 <500 A53 <500 A54 <500 A55 <500 A56 <500 A57 <500 A58 <500 A59 <500 A60 <500 A61 <500 A62 <500 A63 <500 A64 <500 A65 <500 A66 <500 A67 <500 A68 <500 A69 <500 A72 <10000 A73 <500 A74 <500 A75 <500 A76 <500 A77 <500 A78 <500 A79 <1000 A80 <500 A81 <500 A82 <1000 A83 <500 A84 <500 A85 <500 A88 <500 A89 <500 A90 <500 A91 <500 A92 <10000 A93 <2000 A95 <1000 A96 <10000 A97 <500 A98 <500 A99 <10000 A100 <10000 A101 <500 A102 <500 A103 <1000 A104 <1000 A105 <10000 A106 <10000 A107 <1000 A108 <2000 A109 <500 A110 <2000 A111 <1000 A112 <2000 A113 <10000 A114 <500 A115 <500 A118 <500 A119 <2000 A120 <500 A121 <500 A122 <500 A123 <10000 A124 <500 A125 <500 A126 <500 A127 <500 A128 <500 A129 <500 A130 <500 A131 <500 A132 <10000 A133 <2000 A134 <2000 A135 <10000 A136 <2000 A137 <500 A138 <500 A139 <2000 A140 <10000 A141 <2000 A142 <500 A143 <500 A144 <10000 A145 <500 A147 <500 A148 <500 A149 <500 A150 <2000 A151 <1000 A152 <10000 A153 <10000 A154 <2000 A155 <1000 A156 <500 A157 <500 A158 <500 A159 <500 A160 <500 A161 <500 A162 <500 A163 <500 A164 <1000 A165 <500 A166 <10000 A167 <500 A168 <500 A169 <500 A170 <500 A171 <500 A172 <2000 A173 <10000 A174 <500 A175 <500 A176 <500 A177 <2000 A178 <500 A179 <500 A180 <10000 A181 <500 A182 <10000 A183 <2000 A184 <10000 A185 <10000

(87) TABLE-US-00008 TABLE 3 Activity Data of Example Compounds obtained from the RORγ Reporter Assay (Gal4) at 1 μM. Example. Gal4 activity range @ 1 μM No. (% inhibition) T1 >80 x >50 I1 >80 A1 >80 A2 >80 A3 >80 A4 >50 A5 >80 A6 >80 A7 >80 A8 >80 A9 >80 A11 >80 A12 >80 A13 >80 A14 >80 A15 >80 A16 >20 A17 >50 A18 >80 A19 >80 A20 >50 A42 >50 A49 >80 A52 >50 A53 >80 A54 >80 A55 >0 A56 >80 A57 >80 A58 >80 A59 >80 A60 >80 A61 >80 A62 >80 A63 >80 A64 >80 A65 >50 A66 >50 A67 >50 A68 >50 A73 >80 A74 >50 A75 >80 A76 >80 A77 >50 A78 >80 A79 >20 A80 >80 A81 >80 A82 >80 A83 >80 A85 >80 A88 >50 A89 >80 A90 >0 A91 >80 A95 >80 A97 >80 A98 >80 A101 >50 A102 >80 A103 >80 A104 >80 A107 >50 A108 >80 A109 >80 A110 >50 A120 >80 A124 >20 A125 >50 A138 >20 A142 >50 A143 >80 A145 >50 A147 >80 A148 >20 A149 >20 A150 >20 A151 >50 A164 >50 A165 >80 A167 >80 A168 >80 A169 >80 A170 >50 A171 >80 A172 >80 A174 >80 A175 >80 A176 >50 A178 >20 A179 >80 A181 >80

(88) TABLE-US-00009 TABLE 4 Activity Data of Example Compounds obtained from the RORγ Reporter Assay (Gal4) at 0.1 μM. Example. Gal4 activity range @ 0.1 μM No. (% inhibition) T1 >50 x >20 I1 >80 A1 >20 A2 >80 A3 >50 A4 >0 A5 >20 A6 >80 A7 >80 A8 >50 A9 >20 A11 >50 A12 >20 A13 >20 A14 >50 A15 >20 A16 >0 A17 >20 A18 >50 A19 >20 A20 >20 A42 >20 A49 >80 A52 >0 A53 >80 A54 >50 A56 >80 A57 >50 A58 >20 A59 >80 A60 >0 A61 >20 A62 >80 A63 >80 A64 >50 A65 >20 A66 >20 A67 >20 A68 >0 A73 >80 A74 >0 A75 >80 A76 >80 A77 >20 A78 >50 A80 >20 A81 >50 A82 >20 A83 >50 A85 >50 A88 >0 A89 >80 A91 >80 A95 >20 A97 >50 A98 >50 A101 >50 A102 >80 A103 >0 A104 >50 A107 >0 A108 >20 A109 >0 A110 >0 A120 >20 A124 >0 A125 >0 A138 >0 A142 >0 A143 >20 A145 >0 A147 >50 A148 >0 A151 >0 A164 >20 A165 >50 A167 >50 A168 >50 A169 >80 A170 >20 A171 >80 A172 >20 A174 >20 A175 >50 A176 >0 A178 >0 A179 >20 A181 >0

(89) As can be seen from the tables above, the compounds were found to show beneficial activity across the assays.

(90) According to an embodiment, compounds having inhibition values of greater than 80% in the RORγ Reporter Assay (Gal4) are disclosed herein. According to an embodiment the compounds have inhibition values of greater than 80% in a RORγ Reporter Assay (Gal4) and a FP activity range less than 1000 nM, such as less than 500 nM.

(91) According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4). According to an embodiment the compounds have inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4), and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

(92) According to an embodiment the compounds are having inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4). According to an embodiment the compounds have inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4), and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

(93) According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM. According to an embodiment the compounds are having inhibition values of greater than 50% in a RORγ Reporter Assay (Gal4) at 1 μM and inhibition values of greater than 20% in a RORγ Reporter Assay (Gal4) at 0.1 μM, and a FP activity range less than 2000 nM, such as less than 1000 nM, such as less than 500 nM.

Experimental Autoimmune Encephalomyelitis (EAE) Study

(94) EAE is an animal model for multiple sclerosis used to evaluate the efficacy of test compounds. EAE was induced at WuXi AppTec (Shanghai) in female C57BL/6 mice obtained from SLAC Laboratories, Shanghai by injection of 100 μl (100 μg MOG.sub.35-55 peptide in complete Freund's adjuvant containing 200 μg M. tuberculosis/mouse) emulsion (with a 25-G needle) subcutaneously in the shaved back of the mouse. Each mouse was also given 200 ng PTX in 200 μl of PBS by intraperitoneal injection at 0 and 48 hours after immunization. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, and 30 mg/kg, beginning at the day of EAE induction. Treatment lasted for 25 days, and the animals were scored daily for EAE symptoms using the following scoring system: 0, Normal mouse; no overt signs of disease; 1, Limp tail or hind limb weakness but not both; 2 Limp tail and hind limb weakness; 3 Partial hind limb paralysis; 4 Complete hind limb paralysis; 5 Moribund state; death by EAE: sacrifice for humane reasons. The clinical score can be expressed as the mean score for each treatment group+/−S.E.M.

(95) Results: Example A7 was tested in the EAE study at 30 mg/kg. Example A7 was shown to delay onset and significantly lower the clinical score.

(96) Collagen-Induced Arthritis (CIA) Study

(97) Collagen-induced arthritis is an animal model of rheumatoid arthritis used to evaluate the efficacy of test compounds. CIA was induced at Washington Biotechnology Inc. (Baltimore) in male DBA/1J mice (Jackson Laboratories) by subcutaneous injection at the base of the tail with 50 μl of a bovine collagen/complete Freund's adjuvant emulsion. After 21 days, the mice were further boosted by a further subcutaneous injection of 50 μl of a collagen/incomplete Freund's adjuvant emulsion. For treatment, compound or vehicle (2% DMSO, 10% HP-β-CD in MilliQ water) was given orally twice daily at various doses selected from 3, 10, 30 mg/kg, beginning at the day of CIA induction (Prophylactic setting), or after disease initiation (at day 27, therapeutic setting). Treatment lasted until day 41, and the animals were scored three times weekly. Each paw was scored and the sum of all four scores was recorded as the Arthritic Index (AI). The maximum possible AI was 16.0=no visible effects of arthritis; 1=edema and/or erythema of one digit; 2=edema and/or erythema of 2 joints; 3=edema and/or erythema of more than 2 joints; 4=severe arthritis of the entire paw and digits including limb deformation and ankylosis of the joint. The Arthritis Index for each treatment can be expressed as the mean score for each treatment group+/−S.E.M.

(98) Results: Example A7 was tested in the CIA study at 30 mg/kg in therapeutic setting. Example A7 was shown to decrease rate of disease development and significantly reduce disease severity.

(99) In summary, compounds disclosed herein have been found to at least modulate the activity of RORγ. Additionally it has been found that compounds disclosed herein have in vivo usefulness, and could consequently be useful in treating inflammatory, metabolic and autoimmune diseases.