WO2013007768A1 - Tricyclic heterocyclic compounds, compositions and methods of use thereof as jak inhibitors - Google Patents

Abstract

The invention provides novel compounds of formula I having the general formula:(I) wherein R_l s R₂, R₃, X and Y are as described herein. Accordingly, the compounds may be provided in pharmaceutically acceptable compositions and used for the treatment of immunological or hyperproliferative disorders.

Description

TRICYCLIC HETEROCYCLIC COMPOUNDS, COMPOSITIONS AND METHODS

OF USE THEREOF AS JAK INHIBITORS

FIELD OF THE INVENTION

Compounds of formula I, which are inhibitors of a Janus kinase, as well as compositions containing these compounds, and methods of use including, but not limited to, in vitro, in situ and in vivo diagnosis or treatment of mammalian cells. BACKGROUND OF INVENTION

Cytokine pathways mediate a broad range of biological functions, including many aspects of inflammation and immunity. Janus kinases (JAK), including JAK1, JAK2, JAK3 and TYK2 are cytoplasmic protein kinases that associate with type I and type II cytokine receptors and regulate cytokine signal transduction. Cytokine engagement with cognate receptors triggers activation of receptor associated JAKs and this leads to JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately transcriptional activation of specific gene sets (Schindler et al, 2007, J Biol. Chem. 282: 20059-63). JAK1, JAK2 and TYK2 exhibit broad patterns of gene expression, while JAK3 expression is limited to leukocytes. Cytokine receptors are typically functional as heterodimers, and as a result, more than one type of JAK kinase is usually associated with cytokine receptor complexes. The specific JAKs associated with different cytokine receptor complexes have been determined in many cases through genetic studies and corroborated by other experimental evidence.

JAK1 was initially identified in a screen for novel kinases (Wilks A.F., 1989, Proc. Natl. Acad. Sci. U.S.A. 86: 1603-1607). Genetic and biochemical studies have shown that JAK1 is functionally and physically associated with the type I interferon (e.g., IFNalpha), type II interferon (e.g., IFNgamma), IL-2 and IL-6 cytokine receptor complexes (Kisseleva et al, 2002, gene 285: 1-24; Levy et al, 2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al, 2002, Cell, 109 (suppl): S121-S131). JAKl knockout mice die perinatally due to defects in LIF receptor signaling (Kisseleva et al, 2002, gene 285: 1-24; O'Shea et al, 2002, Cell, 109 (suppl): S121- S131). Characterization of tissues derived from JAKl knockout mice demonstrated critical roles for this kinase in the IFN, IL-10, IL-2/IL-4, and IL-6 pathways. A humanized monoclonal antibody targeting the IL-6 pathway (Tocilizumab) was recently approved by the European Commission for the treatment of moderate-to-severe rheumatoid arthritis (Scheinecker et al, 2009, Nat. Rev. Drug Discov. 8:273-274).

Biochemical and genetic studies have shown an association between JAK2 and single- chain (e.g., EPO), IL-3 and interferon gamma cytokine receptor families (Kisseleva et al, 2002, gene 285: 1-24; Levy et al, 2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'Shea et al, 2002, Cell, 109 (suppl): S121-S131). Consistent with this, JAK2 knockout mice die of anemia (O'Shea et al, 2002, Cell, 109 (suppl): S121-S131). Kinase activating mutations in JAK2 (e.g., JAK2 V617F) are associated with myeloproliferative disorders (MPDs) in humans.

JAK3 associates exclusively with the gamma common cytokine receptor chain, which is present in the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 cytokine receptor complexes. JAK3 is critical for lymphoid cell development and proliferation and mutations in JAK3 result in severe combined immunodeficiency (SCID) (O'Shea et al, 2002, Cell, 109 (suppl): S121-S131). Based on its role in regulating lymphocytes, JAK3 and JAK3-mediated pathways have been targeted for immunosuppressive indications (e.g., transplantation rejection and rheumatoid arthritis) (Baslund et al, 2005, Arthritis & Rheumatism 52:2686-2692; Changelian et al, 2003, Science 302: 875-878).

TYK2 associates with the type I interferon (e.g., IFNalpha), IL-6, IL-10, IL-12 and IL-23 cytokine receptor complexes (Kisseleva et al, 2002, gene 285: 1-24; Watford, W.T. & O'Shea, J. J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from a TYK2 deficient human are defective in type I interferon, IL-6, IL-10, IL-12 and IL-23 signaling. A fully human monoclonal antibody targeting the shared p40 subunit of the IL-12 and 11-23 cytokines (Ustekinumab) was recently approved by the European Commission for the treatment of moderate-to-severe plaque psoriasis (Krueger et al, 2007, N. Engl. J. Med. 356:580-92; Reich et al, 2009, Nat. Rev. Drug Discov. 8:355-356). In addition, an antibody targeting the IL-12 and IL-23 pathways underwent clinical trials for treating Crohn's Disease (Mannon et al, 2004, N. Engl. J. Med. 351 :2069-79).

SUMMARY OF INVENTION

One aspect includes a compound of formula I:

stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X, Y, R¹, R² and R³ are defined herein.

Another aspect includes a pharmaceutical composition that includes a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle.

Another aspect includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK1 kinase activity in a patient. The method includes administering to the patient a therapeutically effective amount of a compound of formula I.

Another aspect includes a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in therapy.

Another aspect includes the use of a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease responsive to the inhibition of JAK1 kinase activity.

Another aspect includes a kit for treating a disease or disorder responsive to the inhibition of JAK1 kinase. The kit includes a first pharmaceutical composition comprising a compound of formula I and instructions for use

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

"Acyl" means a carbonyl containing substituent represented by the formula -C(0)-R in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl -substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl (e.g. pyridinoyl).

The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. In one example, the alkyl radical is one to eighteen carbon atoms (Ci-Cis). In other examples, the alkyl radical is Co-C₆, C0-C5, C0-C3, C1-C12, C1-C10, Ci-Cs, Ci- C₆, C1-C5, C1-C4, or C1-C3. Co alkyl refers to a bond. Examples of alkyl groups include methyl (Me, -CH₃), ethyl (Et, -CH₂CH₃), 1 -propyl (n-Pr, n-propyl, -CH₂CH₂CH₃), 2-propyl (i-Pr, i- propyl, -CH(CH₃)₂), 1 -butyl (n-Bu, n-butyl, -CH₂CH₂CH₂CH₃), 2-methyl-l -propyl (i-Bu, i-butyl, -CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, -CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH₃)₃), 1-pentyl (n-pentyl, -CH₂CH₂CH₂CH₂CH₃), 2-pentyl (-CH(CH₃)CH₂CH₂CH₃), 3- pentyl (-CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (- CH(CH₃)CH(CH₃)₂), 3-methyl-l -butyl (-CH₂CH₂CH(CH₃)₂), 2-methyl-l -butyl (- CH₂CH(CH₃)CH₂CH₃), 1-hexyl (-CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (- CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (-CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (- C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (- CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (- CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (- CH(CH₃)C(CH₃)₃, 1 -heptyl and 1 -octyl.

The term "alkenyl" refers to linear or branched- chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. In one example, the alkenyl radical is two to eighteen carbon atoms (C₂-Cis). In other examples, the alkenyl radical is C₂-C₁₂, C₂-C₁₀, C₂-Cs, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethenyl or vinyl (-CH=CH₂), prop-l-enyl (-CH=CHCH₃), prop-2-enyl (- CH₂CH=CH₂), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta-l,3-dienyl, 2- methylbuta-l,3-diene, hex-l-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-l,3-dienyl. The term "alkoxy" refers to a linear or branched monovalent radical represented by the formula -OR in which R is alkyl, alkenyl, alkynyl or cycloalkyl, which can be further optionally substituted as defined herein. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy.

The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. In one example, the alkynyl radical is two to eighteen carbon atoms (C₂-C₁₈). In other examples, the alkynyl radical is C₂-C₁₂, C₂-C₁₀, C₂-Cs, C₂-C₆ or C₂-C₃. Examples include, but are not limited to, ethynyl (-C≡CH), prop-l-ynyl (-C≡CCH₃), prop-2-ynyl (propargyl, -CH₂C≡CH), but-l-ynyl, but-2-ynyl and but-3-ynyl.

"Alkylene" refers to a saturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. In one example, the divalent alkylene group is one to eighteen carbon atoms (Ci-Cis). In other examples, the divalent alkylene group is Co-C₆, C0-C5, C0-C3, C1-C12, C1-C10, Ci-Cs, Ci-C₆, C1-C5, C1-C4, or Ci-C₃. The group Co alkylene refers to a bond. Example alkylene groups include methylene (-CH₂-), 1,1 -ethyl (-CH(CH₃)-), (1,2- ethyl (-CH₂CH₂-), 1,1-propyl (-CH(CH₂CH₃)-), 2,2-propyl (-C(CH₃)₂-), 1,2-propyl (-CH(CH₃)CH₂-), 1,3-propyl (-CH₂CH₂CH₂-), l,l-dimethyleth-l,2-yl (-C(CH₃)₂CH₂-), 1,4-butyl (-CH₂CH₂CH₂CH₂-), and the like.

"Alkenylene" refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. In one example, the alkenylene group is two to eighteen carbon atoms (C₂-Cis). In other examples, the alkenylene group is C₂-C₁₂, C₂- C10, C₂-Cs, C₂-C₆ or C₂-C₃. Example alkenylene groups include: 1,2-ethylene (-CH=CH-).

"Alkynylene" refers to an unsaturated, branched or straight chain hydrocarbon group having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. In one example, the alkynylene radical is two to eighteen carbon atoms (C₂-Cis). In other examples, the alkynylene radical is C₂-C₁₂, C₂- C10, C₂-Cs, C₂-C₆ or C₂-C₃. Example alkynylene radicals include: acetylene (-C≡C-), propargyl (-CH₂C≡C-), and 4-pentynyl (-CH₂CH₂CH₂C≡C-).

"Amidine" means the group -C(NH)-NHR in which R is hydrogen, alkyl, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein. A particular amidine is the group - NH-C(NH)-NH₂.

"Amino" means primary (i.e., -NH₂) , secondary (i.e., -NRH) and tertiary (i.e., -NRR) amines, that are optionally substituted, in which R is alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl-substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein Particular secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylamine, aralkylamine and diaralkylamine wherein the alkyl is as herein defined and optionally substituted. Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine.

"Amino -protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Particular amino protecting groups are Pmb (p- Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy). Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2^nd ed., John Wiley & Sons, Inc., New York, NY, 1991 , chapter 7; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group substituted with one of the above amino -protecting groups.

"Aryl" when used alone, or as part of another term, means a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example inlcudes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1 ,2,3,4- tetrahydronaphthalenyl, lH-indenyl, 2,3-dihydro-lH-indenyl, and the like (see e.g. Lang 's Handbook of Chemistry (Dean, J. A., ed) 13^th ed. Table 7-2 [1985]). A particular aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five, for example 1-2, 1-3 or 1-4 substituents chosen from groups specified herein. In one example, optional substituents on aryl are selected from halogen (F, CI, Br, I), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example Ci-C₆ alkyl), alkoxy (for example Ci-C₆ alkoxy), benzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkylsulfonylamino, alkylsulfonylaminoalkyl, arylsulfonylamino, arylsulfonylaminoalkyl, heterocyclylsulfonylamino, heterocyclylsulfonylaminoalkyl, heterocyclyl, aryl, or other groups specified. One or more methyne (CH) and/or methylene (CH₂) groups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the term "substituted phenyl" include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5- dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4- dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4- nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(lower alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4- (isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4- (isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4- trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4- carboxyphenyl, a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3- chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4- nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino. Particular substituted phenyl groups include the 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3-methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3- ethoxy-4-benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-methoxy-4- (l-chloromethyl)benzyloxy-6-methyl sulfonyl aminophenyl groups. Fused aryl rings may also be substituted with any, for example 1 , 2 or 3, of the substituents specified herein in the same manner as substituted alkyl groups.

The terms "cancer" and "cancerous", "neoplasm", "tumor" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small- cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, as well as head and neck cancer, and associated metastases.

A "chemotherapeutic agent" is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders. Examples of chemotherapeutic agents include NSAIDs; hormones such as glucocorticoids; corticosteroids such as hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate and fluprednidene acetate; immune selective anti-inflammatory peptides (ImSAIDs) such as phenylalanine-glutamine-glycine (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); anti-rheumatic drugs such as azathioprine, ciclosporin (cyclosporine A), D-penicillamine, gold salts, hydroxychloroquine, leflunomide, methotrexate (MTX), minocycline, sulfasalazine, cyclophosphamide, tumor necrosis factor alpha (TNFa) blockers such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), monoclonal antibodies against B cells such as rituximab (RITUXAN®), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/p2 blockers such as Anti-lymphotoxin alpha (LTa); hormone antagonists,

211 131 125 such as tamoxifen, finasteride or LHRH antagonists; radioactive isotopes (e.g., At , 1 , 1 , Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH₃, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSA ®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e. g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; dynemicin, including dynemicin A; an esperamicin; as well as neocarzino statin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin, doxorubicin HC1 liposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®), peglylated liposomal doxorubicin (CAELYX®), and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), an epothilone, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6- azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fioxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoid, e.g., paclitaxel (TAXOL®), albumin- engineered nanoparticle formulation of paclitaxel (ABRAXANE™), and docetaxel (TAXOTERE®); chloranbucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents such as cisp latin, oxalip latin (e.g., ELOXATIN®), and carboplatin; vincas, which prevent tubulin polymerization from forming microtubules, including vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), and vinorelbine (NAVELBINE®); etoposide (VP- 16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as fenretinide, retinoic acid, including bexarotene (TARGRETIN®); bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor (e.g., LURTOTECAN®); rmRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-1 1248 (sunitinib, SUTENT®, Pfizer); perifosine, COX-2 inhibitor (e.g. celecoxib or etoricoxib), proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R1 1577); orafenib, ABT510; Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors (see definition below); farnesyltransferase inhibitors such as lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU and leucovorin. Additional chemotherapeutic agents as defined herein include "anti-hormonal agents" or

"endocrine therapeutics" which act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer. They may be hormones themselves, including, but not limited to: anti-estrogens with mixed agonist/antagonist profile, including, tamoxifen (NOLVADEX®), 4-hydroxytamoxifen, toremifene (FARESTON®), idoxifene, droloxifene, raloxifene (EVISTA®), trioxifene, keoxifene, and selective estrogen receptor modulators (SERMs) such as SERM3; pure anti-estrogens without agonist properties, such as fulvestrant (FASLODEX®), and EM800 (such agents may block estrogen receptor (ER) dimerization, inhibit DNA binding, increase ER turnover, and/or suppress ER levels); aromatase inhibitors, including steroidal aromatase inhibitors such as formestane and exemestane (AROMASIN®), and nonsteroidal aromatase inhibitors such as anastrazole (ARIMIDEX®), letrozole (FEMARA®) and aminoglutethimide, and other aromatase inhibitors include vorozole (RIVISOR®), megestrol acetate (MEGASE®), fadrozole, and 4(5)-imidazoles; lutenizing hormone-releaseing hormone agonists, including leuprolide (LUPRON® and ELIGARD®), goserelin, buserelin, and tripterelin; sex steroids, including progestines such as megestrol acetate and medroxyprogesterone acetate, estrogens such as diethylstilbestrol and premarin, and androgens/retinoids such as fluoxymesterone, all transretionic acid and fenretinide; onapristone; anti-progesterones; estrogen receptor down-regulators (ERDs); anti-androgens such as flutamide, nilutamide and bicalutamide.

Additional chemotherapeutic agents include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idee), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia), and the antibody drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies with therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapineuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab, epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, urtoxazumab, ustekinumab, visilizumab, and the anti-interleukin-12 (ABT- 874/J695, Wyeth Research and Abbott Laboratories) which is a recombinant exclusively human- sequence, full-length IgGi λ antibody genetically modified to recognize interleukin-12 p40 protein.

Chemotherapeutic agents also include "EGFR inhibitors," which refers to compounds that bind to or otherwise interact directly with EGFR and prevent or reduce its signaling activity, and is alternatively referred to as an "EGFR antagonist." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies which bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see, US Patent No. 4,943, 533, Mendelsohn et al.) and variants thereof, such as chimerized 225 (C225 or Cetuximab; ERBUTIX^®) and reshaped human 225 (H225) (see, WO 96/40210, Imclone Systems Inc.); IMC-11F8, a fully human, EGFR-targeted antibody (Imclone); antibodies that bind type II mutant EGFR (US Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in US Patent No. 5,891,996; and human antibodies that bind EGFR, such as ABX-EGF or Panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab) a humanized EGFR antibody directed against EGFR that competes with both EGF and TGF-alpha for EGFR binding (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); fully human antibodies known as El . l, E2.4, E2.5, E6.2, E6.4, E2. l l, E6. 3 and E7.6. 3 and described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29):30375-30384 (2004)). The anti-EGFR antibody may be conjugated with a cytotoxic agent, thus generating an immuno conjugate (see, e.g., EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules such as compounds described in US Patent Nos: 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534, 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6,344,455, 5,760,041, 6,002,008, and 5,747,498, as well as the following PCT publications: W098/14451, WO98/50038, WO99/09016, and WO99/24037. Particular small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA^® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]- 7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD 1839, gefitinib (IRESSAJ) 4-(3'-Chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX- 1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-( 1 -methyl-piperidin-4-yl)-pyrimido [5 ,4-d]pyrimidine- 2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(l-phenylethyl)amino]-lH-pyrrolo[2,3- d]pyrimidin-6-yl] -phenol); (R)-6-(4-hydroxyphenyl)-4-[(l-phenylethyl)amino]-7H-pyrrolo[2,3- d]pyrimidine) ; CL-387785 (N- [4- [(3 -bromophenyl)amino] -6-quinazo linyl] -2-butynamide) ; EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]-4- (dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3- chloro-4- [(3 fluorophenyl)methoxy]phenyl] -6 [5 [ [ [2methylsulfonyl)ethyl] amino]methyl] -2- furanyl] -4-quinazolinamine) . Chemotherapeutic agents also include "tyrosine kinase inhibitors" including the EGFR- targeted drugs noted in the preceding paragraph; small molecule HER2 tyrosine kinase inhibitor such as TAK165 available from Takeda; CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 available from ISIS Pharmaceuticals which inhibit Raf-1 signaling; non-HER targeted TK inhibitors such as imatinib mesylate (GLEEVECJ, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI- 1040 (available from Pharmacia); quinazolines, such as PD 153035,4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5-bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner-Lamber); antisense molecules (e.g. those that bind to HER-encoding nucleic acid); quinoxalines (US Patent No. 5,804,396); tryphostins (US Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affmitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVECJ); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI- 1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-lCl l (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications: US Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

The term "NSAID" and the terms "non-steroidal anti- inflammatory drug" refer to therapeutic agents with analgesic, antipyretic and anti- inflammatory effects. NSAIDs include non-selective inhibitors of the enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin, propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen, acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac, enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam, fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. NSAIDs can be indicated for the symptomatic relief of conditions such as rheumatoid arthritis, osteoarthritis, inflammatory arthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhoea, metastatic bone pain, headache and migraine, postoperative pain, mild-to- moderate pain due to inflammation and tissue injury, pyrexia, ileus, and renal colic.

Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, described herein, as well as combinations of two or more of them. "Cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C₃-C12). In other examples, cycloalkyl is C₃-C8, C₃-Cio or C₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, is C₃-C8, C3-C6 or C5-C6. In another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spiro system, is C₅- C12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclo butyl, cyclopentyl, 1- cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclo hexyl, perdeuteriocyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl, 1 -cyclo hex-3-enyl, cyclo hexadienyl, cyclo heptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

"Carboxy-protecting group" as used herein refers to those groups that are stable to the conditions of subsequent reaction(s) at other positions of the molecule, which may be removed at the appropriate point without disrupting the remainder of the molecule, to give the unprotected carboxy-group. Examples of carboxy protecting groups include, ester groups and heterocyclyl groups. Ester derivatives of the carboxylic acid group may be employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such ester groups include substituted arylalkyl, including substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2',4,4'-tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4- methoxytrityl, 4,4'-dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esters such as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl, 2,2,2- trichloro ethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p- toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, l-(trimethylsilylmethyl)prop- l-en-3-yl, and like moieties. Another example of carboxy-protecting groups are heterocyclyl groups such as 1,3-oxazolinyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2^nd ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy- protecting groups. "Guanidine" means the group -NH-C(NH)-NHR in which R is hydrogen, alkyl, alkoxy, a cycloalkyl, a heterocyclyl, cycloalkyl -substituted alkyl or heterocyclyl-substituted alkyl wherein the alkyl, alkoxy, cycloalkyl and heterocyclyl are as defined herein. A particular guanidine is the group -NH-C(NH)-NH₂. "Hydroxy-protecting group" as used herein refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2^nd ed., John Wiley & Sons, Inc., New York, NY, 1991, chapters 2-3; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected hydroxy" refers to a hydroxy group substituted with one of the above hydroxy- protecting groups.

"Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" alone, and when used as a moiety in a complex group such as a heterocycloalkyl group, are used interchangeably and refer to any mono-, bi-, tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic, ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 3-12 ring atoms and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6- membered monocycles. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g. NO, SO, S0₂), and any nitrogen heteroatom may optionally be quaternized (e.g. [ΝΡ ]⁺0^~, [NPv₄]⁺OFf). Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1 ,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-lH-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1 ,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7- tetrahydrobenzo[d]imidazolyl, 1 ,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8- azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2. ljheptane, azaspiro[3.5]nonanyl, azaspiro [2.5]octanyl, azaspiro [4.5] decanyl, 1 -azaspiro [4.5] decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including l,3,4-thiadiazol-5-yl and 1,2,4- thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl. Example benzo-fused 5- membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and l,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are other example heterocycle groups. Substituents for "optionally substituted heterocycles" include hydroxyl, alkyl, alkoxy, acyl, halogen, mercapto, oxo, carboxyl, halo- substituted alkyl, amino, cyano, nitro, amidino, guanidino.

"Heteroaryl" alone and when used as a moiety in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or, 6- membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry, supra. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups (whether substituted or unsubstituted) include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5-b]pyridazinyl, imidazol[l,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzo thiazolyl, benzo thiadiazolyl, benzo triazolyl, benzoimidazolyl and indolyl. Additional examples of "heteroaryl" groups are: 1 ,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1 ,3-thiazol-2-yl, 4-(carboxymethyl)-5 -methyl- 1,3- thiazol-2-yl sodium salt, l,2,4-thiadiazol-5-yl, 3-methyl-l,2,4-thiadiazol-5-yl, l,3,4-triazol-5-yl, 2-methyl-l,3,4-triazol-5-yl, 2-hydroxy-l,3,4-triazol-5-yl, 2-carboxy-4-methyl-l,3,4-triazol-5-yl sodium salt, 2-carboxy-4-methyl-l,3,4-triazol-5-yl, l,3-oxazol-2-yl, l,3,4-oxadiazol-5-yl, 2- methyl- 1 ,3,4-oxadiazol-5-yl, 2-(hydroxymethyl)- 1 ,3,4-oxadiazol-5-yl, 1 ,2,4-oxadiazol-5-yl, l,3,4-thiadiazol-5-yl, 2-thiol-l,3,4-thiadiazol-5-yl, 2-(methylthio)-l,3,4-thiadiazol-5-yl, 2- amino-l,3,4-thiadiazol-5-yl, lH-tetrazol-5-yl, l-methyl-lH-tetrazol-5-yl, 1-(1- (dimethylamino)eth-2-yl)-lH-tetrazol-5-yl, l-(carboxymethyl)-lH-tetrazol-5-yl, 1-

(carboxymethyl)-lH-tetrazol-5-yl sodium salt, l-(methylsulfonic acid)-lH-tetrazol-5-yl, 1- (methylsulfonic acid)-lH-tetrazol-5-yl sodium salt, 2-methyl-lH-tetrazol-5-yl, l,2,3-triazol-5-yl, 1 -methyl- 1 ,2,3-triazol-5-yl, 2-methyl- 1 ,2,3-triazol-5-yl, 4-methyl- 1 ,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6-hydroxypyridaz-3-yl, l-methylpyrid-2-yl, 1- methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1 ,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, l,4,5,6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy- astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6- hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin- 3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triazin-3-yl, 2,5-dihydro-5-oxo-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-2,6-dimethyl-as-triazin-3-yl, tetrazolo[l,5-b]pyridazin-6-yl and 8-aminotetrazolo[l,5-b]-pyridazin-6-yl. Heteroaryl groups are optionally substituted as described for heterocycles.

In particular embodiments, a heterocyclyl group is attached at a carbon atom of the heterocyclyl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydroiuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way of example, the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2- imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.

"Leaving group" refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (for example /?-toluenesulfonyloxy (tosylate group) and /?-nitrosulfonyloxy (nosylate group)). "Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g. 0, 1, 2, 3 or 4) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In certain embodiments, divalent groups are described generically without specific bonding configurations, for example in the group -CH₂C(0)-. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group R'-R^R³, if the group R² is described as -CH₂C(0)-, then it is understood that this group can be bonded both as R -CH₂C(0)-R³, and as R -C(0)CH₂-R³, unless specified otherwise. "Package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. "Pharmaceutically acceptable salts" include both acid and base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

"Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particularly base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

A "sterile" formulation is aseptic or free from all living microorganisms and their spores. "Stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like. "Chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.

"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water. A "subject," "individual," or "patient" is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as cats, dogs, and horses), primates, mice and rats. In certain embodiments, a mammal is a human.

"Therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of immunological disorders, the therapeutic effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an autoimmune and/or inflammatory disease, or the symptoms of an acute inflammatory reaction (e.g. asthma). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells.

"Treatment" (and variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compounds of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented. The terms "compound(s) of this invention," and "compound(s) of the present invention", unless otherwise indicated, include compounds of formula I and stereoisomers, tautomers, solvates, metabolites, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds of formulas I, II and III, wherein one or more hydrogen atoms are replaced by deuterium or tritium, or one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

INHIBITORS OF JAK1 KINASE

One aspect of the invention provides compounds of formula I:

stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein

X is N or CR⁴; Y is N or CR⁵; R¹ is C3-12 cycloalkyl, or 3-20 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ -C(0)OR^a, -S(0)₂R^a, or Ci_6 alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C_6-14 aryl, or halogen;

R² is absent, Ci_₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, -(Ci_₆ alkylene)-, -(C₂-₆ alkenylene)-, -(C₂-6 alkynylene)-, -(C₀_6 alkylene)CN, -(C_0-3 alkylene)NR^a(C₀_₃ alkylene)-, -(C_0-3 alkylene)0(Co_₃ alkylene)-, -(C0-3 alkylene)C(O)(C₀_₃ alkylene)-, -(C0-3 alkylene)NR^aC(O)(C₀_₃ alkylene)-, -(C₀_₃ alkylene)C(O)NR^a(C₀_₃ alkylene)-, -(C₀_₃ alkylene)C(O)O(C₀_₃ alkylene)-, -(Co-3 alkylene)OC(0)(Co_3 alkylene)-, -(C₀.₃ alkylene)NR^aC(O)NR^b(C₀-₃ alkylene)-, -(C₀.₃ alkylene)OC(0)NR^a(Co_₃ alkylene)-, -(C₀.₃ alkylene)NR^aC(O)O(C₀_₃ alkylene)-, -(C₀.₃ alkylene)S(0)i_₂(Co_₃ alkylene)-, -(C₀-₃ alkylene)NR^aS(O)i_₂(C₀-₃ alkylene)-, -(C₀-₃ alkylene)S(O)i_₂NR^a(C₀-₃ alkylene)- or -(C₀_₃ alkylene)NR^aS(O)i_₂NR^b(C₀-₃ alkylene)-, wherein said alkyl, alkyenyl, alkynyl, alkylene, alkenylene and alkynylene are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen;

R³ is absent, hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, C₃_₇ cycloalkyl, C_6-14 aryl or 3-20 membered heterocyclyl, wherein R³ is independently optionally substituted by R⁶; R⁴ is hydrogen, halogen or Ci_₃ alkyl;

R⁵ is halogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃

alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene) S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C₃_i₂ cycloalkyl, -(C_0-3 alkylene)C6_i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(C_0-3

alkylene)C(0)3-12 membered heterocyclyl, wherein said C₂_i₂ alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(C_{0- 3} alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃

alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen; and wherein said Ci alkyl is independently optionally substituted by halogen, oxo, -(C_0-3

alkylene)CN, -(Ci_₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃

alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d, -OR^k, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen;

R⁶ is independently oxo, halogen, -CN, -C(0)R^a, -C(0)OR^a, -NR^aC(0)R^b, -C(0)NR^aR^b, -NR^aC(0)NR^aR^b, -OC(0)NR^aR^b, -NR^aC(0)OR^b, -S(0)i_₂R^a, -NR^aS(0)₂R^a, -S(0)₂NR^aR^b, -OR^a, -SR^a, -NR^aR^b, Ci_₆ alkyl, C₃_₆ cycloalkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, 3-7 membered heterocycly or C₆-i4 aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₆ alkyl optionally substituted by oxo or halogen; each R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co_₃ alkylene)C₃_6 cycloalkyl, -(Co_₃ alkylene)3-12 membered heterocyclyl, -(Co_₃ alkylene)C(0)3-12 membered heterocyclyl or -(Co_₃ alkylene)C6_i4 aryl, wherein said alkyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₃ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo, halogen, OR^g or NR^gNR^h; each R^c and R^d are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co_₃ alkylene)C₃_6 cycloalkyl, -(Co_₃ alkylene)3-12 membered heterocyclyl, -(Co_₃ alkylene)C(0)3-12 membered heterocyclyl or -(Co_₃ alkylene)C6_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_ ₂NR^gR^h, C₃_6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen; each R^e, R^f, R^g, R^h are independently hydrogen or Ci_₆ alkyl optionally substituted by halogen or oxo; and each R^k is independently hydrogen, C₂_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co_₃ alkylene)C₃_6 cycloalkyl, -(Co_₃ alkylene)3-12 membered heterocyclyl, -(Co_₃ alkylene)C(0)3-12 membered heterocyclyl or -(Co_₃ alkylene)C6_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h,

-NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_ ₂NR^gR^h, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen. In certain embodiments, when R¹ and R² are absent, one of R³, R⁴ and R⁵ is other than hydrogen.

In certain embodiments, R¹, R² and R³ are not absent at the same time.

In certain embodiments, when R² and R³ are absent, R⁵ is other than OH.

In one embodiment, X is CR⁴. In another embodiment, X is N. In one embodiment, Y is CR⁵. In another embodiment, Y is N.

In one embodiment, X is CR⁴ and Y is CR⁵.

In another embodiment, X is CR⁴ and Y is N.

In another embodiment, X is N and Y is CR⁵.

In another embodiment, X is N and Y is N. In one embodiment, R¹ is absent. In one embodiment, R¹ is absent with the proviso that

R¹, R² and R³ are not all absent at the same time.

In one embodiment R¹ is a 3-20 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment R¹ is a 3-12 membered heterocyclyl optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by halogen. In one embodiment R¹ is a 4-7 membered heterocyclyl optionally substituted by halogen, oxo, or Ci_₆ alkyl optionally substituted by halogen, wherein said heterocyclyl is selected from oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, tetrahydrothienyl, 2,3-dihydrothienyl, pyrrolidinyl, 2,3-dihydro-lH-pyrrolyl, imidazolidinyl, 2H- pyranyl, tetrahydropyranyl, morpholinyl, piperazinyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, piperidinyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, oxepanyl and azepanyl. In another embodiment, R¹ is azetidinyl, pyrrolidinyl, imidazolidinyl, morpholinyl, piperazinyl, hexahydropyrimidinyl, or piperidinyl, wherein R¹ is optionally substituted by halogen, oxo, or Ci_₆ alkyl optionally substituted by halogen. In another embodiment, R¹ is 4 , 5 , 6, 7-tetrahydrobenzo imidazo ly 1, 4,5,6 , 7-tetrahydro [2H] indazo ly 1, oxazo lidiny 1, thiazo lidiny 1, isothiazolidinyl, 1 , 1-dioxoisothiazolidinyl, oxazolidinonyl, 3-azabicyclo[3.1.0]hexanyl or imidazo lidinonyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is piperidinyl or tetrahydropyranyl wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment R¹ is a 3-20 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, with the proviso that R⁵ is other than hydrogen or -OH.

In another embodiment, R¹ is a 3-12 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is a 3-12 membered heterocyclyl optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_₆ alkyl, wherein said heterocyclyl is selected from oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, 2,3- dihydrofuranyl, tetrahydrothienyl, 2,3-dihydrothienyl, pyrrolidinyl, 2,3-dihydro-lH-pyrrolyl, imidazo lidiny 1, 2H-pyranyl, tetrahydropyranyl, morpholinyl, piperazinyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, piperidinyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, oxepanyl, azepanyl, 7-oxabicyclo[2.2.1]heptane, octahydro-lH-indolyl, l-azaspiro[4.5]decanyl,

wherein the wav line re resents the point of attachment in formula I. In

embodiment, R¹ represents the point of attachment

formula I. In one embo the wavy line represents the point of attachment in formula I.

In another embodiment, R¹ is azetidinyl, pyrrolidinyl or piperidinyl, optionally substituted by 1 or 2 halogen, oxo, or Ci_₆ alkyl optionally substituted by halogen. In another embodiment, R¹ is azetidinyl, pyrrolidinyl or piperidinyl, optionally substituted by 1 or 2 halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by halogen halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by halogen

In another embodiment, R¹ is morpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octanyl, 8- azabicyclo[3.2.1]octanyl or piperidinyl, optionally substituted by 1 or 2 halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is morpholinyl, piperazinyl, 2-azabicyclo[2.2.2]octanyl, 8- azabicyclo[3.2.1]octanyl or piperidinyl, optionally substituted by 1 or 2 halogen, oxo or Ci_₆ alkyl optionally substituted by halogen.

In another embodiment, R¹ is piperidinyl optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is piperidinyl optionally substituted by 1 or 2 halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_6 alkyl optionally substituted by halogen. In another embodiment, R¹ is piperidinyl optionally substituted by 1 or 2 halogen, oxo or Ci_₆ alkyl. In another embodiment, R¹ is piperidinyl optionally substituted by methyl, oxo, fluoro or methoxy. In another

embodiment, R¹ is piperidin-3-yl, piperidin-4-yl, 2-methylpiperidin-3-yl or 2-methylpiperidin-4- yl. In another embodiment, R¹ is (R)-piperidin-3-yl. In another embodiment, R¹ is (S)- piperidin-3-yl. In another embodiment, R¹ is substituted (R)-piperidin-4-yl, wherein said piperidinyl is substituted by 1-3 groups selected from oxo, Ci_₃ alkyl, halogen or -OR^a. In another embodiment, R¹ is substituted (S)-piperidin-4-yl, wherein said piperidinyl is substituted by 1-3 groups selected from oxo, Ci_₃ alkyl, halogen or -OR^a. In another embodiment, R¹ is (R)- (R)-2-methylpiperidin-4-yl, (R)-(S)-2-methylpiperidin-4-yl, (S)-(R)-2-methylpiperidin-4-yl or (S)-(S)-2-methylpiperidin-4-yl. In another embodiment, R¹ is (R)-(R)-3-fluoropiperidin-4-yl, (R)-(S)-3-fluoropiperidin-4-yl, (S)-(R)-3-fluoropiperidin-4-yl or (S)-(S)-3-fluoropiperidin-4-yl. In another embodiment, R¹ is piperidinonyl, 2-methylpiperidin-4-yl, 3-methylpiperidin-4-yl, 4- methylpiperidin-4-yl, 2-fluoropiperidinyl, 3-fluoropiperidin-4-yl, 3,3-difluoropiperidin-4-yl, 3-

R₂ ^— R₃

I

Ν,, methoxypiperidin-4-yl or , wherein the wavy line represents the point of attachment in formula I.

In another embodiment, R¹ is piperidinyl optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, with the proviso that R⁵ is other than hydrogen or -OH. In another embodiment, R¹ is tetrahydropyranyl optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, with the proviso that R⁵ is other than hydrogen or -OH. In another embodiment, R¹ is tetrahydropyranyl optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, and R² and R³ are both absent, with the proviso that R⁵ is other than hydrogen or -OH.

In another embodiment, R¹ is (R)-pyrrolidin-3-yl. In another embodiment, R¹ is (S)- pyrrolidin-3-yl.

In one embodiment R¹ is a C₄_7 cycloalkyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment R¹ is a C₄-7 cycloalkyl optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by halogen. In one embodiment R¹ is a C₄-7 cycloalkyl optionally substituted by halogen, oxo, or Ci_₆ alkyl optionally substituted by halogen. In one embodiment, said cycloalkyl is cyclopropyl, eye lo butyl, cyclopentyl or cyclohexyl. In one embodiment, R¹ is selected from

represents the point of attachment in formula I. In another embodiment, R¹ is cyclohexyl optionally substituted by halogen, oxo, -CN,

-OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is cyclohexyl optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_6 alkyl optionally substituted by halogen. In another embodiment, R¹ is cyclohexyl optionally substituted by halogen, oxo, or Ci_₆ alkyl optionally substituted by halogen. In another embodiment, R¹ is cyclohexyl. In one embodiment, R¹ is selected from cyclohexyl, 2- hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, bicyclo[2.2.1]heptanyl, 2- methylcyclohexyl or 4,4-difluorocyclohexyl,

wherein R is optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR , or Ci_₆ alkyl optionally substituted by halogen, and wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R¹ is selected from

and R²-R³ is selected from

wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R¹ is selected from r ²-*³ and

_? wherein the wavy line represents the point of attachment in formula I.

In certain embodiments, R² and R³ are absent, and R¹ is selected from

_{? wherein R} ⁱo _is halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, or

Ci_6 alkyl optionally substituted by oxo, -CN or halogen, and wherein the wavy line represents the point of attachment in formula I. In another embodiment of this paragraph, R⁵ is other than hydrogen or -OH. In certain embodiments, R² and R³ are absent, and R¹ is selected from

, wherein R¹⁰ is -OH, -NH(CH₂CF₃), -CN, -CH₂CN, -CH₂CH₂CN or halogen, and wherein the wavy line represents the point of attachment in formula I. In another embodiment of this paragraph, R⁵ is other than hydrogen or -OH. In another embodiment, R¹ is cyclopentyl optionally substituted by halogen, oxo, -CN,

-OR^a, -SR^a, -NR^aR^b, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In another embodiment, R¹ is cyclopentyl optionally substituted by halogen, oxo, -CN, -OR^a, -NR^aR^b, or Ci_6 alkyl optionally substituted by halogen. In another embodiment, R¹ is cyclopentyl.

In one embodiment, R¹ is C₅_6 cycloalkyl or 5-6 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene, -S(0)₂R^a, or Ci_6 alkyl optionally substituted by oxo, -CN or halogen.

In one embodiment, R¹ is cyclohexyl, cyclopentyl, piperidinyl, or tetrahydropyranyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R¹ is selected from:

In one embodiment,-R¹-R²-R³ taken together are selected from:

In one embodiment, R¹ is C₃_8 cycloalkyl, or 4-10 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C₆_i₄ aryl, or halogen.

In one embodiment, R¹ is C₅_6 cycloalkyl or 5-6 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C₆_i₄ aryl, or halogen.

In one embodiment, R¹ is cyclohexyl, cyclopentyl, piperidinyl, or tetrahydropyranyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C_6-14 aryl, or halogen.

In one embodiment, R² is absent. In one embodiment, R² is absent with the proviso that R¹, R² and R³ are not all absent at the same time. In one embodiment, R² and R³ are absent. . In one embodiment, R² and R³ are absent with the proviso that R¹, R² and R³ are not all absent at the same time.

In one embodiment, R² is Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, wherein said alkyl, alkenyl or alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_3 alkyl optionally substituted by halogen, and R³ is absent. In one embodiment, R² is Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, wherein said alkyl, alkenyl or alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen, and R³ is absent. In one embodiment, R² is selected from -CH₂CF₃ -CH₂CH₂CF₃, -

CH₂CH₂F, -C(CH₃)₂OH, -CH₂C(CH₃)₂OH, -CH₂CH₂OH, -CH₂CH₂OCH₃

wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R² is -(Ci_₆ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(Ci_₆ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(Ci_₆ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is methylene, ethylene, -CH(CH₃)-, -C(CH₃)₂-, propylene or butylene, optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d another embodiment, R² is selected from methylene, ethylene,

-C(CH₃)₂- and

in the wavy line represents the point of attachment in formula I. In one embodiment, R² is -(Co-₆ alkylene)CN, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen, and R³ is absent. In one embodiment, R² is -(Ci_₆ alkylene)CN, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen, and R³ is absent. In another embodiment, R² is -CH₂CN, -CH₂CH₂CN, -CH(CH₃)CN or -CH(CH₃)CH₂CN and R³ is absent.

In another embodiment, R¹ is a 3-20 membered heterocyclyl or C₃_i₂ cycloalkyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ alkylene or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, R² is -CN, -CH₂CN, -CH2CH2CN, -CH(CH₃)CN or -CH(CH₃)CH₂CN, and R³ is absent, with the proviso that R⁵ is other than hydrogen or -OH.

In one embodiment, R² is -(C_0-3 alkylene)NR^a(Co-₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C_0-3 alkylene)NR^a(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C_0-3 alkylene)NR^a(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is - H-, -NHCH₂- or -NHCH₂CH₂- In one embodiment, R² is -(C_0-3 alkylene)0(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C_0-3 alkylene)0(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C_0-3 alkylene)0(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is -CH₂0- -CH₂C(CH₂)₂0- or -(CH₂)₂0-

In one embodiment, R² is -(Co_₃ alkylene)NR^aC(0)(Co_₃ alkylene)- or -(Co_₃ alkylene)C(0)NR^a(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C₀_₃ alkylene)NR^aC(O)(C₀_₃ alkylene)- or -(C₀_₃ alkylene)C(O)NR^a(C₀_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(Co_₃ alkylene)NR^aC(0)(Co_₃ alkylene)- or -(C₀_₃ alkylene)C(O)NR^a(C₀_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is -C(0)NH- -CH₂C(0)NH- or -CH₂C(0)N(CH₃)-. In another embodiment, R² is -NHC(O)- or -NHC(0)CH₂-.

In one embodiment R² is -(C_0-3 alkylene)OC(O)NR^a(C₀_₃ alkylene)- or -(C_0-3 alkylene)NR^aC(0)0(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(C0-3 alkylene)OC(O)NR^a(C₀_₃ alkylene)- or -(C₀_₃ alkylene)NR^aC(O)O(C₀_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)OC(0)NR^a(Co-3 alkylene)- or -(C₀_₃ alkylene)NR^aC(O)O(C₀-₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is -NHC(0)0- -N(CH₃)C(0)0-, -NHC(0)OCH₂- or -NHC(0)OCH₂CH₂-.

In one embodiment R² is -(Co_₃ alkylene)C(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)C(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)C(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is selected from:

wherein the wavy lines represent points of attachment.

In one embodiment R² is -(Co_₃ alkylene)C(0)0(Co_₃ alkylene)- or -(Co_₃ alkylene)OC(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co-₃ alkylene)C(0)0(Co_₃ alkylene)- or -(Co_₃ alkylene)OC(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)C(0)0(Co_₃ alkylene)- or -(Co_₃ alkylene)OC(0)(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is selected from -C(0)0-

In one embodiment R² is -(Co_₃ alkylene)S(0)i_₂(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)S(0)i_₂(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment R² is -(Co_₃ alkylene)S(0)i_₂(Co_₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_₃ alkyl. In another embodiment, R² is selected from -C(0)CH₂S(0)2,

wherein the wavy lines represent points of attachment. In one embodiment, R² is -(Co_₃ alkylene)NR^aS(0)i_₂(Co-₃ alkylene)- or -(Co_₃ alkylene)S(0)i_₂NR^a(Co-₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C₀-₃ alkylene)NR^aS(O)i_₂(C₀-₃ alkylene)- or -(C₀_₃ alkylene)S(O)i_₂NR^a(C₀_ 3 alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen. In one embodiment, R² is -(C_0-3 alkylene)NR^aS(0)i_₂(Co_3 alkylene)- or -(C₀-₃ alkylene)S(O)i_₂NR^a(C₀-₃ alkylene)-, wherein said alkylene is optionally substituted by halogen, oxo, -CN or Ci_3 alkyl. In another embodiment, R² is -NHS(0)₂- -N(CH₃)S(0)₂- or -NHS(0)₂CH₂-.

In one embodiment, R² is selected from absent, -NHS(0)₂-, -N(CH₃)S(0)₂- , -NHS(0)₂CH₂- -C(0)CH₂S(0)₂, "C(0)0-, -NHC(0)0-, -N(CH₃)C(0)0-, -NHC(0)OCH₂-, -NHC(0)OCH₂CH₂-, -C(0)NH-, -CH₂C(0)NH-, -CH₂C(0)N(CH₃)-, -NHC(O)-, -NHC(0)CH₂-, -CH₂0-, -CH₂C(CH₂)₂0-, -(CH₂)₂0- -NH-, -NHCH₂-, -NHCH₂CH₂-, -CH₂CN, -CH₂CH₂CN, -CH(CH₃)CN , -CH(CH₃)CH₂CN, methylene, ethylene, -C(CH₃)₂- -CH₂CF₃, -CH₂CH₂CF₃, -CH₂CH₂F, -CH₂C(CH₃)₂OH, -CH₂CH₂OH, - CH₂CH₂OCH₃,

, wherein the wavy line represents the point of attachment in formula

In one embodiment, R² is absent, methylene, ethylene, -CH(CH₃)-, -NH-, - -,

-C(0)0-, -C(0)NH- -NHC(0)0-, -CH₂C(0)N(CH₃)-, -NHS(0)₂

^ ^ , ° , ^'"^ ^v , ^'"^ ^v ^ ,„or ^'""^ ^{^} ^ , wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R 2 is absent, methylene, ethylene,

_? J Ol ₀r

wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R³ is absent.

In one embodiment, R³ is hydrogen.

In one embodiment, -R²-R³ is -CHO.

In one embodiment, R² is absent and R³ is hydrogen.

In one embodiment, R¹ and R² are absent. In one embodiment, R³ is Ci_₆ alkyl optionally substituted by 1 to 3 R⁶. In another embodiment, R³ is Ci_₆ alkyl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, halogen, -CN, -S(0)i_₂(Ci_6 alkyl), -OR^a, -SR^a or -NR^aR^b. In another embodiment, R³ is Ci_₆ alkyl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b. In another embodiment, R³ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl optionally substituted by oxo, Ci_₆ alkyl, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b. In another embodiment, R³ is selected from methyl, ethyl, n-butyl, sec-butyl, t-butyl, -CF₃, -CH₂CF₃, -CH₂CH₂F, -CH₂CH₂CF₃, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH(CH₂CH₃)CH₂OCH₃, -CH(CH₃)CH₂CH₂OH, -CH₂C(CH₃)₂OH, -CH₂C(CF₃)₂OH, -CH₂CH₂OH, -C(CH₃)₂OH, -CH₂CN, -(CH₂)₂CN, -(CH₂)₃CN, -CH(CH₃)CH₂CN, -C(CH₃)₂CN, -CH(CH₃)CN, -CH₂NH₂, -CH(CH₃)N(CH₃)₂ and-CH₂CH₂N(CH₃)₂.

In one embodiment, R³ is C₃_₇ cycloalkyl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is C₃_₇ cycloalkyl optionally substituted by 1 to 3 oxo, halogen, -CN, -S(0)i_ ₂(Ci_6 alkyl), -OR^a, -SR^a, -NR^aR^b or Ci_₆ alkyl optionally substituted by oxo or halogen. In one embodiment, R³ is C₃_₇ cycloalkyl optionally substituted by 1 to 3 oxo, halogen, -CN, -S(0)₂(Ci_6 alkyl), -OR^a, -NR^aR^b or Ci_₆ alkyl optionally substituted by halogen. In another embodiment, R³ is cyclopropyl optionally substituted by 1 to 3 oxo, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a, -NR^aR^b or Ci_₆ alkyl optionally substituted by halogen. In another embodiment, R³ is selected from cyclopropyl, 1-cyanocycloprop-l-yl, 1-trifluoromethylcycloprop-l-yl, 1- methylcycloprop-l-yl, 2-fluorocyclopyrop-l-yl, 2,2-dimethylcycloprop-l-yl, 2- cyanocyclopropyl, eye lo butyl, 4-carboxyclo butyl, 1-cyanocyclobut-l-yl, 4-aminocyclo butyl, cyclopentyl, 3-aminocyclohexyl, 4-aminocyclohexyl, 2-hydroxycyclohexyl, 3- hydroxycyclohexyl, 4-hydroxycyclohexyl and 2-hydroxycyclohexyl.

In one embodiment, R³ is C₆-i4 aryl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is C₆-i4 aryl optionally substituted by 1 to 3 Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)i_₂(Ci_₆ alkyl), -OR^a, -SR^a or -NR^aR^b. In one embodiment, R³ is phenyl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is phenyl optionally substituted by 1 to 3 Ci_6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b. In another embodiment, R³ is phenyl, 2-chloro-4-cyanophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-methylsulfonylphenyl, 3 -fluorophenyl or 4-methoxyphenyl.

In one embodiment, R³ is 5-6 membered heteroaryl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is 5-6 membered heteroaryl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)i_₂(Ci_₆ alkyl), -OR^a, -SR^a or -NR^aR^b. In one embodiment, R³ is 5-6 membered heteroaryl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂-6 alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b. In one embodiment, R³ is pyridinyl, thiazolyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)₂(Ci_6 alkyl), -OR^a or -NR^aR^b. In one embodiment, R³ is selected from pyridinyl, pyridin- 3-yl, 6-cyanopyridinyl, 6-trifluoromethylpyridinyl, 2-cyanopyridin-4-yl, 4-cyanopyridin-2-yl, 5- cyanopyridin-2-yl, 3-fluoropyridin-5-yl, thiazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin- 5-yl, pyrazin-2-yl, oxazol-2-yl, oxazol-4-yl, l-methylpyrazol-5-yl, l-methylpyrazo -

methylimidazo 1-2-yl

\ , wherein the wavy line represents the point of attachment in formula I. In one embodiment, R³ is selected from thiazol-5-yl and isothiazol-5-yl.

In one embodiment, R³ is 3-12 membered heterocyclyl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is 4-7 membered heterocyclyl optionally substituted by 1 to 3 R⁶. In one embodiment, R³ is 4-7 membered heterocyclyl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)i_₂R^a, -C(0)OR^a, -OR^a, -SR^a or -NR^aR^b, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, halogen, -CN, -OR^c or -NR^cR^d In one embodiment, R³ is 4-7 membered heterocyclyl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)₂R^a, -C(0)OR^a, -OR^a or -NR^aR^b, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, halogen, -CN, -OR^c or -NR^cR^d In one embodiment, R³ is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, pyranyl, tetrahydropyranyl, morpholinyl optionally substituted by 1 to 3 oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CN, -S(0)₂R^a, -C(0)OR^a, -OR^a or -NR^aR^b, wherein said alkyl, alkenyl and alkynyl are optionally substituted by oxo, halogen, -CN, -OR^c or -NR^cR^d. In one embodiment, R³ is selected from oxetan-3-yl, piperidin-3-yl, piperidin-4-yl, N-methylpiperidin-2-yl, N-methylmorpholin-2-yl, 1- methylpyrrolidin-2-yl, pyrrolidinyl, pyrrolidinonyl, piperidinonyl, 3,3-difluoropyrrolidin-2-yl, 1- isopropylpyrrolidin-2-yl, 2-methylpyrrolidin-2-yl, l-methylcyanopyrrolidin-2-yl, 1-

cyclobutylpyrrolidin-2-yl, morpholinyl, pyran-4-yl, N-methylpiperazinyl,

,

wherein the wavy line represents the point of attachment in formula I. In one embodiment, R³ is (S)-l-methylpyrrolidin-2-yl. In one embodiment, R³ is selected from N-ethylpiperidin-2-yl, N-

(2-methoxyethyl)piperidin-2-yl, N-methylazepan-2-yl,

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R is absent, hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopropyl, phenyl, pyridinyl, thiazolyl, pyrimidinyl, pyrazinyl, oxazolyl, pyrazolyl, imidazolyl, oxetanyl, pyrrolidinyl, piperidinyl, pyranyl or morpholinyl, optionally substituted by oxo, Ci_₆ alkyl, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b.

In one embodiment, R³ is absent, hydrogen, methyl, -CF₃, -CH₂CN, -(CH₂)₂CN, 1- cyanocycloprop-l-yl, cyclopropyl, phenyl, 3-cyanophenyl, 4-cyanophenyl, 3- methylsulfonylphenyl, 3 -fluorophenyl, 6-cyanopyridinyl, 4-cyanopyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, thiazol-5-yl or oxazol-4-yl. In one embodiment, R is selected from absent, hydrogen, methyl, ethyl, n-butyl, sec- butyl, t-butyl, -CF₃, -CH₂CF₃, -CH₂CH₂F, -CH₂CH₂CF₃, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH(CH₂CH₃)CH₂OCH₃, -CH(CH₃)CH₂CH₂OH, -CH₂C(CH₃)₂OH, -CH₂C(CF₃)₂OH, - CH₂CH₂OH, -C(CH₃)₂OH, -CH₂CN, -(CH₂)₂CN, -(CH₂)₃CN, -CH(CH₃)CH₂CN, - C(CH₃)₂CN, -CH(CH₃)CN, -CH₂NH₂, -CH(CH₃)N(CH₃)₂, -CH₂CH₂N(CH₃)₂, cyclopropyl, 1- cyanocycloprop-l-yl, 1-trifluoromethylcycloprop-l-yl, 1-methylcycloprop-l-yl, 2- fluorocyclopyrop-l-yl, 2,2-dimethylcycloprop-l-yl, 2-cyanocyclopropyl, eye lo butyl, 4- carboxyclo butyl, 1-cyanocyclobut-l-yl, 4-aminocyclo butyl, cyclopentyl, 3-aminocyclohexyl, 4- aminocyclohexyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2- hydroxycyclohexyl, phenyl, 2-chloro-4-cyanophenyl, 2-cyanophenyl, 3-cyanophenyl, 4- cyanophenyl, 3-methylsulfonylphenyl, 3 -fluorophenyl, 4-methoxyphenyl, pyridinyl, pyridin-3- yl, 6-cyanopyridinyl, 6-trifluoromethylpyridinyl, 2-cyanopyridin-4-yl, 4-cyanopyridin-2-yl, 5- cyanopyridin-2-yl, 3-fluoropyridin-5-yl, thiazol-5-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin- -yl, pyrazin-2-yl, oxazol-2-yl, oxazol-4-yl, l-methylpyrazol-5-yl, l-methylpyrazol-4-yl, 1-

methylmorpholin-2-yl, l-methylpyrrolidin-2-yl, pyrrolidinyl, pyrrolidinonyl, piperidinonyl, 3,3- difluoropyrrolidin-2-yl, l-isopropylpyrrolidin-2-yl, 2-methylpyrrolidin-2-yl, 1- methylcyanopyrrolidin-2-yl, l-cyclobutylpyrrolidin-2-yl, morpholinyl, pyran-4-yl, N-

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁴ is hydrogen, methyl or F. In another embodiment, R⁴ is hydrogen.

In certain embodiments, R⁵ is halogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, -(C₀_6 alkylene)CN, -(C₀.₃ alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃ alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene)S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C3-6 cycloalkyl, -(C_0-3 alkylene)C6_i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(Co-3 alkylene)C(0)3-12 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(Co-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(Co-3 alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, with the proviso that R⁵ is other than OH.

In certain embodiments, R⁵ is halogen, C_1-12 alkyl, C₂_i₂ alkenyl, C₂_i₂ alkynyl, -(C₀_6 alkylene)CN, -(C₀.₃ alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃ alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene)S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C3_6 cycloalkyl, -(C_0-3 alkylene)C6_i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(Co-3 alkylene)C(0)3-12 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(Co-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(Co-3 alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i-₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen, with the proviso that R⁵ is other than OH.

In one embodiment, R⁵ is halogen. In one embodiment, R⁵ is F. In one embodiment, R⁵ is C_1-12 alkyl, C₂_i₂ alkenyl, C₂_i₂ alkynyl, wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -(G 0-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i-₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_6 alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from methyl, ethyl, 1 -hydro xyethyl, 2-hydroxyethyl, propyl, isopropyl, butyl, 2-methylbutyl, 3,3-difluorobut-l-yl, isobutyl, -CH₂F, -CHF₂, -CF₃, -CH₂OH, -C(CH₃)₂OH,

HO, HO,,.

wherein the wavy line represents the point of attachment in formula I. In one embodiment, R⁵ is C_1-12 alkyl independently optionally substituted by halogen, oxo, -(Co-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(Co-3 alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is Ci_₆ alkyl optionally substituted by halogen, oxo, -CN, -OR^a or -NR^aR^b. In another embodiment, R⁵ is methyl, ethyl, propyl, isopropyl or 2-methylpropyl, optionally substituted by halogen, oxo, -CN, -OR^a or -NR^aR^b, wherein R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₃_6 cycloalkyl, 4-6 membered heterocyclyl or taken together with the atom to which they are attached to form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group. In another embodiment, R⁵ is methyl, hydro xymethyl, 1 -hydro xyethyl, 2-hydroxyethyl, isopropyl or 2-methylpropyl.

In one embodiment, R⁵ is -(C_0-3 alkylene)CN, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(C_0-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(Co-3 alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(Co-3 alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i-₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)CN, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(Ci_₆ alkylene)CN, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from - CN, -C(CH₃)₂CN.

In one embodiment, R⁵ is -CN.

In one embodiment, R⁵ is -(C_0-3 alkylene)OR^a or -(C_0-3 alkylene)SR^a, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)OR^a, wherein said alkylene is independently optionally substituted by halogen, oxo, -(Co-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)OR^c, -(Co-3 alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)OR^a, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂OH, -CH₂CH₂OH, -C(CH₃)₂OH, -CH₂C(CH₃)₂OH, -

^H0*y^ ^H0'<.^ CH₂OCH₂CH(CH₃)₂, -CH₂OCH₂C(CH₃)₃, '

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aR^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c 0-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(Co-3 alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(Co-3 alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aR^b, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted b oxo -CN or halo en. In one embodiment R⁵ is selected from -NHCH₂CH₂OH, -

, wherein the wavy line represents the point of attachment in formula I. In one embodiment, R⁵ is -(C_0-3 alkylene)C3_i₂ cycloalkyl, wherein said alkylene and cycloalkyl are independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)C₃_6 cycloalkyl, wherein said alkylene and cycloalkyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂cyclopentyl, -CH₂cyclopropyl, -CH₂CH₂cyclopropyl, cyclopropyl, 2,2-difluorocyclopropyl and cyclobutyl.

In one embodiment, R⁵ is -(C_0-3 alkylene)C₃_7 cycloalkyl. In another embodiment, R⁵ is cyclopropyl or cyclobutyl.

In one embodiment, R⁵ is -(C_0-3 alkylene)C(0)NR^aR^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)C(0)NR^aR^b, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂C(0)NH_2, -CH₂C(0)NHcyclopentyl -CH₂C(0)N(CH₃)(cyclopentyl), -CH₂C(0)NHCH₃, -CH(CH₃)C(0)NHCH(CH₃)₂,

-CH₂C(0)(pyrrolidin-l-yl), -CH₂C(0)(4,4-difluorpiperidin-l-yl), -CH₂C(0)(morpholinyl) and

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)C(0)NR^aR^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(Co-₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)C(0)NR^aR^b, wherein said alkylene is optionally substituted by oxo or halogen; and R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₃_₆ cycloalkyl, 4-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR^e or -NR^eR^f, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_6 alkyl. In another embodiment, R⁵ is -CH₂C(0)NR^aR^b, -CH₂C(0)NHR^a, and R^a and R^b are independently hydrogen, Ci_₆ alkyl, C3-6 cycloalkyl, 4-6 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR^e or -NR^eR^f, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl. In another embodiment, R⁵ is -CH₂C(0)NHCH₃, -CH₂C(0)N(CH₃)(cyclopentyl), -CH₂C(0)NH(cyclopentyl), -CH₂C(0)NH(isopropyl), -CH₂C(0)(pyrrolidin- 1 -yl),

-CH₂C(0)(4,4-difiuorpiperidin-l-yl), -CH₂C(0)(morpholinyl) or

, wherein the wavy line represents the point of attachment in formula I. In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aC(0)R^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aC(0)R^b, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂NHC(0)CH₃, -CH₂NHC(0)CH(CH₃)₂, - CH₂NHC(0)CH₂CH₃, -CH₂NHC(0)CH₂OCH₃, -CH₂NHC(0)pyridin-3-yl,

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aS(0)i_2R^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c,

-(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aS(0)i_₂R^b, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂NHS(0)₂CH₃, -CH₂NHS(0)₂CH₂CH₃, - CH₂NHS(0)₂CH₂CH(CH₃)₂, -CH₂NHS(0)₂CH(CH₃)₂, -CH₂NHS(0)₂CH(CH₃)CH₂CH3, - CH₂NHS(0)₂cyclopropyl, -CH₂NHS(0)₂cyclopentyl, -CH₂N(CH₃)₂S(0)₂CH₃,

CH₂CH₂NHS(0)₂CH₃, -CH₂CH₂NHS(0)₂CH₂CH₃,

, , wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)5-12 membered heteroaryl, wherein said alkylene and heteroaryl are independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)5-6 membered heteroaryl, wherein said alkylene and heteroaryl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_6 alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂CH₂triazolyl, triazolyl, pyridinyl, -CH₂pyrazolyl, -CH₂pyridinyl,

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C₀-3 alkylene)4-6 membered heteroaryl, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C₀-3 alkylene)CN, -(C₀-3 alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)4-6 membered heteroaryl, wherein said alkylene is optionally substituted by oxo or halogen, and said heteroaryl is optionally substituted by oxo, halogen, Ci_₃ alkyl, -OR^c or -NR^cR^d. In one embodiment, R⁵ is pyridinyl.

In one embodiment, R⁵ is -(C_0-3 alkylene)3-12 membered heterocyclyl, wherein said alkylene and heterocyclyl are independently optionally substituted by halogen, oxo, -(C 0-3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)3-7 membered heterocyclyl, wherein said alkylene and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from oxetanyl, 1,1-dioxothiomorpholinyl, -CH₂CH₂(l,l-dioxothiomorpholinyl), - CH₂CH₂triazolyl, triazolyl, -CH₂pyrazolyl, -CH₂pyridinyl, pyridinyl, pyrrolidinyl, piperidinyl, -CH₂(4-hydroxypiperidin-l-yl), morpholinyl, azetidinyl, 2-acetylpyrrolidin-3-yl, -CH₂tetrahydropyranyl, -CH₂tetrahydropyran-4-yl, tetrahydropyranyl, tetrahydrofuranyl, -CH₂tetrahydrofuran-2-yl, -CH₂CH₂tetrahydrofuranyl, -CH₂morpholinyl, l-acetylpiperidin-4- -C(0)morpholinyl, -CH₂C(0)morpholinyl, -CH₂C(0)(l,l-dioxothiomorpholin-4-yl),

, , wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)4-6 membered heterocyclyl, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)4-6 membered heterocyclyl, wherein said alkylene is optionally substituted by oxo or halogen, and said heterocyclyl is optionally substituted by oxo, halogen, Ci_₃ alkyl, -OR^c or -NR^cR^d. In one embodiment, R⁵ is -CH₂C(0)(4-6 membered heterocyclyl) or -CH₂(4-6 membered heterocyclyl), wherein said heterocyclyl is optionally substituted by oxo, halogen, Ci_ 3 alkyl, -OR^c or -NR^cR^d. In another embodiment, said heterocyclyl is oxetanyl, pyridinyl, pyrrolindinyl, pyranyl, piperidinyl, morpholinyl or

O \— ' , wherein the wavy line represents the point of attachment in formula I. In another embodiment, R⁵ is pyridin-3-yl, pyrrolidin-l-yl, pyran-4-yl, -CH₂C(0)(pyrrolidin-l-yl), -CH₂C(0)(4,4-difiuorpiperidin-l-yl), -CH₂ (morpholinyl), -CH₂C(0)(morpholinyl), -CH₂(pyrrolidin-2-on-l-yl) or

, wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C0-3 alkylene)S(0)i_2R^a, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C₀-3 alkylene)CN, -(C₀-3 alkylene)OR^c, -(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene) S(0)i_₂R^a, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂S(0)₂CH₃.

In one embodiment, R⁵ is -(C_0-3 alkylene)C6_i₂ aryl, wherein said alkylene and aryl are independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)phenyl, wherein said alkylene and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substitu tteedd 1 by oxo, -CN cted from -CH₂phenyl,

wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is -(C_0-3 alkylene)phenyl, wherein said alkylene is optionally substituted by oxo or halogen, and said phenyl is optionally substituted by halogen, Ci_3 alkyl, -OR^c or -NR^cR^d. In one embodiment, R⁵ is -(C0-3 alkylene)NR^aC(0)OR^b, wherein said alkylene is independently optionally substituted by halogen, oxo, -(C0-3 alkylene)CN, -(C0-3 alkylene)OR^c,

-(Co-3 alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is -(C_0-3 alkylene)NR^aC(0)OR^b, wherein said alkylene is optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d, -C(0)OR^c, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen. In one embodiment, R⁵ is selected from -CH₂NHC(0)OCH₂CH₃ and -CH₂NHC(0)OCH₃.

In one embodiment, R⁵ is selected from hydrogen, fluro, methyl, ethyl, 1 -hydro xyethyl,

2-hydroxyethyl, propyl, isopropyl, butyl, 2-methylbutyl, isobutyl, -CH₂F, -CHF₂, -CF₃, - CH₂OH, -C(CH₃)₂OH, -CN, -C(CH₃)₂CN, -CH₂CH₂OH, -CH₂C(CH₃)₂OH, -

CH

H₂, -CH₂C(0)NH₂,

-CH₂cyclopentyl,

CH₂cyclopropyl, -CH₂CH₂cyclopropyl, cyclopropyl, 2,2-difluorocyclopropyl, cyclobutyl, - CH₂C(0)NH₂, -CH₂C(0)NHcyclopentyl -CH₂C(0)N(CH₃)(cyclopentyl), -CH₂C(0)NHCH₃, - CH(CH₃)C(0)NHCH(CH₃)₂ -CH₂C(0)(pyrrolidin- 1 -yl), -CH₂C(0)(4,4-difluorpiperidin- 1 -yl),

-CH₂C(0)(morpholinyl),

-CH₂NHC(0)CH₃, -CH₂NHC(0)CH(CH₃)₂, - CH₂NHC(0)CH₂CH₃, -CH₂NHC(0)CH₂OCH₃, -CH₂NHC(0)pyridin-3-yl,

I , -CH₂NHS(0)₂CH₃, -CH₂NHS(0)₂CH₂CH₃,

CH₂NHS(0)₂CH₂CH(CH₃)₂, -CH₂NHS(0)₂CH(CH₃)₂, -CH₂NHS(0)₂CH(CH₃)CH₂CH₃, CH₂NHS(0)₂cyclopropyl, -CH₂NHS(0)₂cyclopentyl, -CH₂N(CH₃)₂S(0)₂CH₃,

CH₂CH₂NHS(0)₂CH_3, -CH₂CH₂NHS(0)₂CH₂CH_3,

_s oxetanyl, 1,1-dioxothiomorpholinyl,

-CH₂CH₂(l,l-dioxothiomorpholinyl), -CH₂CH₂triazolyl, triazolyl, -CH₂pyrazolyl, - CH₂pyridinyl, pyridinyl, pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, 2-acetylpyrrolidin-3- yl, -CH₂tetrahydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, -CH₂CH₂tetrahydrofuranyl, -CH₂morpholinyl, l-acetylpiperidin-4-yl, -C(0)morpholi -CH₂C(0)morpholinyl,

-CH₂C(0)(l,l-dioxothiomorpholin-4-yl), -CH₂C(0)pyrrolidinyl,

, -CH₂phenyl, phenyl, , and

wherein the wavy line represents the point of attachment in formula I. In certain embodiments, Y is CR⁵ and R⁵ is methyl, ethyl, propyl, isopropyl, cyclopropyl, eye lo butyl, cyano, 2-methylbutyl, N-(2-hydroxyethyl)amino, N-(2-methoxyethyl)amino, methylsulfonylamino methyl, 2-(methylsulfonylamino)ethyl, cyclopropylmethyl, 2-[N-(2- propylsulfonyl)amino]ethyl, 2-[N-(cyclopropylsulfonyl)-amino]ethyl, 2- (cyclopropylcarbonylamino)ethyl, 2-(acetylamino)ethyl, 2-(methoxymethyl- carbonylamino)ethyl, cyclopentoxymethyl, cyclopropylmethoxymethyl, 2,2,2- trifluoroethoxymethyl, cyclohexyl, methylamino, 2-(N,N-dimethylaminocarbonyl)ethyl, 2-(N- acetyl-N-methylamino)ethyl, 2-(ethoxycarbonylamino)ethyl, 1 -hydro xyethyl, N- acylaminomethyl, 2-amino-l,l-difluoroethyl, Ν,Ν-dimethylamino, hydro xymethyl, methoxy, N- methylamino, N,N-dimethylamino,N-(2,2,2-trifluoroethyl)aminomethyl, (2- carboxycyclopropyl)(hydroxy)methyl, 2-hydro xyethyl, amino carbonylmethyl, methylammocarbonylmethyl, ethylamino carbonylmethyl, 1 -hydro xypropyl, 1 ,2-dihydro xyethyl, N-(2-methylpropyl)aminocarbonylmethyl, eye lopentylamino carbonylmethyl, 2-

(methoxycarbonylamino)ethyl, 2,2,2-trifluoro- 1 -hydro xyethyl, tert-butylaminocarbonylmethyl, cyclobutylaminocarbonylmethyl, 2-hydroxyethoxy, isopropylamino carbonylmethyl, N-(N'N'- diemthylaminocarbonylmethyl)aminocarbonylmethyl, 4,4-difluorocyclohexyl- amino carbonylmethyl, 2,2-difluoroethylaminocarbonylmethyl, N-(2-hydroxyethyl)-N- methylamino carbonylmethyl, cyclopentylmethyl, N-cyclopentyl-N-methylaminocarbonylmethyl,

2- amino-l,l-difluoroethyl, 3-pyridyl, morpho lino methyl, morpholmocarbonylmethyl, 2-cyano-2- methylethyl, trifluoromethyl, 1 -hydroxy- 1-methylethyl, l-(N-isopropylaminocarbonyl)ethyl, 2- hydroxy-2-methylpropyl, N-(methylsulfonyl)-N-methylaminomethyl, difluoromethyl, 2-(2- butylsulfonylamino)ethyl, 2-(4-fluorophenylcarbonylamino)ethyl, 2-(cyclobutylcarbonyl- amino)ethyl, 2-(2-methylbutanoylamino)ethyl, 2-(benzoylamino)ethyl, 2,2-difluorocyclopropyl,

3- cyanobenzyl, 2-methylpropoxymethyl, 2-cyclopropylethyl, 3-pyridylmethyl, methylsulfonylmethyl, ethoxycarbonylaminomethyl, 3 -pyridylcarbonylamino methyl, isopropylsulfonylaminomethyl, 2-pyridylcarbonylaminomethyl, cyclopropylsulfonyl- aminomethyl, cyclopentylsulfonylaminomethyl, 2-methylpropanoylaminomethyl, cyclopropylcarbonylaminomethyl, 2-fluorobenzoylaminomethyl, 3-fluorobenzoylaminomethyl, 1-methylpropylsulfonylaminomethyl, 2-methylpropylsulfonylaminomethyl, methoxyacetylaminomethyl, ethylsylfonylaminomethyl, 2-(3,3,3-trifluoropropylsulfonyl- amino)ethyl, 2-(2,2-difluorocyclopropylcarbonylamino)ethyl, fluoromethyl, 2- hydroxyethylamino, 2-methoxyethylamino, 1-aminoethyl, 2-(ethylsulfonylamino)ethyl, 2,2- dimethylpropo xymethyl, 1-metho xyethyl, tert-butylsulfonylaminomethyl, 2,2,2-trifluoroethyl- aminomethyl,

wherein the wavy line represents the point of attachment in formula I.

In one embodiment, R⁵ is methyl, 1 -hydro xyethyl, hydro xymethyl,

methylsulfonylaminomethyl, aminomethyl, or methoxycarbonyl-aminomethyl.

In one embodiment, R⁵ is (R)-l -hydro xyethyl.

In one embodiment, R⁵ is (S)-l -hydro xyethyl. In one embodiment, R⁵ is C_3-12 alkyl, wherein said C_3-12 alkyl, is independently optionally substituted by halogen, oxo, -(C_0-3 alkylene)CN, -(C_0-3 alkylene)OR^c, -(C_0-3 alkylene)NR^cR^d, -(Co-3 alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d.

In one embodiment, R⁵ is C_1-12 alkyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(C_{0- 3} alkylene)CN, -(C₂_₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d

1. In one embodiment, R⁵ is C_1-12 alkyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(Co-3 alkylene)CN, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀. 2R^C, -(Co-3 alkylene)NR^cS(0)i.₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i-₂NR^cR^d

In one embodiment, R⁵ is halogen, C_1-12 alkyl, C₂_i₂ alkenyl, C₂_i₂ alkynyl, -(C_0-3 alkylene)CN, -(C₀.₃ alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃ alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene) S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C3_i₂ cycloalkyl, -(C_0-3 alkylene)C6_i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(C_0-3 alkylene)C(0)3-12 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(C₀.₃ alkylene)CN, -(C₀.₃ alkylene)OR^k, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen; wherein each R^k is independently hydrogen, C₃-6 alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(C_0-3 alkylene)C₃-₆ cycloalkyl, -(C_0-3 alkylene)3-12 membered heterocyclyl, -(C_0-3 alkylene)C(0)3-12 membered heterocyclyl or -(C_0-3 alkylene)C₆_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_₂NR^gR^h, C₃-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or alkyl optionally substituted by oxo or halogen.

In one embodiment, R⁵ is halogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, -(C₀-3 alkylene)CN, -(C₀.₃ alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃ alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene)S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C3_i₂ cycloalkyl, -(C_0-3 alkylene)C6_i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(C_0-3 alkylene)C(0)3-12 membered heterocyclyl, wherein said alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(C₀.₃ alkylene)CN, -(C₀.₃ alkylene)OR^k, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene) S(O)₀_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen; wherein each R^k is independently hydrogen, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co-3 alkylene)C3_6 cycloalkyl, -(C_0-3 alkylene)3-12 membered heterocyclyl, -(C_0-3 alkylene)C(0)3-12 membered heterocyclyl or -(C_0-3 alkylene)C₆_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_₂NR^gR^h, C₃-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

In certain embodiments, R⁶ is independently oxo, halogen, -CN, -C(0)R^a, -C(0)OR^a, -NR^aC(0)R^b, -C(0)NR^aR^b, -NR^aC(0)NR^aR^b, -OC(0)NR^aR^b, -NR^aC(0)OR^b, -S(0)i_₂R^a, -NR^aS(0)₂R^b, -S(0)₂NR^aR^b, -OR^a, -SR^a, -NR^aR^b, Ci_₆ alkyl, C₃_₆ cycloalkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, 3-7 membered heterocycly or C_6-14 aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₆ alkyl optionally substituted by oxo or halogen. In one embodiment, R⁶ is independently oxo, halogen, -CN, -C(0)(Ci_₆ alkyl), -C(0)0(d_₆ alkyl), -S(0)₂(d_₆ alkyl), -NR^aS(0)₂(d_₆ alkyl), -0(d_₆ alkyl), d_₆ alkyl, C₃_₆ cycloalkyl or 3-7 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₆ alkyl optionally substituted by halogen. In one embodiment, R⁶ is independently oxo, F, CI, -CN, -OH, -C(0)CH₃, -CH₂CN, -CH₂CH₂CN, cyclopropyl, cyclobutyl, -CF₃, -NHS(0)₂CH₃, -S(0)₂CH₃, -C(0)OCH₃, pyrrolidinyl or pyrrolidinonyl.

In one embodiment, R⁶ is independently oxo, halogen, -CN, -C(0)(Ci_₆ alkyl), -S(0)₂(Ci_6 alkyl), -OR^a, -NR^aR^b, Ci_6 alkyl or C₃_₆ cycloalkyl, and wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR^c or -NR^cR^d. In one embodiment, R⁶ is halogen, -S(0)₂CH₃ or -CN.

In one embodiment, R³ is optionally substituted by 1 to 3 R⁶ independently selected from oxo, halogen, -CN, -S(0)₂(Ci_6 alkyl), -OR^a, -NR^aR^b and Ci_6 alkyl, and wherein said alkyl, alkenyl and alkynyl are independently optionally substituted by halogen, oxo, -CN, -OR^c or -NR^cR^d.

In one embodiment, R³ is optionally substituted by 1 to 3 R⁶ independently selected from oxo, halogen, -CN, -C(0)(Ci_₆ alkyl), -C(0)0(Ci_6 alkyl), -S(0)₂(C^ alkyl), -NR^aS(0)₂(Ci_6 alkyl), -0(Ci_₆ alkyl), Ci_₆ alkyl, C₃_₆ cycloalkyl or 3-7 membered heterocyclyl, wherein said alkyl, cycloalkyl and heterocyclyl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -NR^cR^d or Ci_₆ alkyl optionally substituted by halogen.

In certain embodiments, each R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -C₃_₆ cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or -C₆-i4 aryl, wherein said alkyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₃ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo, halogen, OR^g or NR^gNR^h. In certain embodiments, each R^a and R^b are independently hydrogen, Ci_₆ alkyl, C3-6 cycloalkyl, 3-6 membered heterocyclyl, -C(0)3-6 membered heterocyclyl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_₂NR^gR^h, C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₃ alkyl optionally substituted by oxo or halogen.

In one embodiment, each R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f or Ci_₃ alkyl optionally substituted by halogen.

In one embodiment, each R^a and R^b are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, sec-butyl, -CF₃, -CH₂CF₃, -CH₂F, -CHF₂, -CH₂OH, -CH₂CH₂OH, -CH₂NH₂, -CH₂CH₂NH₂, -CH₂CH₂N(CH₃)₂, -CH₂N(CH₃)₂, cyclopropyl, 2,2- difluorocyclopropyl, 2-fluorocyclopropyl, 2-methylcyclopropyl, eye lo butyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrazolyl, N- methylpyrazolyl, azetidinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, pyrrolidinonyl, pyridinyl, cyanopyridinyl, phenyl and fluorophenyl.

In certain embodiments, a R^a and a R^b are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo, halogen, OR^g or NR^gNR^h.

In one embodiment, a R^a and a R^b are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by halogen. In one embodiment, said heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, piperidinonyl, morpholinyl and 1,1-dioxomorpholinyl.

In one embodiment, R^a and R^b are taken together with the atom to which they are attached to form a 4-6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl. In one embodiment, R^a and R^b are independently hydrogen, methyl, isopropyl, cyclopropyl or cyclopentyl.

In one embodiment, R^a and R^b are taken together with the atom to which they are attached to form a 4-6 membered heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl.

In certain embodiments, each R^c and R^d are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -C3-6 cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or -C_6-14 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS (O) 1 _₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

In certain embodiments, each R^c and R^d are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -C₃_₆ cycloalkyl, -3-6 membered heterocyclyl, -C(0)3-6 membered heterocyclyl or phenyll, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS (O) 1 _₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

In one embodiment, each R^c and R^d are independently hydrogen, Ci_₆ alkyl, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein said alkyl, cycloalkyl, heterocyclyl, heteroaryl and phenyl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h or Ci_₆ alkyl optionally substituted by halogen.

In one embodiment, each R^c and R^d are independently hydrogen, methyl, ethyl, isopropyl, butyl, t-butyl, sec-butyl, -CF₃, "CH₂CF₃, -CH₂F, -CHF₂, -CH₂OH, -CH₂CH₂OH, -CH₂NH₂, -CH₂CH₂NH₂, -CH₂CH₂N(CH₃)₂, -CH₂N(CH₃)₂, cyclopropyl, 2,2- difluorocyclopropyl, 2-fluorocyclopropyl, 2-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrazolyl, N- methylpyrazolyl, azetidinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, pyrrolidinonyl, pyridinyl, cyanopyridinyl, phenyl and fluorophenyl.

In certain embodiments, a R^c and a R^d are independently taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

In one embodiment, each R^c and R^d are independently hydrogen, methyl or ethyl, optionally substituted by fluoro or oxo. In one embodiment, each R^c and R^d are independently hydrogen, methyl or ethyl. In one embodiment, a R^c and a R^d are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by halogen. In one embodiment, said heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, piperidinonyl, morpholinyl and 1,1- dioxomorpholinyl. In one embodiment, R^c, R^d, R^e, R^f, R^g and R^h are independently hydrogen or methyl.

In one embodiment, each R^e, R^f, R^g, R^h are independently hydrogen, methyl, ethyl, propyl or isopropyl, optionally substituted by halogen or oxo. In one embodiment, each R^e, R^f, R^g, R^h are independently hydrogen, methyl or ethyl.

In another embodiment, X is CR⁴; Y is N or CR⁵;

R¹ is azetidinyl, piperidinyl, pyrrolidinyl or cyclohexyl, optionally substituted by Ci_₃ alkylene or Ci_₃ alkyl;

R² is absent, Ci_₃ alkyl, - H-, -NHCH₂- -CH₂0- -(CH₂)₂0-, -C(0)NH- -CH₂C(0)NH-, -CH₂C(0)N(CH₃)-, -NHC(0)CH₂-, - HC(0)0-, -C(0)0-, -C(0)CH₂S(0)₂, -NHS(0)₂-, -NHS(0)₂CH₂-, -CH₂C(0)-, -(CH₂)₂C(0)-, -S(0)₂- -CH₂S(0)₂-, -S(0)₂(CH₂)₂-;

R³ is absent, Ci_6 alkyl optionally substituted by oxo, halogen, -CN, -S(0)₂(Ci_6 alkyl), -OR^a or -NR^aR^b;

C3-7 cycloalkyl optionally substituted by oxo, halogen, -CN, -S(0)₂(Ci_6 alkyl), -OR^a, -NR^aR^b or Ci_6 alkyl optionally substituted by halogen, phenyl optionally substituted by Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen,

-CF₃, -CN, -S(0)₂(Ci_6 alkyl), -OR^a or -NR^aR^b,

5-6 membered heteroaryl optionally substituted by oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -CF₃, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b, or

4-7 membered heterocyclyl optionally substituted by oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_6 alkynyl, -CF₃, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b;

R⁴ is hydrogen, F or methyl;

R⁵ is Ci_6 alkyl or C₃_₆ cycloalkyl optionally substituted by halogen, oxo, -CN, -OR^a or -NR^aR^b,

-CH₂C(0)NR^aR^b, -CH₂C(0)NHR^a, -CH₂C(0)(4-6 membered heterocyclyl), -CH₂(4-6 membered heterocyclyl), -(Co_₃ alkylene)4-6 membered heteroaryl or

-(Co-₃ alkylene)phenyl, wherein said alkylene is optionally substituted by oxo or halogen, and said heterocyclyl, heteroaryl and phenyl are independently optionally substituted by oxo, halogen, Ci_₃ alkyl, -OR^c or -NR^cR^d; each R^a and R^b are independently hydrogen, Ci_₃ alkyl or C₃_₆ cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted by oxo or halogen; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen or Ci_₃ alkyl; and each R^c and R^d are independently hydrogen or Ci_₆ alkyl; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, or Ci_₃_ alkyl.

In another embodiment, X is CR⁴; Y is N or CR⁵; R¹ is azetidinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, cyclopentyl or cyclohexyl, optionally substituted by Ci_₃ alkylene, -CN, -OR^a or Ci_₃ alkyl; R² is absent, Ci_₃ alkyl, - H-, -NHCH₂-, -CH₂0-, -(CH₂)₂0- -C(0)NH-, -CH₂C(0)NH-, -CH₂C(0)N(CH₃)-, -NHC(0)CH₂-, - HC(0)0-, -C(0)0-, -C(0)CH₂S(0)₂, -NHS(0)₂-, -NHS(0)₂CH₂-, -CH₂C(0)-, -(CH₂)₂C(0)-, -S(0)₂-, -CH₂S(0)₂-, -S(0)₂(CH₂)₂-;

R³ is absent, hydrogen,

Ci_6 alkyl optionally substituted by oxo, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b;

C₃_7 cycloalkyl optionally substituted by oxo, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a, -NR^aR^b or Ci_6 alkyl optionally substituted by halogen, phenyl optionally substituted by Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, halogen, -CF₃, -CN, -S(0)₂(Ci_6 alkyl), -OR^a or -NR^aR^b,

5-6 membered heteroaryl optionally substituted by oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -CF₃, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b, or

4-7 membered heterocyclyl optionally substituted by oxo, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_6 alkynyl, -CF₃, halogen, -CN, -S(0)₂(Ci_₆ alkyl), -OR^a or -NR^aR^b;

R⁴ is hydrogen, F or methyl;

R⁵ is C_1-12 alkyl or C₃_i₂ cycloalkyl optionally substituted by halogen, oxo, -CN, -OR^a or -NR^aR^b,

-CH₂C(0)NR^aR^b, -CH₂C(0)NHR^a, -CH₂C(0)(4-6 membered heterocyclyl), -CH₂(4-6 membered heterocyclyl), -(Co_₃ alkylene)4-6 membered heteroaryl or -(C_0-3 alkylene)phenyl, wherein said alkylene is optionally substituted by oxo or halogen, and said heterocyclyl, heteroaryl and phenyl are independently optionally substituted by oxo, halogen, Ci_₃ alkyl, -OR^c or -NR^cR^d; each R^a and R^b are independently hydrogen, Ci_₃ alkyl or C₃_₆ cycloalkyl, wherein said alkyl and cycloalkyl are independently optionally substituted by oxo or halogen; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen or Ci_₃ alkyl; and each R^c and R^d are independently hydrogen or Ci_₆ alkyl; or are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, or Ci_₃_ alkyl.

In another embodiment, R¹ is azetidinyl, piperidinyl, pyrrolidinyl or cyclohexyl, optionally substituted by Ci_₃ alkylene or Ci_₃ alkyl; R² is absent; and R³ is hydrogen. In another embodiment, R¹ is azetidinyl, piperidinyl, pyrrolidinyl or cyclohexyl, optionally substituted by Ci_₃ alkylene or Ci_₃ alkyl; R² is absent; R³ is hydrogen; and R⁵ is -CN or Ci_₃ alkyl optionally substituted by halogen or oxo.

In another embodiment, X is CH; Y is CR⁵; R¹ is piperidinyl, tetrahydropyranyl, cyclopentyl or cyclohexyl, wherein R¹ is optionally substituted by Ci_₃ alkylene, halogen, -OR^a, -CN, -NR^aR^b or Ci_₆ alkyl optionally substituted by oxo, -OR^a, -CN, -NR^aR^b or halogen; R² is absent; R³ is absent; R⁵ is C_1-12 alkyl optionally substituted by halogen, oxo, -CN, -OH, -OCH₃, -NH₂ or -N(CH₃)₂; and each R^a and R^b are independently selected from Ci_₃ alkyl optionally substituted by oxo or halogen. In another embodiment, X is CH; Y is CR⁵; R¹ is piperidinyl, tetrahydropyranyl or cyclohexyl, wherein R¹ is optionally substituted by Ci_₃ alkylene, halogen, -OH, -NH₂ or Ci_₃ alkyl optionally substituted by oxo, -CN or halogen; R² is absent; R³ is absent; and R⁵ is Ci_₆ alkyl optionally substituted by halogen, oxo, -CN, -OH, -OCH₃, -NH₂ or -N(CH₃)₂.

In another embodiment, X is CH; Y is CR⁵; R¹ is piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopentyl or cyclohexyl, wherein R¹ is optionally substituted by Ci_₃ alkylene, halogen, -OH, -NH₂ or Ci_₃ alkyl optionally substituted by oxo, -CN or halogen; R² is

3 is absent; and R⁵ is selected from

wherein the wavy line represents the point of attachment in formula I.

In another embodiment, R¹ is piperidinyl optionally substituted by Ci_₃ alkylene or Ci_₃ alkyl; R² is Ci_₃ alkyl optionally substituted by oxo; R³ is Ci_₆ alkyl optionally substituted by oxo, halogen or -CN, phenyl or pyridinyl, wherein said phenyl and pyridinyl are independently optionally substituted by halogen or -CN.

Another embodiment includes a compound selected from Examples 1-56.

and stereoisomers, tautomers and pharmaceutically acceptable salts thereof..

In one embodiment, the compound of formula I is not:

In one embodiment -R'-R^R³ taken together are not morpholino. In one embodiment -R'-R^R³ taken together are not morpholino when R⁵ is ethoxymethyl.

In one embodiment R⁵ is not ethoxymethyl.

Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.

Another aspect includes prodrugs of the compounds of formula I, including known amino -protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the compound of formula I under physiologic conditions. A particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, amino alky leneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy (OH) group, an alkylcarbonyl (-CO-R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyl-alkoxycarbonyl (- CO-O-R-O-CO-R) group where R is a monovalent or divalent group, for example alkyl, alkylene or aryl, or a group having the formula -C(0)-0-CPlP2-haloalkyl, where PI and P2 are the same or different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In a particular embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of formula I. Prodrugs may be prepared by reacting a compound of formula I with an activated group, such as acyl groups, to bond, for example, a nitrogen atom in the compound of formula I to the exemplary carbonyl of the activated acyl group. Examples of activated carbonyl compounds are those containing a leaving group bonded to the carbonyl group, and include, for example, acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are generally carried out in inert solvents at reduced temperatures such as -78 to about 50°C. The reactions may also be carried out in the presence of an inorganic base, for example potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, or the like. SYNTHESIS OF JAK1 INHIBITOR COMPOUNDS

Compounds of formula I may be synthesized by synthetic routes described herein. In certain embodiments, processes well-known in the chemical arts can be used, in addition to, or in light of, the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N.Y. (1967- 1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer- Verlag, Berlin, including supplements (also available via the Beilstein online database)), or Comprehensive Heterocyclic Chemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds of formula I may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds of formula I. Libraries of compounds of formula I may be prepared by a combinatorial "split and mix" approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula I, enantiomers, diastereomers, tautomers or pharmaceutically acceptable salts thereof.

For illustrative purposes, reaction schemes 1-10 depicted below provide routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino -protecting groups (NH-Pg) include acetyl, trifluoro acetyl, benzyl, phenylsulfonyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Compounds of the invention may be prepared from readily available starting materials using the general methods illustrated in Reaction Schemes 1-10 below.

Reaction Scheme 1

General Quinoline synthesis

Reaction Scheme 2

General Naphthyridine synthesis

Reaction Scheme 3

Introducing hindered

Reaction Scheme 4

Introducing C2 amines route I

X = CorN X = CorN n = 1, 2 or 3 n = 1, 2 or 3

MeS0₂CI, Et₃N,

THF

X = C or N

n = 1, 2 or 3 Reaction Scheme 5

Introducing C2 amines route II

X = C or N X = C or N n = 1 , 2 or 3

X = C or N X = C or N

n = 1 , 2 or 3 n = 1 , 2 or 3

Reaction Scheme 6

Introducing C2 amines route III

X = C or N X = C or N

X = C or N X = C or N X = C or N

Reaction Scheme 7 Synthesis of protected amino-cycloalkyls route I

Reaction Scheme 8

Synthesis of protected amino-cycloalkyls route II

Reaction Scheme 9

Synthesis of boc protected piperidine

X = C or N

n = 0 or 1

Reaction Scheme 10

Synthesis of benzyl protected piperidine

X = C or N X = C or N It will be appreciated that where appropriate functional groups exist, compounds of various formulae or any intermediates used in their preparation may be further derivatized by one or more standard synthetic methods employing condensation, substitution, oxidation, reduction, or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

METHODS OF SEPARATION

In each of the exemplary Schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization or trituration from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; supercritical fluid; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like. Selection of appropriate methods of separation depends on the nature of the materials involved. Example separation methods include boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation. Diastereomeric mixtures can be separated into their individual diastereo isomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column or supercritical fluid chromatography.

A single stereoisomer, e.g. an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g. (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem. 47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquino lines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase {Chiral Liquid Chromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. The absolute stereochemistry of chiral centers and enatiomers can be determined by x-ray crystallography.

Positional isomers, for example E and Z forms, of compounds of formula I, and intermediates for their synthesis, may be observed by characterization methods such as NMR and analytical HPLC. For certain compounds where the energy barrier for interconversion is sufficiently high, the E and Z isomers may be separated, for example by preparatory HPLC.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula I may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula I is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula I are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

In one example, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about 0.1 to 20 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, contain from about 5 to about 100 mg of the compound of the invention.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, inhaled and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, vapors, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament). An example of a suitable oral dosage form is a tablet containing about 2 mg, 5 mg, 25mg, 50mg, lOOmg, 250mg, or 500mg of the compound of the present invention compounded with about 95-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about e.g., 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound of the present invention, for example 5-400 mg, in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g. using a 0.2 micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula I, stereoisomers, tautomers or pharmaceutically acceptable salts thereof. In a further embodiment includes a pharmaceutical composition comprising a compound of formula I, or stereoisomers, tautomers or pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of a hyperproliferative disease. Another embodiment includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of cancer. Another embodiment includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of an immunological disorder. Another embodiment includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease (IBD) or asthma. Another embodiment includes a pharmaceutical composition comprising a compound of formula I stereoisomers, tautomers or pharmaceutically acceptable salts thereof for use in the treatment of rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD and transplant rejection.

METHODS OF TREATMENT WITH AND USES OF JAK1 INHIBITORS The compounds of Formula I inhibit the activity of JAK1 kinase. Accordingly, the compounds of Formula I inhibit the phosphorylation of signal transducers and activators of transcription (STATs) by JAK1 kinase as well as STAT mediated cytokine production. Compounds of Formula I are useful for inhibiting JAK1 kinase activity in cells through cytokine pathways, such as IL-6, IL-15, IL-7, IL-2, IL-4, IL-9, IL-10, IL-13, IL-21, G-CSF, IFNalpha, IFNbeta or IFNgamma pathways. The compounds of Formula I can be used for the treatment of immunological disorders driven by aberrant IL-6, IL-15, IL-7, IL-2, IL-4, IL9, IL-10, IL-13, IL- 21, G-CSF, IFNalpha, IFNbeta or IFNgamma cytokine signaling.

Another embodiment includes a method of treating or lessening the severity of a disease or condition responsive to the inhibition of JAK1 kinase activity in a patient. The method includes the step of administering to a patient a therapeutically effective amount of a compound of the present invention.

In one embodiment, the disease or condition is cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, allergic disorders, inflammation, neurological disorders, a hormone- related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathologic immune conditions involving T cell activation, CNS disorders or a myeloproliferative disorder.

In one embodiment, the disease or condition is cancer.

In one embodiment, the disease is a myeloproliferative disorder.

In one embodiment, the myeloproliferative disorder is polycythemia vera, essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia (CML). In one embodiment, the cancer is breast, ovary, cervix, prostate, testis, penile, genitourinary tract, seminoma, esophagus, larynx, gastric, stomach, gastrointestinal, skin, kerato acanthoma, follicular carcinoma, melanoma, lung, small cell lung carcinoma, non-small cell lung carcinoma (NSCLC), lung adenocarcinoma, squamous carcinoma of the lung, colon, pancreas, thyroid, papillary, bladder, liver, biliary passage, kidney, bone, myeloid disorders, lymphoid disorders, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, salivary gland, pharynx, small intestine, colon, rectum, anal, renal, prostate, vulval, thyroid, large intestine, endometrial, uterine, brain, central nervous system, cancer of the peritoneum, hepatocellular cancer, head cancer, neck cancer, Hodgkin's or leukemia.

In one embodiment, the cardiovascular disease is restenosis, cardiomegaly, atherosclerosis, myocardial infarction or congestive heart failure. In one embodiment, the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity or hypoxia.

In one embodiment, the inflammatory diseases is rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, contact dermatitis or delayed hypersensitivity reactions. In one embodiment, the autoimmune disease is lupus or multiple sclerosis.

In one embodiment, the disease or condition responsive to the inhibition of JAK1 kinase is rheumatoid arthritis.

In one embodiment, the disease or condition responsive to the inhibition of JAK1 kinase is rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD or transplant rejection.

Another embodiment includes a method of treating cancer in a mammal in need of such treatment, wherein the method comprises administering to said mammal a therapeutically effective amount of a compound of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof. Another embodiment includes compounds of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in therapy. In another embodiment, the therapy is the treatment of an immunological disorder, for example rheumatoid arthritis. In another embodiment, the therapy is the treatment of cancer.

Another embodiment includes compounds of formula I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in treating a disease selected from rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD and transplant rejection. Another embodiment includes the use of a compound of formulas I, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease described herein (e.g., cancer or immunological disorder). COMBINATION THERAPY

The compounds of formula I may be employed alone or in combination with other chemotherapeutic agents for treatment. The compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-hyperproliferative, anticancer, cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such agents are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially. Such sequential administration may be close or remote in time. In one embodiment, compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. In another embodiment, the cytostatic compound is doxorubicin. In another embodiment, compounds of the present invention are coadministered with an anti-inflammatory agent selected from a NSAID and corticosteroid. In another embodiment, compounds of the present invention are coadministered with an anti-rheumatoid agent, in one example, RITUXAN®. In another embodiment, compounds of the present invention are coadministered with a chemotherapeutic agent selected from etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi), Interleukin 1 (IL-1) blockers such as anakinra (Kineret), monoclonal antibodies against B cells such as rituximab (RITUXAN®), T cell costimulation blockers such as abatacept (Orencia), Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); Interleukin 13 (IL-13) blockers such as lebrikizumab; Interferon alpha (IFN) blockers such as Rontalizumab; Beta 7 integrin blockers such as rhuMAb Beta7; IgE pathway blockers such as Anti-Mi prime; Secreted homotrimeric LTa3 and membrane bound heterotrimer LTal/p2 blockers such as Anti-lymphotoxin alpha (LTa)

The compounds of the present invention can be also used in combination with radiation therapy. The phrase "radiation therapy" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia. Radiation therapy delivers doses of radiation sufficiently high to a target area to cause death of reproducing cells, in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various considerations but two of the most important considerations are the location of the tumor in relation to other critical structures or organs of the body, and the extent to which the tumor has spread. Examples of radiotherapeutic agents are provided in Hellman, Principles of Radiation Therapy, Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al, 4th ed., vol 1, 1993). Alternative forms of radiation therapy include three- dimensional conformal external beam radiation, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery and brachytherapy (interstitial radiation therapy), the latter placing the source of radiation directly into the tumor as implanted "seeds". These alternative treatment modalities deliver greater doses of radiation to the tumor, which accounts for their increased effectiveness when compared to standard external beam radiation therapy. Another embodiment includes a method of preparing a compound of formula I or a pharmaceutically acceptable salt thereof comprising: a, for a compound of formula I wherein Y is CR⁵, cyclizing a correspond

compound of formula 100:

to provide the compound of formula I; b contacting a compound of formula I with an acid or base to provide the corresponding pharmaceutically acceptable salt; c removing a protecting group from a corresponding compound bearing a protecting group to provide the compound of formula I; d, for a compound of formula I wherein R² and R³ are not each absent, converting a compound of formula 101:

to the corresponding compound of formula I wherein R² and R³ are not each absent; e. for a compound of formula I wherein -R¹-R²-R³ taken together are:

reacting a corresponding compound of formula I wherein -R¹-R²-R³ taken together are:

with a compound of formula R^a-Lg, wherein Lg is a suitable leaving group, to provide the compound of formula I; f. for a compound of formula I wherein -R¹-R²-R³ taken together are:

reacting a corresponding compound of formula I wherein -R¹-R²-R³ taken together are:

with a compound of formula R^a-Lg, wherein Lg is a suitable leaving group, to provide the compound of formula I; g. for a compound of formula I wherein -R¹ is:

removing a protecting group Pg from a corresponding compound of formula I wherein -R¹ is

to provide the compound of formula I; or h. for a compound of formula I wherein -R¹ is:

removing a protecting group Pg from a corresponding compound of formula I wherein -R¹ is

to provide the compound of formula I.

ARTICLES OF MANUFACTURE

Another embodiment includes a kit for treating a disease or disorder responsive to the inhibition of JAK1 kinase. The kit includes: (a) a first pharmaceutical composition comprising a compound of formula I; and

(b) instructions for use.

In another embodiment, the kit further includes:

(c) a second pharmaceutical composition, which includes a chemotherapeutic agent.

In one embodiment, the instructions describe the simultaneous, sequential or separate administration of said first and second pharmaceutical compositions to a patient in need thereof. In one embodiment, the first and second compositions are contained in separate containers.

In one embodiment, the first and second compositions are contained in the same container. Containers for use include, for example, bottles, vials, syringes, blister pack, etc. The containers may be formed from a variety of materials such as glass or plastic. The container includes a compound of formula I or formulation thereof which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The container includes a composition comprising at least one compound of formula I. The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer. In one embodiment, the label or package inserts indicates that the composition comprising the compound of formula I can be used to treat a disorder. In addition, the label or package insert may indicate that the patient to be treated is one having a disorder characterized by overactive or irregular kinase activity. The label or package insert may also indicate that the composition can be used to treat other disorders.

The article of manufacture may comprise (a) a first container with a compound of formula I contained therein; and (b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a chemotherapeutic agent. The article of manufacture in this embodiment of the invention may further comprise a package insert indicating that the first and second compounds can be used to treat patients at risk of stroke, thrombus or thrombosis disorder. Alternatively, or additionally, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In order to illustrate the invention, the following examples are included. However, it is to be understood that these examples do not limit the invention and are only meant to suggest a method of practicing the invention. Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare other compounds of formula I, and alternative methods for preparing the compounds of formula I are within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows:

Abbreviations:

AcOH Acetic acid

aq. Aqueous

Bn Benzyl

Boc₂0 Di-tert-butyl dicarbonate

Brine Saturated aqueous sodium chloride solution

CAS Chemical abstract service number

CDCI3 Deuterated chloroform

DCM Dichloromethane

DIAD Diisopropyl azodicarboxylate

DIPEA Diisopropylethylamine / iPr₂EtN

DMAP 4-(Dimethylamino)pyridine

DMSO Dimethylsulfoxide

DMSO-d6 Deuterated DMSO

DMF Dimethylformamide

EDCI l-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride eq equivalents

ESI Electrospray

Et Ethyl

EtOAc Ethyl acetate EtOH Ethanol

Et₃N Triethylamine

Et₂0 Diethyl ether

Fe Iron

h Hour

hr Hour

HC0₂H Formic acid

HC1 Hydrochloric acid

HM-N Isolute® HM-N is a modified form of diatomaceous earth HOBt Hydro xybenzotriazole

HPLC High performance liquid chromatography

IMS Industrial methylated spirit

IPA Isopropyl alcohol / propan-2-ol

iPr Isopropyl

Me Methyl

MeCN Acetonitrile

MeOH Methanol

MeOD Deuterated methanol

MgSC"4 Magnesium sulfate

min minute / minutes

NaOH Sodium Hydroxide

Na₂S0₄ Sodium sulfate

NaHCC"3 Sodium bicarbonate / Sodium hydrogen carbonate

NaOH Sodium hydroxide

NEt₃ Triethylamine

N¾ Ammonia

NH₄C1 Ammonium chloride

Pd Palladium

Pd on C Palladium on Carbon Pr Propyl

p-TsOH /?ara-toluenesulfonic acid

RT Retention time in minutes (for LCMS)

RT Room temperature (for reaction conditions)

SCX-2 Pre-packed Isolute® silica-based sorbent with a chemically

bonded propylsulfonic acid functional group

TEA Triethylamine

TFA Trifluoro acetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

TMSC1 Trimethylsilyl chloride

General Experimental Conditions:

All temperatures are in degrees Celsius (°C). Unless otherwise stated, operations were carried out at room or ambient temperature (18-25 °C).

Unless otherwise stated, the solvents used in preparing the example compounds were commercial anhydrous grade and were used without further drying or purification.

1H NMR spectra were recorded at ambient temperature or at 80 °C where indicated using one of the following machines: Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe, Bruker Avance DRX400 (400MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DPX 300 (300MHz) equipped with a standard 5mm dual frequency probe for detection of 1H and ¹³C, a Bruker AVIII (400 MHz) using a BBI Broad Band Inverse 5mm probe, or a Bruker AVIII (500 MHz) using a QNP ( Quad Nucleus detect) 5mm probe. Chemical shifts are expressed in ppm relative to an internal standard; tetramethylsilane (ppm = 0.00). The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet, or any combination of. High Pressure Liquid Chromatography - Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions (m+H) were performed using one of the following methods:

Method A: Experiments performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer linked to a Waters Acquity UPLC system with a PDA UV detector. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Acquity BEH CI 8 1.7um 100 x 2.1mm column, maintained at 40°C or an Acquity BEH Shield RP18 1.7 μηι 100 x 2.1mm column, maintained at 40°C and a 0.4 ml / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.4 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was maintained for 0.8 minute before returning to 95% solvent A and 5% solvent B over the next 1.2 minutes. Total run time was 8 minutes.

Method B: Experiments performed on a Finnigan AQA single quadrupole mass spectrometer linked to a Hewlett Packard 1050 LC system with UV diode array detector and autosampler. The spectrometer has an electrospray source operating in positive ion mode. Additional detection is achieved using a Sedex 65 evaporative light scattering detector. This system uses a Luna 3 micron CI 8(2) 30 x 4.6mm column at ambient temperature and a 2.0 ml / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4.0 minutes. This was maintained for 1.0 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.

Method C: The system consists of a Waters Quattro Micro triple quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system with a PDA UV detector. Sample injection is done by a CTC HTS PAL autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses a Higgins Clipeus 5micron CI 8 100 x 3.0mm column at ambient temperature and a 2.0 mL / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. This was maintained for 5 minutes before returning to 95% solvent A and 5% solvent B over the next 2 minutes. Total run time was 25 minutes. Method D:

Waters Acquity UPLC Mobile phase A H₂0 with 0.1%Formic Acid Mobile phase B Acetonitrile with 0.1%Formic Acid Column Acquity UPLC BEH C18, 1.7μιη, 2.1

Column temperature 40 degree C LC gradient 5-95%B in 1.4 min, 95% in 0.3 min LC Flow rate 800uL/min

UV wavelength 220nm and 254nm

Mass Spec - Waters SQ Detector Ionization ESI+

Scan range 100-800amu

Method E: Compounds were analysed using the following conditions: Experiments were performed on a The system consists of a Waters ZMD single quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system with UV diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. This system uses an Phenomenex Luna 3micron CI 8(2) 30 x 4.6mm column at ambient temperature, and a 2.0 ml / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5%> solvent A and 95%> solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.

Method F: Experiments were performed on a Waters Platform LC quadrupole mass spectrometer linked to a Hewlett Packard HP 1100 LC system with diode array detector and 100 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection is achieved using a Sedex 85 evaporative light scattering detector. This system uses an Phenomenex Luna 3micron CI 8(2) 30 x 4.6mm column at ambient temperature, and a 2.0 ml / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.

Method G: Experiments were performed on a Waters ZMD quadrupole mass spectrometer linked to a Waters 1525 LC system with Waters 996 diode array detector. The spectrometer has an electrospray source operating in positive and negative ion mode. Additional detection is achieved using a Sedex 85 evaporative light scattering detector. This system uses an Luna 3micron CI 8(2) 30 x 4.6mm column at ambient temperature, and a 2.0 ml / minute flow rate. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first 0.5 minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. This was maintained for 1 minute before returning to 95% solvent A and 5% solvent B over the next 0.5 minute. Total run time was 6 minutes.

Reverse Phase High Performance Liquid Chromatography (HPLC) was used to purify compounds where indicated. Unless otherwise indicated, the conditions were: elution on a Phenomenex Gemini CI 8 column (250 x 21.2 mm, 5 micron) as stationary phase and using mobile phase indicated, operating at a 18 mL/min flow rate using a Gilson UV/Vis -155 dual channel detector and Gilson GX-271 automated liquid handler.

Microwave experiments were carried out using a Biotage Initiator 2.0 (400 W MAGNETRON^®) which uses a single-mode resonator and dynamic field tuning. Temperature from 40-250°C can be achieved, and pressures of up to 20 bar can be reached.

Intermediate 1

H-CI

(S)-(Tetrahydro-pyran-3-yl)amine hydrochloride (S)-Dimethyl 2-(tert-butoxycarbonylamino)pentanedioate

To MeOH (7L) was added TMSC1 slowly at 0 °C, and the mixture was stirred for 30 min, then L-glutamic acid (700 g, 4.76 mol) was added to the mixture. The mixture was stirred at room temperature until complete reaction was observed (monitored by TLC). After cooling to 0 °C, triethylamine (313 g, 31.0 mol) and Boc₂0 (1.14 Kg, 5.23 mol) were added slowly to the reaction solution successively while keeping the internal temperature below 25 °C, and the resultant solution was stirred for 16 hours. After concentration, the residue was poured into water (5 L) and extracted with ethyl acetate (10 L). The organic phase was washed with 4L of 20% citric acid and brine, and dried over sodium sulfate. After filtration and concentration, the crude (S)-dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (1.30 Kg) was obtained as pale yellow oil.

(S)-tert-Butyl 1 ,5-dihydroxypentan-2-ylcarbamate A 20 L reactor was charged with 10 L of dry THF and lithium boro hydride (400 g) and cooled to 0 °C. A solution of (S)-dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (1.00 Kg , 3.63 mol) dissolved in THF (2 L) was then added dropwise while keeping the internal temp, below 15 °C. The mixture was slowly warmed to room temperature and stirred for 16 hours. Cooled to 0 °C, then MeOH (10 L) was added dropwise to the reaction mixture to quench the excess reducing reagent. Concentrated, and the residue was poured into 5L water. After extraction with ethyl acetate, the combined organic phase was dried over sodium sulfate. After filtration the solvent was removed in vacuo to give 730 g of crude (S)-tert-butyl 1,5- dihydroxypentan-2-ylcarbamate as a pale yellow oil.

(S)-tert-Butyl tetrahydro-2H-pyran-3-ylcarbamate A 20-L reactor equipped with a mechanical stirrer was charged with (S)-tert-butyl 1,5- dihydroxypentan-2-ylcarbamate (950 g, 4.33mol), triphenylphosphine (2.27 Kg, 8.66 mol) and DCM (10 L). Then DIAD (1.75 Kg, 8.66 mol) was added dropwise to the reaction solution. The solution was stirred for 48 hours at room temperature until the reaction was complete. After filtration and concentration in vacuo, the residue was purified by column chromatography with petroleum ether as eluent to give 550 g of (S)-tert-butyl tetrahydro-2H-pyran-3-ylcarbamate as white solid. 1H NMR (400 MHz, CDC1₃) δ 4.77 (m, 1H), 3.78 (d, J = 11.1 Hz, 1H), 3.63 (d, J = 8.8 Hz, 3H), 3.38 (m, 1H), 1.88 (td, J = 8.4, 3.8 Hz, 1H), 1.74 (ddd, J = 10.4, 9.1, 4.9 Hz, 1H), 1.65 - 1.51 (m, 2H), 1.45 (s, 9H).

(S)-(Tetrahydro-pyran-3-yl)amine hydrochloride Intermediate (S)-tert-butyl tetrahydro-2H-pyran-3-ylcarbamate (414 g, 2.06 mol) was added to a 6N HC1 solution of MeOH (4 L) at room temperature, and the reaction mixture was stirred until it was complete (monitored by TLC). After concentration in vacuo, 283 g of (S)- (tetrahydro-pyran-3-yl)amine hydrochloride was obtained as a white solid (yield, 99.8%, enantiomeric excess >99%). 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 3H), 3.87 - 3.72 (m, 1H), 3.70 - 3.57 (m, 1H), 3.54 - 3.38 (m, 2H), 3.12 (d, J = 2.1 Hz, 1H), 2.05 - 1.89 (m, 1H), 1.81 - 1.60 (m, 2H), 1.49 (dtd, J= 12.5, 8.3, 4.3 Hz, 1H).

Intermediate 2

(lR,3R)-3-Amino-cyclohexanol

(lR,3R)-3-Amino-cyclohexanol was prepared following the procedures described in P. Bernardelli et al. / Tetrahedron: Asymmetry 15 (2004) 1451-1455.

Intermediate 3

Trans-4-Amino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester cis and trans 4-Benzylamino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester A stirred solution of 3-fluoro-4-oxo-piperidine-l-carboxylic acid tert-butyl ester (2.00 g,

9.21 mmol) in methanol (20 mL) and acetic acid (1 mL) was treated with benzyl amine (1.11 mL, 10.0 mmol) and stirred at ambient temperature for 3 hours. The mixture was then treated with sodium cyanoborohydride (868 mg, 13.8 mmol) and left to stand overnight. The reaction was quenched with a saturated solution of sodium bicarbonate (20 mL) and extracted with three portions of dichloro methane (50 mL). Combined organic layers were dried with magnesium sulfate and concentrated under vacuum to give crude product. Purification by column chromatography on silica gel (gradient: 0 to 60% ethyl acetate in heptane) gave 734 mg (26%) of trans- 4-benzylamino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester and 653 mg (23%) of cis- 4-benzylamino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester. Trans Data: LCMS (Method D, ESI): RT = 0.67 min, m+H =309.2; 1H NMR (500 MHz, DMSO-d6) δ = 7.33 (s, 5H), 4.44 - 4.31 (m, 1H), 3.84 - 3.65 (m, 3H), 3.53 - 3.41 (m, 1H), 3.17

- 3.07 (m, 1H), 2.80 - 2.68 (m, 1H), 2.34 - 2.28 (m, 1H), 1.85 - 1.74 (m, 1H), 1.39 (s, 9H), 1.36

- 1.30 (m, 1H) Cis Data: LCMS (Method D, ESI): RT = 0.63 min, m+H =309.2; 1H NMR (500 MHz, DMSO- d6) δ = 7.32 (dd, J=18.4, 7.3, 5H), 4.84 - 4.69 (m, 1H), 4.21 - 4.06 (m, 1H), 3.97 - 3.86 (m, 1H), 3.77 (s, 2H), 3.09 - 2.88 (m, 2H), 2.85 - 2.69 (m, 1H), 2.65 - 2.55 (m, 1H), 2.07 - 1.97 (m, 1H), 1.72 - 1.61 (m, 1H), 1.48 - 1.42 (m, 1H), 1.38 (s, 9H).

Trans-4-Amino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester A stirred solution of trans-4-benzylamino-3-fluoro-piperidine-l-carboxylic acid tert-butyl ester (0.17 g, 0.55 mmol) in methanol (2 mL) and was treated with ammonium formate (139 mg, 2.20 mmol) and 10% palladium on activated carbon (59.0 mg, 55.0 μιηοΐ) and stirred at 50 °C for 1 hour. The mixture was then filtered through Celite®, washed with copious methanol and concentrated under vacuum to give 118 mg (100%) of trans-4-amino-3-fluoro-piperidine-l- carboxylic acid tert-butyl ester that was used without further purification. LCMS (Method D, ESI): RT = 0.14 min, m+H =219.0; 1H NMR (400 MHz, DMSO-d6) δ 4.22 - 4.01 (m, 1H), 3.96

- 3.68 (m, 2H), 3.62 - 3.52 (m, 1H), 3.22 - 2.94 (m, 2H), 2.89 - 2.77 (m, 1H), 1.81 - 1.63 (m, 2H), 1.39 (s, 10H), 1.28 - 1.16 (m, 1H).

Intermediate 4

Trans 4-Amino-cyclohexanecarbonitrile trifluoro acetic acid salt

Following the procedure outlined in WO2009/145719 the title compound was prepared from trans-4-(t-butoxycarbonylamino)-cyclohexane carboxylic acid in three steps with isolation of the TFA salt of trans 4-amino-cyclohexanecarbonitrile via diethyl ether trituration and filtration to afford a white solid in 63% overall yield. 1H NMR (400 MHz, DMSO-d6) δ: 7.93 (s, 3 H), 3.03 (m, 1 H), 2.66 (m, 1 H), 2.05 (m, 2 H), 1.92 (dd, 2 H), 1.58 (m, 2 H), 1.31 (m, 2 H).

Intermediate 5

Trans (4-Amino-cyclohexyl)-acetonitrile

Trans Methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester

Trans (4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (3.49 g, 15.0 mmol) in DCM (50 mL) was treated with pyridine (4.98 mL, 60.8 mmol). The mixture was cooled to 0 °C and methanesulfonyl chloride (2.36 mL, 30.4 mmol) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 5 hours and then concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous phase extracted with ethyl acetate (x2). The combined organic extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum. The residue was triturated with cyclohexane then dried under vacuum to give a white solid. Further purification by column chromatography on silica gel (eluting with 1 : 1 cyclohexane/ethyl acetate) gave 4.17 g (90%) of trans methanesulfonic acid 4- tert-butoxycarbonylamino-cyclohexylmethyl ester as a white solid. 1H NMR (400 MHz, CDCI₃) δ: 4.37 (br s, 1 H), 4.02 (d, 2 H), 3.39 (br s, 1 H), 3.00 (s, 3 H), 2.11-2.00 (m, 2 H), 1.91-1.81 (m, 2 H), 1.77-1.64 (m, 1 H), 1.43 (s, 9 H), 1.18-1.05 (m, 4 H).

Trans (4-Cyanomethyl-cyclohexyl)-carbamic acid tert-butyl ester

A mixture of trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (0.93 mg, 3.00 mmol) and sodium cyanide (0.44 g, 9.00 mmol) in DMSO (10 mL) was stirred at 90 °C for 4 hours. After cooling the mixture was partitioned between ethyl acetate and brine and the aqueous phase extracted with ethyl acetate (x2). The combined organic extracts were washed (water and brine), dried (sodium sulfate) and concentrated under vacuum to give 0.72 g (100%) of trans (4-cyanomethyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, CDCI3) δ: 4.38 (br s, 1 H), 3.45-3.33 (m, 1 H), 2.26 (d, 2 H), 2.10-2.02 (m, 2 H), 1.96-1.87 (m, 2 H), 1.71-1.57 (m, 1 H), 1.45 (s, 9 H), 1.26-1.03 (m, 4 H). Trans (4-Amino-cyclohexyl)-acetonitrile

A solution of trans (4-cyanomethyl-cyclohexyl)-carbamic acid tert-butyl ester (0.71 g, 3.00 mmol) in DCM (15 mL) was treated with trifluoroacetic acid (2 mL) and the mixture was stirred at ambient temperature for 2.5 hours, then concentrated under vacuum. The residue was purified by column chromatography using Isolute® SCX-2 cartridge (eluting with MeOH then 2M NH₃ in MeOH) to afford 0.40 g (97%) of trans (4-amino-cyclohexyl)-acetonitrile that was used without further purification. 1H NMR (400 MHz, CDC1₃) δ: 3.52-3.42 (m, 2 H), 2.69-2.60 (m, 1 H), 2.26 (d, 2 H), 1.94-1.83 (m, 4 H), 1.70-1.57 (m, 1 H), 1.24-1.06 (m, 4 H).

Intermediate 6

Trans 3-(4-Amino-cyclohexyl)-propionitrile trifluoro acetic acid salt

Trans (4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester

A mixture of trans (4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (10.0 g, 43.7 mmol) in DCM (225 mL) was treated with dimethylsulfoxide (DMSO) (75 mL) and then cooled to 0 °C. Diisopropylethylamine (30.4 mL, 0.17 mol) was added followed by dropwise addition of a fine suspension of sulphur trioxide pyridine complex (27.8 g, 0.17 mol) in DMSO (75 mL). The mixture was stirred at ambient temperature for 10 minutes and then diluted with diethyl ether and IN aqueous hydrochloric acid with cooling in an ice bath. The phases were separated and the aqueous layer was extracted with ether (x2) and the combined organic phases were washed with IN aqueous hydrochloric acid, and brine, dried with sodium sulfate and concentrated under vacuum. Trituration with pentane gave 9.36 g (94%) of trans (4-formyl- cyclohexyl)-carbamic acid tert-butyl ester as a white solid which was used without further purification. 1H NMR (400 MHz, CDC1₃) δ: 9.62 (d, 1 H), 4.40 (br s, 1 H), 3.51-3.28 (m, 1 H), 2.20-1.99 (m, 4 H), 1.44 (s, 9 H), 1.38 (m, 2 H), 1.16 (m, 2 H).

Trans E- and Z- [4-(2-Cyano-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester

To a suspension of potassium tert-butoxide (5.54 g, 49.5 mmol) in dry THF (110 mL) at 0 °C, diethyl cyanomethyl phosphonate (8.00 mL, 49.5 mmol) was added slowly dropwise and the mixture was stirred at 0 °C for 1 hour. A solution of trans (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (9.36 g, 41.2 mmol) in dry THF (290 mL) was added slowly over -15 mins, then the cooling bath was removed and the mixture was stirred at ambient temperature for 1 hour. Ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (x2) and the combined organic phase washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulfate and concentrated under vacuum to give 12.6 g of crude trans [4-(2-cyano-vinyl)- cyclohexyl]-carbamic acid tert-butyl ester as a ~ 1 :2 mixture of E- and Z- isomers which was used without further purification. The golden oil crystallized almost immediately and was used in the next step without further purification.

E-isomer: 1H NMR (400 MHz, CDC1₃) δ: 6.64 (dd, 1 H), 5.29 (dd, 1 H), 4.39 (m, 1 H), 4.26 (m, 1 H), 3.52-3.28 (m, 1 H), 2.08 (m, 2 H), 1.83 (m, 2 H), 1.44 (s, 9 H), 1.35-1.10 (m, 4 H).

Z-isomer: 1H NMR (400 MHz, CDC1₃) δ: 6.28 (dd, 1 H), 5.25 (dd, 1 H), 4.39 (m, 1 H), 4.26 (m, 1 H), 3.52-3.28 (m, 1 H), 2.08 (m, 2 H), 1.83 (m, 2 H), 1.44 (s, 9 H), 1.35-1.10 (m, 4 H).

Trans [4-(2-Cyano-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester

A mixture of trans E- and Z- [4-(2-cyano-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.00 g, 16.0 mmol) in ethanol (50 mL, IMS grade) under nitrogen was treated with 10% palladium/carbon (1.60 g, 1.50 mmol palladium). The mixture was purged with hydrogen gas and stirred under an atmosphere of hydrogen (balloon) for 64 hours. The mixture was filtered through Celite® and the filtrate was concentrated under vacuum. Purification by column chromatography on silica gel (ethyl acetate/cyclohexane 1 :3) gave 2.68 g (76% over 3 steps) of trans [4-(2-cyano-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester. 1H NMR (400 MHz, CDC1₃) δ: 4.37 (br s, 1 H), 3.38 (br s, 1 H), 2.36 (t, 2 H), 2.03 (m, 2H), 1.79 (m, 2 H), 1.56 (q, 2 H), 1.44 (s, 9 H), 1.36 (m, 1 H), 1.19-0.98 (m, 4 H).

Trans 3-(4-Amino-cyclohexyl)-propionitrile trifluoro acetic acid salt

A solution of trans [4-(2-cyano-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.68 g, 10.6 mmol) in DCM (30 mL) was treated with trifluoro acetic acid (30 mL) and the mixture was stirred at ambient temperature for 30 mins then concentrated under vacuum. The residue was azeotroped with toluene (x3) and the resulting oil was triturated (diethyl ether) to give a solid, that was washed with ether and dried to give 2.75 g (97%) of trans 3-(4-amino-cyclohexyl)- propionitrile trifluoro acetic acid salt as a white solid. 1H NMR (400 MHz, CDC1₃) δ: 7.88 (br s, 3 H), 3.01 (m, l H), 2.37 (t, 2 H), 2.08 (m, 2 H), 1.89 (m, 2 H), 1.59 (q, 2 H), 1.49-1.35 (m, 3 H), 1.04 (m, 2 H).

Intermediate 7

Trans 4-(2-Methanesulfonyl-ethyl)-cyclohexylamine

Trans [4-(2-Methanesulfonyl-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester

A solution of diethyl methanesulfonylmethyl phosphonate (900 mg, 3.90 mmol) in THF (20 mL) was treated with sodium hydride (160 mg of a 60% dispersion in mineral oil, 4.00 mmol). The mixture was stirred for 1 hour to give a thick slurry. Trans (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (975 mg, 4.30 mmol) was added and the slurry thinned. The mixture was stirred for 2 hours. A few drops of methanol were added and after 5 minutes the solvent removed under vacuum. The residue was partitioned between water (25 mL) and DCM (25 mL). The aqueous phase was washed with DCM (2 x 10 mL). The combined organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 1.30 g (100%) of crude trans [4- (2-methanesulfonyl-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester as a white solid (Ή NMR showed -4: 1 mixture of double bond geometries).

Major isomer Ή NMR (400 MHz, CDC1₃): δ 6.88 (dd, 1 H), 6.32 (dd, 1 H), 4.39 (br s, 1 H), 3.40 (br s, 1 H), 2.93 (s, 3 H), 2.21-1.98 (m, 3 H), 1.91-1.78 (m, 2 H), 1.44 (s, 9 H), 1.35-1.09 (m, 4 H).

For the minor isomer the following signals were clearly discernable δ 6.20 (d, 1 H), 6.12 (t, 1 H) and 2.96 (s, 3 H). Other signals were either coincident with those for the major isomer or ill- defined. Trans [4-(2-Methanesulfonyl-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester

To trans [4-(2-methanesulfonyl-vinyl)-cyclohexyl]-carbamic acid tert-butyl ester (1.00 g, 3.30 mmol) in ethanol (15 mL, IMS grade), 10% palladium on carbon (100 mg) followed by ammonium formate (1.25 g, 19.8 mmol) were added. The mixture was heated at 90 °C for 45 min, then cooled to room temperature. A further 100 mg portion of palladium on carbon was added and the mixture was heated at 95 °C for 16 hours. The mixture was cooled to room temperature then filtered and concentrated under vacuum. The residue was taken up in water and extracted with ethyl acetate (^x3). The combined organic extracts were washed (brine), dried (sodium sulfate) and concentrated under vacuum to give 928 mg (92%>) of trans [4-(2- methanesulfonyl-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester. LCMS (Method E, ESI): RT = 3.35 min, m+H = 204.1 ; NMR (400 MHz, CDC1₃) δ: 4.36 (br s, 1 H), 3.38 (br s, 1 H), 3.01 (m, 2 H), 2.89 (s, 3 H), 2.07-1.98 (m, 2 H), 1.82-1.72 (m, 4 H), 1.44 (s, 9 H), 1.36-1.08 (m, 5 H).

Trans 4-(2-Methanesulfonyl-ethyl)-cyclohexylamine Trans [4-(2-methanesulfonyl-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (900 mg, 2.95 mmol) was dissolved in DCM (7 mL) and trifluoro acetic acid (7 mL) was added. The mixture was stirred at room temperature for 1 h, then concentrated. The residue was taken up in methanol and purified by I so lute® SCX-2 column (gradient: methanol to 2 M NH₃ in methanol) to give 594 mg (98%) of trans 4-(2-methanesulfonyl-ethyl)-cyclohexylamine. LCMS (Method E, ESI): RT = 0.48 min, m+H = 206.1; NMR (400 MHz, DMSO-d6) δ: 3.09 (m, 2 H), 2.93 (s, 3 H), 2.48- 2.41 (m, 1 H), 1.78-1.64 (m, 4 H), 1.58-1.51 (m, 2 H), 1.30-1.18 (m, 1 H), 1.03-0.82 (m, 4 H).

Intermediate 8

((lR,3R)-3-Amino-cyclopentyl)-carbamic acid tert-butyl ester ((lR,3R)-3-Allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester

A mixture of (lR,3R)-3-tert-butoxycarbonylamino-cyclopentanecarboxylic acid (1.00 g, 4.36 mmol), diphenylphosphoryl azide (1.41 mL, 6.54 mmol) and triethylamine (1.21 mL, 8.72 mmol) in toluene (15 mL) was heated at 90 °C for 2 hours then cooled to ambient temperature. Allyl alcohol (1.63 mL, 24.0 mmol) and DMAP (54.0 mg, 0.44 mmol) were added and the resulting mixture heated at 90 °C for 18 hours. The cooled reaction mixture was concentrated under vacuum and the resulting residue was dissolved in ethyl acetate. The mixture was washed with 10% aqueous citric acid, saturated aqueous sodium carbonate and brine. The combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried (sodium sulfate) and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel (gradient: 0 to 12% ethyl acetate in cyclohexane) to afford 890 mg (72%) of ((lR,3R)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ: 7.23 (d, 1 H), 6.85 (d, 1 H), 5.90 (m, 1 H), 5.26 (dq, 1 H), 5.16 (dq, 1 H), 4.46-4.41 (m, 2 H), 3.93-3.83 (m, 2 H), 1.88 (m, 2 H), 1.65 (t, 2 H), 1.37 (s, 9 H).

((lR,3R)-3-Amino-cyclopentyl)-carbamic acid tert-butyl ester

A mixture of ((lR,3R)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester (890 mg, 3.13 mmol), 1,3-dimethylbarbituric acid (1.47 g, 9.39 mmol) and Pd(PPh₃)₄ (181 mg, 0.15 mmol) in DCM (30 mL) was stirred at ambient temperature for 90 minutes. The reaction mixture was concentrated under vacuum and purified by column chromatography on silica gel (gradient: 2M NH₃ in methanol solution in DCM) to afford 350 mg (56%) ((lR,3R)-3-amino-cyclopentyl)- carbamic acid tert-butyl ester. LCMS (Method F, ESI): RT = 0.36 min, m+H = 200.9; 1H NMR (400 MHz, DMSO-d6) δ: 6.77 (s, 1 H), 3.90 (m, 1 H), 3.31 (m, 1 H), 1.87 (m, 2 H), 1.54 (m, 2 H), 1.37 (s, 10 H), 1.18 (m, 1 H).

Intermediate 9

((lR,3S)-3-Amino-cyclopentyl)-carbamic acid tert-butyl ester ((lR,3S)-3-Allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester

Following the procedure for ((lR,3R)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert- butyl ester the title compound was prepared from (lR,3S)-3-tert-butoxycarbonylamino- cyclopentanecarboxylic acid to afford 760 mg (61%) of ((lR,3S)-3-allyloxycarbonylamino- cyclopentyl)-carbamic acid tert-butyl ester as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.22 (d, 1 H), 6.84 (d, 1 H), 5.90 (m, 1 H), 5.27 (dq, 1 H), 5.16 (dq, 1 H), 4.47-4.42 (m, 2 H), 3.76 (m, 2 H), 2.14 (m, 1 H), 1.78-1.71 (m, 2 H), 1.50-1.44 (m, 2 H), 1.37 (s, 9 H), 1.27 (m, 1 H).

((lR,3S)-3-Amino-cyclopentyl)-carbamic acid tert-butyl ester

Following the procedure for ((lR,3R)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester the title compound was prepared from ((lR,3S)-3-allyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester with further purification by column chromatography on silica gel (gradient: 0 to 5% methanol in DCM then 0 to 10% 2M NH₃ in methanol solution in DCM) to afford 300 mg (56%) of ((lR,3S)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester. LCMS (Method G, ESI): RT = 0.32 min, m+H-Boc = 101.2; 1H NMR (400 MHz, DMSO-d6) δ: 6.84 (s, 1 H), 3.77-3.69 (m, 1 H), 3.21 (m, 2 H), 2.00 (m, 1 H), 1.78-1.63 (m, 2 H), 1.50 (m, 1 H), 1.37 (s, 9 H), 1.17 (m, 1 H).

Intermediate 10

Racemic trans (3-Amino-cyclopentyl)-carbamic acid tert-butyl ester

Racemic trans (3-amino-cyclopentyl)-carbamic acid tert-butyl ester was prepared following the methods outlined in J. Org. Chem. 2004, 69(13), 4538; Tetrahedron 1997, 53(9), 3347; WO94/17090 and Org. Lett. 2000, 2, 4169.

Intermediate 11

Racemic cis (3-Amino-cyclopentyl)-carbamic acid tert-butyl ester Racemic cis (3-amino-cyclopentyl)-carbamic acid tert-butyl ester was prepared following the methods outlined in J. Org. Chem. 2004, 69, 4538; Tetrahedron 1997, 53, 3347; WO2008/065021 ; WO94/17090; and Org Lett 2000, 2, 4169.

Intermediate 12

(( 1 R,3 S)-3-Amino-cyclopentyl)-acetonitrile ((lR,3S)-3-Amino-cyclopentyl)-acetonitrile was prepared following the methods outlined in Thomas, Abraham et al WO 2006040625.

Intermediate 13

( 1 R,3 S)-3-Amino-cyclopentanecarbonitrile

(lR,3S)-3-Amino-cyclopentanecarbonitrile was prepared following the methods outlined in Thomas, Abraham et al WO 2006040625.

Intermediate 14

Trans 3-(4-Amino-cyclohexylamino)-propionitrile

Trans 3-(4-Amino-cyclohexylamino)-propionitrile can be prepared following the methods outlined in WO 1994/15596 or using the route described below.

Trans [4-(2-Cyano-ethylamino)-cyclohexyl]-carbamic acid tert-butyl ester

The titled compound was prepared following the methods outlined in S. Fixon-Owoo et al. Phytochemistry 63 (2003) 315-334.

Trans 3-(4-Amino-cyclohexylamino)-propionitrile

Trans [4-(2-cyano-ethylamino)-cyclohexyl]-carbamic acid tert-butyl ester (5.75 g, 21.5 mmol) in DCM (50 mL) was treated dropwise with TFA (50 mL) at 0 °C. The mixture was then stirred for 30 minutes. The volatiles were removed in vacuo and the residue azeotroped (toluene) and triturated (diethyl ether) to furnish a white solid. Purification by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) afforded 3.32 g (92%) of trans 3-(4-amino-cyclohexylamino)-propionitrile as a golden oil. LCMS (Method B, ESI): RT = 0.53 min.

Example 1

Trans (4-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - acetonitrile

Trans [4-(3-Nitro-[ 1 ,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile A suspension of 4-chloro-3-nitro-[l,5]naphthyridine (prepared according to the procedures outlined in David Ach et al. WO 2006071862) (0.98 g, 4.69 mmol) in propan-2-ol (12 mL) was treated with trans (4-amino-cyclohexyl)-acetonitrile (0.71 g, 5.14 mmol) and N,N- diisopropylethyl amine (DIPEA, 1.22 mL, 7.02 mmol) and the reaction mixture was heated at 120 °C using microwave irradiation for 20 minutes. On cooling, a solid precipitated out of solution. This was filtered, washed with propan-2-ol (2x) and water and dried in vacuo, at 60°C to afford 0.88 g (60%) of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile as a brown solid. LCMS (Method B, ESI): RT = 3.44 min, m+H = 312.2; 1H NMR (400 MHz, CDCI3): δ 9.39 (s, 1 H), 8.83 (dd, 1 H), 8.25 (dd, 1 H), 7.68 (dd, 1 H), 2.39 (m, 4 H), 2.05- 1.96 (m, 2 H), 1.89-1.76 (m, 1 H), 1.66-1.55 (m, 1 H), 1.54-1.38 (m, 4 H). Trans [4-(3-Amino-[ 1 ,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile

A mixture of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile (0.88 g, 2.83 mmol) in ethanol (IMS grade, 8.80 mL) and water (2.90 mL) was treated with ammonium chloride (0.91 g, 17.0 mmol), followed by iron powder (0.63 g, 11.3 mmol) and the reaction mixture was heated at 80 °C for 8 hours. The reaction mixture was treated with further portions of ammonium chloride (0.33 g) and iron powder (0.32 g) and heating continued for 45 minutes. The iron residue was collected on a pad of Celite® and washed several times with ethanol (IMS grade) and water (3: 1). The filtrate was concentrated in vacuo and the aqueous residue was treated with saturated sodium hydro gencarbonate solution and extracted with ethyl acetate (EtOAc) (3x). The combined organic phases were washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo to give 0.66 g of a brown gummy solid. Purification by column chromatography on silica gel (gradient: EtOAc to 5% [2M NH₃ in methanol (MeOH)] in EtOAc) afforded 0.63 g (79%) of trans [4-(3-amino- [l,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile as a pale brown oil, which crystallized on standing. LCMS (Method B, ESI): RT = 2.17 min, m+H = 282.2; 1H NMR (400 MHz, CDC1₃): δ 8.73 (dd, 1 H), 8.44 (s, 1 H), 8.21 (dd, 1 H), 7.41 (dd, 1 H), 5.71 (d, 1 H), 3.70 (s, 2 H), 3.64 (m, 1 H), 2.30 (d, 2 H), 2.11-2.05 (m, 2 H), 1.96-1.88 (m, 2 H), 1.79-1.67 (m, 1 H), 1.44-1.20 (m, 4 H). Trans (4-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - acetonitrile

A solution of (R)-(+)-lactamide (0.64 g, 7.19 mmol) in anhydrous tetrahydrofuran (THF, 9.80 mL), under an atmosphere of nitrogen was treated with triethyloxonium tetrafluoroborate (1.28 g, 6.74 mmol) and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 4.60 mL). This was added to a solution of trans [4-(3-amino-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile (0.63 g, 2.24 mmol) in ethanol (absolute grade, 15 mL) and the reaction mixture was heated to 75 °C, under an atmosphere of nitrogen for 1 hour. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated in vacuo to give 1.96 g of a yellow oil. Purification by column chromatography on silica gel (gradient: EtOAc to 7% [2M NH₃ in MeOH] in EtOAc) afforded 0.62 g of a pale yellow gum, which crystallized on standing. This was triturated (diethyl ether) to afford 0.48 g, (64%) of trans {4-[2-((R)-l- hydroxy-ethyl)-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl]-cyclohexyl}-acetonitrile as a white solid. LCMS (Method A, ESI): RT = 3.02 min, m+H = 336.1; 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1 H), 9.07 (s, 1 H), 8.53 (d, 1 H), 7.75 (dd, 1 H), 5.86 (m, 1 H), 5.26 (m, 1 H), 4.98 (m, 1 H), 3.29-3.16 (m, 1 H), 2.61 (d, 2 H), 2.15-1.92 (m, 4 H), 1.91-1.77 (m, 2 H), 1.69 (d, 3 H), 1.47-1.32 (s, 2 H).

Example 2

(R)-l-{l-[(lS,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl} -ethanol

[(lR,3S)-3-(3-Nitro-[l,5]naphthyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester

A suspension of 4-chloro-3-nitro-[l,5]naphthyridine (175 mg, 0.84 mmol) in propan-2-ol (5 mL) was treated with ((lR,3S)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester (184 mg, 0.92 mmol) and DIPEA (219 uL, 1.26 mmol) and the reaction mixture was heated at 120 °C using microwave irradiation for 20 minutes. On cooling, a solid precipitated out of solution. This was filtered, washed with propan-2-ol (2x) and water and dried in vacuo to afford 111 mg (36%) of [(lR,3S)-3-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a dark yellow solid. The filtrate was re-filtered and the solid obtained was washed and dried in vacuo to produce a second crop of [(lR,3S)-3-(3-nitro-[l,5]naphthyridin-4-ylamino)- cyclopentyTJ-carbamic acid tert-butyl ester (99 mg, 32%). LCMS (Method B, ESI): RT = 3.73 min, m+H = 374.2; 1H NMR (400 MHz, CDC1₃): δ 9.38 (s, 1 H), 8.82 (dd, 1 H), 8.24 (dd, 1 H), 7.66 (dd, 1 H), 4.60 (m, 1 H), 4.09 (m, 1 H), 2.83-2.71 (m, 1 H), 2.38-2.26 (m, 1 H), 2.21- 2.09 (m, 1 H), 1.89-1.77 (m, 1 H), 1.75-1.64 (m, 1 H), 1.62-1.52 (m, 1 H, obscured by water), 1.45 (s, 9 H).

[(lR,3S)-3-(3-Amino-[l,5]naphthyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester

A mixture of [(lR,3S)-3-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclopentyl]-carbamic acid tert- butyl ester (196 mg, 0.53 mmol) in ethanol (IMS grade, 3 mL) and water (1 mL) was treated with ammonium chloride (169 mg, 3.2 mmol), followed by iron powder (118 mg, 2.1 mmol) and the reaction mixture was heated at 80 °C for 1.5 hours. After cooling, the iron residue was collected on a pad of Celite® and washed several times with ethanol (IMS grade) and water (3: 1). The organics were concentrated in vacuo and the aqueous residue was treated with saturated sodium hydro gencarbonate solution and extracted with EtOAc (3x). The combined organic phases were washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo to give a yellow gum. This was purified by column chromatography on silica gel (gradient: EtOAc to 10% [20% (2M NH₃ in MeOH)] in EtOAc) to afford 157 mg (87%>) of [(lR,3S)-3-(3-amino-[l,5]naphthyridin-4-ylamino)-cyclopentyl]- carbamic acid tert-butyl ester as a pale yellow gum. LCMS (Method B, ESI): RT = 2.45 min, m+H = 344.1; 1H NMR (400 MHz, CDC1₃): δ 8.78 (s, 1 H), 8.48 (s, 1 H), 8.24 (dd, 1 H), 7.42 (dd, 1 H), 6.16 (s, 1 H), 5.52 (m, 1 H), 4.30-4.21(m, 1 H), 4.11-4.03 (m, 1 H), 3.84 (s, 2 H), 2.12-1.93 (m, 2 H), 1.88-1.73 (m, 2 H), 1.62-1.54 (s, 2 H), 1.46 (s, 9 H). {(1 R,3 S)-3-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]- cyclopentyl}-carbamic acid tert-butyl ester

A solution of (R)-(+)-lactamide (133 mg, 1.50 mmol) in anhydrous dichloro methane (DCM, 2 mL), under an atmosphere of nitrogen was treated with triethyloxonium tetrafluoroborate (201 mg, 1.40 mmol) and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 1 mL). This was added to a solution of [(lR,3S)-3-(3-amino-[l,5]naphthyridin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester (157 mg, 0.46 mmol) in ethanol (absolute grade, 3 mL) and the reaction mixture was heated to 75 °C, under an atmosphere of nitrogen for 1 hour. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated in vacuo to give a yellow oil. This was purified by column chromatography on silica gel (gradient: EtOAc to 10% [20% (2M NH₃ in MeOH)] in EtOAc) to afford 95 mg (52%) of a colourless gum. LCMS (Method B, ESI): RT = 3.03 min, m+H = 398.2; 1H NMR (400 MHz, CDC1₃): δ 9.37 (s, 1 H), 9.13 (m, 1 H), 8.61 (d, 1 H), 7.69 (dd, 1 H), 6.97 (m, 1 H), 5.29 (m, 1 H), 5.19 (m, 1 H), 4.35 (m, 1 H), 3.10 (d, 1 H), 3.00-2.89 (m, 1 H), 2.71-2.58 (m, 1 H), 2.55-2.45 (m, 1 H), 2.14-1.99 (m, 3 H, obscured by EtOAc), 1.80 (d, 3 H), 1.55 (s, 9 H).

(R)- 1 -[ 1 -(( 1 S,3R)-3-Amino-cyclopentyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-yl]- ethanol

{(1 R,3 S)-3-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]- cyclopentyl}-carbamic acid tert-butyl ester (95.0 mg, 0.24 mmol) was treated with 20% trifluoro acetic acid (TFA) in DCM (5 mL) solution and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue was purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) to afford 54 mg (76%) of (R)-l-[l-((lS,3R)-3-amino-cyclopentyl)-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl] -ethanol as a white solid. LCMS (Method B, ESI): RT = 0.52/1.04 min, m+H = 298.1 ; 1H NMR (400 MHz, CDC1₃): δ 9.35 (s, 1 H), 8.96 (dd, 1 H), 8.55 (dd, 1 H), 7.64 (dd, 1 H), 5.67 (m, 1 H), 5.37 (q, 1 H), 3.63 (m, 1 H), 2.94-2.82 (m, 1 H), 2.69-2.57 (m, 1 H), 2.47-2.38 (m, 1 H), 2.24-2.08 (m, 3 H), 1.81 (d, 3 H).

(R)-l-{l-[(lS,3R)-3-(2,2,2-Trifiuoro-ethylamino)-cyclopentyl]-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl} -ethanol A solution of (R)-l-[l-((lS,3R)-3-amino-cyclopentyl)-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl]-ethanol (51.5 mg, 0.17 mmol) in anhydrous THF (2 mL) was treated with triethylamine (48.0 μί, 0.35 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (26.0 μί, 0.18 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue purified by reverse phase high pressure liquid chromatography (HPLC) (gradient: 5 to 40% MeCN in H₂0 with 0.1% HC0₂H). The material obtained was then purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) to give a colourless gum, which was triturated (EtOAc and diethyl ether) to afford 15.4 mg, (23%) of (R)-l-{l-[(lS,3R)-3- (2,2,2-trifluoro-ethylamino)-cyclopentyl]-lH- 1,3,5, 9-tetraaza-cyclopenta[a]naphthalen-2-yl}- ethanol as a white solid. LCMS (Method A, ESI): RT = 2.19 min, m+H = 380.1; 1H NMR (400 MHz, DMSO-d6): δ 9.30 (s, 1 H), 9.04 (dd, 1 H), 8.55 (dd, 1 H), 7.79 (dd, 1 H), 5.87 (d, 1 H), 5.64 (m, 1 H), 5.27 (m, 1 H), 3.54-3.32 (m, 2 H, obscured by water), 2.70-2.57 (m, 3 H), 2.35- 2.25 (m, 1 H), 2.21-1.97 (m, 3 H), 1.68 (d, 3 H).

Example 3

( 1 R,3R)-3-(2-Methyl- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl)-cyclohexanol

( 1 R,3R)-3 -(3 -Nitro- [ 1 ,5 ]naphthyridin-4-ylamino)-cyclohexano 1 A mixture of 4-chloro-3-nitro-[l,5]naphthyridine (100 mg, 0.48 mmol) in propan-2-ol (2 mL) was treated with (lR,3R)-3-amino-cyclohexanol [prepared following the procedures described in: P. Bernardelli et al. / Tetrahedron: Asymmetry 15 (2004) 1451-1455] (60.5 mg, 0.52 mmol) and DIPEA (207 μί, 1.19 mmol) and the reaction mixture was heated at 120 °C in the microwave for 20 minutes. After cooling, the resulting precipitate was collected and washed with propan-2-ol and air dried. (lR,3R)-3-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexanol (85.6 mg, 62%>) was isolated as a yellow/ green solid. LCMS (Method B, ESI): RT = 2.71 min, m+H = 289.1; 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1 H), 8.92 (dd, 1 H), 8.29 (dd, 1 H), 7.87 (dd, 1 H), 4.60 (d, 1 H), 3.94 (s, 1 H), 2.01-1.89 (m, 2 H), 1.84-1.71 (m, 2 H), 1.64-1.46 (m, 4 H).

(lR,3R)-3-(3-Amino-[l,5]naphthyridin-4-ylamino)-cyclohexanol

To a stirred suspension of (lR,3R)-3-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexanol (82.0 mg, 284 μηιοΐ) and iron powder (62.0 mg, 1.11 mmol) in ethanol (IMS grade, 2 mL) a solution of ammonium chloride (88.3 mg, 1.65 mmol) in water (0.5 mL) was added at room temperature. The mixture was then heated at 80 °C for 2 hours. After cooling, the mixture was filtered through of Celite® and the filter cake washed several times with ethanol (IMS grade) and water (4: 1). The filtrate was concentrated in vacuo and the resulting aqueous residue was treated with saturated sodium hydro gencarbonate solution and extracted with ethyl acetate (3x). The combined organic phases were washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo to afford 67.0 mg (91%) of (lR,3R)-3-(3- amino-[l,5]naphthyridin-4-ylamino)-cyclohexanol as a pale yellow residue. This material was used for the next step without further purification. LCMS (Method B, ESI): RT = 1.88 min, m+H = 259.1; 1H NMR (400 MHz, DMSO-d6): δ 8.71 (dd, 1 H), 8.42 (s, 1 H), 8.11 (dd, 1 H), 7.41 (dd, 1 H), 5.62 (d, 1 H), 5.01 (s, 2 H), 4.39 (d, 1 H), 4.29-4.18 (m, 1 H), 3.91-3.83 (m, 1 H), 1.73-1.23 (m, 8 H).

( 1 R,3R)-3-(2-Methyl- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl)-cyclohexanol

A stirred mixture of (lR,3R)-3-(3-amino-[l,5]naphthyridin-4-ylamino)-cyclohexanol (67.0 mg, 259 μιηοΐ) and triethyl orthoacetate (71.3 μί, 389 μιηοΐ) in acetic acid (2 mL) was heated to 120 °C for 30 minutes. After cooling, the mixture was concentrated in vacuo and the residue purified by column chromatography using an Isolute® SCX-2 cartridge (eluting: MeOH to 2M NH₃ in MeOH solution). The crude product was purified by reverse phase HPLC (gradient: 5 to 98% acetonitrile (MeCN) in water, + 0.1% HC0₂H) and relevant fractions combined and then purified by column chromatography using an Isolute® SCX-2 cartridge (eluting with MeOH to 2M NH₃ in MeOH solution) to provide 21.0 mg (29%) of (lR,3R)-3-(2-methyl-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-l-yl)-cyclohexanol as a pale yellow solid. LCMS (Method A, ESI): RT = 2.46 min, m+H = 283.1; 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1 H), 9.03 (s, 1 H), 8.52 (dd, 1 H), 7.73 (dd, 1 H), 4.86 (br s, 1 H), 4.74 (s, 1 H), 4.21 (m, 1 H), 2.75 (s, 3 H), 2.05-1.90 (m, 2 H), 1.88-1.60 (m, 6 H).

Example 4

Trans [4-(2-Hydroxymethyl- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl)-cyclohexyl]- acetonitrile

A solution of glycolamide (52.4 mg, 698 μηιοΐ) in anhydrous THF (2 mL), under an atmosphere of nitrogen, was treated with triethyloxonium tetrafluoroborate (122 mg, 641 μιηοΐ) and stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 1.5 mL). This was added to a stirred solution of trans [4-(3- amino-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-acetonitrile (60.0 mg, 214 μιηοΐ) in ethanol (absolute grade, 2.5 mL) and the reaction mixture was heated to 75 °C for 2 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase extracted with EtOAc (2x). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to give a gum. Purified by column chromatography on silica gel (gradient: EtOAc to 30% [2M NH₃ in MeOH] in EtOAc) to afford 46.6 mg of trans [4-(2- hydroxymethyl-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl)-cyclohexyl]-acetonitrile as a white solid. LCMS (Method A, ESI): RT = 2.87 min, m+H = 322.0; 1H NMR (400 MHz, DMSO): δ (400 MHz, DMSO-d6): δ 9.27 (s, 1 H), 9.07 (m, 1 H), 8.54 (dd, 1 H), 7.76 (dd, 1 H), 5.84 (t, 1 H), 4.91 (d, 2 H), 4.82 (s, 1 H), 3.22 (s, 1 H), 2.61 (d, 2 H), 2.11-1.79 (m, 6 H), 1.48-1.35 (m, 2 H).

Example 5

Trans (4-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-cyclohexyl} -acetonitrile Trans [4-(3-Nitro-quinolin-4-ylamino)-cyclohexyl]-acetonitrile

A solution of trans (4-amino-cyclohexyl)-acetonitrile (1.74 g) in propan-2-ol (25 mL) was treated with DIPEA (3.00 mL) and 4-chloro-3-nitro-quinoline (CAS: 39061-97-7) (3.00 g) at room temperature. The mixture was then heated to reflux for 2 hours. After cooling, the resulting yellow precipitate was collected, washed (propan-2-ol and diethyl ether) and air dried to provide 3.74 g of trans [4-(3-nitro-quinolin-4-ylamino)-cyclohexyl]-acetonitrile as a yellow solid. 1H NMR (400 MHz, CDC1₃): δ 9.38 (s, 1 H), 9.34 (d, 1 H), 8.14 (d, 1 H), 8.02 (dd, 1 H), 7.80 (ddd, 1 H), 7.53 (ddd, 1 H), 4.21-4.08 (m, 1 H), 2.41-2.30 (m, 4 H), 2.03 (m, 2 H), 1.88-1.77 (m, 1 H), 1.66-1.53 (m, 2 H, partially obscured by water), 1.44-1.30 (m, 2 H). Trans [4-(3-Amino-quinolin-4-ylamino)-cyclohexyl]-acetonitrile

A solution of trans [4-(3-nitro-quinolin-4-ylamino)-cyclohexyl]-acetonitrile (3.50 g) in EtOAc (75 mL) and THF (75 mL) was treated with palladium on carbon (350 mg) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 4 hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The residue was triturated (ethyl acetate) and the resulting solid washed (10% ethyl acetate in diethyl ether) and air dried to provide 1.40 g (44%) of trans [4-(3-amino- quinolin-4-ylamino)-cyclohexyl]-acetonitrile as a yellow solid. The filtrate from the above trituration was concentrated in vacuo and the residue purified by column chromatography on silica gel (gradient: EtOAc to 2.5%[2M NH₃ in MeOH] in EtOAc). The resulting residue was triturated (pentane) to give an additional 1.38 g (43%) of trans [4-(3-amino-quinolin-4-ylamino)- cyclohexyl]-acetonitrile as a red solid, which was analytically identical to the first batch. 1H NMR (400 MHz, CDC1₃): δ 8.49 (s, 1 H), 8.00-7.96 (m, 1 H), 7.80-7.76 (m, 1 H), 7.50-7.42 (m, 2 H), 3.78 (s, 2 H), 3.36-3.26 (m, 1 H), 2.26 (d, 2 H), 2.12-2.03 (m, 2 H), 1.95-1.87 (m, 2 H), 1.78-1.65 (m, 1 H), 1.41-1.29 (m, 2 H), 1.24-1.12 (m, 2 H). Trans (4-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-cyclohexyl} -acetonitrile

A suspension of triethyloxonium tetrafluoroborate (2.44 g) in THF (25 mL) was treated with (R)- (+)-lactamide (1.37 g) at room temperature and stirred for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 25 mL) and trans [4-(3-amino- quinolin-4-ylamino)-cyclohexyl]-acetonitrile (2.40 g) was added. The mixture was heated to 75 °C for 4 hours. TLC analysis indicated remaining starting material, therefore a suspension of triethyloxonium tetrafluoroborate (2.44 g) in THF (25 mL) was treated with (R)-(+)-lactamide (1.37 g) at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in minimal ethanol and added to the above reaction mixture at room temperature and then heated at 75 °C for 18 hours. After cooling, the solvent was removed in vacuo and the resulting residue dissolved EtOAc. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 5% to 10% [2M NH₃ in MeOH] in EtOAc) afforded 1.83 g (64%) trans {4-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l- yl]-cyclohexyl}-acetonitrile as a foam. LCMS (Method A, ESI): RT = 2.42 min, m+H = 335.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.13 (s, 1 H), 8.46 (d, 1 H), 8.16 (dd, 1 H), 7.76- 7.63 (m, 2 H), 5.42 (d, 1 H), 5.26-5.08 (m, 2 H), 2.60-2.52 (m, 3 H), 2.16-1.99 (m, 6 H), 1.70 (d, 3 H), 1.56-1.41 (m, 2 H).

Example 6

Trans (R)- 1 - { 1 -[4-(2,2,2-Trifluoro-ethylamino)-cyclohexyl]- lH-imidazo[4,5-c]quinolin-2-yl} - ethanol

Trans [4-(3-Nitro-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

A suspension of 4-chloro-3-nitro-quinoline (800 mg, 3.80 mmol) in propan-2-ol (10 mL) was treated with (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (903 mg, 4.20 mmol) and DIPEA (1.00 mL, 5.80 mmol) and the reaction mixture was heated at 120 °C using microwave irradiation for 25 minutes. After cooling, the resulting precipitate was collected by filtration, washed (propan-2-ol, water and diethyl ether) and dried between 50-70 °C under vacuum for 90 minutes. Trans [4-(3-nitro-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.30 g, 88%) was isolated as a yellow solid. LCMS (Method B, ESI): RT = 3.17 min, m+H = 387; 1H NMR (400 MHz, CDC1₃): δ 9.37 (s, 1 H), 9.34 (d, 1 H), 8.14 (d, 1 H), 8.01 (dd, 1 H), 7.78 (ddd, 1 H), 7.51 (ddd, 1 H), 4.40 (s, 1 H), 4.18-4.05 (m, 1 H), 3.53 (s, 1 H), 2.28 (m, 2 H), 2.16 (m, 2 H), 1.79-1.59 (m, 2 H), 1.46 (s, 9 H), 1.37-1.24 (m, 2 H).

Trans [4-(3-Amino-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester A suspension of trans [4-(3-nitro-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.30 g, 3.40 mmol) in ethanol (IMS grade, 34 mL) was treated with palladium on carbon (360 mg, 10% Pd, 0.34 mmol) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo. The residue purified by column chromatography on silica gel (gradient: EtOAc to 7%[2M NH₃ in MeOH] in EtOAc) to give 695 mg (58%) of trans [4-(3-amino-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester as an orange foam. LCMS (Method B, ESI): RT = 2.49 min, m+H = 357; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 8.39 (s, 1 H), 7.95 (m, 1 H), 7.72 (m, 1 H), 7.37-7.27 (m, 2 H), 4.75 (m, 2 H), 4.23 (d, 1 H), 3.63 (s, 1 H), 3.27-3.13 (m, 2 H), 1.89-1.74 (m, 4 H), 1.48-1.37 (m, 2 H, partially obscured by water), 1.22- 1.09 (m, 2 H).

Trans {4-[2-((R)-l-Hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]-cyclohexyl}-carbamic acid tert- butyl ester

A solution of (R)-(+)-lactamide (257 mg, 2.90 mmol) in anhydrous DCM (4.1 mL), under an atmosphere of nitrogen was treated with triethyloxonium tetrafluoroborate (514 mg, 2.70 mmol) and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 2.2 mL). This was added to a suspension of trans [4-(3-amino-quinolin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (322 mg, 0.90 mmol) in ethanol (absolute grade, 6 mL) and the reaction mixture was heated to 75 °C for 3 hours. The volatiles were removed in vacuo and the residue was triturated (EtOAc) to provide 229 mg (62%) of trans {4-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]- cyclohexyl}-carbamic acid tert-butyl ester as a white solid. LCMS (Method B, ESI): RT = 2.54 min, m+H = 411; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.44 (d, 1 H), 8.17 (dd, 1 H), 7.75-7.64 (m, 2 H), 6.43 (s, 1 H), 5.44 (m, 1 H), 5.27-5.18 (m, 1 H), 5.17-5.06 (m, 1 H), 3.68-3.54 (m, 1 H), 2.60-2.49 (m, 2 H), 2.14-2.01 (m, 4 H), 1.70 (d, 3 H), 1.65-1.51 (m, 2 H), 1.43 (s, 9 H).

Trans (R)- 1 -[ 1 -(4-Amino-cyclohexyl)- lH-imidazo[4,5-c]quinolin-2-yl]-ethanol

Trans {4-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]-cyclohexyl}-carbamic acid tert- butyl ester (224 mg, 0.55 mmol) was treated with TFA (3 mL) at room temperature for 25 minutes. The mixture was concentrated in vacuo and the resulting residue azeotroped with toluene. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge (eluting with MeOH to 2M NH₃ in MeOH solution) and the isolated product triturated (diethyl ether) to provide 146 mg (86%) of trans (R)-l-[l-(4-amino-cyclohexyl)-lH-imidazo[4,5- c]quinolin-2-yl] -ethanol as a white solid. LCMS (Method B, ESI): RT = 0.63 min, m+H = 311 ; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.15 (s, 1 H), 8.47 (d, 1 H), 8.17 (m, 1 H), 7.76- 7.65 (m, 2 H), 5.43 (s, 1 H), 5.26-5.19 (m, 1 H), 5.18-5.08 (m, 1 H), 2.61-2.50 (m, 2 H, partially obscured by DMSO), 2.09-1.96 (m, 4 H), 1.71 (d, 3 H), 1.50-1.36 (m, 2 H).

Trans (R)- 1 - { 1 -[4-(2,2,2-Trifluoro-ethylamino)-cyclohexyl]- lH-imidazo[4,5-c]quinolin-2-yl} - ethanol

A suspension of trans (R)-l-[l-(4-amino-cyclohexyl)-lH-imidazo[4,5-c]quinolin-2-yl]-ethanol (142 mg, 0.46 mmol) in anhydrous THF (4.6 mL) was treated with triethylamine (0.16 mL, 1.15 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (99.0 μί, 0.69 mmol), the reaction mixture was then heated to 50 °C for 18 hours. The mixture was concentrated in vacuo and the residue dissolved in EtOAc. The mixture was washed (water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: EtOAc to 8%[2M N¾ in MeOH] in EtOAc) provided a gum. The gum was azeotroped (diethyl ether) and then triturated (pentane) to provide 94.0 mg (52%) of trans (R)-l-{l-[4-(2,2,2- trifluoro-ethylamino)-cyclohexyl]-lH-imidazo[4,5-c]quinolin-2-yl}-ethanol as an off-white solid. LCMS (Method A, ESI): RT = 1.64 min, m+H = 393; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.44 (d, 1 H), 8.16 (m, 1 H), 7.74-7.63 (m, 2 H), 5.39 (m, 1 H), 5.24-5.09 (m, 2 H), 3.40-3.29 (m, 2 H), 2.91-2.80 (m, 1 H), 2.59-2.49 (m, 2 H, partially obscured by DMSO), 2.20-2.01 (m, 4 H), 1.70 (d, 3 H), 1.50-1.36 (m, 2 H).

Example 7

Trans [4-(2-Hydroxymethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile A solution of glycolamide (167 mg, 2.20 mmol) in anhydrous THF (3.1 mL), under an atmosphere of nitrogen, was treated with triethyloxonium tetrafluoroborate (397 mg, 2.10 mmol) and stirred at room temperature for 3.5 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 1.3 mL). This was added to a stirred solution of trans [4-(3-amino-quinolin-4-ylamino)-cyclohexyl]-acetonitrile (195 mg, 0.70 mmol) in ethanol (absolute grade, 4.6 mL) and the reaction mixture was heated to 75 °C for 1 hour. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to give a brown gum. Purified by column chromatography on silica gel (gradient: EtOAc to 10% [2M NH₃ in MeOH] in EtOAc) to afford a green gum. This was triturated (diethyl ether) and the solid obtained dried in vacuo, at 60 °C, to afford 136 mg (61%) of trans [4-(2-hydroxymethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile as a pale yellow solid. LCMS (Method A, ESI): RT = 2.32 min, m+H = 321.1 ; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.13 (s, 1 H), 8.42 (d, 1 H), 8.18 (dd, 1 H), 7.76-7.66 (m, 2 H), 5.49- 5.43 (t, 1 H), 5.10-4.98 (m, 1 H), 4.90 (d, 2 H), 2.56 (d, 2 H), 2.53-2.43 (m, 2 H, obscured by DMSO), 2.20-1.95 (m, 5 H), 1.59-1.46 (m, 2 H).

Example 8

(R)- 1 - { 1 -[ 1 S,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]- lH-imidazo[4,5-c]quinolin-2-yl} - ethanol

[(lR,3S)-3-(3-Nitro-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester

A mixture of ((lR,3S)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester (1.06 g, 5.30 mmol) in propan-2-ol (10 mL) was treated with 4-chloro-3-nitroquinoline (1.00 g, 4.80 mmol) and DIPEA (1.30 mL, 7.48 mmol) and the reaction mixture was heated at 120 °C using microwave irradiation for 25 minutes. On cooling, a solid precipitated out of solution. This was filtered, washed with propan-2-ol and water and dried in vacuo, at 60 °C, to afford 1.18 g (66%>) of [(lR,3S)-3-(3-nitro-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a bright yellow solid. LCMS (Method B, ESI): RT = 3.01 min, m+H = 373.1 ; 1H NMR (400 MHz, CDC1₃): δ 9.81 (d, 1 H), 9.36 (s, 1 H), 8.25 (d, 1 H), 7.99 (d, 1 H), 7.77 (t, 1 H), 7.50 (t, 1 H), 4.73-4.576 (m, 2 H), 4.13-4.01 (m, 1 H), 2.79-2.69 (dt, 1 H), 2.33-2.11 (m, 2 H), 2.02-1.90 (m, 1 H), 1.82-1.70 (m, 2 H), 1.45 (s, 9 H). (lS,3R)-N-(3-Nitro-quinolin-4-yl)-cyclopentane-l,3-diamine

A solution of [(lR,3S)-3-(3-nitro-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester (1.18 g, 3.17 mmol) in DCM (6 mL) was treated with TFA (6 mL) and the reaction mixture was stirred at room temperature for 25 minutes. The mixture was concentrated in vacuo and azeotroped with toluene. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) to afford a yellow crystalline solid. This was treated with 40-60% petroleum ether and was stirred vigorously for 10 minutes. The solid was filtered, washed with 40-60% petroleum ether and dried in vacuo, at 60 °C, to afford 0.80 g (93%>) of (lS,3R)-N-(3-nitro-quinolin-4-yl)-cyclopentane-l,3-diamine as a yellow sold. LCMS (Method B, ESI): RT = 0.56 min, m+H = 273.1 ; 1H NMR (400 MHz, CDC1₃): δ 10.27 (m, 1 H), 9.34 (s, 1 H), 8.25 (dd, 1 H), 7.98 (dd, 1 H), 7.75 (ddd, 1 H), 7.47 (ddd, 1 H), 4.73-4.63 (m, 1 H), 3.75-3.68 (m, 1 H), 2.44-2.34 (m, 1 H), 2.30-2.15 (m, 2 H), 2.02-1.91 (m, 1 H), 1.80-1.69 (m, 2 H), 1.44-1.25 (s, 2 H).

(lS,3R)-N-(3-Nitro-quinolin-4-yl)-N'-(2,2,2-trifluoro-ethyl)-cyclopentane-l,3-diamine A solution of (lS,3R)-N-(3-nitro-quinolin-4-yl)-cyclopentane-l,3-diamine (800 mg, 2.94 mmol) in a 1 : 1 mixture of DCM and N,N-dimethylformamide (DMF, 8mL) was treated with triethylamine (0.16 mL, 1.15 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.02 mL, 7.33 mmol). The reaction mixture was heated to 50 °C for 3 hours. The mixture was concentrated in vacuo and the residue was diluted with water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed (water, saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo to afford 1.02 g (98%>) of (lS,3R)-N-(3-nitro-quinolin-4-yl)- N'-(2,2,2-trifluoro-ethyl)-cyclopentane-l,3-diamine as a yellow oil. LCMS (Method B, ESI): RT = 2.00 min, m+H = 355.1; 1H NMR (400 MHz, CDC1₃): δ 9.96 (m, 1 H), 9.34 (s, 1 H), 8.22 (d, 1 H), 7.99 (dd, 1 H), 7.75 (ddd, 1 H), 7.47 (ddd, 1 H), 4.75-4.66 (m, 1 H), 3.57 (m, 1 H), 3.36-3.19 (m, 2 H), 2.42-2.23 (m, 2 H), 2.16-2.07 (m, 1 H), 2.01-1.91 (m, 1 H), 1.90-1.79 (m, 2 H).

N*4*-[(lS,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]-quinoline-3,4-diamine

A solution of (lS,3R)-N-(3-nitro-quinolin-4-yl)-N'-(2,2,2-trifluoro-ethyl)-cyclopentane-l,3- diamine (1.02 g, 2.88 mmol) in ethanol (IMS grade, 10.5 mL) and water (3.5 mL) was treated with ammonium chloride (0.92 g, 17.3 mmol), followed by iron powder (0.65 g, 11.5 mmol) and the reaction mixture was heated at 80 °C overnight. The iron residue was collected on a pad of Celite® and washed several times with ethanol (IMS grade) and water (3: 1). The organics were concentrated in vacuo and the aqueous residue was treated with saturated sodium hydro gencarbonate solution and extracted with ethyl acetate (3x). The combined organic phases were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo to give 0.65 g of a brown oil. This was purified by column chromatography on silica gel (gradient: EtOAc to 15% [2M NH₃ in MeOH] in EtOAc) to afford 396 mg (40%) of N*4*-[(lS,3R)-3-(2,2,2- trifluoro-ethylamino)-cyclopentyl]-quinoline-3,4-diamine as a brown oil. LCMS (Method B, ESI): RT = 1.35 min, m+H = 325.1 ; 1H NMR (400 MHz, CDC1₃): δ 8.45 (s, 1 H), 7.95-7.88 (m, 2 H), 7.47-7.39 (m, 2 H), 4.61 (s, 1 H), 4.23 (s, 1 H), 3.78 (s, 2 H), 3.44-3.38 (m, 1 H), 3.31- 3.20 (qd, 2 H), 2.02-1.66 (m, 6 H).

(R)- 1 - { 1 -[ 1 S,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]- lH-imidazo[4,5-c]quinolin-2-yl} - ethanol

A solution of (R)-(+)-lactamide (257 mg, 2.90 mmol) in anhydrous THF (2.1 mL), under an atmosphere of nitrogen was treated with triethyloxonium tetrafluoroborate (264 mg, 1.39 mmol) and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 0.8 mL). This was added to a suspension of N*4*-[(l S,3R)-3-(2,2,2-trifluoro-ethylamino)-cyclopentyl]-quinoline-3,4-diamine (150 mg, 0.47 mmol) in ethanol (absolute grade, 3.1 mL) and the reaction mixture heated to 75 °C for 5 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated in vacuo to afford 419 mg of a brown oil. This was purified by column chromatography on silica gel (gradient: EtOAc to 8% [2M NH₃ in MeOH] in EtOAc) to afford 107 mg of a colourless gum. The gum was dissolved in acetonitrile and water and lyophilised to afford 96 mg (55%) of (R)-l-{l-[lS,3R)-3-(2,2,2-trifiuoro- ethylamino)-cyclopentyl]-lH-imidazo[4,5-c]quinolin-2-yl}-ethanol as a white solid. LCMS (Method A, ESI): RT = 2.18 min, m+H = 379.1; 1H NMR (400 MHz, CDC1₃): δ 9.24 (s, 1 H), 8.55 (d, 1 H), 8.27 (dd, 1 H), 7.70-7.61 (m, 2 H), 5.55-5.43 (m, 1 H), 5.37-5.29 (q, 1 H), 3.67- 3.59 (m, 1 H), 3.34-3.21 (m, 2 H), 2.74-2.61 (m, 1 H), 2.57-2.47 (m, 1 H), 2.44-2.35 (m, 1 H), 2.34-2.15 (m, 2 H), 2.08-1.98 (m, 1 H), 1.81 (d, 3 H).

Example 9

Trans N-[l-(4-Cyanomethyl-cyclohexyl)-lH-imidazo[4,5-c]quinolin-2-ylmethyl]- methanesulfonamide

N-tert-Butylcarbamate-N- [ 1 -(4-cyanomethyl-cyclohexyl)- 1 H-imidazo [4,5 -c] quino lin-2- ylmethylj-methanesulfonamide

A suspension of trans [4-(2-hydroxymethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]- acetonitrile (110 mg, 0.34 mmol) in anhydrous THF (3 mL), under an atmosphere of nitrogen was treated with tert-butyl N-methanesulfonylcarbamate (147 mg, 0.76 mmol), followed by triphenylphosphine (180 mg, 0.69 mmol) and then diisopropyl azodicarboxylate (135 μί, 0.69 mmol). The reaction mixture was stirred at room temperature, under nitrogen overnight. The mixture was diluted with EtOAc and water and the phases were separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed (brine), dried (sodium sulfate) and concentrated in vacuo to afford a green gel. This was purified by column chromatography on an Isolute® SCX-2 cartridge (eluting with MeOH and then 2M NH₃ in MeOH) to afford 175 mg (100%) of N-tert-butylcarbamate-N-[l-(4-cyanomethyl-cyclohexyl)- lH-imidazo[4,5-c]quinolin-2-ylmethyl]-methanesulfonamide as a colourless gum. LCMS (Method B, ESI): RT = 2.85 min, m+H = 498.2; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.11 (s, 1 H), 8.40 (d, 1 H), 8.18 (dd, 1 H), 7.76-7.68 (m, 2 H), 5.32 (s, 2 H), 5.05 (s, 1 H), 3.70 (m, 1 H), 3.63 (s, 3 H), 2.55 (d, 2 H), 2.39-2.26 (m, 2 H), 2.20-2.11 (m, 2 H), 2.09-2.02 (m, 2 H), 1.63-1.50 (m, 2 H), 1.39 (s, 9 H).

Trans N-[l-(4-Cyanomethyl-cyclohexyl)-lH-imidazo[4,5-c]quinolin-2-ylmethyl]- methanesulfonamide A solution of N-tert-butylcarbamate-N-[l-(4-cyanomethyl-cyclohexyl)-lH-imidazo[4,5- c] quino lin-2-ylmethyl]-methanesulfonamide (166 mg, 0.33 mmol) in TFA (3 mL) was stirred at room temperature for 30 minutes. The mixture was diluted with toluene and concentrated in vacuo. The residue was azeotroped (toluene) and then purified by column chromatography using an Isolute® SCX-2 cartridge (eluting with MeOH and then 2M NH₃ in MeOH) to afford a yellow glass. This was purified by column chromatography on silica gel (gradient: 0 to 10% [NH₃ in MeOH] in EtOAc) to afford 121 mg (91%) of a white foam. This was dissolved in acetonitrile and water and lyophilised to afford 95.0 mg (71%) of trans N-[l-(4-cyanomethyl- cyclohexyl)-lH-imidazo[4,5-c]quinolin-2-ylmethyl]-methanesulfonamide as a white solid. LCMS (Method A, ESI): RT = 2.49 min, m+H = 398.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.16 (s, 1 H), 8.46 (d, 1 H), 8.20 (dd, 1 H), 7.79-7.68 (m, 2 H), 7.50 (s, 1 H), 5.02 (m, 1 H), 4.71 (s, 2 H), 3.03 (s, 3 H), 2.57 (d, 2 H), 2.46 (m, 1 H, partially obscured by DMSO), 2.21- 2.13 (m, 2 H), 2.12-2.03 (m, 4 H), 1.61-1.48 (m, 2 H).

Example 10

{l-[(lS,3R)-3-(2,2,2-Trifiuoro-ethylamino)-cyclopentyl]-lH-imidazo[4,5-c]quinolin-2-yl}- methanol

A suspension of glycolamide (144 mg, 1.93 mmol) in anhydrous THF (2.7 mL), under an atmosphere of nitrogen was treated with triethyloxonium tetrafluoroborate (343 mg, 1.81 mmol) and the mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo and the residue was dissolved in ethanol (absolute grade, 1.1 mL). This was added to a suspension of N*4*-[(l S,3R)-3-(2,2,2-trifluoro-ethylamino)-cyclopentyl]-quinoline-3,4-diamine (195 mg, 0.60 mmol) in ethanol (absolute grade, 4.2 mL) and the reaction mixture was heated to 75 °C for 2 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and saturated sodium hydro gencarbonate solution. The phases were separated and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were washed (brine), dried (sodium sulfate) and concentrated in vacuo to afford 833 mg of a brown oil. This was purified by column chromatography on silica gel (gradient: 0 to 13% [2M N¾ in MeOH] in EtOAc) to afford 180 mg of a pale brown gum. The gum was dissolved in acetonitrile and water and lyophilised to afford 161 mg (74%) of (l-[(lS,3R)-3-(2,2,2-trifluoro-ethylamino)- cyclopentyl]-lH-imidazo[4,5-c]quinolin-2-yl}-methanol as a white solid. LCMS (Method A, ESI): RT = 2.00 min, m+H = 365.0; 1H NMR (400 MHz, CDC1₃): δ 9.21 (s, 1 H), 8.50 (d, 1 H), 8.26 (m, 1 H), 7.65 (m, 2 H), 5.48 (m, 1 H), 5.07 (m, 2 H), 3.63 (m, 1 H), 3.28 (m, 2 H), 2.65 (m, 2 H), 2.26 (m, 3 H), 2.02 (m, 1 H).

Example 11

N-{l-[(lS,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]-lH-imidazo[4,5-c]quinolin-2- ylmethyl} -methanesulfonamide

N-tert-Butylcarbamate-N-{l-[(lS,3R)-3-(2,2,2-trifluoro-ethylamino)-cyclopentyl]-lH- imidazo[4,5-c]quinolin-2-ylmethyl} -methanesulfonamide A suspension of {l-[(lS,3R)-3-(2,2,2-trifluoro-ethylamino)-cyclopentyl]-lH-imidazo[4,5- c]quinolin-2-yl} -methanol (139 mg, 0.38 mmol) in anhydrous THF (3.8 mL), under an atmosphere of nitrogen was treated with tert-butyl N-methanesulfonylcarbamate (164 mg, 0.84 mmol), followed by triphenylphosphine (200 mg, 0.76 mmol) and then diisopropyl azodicarboxylate (150 μί, 0.76 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was extracted with EtOAc (2x) and the combined organic phases washed (brine), dried (sodium sulfate) and concentrated in vacuo to afford 780 mg of a yellow oil. Purification by column chromatography on an Isolute® SCX-2 cartridge (eluting with MeOH and then 2M NH₃ in MeOH) afforded 192 mg of a golden glassy solid. This was purified by filtration through a pad of silica gel (gradient: 0 to 2% [2M NH₃ in MeOH] in EtOAc) to afford 169 mg (82%) of N-tert-butylcarbamate-N- { 1 - [( 1 S ,3R)-3 -(2,2,2-trifluoro-ethylamino)-cyclopentyl] - 1 H- imidazo[4,5-c]quinolin-2-ylmethyl}-methanesulfonamide as a colourless gum. LCMS (Method B, ESI): RT = 2.67 min, m+H = 542.0; 1H NMR (400 MHz, CDC1₃): δ 9.20 (s, 1 H), 8.40 (d, 1 H), 8.28 (d, 1 H), 7.66 (m, 2 H), 5.54-5.30 (m, 3 H), 3.68 (s, 3 H), 3.60 (m, 1 H), 3.30 (m, 2 H), 2.60 (m, 2 H), 2.33 (m, 1 H), 2.15 (m, 2 H), 1.98 (m, 1 H), 1.50 (s, 9 H).

N-{l-[(lS,3R)-3-(2,2,2-Trifluoro-ethylamino)-cyclopentyl]-lH-imidazo[4,5-c]quinolin-2- ylmethyl} -methanesulfonamide A solution of N-tert-butylcarbamate-N-{l-[(lS,3R)-3-(2,2,2-trifluoro-ethylamino)-cyclopentyl]- lH-imidazo[4,5-c]quinolin-2-ylmethyl}-methanesulfonamide (165 mg, 0.30 mmol) in TFA (3 mL) was stirred at room temperature for 10 minutes. The mixture was diluted with toluene and concentrated in vacuo. The residue was azeotroped (toluene) and purified by column chromatography using an Isolute® SCX-2 cartridge (eluting with MeOH and then 2M NH₃ in MeOH) to afford a yellow glass. This was purified by column chromatography on silica gel (gradient: 0 to 10% [NH₃ in MeOH] in EtOAc) to afford 120 mg of a colourless gum. The residue was treated with EtOAc, which gave rise to crystallization of a white solid (33 mg), which was removed by filtration. The resultant filtrate was concentrated and purified by column chromatography on silica gel (gradient: 0 to 10% [2M NH₃ in MeOH] in EtOAc) to afford 110 mg of a white solid. Trituration (diethyl ether) afforded 90.0 mg (67%) of N-{l-[(lS,3R)-3- (2,2,2-trifluoro-ethylamino)-cyclopentyl]-lH-imidazo[4,5-c]quinolin-2-ylmethyl}- methanesulfonamide as a white solid. LCMS (Method A, ESI): RT = 2.28 min, m+H = 442.0; 1H NMR (400 MHz, CDC1₃): δ 9.24 (s, 1 H), 8.49 (d, 1 H), 8.29 (d, 1 H), 7.68 (m, 2 H), 5.81 (m, 1 H), 5.41 (m, 1 H), 4.93-4.72 (m, 2 H), 3.62 (m, 1 H), 3.27 (m, 2 H), 3.07 (s, 3 H), 2.61 (m, 2 H), 2.30 (m, 1 H), 2.17 (m, 2 H), 2.03 (m, 1 H).

Example 12

Trans [4-(2-Aminomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile Trans [4-(2-Chloromethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile

A solution of trans [4-(3-amino-quinolin-4-ylamino)-cyclohexyl]-acetonitrile (500 mg, 1.80 mmol) in acetic acid (1.5 mL) was treated with 2-chloro-l,l,-trimethyoxyethane (0.48 mL, 3.60 mmol). The mixture was heated to 125 °C for 30 minutes. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution. The aqueous phase was extracted with ethyl acetate (2x) and the combined organic phases washed (saturated sodium hydrogencarbonate solution and brine), dried (sodium sulfate) and concentrated. Crude trans [4-(2-chloromethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]- acetonitrile was isolated as a dark green foam solid and was used without further purification. LCMS (Method B, ESI): RT = 2.61 min, m+H = 339 and 341.

Trans [4-(2-Azidomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile

A solution of trans [4-(2-chloromethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile (assumed to be 1.80 mmol) in DMF (18 mL) was treated with sodium azide (360 mg, 5.50 mmol) and stirred at room temperature for 4 hours and then allowed to stand over night. Water was added and the mixture extracted with ethyl acetate (3x). The combined organic extracts were washed (brine), dried (sodium sulfate) and concentrated to provide crude trans [4-(2- azidomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile as a brown oil, which was used for the next step without purification. LCMS (Method B, ESI): RT = 2.52 min, m+H = 346.

Trans [4-(2-Aminomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile

A solution of trans [4-(2-azidomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile (assumed to be 1.80 mmol) in THF (9 mL) and ethanol (9 mL, IMS grade) was treated with palladium on carbon (180 mg, 0.18 mmol, 10% Pd) under nitrogen. The mixture was purged with hydrogen and then stirred under an atmosphere of hydrogen for 90 minutes at room temperature. The mixture was filtered through a pad of Celite® and then concentrated to give a brown oil. Purification by column chromatography on silica gel (gradient: 0 to 20% [2M N¾ in MeOH] in ethyl acetate) afforded a golden gum which was dried in vacuo. Trans [4-(2- aminomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]-acetonitrile (265 mg, 46%) was isolated as a fawn coloured foam solid. LCMS (Method A, ESI): RT = 1.77 min, m+H = 320.1 ; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.11 (s, 1 H), 8.41 (d, 1 H), 8.16 (dd, 1 H), 7.69 (m, 2 H), 5.02 (m, 1 H), 4.19 (s, 2 H), 2.55 (d, 2 H), 2.43 (m, 1 H), 2.06 (m, 6 H), 1.53 (m, 2 H).

Example 13

Trans [l-(4-Cyanomethyl-cyclohexyl)-lH-imidazo[4,5-c]quinolin-2-ylmethyl]-carbamic acid methyl ester formic acid salt A stirred solution of trans [4-(2-aminomethyl-imidazo[4,5-c]quinolin-l-yl)-cyclohexyl]- acetonitrile (100 mg, 0.31 mmol) in THF (3 mL) was treated sequentially with DIPEA (82.0 μί, 0.47 mmol) and a solution of methyl chloroformate (29.0 μί, 0.38 mmol) in THF (0.1 mL) at 0 °C. Stirring was continued for 90 minutes. The mixture was diluted with ethyl acetate and washed (water and brine), dried (sodium sulfate) and concentrated. The residue was purified by reverse phase HPLC (5 to 95% MeCN in H₂0 + 0.1% HC0₂H) and the relevant fractions combined and lyophilised to provide 31.0 mg (26%) of trans [l-(4-cyanomethyl-cyclohexyl)-lH- imidazo[4,5-c]quinolin-2-ylmethyl]-carbamic acid methyl ester formic acid salt as a white solid. LCMS (Method C, ESI): RT = 5.22 min, m+H = 378.2; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.12 (s, 1 H), 8.42 (d, 1 H), 8.24 (br s, 0.4 H, formate), 8.17 (d, 1 H), 7.70 (m, 2 H), 7.41 (br s, 1 H), 4.95 (m, 1 H), 4.70 (d, 2 H), 3.62 (d, 3 H), 2.55 (d, 2 H), 2.41 (m, 2 H), 2.07 (m, 6 H), 1.52 (m, 2 H).

Example 14

4-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidine- 1 -carboxylic acid tert-butyl ester

4-(3-Nitro-quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester

A mixture of 4-amino-l-boc-piperidine (441 mg, 2.20 mmol), DIPEA (514 μΕ, 3.00mmol) and 4-chloro-3-nitro-quinoline (500 mg, 2.00 mmol) in propan-2-ol (8 mL) was heated to reflux for 2 hours. After cooling, the resulting precipitate was collected, washed (propan-2-ol and diethyl ether) and air dried to provide 755 mg of 4-(3-nitro-quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT = 3.37 min, m+H = 373.2; 1H NMR (400 MHz, CDC1₃): δ 9.38 (m, 2 H), 8.15 (d, 1 H), 8.03 (dd, 1 H), 7.79 (m, 1 H), 7.53 (m, 1 H), 4.35 (m, 1 H), 4.06 (m, 2 H), 3.04 (m, 2 H), 2.15 (m, 2 H), 1.71 (m, 2 H), 1.48 (s, 9 H).

4-(3-Amino-quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester A solution of 4-(3-nitro-quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester (745 mg, 2.00 mmol) in EtOAc (10 mL) and THF (10 mL) was treated with palladium on carbon (106 mg, 0.10 mmol, 10% Pd) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 2½ hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to provide 729 mg of 4-(3-amino- quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester as an orange residue. The product was used without further purification. LCMS (Method B, ESI): RT = 2.52 min, m+H = 343.2; 1H NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1 H), 7.99 (dd, 1 H), 7.73 (dd, 1 H), 7.35 (m, 2 H), 5.09 (s, 2 H), 4.52 (d, 1 H), 3.91 (m, 2 H), 2.67 (m, 2 H), 1.75 (br d, 2 H), 1.43 (m, 2 H), 1.40 (s, 9 H).

4-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidine- 1 -carboxylic acid tert-butyl ester

A suspension of triethyloxonium tetrafluoroborate (1.48 g, 7.80 mmol) in DCM (10 mL) was treated with (R)-(+)-lactamide (713 mg, 8.00 mmol) at room temperature and stirred for 2 hours. The volatiles were removed in vacuo and the resulting residue dissolved in ethanol (absolute grade, 5 mL) and stirred for 30 minutes. This was added to a stirred solution of 4-(3-amino- quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester (assumed to be 2.00 mmol) in ethanol (absolute grade, 10 mL) and heated to reflux for 10 minutes. After cooling using an ice bath, the solvent was removed in vacuo and the resulting residue dissolved ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) afforded 684 mg (86%) of 4-[2-((R)-l-hydroxy-ethyl)- imidazo[4,5-c]quinolin-l-yl]-piperidine-l-carboxylic acid tert-butyl ester as an off-white foam solid. LCMS (Method A, ESI): RT = 3.07 min, m+H = 397.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.16 (s, 1 H), 8.34 (d, 1 H), 8.18 (dd, 1 H), 7.68 (m, 1 H), 7.58 (m, 1 H), 5.46 (br s, 1 H), 5.36 (m, 1 H), 5.23 (m, 1 H), 4.27 (m, 2 H), 3.07 (m, 2 H), 2.56 (m, 2 H), 2.04 (br t, 2 H), 1.71 (d, 3 H), 1.52 (s, 9 H).

Example 15

(R)- 1 -( 1 -Piperidin-4-yl- 1 H-imidazo [4,5 -c] quino lin-2-yl)-ethano 1

A solution of 4-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]-piperidine-l-carboxylic acid tert-butyl ester (650 mg, 1.64 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) to provide 435 mg (90%) of (R)-l-(l-piperidin-4-yl-lH-imidazo[4,5-c]quinolin-2-yl)-ethanol as an off-white foam. LCMS (Method A, ESI): RT = 0.97 min, m+H =297.0; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.80 (d, 1 H), 8.16 (m, 1 H), 7.68 (m, 2 H), 5.44 (br s, 1 H), 5.21 (m, 2 H), 3.23 (m, 3 H), 2.76 (m, 2 H), 2.57 (m, 2 H), 1.94 (m, 2 H), 1.70 (d, 3 H).

Example 16

3- (4-[2-((R)- l-Hydroxy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidin- 1 -yl} -propionitrile

A solution of (R)-l-(l-piperidin-4-yl-lH-imidazo[4,5-c]quinolin-2-yl)-ethanol (75.0 mg, 0.25 mmol) in ethanol (2 mL, IMS grade) was treated with acrylonitrile (33.0 μί, 0.51 mmol) at reflux for 2 hours. After cooling, the mixture was concentrated onto diatomaceous earth and purified by column chromatography on silica gel (gradient: 0 to 15% [2M NH₃ in MeOH] in ethyl acetate) to afford a colourless residue. The residue was triturated (diethyl ether) and dried at 50 °C under vacuum to leave 69.0 mg (79%) of 3-{4-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5- c]quinolin-l-yl]-piperidin-l-yl} -propionitrile as a white solid. LCMS (Method A, ESI): RT = 1.64 min, m+H = 350.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.15 (s, 1 H), 8.84 (d, 1 H), 8.16 (dd, 1 H), 7.74 (m, 1 H), 7.66 (m, 1 H), 5.47 (br d, 1 H), 5.20 (m, 2 H), 3.20 (m, 2 H), 2.75 (m, 6 H), 2.39 (m, 2 H), 2.03 (m, 2 H), 1.70 (d, 3 H).

Example 17

(R)- 1 - { 1 -[ 1 -(2,2,2-Trifluoro-ethyl)-piperidin-4-yl]- lH-imidazo[4,5-c]quinolin-2-yl} -ethanol

A mixture of (R)-l-(l-piperidin-4-yl-lH-imidazo[4,5-c]quinolin-2-yl)-ethanol (75.0 mg, 250 μιηοΐ), 2,2,2-trifluoroetfiyl trifluoromethanesulfonate (87.0 mg, 375 μιηοΐ) and triethylamine (61.0 μί, 438 μιηοΐ) in THF (3 mL) was heated to 50 °C for 18 hours. After cooling, the mixture was diluted with ethyl acetate and washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated. Purification by column chromatography on silica gel (gradient: 0 to 15% [2M N¾ in MeOH] in ethyl acetate) afforded a colourless residue. The residue was triturated (pentane) to provide 61.0 mg (64%) of (R)-1-{1- [l-(2,2,2-trifluoro-ethyl)-piperidin-4-yl]-lH-imidazo[4,5-c]quinolin-2-yl}-ethanol as a white solid. LCMS (Method A, ESI): RT = 2.94 min, m+H = 379.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.15 (s, 1 H), 8.79 (d, 1 H), 8.17 (dd, 1 H), 7.66 (m, 2 H), 5.48 (br d, 1 H), 5.20 (m, 2 H), 3.32 (q, 2 H), 3.21 (m, 2 H), 2.74 (m, 4 H), 2.03 (m, 2 H), 1.70 (d, 3 H).

Example 18

Racemic cis (3-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-cyclopentyl} -carbamic acid tert-butyl ester

Racemic cis [3 -(3 -Nitro-quinolin-4-ylamino)-cyclopentyl] -carbamic acid tert-butyl ester A mixture of racemic cis (3-amino-cyclopentyl)-carbamic acid tert-butyl ester (prepared following the methods outlined in J. Org. Chem. 2004, 69, 4538; Tetrahedron 1997, 53, 3347; WO2008/065021 ; WO94/17090; and Org. Lett. 2000, 2, 4169) (441 mg, 2.20 mmol), DIPEA (1.03 mL, 6.00 mmol) and 4-chloro-3-nitro-quinoline (500 mg, 2.00 mmol) in propan-2-ol (8 mL) was heated to reflux for 3 hours. The resulting mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient: 0 to 50% ethyl acetate in cyclohexane) to afford 548 mg (73%) of racemic cis [3-(3-nitro-quinolin-4- ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT = 3.07 min, m+H = 373.2; 1H NMR (400 MHz, CDC1₃): δ 9.83 (br d, 1 H), 9.37 (s, 1 H), 8.25 (d, 1 H), 8.01 (d, 1 H), 7.78 (m, 1 H), 7.50 (m, 1 H), 4.67 (m, 2 H), 4.10 (m, 1 H), 2.73 (m, 1 H), 2.21 (m, 2 H), 1.97 (m, 1 H), 1.76 (m, 2 H), 1.45 (s, 9 H).

Racemic cis [3-(3-Amino-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester

A solution of racemic cis [3-(3-nitro-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester (540 mg, 1.45 mmol) in ethyl acetate (10 mL) and THF (10 mL) was treated with palladium on carbon (77.0 mg, 72.0 μιηοΐ, 10%> Pd) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to provide 539 mg of racemic cis [3-(3-amino-quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester as an orange residue. The product was used without further purification. LCMS (Method B, ESI): RT = 2.47 min, m+H = 343.2; 1H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1 H), 8.01 (m, 1 H), 7.73 (m, 1 H), 7.35 (m, 2 H), 6.96 (m, 1 H), 5.02 (br s, 2 H), 4.68 (d, 1 H), 3.87 (m, 1 H), 3.70 (m, 1 H), 2.17 (m, 1 H), 1.70 (m, 2 H), 1.60 (m, 2 H), 1.41 (m, 1 H), 1.38 (s, 9 H).

Racemic cis (3-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-cyclopentyl} -carbamic acid tert-butyl ester A stirred suspension of triethyloxonium tetrafluoroborate (1.14 g, 6.01 mmol) in DCM (5 mL) was treated with (R)-(+)-lactamide (547 mg, 6.14 mmol) at room temperature for 2 hours. The volatiles were removed in vacuo and the resulting residue dissolved in ethanol (absolute grade, 5 mL) and stirred for 30 minutes. This was added to a stirred solution of racemic cis [3-(3-amino- quinolin-4-ylamino)-cyclopentyl]-carbamic acid tert-butyl ester (526 mg, 1.54 mmol) in ethanol (absolute grade, 10 mL) and heated to reflux for 15 minutes. After cooling using an ice bath, the solvent was removed in vacuo and the resulting residue dissolved ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) afforded 321 mg (53%) of racemic cis (3-[2-((R)-l-hydroxy-ethyl)- imidazo[4,5-c]quinolin-l-yl]-cyclopentyl}-carbamic acid tert-butyl ester as a beige foam solid. LCMS (Method A, ESI): RT = 2.95 min, m+H = 397.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.43 (t, 1 H), 8.16 (dd, 1 H), 7.70 (m, 2 H), 6.91 (m, 1 H), 5.63 (m, 1 H), 5.42 (m, 1 H), 5.24 (m, 1 H), 4.11 (m, 1 H), 2.40 (m, 2 H), 2.20 (m, 3 H), 1.69 (dd, 3 H), 1.42 (d, 9 H).

Example 19

Racemic cis (R)- 1 -[ 1 -(3-Amino-cyclopentyl)- lH-imidazo[4,5-c]quinolin-2-yl]-ethanol

A solution of racemic cis {3-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]- cyclopentyl}-carbamic acid tert-butyl ester (250 mg, 0.63 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography using an Isolute® SCX-2 cartridge (eluting MeOH to 2M NH₃ in MeOH). Subsequent purification by column chromatography on silica gel (gradient: 0 to 10% [2M NH₃ in MeOH] in DCM) followed by trituration (diethyl ether) provided 172 mg (92%) of racemic cis (R)-l-[l-(3-amino-cyclopentyl)-lH-imidazo[4,5-c]quinolin-2-yl]-ethanol as an off-white solid. LCMS (Method A, ESI): RT = 1.49 min, m+H = 297.0; 1H NMR (400

MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.64 (d, 1 H), 8.15 (m, 1 H), 7.68 (m, 2 H), 5.62 (m, 1 H), 5.43 (br s, 1 H), 5.27 (m, 1 H), 3.59 (m, 1 H), 2.55 (m, 1 H), 2.41 (m, 1 H), 2.20 (m, 3 H), 1.87 (m, 1 H), 1.69 (dd, 3 H). Example 20

Racemic cis 3 - {3 - [2-((R)- 1 -Hydro xy-ethyl)-imidazo [4,5 -c] quino lin- 1 -yl] -cyclopentylamino } - propionitrile A solution of racemic cis (R)-l-[l-(3-amino-cyclopentyl)-lH-imidazo[4,5-c]quinolin-2-yl]- ethanol (140 mg, 0.47 mmol) in ethanol (3 mL, IMS grade) was treated with acrylonitrile (62.0 μί, 0.94 mmol) and heated at reflux for 2 hours. After cooling, the mixture was concentrated onto diatomaceous earth and purified by column chromatography on silica gel (gradient: 0 to 15% [2M N¾ in MeOH] in ethyl acetate). The isolated product was re-purified by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) to afford a colourless residue. The residue was dried at 50 °C under vacuum to leave 54.0 mg (33%) of racemic cis 3-{3-[2- ((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]-cyclopentylamino}-propionitrile as an off- white foam solid. LCMS (Method A, ESI): RT = 1.60 min, m+H = 350.0; 1H NMR (400 MHz,

DMSO-d6): δ 9.19 (s, 1 H), 8.71 (t, 1 H), 8.17 (dd, 1 H), 7.74 (m, 2 H), 5.79 (t, 1 H), 5.60 (m, 1 H), 5.25 (m, 1 H), 3.40 (m, 1 H), 2.82 (m, 2 H), 2.66 (m, 2 H), 2.45 (m, 2 H), 2.15 (m, 3 H), 1.96 (m, l H), 1.68 (dd, 3 H).

Example 21

Trans (4-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - carbamic acid tert-butyl ester Trans [4-(3-Nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

A mixture of trans (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (394 mg, 1.80 mmol), DIPEA (0.44 mL, 2.50 mmol) and 4-chloro-3-nitro-[l,5]naphthyridine (350 mg, 1.67 mmol) in propan-2-ol (6 mL) was heated to 120 °C using microwave irradiation for 20 minutes. After cooling, the resulting precipitate was isolated by filtration and the solid washed (propan-2-ol) and dried to afford 233 mg (36%) of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]- carbamic acid tert-butyl ester as a pale yellow solid. The above filtrate was concentrated in vacuo and the residue taken up in to ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated to provide an additional 238 mg (37%) of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT = 3.87 min, m+H = 388; 1H NMR (400 MHz, DMSO-d6): δ 9.44 (br s, 1 H), 9.18 (s, 1 H), 8.92 (dd, 1 H), 8.29 (dd, 1 H), 7.86 (dd, 1 H), 6.78 (m, 1 H), 5.13 (br s, 1 H), 2.13 (m, 2 H), 1.85 (m, 2 H), 1.54-1.51 (m, 2 H), 1.39 (s, 9 H), 1.33 (m, 2 H). Trans [4-(3-Amino-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester

A mixture of trans [4-(3-nitro-[l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (471 mg, 1.20 mmol) in ethanol (IMS grade, 7.3 mL) and water (2.4 mL) was treated with ammonium chloride (390 mg, 7.30 mmol), followed by iron powder (273 mg, 4.90 mmol) and the reaction mixture was heated at 80 °C for 3½ hours. After cooling, the iron residue was collected on a pad of Celite® and washed several times with ethanol (IMS grade) and water (3: 1). The filtrate was concentrated under vacuum and the residue partitioned between saturated sodium hydro gencarbonate solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x) and the combined organic phases washed (brine), dried (sodium sulfate) and concentrated. Purification by column chromatography on silica gel (gradient: 0 to 20% [20%(2M NH₃ in MeOH) in ethyl acetate] in ethyl acetate) afforded 291 mg (68%) of trans [4-(3-amino- [l,5]naphthyridin-4-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester as a yellow solid. LCMS (Method B, ESI): RT = 2.53 min, m+H = 358; 1H NMR 400 MHz, CDC1₃): δ 8.72 (dd, 1 H), 8.42 (s, 1 H), 8.21 (dd, 1 H), 7.41 (dd, 1 H), 5.74 (br s, 1 H), 4.35 (br s, 1 H), 3.68 (s, 2 H), 3.48 (br s, 1 H), 2.04 (m, 2 H), 1.70 (br s, 2 H), 1.43 (m, 11 H), 1.24 (m, 2 H). Trans (4-[2-((R)- 1 -Hydro xy-ethyl)- 1 ,3,5,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - carbamic acid tert-butyl ester A stirred suspension of triethyloxonium tetrafluoroborate (465 mg, 2.45 mmol) in THF (5 mL) was treated with (R)-(+)-lactamide (237 mg, 2.70 mmol) at room temperature for 2 hours. The volatiles were removed in vacuo and the resulting residue dissolved in ethanol (absolute grade, 4 mL) and added to a stirred solution of trans [4-(3-amino-[l,5]naphthyridin-4-ylamino)- cyclohexyl]-carbamic acid tert-butyl ester (291 mg, 815 μιηοΐ) in ethanol (absolute grade, 6 mL) and heated to reflux for 2 hours. After cooling, the solvent was removed in vacuo and the resulting residue dissolved ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 30% [20%(2M N¾ in MeOH) in ethyl acetate] in ethyl acetate) followed by trituration (diethyl ether) provided 159 mg (47%) of trans {4-[2-((R)-l-hydroxy-ethyl)-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl]- cyclohexyl}-carbamic acid tert-butyl ester as a pale green solid. LCMS (Method A, ESI): RT = 7.77 min, m+H = 412; 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1 H), 9.06 (br s, 1 H), 8.54 (dd, 1 H), 7.76 (dd, 1 H), 6.88 (d, 1 H), 5.87 (br d, 1 H), 5.24 (m, 1 H), 4.95 (m, 1 H), 3.68 (m, 1 H), 3.24 (m, 2 H), 1.97 (m, 2 H), 1.80 (m, 2 H), 1.69 (d, 3 H), 1.46 (m, 11 H).

Example 22

Trans (R)- 1 -[ 1 -(4-Amino-cyclohexyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-yl]- ethanol Trans (4-[2-((R)- 1 -hydro xy-ethyl)- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl]-cyclohexyl} - carbamic acid tert-butyl ester (148 mg, 360 μιηοΐ) was treated with DCM (8 mL) and TFA (2 mL) and stirred at room temperature for 45 minutes. The solvent was removed under vacuum and the resulting residue purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M N¾ in MeOH). The isolated product was azeotroped (diethyl ether) to afford 104 mg (92%) of trans (R)-l-[l-(4-amino-cyclohexyl)-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl] -ethanol as a white solid. LCMS (Method A, ESI): RT = 1.60 min, m+H = 312.0; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1 H), 9.05 (d, 1 H), 8.53 (dd, 1 H), 7.74 (dd, 1 H), 5.85 (br s, 1 H), 5.24 (m, 1 H), 4.96 (m, 1 H), 3.24 (m, obscured by water), 3.01 (m, l H), 1.94 (m, 2 H), 1.75 (m, 2 H), 1.69 (d, 3 H), 1.32 (m, 2 H).

Example 23

Trans 3-{4-[2-((R)-l-Hydroxy-ethyl)-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl]- cyclohexylamino } -propionitrile

Trans (R)- 1 -[ 1 -(4-amino-cyclohexyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-yl]-ethanol (50.0 mg, 161 μηιοΐ) was treated with MeOH (2 mL), triethylamine (44.7 μί, 322 μηιοΐ) and acrylonitrile (11.6 μί, 177 μηιοΐ) and then stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue purified by reverse phase HPLC (gradient: 5 to 40% MeCN in H₂0 + 0.1% HC0₂H). The combined fractions were loaded on to an Isolute® SCX-2 cartridge and purified (gradient: MeOH to 2M N¾ in MeOH). The isolated product was triturated (diethyl ether) to provide 24.5 mg (42%) of trans 3-{4-[2-((R)-l-hydroxy-ethyl)- l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl]-cyclohexylamino}-propionitrile as a pale yellow solid. LCMS (Method A, ESI): RT = 1.79 min, m+H = 365.1; 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1 H), 9.07 (s, 1 H), 8.53 (dd, 1 H), 7.75 (dd, 1 H), 5.84 (br d, 1 H), 5.25 (m, 1 H), 4.98 (m, 1 H), 3.23 (m, 2 H), 2.87 (m, 3 H), 2.62 (t, 2 H), 2.07 (m, 2 H), 1.79 (m, 2 H), 1.69 (d, 3 H), 1.29 (m, 2 H).

Example 24

Trans (R)- 1 - { 1 -[4-(2,2,2-Trifluoro-ethylamino)-cyclohexyl]- 1 H- 1 ,3 ,5 ,9-tetraaza- cyclopenta[a]naphthalen-2-yl}-ethanol

Trans (R)- 1 -[ 1 -(4-amino-cyclohexyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-yl]-ethanol (46.0 mg, 148 μηιοΐ) was treated with THF (2 mL), triethylamine (41.0 μί, 296 μηιοΐ) and 2,2,2- trifluoro ethyl trifluoromethanesulfonate (22.4 μΐ_^, 155 μηιοΐ) and then stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue purified by reverse phase HPLC (gradient: 5 to 40% MeCN in H₂0 + 0.1% HC0₂H). The combined fractions were loaded on to an Isolute® SCX-2 cartridge and purified (gradient: MeOH to 2M NH₃ in MeOH). The isolated product was azeotroped (diethyl ether and ethyl acetate) to provide 16.5 mg (28%) of trans (R)-l-{l-[4-(2,2,2-trifluoro-ethylamino)-cyclohexyl]-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl}-ethanol. LCMS (Method A, ESI): RT = 2.15 min, m+H = 394.1 ; 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1 H), 9.03 (dd, 1 H), 8.53 (dd, 1 H), 7.75 (dd, 1 H), 5.85 (br d, 1 H), 5.26 (m, 1 H), 4.98 (m, 1 H), 3.33 (m, 2 H), 3.22 (m, 2 H), 2.90 (m, 1 H), 2.33 (m, l H), 2.09 (m, 2 H), 1.79 (m, 2 H), 1.69 (d, 3 H), 1.31 (m, 2 H).

Example 25

(R)-3-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidine- 1 -carboxylic acid tert- butyl ester

(R)-3-(3-Nitro-quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester

A mixture of R-(-)-3-amino-l-boc-piperidine (441 mg, 2.20 mmol), DIPEA (514 μΕ, 3.00 mmol) and 4-chloro-3-nitro-quinoline (500 mg, 2.00 mmol) in propan-2-ol (8 mL) was heated to reflux for 2 hours. After cooling, the resulting precipitate was collected by filtration and washed with propan-2-ol and diethyl ether. The solid was air dried to provide 689 mg (92%) of (R)-3- (3-nitro-quinolin-4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester as a yellow solid.

LCMS (Method B, ESI): RT = 3.42 min, m+H = 373.2; 1H NMR (400 MHz, CDC1₃): δ 9.48 (br d, 1 H), 9.39 (s, 1 H), 8.24 (br d, 1 H), 8.03 (d, 1 H), 7.79 (m, 1 H), 7.53 (m, 1 H), 4.33 (m, 1 H), 3.96 (br d, 1 H), 3.58 (m, 1 H), 3.37 (m, 2 H), 2.13 (m, 1 H), 1.83 (m, 2 H), 1.63 (m, 1 H), 1.45 (s, 9 H).

(R)-3-(3-Amino-quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester

A solution of (R)-3-(3-nitro-quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester (680 mg, 1.83 mmol) in ethyl acetate (10 mL) and THF (10 mL) was treated with palladium on carbon (96.0 mg, 91.0 μιηοΐ, 10% Pd) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 2 hours. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to provide 641 mg of crude (R)-3-(3-amino-quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester as an orange residue. The product was used without further purification. LCMS (Method B, ESI): RT = 2.41 min, m+H = 343.2; 1H NMR (400 MHz, CDC1₃): δ 8.56 (s, 1 H), 8.05 (d, 1 H), 7.86 (d, 1 H), 7.52 (m, 1 H), 7.43 (m, 1 H), 4.80 (br s, 1 H), 4.21 (br s, 1 H), 3.81 (m, 1 H), 3.74 (m, 1 H), 3.50 (m, 1 H), 3.35 (m, 2 H), 1.97 (m, 1 H), 1.78 (m, 2 H), 1.55 (m, 1 H), 1.43 (s, 9 H).

(R)-3-[2-((R)- 1 -Hydro xy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidine- 1 -carboxylic acid tert- butyl ester

A stirred suspension of triethyloxonium tetrafluoroborate (678 mg, 3.57 mmol) in DCM (5 mL) was treated with (R)-(+)-lactamide (326 mg, 3.66 mmol) at room temperature for 2 hours. The volatiles were removed in vacuo and the resulting residue dissolved in ethanol (absolute grade, 5 mL) and stirred for 30 minutes. This was added to a stirred solution of (R)-3-(3-amino-quinolin- 4-ylamino)-piperidine-l -carboxylic acid tert-butyl ester (310 mg, 0.90 mmol) in ethanol (absolute grade, 5 mL) at reflux. Heating was continued for 35 minutes. After cooling, the solvent was removed in vacuo and the resulting residue dissolved ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) afforded 320 mg (89%) of (R)-3-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5- c]quinolin-l-yl]-piperidine-l -carboxylic acid tert-butyl ester as an off-white foam solid. LCMS (Method A, ESI): RT = 3.13 min, m+H = 397.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.16 (s, 1 H), 8.48 (d, 1 H), 8.17 (m, 1 H), 7.71 (m, 2 H), 5.48 (br d, 1 H), 5.24 (m, 2 H), 4.35 (dd, 1 H), 4.11 (br d, 1 H), 3.74 (t, 1 H), 3.05 (td, 1 H), 2.63 (m, 1 H), 2.16 (m, 1 H), 1.97 (m, 1 H), 1.75 (m, 1 H), 1.71 (d, 3 H), 1.41 (s, 9 H).

Example 26

(R)- 1 -((R)- 1 -Piperidin-3 -yl- 1 H-imidazo [4,5 -c] quino lin-2-yl)-ethano 1

A solution of (R)-3-[2-((R)-l-hydroxy-ethyl)-imidazo[4,5-c]quinolin-l-yl]-piperidine-l- carboxylic acid tert-butyl ester (290 mg, 0.73 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH). Subsequent purification by column chromatography on silica gel (gradient: 0 to 10% [2M NH₃ in MeOH] in DCM) provided 204 mg (94%) of (R)-1-((R)-1 -piperidin-3 -yl-lH- imidazo[4,5-c]quinolin-2-yl)-ethanol as a white foam solid. LCMS (Method A, ESI): RT = 1.54 min, m+H = 297.0; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.14 (s, 1 H), 8.60 (d, 1 H), 8.17 (dd, 1 H), 7.70 (m, 2 H), 5.38 (br s, 1 H), 5.21 (m, 2 H), 3.54 (t, 1 H), 3.26 (dd, 1 H), 3.01 (m, 2 H), 2.80 (m, 1 H), 2.58 (m, 1 H), 2.14 (br d, 1 H), 1.91 (m, 1 H), 1.79 (m, 1 H), 1.70 (d, 3 H).

Example 27

3- {(R)-3-[2-((R)- l-Hydroxy-ethyl)-imidazo[4,5-c]quinolin- 1 -yl]-piperidin- 1 -yl} -3-oxo- propionitrile

A solution of (R)-l-((R)-l-piperidin-3-yl-lH-imidazo[4,5-c]quinolin-2-yl)-ethanol (125 mg, 0.42 mmol) in MeCN (8 mL) was treated with cyanoacetic acid (43.0 mg, 0.51 mmol), N- hydroxybenzotriazole (HOBt) (79.0 mg, 0.59 mmol), 4-dimethylaminopyridine (DMAP) (77.0 mg, 0.63 mmol) and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (120 mg, 0.63 mmol) at room temperature and stirred for 18 hours. The mixture was purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) and then by column chromatography on silica gel (gradient: 0 to 15% [2M NH₃ in MeOH] in ethyl acetate). Further purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) provided a pale yellow glass. Trituration (diethyl ether) and subsequent drying in vacuo at 50 °C provided 1 11 mg (73%) of 3-{(R)-3-[2-((R)-l-hydroxy- ethyl)-imidazo[4,5-c]quinolin-l-yl]-piperidin-l-yl}-3-oxo-propionitrile as a pale yellow solid. LCMS (Method C, ESI): RT = 4..31 min, m+H = 364.2; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.17 (s, 1 H), 8.46 (d, 1 H), 8.18 (dd, 1 H), 7.71 (m, 2 H), 5.55 (br s, 1 H), 5.22 (m, 2 H), 4.80-3.60 (br m, 6 H), 2.66 (m, 1 H), 2.16 (m, 1 H), 1.99 (m, 1 H), 1.83 (m, 1 H), 1.73 (d, 3 H).

Example 28

(R)-3-(2-Methyl-imidazo[4,5-c]quinolin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester

A mixture of (R)-3-(3-amino-quinolin-4-ylamino)-piperidine-l-carboxylic acid tert-butyl ester (310 mg, 0.905 mmol) and triethyl orthoacetate (415 μί, 2.26 mmol) in acetic acid (5 mL) was heated to 90 °C for 4 hours. After cooling, the solvent was removed in vacuo and the residue was taken up in ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated to leave a yellow residue. Purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) provided a gum which was azeotroped (diethyl ether) to afford 296 mg (89%) of (R)-3-(2- methyl-imidazo[4,5-c]quinolin-l-yl)-piperidine-l-carboxylic acid tert-butyl ester as a white foam solid. LCMS (Method C, ESI): RT = 6.57 min, m+H = 367.3; 1H NMR (400 MHz, DMSO- d6, 80 °C): δ 9.07 (s, 1 H), 8.39 (d, 1 H), 8.16 (m, 1 H), 7.66 (m, 2 H), 5.02 (m, 1 H), 4.31 (d, 1 H), 4.09 (d, 1 H), 3.54 (t, 1 H), 3.01 (m, 1 H), 2.78 (s, 3 H), 2.48 (m, 1 H), 2.22 (m, 1 H), 1.93 (m, 1 H), 1.76 (m, 1 H), 1.42 (s, 9 H). Example 29

2-Methyl- 1 -(R)-piperidin-3 -yl- 1 H-imidazo [4,5 -c] quino line

A solution of (R)-3-(2-methyl-imidazo[4,5-c]quinolin-l-yl)-piperidine-l-carboxylic acid tert- butyl ester (270 mg, 0.74 mmol) in TFA (5 mL) was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH). Subsequent azeotroping (diethyl ether and pentane) provided 180 mg (91%) of 2-methyl-l-(R)-piperidin-3- yl-lH-imidazo[4,5-c]quinoline as a sticky solid. LCMS (Method A, ESI): RT = 1.19 min, m+H = 267.1; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.06 (s, 1 H), 8.51 (m, 1 H), 8.16 (m, 1 H), 7.68 (m, 2 H), 5.06 (m, 1 H), 3.28 (m, 3 H), 2.96 (m, 1 H), 2.77 (s, 3 H), 2.68 (m, 1 H), 2.38 (m, 1 H), 2.18 (m, 1 H), 1.89 (m, 1 H), 1.77 (m, 1 H).

Example 30

3-[(R)-3-(2-Methyl-imidazo[4,5-c]quinolin- 1 -yl)-piperidin- 1 -yl]-3-oxo-propionitrile

A solution of 2-methyl-l-(R)-piperidin-3-yl-lH-imidazo[4,5-c]quinoline (100 mg, 375 μιηοΐ) in MeCN (8 mL) was treated with cyanoacetic acid (38.0 mg, 451 μιηοΐ), HOBt (71.0 mg, 525 μιηοΐ), DMAP (69.0 mg, 563 μιηοΐ) and EDCI (107 mg, 563 μιηοΐ) at room temperature and stirred for 18 hours. The mixture was purified by column chromatography using an Isolute® SCX-2 cartridge (gradient: MeOH to 2M NH₃ in MeOH) and then by column chromatography on silica gel (gradient: 0 to 15% [2M NH₃ in MeOH] in ethyl acetate). Further purification by column chromatography on silica gel (gradient: 0 to 10% MeOH in DCM) provided a colourless glass. Trituration (diethyl ether) and subsequent drying in vacuo at 50 °C provided 64.0 mg (51%) of 3-[(R)-3-(2-methyl-imidazo[4,5-c]quinolm^ as a white solid. LCMS (Method A, ESI): RT = 2.00 min, m+H = 334.1 ; 1H NMR (400 MHz, DMSO-d6, 80 °C): δ 9.08 (s, 1 H), 8.39 (s, 1 H), 8.17 (m, 1 H), 7.66 (m, 2 H), 5.05 (br s, 1 H), 4.80-3.40 (br m, 6 H), 2.79 (s, 3 H), 2.49 (m, 1 H), 2.23 (m, 1 H), 1.96 (m, 1 H), 1.85 (m, 1 H).

Example 31

Trans N-[l-(4-Cyanomethyl-cyclohexyl)-lH- 1,3,5, 9-tetraaza-cyclopenta[a]naphthalen-2- ylmethyl] -methanesulfonamide Trans [ 1 -(4-Cyanomethyl-cyclohexyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-ylmethyl]- carbamic acid tert-butyl ester

A stirred solution of boc-glycinamide (701 mg, 4.00 mmol) in DCM (17 mL) was treated with triethyloxonium tetrafluoroborate (702 mg, 3.70 mmol) at room temperature for 2 hours. The volatiles were removed in vacuo and trans [4-(3-amino-[l,5]naphthyridin-4-ylamino)- cyclohexyl]-acetonitrile (346 mg, 1.23 mmol) dissolved in ethanol (absolute grade, 25 mL) was added to the residue. The mixture was stirred at 75 °C for 3 hours and left to stand at room temperature for 16 hours. The solvent was removed in vacuo and the resulting residue dissolved ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution, water and brine), dried (sodium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 10% [20% (2M NH₃ in MeOH) in ethyl acetate] in ethyl acetate) afforded 387 mg (75%) of trans [l-(4-cyanomethyl-cyclohexyl)-lH- 1,3,5, 9-tetraaza- cyclopenta[a]naphthalen-2-ylmethyl]-carbamic acid tert-butyl ester. LCMS (Method B, ESI): RT = 3.27 min, m+H = 421.1; 1H NMR (400 MHz, DMSO-d6): δ 9.26 (s, 1 H), 9.06 (s, 1 H), 8.54 (dd, 1 H), 7.75 (dd, 1 H), 7.62 (br s, 1 H), 4.69 (m, 1 H), 4.67 (d, 2 H), 3.21 (m, 2 H), 2.60 (d, 2 H), 1.99 (m, 2 H), 1.79 (m, 1 H), 1.42 (m, 13 H).

Trans [4-(2-Aminomethyl- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen- 1 -yl)-cyclohexyl]- acetonitrile A stirred solution of trans [ l-(4-cyanomethyl-cyclohexyl)-lH- 1,3,5, 9-tetraaza- cyclopenta[a]naphthalen-2-ylmethyl]-carbamic acid tert-butyl ester (290 mg, 690 μηιοΐ) and dioxane (7.5 mL) was treated with HCl in dioxane (4M, 7.5 mL) at room temperature for 2 hours. The solvent was removed in vacuo and the residue azeotroped (toluene). Purification by column chromatography using Isolute® SCX-2 cartridge (gradient: MeOH to 2M N¾ in MeOH) afforded trans [4-(2-aminomethyl-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl)- cyclohexyl]-acetonitrile as a yellow gum. The product was used for the next step without further purification. LCMS (Method B, ESI): RT = 1.99 min, m+H = 321.

Trans N-[l-(4-Cyanomethyl-cyclohexyl)-lH- 1,3,5, 9-tetraaza-cyclopenta[a]naphthalen-2- ylmethyl] -methanesulfonamide

A stirred solution of trans [4-(2-aminomethyl-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl)- cyclohexyl]-acetonitrile (114 mg, 356 μιηοΐ) in THF (3 mL) was treated with triethylamine (99.0 μί, 712 μιηοΐ) and methane sulfonylchloride (30.0 μί, 392 μιηοΐ) at 0 °C for 10 minutes. The mixture was partitioned between ethyl acetate and saturated sodium hydro gencarbonate solution. The organic phase was washed (brine), dried (sodium sulfate) and concentrated. Purification by column chromatography on silica gel (gradient: 0 to 30% [20% (2M N¾ in MeOH) in ethyl acetate] in ethyl acetate) afforded 77.1 mg (54%) of trans N-[l-(4-cyanomethyl-cyclohexyl)-lH- l,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-ylmethyl]-methanesulfonamide as a white solid. LCMS (Method A, ESI): RT = 3.12 min, m+H = 399.0; 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1 H), 9.08 (br s, 1 H), 8.55 (dd, 1 H), 7.90 (s, 1 H), 7.77 (dd, 1 H), 4.74 (br s, 1 H), 4.71 (br s, 2 H), 3.21 (m, 2 H), 3.02 (s, 3 H), 2.60 (d, 2 H), 2.11-1.82 (m, 5 H), 1.42 (m, 2 H).

Example 32

Trans [ 1 -(4-Cyanomethyl-cyclohexyl)- 1 H- 1 ,3 ,5 ,9-tetraaza-cyclopenta[a]naphthalen-2-ylmethyl]- carbamic acid methyl ester

A stirred solution of trans [4-(2-aminomethyl-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-l-yl)- cyclohexyl]-acetonitrile (114 mg, 356 μιηοΐ) in THF (3 mL) was treated with triethylamine (74.0 μΐ_^, 534 μηιοΐ) and methyl chloro formate (30.0 μί, 392 μmol) at 0 °C for 10 minutes. The mixture was partitioned between ethyl acetate and saturated sodium hydro gencarbonate solution. The organic phase was washed (brine), dried (sodium sulfate) and concentrated. Purification by column chromatography on silica gel (gradient: 0 to 30% [20% (2M N¾ in MeOH) in ethyl acetate] in ethyl acetate) afforded 79.0 mg (59%) of trans [l-(4-cyanomethyl-cyclohexyl)-lH- l,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-ylmethyl]-carbamic acid methyl ester as a white solid. LCMS (Method A, ESI): RT = 3.12 min, m+H = 379.1; 1H NMR (400 MHz, DMSO-d6): δ 9.27 (s, 1 H), 9.06 (br s, 1 H), 8.54 (dd, 1 H), 7.94 (br s, 1 H), 7.75 (dd, 1 H), 4.73 (d, 2 H), 4.63 (br s, 1 H), 3.60 (s, 3 H), 3.21 (m, 2 H), 2.60 (d, 2 H), 1.97 (m, 3 H), 1.80 (m, 2 H), 1.39 (m, 2 H).

Example 33

l-(l-Methanesulfonyl-4-methyl-piperidin-4-yl)-2-methyl-lH-imidazo[4,5-c]quinoline ( 1 -Methanesulfonyl-4-methyl-piperidin-4-yl)-(3 -nitro-quino lin-4-yl)-amine A mixture of l-methanesulfonyl-4-methyl-piperidin-4-ylamine hydrochloride (WO2006062063) (361 mg, 1.58 mmol), DIPEA (1.25 mL, 7.20 mmol) and 4-chloro-3-nitro-quinoline (300 mg, 1.44 mmol) in propan-2-ol (10 mL) was heated to 120 °C for 40 minutes using microwave irradiation. After cooling, the resulting precipitate was collected by filtration, washed with propan-2-ol and sucked dry to provide 352 mg (67%) of (l-methanesulfonyl-4-methyl-piperidin- 4-yl)-(3-nitro-quinolin-4-yl)-amine as a yellow solid. LCMS (Method B, ESI): RT = 2.94 min, m+H = 365.1; 1H NMR (400 MHz, DMSO-d6): δ 9.21 (s, 1 H), 8.33 (d, 1 H), 7.98 (m, 1 H), 7.89 (m, 1 H), 7.86 (s, 1 H), 7.68 (m, 1 H), 3.19 (m, 4 H), 2.87 (s, 3 H), 1.98 (m, 4 H), 1.31 (s, 3 H).

] f*4*-(l-Methanesulfonyl-4-methyl-piperidin-4-yl)-quinoline-3,4-diamine A solution of (l-methanesulfonyl-4-methyl-piperidin-4-yl)-(3-nitro-quinolin-4-yl)-amine (350 mg, 0.96 mmol) in ethyl acetate (10 mL) and THF (10 mL) was treated with palladium on carbon (50 mg, 10% Pd) under a nitrogen atmosphere. The mixture was evacuated and purged with hydrogen and then stirred under an atmosphere of hydrogen for 90 minutes. The mixture was filtered through Celite® and the filtrate concentrated in vacuo to provide 315 mg (98%>) of crude ] f*4*-(l-methanesulfonyl-4-methyl-piperidin-4-yl)-quinoline-3,4-diamine as a pale yellow foam. The product was used without further purification. LCMS (Method B, ESI): RT = 2.05 min, m+H = 335.2; 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1 H), 8.05 (d, 1 H), 7.74 (dd, 1 H), 7.35 (m, 2 H), 5.28 (s, 2 H), 4.12 (s, 1 H), 3.39 (m, 2 H), 2.93 (m, 2 H), 2.85 (s, 3 H), 1.88 (m, 2 H), 1.69 (m, 2 H), 1.12 (s, 3 H). l-(l-Methanesulfonyl-4-methyl-piperidin-4-yl)-2-methyl-lH-imidazo[4,5-c]quinoline A mixture of N*4^!i:-(l-methanesulfonyl-4-methyl-piperidin-4-yl)-quinoline-3,4-diamine (50.0 mg, 149 μιηοΐ) and triethyl orthoacetate (274 μΐ_^, 1.50 mmol) in ethanol (2 mL, IMS grade) was heated at 80 °C for 18 hours in a sealed vial. p-Toluenesulfonic acid (cat) was added and heating continued for 2 hours. After cooling, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate. The mixture was washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated. The residue was purified by column chromatography on silica gel (gradient: 0 to 20% MeOH in ethyl acetate) and the isolated product azeotroped (diethyl ether). l-(l-Methanesulfonyl-4-methyl-piperidin-4-yl)-2-methyl-lH- imidazo[4,5-c]quinoline (28.1 mg, 53%) was isolated as a white solid. LCMS (Method C, ESI): RT = 4.76 min, m+H = 359.2; 1H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1 H), 8.63 (m, 1 H), 8.17 (m, 1 H), 7.66 (m, 2 H), 3.54 (m, 2 H), 3.26 (m, 2 H), 2.97 (s, 3 H), 2.92 (s, 3 H), 2.72 (m, 2 H), 2.50 (m, 2 H), 2.10 (s, 3 H).

Example 34

Mixture of diastereoisomers (R)-l-[l-(l-Benzyl-3,3-difluoro-piperidin-4-yl)-lH-l,3,5,9-tetraaza- eye lopenta[a]naphthalen-2-yl] -ethanol

Racemic (l-Benzyl-3,3-difiuoro-piperidin-4-yl)-(3-nitro-[l,5]naphthyridin-4-yl)-amine A mixture of racemic l-benzyl-3,3-difluoro-piperidin-4-ylamine (prepared according to the procedures outline in WO2008121687) (357 mg, 1.58 mmol), DIPEA (1.25 mL, 7.20 mmol) and 4-chloro-3-nitro-[l,5]naphthyridine (302 mg, 1.44 mmol) in propan-2-ol (10 mL) was heated to 120 °C for 40 minutes using microwave irradiation. After cooling, the resulting precipitate was collected by filtration and washed with propan-2-ol and sucked dry to provide 412 mg (72%) of racemic (l-benzyl-3,3-difluoro-piperidin-4-yl)-(3-nitro-[l,5]naphthyridin-4-yl)-amine as a brown/ green solid. LCMS (Method B, ESI): RT = 3.73 min, m+H = 400.2; 1H NMR (400 MHz, DMSO-d6): δ 9.76 (br s, 1 H), 9.28 (s, 1 H), 8.95 (dd, 1 H), 8.36 (dd, 1 H), 7.91 (dd, 1 H), 7.34 (m, 5 H), 6.07 (br s, 1 H), 3.67 (s, 2 H), 3.19 (m, 1 H), 2.91 (br d, 1 H), 2.55 (m, 1 H), 2.36 (m, 2 H), 1.83 (m, 1 H).

Racemic N*4*-(l-Benzyl-3,3-difiuoro-piperidin-4-yl)-[l,5]naphthyridine-3,4-diamine

To a stirred suspension of racemic (l-benzyl-3,3-difluoro-piperidin-4-yl)-(3-nitro- [l,5]naphthyridin-4-yl)-amine (393 mg, 985 μιηοΐ) and iron powder (215 mg, 3.84 mmol) in ethanol (IMS grade, 5 mL), a solution of ammonium chloride (305 mg, 5.71 mmol) in water (1.5 mL) was added at room temperature. The mixture was then heated at 80 °C for 2 hours. After cooling, the mixture was filtered through of Celite® and the filter cake washed several times with ethanol (IMS grade) and water (4: 1). The filtrate was concentrated in vacuo and the resulting aqueous residue was treated with saturated sodium hydro gencarbonate solution and extracted with ethyl acetate (3x). The combined organic phases were washed (saturated sodium hydro gencarbonate solution and brine), dried (sodium sulfate) and concentrated in vacuo to afford 340 mg (93%) of racemic N*4*-(l-benzyl-3,3-difluoro-piperidin-4-yl)- [l,5]naphthyridine-3,4-diamine as a light brown solid. This material was used for the next step without further purification. LCMS (Method B, ESI): RT = 2.12 min, m+H = 370.2; 1H NMR (400 MHz, DMSO-d6): δ 8.72 (dd, 1 H), 8.44 (s, 1 H), 8.11 (dd, 1 H), 7.42 (dd, 1 H), 7.32 (m, 5 H), 5.88 (d, 1 H), 5.10 (s, 2 H), 4.51 (m, 1 H), 3.61 (q, 2 H), 3.03 (m, 1 H), 2.83 (br d, 1 H), 2.34 (m, 1 H), 2.20 (m, 1 H), 2.04 (m, 1 H), 1.68 (m, 1 H).

Mixture of diastereoisomers (R)-l-[l-(l-Benzyl-3,3-difluoro-piperidin-4-yl)-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl] -ethanol A stirred solution of (R)-(+)-lactamide (205 mg, 2.30 mmol) in anhydrous DCM (4 mL), was treated with triethyloxonium tetrafluoroborate (410 mg, 2.16 mmol) at room temperature for 2 hours. The volatiles were removed in vacuo and the residue dissolved in ethanol (absolute grade, 1 mL). This was added to a solution of racemic N*4^!i:-(l-benzyl-3,3-difluoro-piperidin-4-yl)- [l,5]naphthyridine-3,4-diamine (266 mg, 0.72 mmol) in ethanol (absolute grade, 3 mL) and the reaction mixture was heated to 75°C, in a sealed vial, for 2 hours. The volatiles were removed in vacuo and the residue was purified by column chromatography using Isolute® SCX-2 cartridge (gradient: MeOH to 1M NH₃ in MeOH) followed by column chromatography on silica gel (gradient: 0 to 10% [2M NH₃ in MeOH] in DCM) to afford 198 mg (65%) of a mixture of diastereoisomers of (R)- 1 -[ 1 -( 1 -benzyl-3 ,3-difluoro-piperidin-4-yl)- 1 H- 1 ,3 ,5 ,9-tetraaza- cyclopenta[a]naphthalen-2-yl] -ethanol as a light orange solid. LCMS (Method A, ESI): RT = 3.57 min, m+H = 424.0 (Diastereoisomer I); RT = 3.83 min, m+H = 424.0 (Diastereoisomer II); Ratio 1 : 1; 1H NMR (400 MHz, DMSO-d6): (mixture of diastereoisomers and rotamers) δ 9.34- 9.30 (m, 1 H), 9.09 (dd, 0.25 H), 8.97 (m, 0.75 H), 8.58-8.53 (m, 1 H), 7.80-7.73 (m, 1 H), 7.54-7.36 (m, 5 H), 7.35-7.28 (m, 1 H), 5.96 (m, 0.25 H), 5.60 (m, 0.8 H), 5.57-5.45 (m, 0.2 H), 5.36-5.24 (m, 0.75 H), 5.19-5.11 (m, 0.25 H), 4.92-4.78 (m, 0.25 H), 3.96-3.84 (m, 0.5 H), 3.82-3.69 (m, 1.5 H), 3.31 (m, 1 H), 3.20-3.11 (m, 1 H), 2.92-2.73 (m, 1 H), 2.69-2.36 (m, 3 H), 1.72 (t, 2.3 H), 1.53 (d, 0.7 H).

Example 35

Mixture of diastereoisomers (R)-l-[l-(3,3-Difluoro-piperidin-4-yl)-lH-l,3,5,9-tetraaza- cyclopenta[a]naphthalen-2-yl] -ethanol formic acid salt To a stirred solution of a mixture of diastereoisomers of (R)-l-[l-(l-benzyl-3,3-difluoro- piperidin-4-yl)-lH-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-yl]-ethanol (165 mg, 390 μιηοΐ) in MeOH (3 mL), ammonium formate (245 mg, 3.90 mmol) and palladium hydroxide (28 mg, 20 wt%) were added. The resulting mixture was heated to 60 °C for 1 hour. After cooling, the mixture was filtered through Celite® and the filtrate concentrated. The residue was concentrated on to silica gel and purified by flash chromatography (gradient: 0 to 20% MeOH in DCM). The resulting product was azeotroped (diethyl ether) to afford 95 mg of the crude product as an off- white solid. Purification by reverse phase HPLC (gradient: 5 to 50% MeCN in ¾0 + 0.1% HC0₂H) and subsequent lyophilisation afforded a mixture of diastereoisomers of (R)-l-[l-(3,3- difiuoro-piperidin-4-yl)-lH-l,3,5,9-tetraaza-cyclopenta[a]naphthalen-2-yl]-ethanol as a partial formic acid salt. LCMS (Method A, ESI): RT = 1.71 min, m+H = 334.0 (Diastereoisomer I); RT = 1.86 min, m+H = 334.0 (Diastereoisomer II); Ratio 1 : 1.7; 1H NMR (400 MHz, DMSO-d6): (mixture of diastereoisomers and rotamers) δ 9.35-9.28 (m, 1 H), 9.04 (dd, 0.15 H), 9.00-8.98 (m, 0.85 H), 8.58-8.54 (m, 0.85 H), 8.53-50 (m, 0.15 H), 8.18 (s, 0.4 H, formate), 7.80-7.72 (m, 1 H), 7.61-7.45 (m, 1 H), 6.10-5.85 (br s, 0.2 H), 5.66-5.45 (m, 0.8 H), 5.42-5.30 (m, 0.85 H), 5.21-5.13 (m, 0.15 H), 4.73-4.59 (m, 0.15 H), 3.50-3.15 (m, 4.5 H), 3.06-2.90 (dd, 0.85 H), 2.85-2.70 (m, 1.5 H), 2.40-2.30 (m, 0.85 H), 2.00-1.92 (m, 0.15 H), 1.76-1.67 (m, 2.4 H), 1.52 (d, 0.6 H).

Using procedures similar to those described herein the following compounds

Examples 36-56 were prepared.

TABLE 1

0

1 -( 1 -Methanesulfonyl-4-

56 m ethyl-pi perid i n-4-yl )-2- 33 2.80 / A 360.0 methyl-1 H-1 ,3,5,9-tetraaza- cyclopenta[a]naphthalene

The corresponding JAKl, JAK2, JAK3 and TYK2 inhibitions are shown in Table 2 for Examples 1-56.

Table 4

Example JAKl Ki, μΜ JAK2 Ki, μΜ JAK3 Ki, μΜ TYK2 Ki, μΜ

1 0.00021 0.001677 0.035879 0.00045

2 0.049253 0.346492 1.928896 0.066751

3 0.0131 15 0.039727 0.258109 0.017608

4 0.000026 0.00098 0.032335 0.000327

5 0.001 184 0.015383 0.249131 0.00266

6 0.019848 0.1 18633 1.459569 0.033861

7 0.001451 0.008023 0.216225 0.00156

8 0.090101 0.590916 2.936771 0.219831

9 0.006144 0.037516 1.240689 0.016127

10 0.183261 0.743909 3.163198 0.277747

11 0.291 1 1 2.193043 4.103771 1.552186

12 0.016482 0.064725 2.275882 0.023985

13 0.01545 0.058734 0.590122 0.041 175

14 3.782298 1.629453 4.103771 2.843124

15 0.554504 3.188008 3.167651 3.201208

16 0.057019 0.099813 0.091322 0.077887 17 0.076722 0.195324 0.555883 0.073655

18 0.022435 0.388687 1.680755 0.800049

19 0.797485 3.188008 3.330969 0.782784

20 0.281887 0.814472 1.987808 0.57372

21 0.157837 0.638439 0.870449 1.130425

22 0.12546 0.877731 1.596212 0.44102

23 0.008986 0.044382 0.412137 0.015552

24 0.00295 0.015628 0.247067 0.003289

25 5.621712 3.188008 4.103771 3.472582

26 2.541901 3.188008 3.818807 2.251313

27 0.21 1091 0.693582 1.609237 0.401 197

28 1.233426 1.437416 4.103771 3.472582

29 2.330678 3.188008 1.367924 3.472582

30 0.062102 0.134127 0.908426 0.18751

31 0.00074 0.004727 0.17679 0.002435

32 0.001 183 0.004759 0.084659 0.00309

33 0.128849 0.107103 0.257002 0.10508

34 0.014907 0.022002 0.232793 0.050148

35 0.180148 0.257001 1.648133 0.254747

36 0.00096 0.003286 0.013208 0.001463

37 0.051207 0.312484 2.27131 0.1 1 1679

38 0.020639 0.226953 2.691652 0.03581 1

39 0.174564 1.151221 4.103771 0.525042

40 0.622343 1.334921 3.375212 0.665646

41 0.026162 0.059677 1.123413 0.070278

42 0.008962 0.037038 0.1 16985 0.023126

43 0.002182 0.004491 0.01841 1 0.00198 44 0.005462 0.01271 1 0.07869 0.017251

45 0.003949 0.016464 0.191833 0.00868

46 0.135401 0.728806 1.021745 0.274803

47 0.364822 0.197944 1.998834 0.747173

48 0.68203 3.063791 4.103771 1.217607

49 0.588468 0.672592 2.630907 0.522185

50 0.043841 0.199531 0.405295 0.073614

51 0.06895 0.17071 1 0.436073 0.06081 1

52 0.065437 0.372106 0.34613 0.058302

53 0.070867 0.962636 1.605636 0.197231

54 0.141201 0.736512 1.493751 0.173314

55 0.479593 1.209702 4.103771 2.807143

56 0.077149 0.1 1 1 104 0.408752 0.166796

Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as defined by the claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I:

stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein

X is N or CR⁴; Y is N or CR⁵;

R¹ is C3-12 cycloalkyl, or 3-20 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, Ci_₃ -C(0)OR^a, -S(0)₂R^a, or Ci_6 alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C_6-14 aryl, or halogen;

R² is absent, Ci_₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, -(Ci_₆ alkylene)-, -(C₂_6 alkenylene)-, -(C₂-6 alkynylene)-, -(C₀_6 alkylene)CN, -(C_0-3 alkylene)NR^a(C₀-₃ alkylene)-, -(C_0-3 alkylene)0(Co_3 alkylene)-, -(C₀.₃ alkylene)C(O)(C₀-₃ alkylene)-, -(C₀.₃ alkylene)NR^aC(O)(C₀-₃ alkylene)-, -(C₀.₃ alkylene)C(O)NR^a(C₀-₃ alkylene)-, -(C₀.₃ alkylene)C(O)O(C₀-₃ alkylene)-, -(Co-3 alkylene)OC(0)(Co_3 alkylene)-, -(C₀.₃ alkylene)NR^aC(O)NR^b(C₀-₃ alkylene)-, -(C₀.₃ alkylene)OC(0)NR^a(Co_3 alkylene)-, -(C₀.₃ alkylene)NR^aC(O)O(C₀-₃ alkylene)-, -(C₀.₃ alkylene)S(O)i_₂(C₀-3 alkylene)-, -(C₀.₃ alkylene)NR^aS(O)i_₂(C₀-₃ alkylene)-, -(C₀.₃ alkylene)S(O)i_₂NR^a(C₀-3 alkylene)- or -(C₀.₃ alkylene)NR^aS(O)i_₂NR^b(C₀-₃ alkylene)-, wherein said alkyl, alkyenyl, alkynyl, alkylene, alkenylene and alkynylene are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₃ alkyl optionally substituted by halogen;

R³ is absent, hydrogen, Ci_₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C3-7 cycloalkyl, C_6-14 aryl or 3-20 membered heterocyclyl, wherein R³ is independently optionally substituted by R⁶;

R⁴ is hydrogen, halogen or Ci_₃ alkyl; WO 2013/007768 ^{" i ov "} PCT/EP2012/063632

R⁵ is halogen, C_1-12 alkyl, C_2-12 alkenyl, C_2-12 alkynyl, -(C0-3 alkylene)CN, -(C0-3 alkylene)NR^aR^b, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)SR^a, -(C₀.₃ alkylene)C(0)R^a, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C(0)OR^a, -(C₀.₃

alkylene)OC(0)R^a, -(C₀.₃ alkylene)NR^aC(0)NR^aR^b, -(C₀.₃ alkylene)OC(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene)S(0)i_₂R^a, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)C₃_i₂ cycloalkyl, -(Co-3 alkylene)C6-i4 aryl, -(C_0-3 alkylene)3-12 membered heterocyclyl or -(C_0-3

alkylene)C(0)3-12 membered heterocyclyl, wherein said C₂_i₂ alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, aryl and heterocyclyl are independently optionally substituted by halogen, oxo, -(C_0- 3 alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃

alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen; and wherein said Ci alkyl is independently optionally substituted by halogen, oxo, -(C_0-3

alkylene)CN, -(Ci_₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(C₀.₃ alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃

alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(0)o_₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene) S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d, -OR^k, or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen;

R⁶ is independently oxo, halogen, -CN, -C(0)R^a, -C(0)OR^a, -NR^aC(0)R^b, -C(0)NR^aR^b, -NR^aC(0)NR^aR^b, -OC(0)NR^aR^b, -NR^aC(0)OR^b, -S(0)i_₂R^a, -NR^aS(0)₂R^a, -S(0)₂NR^aR^b, -OR^a, -SR^a, -NR^aR^b, Ci_₆ alkyl, C₃_₆ cycloalkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, 3-7 membered heterocycly or C_6-14 aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₆ alkyl optionally substituted by oxo or halogen; each R^a and R^b are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(C_0-3 alkylene)C3-6 cycloalkyl, -(C_0-3 alkylene)3-12 membered heterocyclyl, -(C_0-3 alkylene)C(0)3-12 membered heterocyclyl or -(C_0-3 alkylene)C6_i4 aryl, wherein said alkyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS (O) 1 _₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₃ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo, halogen, OR^g or NR^gNR^h; each R^c and R^d are independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co_₃ alkylene)C₃_6 cycloalkyl, -(Co_₃ alkylene)3-12 membered heterocyclyl, -(Co_₃ alkylene)C(0)3-12 membered heterocyclyl or -(Co_₃ alkylene)C6_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_ ₂NR^gR^h, C₃_6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen; each R^e, R^f, R^g, R^h are independently hydrogen or Ci_₆ alkyl optionally substituted by halogen or oxo; and each R^k is independently hydrogen, C₂_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -(Co_₃ alkylene)C₃_6 cycloalkyl, -(Co_₃ alkylene)3-12 membered heterocyclyl, -(Co_₃ alkylene)C(0)3-12 membered heterocyclyl or -(Co_₃ alkylene)C6_i4 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h,

-NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_ ₂NR^gR^h, C₃_6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

2. The compound of claim 1, wherein X is CR⁴ and Y is CR⁵.

3. The compound of any one of claims 1-2, wherein R¹ is C₃_8 cycloalkyl, or 4-10 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C₆-i4 aryl, or halogen. WO 2013/007768 ^{" 1} ' ^{1 "} PCT/EP2012/063632

4. The compound of any one of claims 1-2, wherein R¹ is C₅_6 cycloalkyl or 5-6 membered heterocyclyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C₆-i4 aryl, or halogen. 5. The compound of any one of claims 1-2, wherein R¹ is cyclohexyl, cyclopentyl, piperidinyl, or tetrahydropyranyl, wherein R¹ is independently optionally substituted by halogen, oxo, -CN, -OR^a, -SR^a, -NR^aR^b, -C(0)OR^a, -S(0)₂R^a, or Ci_₆ alkyl optionally substituted by oxo, -CN, -S(0)₂R^a, C₆-i4 aryl, or halogen.

6. The compound of any one of claims 1-2, wherein R¹ is selected from:

7. The compound of any one of claims 1-2 wherein -R¹-R²-R³ taken together are selected from:

3632

9. The compound of any one of claims 1-8 wherein R⁴ is hydrogen, methyl or F. 10. The compound of any one of claims 1-9, wherein R⁵ is halogen, C_1-12 alkyl, -(C_0-3 alkylene)CN, -(C₀.₃ alkylene)OR^a, -(C₀.₃ alkylene)NR^aR^b, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)C₃-i2 cycloalkyl, -(C₀.₃ alkylene)C(0)NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)R^b, -(C₀.₃ alkylene)NR^aS(0)i_₂R^b, -(C₀.₃ alkylene)NR^aS(0)i_₂NR^aR^b, -(C₀.₃ alkylene)S(0)i_₂NR^aR^b, -(C₀.₃ alkylene)NR^aC(0)OR^b, -(C₀.₃ alkylene)S(0)i_₂R^a, wherein R⁵ is independently optionally substituted by halogen, oxo, -(C₀.₃ alkylene)CN, -(C₀.₃ alkylene)OR^c, -(C₀.₃ alkylene)NR^cR^d, -(Co-3 alkylene)C(0)R^c, -(C₀.₃ alkylene)C(0)OR^c, -(C₀.₃ alkylene)C(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)R^d, -(C₀.₃ alkylene)OC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)NR^cR^d, -(C₀.₃ alkylene)NR^cC(0)OR^d, -(C₀.₃ alkylene)S(O)₀-₂R^c, -(C₀.₃ alkylene)NR^cS(0)i_₂R^d, -(C₀.₃ alkylene)S(0)i_₂NR^cR^d, -(C₀.₃ alkylene)NR^cS(0)i_₂NR^cR^d or Ci_₆ alkyl optionally substituted by oxo, -CN or halogen.

11. The compound of any one of claims 1-10, wherein R⁵ is methyl, ethyl, propyl, isopropyl, cyclopropyl, eye lo butyl, cyano, 2-methylbutyl, N-(2-hydroxyethyl)amino, N-(2- methoxyethyl)amino , methylsulfonylamino methyl, 2-(methylsulfonylamino)ethyl,

cyclopropylmethyl, 2- [N-(2-propylsulfonyl)amino ] ethyl, 2- [N-(cyclopropylsulfonyl)- amino] ethyl, 2-(cyclopropylcarbonylamino)ethyl, 2-(acetylamino)ethyl, 2-(methoxymethyl- carbonylamino)ethyl, cyclopentoxymethyl, cyclopropylmethoxymethyl, 2,2,2- trifluoroethoxymethyl, cyclohexyl, methylamino, 2-(N,N-dimethylaminocarbonyl)ethyl, 2-(N- acetyl-N-methylamino)ethyl, 2-(ethoxycarbonylamino)ethyl, 1 -hydro xyethyl, N- WO 2013/007768 ^{~ L I}^ ^~ PCT/EP2012/063632 acylaminomethyl, 2-amino-l,l-difluoroethyl, Ν,Ν-dimethylamino, hydro xymethyl, methoxy, N- methylamino, N,N-dimethylamino,N-(2,2,2-trifluoroethyl)aminomethyl, (2- carboxycyclopropyl)(hydroxy)methyl, 2-hydro xyethyl, amino carbonylmethyl,

methylammocarbonylmethyl, ethylamino carbonylmethyl, 1 -hydro xypropyl, 1 ,2-dihydro xyethyl, N-(2-methylpropyl)aminocarbonylmethyl, cyclopentylaminocarbonylmethyl, 2-

(methoxycarbonylamino)ethyl, 2,2,2-trifluoro- 1 -hydro xyethyl, tert-butylamino carbonylmethyl, cyclobutylaminocarbonylmethyl, 2-hydroxyethoxy, isopropylamino carbonylmethyl, N-(N'N'- diemthylaminocarbonylmethyl)aminocarbonylmethyl, 4,4-difluorocyclohexyl- amino carbonylmethyl, 2,2-difluoroethylaminocarbonylmethyl, N-(2-hydroxyethyl)-N- methylammocarbonylmethyl, cyclopentylmethyl, N-cyclopentyl-N-methylaminocarbonylmethyl,

2- amino-l,l-difluoroethyl, 3-pyridyl, morpho lino methyl, morpholmocarbonylmethyl, 2-cyano-2- methylethyl, trifluoromethyl, 1 -hydroxy- 1-methylethyl, l-(N-isopropylaminocarbonyl)ethyl, 2- hydroxy-2-methylpropyl, N-(methylsulfonyl)-N-methylaminomethyl, difluoromethyl, 2-(2- butylsulfonylamino)ethyl, 2-(4-fluorophenylcarbonylamino)ethyl, 2-(cyclobutylcarbonyl- amino)ethyl, 2-(2-methylbutanoylamino)ethyl, 2-(benzoylamino)ethyl, 2,2-difluorocyclopropyl,

3- cyanobenzyl, 2-methylpropo xymethyl, 2-cyclopropylethyl, 3-pyridylmethyl,

methylsulfonylmethyl, ethoxycarbonylamino methyl, 3 -pyridylcarbonylamino methyl,

isopropylsulfonylaminomethyl, 2-pyridylcarbonylaminomethyl, cyclopropylsulfonyl- aminomethyl, cyclopentylsulfonylaminomethyl, 2-methylpropanoylaminomethyl,

cyclopropylcarbonylaminomethyl, 2-fluorobenzoylaminomethyl, 3-fluorobenzoylaminomethyl, 1-methylpropylsulfonylaminomethyl, 2-methylpropylsulfonylaminomethyl,

methoxyacetylaminomethyl, ethylsylfonylaminomethyl, 2-(3,3,3-trifluoropropylsulfonyl- amino)ethyl, 2-(2,2-difluorocyclopropylcarbonylamino)ethyl, fluoromethyl, 2- hydroxyethylamino, 2-methoxyethylamino, 1-aminoethyl, 2-(ethylsulfonylamino)ethyl, 2,2- dimethylpropo xymethyl, 1-metho xyethyl, tert-butylsulfonylaminomethyl, 2,2,2-trifluoroethyl- aminomethyl,

W

, wherein the wavy line represents the point of attachment in formula I.

12. The compound of any one of claims 1-11, wherein R⁶ is independently oxo, halogen, -CN, -C(0)R^a, -C(0)OR^a, -NR^aC(0)R^b, -C(0)NR^aR^b, -NR^aC(0)NR^aR^b,

-OC(0)NR^aR^b, -NR^aC(0)OR^b, -S(0)i_₂R^a, -NR^aS(0)₂R^b, -S(0)₂NR^aR^b, -OR^a, -SR^a,

-NR^aR^b, Ci_6 alkyl, C3-6 cycloalkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, 3-7 membered heterocycly or C_6-14 aryl, and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are

independently optionally substituted by halogen, oxo, -CN, -OR^c, -SR^C, -NR^cR^d or Ci_₆ alkyl optionally substituted by oxo or halogen.

13. The compound of any one of claims 1-12, wherein each R^a and R^b are

independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -C3-6 cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or -C_6-14 aryl, wherein said alkyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^e, -NR^eR^f, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS (O) ₁ _₂NR^gR^h, C₃_₆ cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₃ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo, halogen, OR^g or NR^gNR^h.

14. The compound of any one of claims 1-13, wherein each R^c and R^d are

independently hydrogen, Ci_₆ alkyl, C₂_₆ alkenyl, C₂_₆ alkynyl, -C₃_₆ cycloalkyl, -3-12 membered heterocyclyl, -C(0)3-12 membered heterocyclyl or -C_6-14 aryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl and aryl are independently optionally substituted by halogen, oxo, -CN, -OR^g, -NR^gR^h, -C(0)R^g, -C(0)OR^g, -C(0)NR^gR^h, -NR^gC(0)R^h, -OC(0)NR^gR^h, -NR^gC(0)NR^gR^h, -NR^gC(0)OR^h, -S(0)i_₂R^g, -NR^gS(0)i_₂R^h, -S(0)i_₂NR^gR^h, -NR^gS(0)i_ ₂NR^gR^h, C₃_6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or Ci_₆ alkyl optionally substituted by oxo or halogen, or taken together with the atom to which they are attached to form a 3-6 WO 2013/007768 ^{" 1} " ^" PCT/EP2012/063632 membered heterocyclyl optionally substituted by oxo, halogen, -C(0)Ci_₆ alkyl or Ci_₆ alkyl optionally substituted by oxo or halogen.

15. The compound of any one of claims 1-14, wherein each R^e, R^f, R^g, R^h are independently hydrogen, methyl, ethyl, propyl or isopropyl, optionally substituted by halogen oxo.

A compound of claim 1, selected from

and stereoisomers, tautomers and pharmaceutically acceptable salts thereof.

17. A pharmaceutical composition comprising a compound of any one of claims 1-16, a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

18. A compound of any one of claims 1-16, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in therapy.

19. A compound of any one of claims 1-16, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in treating an immunological disease.

20. A compound of any one of claims 1-16, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, for use in treating an immunological disease selected from rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD and transplant rejection.

21. The use of a compound of any one of claims 1-16, a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease responsive to the inhibition of JAKl kinase activity.

22. A method for preparing a compound of formula I or a pharmaceutically acceptable salt thereof as described in claim 1 comprising: a. for a compound of formula I wherein Y is CR⁵, cyclizing a corresponding compound of formula 100:

to provide the compound of formula I; b. contacting a compound of formula I with an acid or base to provide the corresponding pharmaceutically acceptable salt; c. removing a protecting group from a corresponding compound bearing a protecting group to provide the compound of formula I; d. for a compound of formula I wherein R² and R³ are not each absent, converting a compound of formula 101:

to the corresponding compound of formula I wherein R² and R³ are not each absent; for a compound of formula I wherein -R¹-R²-R³ taken together are:

reacting a corresponding compound of formula I wherein -R¹-R²-R³ taken together are:

with a compound of formula R^a-Lg, wherein Lg is a suitable leaving group, to provide the compound of formula I; for a compound of formula I wherein -R¹-R²-R³ taken together are:

reacting a corresponding compound of formula I wherein -R¹-R²-R³ taken together are: with a compound of formula R^a-Lg, wherein Lg is a suitable leaving group, to provide the compound of formula I;

g. for a compound of formula I wherein -R¹ is:

removing a protecting group Pg from a corresponding compound of formula I wherein -R¹ is

to provide the compound of formula I; or for a compound of formula I wherein -R¹

removing a protecting group Pg from a corresponding compound of formula I wherein -R¹ is

to provide the compound of formula I.