Piperidin-4-yl azetidine derivatives as jak1 inhibitors

Abstract

To provide pharmaceutical compositions comprising piperidin-4-yl azetidine derivatives useful in treatment of diseases associated with the activity of Janus kinase 1 such as systemic lupus erythematosus, sarcoidosis, cutaneous T cell lymphoma (e.g., mycosis fungoides), ankylosing spondylitis, ulcerative colitis, chronic obstructive lung disease, asthma, rhinitis and sinusitis.SOLUTION: Provided herein is a pharmaceutical composition comprising {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides piperidin-4-ylazetidine derivatives, and compositions and methods of use thereof, that modulate the activity of Janus kinase 1 (JAK1) and are useful in the treatment of diseases associated with JAK1 activity, such as inflammatory diseases, autoimmune disorders, cancer, and other diseases. [Background technology]

[0002] Protein kinases (PKs) control a wide variety of biological processes, including cell growth, cell survival, cell differentiation, organogenesis, morphogenesis, angiogenesis, tissue repair, and tissue regeneration, among others. Protein kinases also play specialized roles in many human diseases, including cancer. Many pathways involved in the host inflammatory response to sepsis are controlled by cytokines, small polypeptides or glycoproteins. Cytokines affect cell differentiation, proliferation, and activation, and modulate both pro- and anti-inflammatory responses, allowing the host to respond appropriately to pathogens. A wide range of cytokine signaling includes the Janus kinase family (JAK), which consists of protein tyrosine kinases and signal transducers and activators of transcription (STATs). There are four known mammalian JAKs: JAK1 (Janus kinase 1), JAK2, JAK3 (Janus kinase, leukocyte; also known as JAKL; and L-JAK), and TYK2 (protein tyrosine kinase 2).

[0003] Cytokine-stimulated immune and inflammatory responses are one of the causes of pathology: pathological conditions such as severe combined immunodeficiency (SCID) are due to suppression of the immune system, while hyperactive or inappropriate immune / inflammatory responses contribute to the symptoms of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis), as well as diseases such as scleroderma and osteoarthritis (Non-Patent Document 1).

[0004] Insufficient expression of JAKs is associated with many pathologies. For example, Jak1- / - mice are growth retarded from birth and are unable to lactate, resulting in perinatal death (Non-Patent Document 2). Jak2- / - mouse fetuses are anemic and die approximately 12.5 days after mating due to the absence of erythropoiesis.

[0005] The JAK / STAT pathway, particularly all four JAKs, is believed to be involved in the pathogenesis of asthmatic responses, chronic obstructive pulmonary disease, bronchitis, and other related lower airway inflammatory diseases. Several cytokines that signal through JAKs have been linked to inflammatory diseases / conditions of the upper airway, including those affecting the nose and sinuses (e.g., rhinitis and sinusitis), whether or not they are classical allergic responses. The JAK / STAT pathway has also been implicated in inflammatory diseases / conditions of the eye, and chronic allergic responses.

[0006] Activation of JAK / STAT in cancer can be caused by stimulation with cytokines (e.g., IL-6 or GM-CSF) or by a decrease in endogenous inhibitors of JAK signaling, such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Non-Patent Document 3). Activation of STAT signaling, and other downstream pathways of JAK (e.g., Akt), has been linked to poor prognosis in many cancer types (Non-Patent Document 4). High levels of circulating cytokines that signal through JAK / STAT have been implicated in the pathogenesis of cachexia and / or chronic fatigue. JAK inhibition, by itself, can be beneficial for cancer patients for reasons that extend beyond its potential antitumor activity.

[0007] JAK2 tyrosine kinase may be effective for patients with myeloproliferative disorders such as polycythemia vera (PV), essential thrombocythemia (ET), and myeloid metaplasia with myelofibrosis (MMM) (Non-Patent Document 5). Inhibition of JAK2V617F kinase reduces hematopoietic cell proliferation, indicating that JAK2 is a potential target for pharmacological inhibition in patients with PV, ET, and MMM.

[0008] Inhibition of JAK may be effective in patients with cutaneous immune disorders such as psoriasis, and skin sensitization. The persistence of psoriasis is thought to depend on several inflammatory cytokines, as well as various chemokines and growth factors (Non-Patent Document 6), many of which signal through JAK (Non-Patent Document 7). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Ortmann. RA, T. Cheng, et al.2000) Arthritis Res 2(1): 16-32 [Non-Patent Document 2] Rodig, SJ, MA Meraz, et al. (1998) Cell 93(3): 373~83 [Non-Patent Document 3] Boudny, V., and Kovarik, J., Neoplasm. 49:349~355, 2002 [Non-Patent Document 4] Bowman, T., et al. Oncogene 19:2474~2488, 2000 [Non-Patent Document 5] Levin, et al., Cancer Cell, vol. 7, 2005: 387~397 [Non-Patent Document 6] JCI, 113:1664~1675 [Non-Patent Document 7] Adv Pharmacol. 2000;47:113-74 Summary of the Invention [Problem to be solved by the invention]

[0010] Thus, new or improved agents that inhibit kinases such as JAKs are constantly needed to develop new and more effective medicines aimed at enhancing or suppressing immune and inflammatory pathways (e.g., immunosuppressants for organ transplants), as well as drugs to prevent and treat autoimmune diseases, diseases with hyperactive inflammatory responses (e.g., eczema), allergies, cancers (e.g., prostate, leukemia, multiple myeloma), and some immune responses caused by other medicines (e.g., skin rash or contact dermatitis or diarrhea). The compounds of the present invention, and the compositions and methods thereof described herein, are directed to these needs and other objectives. [Means for solving the problem]

[0011] The present invention relates in particular to compounds of formula (I) [ka] I or a pharma- ceutically acceptable salt thereof; wherein the variables are defined below.

[0012] The present invention further provides a composition comprising a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0013] The present invention further provides a method of modulating the activity of JAK1, the method comprising contacting JAK1 with a compound of formula I, or a pharma- ceutically acceptable salt thereof.

[0014] The present invention further provides a method of treating a disease or disorder associated with aberrant kinase expression or activity in a patient by administering to the patient a therapeutically effective amount of a compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0015] The invention further provides a method of treating an autoimmune disease, cancer, a myeloproliferative disease, an inflammatory disease, a bone resorption disease, or transplant organ rejection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof.

[0016] The invention also provides a compound of Formula I, as described herein, or a pharma- ceutically acceptable salt thereof, for use in the treatment of an autoimmune disease, a cancer, a myeloproliferative disease, an inflammatory disease, a bone resorption disease, or transplant organ rejection.

[0017] The present invention further provides a compound of Formula I, as described herein, or a pharma- ceutically acceptable salt thereof, for use in modulating JAK1.

[0018] The invention also provides the use of a compound of Formula I, as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for use in a method for modulating JAK1.

[0019] The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will become apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0020] [Figure 1] FIG. 1 shows the DSC thermogram for the product of Example 358. [Diagram 2] FIG. 2 shows the TGA thermogram for the product of Example 358. [Diagram 3] FIG. 3 shows the XRPD pattern for the product of Example 358. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] The present invention relates in particular to a compound of formula (I): [ka] I or a pharma- ceutical acceptable salt thereof, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Z is hydrogen, cyano, halo, C 1-3 Alkyl, or C 1-3 is haloalkyl; L is C(R 4 ) 2 , C(=O), C(=O)N(R 4a ), C(=O)C(R 4b ) 2 , S(=O) 2 , C(=O)O, C(=O)OC(R 4b ) 2 or C(=O)N(R 4a )C(R 4b ) 2 and; A is C 1-6 Alkyl, C 3-14 Cycloalkyl, C 2-13 Heterocycloalkyl, C 6-14 Aryl, or C 1-14 heteroaryl; 1-6 Alkyl, C 3-14 Cycloalkyl, C 2-13 Heterocycloalkyl, C 6-14 Aryl, and C 1-14 Heteroaryl is one, two, three, four, five, or six independently selected R 5 each optionally substituted with a group; Each R 1 is independent, C 1-4 Alkyl, Hydroxyl, C 1-4 Alkoxy, Fluoro, Hydroxyl-C 1-4 Alkyl, or C 1-4 Alkoxy-C 1-4 is alkyl; or The Two R's 1 The groups may be joined together to form a two or three carbon bridge or a group of the formula -CH 2 -O-CH 2 - forms a bridge represented by the formula; R 2 is hydrogen, halo, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy;

[0022] R 3 is hydrogen, cyano, nitro, halo, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkylcarbonyl, or C 1-6 is an alkoxycarbonyl; Each R 4 are independently hydrogen or C 1-4 is alkyl; or The Two R's 4 groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; R 4a is hydrogen or C 1-4 is alkyl; Each R 4b are independently hydrogen or C 1-4 is alkyl; or The Two R's 4b groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; Each R 5are independently halo, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c Rd , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group;

[0023] Each R 6 are independently halo, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)ORa1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R heach optionally substituted with a group; Each R a , R b , R c , and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, or C 1-10 Heteroaryl-C 1-3 alkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R g optionally substituted with a group; Or any R c and R d together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl group, each of which may be selected from the group consisting of halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkylcarbonyl and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxycarbonyl;

[0024] Each R e are independently hydrogen, C 1-6 Alkyl, CN, Hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfonyl, carboxy, C 1-6 Alkylcarbonyl, Aminosulfonyl, C 1-6 Alkylaminosulfonyl, di-C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, or di-C 1-6 is alkylcarbamyl; Each R a1 , R b1 , R c1 , and R d1 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, or C 1-10 Heteroaryl-C 1-3 alkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R g’ optionally substituted with a group; or any R c1 and R d1 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl group, each of which may be selected from the group consisting of halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6Alkyl carbonyl, C 1-6 Alkoxycarbonyl, and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkylcarbonylamino;

[0025] Each R e1 are independently hydrogen, C 1-6 Alkyl, CN, Hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfonyl, carboxy, C 1-6 Alkylcarbonyl, Aminosulfonyl, C 1-6 Alkylaminosulfonyl, di-C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, or di-C 1-6 is alkylcarbamyl; Each R g , R g’ , and R h are independently halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, or C 1-6 alkylcarbonylamino; and n is 0, 1, 2, 3, or 4.

[0026] In some embodiments, X is nitrogen or CR2 and; Y is nitrogen or CR 3 and; Z is hydrogen, cyano, halo, C 1-3 Alkyl, or C 1-3 is haloalkyl; L is C(R 4 ) 2 , C(=O), C(=O)N(R 4a ), C(=O)C(R 4b ) 2 , or S(=O) 2 and; A is C 1-6 Alkyl, C 3-14 Cycloalkyl, C 2-13 Heterocycloalkyl, C 6-14 Aryl, or C 1-14 heteroaryl; 1-6 Alkyl, C 3-14 Cycloalkyl, C 2-13 Heterocycloalkyl, C 6-14 Aryl, and C 1-14 Heteroaryl is one, two, three, four, five, or six independently selected R 5 each optionally substituted with a group; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 the groups together form a two or three carbon bridge; R 2 is hydrogen, halo, hydroxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-4 is alkoxy; R 3 is hydrogen, cyano, nitro, halo, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6Alkylamino, Di-C 1-6 Alkylamino, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkylcarbonyl, or C 1-6 is an alkoxycarbonyl; Each R 4 are independently hydrogen or C 1-4 is alkyl; or The Two R's 4 groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring;

[0027] R 4a is hydrogen or C 1-4 is alkyl; Each R 4b are independently hydrogen or C 1-4 is alkyl; or The Two R's 4b groups, together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered cycloalkyl ring; Each R 5 are independently halo, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a , S.R. a , C(O)R b , C(O)NR c Rd , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , N.R. c C(=NR e )NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3Alkyl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; Each R 6 are independently halo, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a1 , S.R. a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , O.C.(O)R b1 , O-C(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , N.R. c1 C(=NR e1 )NR c1 R d1 , N.R. c1 R d1 , N.R. c1 C(O)R b1 , N.R. c1 C(O)OR a1 , N.R. c1 C(O)NR c1 R d1 , N.R. c1 S(O)R b1 , N.R. c1 S(O) 2 R b1 , N.R. c1 S(O) 2 NR c1 Rd1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , or S(O) 2 NR c1 R d1 where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R h each optionally substituted with a group;

[0028] Each R a , R b , R c , and R d are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, or C 1-10 Heteroaryl-C 1-3 alkyl;1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R g optionally substituted with a group; Or any R c and R d together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl group, each of which may be selected from the group consisting of halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkylcarbonyl, and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkoxycarbonyl; Each R e are independently hydrogen, C 1-6Alkyl, CN, Hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfonyl, carboxy, C 1-6 Alkylcarbonyl, Aminosulfonyl, C 1-6 Alkylaminosulfonyl, di-C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, or di-C 1-6 is alkylcarbamyl;

[0029] Each R a1 , R b1 , R c1 , and R d1 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, or C 1-10 Heteroaryl-C 1-3 alkyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C1-3 Alkyl is one, two, three, four, or five independently selected R g’ optionally substituted with a group; Or any R c1 and R d1 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered heterocycloalkyl or heteroaryl group, each of which may be selected from the group consisting of halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, and C 1-6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkylcarbonylamino; Each R e1 are independently hydrogen, C 1-6 Alkyl, CN, Hydroxyl, C 1-6 Alkoxy, C 1-6 Alkyl sulfonyl, carboxy, C 1-6 Alkylcarbonyl, Aminosulfonyl, C 1-6 Alkylaminosulfonyl, di-C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, or di-C 1-6 is alkylcarbamyl; Each R g , R g’ , and R hare independently halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, or C 1-6 alkylcarbonylamino; and n is 0, 1, 2, 3, or 4.

[0030] In some embodiments, X is nitrogen. In some embodiments, X is CR 2 It is. In some embodiments, X is C(H), C(F), or C(CN). In some embodiments, X is CH. In some embodiments, Y is nitrogen. In some embodiments, Y is CR 3 It is. In some embodiments, Y is CH. In some embodiments, Z is cyano.

[0031] In some embodiments, L is C(=O)NH, C(=O), S(=O). 2 , C.H. 2 , C(=O)CH 2 ,or [ka] It is.

[0032] In some embodiments, L is C(=O)NH, C(=O), S(=O). 2 , C.H. 2 , C(=O)CH 2 , [ka] , C(=O)O, or C(=O)OCH 2 It is.

[0033] In some embodiments, L is C(=O). In some embodiments, L is C(=O)O. In some embodiments, L is C(=O)OCH 2 It is. In some embodiments, L is C(=O)NH. In some embodiments, L is S(=O). 2 It is. In some embodiments, L is C(R 4 ) 2 It is. In some embodiments, L is CH 2 It is.

[0034] In some embodiments, L is C(=O)CH 2 or [ka] It is. In some embodiments, L is C(=O)CH 2 It is. In some embodiments, L is [ka] It is. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, R 1 is C 1-4 It is an alkyl. In some embodiments, R 1 is methyl.

[0035] In some embodiments, two R 1 The group forms a two-carbon bridge. In some embodiments, A is selected from 1, 2, 3, 4, 5, or 6 independently selected R 5 C optionally substituted with a group 6-14 It is aryl. In some embodiments, A is selected from 1, 2, 3, 4, or 5 independently selected R 5 and phenyl optionally substituted with a group.

[0036] In some embodiments, A is a monocyclic C 3-9 Cycloalkyl or bicyclic C 3-9 cycloalkyl, each of which is independently selected from 1, 2, 3, 4, 5, or 6 R 5 The group is optionally substituted.

[0037] In some embodiments, A is a monocyclic C 2-10 Heterocycloalkyl or bicyclic C 2-10 heterocycloalkyl, each of which is independently selected from 1, 2, 3, 4, 5, or 6 R 5 The group is optionally substituted.

[0038] In some embodiments, A is a monocyclic C 1-10 Heteroaryl or bicyclic C 1-10 heteroaryl, each of which is independently selected from 1, 2, 3, 4, 5, or 6 R 5 The group is optionally substituted.

[0039] In some embodiments, A is selected from 1, 2, 3, 4, 5, or 6 independently selected R 5 optionally substituted with a group, C 1-6 It is an alkyl.

[0040] In some embodiments, A is C 1-6 It is an alkyl.

[0041] In some embodiments, A is C 1-6 Alkyl, phenyl, naphthyl ring, monocyclic or bicyclic C 3-10 Cycloalkyl, monocyclic or bicyclic C 2-10 Heterocycloalkyl, or monocyclic or bicyclic C 1-10 heteroaryl, each of which is independently selected from 1, 2, 3, 4, or 5 R 5 The group is optionally substituted.

[0042] In some embodiments, A is a phenyl, a naphthyl ring, a monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl, each of which is independently selected from 1, 2, 3, 4, or 5 R 5 The group is optionally substituted.

[0043] In some embodiments, A is methyl, ethyl, isopropyl, phenyl, a naphthalene ring, a pyridine ring, a pyrimidine ring, a thiophene ring, a pyrazine ring, an oxazole ring, an isoxazole ring, an imidazole ring, a thiazole ring, a furan ring, a pyrazole ring, a quinoline ring, a benzothiophene ring, a benzothiazole ring, a benzimidazole ring, a benzofuran ring, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, an indene ring, a tetrahydronaphthalene ring, a dihydro-1,4-benzodioxoxine ring, or a piperidine ring, each of which, where valences permit, is selected from 1, 2, 3, 4, or 5 R 5 The group is optionally substituted.

[0044] In some embodiments, A is a phenyl, a naphthalene ring, a pyridine ring, a pyrimidine ring, a thiophene ring, a pyrazine ring, an oxazole ring, an isoxazole ring, an imidazole ring, a thiazole ring, a furan ring, a pyrazole ring, a quinoline ring, a benzothiophene ring, a benzothiazole ring, a benzimidazole ring, a benzofuran ring, a cyclopropyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, an indene ring, a tetrahydronaphthalene ring, a dihydro-1,4-benzodioxoxine ring, or a piperidine ring; each of which, when permitted by valences, is selected from 1, 2, 3, 4, or 5 R 5 The group is optionally substituted.

[0045] In some embodiments, A is a phenyl or pyridine ring, each of which is represented by 1, 2, 3, or 4 independently selected R 5 The group is optionally substituted.

[0046] In some embodiments, A is selected from 1, 2, 3, or 4 independently selected R 5 and pyridin-4-yl, optionally substituted with a group.

[0047] In some embodiments, A is selected from 1, 2, 3, or 4 independently selected R 5is a pyridine ring, optionally substituted with a group.

[0048] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NRc R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6 Each is optionally substituted with a group.

[0049] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-10 Heterocycloalkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. cS(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6 Each is optionally substituted with a group.

[0050] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c R d , or N.R. c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four, or five independently selected R 6Each is optionally substituted with a group.

[0051] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c R d , or N.R. c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; and Each R a , R b , R c , and R d are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 6-10 aryl; 1-6 Alkyl and C 6-10 Aryl is one, two, three, four, or five independently selected R g The group is optionally substituted.

[0052] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, Hydroxyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 6-12 Aryloxy, Amino, C 1-6 Alkylamino, Di-C 1-6 Alkylamino, C 1-6 Alkylcarbonylamino, C 1-6 Alkoxycarbonyl, C 1-6Alkylthio, C 6-12 Aryl, or C 1-9 heteroaryl; 6-12 Aryl or C 1-9 Heteroaryl is one, two, three, four, or five independently selected R 6 Each is optionally substituted with a group.

[0053] In some embodiments, each R 5 are independently chloro, fluoro, bromo, cyano, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, phenoxy, dimethylamino, t-butylcarbonylamino, methoxycarbonyl, methylthio, phenyl, a pyridine ring, a thiazole ring, a quinoline ring, an isoquinoline ring, an imidazo[1,2-a]pyrimidine ring, a benzoxazole ring, or an oxadiazole ring; wherein the phenyl, pyridine ring, thiazole ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyrimidine ring, benzoxazole ring, and oxadiazole ring are independently selected from 1, 2, 3, 4, or 5 R 6 Each is optionally substituted with a group.

[0054] In some embodiments, each R 5 are independently halo or C 1-6 It is haloalkyl. In some embodiments, each R 5 is independently fluoro or trifluoromethyl.

[0055] In some embodiments, each R 6 are independently halo, cyano, nitro, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Amino, C 1-6 Alkylamino, Di-C1-6 Alkylamino, thio, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, Di-C 1-6 Alkylcarbamyl, Carboxy, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, or C 1-6 It is alkylcarbonylamino.

[0056] In some embodiments, each R 6 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a1 , N.R. c1 R d1 , or O.C.(O)R b1 and Each R a1 , R b1 , R c1 , and R d1 are independently hydrogen or C 1-6 alkyl; 1-6 Alkyl is C 1-4 optionally substituted with substituents independently selected from alkoxy and hydroxyl; Or any R c1 and R d1 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo.

[0057] In some embodiments, each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c Rd , orNR c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; Each R a , R b , R c , and R d are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 6-10 aryl; 1-6 Alkyl and C 6-10 Aryl is one, two, three, four, or five independently selected R g optionally substituted with a group; Each R 6 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a1 , N.R. c1 R d1 , or O.C.(O)R b1 and Each R a1 , R b1 , R c1 , and R d1 are independently hydrogen or C 1-6 alkyl; 1-6 Alkyl is C 1-4 optionally substituted with substituents independently selected from alkoxy and hydroxyl; Or any R c1 and R d1 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo.

[0058] In some embodiments, each R 6are independently halo, cyano, or C 1-6 It is an alkyl. In some embodiments, each R 6 is independently chloro, fluoro, cyano, or methyl. In some embodiments, R 2 is hydrogen, halo, or cyano. In some embodiments, R 2 is hydrogen, fluorine, or cyano. In some embodiments, R 3 is hydrogen.

[0059] In some embodiments, the compound has formula (II): [ka] II or a pharma- ceutically acceptable salt thereof.

[0060] In some embodiments, the compound has the formula (IIa): [ka] IIa or a pharma- ceutically acceptable salt thereof.

[0061] In some embodiments, the compound has formula (III): [ka] III or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the compound has formula (IIIa): [ka] IIIa or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is H; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is C 1-6 Alkyl, phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, C 1-10 Heteroaryl-C 1-3 Alkyl, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O)R b , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0064] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is H; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is C 1-6 Alkyl, phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C2-10 Heterocycloalkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6each optionally substituted with a group; and n is 0, 1, or 2.

[0065] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is a phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 2-10 Heterocycloalkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, ORa , S.R. a , C(O)R b , C(O)NR c R d , C(O)OR a , O.C.(O)R b , O-C(O)NR c R d , N.R. c R d , N.R. c C(O)R b , N.R. c C(O)OR a , N.R. c C(O)NR c R d , N.R. c S(O) 2 R b , N.R. c S(O) 2 NR c R d , S(O) 2 R b , or S(O) 2 NR c R d where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, halosulfanyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl-C 1-3 Alkyl, C 2-10 Heterocycloalkyl, C 2-10 Heterocycloalkyl-C 1-3 Alkyl, C 6-10 Aryl, C 6-10 Aryl-C 1-3 Alkyl, C 1-10 Heteroaryl, and C 1-10 Heteroaryl-C 1-3 Alkyl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0066] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is C 1-6 Alkyl, phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c R d , N.R. c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C1-10 Heteroaryl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0067] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is a phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)ORa , N.R. c R d , N.R. c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0068] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independently methyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is methyl, ethyl, isopropyl, phenyl, a naphthalene ring, a pyridine ring, a pyrimidine ring, a thiophene ring, a pyrazine ring, an oxazole ring, an isoxazole ring, an imidazole ring, a thiazole ring, a furan ring, a pyrazole ring, a quinoline ring, a benzothiophene ring, a benzothiazole ring, a benzimidazole ring, a benzofuran ring, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, an indene ring, a tetrahydronaphthalene ring, a dihydro-1,4-benzodioxoxine ring, or a piperidine ring; each of which, where valences permit, is selected from 1, 2, 3, 4, 5, or 6 R 5 optionally substituted with a group; Each R 5 are independently chloro, fluoro, bromo, cyano, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, phenoxy, dimethylamino, t-butylcarbonylamino, methoxycarbonyl, methylthio, phenyl, a pyridine ring, a thiazole ring, a quinoline ring, an isoquinoline ring, an imidazo[1,2-a]pyrimidine ring, a benzoxazole ring, or an oxadiazole ring; wherein the phenyl, pyridine ring, thiazole ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyrimidine ring, benzoxazole ring, and oxadiazole ring are independently selected from 1, 2, 3, 4, or 5 R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0069] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1 is independently methyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is H; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 ,or [ka] and; A is a phenyl, a naphthalene ring, a pyridine ring, a pyrimidine ring, a thiophene ring, a pyrazine ring, an oxazole ring, an isoxazole ring, an imidazole ring, a thiazole ring, a furan ring, a pyrazole ring, a quinoline ring, a benzothiophene ring, a benzothiazole ring, a benzimidazole ring, a benzofuran ring, a cyclopropyl, a cyclopentyl, a cyclohexyl, a cycloheptyl, an indene ring, a tetrahydronaphthalene ring, a dihydro-1,4-benzodioxoxine ring, or a piperidine ring; each of which is selected from 1, 2, 3, 4, 5, or 6 R 5 optionally substituted with a group; Each R 5 are independently chloro, fluoro, bromo, cyano, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, phenoxy, dimethylamino, t-butylcarbonylamino, methoxycarbonyl, methylthio, phenyl, a pyridine ring, a thiazole ring, a quinoline ring, an isoquinoline ring, an imidazo[1,2-a]pyrimidine ring, a benzoxazole ring, or an oxadiazole ring; wherein the phenyl, pyridine ring, thiazole ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyrimidine ring, benzoxazole ring, and oxadiazole ring are independently selected from 1, 2, 3, 4, or 5 R 6 each optionally substituted with a group; and n is 0, 1, or 2.

[0070] In some embodiments, X is nitrogen or CR 2 and; Y is nitrogen or CR 3 and; Each R 1is independent, C 1-4 is alkyl; or The Two R's 1 The group forms a two-carbon bridge. R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is S(=O) 2 and; A is C 1-6 is alkyl; and n is 0, 1, or 2.

[0071] In some embodiments, X is nitrogen or CH; Y is nitrogen; Z is cyano; L is C(=O) or C(=O)NH; A is a phenyl or pyridine ring, each of which is represented by 1, 2, 3, or 4 independently selected R 5 optionally substituted with a group; Each R 5 are independently halo or C 1-6 haloalkyl; and n is 0.

[0072] In some embodiments, X is nitrogen or CH; Y is nitrogen; Z is cyano; L is C(=O) or C(=O)NH; A is phenyl or pyridin-4-yl, each of which is selected from one or two independently selected R 5 optionally substituted with a group; Each R 5 is independently fluoro or trifluoromethyl; and n is 0.

[0073] In some embodiments, X is nitrogen or CR2 and; Y is nitrogen or CR 3 and; Each R 1 is independent, C 1-4 Alkyl, Hydroxyl, C 1-4 alkoxy, or fluoro; The Two R's 1 The groups taken together form a two or three carbon bridge, or a group of the formula -CH 2 -O-CH 2 - forms a bridge represented by the formula; R 2 is hydrogen, halo, or cyano; R 3 is hydrogen; Z is cyano; L is C(=O)NH, C(=O), S(=O) 2 , C.H. 2 , C(=O)CH 2 , [ka] C(=O)O or C(=O)OCH 2 and; A is C 1-6 Alkyl, phenyl, naphthyl ring, monocyclic C 3-10 Cycloalkyl, Bicyclic C 3-10 Cycloalkyl, monocyclic C 2-10 Heterocycloalkyl, Bicyclic C 2-10 Heterocycloalkyl, monocyclic C 1-10 Heteroaryl, or bicyclic C 1-10 heteroaryl; each of which is independently selected from 1, 2, 3, 4, or 5 R 5 optionally substituted with a group; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c R d , N.R.c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four or five independently selected R 6 each optionally substituted with a group; n is 0, 1, or 2; Each R 5 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 1-10 Heteroaryl, OR a , S.R. a , C(O)OR a , N.R. c R d , or N.R. c C(O)R b where C 1-6 Alkyl, C 1-6 Haloalkyl, C 6-10 Aryl, and C 1-10 Heteroaryl is one, two, three, four, or five independently selected R 6 each optionally substituted with a group; Each R a , R b , R c , and R d are independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 6-10 aryl; 1-6 Alkyl and C 6-10 Aryl is one, two, three, four, or five independently selected R g optionally substituted with a group; Each R 6 are independently halo, cyano, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a1 , N.R. c1 R d1 , or O.C.(O)R b1 and Each R a1 , R b1 , R c1 , and R d1 are independently hydrogen or C 1-6 alkyl; 1-6 Alkyl is C 1-4 optionally substituted with substituents independently selected from alkoxy and hydroxyl; Or any R c1 and R d1 together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo.

[0074] In some embodiments, the compound is: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(3,4,5-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0075] {1-[1-(cyclohexylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-benzoylpiperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; {1-{1-[(6-chloropyridin-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(pyrazin-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(3-thienylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(1,3-oxazol-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0076] {1-(1-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile; {1-[1-(3-chlorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-bromobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-(trifluoromethoxy)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-{1-[3-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dichlorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-fluoro-3-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0077] {1-[1-(2-fluoro-5-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-chloro-5-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-bromo-5-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2,5-dichloro-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,5-trifluoro-3-methoxybenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dimethoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0078] {1-[1-(3-chloro-4-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,4-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-5-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-6-methoxyisonicotinoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(5-fluoro-2-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-6-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-fluoro-2-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,4-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0079] {1-[1-(2,5-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-6-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,4-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,5-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dibromo-4-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0080] 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-{1-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[4-chloro-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,4,5-tetrafluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-methoxybenzonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,5,6-tetrafluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-[1-(4-fluoro-3-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-(dimethylamino)benzonitrile;

[0081] {1-{1-[4-(dimethylamino)-2,3,5,6-tetrafluorobenzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluoroisonicotinoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-4-(methylthio)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-chloro-3-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-methylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,5-dimethyl-3-furoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-[1-(2-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0082] {1-[1-(4-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-thienylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-methoxy-5-(trifluoromethyl)-2-thienylcarbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-hydroxy-5-(trifluoromethyl)-2-thienylcarbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-methoxy-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-methyl-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-chloro-4-methoxy-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-bromo-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0083] {1-{1-[(5-chloro-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methoxy-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3,5-difluorobenzonitrile; {1-[1-(3-chloro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0084] [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(1-naphthoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(quinolin-3-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(quinolin-6-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(1-benzothien-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-6-fluoro-1-benzothien-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-4-fluoro-1-benzothien-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0085] [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[7-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(1-benzothien-3-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)cyclohexyl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[0086] {1-[1-(2,3-dihydro-1H-inden-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopentylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cycloheptylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methoxycyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-phenylcyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[4-(4-chlorophenyl)cyclohexyl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 6-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]piperidin-1-yl}nicotinonitrile;

[0087] {1-(1-{[1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]piperidin-1-yl}-6-methylnicotinonitrile; {1-[1-(phenylacetyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-phenylcyclopropyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2,6-dichlorophenyl)acetyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(mesitylacetyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0088] {1-[1-(3-fluoro-4-isoquinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-pyridin-4-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4 ’-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -Fluorobiphenyl-4-carbonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ ,3-difluorobiphenyl-4-carbonitrile; {1-[1-(2-fluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-fluoro-3-(1,3-thiazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0089] {1-{1-[3-fluoro-4-(1,3-thiazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -Fluorobiphenyl-2-carbonitrile; 4 ’-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -Fluorobiphenyl-3-carbonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]biphenyl-4-carbonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[(2,3 ’ ,4 ’ -trifluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ ,5-difluorobiphenyl-3-carbonitrile;

[0090] {1-[1-(3-fluoro-4-quinolin-5-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-5-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-8-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-8-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-7-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-7-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0091] {1-[1-(3-fluoro-4-imidazo[1,2-a]pyridin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-(1,3-benzoxazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-(1,3-benzoxazol-2-yl)-3-fluorobenzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-5-fluorobenzonitrile; {1-[8-(3,4-difluorobenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-2-fluorobenzonitrile; {1-[8-(4-chloro-3-fluorobenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0092] {1-{8-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(8-{[6-(trifluoromethyl)pyridin-3-yl]carbonyl}-8-azabicyclo[3.2.1]oct-3-yl)azetidin-3-yl]acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{8-[2-(trifluoromethyl)isonicotinoyl]-8-azabicyclo[3.2.1]oct-3-yl}azetidin-3-yl)acetonitrile; {1-[8-(cyclopentylcarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[8-(tetrahydro-2H-pyran-4-ylcarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]azetidin-3-yl}acetonitrile; {1-[8-(cyclohexylcarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{8-[(4,4-difluorocyclohexyl)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0093] {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]-2-methylpiperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclohexylcarbonyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-difluorophenyl)piperidine-1-carboxamide;

[0094] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(trifluoromethoxy)phenyl]piperidine-1-carboxamide; N-(4-bromo-3-thienyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-dichlorophenyl)piperidine-1-carboxamide; N-(2-chloro-6-methylphenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide;

[0095] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(difluoromethoxy)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)phenyl]piperidine-1-carboxamide; N-(5-chloro-2-methylphenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide;

[0096] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,3,4-trifluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,3,5-trifluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,5-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,5-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,4-difluorophenyl)piperidine-1-carboxamide; N-(3-chloro-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(4-chloro-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide;

[0097] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-3-thienylpiperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3-methoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide; N-(3-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(4-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methylphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,5-dimethoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4-fluoro-2-methylphenyl)piperidine-1-carboxamide;

[0098] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[6-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-dimethylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-1,3-thiazol-2-ylpiperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4-methyl-1,3-thiazol-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine-1-carboxamide; N-1,3-Benzothiazol-2-yl-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxamide;

[0099] N-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1-ethyl-1H-pyrazol-5-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1,3-dimethyl-1H-pyrazol-5-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(6-fluoro-2-methylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluoro-6-methylpyridin-3-yl)piperidine-1-carboxamide;

[0100] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3-fluoropyridin-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,5-difluoropyridin-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; Methyl 2-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}benzoate; Methyl 2-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}-5-fluorobenzoate; Methyl 4-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}-3-fluorobenzoate;

[0101] 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-[1-(3,5-dichlorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-chloro-5-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-6-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-chloroquinolin-3-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-4-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0102] {1-[1-(2,4-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-6-methoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-dichlorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-fluorobenzonitrile; {1-{1-[4-(1,2,3-oxadiazol-4-yl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]benzonitrile; 6-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-methoxynicotinonitrile;

[0103] {1-{1-[(2,6-dibromopyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-bromopyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-6-fluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-chloro-2,6-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-fluorobenzonitrile; {1-{1-[(5-methyl-3-phenylisoxazol-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(1-benzofuran-2-ylmethyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0104] {1-[1-(3-phenoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; N-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]pyridin-2-yl}-2,2-dimethylpropanamide; {1-{1-[3-chloro-2-fluoro-6-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3,5-dichloropyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-chloro-6-methoxyquinolin-3-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-3,4-dimethoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile;

[0105] {1-[8-(2-chloro-3,6-difluorobenzyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-[1-(2-chloro-6-fluorobenzyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-6-fluorobenzyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0106] 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]-2-(dimethylamino)benzonitrile; {1-{1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclohexylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopentylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(ethylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopropylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0107] {1-[1-(isopropylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile;

[0108] 3-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile; 4-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; 4-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3,5-difluorobenzonitrile; {1-{1-[5-fluoro-2-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; (3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-{1-[2-fluoro-5-(trifluoromethoxy)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2,3,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2-thienylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile;

[0109] {1-{1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-fluoro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,4-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,5-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile;

[0110] {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2,3,4-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethoxy)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-hydroxy-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide;

[0111] 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-cyanophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-methoxyphenyl)piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(3-fluoropyridin-2-yl)piperidine-1-carboxamide; N-(4-chloro-2-cyanophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide;

[0112] {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[0113] {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide;

[0114] 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluorophenyl)piperidine-1-carboxamide; N-(2-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-cyano-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; N-(4-cyano-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chloro-4-cyanophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; (3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]isophthalonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile;

[0115] 4-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-{1-[(5-fluoropyridin-2-yl)carbonyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoroisonicotinoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluoroisonicotinoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0116] 2-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]terephthalonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide;

[0117] 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-[1-(3-(cyanomethyl)-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(3-cyano-5-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(4-cyano-3-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-(1-{3-(cyanomethyl)-1-[1-(2,5-dibromobenzoyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-(1-{3-(cyanomethyl)-1-[1-(3,5-dibromobenzoyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]terephthalonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]isophthalonitrile;

[0118] 4-{1-[1-[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(4-cyano-2,6-difluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[0119] [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile;

[0120] [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-pyrazol-1-yl]-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; 4-[1-(3-(cyanomethyl)-1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; and 4-(1-{3-(cyanomethyl)-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; Or a pharma- ceutically acceptable salt of any of the above.

[0121] In some embodiments, the compound is: cis-{1-{(3-methoxy-1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-3-methoxy-1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{cis-3-fluoro-1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(cis-3-fluoro-1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]-4-deuteropiperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]3,3,4,5,5-pentadeuteropiperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{7-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]-3-oxa-7-azabicyclo[3.3.1]non-9-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[4-[(dimethylamino)methyl]-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0122] 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpiperidine-1-carboxamide; {1-{1-[6-[(dimethylamino)methyl]-3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-[(dimethylamino)methyl]benzonitrile; {1-(1-{[6-[(dimethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-[(methylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-(azetidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-[(diethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0123] {1-(1-{[6-{[ethyl(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-[(3,3-difluoropyrrolidin-1-yl)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile;

[0124] {1-(1-{[6-[(tert-butylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-[(isopropylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-[(ethylamino)methyl]-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-{[(2-methoxyethyl)(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[6-{[(3-hydroxypropyl)(methyl)amino]methyl}-2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; Propyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate;

[0125] Cyclobutyl methyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Ethyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Benzyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Isobutyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Cyclopropylmethyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; (1-Methylcyclopropyl)methyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; 2,4-Difluorobenzyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; 3,4-Difluorobenzyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; 3,5-Difluorobenzyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Cyclopentylmethyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; and Cyclohexylmethyl 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate; Or a pharma- ceutically acceptable salt of any of the above.

[0126] In some embodiments, the salt is 1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate. In some embodiments, the salt is 1:1 1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and adipate. In some embodiments, the salt is as described in Example 358.

[0127] In some embodiments, the salt is characterized by a melting point of about 178° C. In some embodiments, the salt has a differential scanning calorimetry thermogram characterized by an endothermic peak having an onset temperature of about 176° C. In some embodiments, the salt has a differential scanning calorimetry thermogram substantially as shown in FIG.

[0128] In some embodiments, the salt has a thermogravimetric analysis thermogram substantially as shown in FIG. 2. In some embodiments, the salt has a powder X-ray diffraction pattern including a characteristic peak expressed in degrees 2θ at about 10.4. In some embodiments, the salt has a powder X-ray diffraction pattern including a characteristic peak expressed in degrees 2θ at about 6.9. In some embodiments, the salt has a powder X-ray diffraction pattern including a characteristic peak expressed in degrees 2θ at about 21.0. In some embodiments, the salt has a powder X-ray diffraction pattern including a characteristic peak expressed in degrees 2θ at about 23.3. In some embodiments, the salt has a powder X-ray diffraction pattern including characteristic peaks expressed in degrees 2θ at about 6.9, 10.4, 21.0, and 23.3. In some embodiments, the salt has a powder X-ray diffraction pattern substantially as shown in FIG. 3.

[0129] XRPD patterns of reflections (peaks) are typically considered as fingerprints of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely depending on, among other things, sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument used. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type or settings of the instrument (e.g., whether a Ni filter was used, etc.). As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Furthermore, instrumental differences and other factors may affect the 2-theta values. Thus, peak assignments, as described herein, may vary by plus or minus about 0.2 degrees (2-theta), and the term "substantially" as used herein with respect to XRPD is intended to encompass the above-mentioned variations.

[0130] In a similar manner, temperature readings associated with DSC, TGA, or other temperature experiments may vary by about ±3° C. depending on the instrument, the particular settings, sample preparation, etc. Thus, crystalline forms described herein having DSC thermograms "substantially" as shown in any figure are understood to accommodate such variations.

[0131] It will be further understood that certain features of the invention which are, for clarity, described in the context of separate embodiments, may also be provided in a single embodiment in combination. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0132] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups or ranges. For example, "C 1-6 The term "alkyl" includes methyl, ethyl, C 3Alkyl, C 4 Alkyl, C 5 Alkyl, and C 6 It is specifically intended to represent alkyl individually.

[0133] At various points in the present specification, linking substituents are described. It is specifically intended that each linking substituent includes both the forward and reverse forms of that linking substituent. For example, -NR(CR ’ R ’’ ) n - is -NR(CR ’ R ’’ ) n -and-(CR ’ R ’’ ) n Both NR- and NR- are included. Where a structure clearly calls for a linking group, the Markush type variable recited for the group is understood to be the linking group. For example, where a structure calls for a linking group and the Markush group definition for such variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" represent a linking alkylene or arylene group, respectively.

[0134] In various places in this specification, rings (e.g., "piperidine rings") are described. Unless otherwise indicated, these rings can be attached to other parts of the molecule at any ring member, if allowed by valence. For example, the term "pyridine ring" can refer to a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl ring.

[0135] In the term "n-membered", where n is an integer, n is typically an integer representing the number of ring-forming atoms in the moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0136] In compounds of the invention where a variable is described more than once, each variable can be a different moiety independently selected from the group defining the variable. For example, where a structure is described with two R groups present simultaneously on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. In another example, optionally multiple substituents can be of the form: [ka] When a group is specified in the formula (I), it is understood that the substituent R can occur p times on the ring and that R can be a different moiety at each occurrence. Each R group can be any of the groups listed below, such as (CH 2 ) n It is understood that any hydrogen atom attached to a ring atom may be replaced, including one or both hydrogen atoms of the following ring atoms: 2 If the variable Q is defined to include hydrogen, such as when it is taken to be NH, then any floating substituents, such as R in the above example, can replace hydrogens of the Q variable as well as hydrogens of any other non-variable components of the ring.

[0137] As used herein, the phrase "optionally substituted" means substituted or unsubstituted. As used herein, the term "substituted" means that a hydrogen atom has been removed and replaced with a substituent. It is understood that substitution at a given atom is limited by the valence of the atom.

[0138] As used herein, alone or in combination with other terms, n-mThe term "alkyl" refers to a saturated hydrocarbon group, which may be straight or branched, having n to m carbon atoms. In some embodiments, the alkyl group contains 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-1-butyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, and n-octyl.

[0139] As used herein, alone or in combination with other terms, n-m "Alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and n to m carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0140] As used herein, alone or in combination with other terms, n-m "Alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds and n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0141] As used herein, "halo" or "halogen", either alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo.

[0142] As used herein, "hydroxyl" or "hydroxy" refers to a group represented by the formula -OH.

[0143] As used herein, alone or in combination with other terms, n-mThe term "haloalkyl" refers to a C alkyl group having up to {2(n~m)+1} halogen atoms, which may be the same or different. n-m In some embodiments, the halogen atom is a fluoro atom. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. Examples of haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.

[0144] As used herein, alone or in combination with other terms, n-m The term "fluoroalkyl" refers to a group in which the halogen atoms are selected from fluorine. n-m In some embodiments, C n-m Fluoroalkyl is fluoromethyl, difluoromethyl, or trifluoromethyl.

[0145] As used herein, alone or in combination with other terms, n-m The term "alkoxy" refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0146] As used herein, alone or in combination with other terms, n-m "Haloalkoxy" refers to a group of the formula -O-(haloalkyl), where the haloalkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. An example of a haloalkoxy group is -OCF 3In some embodiments, the haloalkoxy group is a fluoroalkoxy group.

[0147] As used herein, alone or in combination with other terms, n-m The term "fluoroalkoxy" refers to a C alkyl group in which the halogen atoms are selected from fluorine. n-m Refers to an alkoxy group.

[0148] As used herein, the term "amino" as used alone or in combination with other terms means -NH 2 Refers to...

[0149] As used herein, alone or in combination with other terms, n-m The term "alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. n-m Examples of alkylamino groups include methylamino, ethylamino, propylamino (eg, n-propylamino and isopropylamino), and the like.

[0150] As used herein, the term "di-C n-m The term "-alkylamino" refers to a group of the formula -N(alkyl) 2 In the formula, each alkyl group independently has n to m carbon atoms. n-m Examples of -alkylamino groups include dimethylamino, diethylamino, dipropylamino (e.g., di(n-propyl)amino and di(isopropyl)amino), etc. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms.

[0151] As used herein, the term "carboxy", alone or in combination with other terms, refers to a group represented by the formula -C(O)OH.

[0152] As used herein, alone or in combination with other terms, n-m The term "alkoxycarbonyl" refers to a radical of the formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0153] As used herein, alone or in combination with other terms, n-m The term "alkylcarbonyl" refers to a radical of the formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0154] As used herein, alone or in combination with other terms, n-m The term "alkylcarbonylamino" refers to a radical of the formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0155] As used herein, the term "carbamyl", alone or in combination with other terms, refers to a group having the formula -C(O)-NH 2 It refers to a group represented by the formula:

[0156] As used herein, alone or in combination with other terms, n-m The term "alkylcarbamyl" refers to a group of the formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0157] As used herein, the term "di-C n-m The term "alkylcarbamyl" refers to a group of the formula -C(O)-N(alkyl) 2where each alkyl group independently has n to m carbon atoms. In some embodiments, the alkyl groups independently have 1 to 6 or 1 to 4 carbon atoms.

[0158] The term "thio," as used herein, refers to a group represented by the formula --SH.

[0159] As used herein, alone or in combination with other terms, n-m The term "alkylthio" refers to a group of the formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0160] As used herein, alone or in combination with other terms, n-m The term "alkylsulfinyl" refers to a radical of the formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0161] As used herein, alone or in combination with other terms, n-m The term "alkylsulfonyl" refers to a group of the formula -S(O) 2 -alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0162] As used herein, the term "halosulfanyl" refers to a sulfur group having one or more halogen substituents. Examples of halosulfanyl groups include SF 5 and the like pentahalosulfanyl groups.

[0163] As used herein, the term "two or three carbon bridge" refers to a bridge (-CH) between two ring atoms in which two different R groups on different ring atoms form a bridge (-CH 2 -CH 2-or-CH 2 -CH 2 -CH 2 -), where 2 or 3 carbons do not include ring atoms. 1 The group forms a two-carbon bridge, see Example 138.

[0164] As used herein, "a compound of the formula -CH 2 -O-CH 2 The term "bridge represented by the formula -CH" means that two different R groups on different ring atoms are 2 -O-CH 2 -, where the ring atoms are represented by the formula -CH 2 -O-CH 2 -Not part of.

[0165] As used herein, "hydroxyl-C 1-4 The term "alkyl" refers to a group of the formula -C 1-4 This refers to a group represented by alkylene-OH.

[0166] As used herein, "C 1-4 Alkoxy-C 1-4 The term "alkyl" refers to a group of the formula -C 1-4 Alkylene-O-(C 1-4 It refers to a group represented by the formula (alkyl).

[0167] As used herein, alone or in combination with other terms, n-mThe term "cycloalkyl" refers to a non-aromatic cyclic hydrocarbon, including cyclized alkyl, alkenyl, and alkynyl groups, having n to m ring carbon atoms. Cycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., sharing a bond) to the cycloalkyl ring, such as benzo derivatives, such as cyclopentane, cyclopentene, and cyclohexane. The ring-forming carbon atoms of a cycloalkyl group can be optionally substituted with oxo. Cycloalkyl groups also include cycloalkylidenes. The term "cycloalkyl" also includes bridgehead cycloalkyl groups and spirocycloalkyl groups. As used herein, "bridgehead cycloalkyl group" refers to a non-aromatic cyclic hydrocarbon moiety containing at least one bridgehead carbon, such as admantan-1-yl. As used herein, "spirocycloalkyl group" refers to a non-aromatic hydrocarbon moiety containing at least two rings fused through a single carbon atom, e.g., spiro[2.5]octane. In some embodiments, the cycloalkyl group has 3-14 ring members, 3-10 ring members, or 3-7 ring members. In some embodiments, the cycloalkyl group is monocyclic, bicyclic, or tricyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is C 3-7 It is a monocyclic cycloalkyl group. One or more ring-forming carbon atoms of the cycloalkyl group can be oxidized to form a carbonyl bond. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, tetrahydronaphthalenyl, octahydronaphthalenyl, indanyl, etc.

[0168] As used herein, alone or in combination with other terms, n-m Cycloalkyl-C o-pThe term "alkyl" refers to a group of the formula -alkylene-cycloalkyl, where the cycloalkyl portion has n to m carbon atoms and the alkylene portion has op carbon atoms. In some embodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkylene portion is methylene. In some embodiments, the cycloalkyl portion has 3 to 14 ring members, 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl portion is monocyclic. In some embodiments, the cycloalkyl portion is C 3-7 It is a monocyclic cycloalkyl group.

[0169] As used herein, alone or in combination with other terms, n-m Heterocycloalkyl, C n-m Heterocycloalkyl ring", or "C n-mThe term "heterocycloalkyl group" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene or alkynylene groups as part of the cyclic structure, has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen, and phosphorus, and has n to m ring carbon atoms. Heterocycloalkyl groups can include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, bridged, or spiro rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic or bicyclic groups having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Also included within the definition of heterocycloalkyl are moieties that have one or more aromatic rings (e.g., aryl or heteroaryl rings) fused (i.e., having a covalent bond) to a non-aromatic ring, such as 1,2,3,4-tetrahydro-quinoline. Heterocycloalkyl groups can also include bridgehead heterocycloalkyl groups and spiroheterocycloalkyl groups. As used herein, a "bridgehead heterocycloalkyl group" refers to a heterocycloalkyl moiety that contains at least one bridgehead atom, such as azaadmantan-1-yl. As used herein, a "spiroheterocycloalkyl group" refers to a heterocycloalkyl moiety that contains at least two rings fused together by a single atom, such as [1,4-dioxa-8-aza-spiro[4.5]decane-N-yl]. In some embodiments, a heterocycloalkyl group has 3 to 20 ring-forming atoms, 3 to 14 ring-forming atoms, 3 to 10 ring-forming atoms, or about 3 to 8 ring-forming atoms. In some embodiments, a heterocycloalkyl group has 2 to 20 carbon atoms, 2 to 15 carbon atoms, 2 to 10 carbon atoms, or about 2 to 8 carbon atoms. In some embodiments, a heterocycloalkyl group has 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 to 2 heteroatoms. Carbon atoms or heteroatoms in the ring of a heterocycloalkyl group can be oxidized to form a carbonyl, N-oxide, or sulfonyl group (or other oxidized bond), or a nitrogen atom can be quaternized.In some embodiments, the heterocycloalkyl moiety is C. 2-7 Monocyclic heterocycloalkyl groups. Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydro-quinoline, azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, and pyran.

[0170] As used herein, alone or in combination with other terms, n-m Heterocycloalkyl-C o-p The term "alkyl" refers to a group of the formula -alkylene-heterocycloalkyl, where the heterocycloalkyl portion has n to m carbon atoms and the alkylene portion has op carbon atoms. In some embodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkylene portion is methylene. In some embodiments, the heterocycloalkyl portion has 3 to 14 ring members, 3 to 10 ring members, or 3 to 7 ring members. In some embodiments, the heterocycloalkyl group is monocyclic or bicyclic. In some embodiments, the heterocycloalkyl portion is monocyclic. In some embodiments, the heterocycloalkyl portion is C 2-7 It is a monocyclic heterocycloalkyl group.

[0171] As used herein, alone or in combination with other terms, n-m The term "aryl" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon moiety having n to m ring carbon atoms, such as, but not limited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 10 carbon atoms, or 6 carbon atoms. In some embodiments, an aryl group is a monocyclic or bicyclic group.

[0172] As used herein, alone or in combination with other terms,n-m Aryl-C o-p The term "-alkyl" refers to a group of the formula -alkylene-aryl, where the aryl portion has n to m ring carbon atoms and the alkylene portion has op carbon atoms. In some embodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkylene portion is methylene. In some embodiments, the aryl group is a monocyclic or bicyclic group. In some embodiments, the arylalkyl group is benzyl.

[0173] As used herein, alone or in combination with other terms, n-m Heteroaryl, C n-m Heteroaryl ring", or "C n-mThe term "heteroaryl group" refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbon moiety having one or more heteroatom ring members independently selected from nitrogen, sulfur, and oxygen, and having n to m ring carbon atoms. In some embodiments, the heteroaryl group is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, pyrrolyl, azolyl, oxazolyl, quinolinyl, isoquinolinyl, indolyl, benzothienyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, etc. Carbon atoms or heteroatoms in the rings of heteroaryl groups can be oxidized to form carbonyl, N-oxide, or sulfonyl groups (or other oxidized bonds), or nitrogen atoms can be quaternized, provided that the aromatic nature of the ring is retained. In some embodiments, the heteroaryl group has 1 to 20 carbon atoms, 3 to 20 carbon atoms, 3 to 15 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 5 carbon atoms, 1 to 5 carbon atoms, or 5 to 10 carbon atoms. In some embodiments, the heteroaryl group contains 3 to 14, 4 to 12, 4 to 8, 9 to 10, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to 4, 1 to 3, or 1 to 2 heteroatoms.

[0174] As used herein, alone or in combination with other terms, n-m Heteroaryl-C o-pThe term "-alkyl" refers to a group of the formula -alkylene-heteroaryl, where the heteroaryl portion has n to m ring carbon atoms and the alkylene portion has op carbon atoms. In some embodiments, the alkylene portion has 1 to 4, 1 to 3, 1 to 2, or 1 carbon atoms. In some embodiments, the alkylene portion is methylene. In some embodiments, the heteroaryl portion is a monocyclic or bicyclic group having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl portion has 5 to 10 carbon atoms.

[0175] As used herein, "C n-m The term "aryloxy" refers to a moiety of the formula -O-aryl, where the aryl ring has n to m carbon atoms.

[0176] As used herein, the term "bicyclic," when used before the name of a moiety, indicates that the moiety has two fused rings.

[0177] As used herein, the term "monocyclic", when used before the name of a moiety, indicates that the moiety has a single ring.

[0178] The compounds described herein may be asymmetric compounds (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like, may also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as isomeric mixtures or as separated isomeric forms.

[0179] The resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. One example of the method is fractional recrystallization using chiral resolving acids that are optically active and salt-forming organic acids. Suitable resolving agents for fractional recrystallization are optically active acids, such as D- and L-tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Other resolving agents suitable for fractional recrystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0180] Resolution of racemic mixtures can also be carried out by elution on a column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

[0181] The compounds of the present invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond, with the concomitant migration of a proton. Tautomeric forms also include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactimer pairs, enamine-imine pairs, and cyclic forms in which protons can occupy more than one position of a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or may be sterically fixed in one form by appropriate substitution.

[0182] The compounds of the present invention may also include all isotopes of atoms occurring in intermediates or final compounds. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, one, two, or three CH in the azetidine ring of formula I are 2 The group is CHD or CD 2 In some embodiments, the piperidine ring of formula I is substituted with one, two, or three CH 2 or CH group, CHD, CD 2 or CD groups, respectively. In some embodiments, the piperidine ring of formula I is substituted with 1, 2, 3, 4, or 5 CH 2 or CH group, CHD, CD 2 or CD groups, respectively.

[0183] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.

[0184] All compounds, and pharma- ceutically acceptable salts thereof, may be present in association with other substances such as water and solvents (eg, hydrates and solvates) or may be isolated.

[0185] In some embodiments, the compound of the present invention, or its salt, is substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which the compound is formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present invention. Substantial separation can include a composition comprising at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound of the present invention, or its salt. Methods for isolating compounds and their salts are known in the art.

[0186] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0187] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature such as the reaction temperature, which is about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0188] The present invention also includes pharma- ceutically acceptable salts of the compounds described herein. As used herein, "pharma- ceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound has been modified by converting an acid or base moiety present therein into its salt form. Examples of pharma- ceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharma- ceutically acceptable salts of the present invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharma- ceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from the parent compound containing a basic or acidic moiety. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol) or acetonitrile (ACN) are preferred. A list of suitable salts can be found in Remington, 1999, each of which is incorporated herein by reference in its entirety. ’ s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). In some embodiments, the compounds described herein include N-oxide forms.

[0189] synthesis The compounds of the present invention, including the compounds of the present invention, their salts and N-oxides, can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes, such as those shown in the following schemes. The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent, which can be readily selected by one skilled in the art of organic synthesis. A suitable solvent can be one that does not substantially react with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by one skilled in the art.

[0190] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups.The necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art.The chemical reactions of protecting groups are described, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), the entirety of which is incorporated herein by reference.

[0191] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0192] Compounds of formula I can be prepared using the methods outlined in Schemes 1-4. Intermediates of formula 1-5 can be synthesized according to the method described in Scheme 1. Commercially available starting materials pyrrolo[2,3-d]pyrimidine-4-halide or 5-substituted pyrrolo[2,3-b]pyridine-4-halide (1-1) can be converted to SEM (2-(trimethylsilyl)ethoxymethyl) protected intermediates of formula 1-2 by treatment with sodium hydride followed by 2-(trimethylsilyl)ethoxymethyl chloride. Suzuki coupling of 1-2 with a pyrazole boronic acid, for example 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1-3), using a palladium reagent such as tetrakis(triphenylphosphine)palladium(0) affords intermediate 1-4, which can be converted in situ to the desired product 1-5 after extended reaction.

[0193] Scheme 1 [ka]

[0194] The intermediate of formula 2-3 can be synthesized according to the sequence shown in Scheme 2. Using a palladium reagent such as tetrakis(triphenylphosphine)palladium(0), the SEM-protected intermediate 1-2 undergoes Suzuki coupling with a protected pyrrole boronic acid, such as 1-(triisopropylsilyl)pyrrole-3-boronic acid (2-1), in the presence of base. The coupling product of formula 2-2 can be converted in situ to the desired product of formula 2-3 by reacting overnight in the same medium.

[0195] Scheme 2 [ka]

[0196] The intermediates of formula 3-7 can be prepared according to the procedure shown in Scheme 3. The Boc-protected azetidinones of formula 3-1 undergo a Wittig reaction with a phosphonic acid such as diethyl cyanomethylphosphonate in the presence of a base such as sodium hydride to give the cyano derivatives of formula 3-2. The intermediates of formula 1-5 or 2-3 undergo a Michael addition to the derivatives of formula 3-2 in the presence of a base such as DBU to give the addition products of formula 3-3. After removing the Boc group (e.g., by using an acid such as 4N HCl in dioxane), the resulting azetidines of formula 3-4 are reductively aminated with N-Boc-protected piperidinones of formula 3-5 using a reducing agent such as sodium triacetoxyborohydride to give the compounds of formula 3-6. The Boc group in the compounds of formula 3-6 is removed (e.g., by using an acid such as 4N HCl in dioxane) to give the desired intermediates of formula 3-7.

[0197] Scheme 3 [ka]

[0198] As shown in Scheme 4, intermediates of formula 3-7 can be derivatized at the piperidine nitrogen to produce a series of compounds of formula I. Compounds of formula 3-7 can be reacted with a sulfonyl chloride followed by removal of the SEM group by treatment first with TFA and then with ethylenediamine to give sulfonamide derivatives of formula 4-1. Compounds of formula 3-7 can be coupled with carboxylic acids using a coupling agent such as BOP or with acyl chlorides followed by removal of the SEM group to give amide compounds of formula 4-2. Compounds of formula 3-7 can be reductively aminated with aldehydes using a reducing agent such as sodium triacetoxyborohydride followed by removal of the SEM group to give N-alkyl derivatives of formula 4-3. Compounds of formula 3-7 can be reacted with isocyanic acid followed by removal of the SEM group to give ureas of formula 4-4.

[0199] Scheme 4 [ka]

[0200] method The compounds of the present invention are JAK inhibitors, and most of the compounds of the present invention are JAK1 selective inhibitors. A JAK1 selective inhibitor is a compound that inhibits JAK1 activity preferentially over other Janus kinases. For example, the compounds of the present invention inhibit JAK1 preferentially over one or more of JAK2, JAK3, and TYK2. In some embodiments, the compounds inhibit JAK1 preferentially over JAK2 (e.g., IC of JAK1 / JAK2). 50 In some embodiments, the compound is about 10-fold more selective for JAK1 over JAK2. In some embodiments, the compound has an IC 50 The antibodies are about 3-fold, about 5-fold, about 10-fold, about 15-fold, or about 20-fold more selective for JAK1 over JAK2, as calculated by antibody titers (see, e.g., Example A).

[0201] JAK1 plays a central role in several cytokine and growth factor signaling pathways, and when dysregulated, it can lead to or contribute to disease states.For example, IL-6 levels are elevated in rheumatoid arthritis, a disease that has been suggested to have deleterious effects (Fonesca, JE et al., Autoimmunity Reviews, 8:538-42, 2009).Because IL-6 signals, at least in part, through JAK1, directly or indirectly antagonizing IL-6 by inhibiting JAK1 is expected to provide clinical benefit (Guschin, D., N., et al Embo J 14:1421, 1995; Smolen, JS, et al. Lancet 371:987, 2008). Furthermore, in some cancers, JAK1 is mutated, resulting in constant, unwanted tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci US A.106:9414-8, 2009; Flex E., et al.J Exp Med. 205:751-8, 2008). In other autoimmune diseases and cancers, elevated systemic levels of inflammatory cytokines that activate JAK1 may also contribute to disease and / or associated symptoms. Thus, patients suffering from such diseases may benefit from inhibition of JAK1. A selective inhibitor of JAK1 may be effective, avoiding the unnecessary and potentially undesirable effects of inhibiting other JAK kinases.

[0202] Selective inhibitors of JAK1 may have more therapeutic advantages than less selective inhibitors compared to other JAK kinases. Regarding selectivity for JAK2, several important cytokines and growth factors signal through JAK2, including erythropoietin (Epo) and thrombopoietin (Tpo) (Parganas E, et al. Cell. 93:385-95, 1998). Epo is a key growth factor in erythropoiesis, and thus, lack of Epo-dependent signaling can result in reduced red blood cell count and anemia (Kaushansky K, NEJM 354:2034-45, 2006). Tpo, another example of a JAK2-dependent growth factor, plays a central role in controlling the proliferation and maturation of megakaryocytes, the cells that produce platelets (Kaushansky K, NEJM 354:2034-45, 2006). The reduction of Tpo signaling itself reduces the number of megakaryocytes (megakaryocytopenia) and reduces the number of circulating platelets (thrombocytopenia). This can result in undesirable and / or uncontrollable bleeding. The reduction of other JAK inhibition, such as JAK3 and Tyk2, may also be desirable, since humans lacking functional versions of these kinases have been shown to suffer from a number of diseases, such as severe combined immunodeficiency or hyper-IgE syndrome (Minegishi, Y, et al. Immunity 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Thus, JAK1 inhibitors with reduced affinity for other JAK kinases would have a significant advantage over less selective inhibitors in terms of reducing side effects associated with immunosuppression, anemia, and thrombocytopenia.

[0203] Another aspect of the present invention relates to a method for treating a JAK-associated disease or disorder in an individual (e.g., a patient) by administering a therapeutically effective amount or volume of a compound of the present invention or a pharmaceutical composition thereof to the individual in need of such treatment. A JAK-associated disease may include any disease, disorder, or condition that is directly or indirectly linked to the expression or activity of JAK, including overexpression and / or abnormal activity levels of JAK. A JAK-associated disease may also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating JAK activity.

[0204] Examples of JAK-associated diseases include diseases involving the immune system, including, for example, organ transplant rejection (eg, allograft rejection and graft-versus-host disease).

[0205] Further examples of JAK-associated diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, myasthenia gravis, immunoglobulin nephropathy, myocarditis, autoimmune thyroid disorders, chronic obstructive pulmonary disease (COPD), etc. In some embodiments, the autoimmune disease is an autoimmune blistering skin disease such as pemphigus vulgaris (PV) or pemphigoid (BP).

[0206] Further examples of JAK-associated diseases include allergic conditions such as asthma, food allergies, eczematous dermatitis, contact dermatitis, atopic dermatitis (atopic eczema), and rhinitis. Further examples of JAK-associated diseases include viral diseases such as Epstein-Barr virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicella-Zoster virus (VZV), and Human Papillomavirus (HPV).

[0207] Further examples of JAK-associated diseases include cartilage turnover-related diseases such as, for example, gouty arthritis, suppurative or inflammatory arthritis, reactive arthritis, reflex sympathetic dystrophy, painful osteodystrophy, Tieze's syndrome, costoarthropathy, endemic osteoarthritis (osteoarthritis deformans endemica), Mseleni's disease, Handigodu's disease, fibromyalgia degeneration, systemic lupus erythematosus, scleroderma, or ankylosing spondylitis.

[0208] Further examples of JAK-associated diseases include congenital chondrodysplasias, including hereditary chondrolysis, chondrodysplasias, and pseudochondrodysplasias (eg, microtia, anotia, and metaphyseal chondrodysplasia).

[0209] Further examples of JAK-related diseases or conditions include skin disorders such as psoriasis (e.g., plaque psoriasis), atopic dermatitis, skin rashes, skin irritation, and skin sensitization (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances, including some pharmaceuticals, can cause skin sensitization when applied topically. In some embodiments, co-administration or sequential administration of at least one JAK inhibitor of the present invention with an agent that causes undesired sensitization can help treat such undesired sensitization or dermatitis. In some embodiments, topical administration of at least one JAK inhibitor of the present invention treats skin disorders.

[0210] In further embodiments, the JAK-associated disease is a cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of cutaneous T-cell lymphomas include Sezary syndrome and mycosis fungoides.

[0211] In some embodiments, the JAK inhibitors described herein or in combination with other JAK inhibitors, such as those described in U.S. Patent Application No. 11 / 637,545, the entirety of which is incorporated herein by reference, can be used to treat cancer associated with inflammation. In some embodiments, the cancer is associated with inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is ulcerative colitis. In some embodiments, the inflammatory bowel disease is Crohn's disease. In some embodiments, the cancer associated with inflammation is cancer associated with colitis. In some embodiments, the cancer associated with inflammation is colon cancer or colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.

[0212] JAK-associated diseases may further include those characterized by JAK2 mutants, such as those with at least one mutation in the pseudokinase domain (e.g., JAK2V617F); JAK2 mutants with at least one mutation outside the pseudokinase domain; JAK1 mutants; JAK3 mutants; expression of erythropoietin receptor (EPOR) mutants, or deregulated expression of CRLF2.

[0213] JAK-associated diseases may further include myeloproliferative disorders (MPDs), such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with myeloid metaplasia (MMM), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), systemic mastocytosis (SMCD), etc. In some embodiments, the myeloproliferative disease is myelofibrosis (e.g., primary myelofibrosis (PMF) or polycythemia vera / post-essential thrombocythemia (Post-PV / ET MF). In some embodiments, the myeloproliferative disease is myelofibrosis after essential thrombocythemia (Post-ET). In some embodiments, the myeloproliferative disease is myelofibrosis after polycythemia vera (Post-PV MF).

[0214] The present invention further provides a method of treating psoriasis or other skin disorders by administration of a topical formulation containing a compound of the present invention.

[0215] In some embodiments, the JAK inhibitors described herein can be used to treat pulmonary arterial hypertension.

[0216] The present invention further provides a method for treating the dermatological side effects of other medicines by administering the compounds of the present invention. For example, many medicines cause unwanted allergic reactions that may manifest as acne-like rashes or related dermatitis. Examples of medicines with such unwanted side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, etc. The compounds of the present invention can be administered systemically or locally (e.g., localized near dermatitis) in combination (e.g., simultaneously or sequentially) with medicines that have unwanted dermatological side effects. In some embodiments, the compounds of the present invention can be administered topically with one or more other medicines that cause contact dermatitis, allergic contact sensitization, or similar skin disorders when applied topically without the compounds of the present invention. Thus, the compositions of the present invention include topical formulations containing the compounds of the present invention and medicines that may cause dermatitis, skin disorders, or related side effects.

[0217] Further, JAK-related diseases include inflammation and inflammatory diseases. Examples of inflammatory diseases include sarcoidosis, ocular inflammatory diseases (e.g., iritis, uveitis, scleritis, conjunctivitis, or related diseases), respiratory tract inflammatory diseases (e.g., diseases of the upper respiratory tract, including the nose and sinuses, such as rhinitis or sinusitis, or diseases of the lower respiratory tract, including bronchitis, chronic obstructive pulmonary disease, etc.), inflammatory myopathies, such as myocarditis, and other inflammatory diseases. In some embodiments, the ocular inflammatory disease is blepharitis.

[0218] The JAK inhibitors described herein can further be used to treat diseases or conditions associated with ischemia-reperfusion injury or inflammatory ischemic events, such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used to treat endotoxin-driven disease states (e.g., complications following bypass surgery or chronic endotoxin conditions contributing to chronic heart failure). The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue, etc., resulting from or associated with cancer. The JAK inhibitors described herein can further be used to treat restenosis, sclerosing dermatitis, or fibrosis. The JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or astrogliosis, such as, for example, diabetic retinopathy, cancer, or neurodegeneration. See, e.g., Dudley, AC et al. Biochem. J. 2005, 390(Pt 2):427-36 and Sriram, K. et al. J. Biol. Chem. 2004, 279(19):19936-47. Epub 2004 Mar 2, both of which are incorporated by reference in their entireties. The JAK inhibitors described herein can be used to treat Alzheimer's disease.

[0219] The JAK inhibitors described herein can further be used to treat other inflammatory diseases, such as systemic inflammatory response syndrome (SIRS) and septic shock.

[0220] The JAK inhibitors described herein can further be used to treat gout and increased prostate size due to, for example, benign prostatic hyperplasia or benign prostatic hyperplasia.

[0221] Further, JAK-associated diseases include bone resorption diseases such as osteoporosis, osteoarthritis, etc. Bone resorption may also be associated with other conditions, such as hormonal imbalance and / or hormone therapy, autoimmune diseases (e.g., bone sarcoidosis), or cancer (e.g., myeloma). The reduction in bone resorption due to JAK inhibitors may be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.

[0222] In some embodiments, the JAK inhibitors described herein can further be used to treat dry eye disease. As used herein, "dry eye disease" is intended to encompass disease states summarized in the recent official report of the Dry Eye Workshop (DEWS), which defines dry eye as "a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability, with potential damage to the ocular surface. It is associated with increased osmolality of the tear film and inflammation of the ocular surface." Lemp, "The Definition and Classification of Dry Eye Disease: Report of the Definition and Classification Subcommittee of the International Dry Eye Workshop", The Ocular Surface, 5(2), 75-92 April 2007, is incorporated herein by reference in its entirety. In some embodiments, the dry eye disease is selected from aqueous deficient dry eye (ADDE) or evaporative dry eye disorder, or a suitable combination thereof. In some embodiments, the dry eye disease is Sjogren's syndrome dry eye (SSDE). In some embodiments, the dry eye disease is non-Sjogren's syndrome dry eye (NSSDE).

[0223] In a further aspect, the present invention provides a method of treating conjunctivitis, uveitis (including chronic uveitis), choroiditis, retinitis, cyclitis, scleritis, episcleritis, or iritis; treating inflammation or pain associated with corneal transplantation, LASIK (laser assisted in situ keratomileusis), laser photorefractive keratectomy, or LASEK (laser assisted sub-epithelial keratomileusis); inhibiting vision loss associated with corneal transplantation, LASIK, laser photorefractive keratectomy, or LASEK; or inhibiting graft rejection in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a pharma- ceutical acceptable salt thereof.

[0224] Additionally, compounds of the present invention or combinations with other JAK inhibitors, such as those described in U.S. patent application Ser. No. 11 / 637,545, which is incorporated by reference in its entirety, can be used to treat respiratory dysfunction or failure, such as those associated with viral infections, such as influenza and severe acute respiratory syndrome (SARS).

[0225] In some embodiments, the present invention provides a compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in a method of treating any disease or disorder described herein, as described in any embodiment herein. In some embodiments, the present invention provides a use of a compound of formula I for the preparation of a medicament for use in a method of treating any disease or disorder described herein, as described in any embodiment herein.

[0226] In some embodiments, the present invention provides a compound of formula I, as described herein, or a pharma- ceutically acceptable salt thereof, for use in a method of modulating JAK1.In some embodiments, the present invention also provides the use of a compound of formula I, as described herein, or a pharma- ceutically acceptable salt thereof, for the preparation of a medicament for use in a method of modulating JAK1.

[0227] As used herein, the term "contacting" refers to bringing the indicated moieties together in an in vitro system or in vivo system. For example, "contacting" a JAK with a compound of the invention includes administering a compound of the invention to an individual or patient, such as a human, having a JAK, as well as introducing a compound of the invention into a sample, including, for example, a cell preparation or purified preparation containing a JAK.

[0228] The terms "individual" or "patient", used interchangeably herein, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cattle, sheep, horse, or primate, most preferably a human.

[0229] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response desired in a tissue, system, animal, individual or human by a researcher, veterinarian, physician or other clinician. In some embodiments, the therapeutically effective amount is from about 5 mg to about 1000 mg, or from about 10 mg to about 500 mg.

[0230] The terms "treat" or "treatment" as used herein refer to one or more of the following: (1) Prevention of disease; for example, prevention of a disease, condition, or disorder in an individual who may be predisposed to suffering from the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptomology of the disease; (2) Inhibition of a disease; for example, inhibition of a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder (i.e., arresting further progression of the pathology and / or symptomology); and (3) Disease amelioration; e.g., amelioration of a disease, condition, or disorder (i.e., reversal of the pathology and / or symptomology) in an individual experiencing or exhibiting the pathology or symptomology of the disease, condition, or disorder, e.g., reducing the severity of the disease.

[0231] Combination therapy For example, one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, and Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors, such as those described in WO 2006 / 056399, which is incorporated herein by reference in its entirety, or other agents, can be used in combination with the compounds described herein to treat a JAK-associated disease, disorder or condition. The one or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0232] Examples of chemotherapeutic agents include proteosome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0233] Examples of steroids include corticosteroids such as dexamethasone or prednisone.

[0234] Examples of Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. patent application Ser. No. 60 / 578,491, the entire contents of which are incorporated herein by reference in their entirety, and pharma- ceutically acceptable salts thereof.

[0235] Examples of suitable Flt-3 inhibitors include compounds such as those disclosed in WO 03 / 037347, WO 03 / 099771, and WO 04 / 046120, the entire contents of which are incorporated herein by reference in their entirety, and pharma- ceutically acceptable salts thereof.

[0236] Examples of suitable RAF inhibitors include compounds such as those disclosed in WO 00 / 09495 and WO 05 / 028444, the entire contents of which are incorporated herein by reference in their entirety, and pharma- ceutically acceptable salts thereof.

[0237] Examples of suitable FAK inhibitors include compounds such as those disclosed in WO 04 / 080980, WO 04 / 056786, WO 03 / 024967, WO 01 / 064655, WO 00 / 053595, and WO 01 / 014402, the entire contents of which are incorporated herein by reference in their entirety, and pharma- ceutically acceptable salts thereof.

[0238] In some embodiments, one or more compounds of the invention can be used in combination with one or more other kinase inhibitors, including imatinib, particularly for the treatment of patients who are resistant to imatinib or other kinase inhibitors.

[0239] In some embodiments, one or more JAK inhibitors of the present invention can be used in combination with chemotherapy drugs in the treatment of cancers such as multiple myeloma, and can improve the therapeutic response compared to the response to chemotherapy drugs alone without worsening the toxic effects. Examples of additional pharmaceutical agents used in the treatment of multiple myeloma include, but are not limited to, for example, melphalan, melphalan + prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase inhibitors. It is desirable that the combination of the JAK inhibitors of the present invention with the additional agent results in additive or synergistic effects. Furthermore, the resistance of multiple myeloma cells to agents such as dexamethasone can be reversed by the treatment of the JAK inhibitors of the present invention. The agents can be combined with the compounds of the present invention in a single dosage form or a sequential dosage form, or can be administered simultaneously or sequentially as separate dosage forms.

[0240] In some embodiments, a corticosteroid, such as dexamethasone, is administered to a patient in combination with at least one JAK inhibitor, where the dexamethasone is administered intermittently rather than continuously.

[0241] In some further embodiments, a combination of one or more JAK inhibitors of the present invention and other therapeutic agents may be administered to a patient before, during, and / or after bone marrow or stem cell transplantation.

[0242] In some embodiments, the additional therapeutic agent is fluocinolone acetonide (Retisert®), or rimexolone (AL-2178, Vexol, Alcon).

[0243] In some embodiments, the additional therapeutic agent is cyclosporine (Restasis®).

[0244] In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, or flumetholone.

[0245] In some embodiments, the additional therapeutic agent is selected from the group consisting of Dehydrex™ (Holles Labs), Civamid (Opko), sodium hyaluronate (Vismed, Lantibio / TRB Chemedia), cyclosporine (ST-603, Sirion Therapeutics), and cyclosporine (ST-603, Sirion Therapeutics). Therapeutics), ARG101(T) (testosterone, Algentis), AGR1012(P) (Argentis), ecabet sodium (Senju Pharmaceutical Co., Ltd.-Ista), gefarnate (Santen Pharmaceutical Co., Ltd.), 15-(s)-hydroxyeicosatetraenoic acid (15(S)-HETE), cevilemine, doxycycline (ALTY-0501, Alacrity), minocycline, iDestrin™ (NP50301, Nascent Pharmaceuticals Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (duramycin, MOLI1901, Lantibio), CF101(2S,3S,4R,5R)-3,4-Dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carbamyl, Can-Fite BioPharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103 (Argentis), RX-10045 (synthetic resolvin analog, Resolvyx), DYN15 (Dynamis Therapeutics), rivoglitazone (DE011, Daiichi Sankyo Co., Ltd.), TB4(8), OPH-01 (Ophtalmis Monaco), PCS101 (Pericor Sciences), Science), REV1-31 (Evolutec), Lacritin (Senju Pharmaceutical Co., Ltd.), Rebamipide (Otsuka Pharmaceutical Co., Ltd.-Novartis), OT-551 (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, tacrolimus, pimecrolimus (AMS981, Novartis), loteprednol etabonate, The therapeutic agent is selected from rituximab, diquafosol tetrasodium (INS365, Inspire), KLS-0611 (Kissei Pharmaceutical Co., Ltd.), dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (Torrey Pines Therapeutics), Actemra, gemcitabine, oxaliplatin, L-asparaginase, or thalidomide.

[0246] In some embodiments, the additional therapeutic agent is an antiangiogenic agent, an acetylcholine receptor agonist, a TRP-1 receptor modulator, a calcium channel blocker, a mucin secretagogue, a MUC1 stimulator, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, a Bcr-Abl kinase inhibitor, an Flt-3 kinase inhibitor, a RAF kinase inhibitor, and a FAK kinase inhibitor, such as those disclosed in WO2006 / 056399, the entirety of which is incorporated herein by reference.In some embodiments, the additional therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycycline).In some embodiments, the additional therapeutic agent binds to FKBP12.

[0247] In some embodiments, the additional therapeutic agent is an alkylating or DNA crosslinking agent; antimetabolite / demethylating agent (e.g., 5-flurouracil, capecitabine, or azacitidine); an anti-hormonal therapy (e.g., a hormone receptor antagonist, a selective estrogen receptor modulator (SERM), or an aromatase inhibitor); a mitotic inhibitor (e.g., vincristine or paclitaxel); a topoisomerase (I or II) inhibitor (e.g., mitoxantrone and irinotecan); an apoptosis inducer (e.g., ABT-737); a nucleic acid therapy (e.g., antisense or RNAi); a nuclear receptor ligand (e.g., an agonist and / or antagonist: all-trans retinoic acid or bexarotene); an epigenetic targeting agent (e.g., an agonist and / or antagonist: all-trans retinoic acid or bexarotene); agents), such as histone deacetylase inhibitors (e.g., vorinostat), hypomethylating agents (e.g., decitabine); regulators of protein stability, such as Hsp90 inhibitors, ubiquitin and / or ubiquitin-like conjugating or deconjugating molecules; or EGFR inhibitors (erlotinib).

[0248] In some embodiments, the additional therapeutic agent is a demulcent eye drop (also known as "artificial tears"), including, but not limited to, compositions containing polyvinyl alcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol (e.g., PEG 400), or carboxymethylcellulose. Artificial tears can help treat dry eye by compensating for the reduced wetting and lubricating ability of the tear film. In some embodiments, the additional therapeutic agent is a mucolytic agent, such as N-acetylcysteine, which can decrease the viscosity of the tear film by interacting with mucoproteins.

[0249] In some embodiments, the additional therapeutic agent includes antibiotics, antivirals, antifungals, anesthetics, anti-inflammatory agents, including steroidal and non-steroidal anti-inflammatory agents, and anti-allergy agents. Examples of suitable drugs include aminoglycosides, such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin sulfate, and kanamycin; fluoroquinolones, such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxins; chloramphenicol; neomycin; paromomycin; colitimethate; bacitracin; vancomycin; tetracyclines; rifampin and its derivatives ("rifampins"); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxamide; levocabastine; naphazoline; antazoline; pheniramine; or azalide antibiotics.

[0250] Pharmaceutical Formulations and Dosage Forms When used as a pharmaceutical, the compounds of the present invention can be administered in the form of pharmaceutical compositions. These compositions can be prepared by methods well known in the pharmaceutical art and can be administered by a variety of routes depending on whether local or systemic treatment is desired and on the location to be treated. Administration can be topical (including transdermal, epithelial, intraocular, and mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose or, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0251] The present invention also includes pharmaceutical compositions comprising a combination of the compound of the present invention or its pharma- ceutically acceptable salt as an active ingredient and one or more pharma- ceutical acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing the compositions of the present invention, the active ingredient is generally mixed with an excipient, diluted with an excipient, or enclosed in such a carrier, for example in the form of a capsule, sachet, paper or other container. When an excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders, for example, containing up to 10% by weight of the active compound.

[0252] When preparing the formulation, the active compound can be milled to a suitable particle size before combining with other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of 200 mesh or less. If the active compound is substantially water-soluble, the particle size can be adjusted by milling, for example, to about 40 mesh, to provide a substantially uniform distribution in the formulation.

[0253] The compound of the present invention can be milled using known milling procedures, such as wet milling, to obtain particle sizes suitable for tablet formation and other formulation types.The finely divided (nanoparticulate) formulation of the compound of the present invention can be prepared by methods known in the art.See, for example, International Patent Application Publication No. WO2002 / 000196.

[0254] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl-benzoic acid and propylhydroxy-benzoic acid; sweeteners; and flavoring agents.The composition of the present invention may also be formulated so that the active ingredient is released quickly, sustained, or delayed after administration to a patient by methods known in the art.

[0255] In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% w / w microcrystalline cellulose and about 2% w / w silicon dioxide.

[0256] In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable carrier. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and / or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).

[0257] In some embodiments, the composition is produced using a wet granulation process. In some embodiments, the composition is produced using a dry granulation process.

[0258] The compositions may be formulated in unit dosage form, each dose containing from about 5 to about 1,000 mg (1 g), more typically from about 100 mg to about 500 mg, of active ingredient. In some embodiments, each dose contains about 10 mg of active ingredient. In some embodiments, each dose contains about 50 mg of active ingredient. In some embodiments, each dose contains about 25 mg of active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with suitable pharmaceutical excipients.

[0259] In some embodiments, the compositions of the invention contain from about 5 mg to about 50 mg of active ingredient. One of skill in the art will recognize that this embodies a compound or composition containing from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, from about 35 mg to about 40 mg, from about 40 mg to about 45 mg, or from about 45 mg to about 50 mg of active ingredient.

[0260] In some embodiments, the compositions of the invention contain from about 50 mg to about 500 mg of active ingredient. One of skill in the art will recognize that this embodies a compound or composition containing from about 50 mg to about 100 mg, from about 100 mg to about 150 mg, from about 150 mg to about 200 mg, from about 200 mg to about 250 mg, from about 250 mg to about 300 mg, from about 350 mg to about 400 mg, or from about 450 mg to about 500 mg of active ingredient.

[0261] In some embodiments, the compositions of the invention contain from about 500 mg to about 1,000 mg of active ingredient. One of skill in the art will recognize that this embodies a compound or composition containing from about 500 mg to about 550 mg, about 550 mg to about 600 mg, about 600 mg to about 650 mg, about 650 mg to about 700 mg, about 700 mg to about 750 mg, about 750 mg to about 800 mg, about 800 mg to about 850 mg, about 850 mg to about 900 mg, about 900 mg to about 950 mg, or about 950 mg to about 1,000 mg of active ingredient.

[0262] The active compounds may be effective over a wide dosage range and are generally administered in a pharma- ceutical effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0263] To prepare solid compositions such as tablets, the primary active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compound of the present invention. When these preformulation compositions are referred to as homogeneous, the active ingredient is generally evenly dispersed throughout the composition, and the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, for example, containing from about 0.1 to about 1000 mg of the active ingredient of the present invention.

[0264] The tablet or pill of the present invention can be coated or otherwise constructed to provide a dosage form that provides the advantage of long-acting action.For example, the tablet or pill can comprise an inner dosage component and an outer dosage component, where the outer dosage component is in the form of an envelope covering the inner dosage component.The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0265] Liquid forms which may incorporate the compounds and compositions of the present invention for oral administration or injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0266] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma-ceutically acceptable excipients, as described above. In some embodiments, compositions are administered by oral or nasal respiratory route for local or systemic effect. Inert gases may be used to nebulize the compositions. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or intranasally from a device that delivers the formulation in an appropriate manner.

[0267] Topical formulations may include one or more conventional carriers. In some embodiments, ointments may include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. Creamy carrier compositions may be based on a combination of water, glycerol, and one or more other ingredients, such as glycerol monostearate, PEG-glycerol monostearate, and cetylstearyl alcohol, and the like. Gels may be formulated using a suitable combination of isopropyl alcohol and water, and other ingredients, such as, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations include at least about 0.1, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of a compound of the invention. Topical formulations may also be suitably packaged, for example, in 100 g tubes, optionally accompanied by instructions for the treatment of a select indication, such as, for example, psoriasis or other skin conditions.

[0268] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis and therapy, the condition of the patient, the method of administration, etc. In therapeutic applications, a patient already suffering from a disease may be administered an amount of the composition sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the disease state being treated, as well as the judgment of the attending physician depending on factors such as the severity of the disease, the age, weight, and general condition of the patient.

[0269] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions may be packaged for ready use or lyophilized, the lyophilized preparations being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulations will generally be 3-11, more preferably 5-9, most preferably 7-8. It will be understood that the use of certain of the aforementioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0270] The therapeutic dosage of a compound of the invention may vary according to, for example, the particular use for treatment, the method of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and route of administration. For example, a compound of the invention may be provided in an aqueous physiological buffer containing about 0.1% w / v to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the compound selected, the excipient formulation, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0271] The compositions of the present invention may further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed above.

[0272] In some embodiments, the compound or its pharma- ceutically acceptable salt is administered as an ophthalmic composition.Thus, in some embodiments, the method comprises administering the compound or its pharma- ceutically acceptable salt and an ophthalmologically acceptable carrier.In some embodiments, the ophthalmic composition is a liquid composition, a semi-solid composition, an insert, a film, a microparticle, or a nanoparticle.

[0273] In some embodiments, the ophthalmic composition is a liquid composition. In some embodiments, the ophthalmic composition is a semi-solid composition. In some embodiments, the ophthalmic composition is a topical composition. Topical compositions include, but are not limited to, liquid and semi-solid compositions. In some embodiments, the ophthalmic composition is a topical composition. In some embodiments, the topical composition comprises an aqueous solution, an aqueous suspension, an ointment, or a gel. In some embodiments, the ophthalmic composition is applied topically to the front of the eye, under the upper eyelid, on the lower eyelid, and in the conjunctival sac. In some embodiments, the ophthalmic composition is sterilized. Sterilization can be achieved by known techniques such as sterile filtration of the solution or by heating the solution in a ready-to-use ampoule. The ophthalmic composition of the present invention may further comprise pharmaceutical excipients suitable for the preparation of ophthalmic formulations. Examples of such excipients are preservatives, buffers, chelating agents, antioxidants, and salts to control osmotic pressure.

[0274] The term "ophthalmically acceptable carrier" as used herein refers to any material capable of containing and releasing the compound, or a pharma- ceutically acceptable salt thereof, and compatible with the eye. In some embodiments, the ophthalmically acceptable carrier is water or an aqueous solution or suspension, but also includes ointments used in ocular inserts and oils used in making polymeric matrices. In some embodiments, the composition may be an aqueous suspension containing the compound, or a pharma- ceutical acceptable salt thereof. Liquid ophthalmic compositions, including both ointments and suspensions, may have a viscosity suitable for the selected route of administration. In some embodiments, the ophthalmic composition has a viscosity in the range of about 1,000 to about 30,000 centipoise.

[0275] In some embodiments, the ophthalmic composition may further comprise one or more of surfactants, adjuvants, buffers, antioxidants, isotonicity agents, preservatives (e.g., EDTA, BAK (benzalkonium chloride), sodium chlorite, sodium perborate, polyquaternium-1), thickeners or viscosity modifiers (e.g., carboxymethylcellulose, hydroxymethylcellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethylcellulose, hydroxypropyl guar, hyaluronic acid, and hydroxypropylcellulose), and the like. Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, methylparaben, propylparaben, chlorhexidine, castor oil, and sodium perborate.

[0276] Aqueous ophthalmic compositions (solutions or suspensions) generally do not contain physiologically or ophthalmically harmful components. In some embodiments, purified or deionized water is used in the composition. The pH can be adjusted to within the range of about 5.0 to 8.5 by adding any physiologically and ophthalmically acceptable pH adjusting acid, base or buffer. Examples of ophthalmically acceptable acids include acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, hydrochloric acid, etc., and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, trihydroxymethylamino-methane, etc. Salts and buffers include citrate / dextrose, sodium bicarbonate, ammonium chloride, and mixtures of the above-mentioned acids and bases.

[0277] In some embodiments, the method includes forming or delivering a depot of a therapeutic agent in contact with the external surface of the eye. A depot refers to a source of a therapeutic agent that is not rapidly removed by tears or other ocular clearance mechanisms. A depot allows a high concentration of a therapeutic agent to be present in the fluid on the external surface of the eye continuously and sustained. Without being bound by any theory, it is believed that absorption and penetration may depend on both the concentration of dissolved drug and the time of contact of the external tissue with the drug-containing fluid. As the drug is removed by clearance by the ocular fluid and / or absorption into the ocular tissue, additional drug is provided, e.g., dissolved, from the depot into the replenished ocular fluid. Thus, the use of a depot can more easily facilitate the delivery of more insoluble therapeutic agents to the ocular tissue. In some embodiments, the depot can be retained for up to 8 hours or more. In some embodiments, ophthalmic depot forms include, but are not limited to, aqueous polymeric suspensions, ointments, and solid inserts.

[0278] In some embodiments, the ophthalmic composition is an ointment or gel. In some embodiments, the ophthalmic composition is an oil-based delivery vehicle. In some embodiments, the composition comprises a petroleum or lanolin base, to which is added an active ingredient, typically 0.1-2%, and excipients. Typical bases include, but are not limited to, mineral oil, petrolatum, and combinations thereof. In some embodiments, the ointment is applied as a ribbon on the lower eyelid.

[0279] In some embodiments, the ophthalmic composition is an ophthalmic insert. In some embodiments, the ophthalmic insert is biologically inert, soft, bio-erodible, viscoelastic, stable to sterilization after exposure to the therapeutic agent, resistant to infection from airborne bacteria, bio-erodible, biocompatible, and / or viscoelastic. In some embodiments, the insert comprises an ophthalmologically acceptable matrix, such as a polymeric matrix. The matrix is ​​typically a polymer, and the therapeutic agent is generally dispersed in or bound to the polymeric matrix. In some embodiments, the therapeutic agent can be gradually released from the matrix via dissolution or hydrolysis of covalent bonds. In some embodiments, the polymer is bioerodible (soluble), and its dissolution rate can control the release rate of the therapeutic agent dispersed therein. In another embodiment, the polymeric matrix is ​​a biodegradable polymer, and the polymer degrades, such as by hydrolysis, to release the therapeutic agent bound to or dispersed therein. In further embodiments, the matrix and the therapeutic agent can be surrounded by an additional polymeric membrane to further control the release. In some embodiments, the insert comprises a biodegradable polymer such as polycaprolactone (PCL), ethylene / vinyl acetate copolymer (EVA), polyalkylcyanoacrylate, polyurethane, nylon, or poly(dl-lactide-co-glycolide) (PLGA), or a copolymer of any of these. In some embodiments, the therapeutic agent is dispersed in the matrix material or dispersed in the monomer composition used to make the matrix material prior to polymerization. In some embodiments, the amount of therapeutic agent is about 0.1 to about 50%, or about 2 to about 20%. In further embodiments, a biodegradable or bioerodible polymer matrix is ​​used so that there is no need to remove the used insert. As the biodegradable or bioerodible polymer degrades or dissolves, the therapeutic agent is released.

[0280] In further embodiments, the ophthalmic insert comprises a polymer, including but not limited to those described in Wagh, et al., "Polymers used in ocular dosage forms and drug delivery systems", Asian J. Pharm., pages 12-17 (Jan. 2008), which is incorporated herein by reference in its entirety. In some embodiments, the insert comprises a polymer selected from polyvinylpyrrolidone (PVP), acrylate or methacrylate polymers or copolymers (e.g., the Eudragit® family of polymers from Rohm or Degussa), hydroxymethylcellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethylsiloxane), polyethylene oxide, poly(lactide-co-glycolide), poly(2-hydroxyethyl methacrylate), poly(vinyl alcohol) or poly(propylene fumarate). In some embodiments, the insert comprises Gelfoam® R. In some embodiments, the insert is a 450 kDa cysteine-conjugated polyacrylic acid.

[0281] In some embodiments, the ophthalmic composition is an ophthalmic film.Suitable polymers for such films include, but are not limited to, those described in Wagh, et al. (supra).In some embodiments, the film is a soft contact lens, such as one made from a copolymer of N,N-diethylacrylamide and methacrylic acid crosslinked with ethylene glycol dimethacrylate.

[0282] In some embodiments, the ophthalmic composition comprises microspheres or nanoparticles. In some embodiments, the microspheres comprise gelatin. In some embodiments, the microspheres are injected into the posterior segment, into the chroroidal space, into the sclera, into the vitreous, or subretinal. In some embodiments, the microspheres or nanoparticles comprise a polymer, including but not limited to those described in Wagh, et al., supra, which is incorporated herein by reference in its entirety. In some embodiments, the polymer is chitosan, a polycarboxylic acid such as polyacrylic acid, an albumin particle, a hyaluronic acid ester, polyitaconic acid, poly(butyl) cyanoacrylate, polycaprolactone, poly(isobutyl) caprolactone, poly(lactic-co-glycolic acid) or poly(lactic acid). In some embodiments, the microspheres or nanoparticles comprise solid lipid particles.

[0283] In some embodiments, the ophthalmic composition comprises an ion exchange resin. In some embodiments, the ion exchange resin is an inorganic zeolite or a synthetic organic resin. In some embodiments, the ion exchange resin includes, but is not limited to, those described in Wagh, et al., supra, which is incorporated herein by reference in its entirety. In some embodiments, the ion exchange resin is a partially neutralized polyacrylic acid.

[0284] In some embodiments, the ophthalmic composition is an aqueous polymeric suspension. In some embodiments, the therapeutic agent or polymeric suspending agent is suspended in an aqueous medium. In some embodiments, the aqueous polymeric suspensions can be formulated to maintain the same or substantially the same viscosity in the eye as they had before being administered to the eye. In some embodiments, the aqueous polymeric suspensions can be formulated to have increased gelation after contact with tear fluid.

[0285] Labeled Compounds and Assay Methods Another aspect of the invention relates to labeled compounds of the invention (radiolabeled, fluorescently labeled, etc.) that are useful in both in vitro and in vivo assays, including imaging techniques, to localize and quantify JAK in tissue samples, including humans, and to identify JAK ligands by inhibiting binding of labeled compounds. Thus, the invention encompasses JAK assays that include such labeled compounds.

[0286] The present invention further includes isotopically labeled compounds of the present invention. An "isotopically labeled" or "radiolabeled" compound is a compound of the present invention in which one or more atoms are replaced or substituted with an atom having an atomic mass or mass number different from the atomic mass or mass number generally found in nature (i.e., naturally occurring). Suitable radionuclides that can be incorporated into the compounds of the present invention include: 3 H (also written as T to represent tritium), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 The radionuclide incorporated into the radiolabeled compounds of the invention will depend on the particular application of the radiolabeled compound. For example, in vitro JAK labeling and competition assays include: 3 H, 14 C. 82 Br, 125 I, 131 I, 35 Compounds incorporating S or will generally be most useful. For radiation imaging applications, 11 C.18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br or 77 Br will generally be the most useful.

[0287] By "radiolabeled" or "labeled compound" is understood a compound that incorporates at least one radionuclide. In some embodiments, the radionuclide is 3 H, 14 C. 125 I, 35 S and 82 Br In some embodiments, the compound incorporates 1, 2, or 3 deuterium atoms.

[0288] The present invention further encompasses synthetic methods for incorporating radioisotopes into the compounds of the present invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and one of ordinary skill in the art will readily recognize methods that are applicable to the compounds of the present invention.

[0289] The labeled compounds of the present invention can be used in screening assays to identify / evaluate compounds. For example, a labeled newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to bind to JAK by monitoring its concentration change upon contact with JAK via tracking the label. For example, a (labeled) test compound can be evaluated for its ability to reduce the binding of another compound (i.e., a standard compound) known to bind to JAK. Thus, the ability of a test compound to compete with a standard compound for binding to JAK directly correlates with its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and the test compound is not labeled. Thus, the relative binding affinity of the test compound is elucidated by monitoring the concentration of a labeled standard compound to evaluate the competition between the standard compound and the test compound.

[0290] kit The present invention also includes pharmaceutical kits useful for treating or preventing JAK-associated diseases or disorders, such as cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention. Such kits may further comprise one or more of various conventional pharmaceutical kit components, such as, for example, a container with one or more pharma- ceutically acceptable carriers, additional containers, etc., as would be readily apparent to one of skill in the art, if desired. Instructions, either inserts or labels, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing components, may also be included in the kit.

[0291] The present invention will be described in more detail by specific examples.The following examples are provided for illustrative purposes and do not limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to provide essentially the same results.The compounds described in the examples have been found to be JAK inhibitors according to at least one of the assays described herein. EXAMPLES

[0292] The compounds in the following examples containing one or more chiral centers were obtained in enantiomerically pure form or as heterogeneous mixtures of enantiomers, unless otherwise noted.

[0293] Unless otherwise stated, the compounds in the above examples were purified by preparative HPLC using acidic conditions (Method A) and obtained as the TFA salt, or using basic conditions (Method B) and obtained as the free base.

[0294] Method A: Column: Waters Sun Fire C18, 5 μm particle size, 30 × 100 mm; Mobile phase: Water (0.1% TFA) / acetonitrile Flow rate: 60mL / min Gradient: 5% acetonitrile / 95% water to 100% acetonitrile in 5 or 12 min.

[0295] Method B: Column: Waters X Bridge C18, 5 μm particle size, 30 × 100 mm; Mobile phase: water (0.15%NH 4 OH) / acetonitrile

[0296] Method C: Column: C18 column, 5μm OBD Mobile phase: water +0.05%NH 4 OH(A), CH 3 CN+0.05%NH 4 OH(B) Gradient: 5% B to 100% B in 15 minutes Flow rate: 60mL / min

[0297] Example 1 {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0298] Step A: tert-Butyl 3-oxoazetidine-1-carboxylate [ka] To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) in portions at 0° C. The mixture was stirred for 3 h, quenched with brine and extracted with methylene chloride. The combined extracts were washed with anhydrous Na 2 SO4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The residue was purified on a silica gel column (0-6% ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52% yield).

[0299] Step B: tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate [ka] An oven-dried 1 L 4-neck round-bottom flosser equipped with a stir bar, septum, nitrogen inlet, 250 mL addition funnel, and thermocouple was charged with sodium hydride (5.6 g, 0.14 mol) and tetrahydrofuran (THF) (140 mL) under a nitrogen atmosphere. The mixture was cooled to 3° C. and then diethyl cyanomethylphosphonate (22.4 mL, 0.138 mol) was charged dropwise from a syringe over 20 minutes. The solution became a pale yellow slurry. The reaction was then stirred for 75 minutes while warming to 18.2° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (20 g, 0.1 mol) in tetrahydrofuran (280 mL) was prepared in an oven-dried round-bottom and charged to the addition funnel via cannula and then added dropwise to the reaction mixture over 25 minutes. The reaction became red in color. The reaction was stirred overnight. The reaction was checked by TLC (70% hexanes / EtOAc) after 24 hours and found to be complete. The reaction was diluted with 200 mL of 20% brine and 250 mL of EtOAc. The solution was partitioned and the aqueous phase was extracted with 250 mL of EtOAc. The combined organic phase was washed with MgSO 4 Drying at 40° C., filtration, evaporation in vacuo, and purification by flash chromatography (0% to 20% EtOAc / hexanes, 150 g flash column) afforded the desired product, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (15 g, 66.1% yield).

[0300] Step C: 4-Chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine [ka] To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at -5°C (ice / salt bath) was slowly added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL). The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0°C for 60 minutes, resulting in a light brown cloudy mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0°C for 1 hour. The reaction was diluted with 12 mL of H 2 The reaction was quenched by slow addition of O. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted once more with MTBE (120 mL). The combined organic extracts were washed with brine (120 mL x 2) and concentrated under reduced pressure to give the crude product 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC / MS: 284.1 (M+H). + The crude product was used in the next reaction without purification.

[0301] Step D: 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine [ka] A 1000 mL round bottom floss was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.00 g, 35.23 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.66 g, 52.85 mmol), water (25.0 mL) and potassium carbonate (12.17 g, 88.08 mmol). The solution was degassed four times, filling with nitrogen each time. Tetrakis(triphenylphosphine)palladium(0) (4.071 g, 3.523 mmol) was added to the solution. The solution was degassed four times, filling with nitrogen each time. The mixture was stirred at 100 °C overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was rinsed with ethyl acetate (42 mL). The filtrates were combined and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated in vacuo at a bath temperature of 30-70°C to give the final compound 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 78%. LC / MS: 316.2 (M+H). + .

[0302] Step E: tert-Butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate [ka] A 2 L round bottom flosser equipped with overhead stirring, septum and nitrogen inlet was charged with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) in portions via syringe over 3 min at room temperature. The solution gradually became homogeneous and yellow in color. The reaction was stirred at room temperature for 3 h. The reaction was completed by HPLC and LC / MS and concentrated by rotary evaporation to remove acetonitrile (approximately 150 mL). EtOAc (100 mL) was added, followed by 100 ml of 20% brine. The two phases were split. The aqueous phase was extracted with 150 mL of EtOAc. The combined organic phase was washed with MgSO 4 The product was dried at 4°C, filtered and concentrated to give an orange oil. Flash chromatography (150 grams silica, 60% EtOAc / hexanes, CH 2 Cl 2 (charged with hexanes) to give the title compound tert-butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a yellow oil (21.1 g, 88% yield). LC / MS: [M+H] + =510.3.

[0303] Step F: {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride [ka] To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2 g, 3.9 mmol) in 10 mL of THF was added 10 mL of 4N HCl in dioxane. The solution was stirred at room temperature for 1 h and concentrated in vacuo to give 1.9 g (99%) of the title compound as a white powder solid, which was used in the next reaction without purification. LC / MS: [M+H] + =410.3.

[0304] Step G: tert-Butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate [ka] To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.3 g, 6.3 mmol) in THF (30 mL) was added N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. After adding 20 mL of brine, the solution was extracted with EtOAc. The extract was washed with anhydrous Na 2 SO 4The residue was purified on a CombiFlash column eluting with 30-80% EtOAc in hexane to give the desired product, tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate. Yield: 3.2 g (86%); LC / MS: [M+H] + =593.3.

[0305] Step H: {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride [ka] To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.2 g, 5.4 mmol) in THF (10 mL) was added 10 mL of 4N HCl in dioxane. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure to give 3.25 g (100%) of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used directly in the next reaction. LC / MS: [M+H] + =493.3. 1 H NMR (400 MHz, DMSO-d 6): δ 9.42 (s 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 7.97 (s, 1H), 7.39 (d, 1H), 5.68 (s, 2H), 4.96 (d, 2H), 4.56 (m, 2H), 4.02-3.63 (m, 2H), 3.55 (s, 2H), 3.53 (t, 2H), 3.49-3.31 (3, 3H), 2.81 (m, 2H), 2.12 (d, 2H), 1.79 (m, 2H), 0.83 (t, 2H), -0.10 (s, 9H).

[0306] Step I: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol), and triethylamine (2.0 mL, 14 mmol) in dimethylformamide (DMF) (20.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction to be complete. EtOAc (60 mL) and saturated NaHCO 3 Aqueous solution (60 mL) was added to the reaction mixture. After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer was extracted three times with EtOAc. The combined organic phase was washed with brine and anhydrous Na 2 SO 4The residue was dried at 40° C., filtered and evaporated in vacuo. Purification by flash chromatography gave the desired product, {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC / MS: 684.3 (M+H). + .

[0307] Step J: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] To a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 h. After removing the solvent in vacuo, the residue was dissolved in a 20% ethylenediamine solution in methanol. After stirring at room temperature for 1 h, the solution was purified by HPLC (Method B) to give the title compound. LC / MS: 554.3 (M+H) + ; 1 H NMR (400 MHz, CDCl 3 ): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J 1 =3.4 Hz, J 2 =1.5 Hz, 1H), 6.77 (dd, J 1=3.6 Hz, J 2 =0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J 1 =7.8 Hz, J 2 =3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H).

[0308] Example 2 {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0309] Step A: {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid [ka] To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.0 g, 2.0 mmol) in methylene chloride (DCM) (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.2 g, 2.6 mmol), N,N-diisopropylethylamine (1.1 mL, 6.1 mmol), and 4-(dihydroxyboryl)-3-fluorobenzoic acid (0.37 g, 2.0 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified using HPLC to give 0.54 g (41%) of the desired product, {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid. LC / MS: 659.3 (M+H). + .

[0310] Step B: {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile To a solution of {4-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorophenyl}boronic acid (50 mg, 0.08 mmol) in DMF (2 mL) was added 6-bromoquinoline (15 mg, 0.076 mmol), triethylamine (0.021 mL, 0.15 mmol) and 3 drops of 2N K 2 CO 3Aqueous solution was added. The mixture was degassed and bis(triphenylphosphine)palladium(II) chloride (5.4 mg, 0.0076 mmol) was added. The reaction mixture was stirred at 140° C. in a microwave oven for 25 min, then cooled to room temperature and filtered. The filtrate was purified by HPLC to give a white powder. The white powder was dissolved in 5 mL of DCM / TFA (1:2). After stirring at room temperature for 1 h, the solution was concentrated. The residue was dissolved in 5 mL of 10% ethylenediamine in THF. After stirring at room temperature for 2 h, the solution was concentrated. The residue was purified by HPLC (Method B) to give the title compound {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC / MS: 612.2 (M+H) + .

[0311] The following compounds were prepared in a manner similar to that of Example 1 or Example 2.

[0312] [ka]

[0313] [Table 1-1]

[0314] [Table 1-2]

[0315] [Table 1-3]

[0316] [Table 1-4]

[0317] [Table 1-5]

[0318]

Table 1-6

[0319]

Table 1-7

[0320]

Table 1-8

[0321]

Table 1-9

[0322]

Table 1-10

[0323]

Table 1-11

[0324]

Table 1-12

[0325]

Table 1-13

[0326]

Table 1-14

[0327]

Table 1-15

[0328]

Table 1-16

[0329]

Table 1-17

[0330]

Table 1-18

[0331]

Table 1-19

[0332]

Table 1-20

[0333]

Table 2-1

[0334]

Table 2-2

[0335]

Table 2-3

[0336]

Table 2-4

[0337]

Table 2-5

[0338] [Table 2-6]

[0339] [Table 2-7]

[0340] [Table 2-8]

[0341] [Table 2-9]

[0342] Example 138 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-5-fluorobenzonitrile [ka]

[0343] Step A: tert-Butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol) in THF (30 mL) was added tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (1.3 g, 6.3 mmol), N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight and quenched by the addition of 20 mL of brine. The solution was extracted with EtOAc. The extract was washed with anhydrous Na 2 SO 4 After removal of the solvent, the residue was purified on a CombiFlash column eluted with 30-80% EtOAc in hexane to give the desired product tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate. LC / MS: 619.3 (M+H). + .

[0344] Step B: {1-(8-azabicyclo[3.2.1]oct-3-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride [ka] To a solution of tert-butyl 3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (123 mg, 0.2 mmol) in THF (3 mL) was added 4N HCl solution in dioxane (3 mL). After stirring at room temperature for 2 h, the solution was concentrated. The resulting residue was used in the next reaction. LC / MS: 519.3 (M+H) + .

[0345] Step C: 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-5-fluorobenzonitrile A mixture of {1-(8-azabicyclo[3.2.1]oct-3-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (100.0 mg, 0.193 mmol), 3-cyano-5-fluorobenzoic acid (31.8 mg, 0.193 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (93.8 mg, 0.212 mmol), and triethylamine (0.108 mL, 0.771 mmol) in DMF (3.0 mL) was stirred at room temperature for 2 h. Purification by HPLC afforded the coupling product as a white powder. LCMS found: 666.3 (M+1). +The white powder was dissolved in trifluoroacetic acid (2 mL) and methylene chloride (2 mL). The resulting solution was stirred at room temperature for 1 h. The solvent was evaporated to dryness. The residue was treated with methanol (3 mL) and ethylenediamine (0.3 mL, 4 mmol) at room temperature for 1 h. Purification using HPLC (Method A) afforded the title compound 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-5-fluorobenzonitrile as the TFA salt. LCMS found: 536.3 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.93 (s, 1H), 8.81 (s, 1H), 8.51 (s, 1H), 7.97 (s, 1H), 7.81 (s, 1H), 7.72 (m, 3H), 7.18 (s, 1H), 4.53 (m, 2H), 3.80 (m, 1H), 3.57 (m, 6H), 1.55-2.08 (m, 8H).

[0346] The following compounds were prepared in a manner similar to that of Example 138.

[0347] [ka]

[0348] [Table 3-1]

[0349] [Table 3-2]

[0350] [Table 4]

[0351] Examples 149 and 150 Diastereomers of {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0352] Step A: tert-Butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate [ka] To a solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol) and tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1.3 g, 6.3 mmol) in THF (30 mL) was added N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. After adding 20 mL of brine, the solution was extracted with EtOAc. The extract was washed with anhydrous Na 2 SO 4After removal of the solvent, the residue was purified by CombiFlash chromatography eluting with 30-80% EtOAc in hexane to give 2.6 g (81%) of the desired product, tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate. LC / MS: 607.3 (M+H). + .

[0353] Step B: {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidine-1-carboxylate (0.5 g) in methanol (2 mL) was added 10 mL of a 4.0 N solution of hydrogen chloride in 1,4-dioxane (40 mmol). The resulting solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to give 0.5 g (99%) of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white solid. LC / MS: 507.1 (M+H) + .

[0354] Step C: {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile To a solution of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in DMF (3 mL) was added 3-fluorobenzoic acid (12.51 mg, 0.0893 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (53.86 mg, 0.122 mmol) and triethylamine (0.0396 mL, 0.284 mmol). The mixture was stirred at room temperature overnight and purified by preparative LC / MS to give 20 mg of {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a white powder. LC / MS found: 629.3 (M+H). + .

[0355] The above white powder (20 mg, 0.03 mmol) was dissolved in 2 mL of trifluoroacetic acid and 2 mL of methylene chloride. The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in methanol (2 mL) and ethylenediamine (0.03 mL, 0.4 mmol). The mixture was stirred at room temperature for 1 h. Purification by HPLC (Method B) gave 4.5 mg of diastereomer 1 (Example 149) and 4.5 mg of diastereomer 2 (Example 150) as white solids. Both diastereomers were mixtures of two enantiomers. LC / MS found: 499.3 (M+H) for both diastereomers. + .

[0356] Example 151 {1-{1-[(4,4-difluorocyclohexyl)carbonyl]-2-methylpiperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] The title compound was prepared as a mixture of four isomers in a manner similar to Examples 149 and 150. LC / MS: 523.2 (M+H) + .

[0357] Example 152 {1-[1-(3-fluorobenzoyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0358] Step A: tert-Butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate [ka] A round-bottom flask was charged with {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.0 g, 2.4 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (0.49 g, 2.4 mmol), titanium tetraisopropoxide (0.72 mL, 2.4 mmol), triethylamine (1.0 mL, 7.3 mmol), and 10 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight and then rotary evaporated to give an oily residue that was used directly in the next step.

[0359] The above residue was dissolved in 25 mL of THF. To the resulting solution was added 1.0 M solution of cyanodiethylaluminum in toluene (8.4 mL, 8.4 mmol). The mixture was stirred at 30° C. for 5 h. The reaction was quenched with 1 mL of water and 20 mL of EtOAc, stirred for 30 min, and filtered through Celite. The Celite was washed with 20 mL of EtOAc. The filtrate was diluted with Na 2 SO 4 and concentrated to dryness to give 1.3 g of the desired product as a colorless oil. MS found: 618 (M+H). + .

[0360] The colorless oil was dissolved in THF (20 mL) and a 3M solution of methylmagnesium bromide in THF (0.45 mL, 1.3 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched by adding 15 mL of water and 25 mL of EtOAc. After stirring for 30 min, the solution was filtered through Celite. The organic layer was separated and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. and evaporated in vacuo. Purification by HPLC gave the desired product, tert-butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate. LC / MS: 292.1 (M+H). + .

[0361] Step B: tert-Butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-4-methylpiperidine-1-carboxylate [ka] A round bottom flask equipped with overhead stirring, a septum and a nitrogen inlet was charged with tert-butyl 4-[3-(cyanomethylene)azetidin-1-yl]-4-methylpiperidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) in portions via syringe over 3 minutes at room temperature. The solution gradually became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated by rotary evaporation to remove approximately 150 mL of acetonitrile. After adding 100 mL of EtOAc and 100 mL of 20% brine, the organic phase was separated. The aqueous layer was extracted with 150 mL of EtOAc. The combined organic phase was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give an orange oil. It was purified by flash chromatography (150 grams silica, 60% EtOAc / hexanes, CH 2 Cl 2 (charged) to give the title compound as a white foam. LC / MS: 607.2 (M+H) + .

[0362] Step C: {1-(4-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-4-methylpiperidine-1-carboxylate (30 mg, 0.05 mmol) in THF (2 mL) was added 4N HCl solution in dioxane (2 mL). After stirring at room temperature for 2 h, the reaction mixture was evaporated in vacuo to give the title compound (31 mg, 99%) which was used in the next reaction. LC-MS found: 507.2 (M+H). + .

[0363] Step D: {1-[1-(3-fluorobenzoyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile To a solution of {1-(4-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in DMF (3 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (45 mg, 0.10 mmol), N,N-diisopropylethylamine (0.041 mL, 0.24 mmol), and 3-fluorobenzoic acid (11 mg, 0.079 mmol). The reaction mixture was stirred at room temperature overnight. Purification by HPLC afforded the desired intermediate as a white powder, which was then treated with TFA (1 mL) and DCM (1 mL) at room temperature for 1 h. After removal of the solvent, the residue was treated with ethylenediamine (1 mL) in methanol (5 mL) for 2 h. Purification using HPLC (Method A) gave the final product {1-[1-(3-fluorobenzoyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile as a TFA salt. LC-MS found: 499.3 (M+H). + . 1H NMR (400 MHz, DMSO-d 6 ): δ 12.36 (s, 1H), 8.81-9.11 (m, 2H), 8.77 (s, 1H), 8.57 (s, 1H), 7.71 (t, 1H), 7.31 (m, 1H), 7.25 (dd, 2H), 7.17 (s, 1H), 4.5-4.85 (m, 4H), 3.82 (m, 2H), 3.56 (s, 4H), 3.21 (m, 1H), 2.60 (m, 1H), 1.55-1.75 (m, 2H), 1.37 (s, 3H).

[0364] Example 153 {1-[1-(cyclohexylcarbonyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] The title compound was prepared in a manner similar to Example 152 and purified by HPLC (Method A) to give the TFA salt. LC / MS: 487.2 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.28(s, 1H), 8.81-9.11(m, 1H), 8.74 (s, 1H), 8.55(s, 1H),7.68 (t, 1H), 7.11 (m, 1H), 4.40-4.85 (m, 4H), 3.80-3.95 (m, 1H), 3.56 (s, 2H), 3.15 (m, 1H), 2.60 (m, 1H), 1.63 (m, 10H), 1.43 (s, 3H), 1.12-1.28 (m, 6H).

[0365] Example 154 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide [ka]

[0366] Step A: 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide [ka] To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (500 mg, 1 mmol) in tetrahydrofuran (30 mL) was added triethylamine (0.29 g, 2.8 mmol) and 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.95 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by CombiFlash using 30-100% EtOAc / Hexanes gave 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a powder. LC / MS: 698.1 (M+H). + .

[0367] Step B: 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide

[0368] 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide (210 mg, 0.3 mmol) was dissolved in a 50 M solution of trifluoroacetic acid in methylene chloride (20 mL). After stirring at room temperature for 1 h, the solvent was removed under reduced pressure. The residue was dissolved in methanol (20 mL) and ethylenediamine (1.0 g, 17 mmol). After stirring at room temperature for 1 hour, the mixture was purified by HPLC (Method B) to give 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a white powder. LC / MS: 568.1 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.10 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.18 (s, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.50 (m, 1H), 7.43 (m, 1H), 7.34 (m, 1H), 7.01(d, J=3.6 Hz, 1H), 3.79 (m, 2H), 3.67 (d, J=8 Hz, 2H), 3.51 (m, 4H), 2.92(m, 2H), 2.38 (m, 1H), 1.62 (m, 2H), 1.09 (m, 2H).

[0369] Example 155 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide [ka]

[0370] Step A: 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide [ka] A 20 mL vial was charged with 4-(trifluoromethyl)pyridin-3-amine (15.6 mg, 0.0963 mmol), THF (2 mL), a 20 M solution of phosgene in toluene (0.50 mL, 1 mmol) and triethylamine (0.017 mL, 0.12 mmol). The mixture was stirred at room temperature for 1 h and concentrated. To the vial was added {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (40 mg, 0.08 mmol), THF (2 mL) and triethylamine (0.025 g, 0.24 mmol). The mixture was stirred for 2 hours and purified by HPLC to give 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide as a white solid. LC / MS: 681.3 (M+H). + .

[0371] Step B: 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide A 20 mL vial was charged with 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL, 19 mmol) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in 3 mL of 20% ethylenediamine in methanol. After stirring at room temperature for 1 hour, HPLC purification (Method B) gave the title compound 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide. LC / MS: 551.2 (M+H). + .

[0372] The following compounds were prepared in a manner similar to that of Example 154 or Example 155.

[0373] [ka]

[0374] [Table 5-1]

[0375] [Table 5-2]

[0376] [Table 5-3]

[0377]

Table 5-4

[0378]

Table 5-5

[0379]

Table 5-6

[0380]

Table 5-7

[0381]

Table 5-8

[0382]

Table 6-1

[0383]

Table 6-2

[0384]

Table 6-3

[0385]

Table 6-4

[0386] [Table 6-5]

[0387] [Table 6-6]

[0388] [Table 6-7]

[0389] Example 209 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile [ka]

[0390] Step A: 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile [ka] To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (200 mg, 0.4 mmol) in THF (10 mL) and triethylamine (0.1643 mL, 1.179 mmol) was added 6-(dimethylamino)-2-fluoro-3-formylbenzonitrile (75.52 mg, 0.3929 mmol). The solution was stirred at room temperature for 30 min, after which sodium triacetoxyborohydride (249.8 mg, 1.179 mmol) was added. The mixture was stirred at room temperature overnight. Aqueous NaHCO 3 After addition of EtOAc, the organic layer was separated and washed with brine and anhydrous Na 2 SO 4 Dry at 40° C. and concentrate. Purification by HPLC gave 150 mg of product, 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile as a white solid. LC / MS: 669.2 (M+H). + .

[0391] Step B: 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile To a reaction vial was added 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was dissolved in 5 mL of a 20% solution of ethylenediamine in methanol. After stirring at room temperature for 1 h, the mixture was purified by HPLC (Method B) to give the title compound. LC / MS: 539.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.10 (s, 1H), 8.79 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 7.59 (d, J=3.6 Hz, 1H), 7.42 (t, J=8.8 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 3.68 (d, J=8.4 Hz, 2H), 3.51 (m, 4H), 3.38 (s, 2H), 3.01 (s, 6H), 2.67 (m, 2H), 2.17 (m, 1H), 1.97 (m, 2H), 1.63 (m, 2H), 1.15 (m, 2H).

[0392] The following compounds were prepared in a manner similar to that of Example 209.

[0393] [ka]

[0394] [Table 7-1]

[0395] [Table 7-2]

[0396] [Table 7-3]

[0397] [Table 7-4]

[0398] [Table 7-5]

[0399] [Table 8-1]

[0400] [Table 8-2]

[0401] [Table 8-3]

[0402] [Table 8-4]

[0403] Example 240 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile [ka] To a solution of {1-(8-azabicyclo[3.2.1]oct-3-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in THF (2 mL) was added 6-(dimethylamino)-2-fluoro-3-formylbenzonitrile (17.2 mg, 0.089 mmol), and triethylamine (0.034 mL, 0.24 mmol). The mixture was stirred at room temperature for 30 min, after which sodium triacetoxyborohydride (51.6 mg, 0.24 mmol) was added. The mixture was stirred at room temperature overnight. The resulting solution was dissolved in aqueous NaHCO 3 and EtOAc. The organic layer was washed with brine and 2 SO 4 Dry at 40° C. and concentrate under reduced pressure. Purification by acidic preparative LCMS afforded 25 mg (41.6%) of the desired intermediate 3-[(3-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile. LC / MS found: 695.3 (M+H). + .

[0404] The above white solid (25 mg, 0.036 mmol) was dissolved in a 50 M solution of trifluoroacetic acid in methylene chloride (2 mL, 100 mmol). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was dissolved in methanol (2 mL, 50 mmol) and ethylenediamine (0.03 mL, 0.4 mmol). After stirring at room temperature for 1 h, the mixture was purified by HPLC (Method B) to give approximately 10 mg (50%) of the title compound as a white solid. LC / MS found: 565.3 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6): δ 12.20 (s, 1H), 8.90 (s, 1H), 8.79 (s, 1H), 8.50 (s, 1H), 7.71 (d, J=3.2 Hz, 1H), 7.67 (t, J=8.8 Hz, 1H), 7.15 (d, J=3.2 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.65 (m, 6H), 3.48 (s, 2H), 3.12 (s, 6H), 3.07 (m, 2H), 2.60 (m, 1H), 2.05 (m, 2H), 1.96 (m, 2H), 1.80 (m, 2H), 1.57 (m, 2H).

[0405] Example 241 {1-[8-(2-chloro-3,6-difluorobenzyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] The title compound was prepared in a manner similar to Example 240. LC / MS: 549.1 (M+H) + .

[0406] Examples 242 and 243 Diastereomers of 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile [ka] To a solution of {1-(2-methylpiperidin-4-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (40 mg, 0.08 mmol) in THF (2 mL) was added 6-(dimethylamino)-2-fluoro-3-formylbenzonitrile (17.16 mg, 0.0893 mmol) and triethylamine (0.034 mL, 0.244 mmol). The solution was stirred at room temperature for 30 min, after which sodium triacetoxyborohydride (51.62 mg, 0.244 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was diluted with aqueous NaHCO 3 and quenched with EtOAc. The organic layer was separated and washed with brine and 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by acidic preparative LCMS to give 25 mg (47%) of intermediate 3-[(4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile as a white solid. LC / MS found: 683.2 (M+H). + .

[0407] The above white powder solid (25 mg, 0.037 mmol) was dissolved in 2 mL of trifluoroacetic acid and 2 mL of methylene chloride. The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The residue was dissolved in methanol (2 mL) and ethylenediamine (0.03 mL, 0.4 mmol). After stirring at room temperature for 1 h, the mixture was purified by HPLC (Method B) to give the two desired products (Example 245 and Example 246) as white solids. Example 245 (7 mg) was the faster diastereomer on HPLC and Example 246 (7 mg) was the slower diastereomer on HPLC. LC / MS Found: 553.2 (M+H) for both isomers. + .

[0408] Examples 244 and 245 Diastereomers of {1-[1-(2-chloro-6-fluorobenzyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] The title compound was prepared in a manner similar to Examples 242 and 243. Example 247 was the faster diastereomer on HPLC and Example 248 was the slower diastereomer on HPLC. LC / MS Found: 519.2 (M+H) for both isomers. + .

[0409] Example 246 {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0410] Step A: {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] A mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (44.4 mg, 0.108 mmol), 1-methyl-1H-pyrazole-5-sulfonyl chloride (19.6 mg, 0.108 mmol) and triethylamine (0.0412 mL, 0.296 mmol) in THF (10.0 mL) was stirred at room temperature for 2 h. Purification on a silica gel column gave the desired product {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. Yield: 58.8%. LC / MS: 637.3 (M+H). + .

[0411] Step B: {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile To a solution of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 h and concentrated in vacuo. The residue was dissolved in 2 mL of 20% ethylenediamine in methanol. After stirring at room temperature for 1 h, the mixture was purified by HPLC (method B) to give 20 mg (64.5%) of {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC / MS: 507.2 (M+H).+1 H NMR (300 MHz, DMSO-d 6 ): δ 12.08 (brs, 1H), 8.72 (d, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.55 (d, 2H), 6.99 (d, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.62 (dd, 2H), 3.45 (dd, 2H), 3.40 (m, 2H), 3.25 (s, 2H), 3.19 (m, 1H), 2.75 (m, 2H), 1.70 (m, 2H), 1.25 (m, 2H).

[0412] The following compounds were prepared in a manner similar to that of Example 246.

[0413] [ka]

[0414] [Table 9-1]

[0415] [Table 9-2]

[0416] [Table 10]

[0417] Example 261 {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0418] Step A: 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine [ka] A 100 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 3.52 mmol), 1-butanol (25.0 mL), [1-(triisopropylsilyl)-1H-pyrrol-3-yl]boronic acid (1.41 g, 5.28 mmol), water (25.0 mL) and potassium carbonate (1.27 g, 8.8 mmol). The solution was degassed four times, flushing with nitrogen each time. Tetrakis(triphenylphosphine)-palladium(0) (0.41 g, 0.35 mmol) was added and the mixture was degassed four times, flushing with nitrogen each time. The reaction was stirred at 100 °C overnight and cooled to room temperature. The mixture was filtered through Celite and the Celite was rinsed with ethyl acetate (42 mL). The filtrates were combined and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated in vacuo at a bath temperature of 30-70° C. to give the title compound 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 83%; LC / MS: 315.2 (M+H). + .

[0419] Step B: tert-Butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate [ka] A 100 mL round bottom flask equipped with overhead stirring, septum and nitrogen inlet was charged with tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (1.8 g, 9.5 mmol), 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.5 mmol) and acetonitrile (60 mL). The resulting solution was heterogeneous. 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.5 mmol) was added in portions via syringe over 3 min at room temperature. The solution gradually became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 h. The solution was concentrated by rotary evaporation to remove acetonitrile. EtOAc (100 mL) and brine (100 mL) were added. The organic phase was separated and the aqueous layer was extracted with 3×30 mL of EtOAc. The combined extracts were washed with anhydrous MgSO 4 The product was dried at 4°C, filtered, and concentrated in vacuo to give an orange oil which was purified by flash chromatography (120 g silica, 30-55% EtOAc / hexanes, CH 2 Cl 2 The desired fractions were combined and concentrated to give a yellow oil which was subjected to high vacuum pump to give 4 g (83%) of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate as a white foam. LC-MS: [M+H] + =509.3.

[0420] Step C: {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride [ka] To a solution of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate (4 g, 7.87 mmol) in 20 mL of THF was added 20 mL of 4N HCl in dioxane. After stirring at room temperature for 1 h, the solvent was removed in vacuo to give 3.9 g (99%) of the desired product {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride, which was used in the next reaction. LC-MS: [M+H] + =409.3.

[0421] Step D: tert-Butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate [ka] To a suspension of {3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (3.0 g, 7.3 mmol) in THF (30 mL) was added tert-butyl 4-oxo-1-piperidinecarboxylate (1.4 g, 7.3 mmol), N,N-diisopropylethylamine (6.4 mL, 37 mmol) and sodium triacetoxyborohydride (3.1 g, 15 mmol). The reaction mixture was stirred at room temperature overnight. Brine (20 mL) and EtOAc (20 mL) were added. The organic phase was separated and the aqueous layer was extracted with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified using a CombiFlash column eluting with 20-50% EtOAc in hexane to give tert-butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate as an oil. Yield: 3.37 g (78%); LC-MS: [M+H] + =592.3.

[0422] Step E: {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride [ka] To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.3 g, 5.6 mmol) in THF (17 mL) was added 4N HCl solution in dioxane (17 mL). The mixture was stirred at room temperature for 2 h and concentrated to give {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used in the next reaction. Yield: 99%; LC-MS: [M+H] + =492.3.

[0423] Step F: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol) and triethylamine (2.0 mL, 14 mmol) in DMF (20.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction was complete. EtOAc (60 mL) and NaHCO 3 Saturated aqueous solution (60 mL) was added to the reaction mixture. After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer was extracted three times with EtOAc. The combined extracts were washed with brine and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and evaporated in vacuo and purified by flash chromatography to give {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile as a white powder.

[0424] The white powder was dissolved in trifluoroacetic acid (5 mL) and methylene chloride (5 mL). The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was dissolved in 10 mL of a 20% ethylenediamine solution in methanol. After stirring at room temperature for 1 hour, HPLC purification (Method B) afforded the title compound {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile. LC / MS: 553.3 (M+H). + . 1 H NMR (400 MHz, CDCl 3 ): δ 9.10 (m, 1H), 8.77 (s, 1H), 8.57 (d, J=4.8 Hz, 1H), 7.57 (s, 1H), 7.53 (t, J=4.7 Hz, 1H), 7.31 (dd, J 1 =3.6 Hz, J 2 =2.2 Hz, 1H), 6.97 (dd, J 1 =2.9 Hz, J 2 =1.5 Hz, 1H), 6.83 (dd, J 1 =3.8 Hz, J 2 =2.1 Hz, 1H), 6.81 (t, J=2.6 Hz, 1H), 4.17 (m, 1H), 3.76 (m, 2H), 3.50 (dd, J 1 =9.1 Hz, J 2=7.4 Hz, 2H), 3.44 (m, 2H), 3.21 (s, 2H), 3.09 (m, 1H), 2.52 (m, 1H), 1.81 (m, 1H), 1.69 (m, 1H), 1.51 (m, 1H), 1.23 (m, 1H).

[0425] The following compounds were prepared in a manner similar to that of Example 261:

[0426] [ka]

[0427] [Table 11-1]

[0428] [Table 11-2]

[0429] [Table 11-3]

[0430] [Table 12-1]

[0431] [Table 12-2]

[0432] Example 283 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide [ka] To a solution of {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (500 mg, 1 mmol) in THF (30 mL) was added triethylamine (0.29 g, 2.8 mmol), and 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (190 mg, 0.95 mmol). The mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. Purification by Combi-Flash using 30-100% EtOAc / Hexanes gave the product as a powder. LC / MS: 697.1 (M+H) + .

[0433] To the above solid was added a 50M solution of trifluoroacetic acid in methylene chloride (20 mL, 1000 mmol). After stirring at room temperature for 1 h, the solvent was removed. The residue was dissolved in methanol (20 mL) and ethylenediamine (1.0 g, 17 mmol). After stirring at room temperature for 1 h, the mixture was purified by HPLC (Method B) to give 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a white powder. LC / MS: 567.2 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 8.60 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H), 7.55 (m, 1H), 7.49 (m, 2H), 7.40 (m, 1H), 7.07 (m, 1H), 6.94 (m, 2H), 3.83 (m, 2H), 3.60 (d, J=8.0 Hz, 2H), 3.54 (d, J=8.0 Hz, 2H), 3.47 (s, 2H), 2.97 (t, J=10.4 Hz, 2H), 2.39 (m, 1H), 1.65 (m, 2H), 1.14 (m, 2H).

[0434] The following compounds were prepared in a manner similar to that of Example 283.

[0435] [ka]

[0436] [Table 13-1]

[0437] [Table 13-2]

[0438] [Table 14-1]

[0439] [Table 14-2]

[0440] Example 294 {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka]

[0441] Step A: 4-Bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] A solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (10.0 g, 0.0508 mol) in DMF (40 mL) was cooled to 0° C. under nitrogen. Sodium hydride (3.0 g, 0.075 mol) was added in portions. The reaction was stirred for 1 h. To this mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (10.8 mL, 0.061 mol). After stirring at 0° C. for 1 h, the reaction was quenched with water and extracted twice with EtOAc. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-25% EtOAc / hexane to give 15.7 g (94.5%) of the desired product as a yellowish oil. LC / MS found: 327.1, 329.1 (M+H). + .

[0442] Step B: 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] A mixture of 4-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (15.70 g, 47.97 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14.04 g, 52.77 mmol), tetrakis(triphenylphosphine)palladium(0) (2.772 g, 2.398 mmol) and sodium carbonate (15.25 g, 143.9 mmol) in 1,4-dioxane (150 mL) and water (75 mL) was stirred at 110° C. for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water and brine, and purified by filtration with NaCl. 2 SO 4The mixture was dried at 40° C. and concentrated. The residue was purified by flash chromatography on silica gel eluting with 10-30% EtOAc / hexanes. The purified intermediate was dissolved in THF (21 mL), water (90 mL) and hydrogen chloride (75 mL, 240 mmol). The resulting suspension was stirred at room temperature for 2 h. The mixture was adjusted to pH 9-10 with 6N NaOH. Hexanes (150 mL) was added. The solid that formed was filtered and washed with water (3×) to give 12.9 g (85%) of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a white solid. LC / MS found: 315.2 (M+H) + .

[0443] Step C: tert-Butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate [ka] To a solution of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (230 mg, 0.73 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (142 mg, 0.73 mmol) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL, 0.73 mmol). After stirring at room temperature for 5 minutes, the mixture became a solution. LC-MS showed the reaction was complete. The acetonitrile was evaporated and ethyl acetate was added. The mixture was washed with 1N HCl, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc / Hexanes) to give 341 mg of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC / MS found: 509.2 (M+H). + .

[0444] Step D: {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile-2[HCl] [ka] To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (341 mg, 0.67 mmol) in THF (5 mL) and methanol (5 mL) was added 4.0 M hydrogen chloride solution in 1,4-dioxane (5 mL, 20 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 347 mg (100%) of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile·2[HCl] as a yellowish solid. LC / MS measured value: 409.2 (M+H) + .

[0445] Step E: {1-piperidin-4-yl-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride [ka] To a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile·2[HCl] (347 mg, 0.70 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (134 mg, 0.70 mmol) and N,N-diisopropylethylamine (0.467 mL, 2.68 mmol) in THF (10.0 mL) was added sodium triacetoxyborohydride (284 mg, 1.34 mmol). The mixture was stirred at room temperature for 2 h and quenched with brine. The resulting solution was extracted with EtOAc (2×). The combined extracts were washed with water, brine and concentrated with Na 2 SO 4After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc / Hexanes. The purified intermediate (MS: [M+H] + =592.3) was dissolved in THF (6 mL). To the solution was added 4.0 M HCl solution in 1,4-dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 260 mg of {1-piperidin-4-yl-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a yellowish solid. LC / MS found: 492.0 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ), δ 9.45 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.35 (d, 1H), 8.46 (s, 1H), 8.33 (d, 1H), 7.81 (d, 1H), 7.50 (d, 1H), 7.10 (m, 1H), 5.69 (s, 2H), 4.93 (d, 2H), 4.54 (d, 2H), 3.75-3.60 (m, 1H), 3.55 (s, 2H), 3.55 (s, 2H), 3.52 (t, 2H), 3.49-3.37 (m, 2H), 2.81 (m, 2H), 2.12 (d, 2H), 1.80 (m, 2H), 0.82 (t, 2H), -0.11 (s, 9H).

[0446] Step F: {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol) and triethylamine (2.0 mL, 14 mmol) in DMF (10.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction to be complete. EtOAc (60 mL) and NaHCO 3 Saturated aqueous solution (60 mL) was added to the reaction mixture. After stirring at room temperature for 10 min, the organic phase was separated and the aqueous layer was extracted three times with EtOAc. The combined extracts were washed with brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and evaporated in vacuo. The residue was purified by flash chromatography to give {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile as a white powder. The powder was dissolved in 10 mL of TFA / DCM (1:1). After stirring at room temperature for 2 hours, the solution was concentrated. The residue was dissolved in 10 mL of 20% ethylenediamine / MeOH solution. After stirring at room temperature for 2 hours, the solution was concentrated. Purification by HPLC (Method B) gave the final compound {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC / MS: 553.3 (M+H). + . 1 H NMR (400 MHz, CDCl 3): δ 9.42 (s, 1H), 8.82 (s, 1H), 8.57 (d, J=4.7 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.06 (d, J=5.8 Hz, 1H), 7.53 (t, J=4.5 Hz, 1H), 7.38 (dd,J 1 =3.6 Hz, J 2 =2.4 Hz, 1H), 7.16 (d, J=5.1 Hz, 1H), 6.69 (dd, J 1 =3.7 Hz, J 2 =2.1 Hz, 1H), 4.21 (m, 1H), 3.76 (m, 2H), 3.63 (dd, J 1 =7.4 Hz, J 2 =5.8 Hz, 2H), 3.46(m, 2H), 3.35 (s, 2H), 3.11(m, 1H), 2.56 (m, 1H), 1.84 (m, 1H), 1.71(m, 1H), 1.49 (m, 1H), 1.40 (m, 1H).

[0447] The following compounds were prepared in a manner similar to that of Example 294.

[0448]

change

[0449]

Table 15-1

[0450]

Table 15-2

[0451]

Table 16

[0452] Example 303 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide [ka] To a solution of {1-piperidin-4-yl-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (40 mg, 0.08 mmol) in THF (8 mL) was added triethylamine (0.025 g, 0.24 mmol), and 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (18 mg, 0.086 mmol). The mixture was stirred at room temperature for 1 h and concentrated. Purification by Combi-Flash chromatography using 30-100% EtOAc / Hexane gave the product as a powder. LC / MS: 697.1 (M+H) + .

[0453] The above solid was dissolved in a 50M solution of trifluoroacetic acid in methylene chloride (2 mL, 100 mmol). After stirring at room temperature for 1 h, the solvent was removed. The residue was dissolved in methanol (2 mL) and ethylenediamine (0.024 g, 0.40 mmol). After stirring at room temperature for 1 h, the solution was purified by HPLC (Method B) to give 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide as a white powder. LC / MS: 567.2 (M+H). 1 H NMR (400 MHz, DMSO-d 6 ): δ 11.70 (s, 1H), 8.68 (s, 1H), 8.26 (m, 1H), 8.23 ​​(s, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.57 (dd, J 1 =7.2 Hz, J2 =3.2 Hz, 1H), 7.50(m, 2H), 7.41(m, 1H), 7.32 (d, J=7.2 Hz, 1H), 6.86 (d, J=3.6 Hz, 1H), 3.86 (m, 2H), 3.73 (d, J=8.0 Hz, 2H), 3.58 (d, J=8.4 Hz, 2H), 3.52 (s, 2H), 2.99 (t, J=10.6 Hz, 2H), 2.43 (m, 1H), 1.68 (m, 2H), 1.12 (m, 2H).

[0454] The following compounds were prepared in a manner similar to that of Example 303:

[0455] [ka]

[0456] [Table 17-1]

[0457] [Table 17-2]

[0458] [Table 18-1]

[0459] [Table 18-2]

[0460] Example 314 (3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile [ka]

[0461] Step A: 5-Fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] To a solution of 5-fluoro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 0.019 mol) in DMF (30.0 mL) cooled to 0° C. under nitrogen was added sodium hydride (1.13 g, 0.0282 mol) in portions. The reaction was stirred for 1 h. To the mixture was slowly added [β-(trimethylsilyl)ethoxy]methyl chloride (4.05 mL, 0.0229 mol). The reaction was stirred at 0° C. for 1 h and quenched with water. The resulting solution was extracted with EtOAc (2×). The combined extracts were washed with water, brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-25% EtOAc / Hexanes to give 7.1 g (95%) of 5-fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a yellowish oil. LC / MS found: 393.0 (M+H). + .

[0462] Step B: 4-(1H-pyrazol-4-yl)-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] A mixture of 5-fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (7.20 g, 18.4 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.36 g, 20.1 mmol), tetrakis(triphenylphosphine)palladium(0) (1.06 g, 0.918 mmol) and sodium carbonate (5.84 g, 55.1 mmol) in 1,4-dioxane (50 mL) and water (25 mL) was stirred at 110° C. under nitrogen for 1 h. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water and brine, and purified by HPLC. 2 SO 4 The mixture was dried over 1000 ml and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 10-30% EtOAc / hexanes. The purified intermediate was added to a mixture of THF (8.0 mL), water (30 mL) and hydrogen chloride (30 mL, 100 mmol). The resulting suspension was stirred at room temperature for 2 h. The mixture was adjusted to pH 9-10 with 6N NaOH and extracted with EtOAc (2x). The combined extracts were washed with water, brine and anhydrous Na 2 SO 4 The mixture was dried at 40° C. After filtration and concentration, the residue was taken up in a mixture of hexane and EtOAc (9 / 1, 50 mL). The solid formed was filtered to give 4.2 g (69%) of 4-(1H-pyrazol-4-yl)-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a light green solid. LC / MS found: 333.2 (M+H). + .

[0463] Step C: {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile-2[HCl] [ka] To a solution of 5-fluoro-4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (2.00 g, 6.02 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.168 g, 6.02 mmol) in acetonitrile (20 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8996 mL, 6.02 mmol). The mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel chromatography (0-80% EtOAc / Hexanes) to give 3.05 g (96.3%) of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC / MS found: 527.3 (M+H). + .

[0464] To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (3.05 g, 5.79 mmol) in THF (40 mL) was added 4.0 M hydrogen chloride solution in 1,4-dioxane (70 mL, 280 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 3.08 g (99.2%) of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile·2[HCl] as a yellowish solid. LC / MS measured value: 427.2 (M+H) + .

[0465] Step D: {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile-3[HCl] [ka] To a mixture of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile·2[HCl] (3.10 g, 5.78 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.152 g, 5.784 mmol) and N,N-diisopropylethylamine (3.022 mL, 17.35 mmol) in THF (100.0 mL) was added sodium triacetoxyborohydride (2.452 g, 11.57 mmol). The mixture was stirred at room temperature for 2 h and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and concentrated with Na 2 SO 4 After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc / Hexanes. The purified intermediate ([M+H] + =610.3) was dissolved in THF (50 mL). To the solution at 10° C. was added 4.0 M solution of hydrogen chloride in 1,4-dioxane (50.0 mL, 200 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 3.57 g of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] as an off-white solid. LC / MS found: 510.3 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6), δ 9.41 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.35 (d, 1H), 8.32 (s, 1H), 7.85 (d, 1H), 7.00 (d, 1H), 5.63 (s, 2H), 4.93 (d, 2H), 4.55 (d, 2H), 3.78-3.60 (m, 1H), 3.55 (s, 2H), 3.51 (t, 2H), 3.47-3.37 (m, 2H), 2.79 (m, 2H), 2.11 (m, 2H), 1.80 (m, 2H), 0.81 (t, 2H), -0.12 (s, 9H).

[0466] Step E: (3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile

[0467] A solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (70.0 mg, 0.335 mmol), {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] (207 mg, 0.335 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (148 mg, 0.335 mmol) and triethylamine (0.234 mL, 1.68 mmol) in methylene chloride (2 mL) was stirred at room temperature for 1 h. To the mixture was added trifluoroacetic acid (2 mL, 20 mmol). The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was dissolved in methanol (2 mL) and ethylenediamine (0.5 mL, 7 mmol). After stirring at room temperature for 2 h, the mixture was purified by HPLC (Method B) to give 11.2 mg of the title compound as a white solid. LC / MS found: 571.3 (M+H). + . 1 H NMR (400 MHz, CDCl3 ): δ 11.85 (brs, 1H), 8.65 (d, J = 4.4 Hz, 1H), 8.59 (s, 1H), 8.23 ​​(d, J = 3.2 Hz, 1H), 8.20 (s, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 6.85 (s, 1H), 4.04 (m,1 H), 3.72 (m, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.53 (m, 2H), 3.40 (m, 1H), 3.25 (m, 1H), 3.06 (t, J = 9.2 Hz, 1H), 2.54 (m, 1H), 1.75 (m, 1H), 1.62 (m, 1H), 1.26 (m, 1H), 1,21 (m, 1H).

[0468] The following compounds were prepared according to the method described in Example 314.

[0469] [ka]

[0470] [Table 19-1]

[0471] [Table 19-2]

[0472] [Table 20-1]

[0473] [Table 20-2]

[0474] Example 328 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide [ka] To a mixture of {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] (70.0 mg, 0.113 mmol) and triethylamine (41.3 uL, 0.296 mmol) in THF (4 mL) was added 4-fluoro-1-isocyanato-2-(trifluoromethyl)benzene (23.1 mg, 0.113 mmol). The mixture was stirred at room temperature for 1 h and concentrated. The residue was diluted with acetonitrile (2 mL) and water (2 mL). The mixture was subjected to HPLC purification to give 34 mg (49%) of the desired intermediate. LC-MS found: 715.3 (M+H) + .

[0475] The purified intermediate was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL, 10 mmol). The solution was stirred at room temperature for 1 h and concentrated. The residue was treated with methanol (1 mL) and ethylenediamine (0.2 mL, 3 mmol). The solution was stirred at room temperature for 1 h and purified by HPLC (Method B) to give the title compound. LC-MS found: 585.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6): δ 11.86 (brs, 1H), 8.60 (s, 1H), 8.24 (d, J = 3.30 Hz, 1H), 8.21 (d, J = 2.40 Hz, 1H), 7.61 (t, J = 3.30 Hz, 1H), 7.49 (m, 3H), 6.86 (m, 1H), 3.83 (m, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.54 (s, 2H), 2.97 (m, 2H), 2.44 (m, 1H), 1.66 (m, 2H), 1.13 (m, 2H).

[0476] The following compounds were prepared according to the method described in Example 328.

[0477] [ka]

[0478] [Table 21]

[0479] [Table 22]

[0480] Example 332 4-[1-(3-(cyanomethyl)-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile [ka]

[0481] Step A: 4-Chloro-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka] To a suspension of sodium hydride (1.8 g, 45.1 mmol) in N,N-dimethylacetamide (10 mL) at -5 °C (ice / salt bath) was slowly added a dark solution of 4-chloro-5-cyano-pyrrolo[2,3-d]pyridine (6.0 g, 39 mmol) in N,N-dimethylacetamide (10 mL). The flask and addition funnel were rinsed with N,N-dimethylacetamide (5 mL). A large amount of gas was evolved immediately. The mixture changed color to a slightly cloudy orange mixture. The mixture was stirred at 0 °C for 1 h, giving a light brown, cloudy mixture. To the mixture was slowly added [β-(trimethylsilyl)ethoxy]methyl chloride (7.6 g, 45 mmol). The reaction was stirred at 0 °C for 1 h and H 2 The reaction was quenched by adding 12 mL of O. 2 O (120 mL) was added, followed by MTBE (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted once more with MTBE (120 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 10 g (95%) of crude product 4-chloro-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a dark oil. LC / MS: 308.1 (M+H). + The crude product was used in the next reaction without further purification.

[0482] Step B: 4-(1H-pyrazol-4-yl)-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine [ka]

[0483] A 250 mL round-bottom flask was charged with 4-chloro-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-d]pyridine (5.00 g, 17.6 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (7.06 g, 26.4 mmol), water (25.0 mL) and potassium carbonate (6.17 g, 44.08 mmol). The solution was degassed four times, filling with nitrogen each time, and tetrakis(triphenylphosphine)palladium(0) (2.071 g, 1.773 mmol) was added. The solution was degassed four times, filling with nitrogen each time, and stirred at 100 °C for 3 h. After cooling to room temperature, the mixture was filtered through Celite and the Celite was rinsed with ethyl acetate (42 mL). The filtrates were combined and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and evaporation under reduced pressure gave an oily residue which was purified using a Combi-Flash column to give 3.8 g (53%) of the desired intermediate. LC / MS: 412.2 (M+H). + .

[0484] 3.8 g of the above intermediate in 20 mL of 2N HCl aqueous solution and 20 mL of CHCl 3 The mixture was stirred at room temperature over the weekend. The organic layer was separated and the aqueous phase was extracted with EtOAc (3x50 mL). The combined extracts were washed with anhydrous Na 2 SO 4 Drying at 40° C., filtration and evaporation in vacuo gave 2.9 g (97%) of 4-(1H-pyrazol-4-yl)-5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine. LC / MS: 340.2 (M+H). + .

[0485] Step C: 4-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·2[HCl] [ka] To a solution of 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (2.26 g, 6.66 mmol) and tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (1.293 g, 6.66 mmol) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.996 mL, 6.66 mmol). The mixture was stirred at room temperature overnight and concentrated. Purification by silica gel chromatography (0-80% EtOAc / Hexanes) afforded 2.20 g (62%) of the intermediate tert-butyl 3-(cyanomethyl)-3-[4-(5-cyano-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a colorless oil. LC-MS found: 534.3 (M+H). + .

[0486] To a solution of the above oily intermediate (2.20 g, 4.12 mmol) in THF (40 mL) was added 4.0 M hydrogen chloride solution in 1,4-dioxane (70 mL, 280 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 2.23 g (99.6%) of the desired product as a yellowish solid. LC / MS: 434.2 (M+H). + .

[0487] Step D: 4-{1-[3-(cyanomethyl)-1-piperidin-4-ylazetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·3[HCl] [ka] To a mixture of 4-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·2[HCl] (2.0 g, 3.68 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (0.734 g, 3.68 mmol) and N,N-diisopropylethylamine (3.21 mL, 18.4 mmol) in THF (70.0 mL) was added sodium triacetoxyborohydride (1.56 g, 7.37 mmol). The mixture was stirred at room temperature for 2 h and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and concentrated with Na 2 SO 4 The mixture was dried at 40° C. After filtration and evaporation, the residue was purified by silica gel flash chromatography eluting with 50-100% EtOAc / Hexanes. The purified intermediate was dissolved in THF (30 mL). To the solution at 10° C. was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (30.0 mL, 1.20 mmol). The mixture was stirred at room temperature for 2 h and concentrated to give 2.01 g (87.2%) of the desired product as an off-white solid. LC / MS found: 517.3 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 9.29 (s, 1H), 8.88 (s, 1H), 8.74 (s, 1H), 8.37 (s, 1H), 7.97 (d, 1H), 6.97 (s, 1H), 5.69 (s, 2H), 5.94 (m, 2H), 4.55 (m, 2H), 3.73-3.56 (m, 2H), 3.63 (t, 2H), 3.52 (m, 2H), 3.47-3.35 (m, 3H), 2.81 (m, 2H), 2.10 (m, 2H), 1.75 (m, 2H), 0.82 (t, 2H), -0.11 (s, 9H).

[0488] Step E: 4-[1-(3-(cyanomethyl)-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile A mixture of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (70.0 mg, 0.335 mmol), 4-{1-[3-(cyanomethyl)-1-piperidin-4-ylazetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·3[HCl] (210 mg, 0.335 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (149 mg, 0.335 mmol) and triethylamine (0.234 mL, 1.68 mmol) in DMF (2.0 mL) was stirred at room temperature for 2 h. The mixture was diluted with water and then extracted with EtOAc (2×). The combined extracts were washed with saturated NaHCO 3 , water, brine, Na 2 SO 4 After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 0-10% MeOH / EtOAc to give 143 mg of intermediate. LC-MS found: 708.1 (M+H). + .

[0489] The above purified intermediate (143 mg) was dissolved in methylene chloride (10 mL) and trifluoroacetic acid (10 mL, 100 mmol). The resulting solution was stirred at room temperature for 1 h and concentrated. The residue was treated with methanol (10 mL) and ethylenediamine (5 mL, 70 mmol). The solution was stirred at room temperature for 1 h. Purification by silica gel flash chromatography eluting with 5-15% MeOH / EtOAc afforded 63 mg (55%) of the title compound as an off-white solid. LC / MS found: 578.2 (M+1). + . 1 H NMR (400 MHz, CDCl 3): δ 12.34 (brs, 1H), 8.66 (s, 1H), 8.60 (d, J = 4.80 Hz, 1H), 8.56 (s, 1H), 8.19 (s, 1H), 7.84 (t, J = 4.80 Hz, 1H), 7.68 (d, J = 3.60 Hz, 1H), 6.79 (d, J = 3.60 Hz, 1H), 4.01 (m, 1H), 3.68 (m, 2H), 3.54 (m, 2H), 3.49 (m, 2H), 3.36 (m, 1H), 3.22 (m, 1H), 3.03 (m, 1H), 2.50 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H), 1.16 (m, 2H).

[0490] The following compounds were prepared according to the method described in Example 332.

[0491] [ka]

[0492] [Table 23-1]

[0493] [Table 23-2]

[0494] [Table 24]

[0495] Example 342 {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] The title compound was obtained by reacting {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride with 5-chloro-2-5-chloro-2-trifluoromethylisonicotinic acid according to the method described in Example 1, followed by HPLC purification (Method B). LC / MS: 570.2 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.08 (brs, 1H),8.92 (, 1H), 8.80 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.11 (d, J = 14.09 Hz, 1H), 7.59 (d, J = 3.30 Hz, 1H), 7.04 (d, J = 3.30 Hz, 1H), 4.07 (m, 1H), 3.73 (m, 2H), 3.56 (m, 2H), 3.52 (s, 2H), 3.26 (m, 2H), 2.98 (m, 1H), 2.53 (m, 1H), 1.69 (m, 2H), 1.25 (m, 2H).

[0496] Example 343 {1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] Following the method described in Example 1, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 5-fluoro-2-5-chloro-2-trifluoromethylisonicotinic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 554.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.08 (brs, 1H), 8.84 (s, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 8.36 (s, 1H), 8.09 (d, J = 4.80 Hz, 1H), 7.55 (d, J = 3.60 Hz, 1H), 7.00 (d, J = 3.60 Hz, 1H), 4.02 (m, 1H), 3.69 (m, 2H), 3.52 (m, 2H), 3.49 (s, 2H), 3.34 (m, 1H), 3.20 (m, 1H), 3.00 (m, 1H), 2.49 (m, 1H), 1.70 (m, 1H), 1.57 (m, 1H), 1.22 (m, 2H).

[0497] Example 344 [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the method described in Example 1, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 4-trifluoromethylthiazol-2-yl carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 542.2 (M+H) + .

[0498] Example 345 [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 261, {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 2-trifluoromethylpyrimidine-4-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 536.2 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.93 (brs, 1H), 9.18 (d, 1H), 8.59 (s, 1H), 7.95 (d, 1H), 7.79 (s, 1H), 7.48 (d, 1H), 7.05 (d, 1H), 6.91 (d, 2H), 4.00 (m, 1H), 3.55 (d, 2H), 3.40 (d, 2H), 3.35 (m, 1H), 3.30 (s 2H), 3.23 (m, 2H), 3.11 (m, 1H), 2.58 (m, 1H), 1.80-1.52 (m, 2H), 1.22 (m, 2H).

[0499] Example 346. [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 261, {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 4-trifluoromethylthiazol-2-yl carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 541.2 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.92 (brs, 1H), 8.75 (s, 1H), 8.57 (s, 1H), 7.78 (s, 1H), 7.43 (d, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 4.45 (m, 1H), 3.95 (m, 1H), 3.70 (m, 1H), 3.55 (d, 2H), 3.45 (d, 2H), 3.37 (s, 2H), 3.20 (m, 2H), 1.80-1.60 (m, 2H), 1.25 (m, 2H).

[0500] Example 347 [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 261, {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 5-trifluoromethylpyrazin-2-yl carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 536.1 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.99 (brs, 1H), 9.23 (s, 1H), 9.07 (s, 1H), 8.62 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.11 (s, 1H), 6.98 (d, 2H), 4.12 (m 1H), 3.65 (d, 2H), 3.55 (d, 2H), 3.41 (m, 1H), 3.31 (s, 2H), 3.15 (m, 2H), 2.60 (m, 1H), 1.90-1.60 (m, 2H), 1.30 (m, 2H).

[0501] Example 348 {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile [ka] Following the procedure described in Example 246, {1-piperidin-4-yl-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with methanesulfonyl chloride, followed by HPLC purification (Method B) to give the title compound. LC / MS: 440.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6): δ 11.91 (brs, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.01 (d, 1H), 6.88 (d, 2H), 3.52 (d, 2H), 3.47 (d, 2H), 3.30 (m, 2H), 3.27 (s, 2H), 2.80 (m, 2H), 2.75 (s, 3H), 2.27 (m, 1H), 1.65 (m, 2H), 1.23 (m, 2H).

[0502] Example 349 [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the method described in Example 294, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 5-trifluoromethylpyrazine-2-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 536.2 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.07 (brs, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 8.68 (s, 2H), 8.41 (s, 2H), 7.61 (d, 1H), 7.06 (d, 1H), 4.55 (m, 1H), 4.05 (m, 1H), 3.75 (dd, 2H), 3.59 (dd, 2H), 3.55 (m, 2H), 3.32 (s, 2H), 3.30 (m, 1H), 1.80 (m, 2H), 1.30 (m, 2H).

[0503] Example 350 [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 294, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with 4-trifluoromethylthiazole-2-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 541.2 (M+H) + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.01 (brs, 1H), 9.09 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 8.48 (d, 1H), 7.82 (dd, 1H), 7.62 (d, 1H), 7.16 (d, 1H), 4.85 (m, 1H), 4.35 (m, 1H), 4.05 (d, 2H), 4.03 (m, 1H), 3.90 (d, 1H), 3.80 (m, 1H), 3.62 (s, 2H), 3.58 (m, 1H), 2.90 (m, 1H), 2.08 (m, 2H), 1.62 (m, 2H).

[0504] Example 351 {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile [ka] Following the procedure described in Example 246, {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride was reacted with methanesulfonyl chloride, followed by HPLC purification (Method B) to give the title compound. LC / MS: 440.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.91 (brs, 1H), 8.55 (s, 1H), 7.76 (s, 1H), 7.43 (d, 1H), 7.01 (d, 1H), 6.88 (d, 2H), 3.52 (d, 2H), 3.47 (d, 2H), 3.30 (m, 2H), 3.27 (s, 2H), 2.80 (m, 2H), 2.75 (s, 3H), 2.27 (m, 1H), 1.65 (m, 2H), 1.23 (m, 2H).

[0505] Example 352 [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 314, {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] was reacted with 6-trifluoromethylpyrazine-2-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 554.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6): δ 12.11 (brs, 1H), 9.23 (s, 1H), 9.12 (s, 1H), 8.56 (s, 1H), 8.19 (d, 1H), 8.15 (d, 1H), 7.58 (d, 1H), 6.82 (d, 1H), 4.03 (m, 1H), 3.68 (d, 2H), 3.55 (d, 2H), 3.45 (m, 1H), 3.26 (s 2H), 3.24 (m, 1H), 3.11 (m, 1H), 2.55 (m, 1H), 1.80-1.57 (m, 2H), 1.25 (m, 2H).

[0506] Example 353 [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 314, {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] was reacted with 2-trifluoromethylpyrimidine-4-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 554.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6): δ 11.83 (brs, 1H), 9.15 (d, 1H), 8.56 (s, 1H), 8.21 (d, 1H), 8.18 (d, 1H), 7.94 (d, 1H), 7.58 (d, 1H), 6.82 (d, 1H), 4.00 (m, 1H), 3.70 (d, 2H), 3.55 (d, 2H), 3.45 (m, 1H), 3.40 (s, 2H), 3.15 (m, 1H), 3.08 (m, 1H), 2.52 (m, 1H), 1.80 -1.52 (m, 2H), 1.23 (m, 2H).

[0507] Example 354 [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile [ka] Following the procedure described in Example 314, {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] was reacted with 5-trifluoromethylpyrazine-2-carboxylic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 554.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6): δ 11.82 (brs, 1H), 9.16 (s, 1H), 8.99 (s, 1H), 8.59 (s, 1H), 8.20 (d, 2H), 7.59 (s, 1H), 6.82 (s, 1H), 4.05 (m, 1H), 3.70 (d, 2H), 3.55 (d, 2H), 3.45 (m, 1H), 3.35 (s, 2H), 3.15 (m, 2H), 2.59 (m, 1H), 1.80-1.55 (m, 2H), 1.22 (m, 2H).

[0508] Example 355 {3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile [ka] Following the procedure described in Example 246, {3-[4-(5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-piperidin-4-ylazetidin-3-yl}acetonitrile·3[HCl] was reacted with methanesulfonyl chloride, followed by HPLC purification (Method B) to give the title compound. LC / MS: 458.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 11.87 (brs, 1H), 8.59 (s, 1H), 8.23 ​​(d, J = 3.60 Hz, 1H), 8.20 (d, J = 2.10 Hz, 1H), 7.61 (d, J = 3.60 Hz, 1H), 6.86 (d, J = 3.30 Hz, 1H), 3.71 (m, 2H), 3.57 (m, 2H), 3.54 (s, 2H), 3.36 (m, 2H), 2.86 (m, 2H), 2.83 (s, 3H), 2.37 (m, 1H), 1.73 (m, 2H), 1.30 (m, 2H).

[0509] Example 356 4-[1-(3-(cyanomethyl)-1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile [ka] Following the procedure described in Example 332, 4-{1-[3-(cyanomethyl)-1-piperidin-4-ylazetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·3[HCl] was reacted with 5-fluoro-2-trifluoromethylisonicotinic acid, followed by HPLC purification (Method B) to give the title compound. LC / MS: 578.2 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6 ) : δ 8.84 (s, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 4.80 Hz, 1H), 7.68 (d, J = 3.60 Hz, 1H), 6.79 (d, J = 3.60 Hz, 1H), 3.99 (m, 1H), 3.69 (m, 2H), 3.54 (m, 2H), 3.49 (s, 2H), 3.42 (m, 2H), 3.00 (m, 1H), 2.51 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H), 1.20 (m, 2H).

[0510] Example 357 4-(1-{3-(cyanomethyl)-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile [ka] Following the procedure described in Example 246, 4-{1-[3-(cyanomethyl)-1-piperidin-4-ylazetidin-3-yl]-1H-pyrazol-4-yl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile·3[HCl] was reacted with methanesulfonyl chloride, followed by HPLC purification (Method B) to give the title compound. LC / MS: 465.1 (M+H). + . 1 H NMR (300 MHz, DMSO-d 6 ): δ 12.28 (brs, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.20 (s, 1H), 7.68 (d, J = 3.60 Hz, 1H), 6.79 (d, J = 3.90 Hz, 1H), 3.67 (m, 2H), 3.53 (m, 2H), 3.50 (s, 2H), 3.31 (m, 2H), 2.81 (m, 2H), 2.78 (s, 3H), 2.35 (m, 1H), 1.68 (m, 2H), 1.26 (m, 2H).

[0511] Example 358 {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate [ka] Screening: 1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl)acetonitrile (Example 1) free base is an amorphous material. Salt screening studies were conducted using pharma- ceutically acceptable acids to form crystalline Example 1 salts. It was found that adipic acid was used to obtain crystalline Example 1 adipate salts. The first obtained solid (Form I) Example 1 adipate salt with a melting point of 178° C. was selected for optimization. This form is crystalline as confirmed by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The stoichiometry of the salts is: 1 It was determined to be 1:1 (free base:adipic acid) by 1 H NMR spectroscopy and elemental analysis.

[0512] A polymorph screening study was carried ...

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, X is N or CR ２ and Y is N or CR ３ and Z is cyano; L is C(=O)NH, C(=O), S(=O) ２ , C.H. ２ , C(=O)CH ２ ,or 【Chemistry 2】 and A is methyl, ethyl, isopropyl, phenyl, a naphthalene ring, a pyridine ring, a pyrimidine ring, a thiophene ring, a pyrazine ring, an oxazole ring, an isoxazole ring, an imidazole ring, a thiazole ring, a furan ring, a pyrazole ring, a quinoline ring, a benzothiophene ring, a benzothiazole ring, a benzimidazole ring, a benzofuran ring, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, an indene ring, a tetrahydronaphthalene ring, a dihydro-1,4-benzodioxine ring, or a piperidine ring; each of which is unsubstituted or, where permitted by valences, is selected from 1, 2, 3, 4, 5, or 6 R ５ is substituted with a group; Each R １ is independent, C １－４ is alkyl; or Two R's １ the groups together form a two-carbon bridge; R ２ is H, halo, or cyano; R ３ is H; Each R ５ are independently chloro, fluoro, bromo, cyano, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, trifluoromethoxy, difluoromethoxy, phenoxy, dimethylamino, t-butylcarbonylamino, methoxycarbonyl, methylthio, phenyl, a pyridine ring, a thiazole ring, a quinoline ring, an isoquinoline ring, an imidazo[1,2-a]pyrimidine ring, a benzoxazole ring, or an oxadiazole ring; wherein said phenyl, pyridine ring, thiazole ring, quinoline ring, isoquinoline ring, imidazo[1,2-a]pyrimidine ring, benzoxazole ring, and oxadiazole ring are each unsubstituted or, where permitted by valences, are each independently selected from 1, 2, 3, 4, or 5 R ６ each substituted with a group; Each R ６ are independently halo, cyano, or C １－６ is alkyl; and n is 0, 1, or 2. or a pharma- ceutical acceptable salt thereof, wherein the cancer is prostate cancer.

2. The pharmaceutical composition of claim 1 , wherein X is N.

3. X is CR ２ The pharmaceutical composition of claim 1 ,

4. 2. The pharmaceutical composition of claim 1, wherein X is C(H), C(F), or C(CN).

5. 2. The pharmaceutical composition of claim 1, wherein X is CH.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein Y is nitrogen.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein Y is CH.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein n is 0.

9. R １ C １－４ The pharmaceutical composition according to any one of claims 1 to 7, wherein the aryl group is alkyl.

10. R １ The pharmaceutical composition according to any one of claims 1 to 7 and 9, wherein is methyl.

11. Two R's １ The pharmaceutical composition according to any one of claims 1 to 7, wherein the group forms a two-carbon bridge.

12. A is a phenyl or pyridine ring, each of which is unsubstituted or has 1, 2, 3, or 4 independently selected R ５ The pharmaceutical composition according to any one of claims 1 to 11, which is substituted with a group.

13. A is pyridin-4-yl, which is unsubstituted or has 1, 2, 3, or 4 independently selected R ５ The pharmaceutical composition according to any one of claims 1 to 12, which is substituted with a group.

14. Each R ５ The pharmaceutical composition of any one of claims 1 to 13, wherein is independently fluoro or trifluoromethyl.

15. The compound represented by formula (I) is represented by formula (II): 【Chemistry 3】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of aryl, aryl, phenyl ...

16. The compound represented by formula (I) may be represented by formula (III): 【Chemistry 4】 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of aryl, aryl, phenyl ...

17. X is N or CH; Y is N; L is C(=O) or C(=O)NH; A is phenyl or pyridin-4-yl, each of which is unsubstituted or contains one or two independently selected R ５ is substituted with a group; Each R ５ is independently fluoro or trifluoromethyl; and n is 0; The pharmaceutical composition of claim 1.

18. The compound is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(3,4,5-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclohexylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-benzoylpiperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; {1-{1-[(6-chloropyridin-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(pyrazin-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(3-thienylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(1,3-oxazol-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[2-methyl-5-(trifluoromethyl)-1,3-oxazol-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile; {1-[1-(3-chlorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-bromobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-(trifluoromethoxy)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-{1-[3-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dichlorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-fluoro-3-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-5-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-chloro-5-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-bromo-5-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2,5-dichloro-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,5-trifluoro-3-methoxybenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dimethoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-chloro-4-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,4-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-5-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-6-methoxyisonicotinoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(5-fluoro-2-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-6-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-fluoro-2-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,4-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,5-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-6-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,4-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,5-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,4,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-dibromo-4-methoxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-{1-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[4-chloro-6-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,4,5-tetrafluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-methoxybenzonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(2,3,5,6-tetrafluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-[1-(4-fluoro-3-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-(dimethylamino)benzonitrile; {1-{1-[4-(dimethylamino)-2,3,5,6-tetrafluorobenzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluoroisonicotinoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-4-(methylthio)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-chloro-3-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-methylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,5-dimethyl-3-furoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-[1-(2-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(4-fluorobenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-thienylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-methoxy-5-(trifluoromethyl)-2-thienylcarbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-hydroxy-5-(trifluoromethyl)-2-thienylcarbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-methoxy-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-methyl-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-chloro-4-methoxy-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-bromo-3-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-chloro-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(5-methyl-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methoxy-2-thienyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3,5-difluorobenzonitrile; {1-[1-(3-chloro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(1-naphthoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(quinolin-3-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(quinolin-6-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-[1-(1-benzothien-2-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-6-fluoro-1-benzothien-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-chloro-4-fluoro-1-benzothien-2-yl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[7-(trifluoromethyl)-1-benzothien-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(1-benzothien-3-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-[1-(1,2,3,4-tetrahydronaphthalen-2-ylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)cyclohexyl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopentylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cycloheptylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3-methoxycyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4-phenylcyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[4-(4-chlorophenyl)cyclohexyl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 6-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]piperidin-1-yl}nicotinonitrile; {1-(1-{[1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]piperidin-1-yl}-6-methylnicotinonitrile; {1-[1-(phenylacetyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-phenylcyclopropyl)carbonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2,6-dichlorophenyl)acetyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(mesitylacetyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(biphenyl-4-ylcarbonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-6-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-pyridin-4-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -fluorobiphenyl-4-carbonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ , 3-difluorobiphenyl-4-carbonitrile; {1-[1-(2-fluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-fluoro-3-(1,3-thiazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-4-(1,3-thiazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-pyridin-3-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -fluorobiphenyl-2-carbonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ -fluorobiphenyl-3-carbonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]biphenyl-4-carbonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{1-[(2,3 ’ , 4 ’ -trifluorobiphenyl-4-yl)carbonyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; 4 ’ -[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2 ’ , 5-difluorobiphenyl-3-carbonitrile; {1-[1-(3-fluoro-4-quinolin-5-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-5-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-8-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-8-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-isoquinolin-7-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-quinolin-7-ylbenzoyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-(1,3-benzoxazol-2-yl)benzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-(1,3-benzoxazol-2-yl)-3-fluorobenzoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-5-fluorobenzonitrile; {1-[8-(3,4-difluorobenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-2-fluorobenzonitrile; {1-[8-(4-chloro-3-fluorobenzoyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{8-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(8-{[6-(trifluoromethyl)pyridin-3-yl]carbonyl}-8-azabicyclo[3.2.1]oct-3-yl)azetidin-3-yl]acetonitrile; (3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-{8-[2-(trifluoromethyl)isonicotinoyl]-8-azabicyclo[3.2.1]oct-3-yl}azetidin-3-yl)acetonitrile; {1-[8-(cyclopentylcarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[8-(cyclohexylcarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{8-[(4,4-difluorocyclohexyl)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]-2-methylpiperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluorobenzoyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclohexylcarbonyl)-4-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(trifluoromethoxy)phenyl]piperidine-1-carboxamide; N-(4-bromo-3-thienyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-dichlorophenyl)piperidine-1-carboxamide; N-(2-chloro-6-methylphenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-(difluoromethoxy)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)phenyl]piperidine-1-carboxamide; N-(5-chloro-2-methylphenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,3,4-trifluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,3,5-trifluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,5-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,5-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,4-difluorophenyl)piperidine-1-carboxamide; N-(3-chloro-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(4-chloro-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-3-thienylpiperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3-methoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethoxy)phenyl]piperidine-1-carboxamide; N-(3-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(4-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methylphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,5-dimethoxyphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4-fluoro-2-methylphenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[6-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,6-dimethylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-1,3-thiazol-2-ylpiperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4-methyl-1,3-thiazol-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(4,5-dimethyl-1,3-thiazol-2-yl)piperidine-1-carboxamide; N-1,3-benzothiazol-2-yl-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1-methyl-1H-benzimidazol-2-yl)piperidine-1-carboxamide; N-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1-ethyl-1H-pyrazol-5-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(1,3-dimethyl-1H-pyrazol-5-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(6-fluoro-2-methylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluoro-6-methylpyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3-fluoropyridin-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(3,5-difluoropyridin-2-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; Methyl 2-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}benzoate; Methyl 2-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}-5-fluorobenzoate; Methyl 4-{[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]amino}-3-fluorobenzoate; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-[1-(3,5-dichlorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-chloro-5-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-6-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-chloroquinolin-3-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-4-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,4-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-6-methoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-dichlorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-fluorobenzonitrile; {1-{1-[4-(1,2,3-oxadiazol-4-yl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]benzonitrile; 6-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-methoxynicotinonitrile; {1-{1-[(2,6-dibromopyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-bromopyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-6-fluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-chloro-2,6-difluorobenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]-2-fluorobenzonitrile; {1-{1-[(5-methyl-3-phenylisoxazol-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-(1-{[3-fluoro-2-(trifluoromethyl)pyridin-4-yl]methyl}piperidin-4-yl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(1-benzofuran-2-ylmethyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-phenoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; N-{4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)methyl]pyridin-2-yl}-2,2-dimethylpropanamide; {1-{1-[3-chloro-2-fluoro-6-(trifluoromethyl)benzyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3,5-dichloropyridin-4-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(2-chloro-6-methoxyquinolin-3-yl)methyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-chloro-3,4-dimethoxybenzyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(3-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-8-azabicyclo[3.2.1]oct-8-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-[8-(2-chloro-3,6-difluorobenzyl)-8-azabicyclo[3.2.1]oct-3-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-methylpiperidin-1-yl)methyl]-6-(dimethylamino)-2-fluorobenzonitrile; {1-[1-(2-chloro-6-fluorobenzyl)-2-methylpiperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-methyl-1H-pyrazol-5-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]benzonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)sulfonyl]-2-(dimethylamino)benzonitrile; {1-{1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclohexylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopentylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(ethylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(cyclopropylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(isopropylsulfonyl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; 3-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]benzonitrile; 3-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile; 4-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; 4-[(4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3,5-difluorobenzonitrile; {1-{1-[5-fluoro-2-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; (3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-{1-[3-(trifluoromethyl)benzoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; {1-{1-[2-fluoro-5-(trifluoromethoxy)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2,3,6-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2-thienylcarbonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-4-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[3-fluoro-5-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-fluoro-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,3-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,4-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,5-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2,6-difluorobenzoyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-[1-(2,3,4-trifluorobenzoyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; {1-{1-[2-fluoro-3-(trifluoromethoxy)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[4-hydroxy-3-(trifluoromethyl)benzoyl]piperidin-4-yl}-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[2-methyl-6-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-cyanophenyl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(2-methoxyphenyl)piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-1-yl}-N-(3-fluoropyridin-2-yl)piperidine-1-carboxamide; N-(4-chloro-2-cyanophenyl)-4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2,4-difluorophenyl)piperidine-1-carboxamide; N-(2-chloro-4-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-methoxypyridin-3-yl)piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-(2-fluorophenyl)piperidine-1-carboxamide; N-(2-chlorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-cyano-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; N-(4-cyano-2-fluorophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; N-(2-chloro-4-cyanophenyl)-4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxamide; (3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)acetonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]isophthalonitrile; 3-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-5-fluorobenzonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-3-fluorobenzonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-{1-[(5-fluoropyridin-2-yl)carbonyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoroisonicotinoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3,5-difluoroisonicotinoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(3-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-[1-(2-fluoro-4-hydroxybenzoyl)piperidin-4-yl]-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]terephthalonitrile; 4-[(4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]-2-fluorobenzonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[(4,4-difluorocyclohexyl)carbonyl]piperidin-4-yl}-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-fluoro-2-(trifluoromethyl)phenyl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[4-(trifluoromethyl)pyridin-3-yl]piperidine-1-carboxamide; 4-{3-(cyanomethyl)-3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide; 4-[1-(3-(cyanomethyl)-1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(3-cyano-5-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(4-cyano-3-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-(1-{3-(cyanomethyl)-1-[1-(2,5-dibromobenzoyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-(1-{3-(cyanomethyl)-1-[1-(3,5-dibromobenzoyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 2-[(4-{3-(cyanomethyl)-3-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]terephthalonitrile; 5-[(4-{3-(cyanomethyl)-3-[4-(5-cyano-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidin-1-yl)carbonyl]isophthalonitrile; 4-{1-[1-[1-(4-cyano-2-fluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-[1-(4-cyano-2,6-difluorobenzoyl)piperidin-4-yl]-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; 4-{1-[1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; {1-{1-[5-chloro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; {1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {1-[1-(methylsulfonyl)piperidin-4-yl]-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile; [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[6-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[2-(trifluoromethyl)pyrimidin-4-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; [3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-(1-{[5-(trifluoromethyl)pyrazin-2-yl]carbonyl}piperidin-4-yl)azetidin-3-yl]acetonitrile; {3-[4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}acetonitrile; 4-[1-(3-(cyanomethyl)-1-{1-[5-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}azetidin-3-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; and 4-(1-{3-(cyanomethyl)-1-[1-(methylsulfonyl)piperidin-4-yl]azetidin-3-yl}-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile; and 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylpiperidine-1-carboxamide 2. The pharmaceutical composition of claim 1, wherein said compound is selected from the group consisting of:

19. 2. The pharmaceutical composition of claim 1, wherein the compound is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile or a pharma- ceutically acceptable salt thereof.

20. 20. The pharmaceutical composition of claim 19, wherein the salt is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipate.

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