NZ713999B2 - Bipyrazole derivatives as jak inhibitors - Google Patents

Abstract

The present invention provides compounds of Formula I: or pharmaceutically acceptable salts thereof, as well as their compositions and methods of use, that inhibit the activity of Janus kinase (JAK) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases. flammatory disorders, autoimmune disorders, cancer, and other diseases.

Description

BIPYRAZOLE TIVES AS JAK INHIBITORS This ation claims the benefit of priority ofUS. Provisional Appl. No. 61/824,683, filed May 17, 2013, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD The present invention es bipyrazole derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAK) and are useful in the ent of diseases d to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases. 1O BACKGROUND Protein kinases (PKs) regulate diverse biological processes including cell growth, al, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight ptides or glycoproteins, regulate many pathways involved in the host inflammatory response to sepsis. Cytokines influence cell differentiation, proliferation and activation, and can modulate both pro-inflammatory and anti-inflammatory responses to allow the host to react riately to pathogens. Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription (STATs). There are four known ian JAKs: JAKl (Janus kinase-l), JAK2, JAK3 (also known as Janus , leukocyte; JAKL; and L- JAK), and TYK2 (protein-tyrosine kinase 2).

Cytokine-stimulated immune and inflammatory ses contribute to pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune/inflammatory response contributes to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T.

Cheng, et al. (2000) Arthritis Res 2(1): 16-32).

Deficiencies in expression of JAKs are associated with many disease states. For example, Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J ., M. A. Meraz, et al. (1998) Cell 93(3): 373-83). Jak2-/— mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive erythropoiesis.

The JAK/STAT pathway, and in particular all four JAKs, are believed to play a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. 1O Multiple cytokines that signal through JAKs have been linked to inflammatory diseases/conditions of the upper respiratory tract, such as those affecting the nose and sinuses (e.g., rhinitis and sinusitis) whether classically allergic reactions or not. The JAK/STAT pathway has also been ated in inflammatory diseases/conditions of the eye and c allergic responses. tion of JAK/STAT in s may occur by cytokine stimulation (e.g. IL-6 or ) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002). Activation of STAT signaling, as well as other pathways downstream of JAKs (e.g., Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Elevated levels of circulating cytokines that signal through JAK/STAT play a causal role in cachexia and/or c fatigue. As such, JAK inhibition may be beneficial to cancer patients for s that extend beyond potential anti-tumor activity.

JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorders, e.g., polycythemia vera (PV), essential ocythemia (ET), d metaplasia with myelofibrosis (MMM) (Levin, et al., Cancer Cell, vol. 7, 2005: 387- 397). Inhibition of the JAK2V6l7F kinase decreases proliferation of poietic cells, suggesting JAK2 as a potential target for pharmacologic inhibition in patients with PV, ET, and MMM.

Inhibition of the JAKs may benefit patients suffering from skin immune disorders such as psoriasis, and skin sensitization. The maintenance of psoriasis is believed to depend on a number of inflammatory cytokines in addition to s ines and growth s (JCI, 113 : 1664-1675), many of which signal through JAKs (Adv Pharmacol. 2000;47:113-74).

Thus, new or improved agents which inhibit kinases such as JAKs are continually needed for developing new and more effective pharmaceuticals that are aimed at augmentation or suppression of the immune and inflammatory pathways (such as immunosuppressive agents for organ lants), as well as agents for the prevention and 1O treatment of autoimmune diseases, diseases involving a hyperactive inflammatory response (e.g., eczema), allergies, cancer (e.g., prostate, leukemia, multiple myeloma), and some immune reactions (6.g. skin rash or contact dermatitis or diarrhea) caused by other therapeutics. The compounds of the invention, as well as its compositions and methods described herein are directed toward these needs and other ends.

SUMMARY The present invention provides, inter alia, compounds of Formula I: N: O x ;Y—Cy1-< N-N “W R7 // R8 R1 R9 // R10 HN—N and pharmaceutically acceptable salts thereof; wherein Y, Cyl, R1, R2, R7, R8, R9, and R10 are defined infra.

The present invention fiarther provides compositions sing a compound of Formula I, or a pharmaceutically able salt thereof, and a pharmaceutically able carrier.

The present invention r provides methods of modulating an activity of JAKl comprising contacting JAKl with a compound of Formula I, or a pharmaceutically acceptable salt thereof.

The t invention fiarther es methods of treating a disease or a disorder associated with abnormal kinase expression or activity in a patient by stering to a patient a therapeutically effective amount of a nd of Formula I, or a pharmaceutically acceptable salt thereof.

The present invention fiarther provides methods of treating an autoimmune disease, a cancer, a myeloproliferative er, a myelodysplastic syndrome (MDS), an 1O atory disease, a bone resorption disease, or organ transplant rejection in a patient in need thereof, comprising administering to said patient a therapeutically ive amount of a compound of Formula I, or a pharmaceutically acceptable salt f The present invention also provides compounds of a I, or pharmaceutically acceptable salts thereof, as described herein for use in treatment of autoimmune diseases, cancer, myeloproliferative disorders, myelodysplastic syndromes (MDS), inflammatory diseases, a bone resorption disease, or organ transplant rejection.

The present invention fiarther provides compounds of Formula I as described herein, or pharmaceutically acceptable salts thereof, for use in modulating JAKl.

The t invention also provides uses of compounds of Formula I as described herein, or pharmaceutically acceptable salts thereof, for the preparation of medicaments for use in methods of modulating JAKl.

DESCRIPTION OF DRAWINGS Figure 1 shows an XRPD pattern characteristic of the salt of Example 14.

Figure 2 shows an XRPD n teristic of the salt of e 15.

Figure 3 shows an XRPD pattern characteristic of the salt of Example 16.

Figure 4A shows a DSC thermogram characteristic of the salt of Example 17.

Figure 4B shows TGA data characteristic of the salt of Example 17.

Figure 4C shows an XRPD pattern characteristic of the salt of Example 17.

Figure 5A shows a DSC thermogram characteristic of the salt of Example 18.

Figure 5B shows TGA data characteristic of the salt of Example 18.

Figure 5C shows an XRPD pattern characteristic of the salt of e 18.

Figure 6 shows an XRPD n characteristic of the salt of Example 19.

Figure 7A shows a DSC gram characteristic of the salt of Example 20.

Figure 7B shows TGA data characteristic of the salt of Example 20.

Figure 7C shows an XRPD pattern characteristic of the salt of Example 20.

Figure 8A shows a DSC gram characteristic of the salt of Example 21.

Figure 8B shows an XRPD pattern characteristic of the salt of Example 21.

Figure 9 shows an XRPD pattern characteristic of the salt of Example 22. 1O DETAILED DESCRIPTION The present invention provides, inter alia, a compound of Formula I: N: O X LY—Cy1—< Dl—N “FRZ R7 / R8 R1 R9 / R10 HN—N or a pharmaceutically acceptable salts thereof; wherein: Cy1 is phenyl, pyridyl, pyrimidinyl, nyl, or pyridazinyl, each of which is ally substituted by 1, 2, 3, or 4 groups independently selected from R3, R4, R5, and Y is N or CH; R1 is C1_6 alkyl, C1_6 haloalkyl, C3_7 cycloalkyl, C3_7 cycloalkyl-C1_3 alkyl, 4-7 ed heterocycloalkyl, 4-7 membered heterocycloalkyl-C1_3 alkyl, phenyl, phenyl- C1_3 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C1_3 alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C1_3 alkyl, -OH, -O(C1_3 alkyl), -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(C1_3 alkyl), - N(C1_3 alkyl)2, -C(=O)N(C1_3 alkyl)2, -C(=O)NH(C1_3 alkyl), -C(=O)NH2, -C(=O)O(C1_3 , -S(=O)2(C1_3 alkyl), -S(=O)2(C3_6 cycloalkyl), -C(=O)(C3_6 cycloalkyl), and - C(=0)(Ci-s alkyl); R2 is H or C1_3 alkyl; wherein said C1_3 alkyl is optionally substituted by l, 2, or 3 substituents independently selected from fluoro, chloro, -OH, -O(C1_3 alkyl), -CN, -CF3, - CHF2, -CH2F, NH2, -NH(C1_3 alkyl), and -N(C1_3 alkyl)2; or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, - or 6-membered heterocycloalkyl ring, which is optionally substituted with l, 2, or 3 substitutents independently selected from F, Cl, -OH, -O(C1_3 alkyl), -CN, C1_3 alkyl, C1_3 haloalkyl, -NH2, -NH(C1_3 alkyl), -N(C1_3 alkyl)2, , and -CHzOH; 1O R3 is H, F, Cl, -CN, C1_3 alkyl, C1_3 lkyl, -O(C1_3 alkyl), or -O(C1_3 fluoroalkyl); R4 is H, F, Cl, -CN, C1_3 alkyl, C1_3 fluoroalkyl, -O(C1_3 alkyl), or -OC(C1_3 fluoroalkyl); R5 is H, F, Cl, -CN, C1_3 alkyl, C1_3 lkyl, -O(C1_3 alkyl), or -OC(C1_3 fluoroalkyl); R6 is H, F, Cl, -CN, C1_3 alkyl, C1_3 fluoroalkyl, -O(C1_3 alkyl), or -OC(C1_3 alkyl); R7 is H, F, Cl, C1_3 alkyl, C1_3 haloalkyl, 17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b, or -S(=O)2NR17aR17b, wherein said C1_3 alkyl is optionally substituted with l, 2, or 3 substituents selected from F, Cl, -CN, -CF3, -CHF2, - CH2F, -NH2, -NH(CH3), -N(CH3)2, OH, -OCH3, and -OCF3, -OCHF2, and ; R8 is H, F, Cl, c1.3 alkyl, or c1.3 haloalkyl; R9 is H, F, Cl, C1_3 alkyl, C1_3 haloalkyl, cyclopropyl, -CN, -NH2, -NH(C1_3 , or -N(C1_3 alkyl)2, wherein said C1_3 alkyl is optionally substituted with l, 2, or 3 substituents selected from F, , -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R10 is H, F, Cl, c1.3 alkyl, c1.3 haloalkyl, cyclopropyl, -CN, -NH2, -NH(C1_3 alkyl), or -N(C1_3 alkyl)2, wherein said C1_3 alkyl is optionally substituted with l, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R17 is C1_6 alkyl, phenyl or 5-6 ed heteroaryl, each of which is optionally substituted with l, 2, 3 or 4 ndently selected R27 substituents; R1721 is H or C1_3 alkyl; R17bis C1_3 alkyl ally tuted with l, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(CH3), -N(CH3)2, OH, -OCH3, and - OCF3, -OCHF2, and -OCH2F; and each R27 is independently selected from halo, -OH, N02, -CN, C1_3 alkyl, C23 alkenyl, C23 alkynyl, C1_3 kyl, cyano-C1_3 alkyl, HO-C1_3 alkyl, CF3-C1_3 hydroxyalkyl, C1_3 alkoxy-C1_3 alkyl, C3_7 lkyl, C1_3 alkoxy, C1_3 haloalkoxy, H2N—, (C1_3 alkyl)NH-, (C1_3 alkyl)2N-, HS-, C1_3 alkyl-S-, C1_3 alkyl-S(=O)-, C1_3 alkyl-S(=O)2-, carbamyl, C1_3 arbamyl, di(C1_3 alkyl)carbamyl, carboxy, C1_3 alkyl-C(=O)-, C1_4 1O alkoxy-C(=O)-, C1_3 alkyl-C(=O)O-, C1_3 C(=O)NH-, C1_3 alkyl-S(=O)2NH-, HzN-SOz-, C1_3 alkyl-NH-S(=O)2-, (C1_3 alkyl)2N-S(=O)2-, H2N—S(=O)2NH-, C1_3 alkyl- NHS(=O)2NH-, (C1_3 alkyl)2N-S(=O)2NH-, H2N—C(=O)NH-, C1_3 alkyl-NHC(=O)NH-, and (C1_3 alkyl)2N-C(=O)NH-.

In some embodiments, the compound is a compound of Formula Ia: Li;,5? or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula Ia: Li;5? la or a pharmaceutically acceptable salt thereof; wherein: X is N or CR4; W is N or CR6; Y is N or CH; R1 is C1_6 alkyl, C1_6 kyl, C3_6 cycloalkyl, C3_6 cycloalkyl-C1_3 alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C1_3 alkyl, each of which is optionally substituted with l, 2, or 3 substituents independently selected from fluoro, chloro, C1_3 alkyl, -OH, 3 alkyl), -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(C1_3 alkyl), N(C1_3 alkyl)2, -C(=O)N(C1_3 alkyl)2, -C(=O)NH(C1_3 alkyl), -C(=O)NH2, -C(=O)O(C1_3 alkyl), -S(=O)2(C1_3 alkyl), -S(=O)2(C3_6 cycloalkyl), -C(=O)(C3_6 cycloalkyl), and - 1O C(=0)(Ci-s alkyl); R2 is H or C1_3 alkyl; wherein said C1_3 alkyl is optionally substituted by l, 2, or 3 substituents independently selected from fluoro, chloro, -OH, -O(C1_3 alkyl), -CN, -CF3, - CHF2, -CH2F, NH2, -NH(C1_3 alkyl), and -N(C1_3 alkyl)2; or R1 and R2, together with the nitrogen atom to which they are ed, form a 4-, 5- or ered heterocycloalkyl ring, which is optionally substituted with l, 2, or 3 substitutents independently selected from fluoro, -OH, -O(C1_3 alkyl), -CN, C1_3 alkyl, C1_3 haloalkyl, -NH2, _3 alkyl), -N(C1_3 alkyl)2, and -CH2CN; R3 is H, F, Cl, -CN, C1_3 alkyl, -OCF3, -CF3, or —0(c1_3 alkyl); R4 is H, F, Cl, -CN, C1_3 alkyl, or —0(c1_3 alkyl); R5 is H, F, Cl, -CN, c1.3 alkyl, or —0(c1_3 alkyl); R6 is H, F, Cl, -CN, or C1_3 alkyl; R7 is H, F, Cl, c1.3 alkyl, c1.3 haloalkyl, -NR17R17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b, or -S(=O)2NR17aR17b, n said C1_3 alkyl is optionally substituted with l, 2, or 3 substituents selected from F, Cl, -CN, -CF3, -CHF2, - CH2F, -NH2, and OH; R8 is H, F, Cl, c1.3 alkyl, or c1.3 haloalkyl; R9 is H, F, Cl, C1_3 alkyl, C1_3 haloalkyl, ropyl, -CN, -NH2, _3 alkyl), or -N(C1_3 alkyl)2, wherein said C1_3 alkyl is optionally substituted with l, 2, or 3 substituents ed from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; 2014/038388 R10 is H, F, Cl, c1.3 alkyl, c1.3 haloalkyl, cyclopropyl, -CN, -NH2, _3 alkyl), or -N(C1_3 2, wherein said C1_3 alkyl is optionally tuted with l, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R17 is C1_6 alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with l, 2, 3 or 4 substituents independently selected from R27; R1721 is H or C1_3 alkyl; R17b is C1_3 alkyl optionally substituted with l, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH and each R27 is independently selected from halo, -OH, N02, -CN, C1_3 alkyl, C23 1O alkenyl, C23 alkynyl, C1_3 haloalkyl, cyano-C1_3 alkyl, HO-C1_3 alkyl, CF3-C1_3 hydroxyalkyl, C1_3 alkoxy-C1_3 alkyl, C3_7 cycloalkyl, C1_3 alkoxy, C1_3 haloalkoxy, H2N—, (C1_3 alkyl)NH-, (C1_3 alkyl)2N-, HS-, C1_3 alkyl-S-, C1_3 alkyl-S(=O)-, C1_3 alkyl-S(=O)2-, carbamyl, C1_3 alkylcarbamyl, di(C1_3 alkyl)carbamyl, carboxy, C1_3 alkyl-C(=O)-, C1_4 alkoxy-C(=O)-, C1_3 alkyl-C(=O)O-, C1_3 alkyl-C(=O)NH-, C1_3 S(=O)2NH-, HzN-SOz-, C1_3 NH-S(=O)2-, (C1_3 alkyl)2N-S(=O)2-, H2N—S(=O)2NH-, C1_3 alkyl- NHS(=O)2NH-, (C1_3 alkyl)2N-S(=O)2NH-, H2N—C(=O)NH-, C1_3 alkyl-NHC(=O)NH-, and (C1_3 alkyl)2N-C(=O)NH-.

In some embodiments: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 lkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R6 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-.

In some embodiments, Y is N.

In some embodiments, Y is CH.

In some embodiments, X is N.

In some embodiments, X is CR4.

In some embodiments, R4 is H or F.

In some embodiments, R4 is H.

In some ments, R4 is F.

In some embodiments, W is N.

In some embodiments, W is CR6.

In some embodiments, R6 is H, F, or Cl.

In some embodiments, R6 is H or F.

In some embodiments, R6 is H.

In some embodiments, R6 is F.

In some embodiments, R3 is H or F.

In some embodiments, R5 is H or F.

In some embodiments, R2 is H or methyl.

In some embodiments, R2 is H.

In some embodiments, R2 is methyl.

In some embodiments, R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl.

In some embodiments, R1 is isopropyl, ethyl, l-methylpropyl, 2,2,2-trifluoro-l- methylethyl, l-cyclopropylethyl, ropyl, uoromethylcyclopropyl, propyl-Z ,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl.

In some ments, R1 is isopropyl, ethyl, l-methylpropyl, or 2,2,2-trifluoro-l- methylethyl.

In some embodiments, R1 is isopropyl In some embodiments, R1 is ethyl.

In some embodiments, R1 is l-methylpropyl.

In some embodiments, R1 is 2,2,2-trifluoro-l-methylethyl.

In some embodiments, R7 is H, methyl, ethyl, or HO-CH2-.

In some embodiments, R7 is H.

In some embodiments, R7 is methyl.

In some embodiments, R8 is H or methyl.

In some embodiments, R8 is H.

In some embodiments, R9 is H, methyl or ethyl.

In some embodiments, R9 is H. 1O In some embodiments, R9 is methyl.

In some embodiments, R10 is H, methyl, ethyl, or -.

In some embodiments, R10 is H.

In some embodiments, R10 is methyl.

In some embodiments, R10 is ethyl.

In some ments, R10 is HO-CH2-.

In some embodiments, the compound is a compound of Formula II: R6 R5 NZ: 0 X N N-N N—R1 R7 / R8 R3 R4 R9 / R10 HN-N or a pharmaceutically acceptable salt thereof.

In some ments, the compound is a compound of Formula III: R6 R5 NEE—i><> —— o N \ / N-N N N-R1 R7 / R3 R8 R2 R9 /' R10 HN-N or a pharmaceutically acceptable salt thereof.

In some ments, the compound is a compound of Formula IV: N:—>CN—{§—NNW0/ u-N u-R1 R7 / R3 R8 R2 R9 /' R10 HN—N or a pharmaceutically acceptable salt thereof.

In some ments, the compound is a compound of Formula Ila: R6 R5 NZ: 0 R3 R4 u-R1 R7 / R8 R2 R9 /' R10 HN—N 1O or a pharmaceutically acceptable salt f.

In some embodiments, the compound is a compound of Formula IIIa: IIIa or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IVa: \ =<>_<p/ N—N N / R3 N—Rl R7 R8 2 R9 /’ R10 HN—N or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein: X is N or CR4; W is N or CR6; Y is N or CH; R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 lkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R6 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, , ethyl or HO-CH2-.

In some ments, the compound is a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, n said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally 2014/038388 substituted with l, 2, or 3 substituents ndently selected from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R6 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, , ethyl or HO-CH2-.

In some embodiments, the compound is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-.

In some embodiments, the compound is a compound of Formula IV, or a pharmaceutically able salt thereof, wherein: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents ndently ed from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R5 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-. 1O In some embodiments, the compound is a compound of a Ha, or a pharmaceutically acceptable salt thereof, n: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R6 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or -.

In some embodiments, the compound is a compound of Formula IIIa, or a pharmaceutically acceptable salt thereof, wherein: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, wherein said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl; R2 is H or methyl; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-.

In some embodiments, the compound is a compound of Formula IVa, wherein: R1 is C1_6 alkyl, C1_6 haloalkyl, C3_6 cycloalkyl, or C3_6 cycloalkyl-C1_3 alkyl, n said C1_6 alkyl, C3_6 cycloalkyl, and C3_6 cycloalkyl-C1_3 alkyl, are each optionally substituted with l, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl; R2 is H or ; R3 is H, F, or Cl; R5 is H or F; R7 is H, methyl, ethyl or HO-CH2-; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-.

In some embodiments, the present application es 5-[3-(cyanomethyl)—3-(3'- methyl- 1 H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl]-N-[(l S)-2,2,2-trifluoro- l - methylethyl]pyrazinecarboxamide, or a pharmaceutically able salt thereof.

In some ments, the present application provides 5-[3-(cyanomethyl)(3'- methyl- 1 H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] propylpyrazinecarboxamide. or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 4-[3-(cyanomethyl)—3-(3'- methyl- 1 H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -N-isopropylbenzamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 4-[3-(cyanomethyl)(3'- - 1 H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N— [(l S)-2,2,2-trifluoro- l - methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 4-[3-(lH,l'H-4,4'- bipyrazol- l -yl)-3 -(cyanomethyl)azetidin- l -yl]-2,5 -difluoro-N— [(l S)—2,2 ,2-trifluoro- l - ethyl]benzamide, or a ceutically acceptable salt f.

In some embodiments, the present application provides 5-[3-(cyanomethyl) (3 ,3 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -N-isopropylpyrazine carboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 4-[3-(cyanomethyl) (3 ',5 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N—[(l S)-2,2,2- trifluoro-l-methylethyl]benzamide, or a ceutically acceptable salt thereof.

In some embodiments, the present application provides 5-[3-(cyanomethyl) (3 ',5 thyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -N-isopropylpyrazine amide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application 5-[3-(cyanomethyl)(3',5'- dimethyl- l H, l '-bipyrazol- l -yl)azetidin- l -yl] -N- [(l S)-2,2,2-trifluoro- l - methylethyl]pyrazinecarboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application es 5-[3-(cyanomethyl)(3- methyl- 1 H, l '-bipyrazol- l -yl)azetidin- l -yl] -N-isopropylpyrazinecarboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 5-[3-(cyanomethyl)—3-(3'- ethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -N-[(l S)-2,2,2-trifluoro- l - ethyl]pyrazinecarboxamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the present application provides 4-{3-(cyanomethyl)[3'- (hydroxymethyl)— l H, l 'H-4,4'-bipyrazol- l -yl] azetidin- l -yl} -2,5 -difluoro-N—[(l S)—2,2,2- trifluoro-l-methylethyl]benzamide, or a pharmaceutically acceptable salt f.

In some embodiments, the present application provides 4-{3-(cyanomethyl)[3- (hydroxymethyl)-3'-methyl- 1 H, l 'H-4,4'-bipyrazol- l -yl] azetidin- l -yl} -2,5 -difluoro-N— [(l S)-2,2,2—trifluoro-l-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

In some embodiments, the t ation provides a salt selected from: 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl-1H l 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl]- 2,5-difluoro-N—[(l S)-2,2,2-trifluoro- l -methylethyl]benzamide phosphoric acid salt; 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl-1H l 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl]- 2,5-difluoro-N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide hydrochloric acid salt; 4- [3 omethyl)-3 -(3',5 '-dimethyl-1H l 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl]- 2,5-difluoro-N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide hydrobromic acid salt; and 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl-1H l '-bipyrazol- l -yl)azetidin- l -yl]- fluoro-N—[(l ,2-trifluoro-l-methylethyl]benzamide SlllfilI'lC acid salt. 1O In some embodiments, the salt is 4-[3 omethyl)(3',5'-dimethyl-1H,l'H— 4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N—[(l S)—2,2,2-trifluoro- l - methylethyl]benzamide phosphoric acid salt. In some embodiments, the salt is a 1:1 stoichiometric ratio of 4-[3 omethyl)-3 -(3 ',5 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l - yl)azetidin- l -yl] -2,5 -difluoro-N-[(l S)-2,2,2-trifluoro- l -methylethyl]benzamide to phosphoric acid. In some embodiments, the salt is crystalline. In some embodiments, the salt is substantially isolated.

In some embodiments, the salt is 4-[3 -(cyanomethyl)(3',5'-dimethyl-1H,l'H— 4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N—[(l S)—2,2,2-trifluoro- l - methylethyl]benzamide hydrochloric acid salt. In some embodiments, the salt is a 1:1 stoichiometric ratio of 4-[3 -(cyanomethyl)-3 -(3 ',5 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l - yl)azetidin- l -yl] -2,5 -difluoro-N-[(l S)-2,2,2-trifluoro- l -methylethyl]benzamide to hydrochloric acid. In some embodiments, the salt is crystalline. In some embodiments, the salt is substantially isolated.

In some embodiments, the salt is 4-[3 -(cyanomethyl)(3',5'-dimethyl-1H,l'H— 4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N—[(l S)—2,2,2-trifluoro- l - methylethyl]benzamide hydrobromic acid salt. In some embodiments, the salt is a 1:1 stoichiometric ratio of 4-[3 -(cyanomethyl)-3 -(3 ',5 thyl- l H, l '-bipyrazol- l - yl)azetidin- l -yl] -2,5 -difluoro-N-[(l S)-2,2,2-trifluoro- l -methylethyl]benzamide to WO 86706 hydrobromic acid. In some embodiments, the salt is crystalline. In some embodiments, the salt is substantially isolated.

In some embodiments, the salt is 4-[3 -(cyanomethyl)(3',5'-dimethyl-1H,l'H— 4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N—[(l S)—2,2,2-trifluoro- l - methylethyl]benzamide SlllfilI'lC acid salt. In some embodiments, the salt is a 1:1 stoichiometric ratio of 4-[3-(cyanomethyl)(3',5'-dimethyl- l H, l 'H-4,4'-bipyrazol- l - yl)azetidin- l -yl] -2,5 -difluoro-N-[(l S)-2,2,2-trifluoro- l -methylethyl]benzamide to sulfuric acid. In some ments, the salt is crystalline. In some ments, the salt is substantially isolated. 1O In some embodiments, the 4-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'- zol- l -yl)azetidin- l -yl] -2,5 -difluoro-N- [(l S)-2,2,2-trifluoro- l - methylethyl]benzamide phosphoric acid salt is characterized by a DSC gram having an endothermic peak at about 228 0C. In some ments, the phosphoric acid salt has a DSC thermogram substantially as shown in Figure 4A. In some embodiments, the phosphoric acid salt has at least one XRPD peak, in terms of 2-theta, selected from about 6.80, about 16.50, about 19.80, about 20.70, and about 23.60. In some embodiments, the phosphoric acid salt has at least two XRPD peaks, in terms of a, selected from about 6.80, about 16.50, about 19.80, about 20.70, and about 23.60. In some embodiments, the phosphoric acid salt has at least three XRPD peaks, in terms of 2-theta, selected from about 6.80, about 16.50, about 19.80, about 20.70, and about 23.60. In some embodiments, the phosphoric acid salt has at least four XRPD peaks, in terms of 2-theta, selected from about 6.80, about 16.50, about 19.80, about 20.70, and about 23.60. In some embodiments, the phorphoric acid salt has an XRPD profile substantially as shown in Figure 4C.

In some embodiments, the 4-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'- bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N- [(l S)-2,2,2-trifluoro- l - methylethyl]benzamide hydrochloric acid salt is characterized by a DSC thermogram haVing an endothermic peak at about 213 0C. In some embodiments, the hydrochloric acid salt has a DSC thermogram substantially as shown in Figure 5A. In some embodiments, the hydrochloric acid salt has at least one XRPD peak, in terms of 2-theta, selected from about 7.0°, about 121°, about 13.7°, about 148°, about 155°, about 16.6°, about 17.1°, about 19.7°, about 20.4°, about 208°, about 23.9°, about 24.7°, about 251°, about 257°, about 27.4°, and about 283°. In some embodiments, the hydrochloric acid salt has at least two XRPD peaks, in terms of 2-theta, selected from about 7.0°, about 121°, about 13.7°, about 148°, about 155°, about 16.6°, about 17.1°, about 19.7°, about .4°, about 208°, about 23.9°, about 24.7°, about 251°, about 257°, about 27.4°, and about 283°. In some embodiments, the hydrochloric acid salt has at least three XRPD peaks, in terms of 2-theta, selected from about 7.0°, about 121°, about 13.7°, about 148°, about 155°, about 16.6°, about 17.1°, about 19.7°, about 20.4°, about 208°, about 1O 23.9°, about 24.7°, about 251°, about 257°, about 27.4°, and about 283°. In some ments, the hydrochloric acid salt has at least four XRPD peaks, in terms of 2- theta, selected from about 7.0°, about 121°, about 13.7°, about 148°, about 155°, about 16.6°, about 17.1°, about 19.7°, about 20.4°, about 208°, about 23.9°, about 24.7°, about 251°, about 257°, about 27.4°, and about 283°. In some embodiments, the hydrochloric acid salt has an XRPD profile substantially as shown in Figure 5C.

In some embodiments, the cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'- bipyrazolyl)azetidinyl] -2,5 -difluoro-N- [(1 S)-2,2,2-trifluoro methylethyl]benzamide hydrobromic acid salt is characterized by a DSC thermogram having an endothermic peak at about 203 0C. In some ments, the hydrobromic acid salt has a DSC thermogram ntially as shown in Figure 7A. In some embodiments, the hydrobromic acid salt has at least one XRPD peak, in terms of 2-theta, selected from about 7.0°, about 14.4°, about 17.1°, about 202°, about 21.1°, about 228°, about 235°, about 24.9°, about 26.6°, about 27.1°, and about 282°. In some embodiments, the hydrobromic acid salt has least two XRPD peaks, in terms of 2-theta, selected from about 7.0°, about 14.4°, about 17.1°, about 202°, about 21.1°, about 228°, about 235°, about 24.9°, about 26.6°, about 27.1°, and about 282°. In some embodiments, the hydrobromic acid salt has least three XRPD peaks, in terms of 2-theta, selected from about 7.0°, about 14.4°, about 17.1°, about 202°, about 21.1°, about 228°, about 235°, about 24.9°, about 26.6°, about 27.1°, and about 282°. In some embodiments, the hydrobromic acid salt has least four XRPD peaks, in terms of 2-theta, selected from about 7.00, about 14.40, about 17.10, about 20.20, about 21.10, about 228", about 23.50, about 24.90, about 26.60, about 27.10, and about 28.20. In some embodiments, the romic acid salt has an XRPD profile substantially as shown in Figure 7C.

In some embodiments, the 4-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'- bipyrazol-l-yl)azetidinyl]-2,5-difluoro-N- [(1 S)-2,2,2-trifluoro- l - methylethyl]benzamide sulfuric acid salt is characterized by a DSC thermogram having an endothermic peak at about 259 0C. In some embodiments, the I'lC acid salt is characterized by a DSC thermogram haVing three endothermic peaks at about 136 0C, 1O about 147 0C, and about 259 0C. In some embodiments, the ic acid salt has a DSC thermogram substantially as shown in Figure 8A. In some embodiments, the sulfuric acid salt has at least one XRPD peak, in terms of 2-theta, selected from about 7.30, about 14.70, about 9.90, about 19.0°,about 19.60, about 21.30, and about 24.60. In some embodiments, the sulfuric acid salt has at least two XRPD peaks, in terms of 2-theta, ’15 selected from about 7.30, about 14.70, about 9.90, about 19.0°,about 19.60, about 21.30, and about 24.60. In some embodiments, the sulfiaric acid salt has at least three XRPD peaks, in terms of 2-theta, selected from about 7.30, about 14.70, about 9.90, about 19.0°,about 19.60, about 21.30, and about 24.60. In some ments, the SlllfilI'lC acid salt has at least four XRPD peaks, in terms of 2-theta, selected from about selected from about 7.30, about 14.70, about 9.90, about 19.0°,about 19.60, about 21.30, and about 24.60. In some ments, the sulfuric acid salt has an XRPD profile substantially as shown in Figure 8B.

Different crystalline forms may have different crystalline lattices (e. g., unit cells) and, y as a result, have different physical properties. The different salt forms can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other terization methods such as differential scanning calorimetry (DSC), thermograVimetric analysis (TGA), dynamic vapor sorption (DVS), and the like r help identify the form as well as help determine stability and solvent/water content.

An XRPD pattern of reflections (peaks) is typically considered a fingerprint of a particular crystalline form. It is well known that the relative ities of the XRPD peaks can widely vary depending on, inter alia, the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument ed. In some instances, new peaks may be observed or existing peaks may disappear, depending on the type of the instrument or the settings. As used herein, the term “pea ” refers to a reflection having a ve height/intensity of at least about 4% of the m peak height/intensity. Moreover, instrument variation and other factors can affect the 2-theta values. Thus, peak assignments, such as those reported 1O herein, can vary by plus or minus about 0.20 (2-theta), and the term “substantially” and “about” as used in the context ofXRPD herein is meant to encompass the above- mentioned variations.

In the same way, temperature readings in connection with DSC, TGA, or other thermal ments can vary about :3 CC depending on the instrument, ular gs, sample preparation, etc. Accordingly, a crystalline form reported herein having a DSC thermogram “substantially” as shown in any of the Figures or the term “about” is understood to odate such variation.

In some embodiments, the salts described herein are substantially ed. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the salts bed herein. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the salts described herein, or salt thereof.

Methods for isolating compounds and their salts are routine in the art.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate ments, can also be provided in ation in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be ed separately or in any suitable subcombination.

At various places in the present cation, substituents of compounds of the invention are disclosed in groups or in . It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For e, the term “C1_6 alkyl” is specifically ed to individually disclose , ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

At various places in the present specification, linking substituents are described.

Where the structure clearly requires a linking group, the Markush variables listed for that 1O group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is to be understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.

At various places in the present specification, rings are described (e. g., “a dine ring”). Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For e, the term “a 2H- tetrahydropyran ring” may refer to a 2H-tetrahydropyran yl, 2H-tetrahydropyran yl, 2H-tetrahydropyranyl ring, etc.

The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, 2H-tetrahydropyran is an example of a 6-membered heterocycloalkyl ring, lH- l,2,4-triazole is an example of a 5-membered aryl ring, pyridine is an e of a 6-membered heteroaryl ring, and l,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.

For nds of the invention in which a variable appears 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 having two R groups that are simultaneously t on the same compound, the two R groups can represent different moieties independently selected from the group defined for R. In another example, when an optionally multiple substituent is designated in the form: p/(R)p(CI—I2)" then it is to be understood that tuent R can occur p number of times on the ring, and R can be a ent moiety at each occurrence. It is to be understood that each R group may replace any hydrogen atom attached to a ring atom, including one or both of the (CH2), en atoms. Further, in the above example, should the variable Q be defined to e hydrogens, such as when Q is said to be CH2, NH, etc., any floating tuent such as R in the above example, can replace a hydrogen of the Q variable as well as a hydrogen in any other non-variable component of the ring.

As used herein, the phrase “optionally substituted” means unsubstituted or 1O substituted. As used herein, the term “substituted” means that a hydrogen atom is d and replaced by a substituent. It is to be understood that substitution at a given atom is limited by valency.

As used herein, the term “CH—m alkyl”, ed alone or in combination with other terms, refers to a saturated arbon group that may be ht-chain or branched, having 11 to m carbon atoms. In some embodiments, the alkyl group contains 1 to 6, l 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-l-butyl, 3-pentyl, n-hexyl, l,2,2-trimethylpropyl, and the like.

As used herein, the term “alkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group, which can be branched or straight-chain, where the two substituents may be attached any position of the alkylene linking group.

Examples of alkylene groups include, but are not limited to, ethan-l,2-diyl, propan-l,3- diyl, propan-l,2-diyl, and the like.

As used herein, “Cn—m alkenyl” refers to an alkyl group having one or more double carbon-carbon bonds and having 11 to m carbons. In some embodiments, the alkenyl moiety contains 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “Cn—m alkynyl” refers to an alkyl group having one or more triple -carbon bonds and having 11 to m s. Example alkynyl groups include, but are not limited to, ethynyl, propyn-l-yl, propynyl, and the like. In some embodiments, the alkynyl moiety ns 2 to 3 carbon atoms.

As used herein, the term “C1_3 alkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, n the alkyl group has 1 to 3 carbons. Example alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy).

As used herein, the term “CF3-C1_3 hydroxyalkyl” refers to a C1_3 alkyl group 1O substituted by one CF3 group and one OH group.

The C1_3 groups in (C1_3 alkyl)2N-, (C1_3 alkyl)2N-S(=O)2NH-, and (C1_3 alkyl)2N- C(=O)NH- can be the same or different.

As used herein, the term “carboxy” refers to a group of formula -C(=O)OH.

As used , the term “carbamyl” refers to a group of formula -NH2.

As used herein, the term “C1_3 alkylcarbamyl” refers to a group of formula -NH(alkyl), wherein the alkyl group has 1 to 3 carbon atoms.

As used herein, the term “di(C1alkyl)carbamyl” refers to a group of formula -C(=O)N(alkyl)2, wherein the two alkyl groups each has, independently, l to 3 carbon atoms.

As used herein, the term “HO-Cn_m-alkyl” refers to a group of formula -alkylene- OH, wherein said alkylene group has n to m carbon atoms. In some embodiments, the alkylene group has 1 to 3 carbon atoms.

As used herein, the term “C0_p alkoxy-Cn_m-alkyl” refers to a group of formula - alkylene-O-alkyl, wherein said alkylene group has n to m carbon atoms and said alkyl group has 0 to p carbon atoms. In some embodiments, the alkyl and alkylene groups each independently have 1 to 3 carbon atoms.

As used herein, “halo” or en”, employed alone or in combination with other terms, includes fluoro, chloro, bromo, and iodo. In some embodiments, the halo group is fluoro or chloro.

As used herein, the term “CH—m haloalkyl”, ed alone or in combination with other terms, refers to an Cn—m alkyl group having up to {2(n to m)+l} halogen atoms which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the alkyl group has 1-6 or 1-3 carbon atoms.

Example haloalkyl groups e CF3, C2F5, CHFZ, CClg, CHClz, C2Cls, and the like. In some embodiments, the kyl group is a fluoroalkyl group.

As used herein, the term “C1_3 fluoroalkyl” refers to a C1_3 alkyl group that may be partially or completely substituted by fluoro atoms.

As used herein, “Cn_m haloalkoxy” refers to a group of formula -O-haloalkyl 1O having 11 to m carbon atoms. An example koxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “cyano-CH.m alkyl” refers to a CH.m alkyl substituted by a cyano group. In some embodiments, the alkyl group has 1 to 3 carbon atoms.

As used herein, the appearance of the term “monocyclic” before the name of a moiety indicates that the moiety has a single ring.

As used herein, the term “phenylalkyl” refers to a group of formula —alkylene- phenyl In some ments, phenylalkyl is phenyl-C1_3 alkyl.

As used herein, the term “cycloalkyl”, employed alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety, which may optionally contain one or more alkenylene groups as part of the ring structure. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, yclic, or bridged rings) ring systems. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fiased (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo derivatives of cyclopentane, cyclopentene, cyclohexane, and the like. One or more ring-forming carbon atoms of a cycloalkyl group can be oxidized to form carbonyl linkages. In some embodiments, cycloalkyl is a 3-7 membered cycloalkyl, which is monocyclic or bicyclic. In some embodiments, cycloalkyl is a 3-6 or 3-7 monocyclic cycloalkyl. Examplary lkyl groups include l,2,3,4-tetrahydro- alene, ropyl, utyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term “cycloalkylalkyl” refers to a group of a —alkylene- cycloalkyl. In some embodiments, cycloalkylalkyl is C3_7 cycloalkyl-C1_3 alkyl, wherein the cycloalkyl portion is monocyclic.

As used , the term “heteroaryl”, employed alone or in combination with other terms, 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 selected 1O from nitrogen, sulfur and oxygen. In some embodiments, heteroaryl is a 5-6 membered heteroaryl, which is monocyclic or bicyclic, comprising 1 to 5 carbon atoms and l, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

When the heteroaryl group contains more than one atom ring member, the heteroatoms may be the same or different. Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, thiazole, ole, furan, ene, or the like.

A five-membered ring aryl is a heteroaryl with a ring haVing five ring atoms wherein one or more (e. g., l, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, lyl, oxazolyl, lyl, isothiazolyl, isoxazolyl, l,2,3-triazolyl, tetrazolyl, l,2,3-thiadiazolyl, l,2,3-oxadiazolyl, l,2,4-triazolyl, l,2,4-thiadiazolyl, l,2,4- oxadiazolyl, l,3,4-triazolyl, l,3,4-thiadiazolyl, and l,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring haVing six ring atoms n one or more (e.g., l, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring heteroaryls are pyridyl, nyl, pyrimidinyl, triazinyl and zinyl.

As used herein, the term “heteroarylalkyl” refers to a group of a —alkylene- heteroaryl. In some embodiments, arylalkyl is 5-6 membered heteroaryl-C1_3 alkyl, wherein the heteroaryl portion is monocyclic, comprising 1 to 5 carbon atoms and l, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

As used herein, the term “heterocycloalkyl”, employed alone or in combination with other terms, refers to non-aromatic ring system, which may optionally contain one or more alkenylene or alkynylene groups as part of the ring structure, and which has at least one heteroatom ring member independently selected from nitrogen, sulfur and . When the heterocycloalkyl groups contains more than one heteroatom, the atoms may be the same or different. Heterocycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused, spirocyclic, or bridged rings) ring systems. Also included in the definition of heterocycloalkyl are moieties that have one or more ic rings filsed (i.e., having a bond in common with) to the non-aromatic ring, for e, 1O l,2,3,4-tetrahydro-quinoline and the like. The carbon atoms or heteroatoms in the ring(s) of the heterocycloalkyl group can be oxidized to form a carbonyl, or sulfonyl group (or other oxidized linkage) or a nitrogen atom can be quatemized. In some ments, heterocycloalkyl is 4-7 membered heterocycloalkyl, which is monocyclic, comprising 2-6 carbon atoms and l, 2, 3, or 4 heteroatom ring s independently ed from nitrogen, sulfur, and oxygen. Examples of heterocycloalkyl groups include azetidine, azepane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, pyran, and a 2- oxo- l ,3-oxazolidine ring.

As used herein, the term “heterocycloalkylalkyl” refers to a group of formula -alkylene-heterocycloalkyl. In some embodiments, heterocycloalkylalkyl is 4-7 membered heterocycloalkyl-C1_3 alkyl, wherein the heterocycloalkyl portion is clic, comprising 2-6 carbon atoms and l, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.

The compounds described herein can be asymmetric (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 c forms. Methods on how to prepare optically active forms from optically ve starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described , 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 may be isolated as a mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. An example method includes fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for onal recrystallization s are, for e, optically active acids, such as the D and L forms of tartaric acid, yltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically 1O active rsulfonic acids such as [3-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include isomerically pure forms of 0t- methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2- phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, l,2- diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., obenzoylphenylglycine).

Suitable elution solvent composition can be determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same cal formula and total charge. Example prototropic ers include ketone — enol pairs, amide - imidic acid pairs, lactam — lactim pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic , for example, lH- and 3H- imidazole, lH-, 2H- and 4H- l,2,4-triazole, lH- and 2H- isoindole, and lH- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate tution. For example, it will be recognized that the following pyrazole ring may form two tautomers: R9\2>/R1o R%/R1° HN—N N—NH It is intended that the claims cover both tautomers.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and ium. In some embodiments, l, 2, or 3 CH2 groups in the azetidine ring of Formula I are replaced by a CHD or CD2 group. In some embodiments, l, 2, or 3 CH2 or CH groups in the piperidine ring of Formula I are replaced by a CHD, CD2 or CD group, respectively. In some embodiments, l, 2, 3, 4, or 5 CH2 or CH groups in the piperidine ring of Formula I are replaced by a CHD, CD2 or CD group, respectively.

The term, und,” as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures ed. Further, compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., es and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least lly or ntially separated from the environment in which it was formed or detected. Partial separation can e, for example, a composition ed in the nds of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds of the invention, or salt thereof Methods for isolating compounds and their salts are routine in the art.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient ature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g. a reaction temperature, that is about the temperature of the room in which the reaction is carried out, for example, a temperature from about 20 0C to about 30 0C.

The present invention also includes pharmaceutically acceptable salts of the compounds bed herein. As used herein, "pharmaceutically acceptable salts" refers 1O to derivatives of the disclosed compounds wherein the parent compound is modified by ting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts e, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present ion include the non-toxic salts of the parent compound formed, for example, from xic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by tional chemical methods. Generally, such salts can be prepared by ng the free acid or base forms of these compounds with a iometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, l, iso-propanol, or l) or acetonitrile (ACN) are preferred. Lists of suitable salts are found in Remington 's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is orated herein by reference in its entirety. In some embodiments, the compounds described herein include the N—oxide forms.

Synthesis Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below. The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. le solvents can be substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are d out, e.g., temperatures which can range from the solvent's freezing temperature to the t's boiling ature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan. 1O Preparation of compounds of the invention can involve the protection and deprotection of various al groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th ed., John Wiley & Sons: New Jersey, (2007), which is incorporated herein by reference in its entirety.

Reactions can be red according to any suitable method known in the art.

For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic nce spectroscopy (e. g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., ible), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

Compounds of Formula I can be synthesized by procedures analogous to those in the schemes below. A series of bi-pyrazole derivatives 9 can be prepared according to the s outlined in Scheme 1. An aromatic acid 1 can be conveniently converted to the corresponding amide 2 by using the amide coupling reagent such as BOP, PyOP, HATU, HBTU, EDC, or CD1. Replacement of the leaving group Hal (Hal can be halogen, OTs or OTf) in 2 by 3-hydroxyazetidine to produce compound 3 can be achieved under thermal ions in a suitable t such as, but not limited to, DMSO, e, DMF, or NMP in the ce of a base such as potassium ate, cesium carbonate, or sodium carbonate; or under copper-catalyzed Ullmann type N- 2014/038388 arylation reaction conditions by using copper(I) iodide and potassium carbonate; or under palladium-catalyzed C-N bond forming reaction conditions using xanthpos, BINAP, or P(o-Tol)3 as the ligand and potassium carbonate or cesium carbonate as the base. afi- Unsaturated nitrile 5 can be obtained by Wittig’s reaction of diethyl cyanomethylphosphonate with the ketone 4 which can be prepared by Swem oxidation of 3. Michael addition of 6 with 0t,B-unsaturated nitrile 5 can afford the boronic ester 7.

Suzuki coupling of the c ester 7 with a suitable pyrazole halide 8 can afford the corresponding azole derivative 9. 1O Scheme 1 Hallg: R5 R1 2 d R5 N'R w_ o HN w_ o —>Halgg\7/ —>HO<>N \ , X N—R1 X N_R1 R3 R2 R3 R2 x N—R1 NC R3 R2 R3 RZN 4 5 R5 R5 N:—><: W140 N: W— O N N / \ N_N 4&/ X N R1 _ RWRW// x N—R1 R7/K%\R8, HN—N / R3 2 R3 R2 R7 / R8 R B SUZUKI coupling R9 / R10 0/ \O / % HN—N 7 9 A series of boronic ester derivatives 7 can be prepared according to the procedures ed in Scheme 2. Michael addition of 6 with 0t,B-unsaturated nitrile 10 can afford the boronic ester 11. Removal of the oup can be achieved under acid conditions to afford the corresponding amine 12. Replacement of the leaving group Hal in 2 by 12 can e the boronic ester 7 under thermal conditions in a le t such as, but not limited to, acetonitrile, DMSO, dioxane, DMF, or NMP in the ce of a base such as potassium carbonate, cesium carbonate, sodium carbonate, hunig’s base or DBU.

Scheme2 O 13 NJ< /:<:N% N—N o R7 6 / { NC 0% R / R8 o’B‘o 4+11 W_ o R5 N: Hal—g\_/ N: w_ o X jNH x N—Rl >< N \ , N-N R3 R2 N—N X N—R1 R7/S)\R8 2 R7MR8 R3 R2 ,B\ ,B\ 40—0“ 40—@ 12 7 A series of bi-pyrazole derivatives 21 can be prepared according to the methods 1O outlined in Scheme 3. Halo-aromatic esters 13 can be converted to the corresponding alkenes 14 by Suzuki coupling of the halo-aromatic esters 13 with vinyl boronic esters.

Alkenes 14 can be reacted with appropriately substituted ketenes (such as dichcloroketene) under 2+2 cycloadditions to give the dichlorocyclobutanones 15. Under reducing conditions (such as zinc in acetic acid under thermal conditions) the dichlorocyclobutanones 15 can be converted to cyclobutanones 16. 0t,[3-Unsaturated nitriles 17 can be formed by reaction of the cyclobutanones 16 with Homer-Wadsworth- Emmons reagent. Boronic esters 6 can be reacted with nsaturated nitriles 17 in WO 86706 Michael addition conditions in the presence of coupling agents to give the compounds 18.

Suzuki coupling of the boronic esters 18 with suitable pyrazole halides 8 can afford the ponding bi-pyrazoles 19. Hydrolysis of esters 19 under basic conditions can give the acids 20. The amides 21 can be synthesized by coupling of acids 20 with appropriately substituted amines using amide coupling reagents such as BOP, PyBop, HATU, HBTU, EDC, or CD1.

Scheme3 R5 R5 R5 CI CI W_ o \ W_ 0 W_ o Hali/ —> \ / —> O \ / x 0R11 x 0R11 X OR11 R3 R3 R3 13 14 15 R5 R5 HI}! \ B’ w_ o N\ o I —> O:<>—$\7/ /—<— >—<\wwo/ R76 X OR11 NC X OR11 —> R3 R3 16 17 R5 R5 N: wi/{o N: W— O MX 9 10 0R11 HN_,(I 8 5H“ X OR“ R7/VR8 3 R3 R7 / R8 R ,B\ Suzuki coupling R9 / R10 0 o / W HN—N 18 19 NWO N: W_ O \ / R R2 M l;l—N x OH fl \ N—N x N—R1 / R3 R7 R8 l —> 7 R3 R, R / R8 2 R9 // R10 R9 R10 HN—N HN—N 21 Processes The t application provides a process of forming the salts described herein comprising reacting 4-[3-(cyanomethyl)(3',5'-dimethyl- 1H, 1 'H—4,4'-bipyrazol- l - yl)azetidin- l -yl] -2,5 ro-N—[(l S)—2,2,2-trifluoro- l -methylethyl]benzamide with an acid selected from phosphoric acid, hydrochloric acid, hydrobromic acid, and sulfiaric acid to form the salt thereof. In some embodiments, the process utilizes from about 0.55 to 1.5 equivalents of the acid per equivalent of cyanomethyl)(3',5'-dimethyl- 1H, 1 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl]-2,5-difluoro-N—[(l S)-2,2,2-trifluoro- l - ethyl]benzamide. 1O In some embodiments, the process comprises reacting 4-[3-(cyanomethyl) (3',5'-dimethyl- 1H, 1 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl]-2,5-difluoro-N—[(l S)—2,2,2- trifluoro-l-methylethyl]benzamide with phosphoric acid in a solvent component at a temperature above room temperature to form the phosphoric acid salt of 4-[3- (cyanomethyl)-3 -(3',5 '-dimethyl- 1H, 1 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 ro- N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide. In some embodiments, the temperature is from about 40 0C to about 70 0C. In some embodiments, the temperature is about 45 0C to about 55 0C. In some embodiments, the solvent component comprises ethanol. In some embodiments, the solvent component comprises acetonitrile. In some embodiments, the solvent component comprises isopropanol. In some ments, the t component ses ol. In some embodiments, the solvent ent comprises ol and isopropanol. In some embodiments, the solvent component comprises methanol, isopropanol, and n-heptane. In some embodiments, the process fiarther comprises cooling the mixture to room temperature and filtering to isolate the salt.

In some embodiments, the process fithher comprises removing a portion of the solvent to form a concentrated mixture before said filtering. In some embodiments, a portion of the solvent is removed by distillation.

The present application fiarther provides a process of g 4-[3 -(cyanomethyl)- 3-(3',5'-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl]-2,5-difluoro-N—[(l S)—2,2,2- trifluoro-l-methylethyl]benzamide phosphoric acid salt, sing reacting 4-[3- (cyanomethyl)-3 -(3 ',5 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl]-2,5 -difluoro- 2014/038388 N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide with phosphoric acid in a solvent component comprising methanol and isopropanol at a temperature from about 40 0C to about 70 0C form a mixture comprising phosphoric acid salt of 4-[3-(cyanomethyl)—3- (3',5'-dimethyl- l H, l 'H-4,4'-bipyrazol- l etidin- l -yl]-2,5-difiuoro-N—[(l S)-2,2,2- trifiuoro-l-methylethyl]benzamide phosphoric acid salt. In some embodiments, the process fiarther comprises adding n-heptane to the mixture at a temperature from about 40 0C to about 70 0C to form a second mixture. In some ments, the reacting is conducted at a temperature from about 45 0C to about 55 0C. In some embodiments, the reacting is conducted at a temperature of about 50 0C. 1O In some embodiment, the present application further provides a process of preparing 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l - yl]-2,5-difluoro-N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide phosphoric acid salt, comprising: (a) dissolving the 4-[3-(cyanomethyl)(3',5'-dimethyl- l H, l 'H-4,4'- bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N- [(l S)-2,2,2-trifiuoro- l - methylethyl]benzamide phosphoric acid salt in ol at a temperature from about 40 0C to about 70 0C to form a first e; (b) adding n-heptane to the first mixture at a temperature from about 40 0C to about 70 0C to form a second mixture; and (c) cooling the second mixture to provide 4-[3-(cyanomethyl)—3-(3',5'- dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro-N- [(l S)-2,2,2-trifiuoro- l-methylethyl]benzamide phosphoric acid salt.

In some embodiments, the process of the preceding embodiment further comprises distilling at least a portion of the ol from the first mixture prior to step (b). In some embodiments, the s the preceding embodiment further comprises distilling at least a portion of the methanol and/or n-heptane from the second e prior to step (c). In some embodiments, steps (a) and (b) are conducted at a temperature from about 45 0C to about 55 0C. In some embodiments, steps (a) and (b) are conducted at a temperature of about 50 0C.

In some embodiments, the process comprises reacting 4-[3-(cyanomethyl) (3',5'-dimethyl- 1H, l 'H—4,4'-bipyrazol- l etidin- l -yl]-2,5-difluoro-N—[(l S)—2,2,2- trifluoro-l-methylethyl]benzamide with hydrochloric acid in a solvent component at a ature above room temperature to form the hydrochloric acid salt of 4-[3- (cyanomethyl)-3 -(3',5 '-dimethyl-1H, l 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro- N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide. In some embodiments, the reacting is conducted at a temperature at about room temperature. In some embodiments, the solvent component comprises 2-butanol. In some embodiments, the solvent component ses isopropanol. In some embodiments, the solvent component comprises 1O isopropanol and isopropylacetate. In some ments, the process further comprises filtering to e the salt. In some embodiments, the process further comprises washing the ed salt with methyl tert—butyl ether.

In some embodiments, the process comprises reacting 4-[3-(cyanomethyl) (3',5'-dimethyl- 1H, l 'H—4,4'-bipyrazol- l -yl)azetidin- l ,5-difluoro-N—[(l S)—2,2,2- ro-l-methylethyl]benzamide with hydrobromic acid in a t component at a temperature above room temperature to form the hydrobromic acid salt of 4-[3- (cyanomethyl)-3 -(3',5 thyl-1H, l 'H—4,4'-bipyrazol- l -yl)azetidin- l -yl] -2,5 -difluoro- N—[(l S)-2,2,2-trifluoro-l-methylethyl]benzamide. In some embodiments, the reacting is conducted at a temperature at about room ature. In some embodiments, the solvent component comprises isopropanol. In some embodiments, the solvent component comprises isopropanol and water. In some embodiments, the process further comprises filtering to isolate the salt. In some ments, the process further comprises washing the isolated salt with methyl tert—butyl ether.

In some ments, the process comprises reacting 4-[3-(cyanomethyl) (3',5'-dimethyl- l H, l 'H-4,4'-bipyrazol- l -yl)azetidin- l -yl]-2,5-difluoro-N—[(l S)-2,2,2- trifluoro-l-methylethyl]benzamide with sulfuric acid in a solvent component to form the sulfuric acid salt of 4-[3-(cyanomethyl)(3',5'-dimethyl-lH,l'H-4,4'-bipyrazol-l- yl)azetidin- l -yl] -2,5 -difluoro-N- [(l S)-2,2,2-trifluoro- l lethyl]benzamide. In some embodiments, the reacting is conducted at a temperature at about room temperature. In some embodiments, the solvent component comprises isopropanol. In some embodiments, the process fithher comprises filtering to e the salt. In some embodiments, the reacting is conducted at a temperature at about 60 0C. In some embodiments, the solvent component comprises isopropanol and water. In some embodiments, the process fithher ses cooling the mixture to room temperature and filtering to isolate the salt. In some embodiments, the process further comprises g the isolated salt with methyl tert—butyl ether.

Methods nds of the invention are JAK inhibitors, and the majority of the 1O compounds of the invention, are JAKl selective inhibitors. A JAKl selective inhibitor is a compound that inhibits JAKl activity entially over other Janus kinases. For example, the compounds of the invention preferentially t JAKl over one or more of JAK2, JAK3, and TYK2. In some embodiments, the compounds inhibit JAKl preferentially over JAK2 (e. g., have a JAKl/JAK2 IC50 ratio >l). In some embodiments, the compounds are about 10-fold more selective for JAKl over JAK2. In some embodiments, the compounds are about 3-fold, about 5-fold, about 10-fold, about 15- fold, or about 20-fold more selective for JAKl over JAK2 as calculated by ing IC50 at 1 mM ATP (e.g., see Example A).

JAKl plays a central role in a number of cytokine and growth factor signaling pathways that, when dysregulated, can result in or contribute to e states. For e, IL-6 levels are elevated in toid arthritis, a disease in which it has been suggested to have detrimental effects (Fonesca, J.E. et al., Autoimmunity Reviews, 8:538-42, 2009). Because IL-6 signals, at least in part, h JAKl, antagonizing IL-6 directly or indirectly through JAKl inhibition is expected to provide clinical benefit (Guschin, D., N., et al Embo J l4:l42l, 1995; Smolen, J. S., et al. Lancet 371 :987, 2008).

Moreover, in some cancers JAKl is mutated resulting in constitutive undesirable tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci U S A.106:94l4-8, 2009; Flex E., et al.] Exp Med. 205:751-8, 2008). In other autoimmune diseases and cancers elevated systemic levels of inflammatory cytokines that activate JAKl may also contribute to the disease and/or associated symptoms. Therefore, patients with such 2014/038388 diseases may benefit from JAKl inhibition. ive inhibitors of JAKl may be efficacious while avoiding ssary and potentially rable effects of inhibiting other JAK kinases.

Selective inhibitors of JAKl relative to other JAK kinases, may have multiple therapeutic advantages over less selective inhibitors. With respect to selectivity against JAK2, a number of important cytokines and growth factors signal h JAK2 ing, for example, erythropoietin (Epo) and opoietin (Tpo) nas E, et al.

Cell. 93:385-95, 1998). Epo is a key growth factor for red blood cells production; hence a paucity of Epo-dependent signaling can result in reduced numbers of red blood cells 1O 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 from which platelets are produced (Kaushansky K, NEJM 354:2034-45, 2006). As such, reduced Tpo signaling would decrease megakaryocyte numbers (megakaryocytopenia) and lower circulating platelet counts (thrombocytopenia). This can result in undesirable and/or uncontrollable ng.

Reduced inhibition of other JAKs, such as JAK3 and Tyk2, may also be desirable as humans lacking filnctional version of these s have been shown to suffer from us maladies such as severe-combined immunodeficiency or hyperimmunoglobulin E syndrome ishi, Y, et al. Immunity 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Therefore a JAKl inhibitor with reduced affinity for other JAKs would have significant advantages over a less-selective tor with respect to reduced side effects involving immune suppression, anemia and thrombocytopenia.

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

Examples of JAK-associated diseases include diseases involving the immune system including, for example, organ transplant rejection (6.g. , allograft rejection and graft versus host disease).

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 s, Crohn’s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, mune thyroid 1O disorders, chronic obstructive pulmonary disease , and the like. In some embodiments, the autoimmune disease is an autoimmune bullous skin disorder such as pemphigus vulgaris (PV) or bullous pemphigoid (BP).

Further es of JAK-associated diseases include allergic conditions such as asthma, food allergies, eszematous dermatitis, contact dermatitis, atopic dermatitis ic eczema), and rhinitis. Further examples of JAK-associated diseases include viral es such as Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV l, lla-Zoster Virus (VZV) and Human oma Virus (HPV).

Further examples of JAK-associated disease include diseases associated with cartilage turnover, for example, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze me, costal athropathy, rthritis deformans endemica, Mseleni e, Handigodu disease, degeneration resulting from f1bromyalgia, systemic lupus erythematosus, derma, or ankylosing spondylitis.

Further examples of JAK-associated disease e congenital cartilage mations, including hereditary chrondrolysis, chrondrodysplasias, and pseudochrondrodysplasias (e. g., microtia, enotia, and metaphyseal chrondrodysplasia). r examples of JAK-associated diseases or conditions include skin disorders such as psoriasis (for example, psoriasis vulgaris), atopic dermatitis, skin rash, skin irritation, skin sensitization (e.g., contact dermatitis or allergic t dermatitis). For e, certain substances including some pharmaceuticals when topically applied can WO 86706 cause skin sensitization. In some embodiments, inistration or sequential administration of at least one JAK inhibitor of the invention er with the agent causing unwanted sensitization can be helpful in treating such unwanted sensitization or itis. In some embodiments, the skin disorder is treated by topical administration of at least one JAK inhibitor of the invention.

In further embodiments, the JAK-associated disease is cancer including those characterized by solid tumors (e.g., prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi’s sarcoma, Castleman’s disease, uterine 1O leiomyosarcoma, melanoma etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic ia (ALL), acute enous leukemia (AML) or multiple myeloma), and skin cancer such as ous T-cell ma (CTCL) and cutaneous B-cell ma. Example CTCLs include Sezary syndrome and s fiJngoides.

In some embodiments, the JAK tors described herein, or in combination with other JAK inhibitors, such as those reported in US. Ser. No. 11/637,545, which is incorporated herein by reference in its entirety, can be used to treat inflammation- associated cancers. 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 atory bowel disease is s disease. In some embodiments, the inflammation-associated cancer is colitis-associated cancer. In some embodiments, the inflammation-associated cancer is colon cancer or colorectal cancer. In some embodiments, the cancer is gastric cancer, gastrointestinal carcinoid tumor, intestinal stromal tumor (GIST), adenocarcinoma, small intestine cancer, or rectal cancer.

JAK-associated diseases can fithher include those characterized by expression of: JAKZ mutants such as those haVing at least one mutation in the pseudo-kinase domain (e.g, JAK2V617F); JAKZ mutants having at least one mutation outside of the pseudo- kinase domain; JAKl mutants; JAK3 mutants; erythropoietin receptor (EPOR) mutants; or deregulated expression of CRLFZ.

JAK-associated diseases can fithher include myeloproliferative disorders (MPDs) such as polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis with d metaplasia (MMM), primary myelofibrosis (PMF), c myelogenous leukemia (CML), chronic myelomonocytic leukemia , hypereosinophilic syndrome (HES), ic mast cell disease (SMCD), and the like. In some embodiments, the roliferative disorder is brosis (e.g., primary myelofibrosis (PMF) or post polycythemia vera/essential thrombocythemia myelofibrosis PV/ET MF)). In some embodiments, the myeloproliferative disorder is post- essential thrombocythemia myelofibrosis (Post-ET MF). In some embodiments, the 1O myeloproliferative er is post polycythemia vera myelofibrosis (Post-PV MF).

In some embodiments, JAK inhibitors described herein can be further used to treat myelodysplastic me (MDS) in a t in need thereof. In some embodiments, said patient is red blood cell transfiJsion dependent.

As used herein, myelodysplastic syndromes are intended to encompass heterogeneous and clonal hematopoietic disorders that are characterized by ctive hematopoiesis on one or more of the major myeloid cell lineages. Myelodysplastic syndromes are associated with bone marrow failure, eral blood cytopenias, and a propensity to progress to acute myeloid leukemia (AML). Moreover, clonal cytogenetic abnormalities can be detected in about 50% of cases with MDS. In 1997, The World Health Organization (WHO) in conjunction with the Society for Hematopathology (SH) and the European Association of Hematopathology (EAHP) proposed new classifications for hematopoietic neoplasms (Harris, et al., J Clin Oncol 1999;17:3835-3 849; Vardiman, et al., Blood 2002;100:2292-2302). For MDS, the WHO utilized not only the morphologic criteria from the French-American-British (FAB) classification but also incorporated available genetic, biologic, and clinical characteristics to define subsets of MDS (Bennett, et al., Br J Haematol 1982;51:189-199). In 2008, the WHO classification ofMDS (Table l) was further refined to allow precise and prognostically relevant ssification of unilineage dysplasia by incorporating new clinical and ific information (Vardiman, et al., Blood 2009;114:937-951; Swerdlow, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th Edition. Lyon WO 86706 France: IARC Press; 2008:88-103; Bunning and Germing, “Myelodysplastic mes/neoplasms” in Chapter 5, Swerdlow, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. (ed. 4th edition): Lyon, France: IARC Press;2008:88-103).

Table 1. 2008 WHO Classification for De Novo Myelodysplastic Syndrome tory cytopenia with . . . Dysplasia in Z 10% of 1 cell line, Slngle or Blcytopema unilineage sia (RCUD) < 5% blasts tory anemia with ring . 15. A) of erythr01d precursors0 Anemla, no blasts w/nng Slderoblasts, erythr01d sideroblasts (RARS) dysplasia only, < 5% blasts Dysplasia in Z 10% of cells in Rjfiiffiz:):?esmg¥;th. . Cympeflffiggiésx 10 /L. 9 2 2 hematopoietic lineages, :: 15% g y p y ring sideroblasts, < 5% blasts tory anemla Wlth. . Cytopenia(s), S 2% to 4% Unilineage or multilineage blasts, < 1 X 109/L dysplasia, No Auer rods, 5% to 9% excess blasts-1 (RAEB-l) monocytes blasts Cytolplen1a(s), S 5 A) 9to 19 A). 0 0 Umhneage or mult111neaége. . . .

Refractory anemia with asts, < 1 X 10 /L dyspla51a, :: Auer rods, 10%) to excess blasts-2 (RAEB-Z) monocytes 19 A) blasts0 . Unilineage or no dysplasia but Mgggiz?é:filaién§%3ne’ Cytopenias teristic MDS cytogenetics, < 5% blasts MDS associated with isolated , platelets normal Unilineage erythroid. Isolated del(5q) or increased del(5q), < 5% blasts In some embodiments, the myelodysplastic syndrome is refractory cytopenia with unilineage dysplasia (RCUD).

In some embodiments, the myelodysplastic syndrome is refractory anemia with ring sideroblasts (RARS).

In some ments, the myelodysplastic syndrome is refractory cytopenia with multilineage dysplasia.

In some embodiments, the myelodysplastic syndrome is refractory anemia with excess blasts-l (RAEB- l ).

In some embodiments, the ysplastic syndrome is refractory anemia with excess blasts-2 (RAEB-Z).

In some embodiments, the myelodysplastic syndrome is myelodysplastic syndrome, sified (MDS-U).

In some embodiments, the ysplastic syndrome is myelodysplastic syndrome associated with isolated ).

In some embodiments, the myelodysplastic syndrome is refractory to erythropoiesis-stimulating agents.

The present invention fiarther provides methods of treating psoriasis or other skin 1O disorders by administration of a l formulation containing a compound of the invention.

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

The present invention fiarther provides a method of ng dermatological side s of other pharmaceuticals by administration of the compound of the invention. For example, numerous ceutical agents result in unwanted allergic ons which can manifest as acneiform rash or related dermatitis. Example pharmaceutical agents that have such undesirable side effects include anti-cancer drugs such as gefitinib, cetuximab, erlotinib, and the like. The compounds of the invention can be administered systemically or topically (e. g., localized to the vicinity of the itis) in ation with (e.g., simultaneously or sequentially) the pharmaceutical agent having the undesirable dermatological side effect. In some embodiments, the compound of the invention can be administered topically er with one or more other pharmaceuticals, where the other pharmaceuticals when topically applied in the absence of a compound of the invention cause contact dermatitis, allergic contact sensitization, or similar skin disorder.

Accordingly, itions of the invention include topical formulations containing the compound of the ion and a further pharmaceutical agent which can cause dermatitis, skin disorders, or related side effects.

Further JAK-associated diseases include inflammation and inflammatory diseases.

Example inflammatory diseases include sarcoidosis, inflammatory diseases of the eye (e.g., iritis, uveitis, scleritis, conjunctivitis, or related disease), atory diseases of the respiratory tract (e.g., the upper respiratory tract including the nose and sinuses such as rhinitis or sinusitis or the lower atory tract including bronchitis, chronic obstructive pulmonary disease, and the like), inflammatory myopathy such as ditis, and other atory diseases. In some embodiments, the inflammation disease of the eye is blepharitis.

The JAK inhibitors described herein can fiarther be used to treat ischemia reperfilsion injuries or a disease or condition related to an inflammatory ischemic event such as stroke or cardiac arrest. The JAK inhibitors described herein can further be used 1O to treat endotoxin-driven disease state (e.g., complications after bypass surgery or chronic endotoxin states contributing to chronic cardiac failure). The JAK inhibitors described herein can further be used to treat anorexia, cachexia, or fatigue such as that resulting from or ated with cancer. The JAK inhibitors described herein can fiarther be used to treat restenosis, sclerodermitis, or fibrosis. The JAK inhibitors described herein can further be used to treat conditions associated with hypoxia or liosis such as, for example, ic retinopathy, cancer, or neurodegeneration. See, e. g., Dudley, A.C. 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 herein by reference in their entirety. The JAK inhibitors described herein can be used to treat Alzheimer’s disease.

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

The JAK tors bed herein can further be used to treat gout and sed prostate size due to, e.g., benign prostatic hypertrophy or benign prostatic hyperplasia.

Further JAK-associated diseases include bone resorption diseases such as osteoporosis, osteoarthritis. Bone resorption can also be associated with other conditions such as hormonal imbalance and/or al therapy, autoimmune disease (e.g. osseous sarcoidosis), or cancer (e.g. myeloma). The ion of the bone resorption due to the JAK inhibitors can be about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%.

In some embodiments, JAK inhibitors described herein can further be used to treat a dry eye disorder. As used herein, “dry eye disorder” is ed to ass the disease states summarized in a recent official report of the Dry Eye Workshop (DEWS), which defined 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 accompanied by sed osmolarity of the tear film and inflammation of the ocular surface.” Lemp, “The Definition and 1O 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, which is orated herein by reference in its entirety. In some embodiments, the dry eye disorder is selected from aqueous eficient dry eye (ADDE) or evaporative dry eye er, or appropriate combinations thereof. In some embodiments, the dry eye disorder is Sjogren syndrome dry eye (SSDE). In some embodiments, the dry eye disorder is non-Sjogren me dry eye (NSSDE).

In a filrther aspect, the present invention provides a method of treating conjunctivitis, uveitis (including chronic uveitis), chorioditis, retinitis, cyclitis, sclieritis, episcleritis, or ; treating ation or pain related to corneal transplant, LASIK (laser assisted in situ mileusis), photorefractive keratectomy, or LASEK (laser assisted sub-epithelial keratomileusis); inhibiting loss of visual acuity related to corneal transplant, LASIK, photorefractive keratectomy, or LASEK; or inhibiting transplant rejection in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of the invention, or a pharmaceutically acceptable salt thereof Additionally, the compounds of the invention, or in combination with other JAK inhibitors, such as those ed in US. Ser. No. 11/637,545, which is incorporated herein by reference in its entirety, can be used to treat respiratory dysfunction or failure ated wth viral infection, such as influenza and SARS.

In some embodiments, the present invention provides a nd of Formula I, pharmaceutically acceptable salt thereof, as described in any of the ments herein, for use in a method of treating any of the diseases or ers described herein. In some ments, the present invention provides the use of a compound of Formula I as described in any of the embodiments herein, for the preparation of a medicament for use in a method of ng any of the es or disorders described herein.

In some ments, the present invention provides a compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for use in a method of modulating JAKl. In some embodiments, the present invention also provides use of a 1O compound of Formula I as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in a method of modulating JAKl.

As used herein, the term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in viva system. For example, “contacting” a JAK with a compound of the invention includes the administration of a nd of the present invention to an individual or patient, such as a human, having a JAK, as well as, for example, introducing a compound of the ion into a sample containing a cellular or purified ation containing the JAK.

As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including s, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a , system, animal, individual or human by a researcher, narian, medical doctor or other clinician. In some embodiments, the therapeutically effective amount is about 5 mg to about 1000 mg, or about 10 mg to about 500 mg.

As used herein, the term “treating” or “treatment” refers to one or more of (l) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the ogy or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting r development of the ogy and/or symptomatology); and (3) ameliorating the disease; for example, rating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as sing the severity of disease.

Combination Therapies 1O The methods described herein can further comprise administering one or more additional eutic agents. The one or more additional therapeutic agents can be administered to a patient simultaneously or sequentially.

In some ments, the method fiarther comprises administering an additional therapeutic agent selected from IMiDs, an anti-IL-6 agent, an anti—TNF-(x agent, a hypomethylating agent, and a biologic response modifier (BRM).

Generally, a BRM is a substances made from liVing organisms to treat disease, which may occur naturally in the body or may be made in the laboratory. Examples of BRMs include IL-2, interferon, various types of colony-stimulating s (CSF, GM- CSF, G-CSF), monoclonal antibodies such as abciximab, etanercept, infliximab, rituximab, trasturzumab, and high dose ate.

In some embodiments, the anti—TNF-u agent is infliximab, and etanercept.

In some embodiments, the hypomethylating agent is a DNA transferase inhibitor. In some embodiments, the DNA methyltransferase inhibitor is selected from 5 azacytidine and decitabine.

Generally, IMiDs are as immunomodulatory agents. In some ments, the IMiD is selected from thalidomide, lenalidomide, pomalidomide, CC-l 1006, and CC- 1 00 l 5 .

In some ments, the method fiarther comprises administering an additional therapeutic agent selected from anti-thymocyte globulin, recombinant human granulocyte 2014/038388 colony-stimulating factor (G CSF), granulocyte-monocyte CSF (GM-CSF), a erythropoiesis-stimulating agent (ESA), and cyclosporine.

In some ments, the method filrther comprises administering an additional JAK inhibitor to the patient. In some embodiments, the additional JAK inhibitor is tofacitinib or ruxolitinib.

One or more additional pharmaceutical agents such as, for example, chemotherapeutics, anti-inflammatory agents, ds, immunosuppressants, as well as PI3K8, mTor, Bcr—Abl, Flt-3, RAF and FAK kinase inhibitors such as, for example, those described in WC 2006/056399, which is incorporated herein by nce in its entirety, 1O or other agents can be used in combination with the compounds described herein for treatment of JAK-associated diseases, disorders or conditions. The one or more additional pharmaceutical agents can be administered to a patient simultaneously or sequentially.

Example chemotherapeutics include proteosome inhibitors (e.g., omib), thalidomide, reVlimid, and DNA-damaging agents such as melphalan, doxorubicin, cyclophosphamide, Vincristine, etoposide, tine, and the like.

Example steroids include coriticosteroids such as dexamethasone or prednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and s disclosed in US. Pat. No. 5,521,184, WO 04/005281, and US. Ser. No. 60/578,491, all of which are incorporated herein by reference in their entirety.

Example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as sed in WC 03/037347, WO 03/099771, and WO 04/046120, all of which are incorporated herein by reference in their entirety.

Example suitable RAF inhibitors e compounds, and their pharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO 05/028444, both of which are orated herein by reference in their ty.

Example suitable FAK inhibitors include compounds, and their pharmaceutically acceptable salts, as sed in WC 04/080980, WO 04/056786, WO 03/024967, W0 WO 86706 01/064655, WO 00/053595, and WO 01/014402, all of Which are incorporated herein by nce in their entirety.

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

In some embodiments, a suitable chemotherapeutical agent can be selected from antimetabolite agents, topoisomerase 1 inhibitors, um analogs, taxanes, anthracyclines, and EGFR inhibitors, and combinations thereof.

In some embodiments, antimetabolite agents include tabine, gemcitabine, 1O and fluorouracil (5-FU).

In some embodiments, taxanes include paclitaxel, Abraxane® (paclitaxel protein- bound particles for injectable suspension), and Taxotere® (docetaxel).

In some embodiments, platinum analogs include oxaliplatin, cisplatin, and carboplatin.

In some ments, topoisomerase 1 inhibitors include irinotecan and topotecan.

In some embodiment, anthracyclines include doxorubicin or liposomal formulations of doxorubicin.

In some ments, the chemotherapeutic is FOLFIRINOX (5-FU, lecovorin, irinotecan and oxaliplatin). In some embodiments, the chemotherapeutic agent is gemcitabine and Abraxane® (paclitaxel protein-bound particles for inj ectable sion).

In some embodiments, one or more JAK inhibitors of the invention can be used in combination with a chemotherapeutic in the treatment of cancer, such as multiple myeloma, and may improve the treatment response as compared to the response to the chemotherapeutic agent alone, Without exacerbation of its toxic effects. es of additional pharmaceutical agents used in the treatment of multiple myeloma, for example, can include, Without limitation, melphalan, melphalan plus prednisone [MP], doxorubicin, thasone, and Velcade zomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAK kinase WO 86706 inhibitors. Additive or synergistic s are desirable es of combining a JAK inhibitor of the present invention with an additional agent. Furthermore, resistance of multiple myeloma cells to agents such as dexamethasone may be reversible upon treatment with a JAK inhibitor of the present invention. The agents can be combined with the present compounds in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

In some embodiments, a corticosteroid such as dexamethasone is stered to a patient in combination with at least one JAK inhibitor where the dexamethasone is administered intermittently as d to continuously. 1O In some further embodiments, combinations of one or more JAK inhibitors of the invention with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow lant or stem cell transplant.

In some embodiments, the additional therapeutic agent is fluocinolone ide (Retisert®), or rimexolone (AL-2178, Vexol, .

In some embodiments, the onal therapeutic agent is cyclosporine (Restasis®).

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

In some embodiments, the additional therapeutic agent is selected from DehydrexTM (Holles Labs), Civamide (Opko), sodium hyaluronate (Vismed, Lantibio/TRB Chemedia), porine (ST-603, Sirion Therapeutics), ARGlOl(T) (testosterone, Argentis), AGRIOl2(P) (Argentis), ecabet sodium -Ista), gefamate (Santen), l5-(s)-hydroxyeicosatetraenoic acid (lS(S)-HETE), mine, doxycycline (ALTY-OSOl, Alacrity), minocycline, iDestrinTM (NP50301, Nascent Pharmaceuticals), cyclosporine A (Nova22007, Novagali), oxytetracycline (Duramycin, MOLIl901, Lantibio), CF I 01 (2S ,3 S ,4R,5R)-3 ,4-dihydroxy-5 - [6-[(3 -iodophenyl)methylamino]purin- 9-yl]-N-methyl-oxolanecarbamyl, Can-Fite Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARGlO3 (Agentis), RX-lOO45 (synthetic resolvin , Resolvyx), DYNlS (Dyanmis Therapeutics), itazone (DEOl l, Daiichi Sanko), TB4 eRx), OPH-Ol (Ophtalmis ), PCSlOl (Pericor Science), REVl-3l (Evolutec), in (Senju), rebamipide (Otsuka-Novartis), OT-SSl (Othera), PAI-2 (University of Pennsylvania and Temple University), pilocarpine, imus, pimecrolimus 1, Novartis), loteprednol etabonate, mab, diquafosol tetrasodium (INS365, Inspire), KLS-06ll (Kissei Pharmaceuticals), dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept (Embrel®), hydroxychloroquine, NGX267 (TorreyPines Therapeutics), actemra, gemcitabine, oxaliplatin, L-asparaginase, or thalidomide.

In some embodiments, the additional therapeutic agent is an anti-angiogenic 1O agent, cholinergic agonist, TRP-l receptor modulator, a calcium channel blocker, a mucin secretagogue, MUCl stimulant, a calcineurin inhibitor, a corticosteroid, a P2Y2 receptor agonist, a muscarinic receptor agonist, an mTOR inhibitor, another JAK inhibitor, Bcr—Abl kinase inhibitor, Flt-3 kinase tor, RAF kinase inhibitor, and FAK kinase inhibitor such as, for example, those described in , which is orated herein by reference in its entirety. In some embodiments, the additional therapeutic agent is a tetracycline derivative (e.g., minocycline or doxycline). In some embodiments, the additional eutic agent binds to FKBPlZ.

In some embodiments, the additional therapeutic agent is an alkylating agent or DNA cross-linking agent; an anti-metabolite/demethylating agent (e.g., S-flurouracil, tabine or idine); an anti-hormone therapy (e.g., hormone receptor antagonists, SERMs, or aromotase inhibitor); a mitotic inhibitor (e.g. vincristine or paclitaxel); an omerase (I or II) inhibitor (e.g. mitoxantrone and irinotecan); an apoptotic inducers (e.g. ABT-737); a nucleic acid therapy (e.g. antisense or RNAi); nuclear receptor ligands (e.g., agonists and/or antagonists: all-trans retinoic acid or bexarotene); epigenetic targeting agents such as histone deacetylase tors (e.g. vorinostat), hypomethylating agents (e.g. decitabine); regulators of protein stability such as Hsp90 inhibitors, ubiquitin and/or ubiquitin like conjugating or deconjugating les; or an EGFR inhibitor (erlotinib).

In some ments, the onal therapeutic agent(s) are demulcent eye drops (also known as “artificial tears”), which include, but are not limited to, compositions containing polyvinylalcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol (e. g. PEG400), or carboxymethyl cellulose. Artificial tears can help in the treatment of dry eye by compensating for reduced moistening and lubricating capacity of the tear film. In some embodiments, the additional therapeutic agent is a mucolytic drug, such as N—acetyl-cysteine, which can interact with the mucoproteins and, therefore, to decrease the viscosity of the tear film.

In some embodiments, the additional therapeutic agent includes an antibiotic, ral, antifilngal, etic, anti-inflammatory agents including dal and non- steroidal anti-inflammatories, and anti-allergic agents. Examples of suitable medicaments 1O include aminoglycosides such as amikacin, gentamycin, tobramycin, streptomycin, netilmycin, and kanamycin; fluoroquinolones such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin, and enoxacin; naphthyridine; sulfonamides; polymyxin; chloramphenicol; neomycin; mycin; colistimethate; bacitracin; vancomycin; yclines; rifampin and its derivatives (“rifampins”); cycloserine; beta-lactams; cephalosporins; amphotericins; fluconazole; flucytosine; natamycin; miconazole; ketoconazole; corticosteroids; diclofenac; flurbiprofen; ketorolac; en; yn; lodoxamide; levocabastin; naphazoline; antazoline; pheniramine; or azalide antibiotic.

Pharmaceutical Formulations and Dosage Forms When employed as pharmaceuticals, the compounds of the invention can be stered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic ent is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), ary (e.g, by inhalation or ation of powders or aerosols, ing by nebulizer; intratracheal or intranasal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, aneous, intraperitoneal intramuscular or injection or on; or intracranial, e.g. , intrathecal or intraventricular, administration.

Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may 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.

This invention also includes pharmaceutical itions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers 1O (excipients). In some embodiments, the composition is suitable for l stration. In making the compositions of the invention, the active ient is lly mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, , paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, s, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is ntially water soluble, the particle size can be adjusted by milling to provide a substantially m distribution in the formulation, 6.g. about 40 mesh.

The compounds of the ion may be milled using known milling procedures such as wet milling to obtain a particle size riate for tablet formation and for other formulation types. Finely divided articulate) preparations of the compounds of the invention can be prepared by processes known in the art, e.g., see ational App. No.

. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, m silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl ose. The formulations can additionally include: lubricating agents such as talc, magnesium te, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. 1O In some embodiments, the pharmaceutical ition comprises silicif1ed microcrystalline cellulose (SMCC) and at least one compound described , or a pharmaceutically acceptable salt thereof. In some ments, the silicified microcrystalline ose comprises about 98% microcrystalline cellulose and about 2% silicon e w/w.

In some embodiments, the composition is a sustained release composition comprising at least one nd described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt f, and at least one component ed from microcrystalline ose, lactose monohydrate, hydroxypropyl methylcellulose, and polyethylene oxide.

In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate, and hydroxypropyl cellulose. In some embodiments, the ition comprises at least one nd described herein, or a pharmaceutically 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 PHlOZTM. 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 PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LVTM). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e. g., Polyox WSR 1105““).

In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry ation s is used to produce the composition.

The compositions can be formulated in a unit dosage form, each dosage ning from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from 1 mg to about 50 mg, and from about 1 mg to 10 mg of active ingredient. Preferably, the dosage is from about 1 mg to about 50 mg or about 1 mg to about 10 mg of active 1O ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term "unit dosage forms" 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, in association with a suitable pharmaceutical excipient.

In some embodiments, the compositions se from about 1 to about 1,000 mg, from about 1 mg to about 100 mg, from 1 mg to about 50 mg, and from about 1 mg to 10 mg of active ingredient. Preferably, the compositions comprise from about 1 mg to about 50 mg or about 1 mg to about 10 mg of active ingredient. One having ordinary skill in the art will appreciate that this embodies compounds or compositions ning about 1 mg to about 10 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 50 mg of the active ingredient.

The active compound may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, ing to the relevant circumstances, ing the condition to be treated, the chosen route of administration, the actual compound stered, the age, , and response of the individual patient, the severity of the patient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition ning a homogeneous mixture of a nd of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically sed evenly throughout the ition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then ided into unit dosage forms of the type described above containing from, for example, about 0.1 to about 1000 mg of the active ingredient of the t ion. 1O The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For e, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the . The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit 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, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the present invention can be incorporated for stration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, t oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. itions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the zing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from s which deliver the formulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. In some embodiments, ointrnents can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other ents, e.g. glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be 1O formulated using isopropyl alcohol and water, suitably in combination with other components such as, for example, glycerol, hydroxyethyl cellulose, and the like. In some ments, l formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, for example, 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the stration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.

In therapeutic ations, compositions can be administered to a patient already suffering from a e in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its cations. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

The compositions administered to a t can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a e aqueous carrier prior to administration. The pH of the compound ations typically will be between 3 and 11, more preferably from 5 to 9 and most ably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the nt of the ibing physician. The proportion or tration of a compound of the invention in a pharmaceutical ition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of 1O administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ug/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the ent, and its route of administration. ive doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compositions of the invention can r include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.

In some embodiments, the nd, or pharmaceutically acceptable salt thereof, is administered as an lmic composition. Accordingly, in some embodiments, the methods comprise administration of the compound, or pharmaceutically acceptable salt thereof, and an ophthalmically acceptable carrier. In some embodiments, the ophthalmic composition is a liquid composition, semi-solid composition, insert, film, microparticles or nanoparticles.

In some embodiments, the lmic composition is a liquid composition. In some embodiments, the ophthalmic composition is a olid composition. In some embodiments, the ophthalmic composition is a topical composition. The topical itions include, but are not limited to liquid and semi-solid compositions. In some embodiments, the ophthalmic composition is a topical ition. In some ments, the topical composition comprises s solution, an aqueous suspension, an ointment or a gel. In some embodiments, the ophthalmic composition is topically d to the front of the eye, under the upper eyelid, on the lower eyelid and in the cul-de-sac. In some embodiments, the ophthalmic composition is sterilized. The sterilization can be accomplished by known techniques like sterilizing filtration of the on or by heating of the solution in the ampoule ready for use. The ophthalmic 1O compositions of the invention can further contain pharmaceutical excipients le for the ation of ophthalmic formulations. Examples of such excipients are preserving agents, buffering agents, chelating agents, antioxidant agents and salts for regulating the osmotic pressure.

As used herein, the term “ophthalmically acceptable r” refers to any material that can contain and release the compound, or pharmaceutically acceptable salt thereof, and that is compatible with the eye. In some embodiments, the ophthalmically acceptable carrier is water or an aqueous solution or suspension, but also includes oils such as those used to make ointments and polymer matrices such as used in ocular inserts. In some embodiments, the composition may be an s sion comprising the compound, or pharmaceutically acceptable salt thereof. Liquid ophthalmic compositions, including both ointments and suspensions, may have a viscosity that is suited for the selected route of administration. In some embodiments, the ophthalmic composition has a ity in the range of from about 1,000 to about 30,000 centipoise.

In some embodiments, the ophthalmic itions may further comprise one or more of surfactants, adjuvants, buffers, antioxidants, tonicity adjusters, preservatives (e. g., EDTA, BAK lkonium chloride), sodium chlorite, sodium perborate, polyquaterium-l), thickeners or viscosity modifiers (e.g., carboxymethyl cellulose, hydroxymethyl cellulose, polyvinyl alcohol, polyethylene glycol, glycol 400, propylene glycol hydroxymethyl cellulose, propyl-guar, hyaluronic acid, and hydroxypropyl cellulose) and the like. Additives in the formulation may include, but are not limited to, sodium chloride, sodium bicarbonate, sorbic acid, methyl paraben, propyl paraben, chlorhexidine, castor oil, and sodium perborate.

Aqueous ophthalmic compositions (solutions or suspensions) generally do not n physiologically or ophthalmically harmful constituents. In some embodiments, purified or zed water is used in the composition. The pH may be adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0 to 8.5. Ophthalmically acceptable examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium ide, sodium phosphate, sodium borate, sodium 1O citrate, sodium acetate, sodium lactate, hamine, trishydroxymethylamino-methane, and the like. Salts and buffers include citrate/dextrose, sodium onate, ammonium chloride and mixtures of the aforementioned acids and bases.

In some embodiments, the methods involve forming or supplying a depot of the therapeutic agent in contact with the external surface of the eye. A depot refers to a source of therapeutic agent that is not rapidly d by tears or other eye clearance mechanisms. This allows for continued, sustained high concentrations of eutic agent to be present in the fluid on the external surface of the eye by a single ation.

Without g to be bound by any theory, it is believed that absorption and penetration may be dependent on both the dissolved drug tration and the contact duration of the external tissue with the drug containing fluid. As the drug is removed by clearance of the ocular fluid and/or tion into the eye tissue, more drug is provided, e.g. dissolved, into the ished ocular fluid from the depot. Accordingly, the use of a depot may more easily facilitate loading of the ocular tissue for more insoluble therapeutic . In some embodiments, the depot can remain for up to eight hours or more. In some embodiments, the ophthalmic depot forms includes, but is not limited to, aqueous polymeric suspensions, ointments, and solid inserts.

In some embodiments, the ophthalmic composition is an ointment or gel. In some embodiment, the ophthalmic composition is an oil-based delivery vehicle. In some embodiments, the composition comprises a petroleum or lanolin base to which is added the active ingredient, usually as 0.1 to 2%, and excipients. Common bases may include, but are not limited to, mineral oil, petrolatum and ations thereof In some embodiments, the ointment is applied as a ribbon onto the lower eyelid.

In some embodiment, the ophthalmic composition is an ophthalmic insert. In some embodiments, the ophthalmic insert is ically inert, soft, bio-erodible, viscoelastic, stable to ization after exposure to eutic agents, resistant to infections from air borne bacteria, bio- le, biocompatible, and/or viscoelastic. In some embodiments, the insert ses an ophthalmically acceptable , e. g., a polymer matrix. The matrix is typically a polymer and the therapeutic agent is generally dispersed therein or bonded to the polymer matrix. In some embodiments, the therapeutic 1O agent may be slowly released from the matrix through dissolution or hydrolysis of the covalent bond. In some embodiments, the polymer is bioerodible (soluble) and the dissolution rate thereof can control the e rate of the therapeutic agent dispersed therein. In another form, the polymer matrix is a biodegradable polymer that breaks down such as by hydrolysis to thereby release the therapeutic agent bonded o or dispersed therein. In further ments, the matrix and therapeutic agent can be surrounded with an additional polymeric coating to further control release. In some embodiments, the insert comprises a biodegradable polymer such as polycaprolactone (PCL), an ethylene/vinyl acetate copolymer (EVA), polyalkyl cyanoacrylate, polyurethane, a nylon, or poly (dl-lactide-co-glycolide) (PLGA), or a copolymer of any of these. In some embodiments, the therapeutic agent is dispersed into the matrix material or dispersed amongst the monomer composition used to make the matrix material prior to polymerization. In some ments, the amount of therapeutic agent is from about 0.1 to about 50%, or from about 2 to about 20%. In fiarther embodiments, the biodegradable or bioerodible polymer matrix is used so that the spent insert does not have to be removed. As the biodegradable or bioerodible polymer is degraded or dissolved, the therapeutic agent is released.

In further embodiments, the ophthalmic insert ses a polymer, including, but are not limited to, those described in Wagh, et al., “Polymers used in ocular dosage form and drug ry systems”, Asian J. , pages 12-17 (Jan. 2008), which is incorporated herein by reference in its entirety. In some embodiments, the insert WO 86706 comprises a polymer selected from polyvinylpyrrolidone (PVP), an acrylate or methacrylate polymer or copolymer (e.g., Eudragit® family of polymers from Rohm or Degussa), hydroxymethyl cellulose, polyacrylic acid, poly(amidoamine) dendrimers, poly(dimethyl siloxane), polyethylene oxide, actide-co-glycolide), - yethylmethacrylate), poly(Vinyl alcohol), or poly(propylene fumarate). In some embodiments, the insert comprises Gelfoam® R. In some embodiments, the insert is a polyacrylic acid of 450 kDa-cysteine conjugate.

In some embodiments, the ophthalmic composition is a lmic film.

Polymers le for such films include, but are not limited to, those described in Wagh, 1O et al. (ibid), In some embodiments, the film is a soft-contact lens, such as ones made from copolymers ofN,N—diethylacrylamide and methacrylic acid crosslinked with ethyleneglycol dimethacrylate.

In some embodiments, the ophthalmic compositon comprises microspheres or nanoparticles. In some embodiment, the pheres se gelatin. In some embodiments, the microspheres are injected to the posterior segment of the eye, in the chroroidal space, in the sclera, intraVitreally or sub-retinally. In some embodiments, the microspheres or nanoparticles comprises a polymer including, but not limited to, those described in Wagh, et al. (ibid), which is incorporated herein by reference in its entirety.

In some embodiments, the polymer is chitosan, a polycarboxylic acid such as polyacrylic acid, n particles, hyaluronic acid esters, polyitaconic acid, poly(butyl)cyanoacrylate, polycaprolactone, poly(isobutyl)caprolactone, poly(lactic acid- co-glycolic acid), or poly(lactic acid). In some embodiments, the microspheres or nanoparticles comprise solid lipid particles.

In some embodiments, the lmic composition comprises an ion-exchange resin. In some embodiments, the ion-exchange resin is an inorganic zeolite or synthetic organic resin. In some embodiments, the ion-exchange resin includes, but is not limited to, those described in Wagh, et al. (ibid), which is incorporated herein by reference in its entirety. In some embodiments, the ion-exhange resin is a lly neutralized polyacrylic acid.

In some embodiments, the ophthalmic composition is an aqueous polymeric suspension. In some embodiments, the therapeutic agent or a polymeric suspending agent is suspended in an aqueous medium. In some embodiments, the s polymeric suspensions may be formulated so that they retain the same or substantially the same viscosity in the eye that they had prior to administration to the eye. In some embodiments, they may be formulated so that there is increased gelation upon contact with tear fluid.

Labeled Compounds and Assay Methods 1O r aspect of the present invention relates to labeled compounds of the invention -labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating JAK in tissue samples, including human, and for identifying JAK ligands by inhibition binding of a labeled compound. ingly, the present invention includes JAK assays that contain such labeled compounds.

The present invention fiarther includes isotopically-labeled compounds of the invention. An “isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or tuted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e. Suitable radionuclides that may be , naturally occurring). incorporated in nds of the present invention include but are not limited to 3H (also n as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 358, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro JAK labeling and competition , nds that incorporate 3H, 14C, 82Br, 125I , 131I, 358 or will generally be most useful. For radio- imaging applications 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful.

It is to be understood that a -labeled ” or “labeled compound” is a nd that has incorporated at least one radionuclide. In some embodiments the WO 86706 radionuclide is selected from the group consisting of 3H, 14C, 125I 358 and 82Br. In some embodiments, the compound incorporates l, 2, or 3 deuterium atoms.

The present invention can further include synthetic methods for incorporating radio-isotopes into compounds of the invention. Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and an ordinary skill in the art will readily ize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its y to bind a JAK by 1O monitoring its concentration variation when contacting with the JAK, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another nd which is known to bind to a JAK (z'.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the JAK directly correlates to its g affinity. Conversely, in some other ing assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled rd nd is monitored in order to te the ition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

Kits The present invention also includes pharmaceutical kits useful, for example, in the treatment or prevention of JAK-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the ion. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.

Instructions, either as s or as , indicating ties of the components to be administered, guidelines for stration, and/or guidelines for mixing the components, can also be included in the kit.

The invention will be bed in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non- critical parameters which can be changed or modified to yield essentially the same results. The compounds of the es have been found to be JAK inhibitors according to at least one assay described herein.

EXAMPLES mental procedures for compounds of the invention are provided below. 1O Open access prep. LC-MS purification of some of the compounds prepared was med on Waters mass directed fractionation systems. The basic equipment setup, protocols, and control software for the operation of these systems have been described in detail in literature. See e.g. “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem, 4, 295 (2002); “Optimizing ative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R.

Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem, 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem, 6, 874-883 (2004). The compounds separated were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity under the following ions: Instrument; Agilent 1100 series, , Column: Waters SunfireTM C18 5 um, 21 x .0 mm, Buffers: mobile phase A: 0.025% TFA in water and mobile phase B: 0.025% TFA in acetonitrile; gradient 2% to 80% of B in 3 minutes with flow rate 1.5 mL/minute.

Some of the nds prepared were also separated on a preparative scale by reverse-phase high performance liquid chromatography (RP-HPLC) with MS detector or flash chromatography (silica gel) as indicated in the examples. l preparative reverse-phase high mance liquid chromatography (RP-HPLC) column ions are as follows: pH = 2 purifications: Waters TM C18 5 um, 19 x 100 mm column, eluting with mobile phase A: 0. l% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile; the flow rate was 30 ute, the separating gradient was optimized for each nd using the Compound Specific Method Optimization protocol as described in the literature [See "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb.

Chem, 6, 874-883 (2004)]. Typically, the flow rate used with 30 x 100 mm column was 60 ute. pH = 10 ations: Waters XBridge C18 5 um, 19 x 100 mm column, eluting with mobile phase A: 0.15% NH4OH in water and mobile phase B: acetonitrile; the flow rate was 30 mL/minute, the separating nt was optimized for each compound using 1O the Compound Specific Method Optimization protocol as described in the ture [See "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem, 6, 3 (2004)].

Typically, the flow rate used with 30 x 100 mm column was 60 mL/minute.

Some of the compounds prepared were also analyzed Via Differential Scanning Calorimetry (DSC). l DSC instrument conditions are as follows: TA Instruments Differential Scanning Calorimetry, Model Q200 with autosampler. General conditions: 30 - 350 °C at 10 °C/min; Tzero aluminum sample pan and lid; nitrogen gas flow at 50 .

Some of the compounds prepared were also analyzed Via ThermograVimetric Analysis (TGA). Typical TGA instrument conditions are as follows: TA Instrument ThermograVimetric Analyzer, Model Q500. General method conditions: ramp from 20°C to 600 °C at 20 °C/min; nitrogen purge, gas flow at 40 mL/min followed by balance of the purge flow; sample purge flow at 60 mL/min; platinum sample pan.

Some of the compounds prepared were also analyzed Via X-Ray Power Diffraction (XRPD). Typical XRPD instrument conditions are as follows: Rigaku MiniFleX X-ray Powder ctometer . General experimental procedures: X-ray radiation from Copper at 1.054056A with KB filter; X-ray power is 30 KV, 15 mA; sample powder is dispersed on a zero-background sample holder. General measurement conditions: Start Angle — 3 degrees; Stop Angle — 45 degrees; Sampling — 0.02 degrees; Scan speed — 2 degree/min.

Example 1. 5-[3-(Cyan0methyl)—3-(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidin yl]-N—[(1S)-2,2,2-triflu0r0-l-methylethyl]pyrazine—Z-carboxamide trifluoroacetate NEBCNijo”mi /, I:F HN-N Step I.‘ tert—Butyl 3-(cyanomethylene)azetl'dl'ne-I—carboxylate (,FCNJ<:% To a solution of 1.0 M potassium tert—butoxide in ydrofuran (30.7 mL, 30.7 mmol) at 0 0C was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 32.2 mmol) in tetrahydrofuran (39 mL). The reaction was warmed to room ature and then cooled at 0 CC again. To the reaction e was added a solution of tert—butyl zetidine-l-carboxylate (5.0 g, 0.029 mol, from Aldrich) in tetrahydrofuran (8 mL). The on was allowed to warm to room temperature and stirred overnight. After quenched with water, the mixture was extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4, and evaporated under reduced pressure. The crude mixture was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0 - 70%) to give the desired product (5.40 g, 95%). LCMS cacld. for N202Na (M+Na)+: m/z = 217.1; Found: 2l7.l Step 2.‘ tert—Butyl 3-(cyan0methyU[4-(4, 4,5, 5-tetramethyl—1,3,2-di0xab0rolany0- IH-pyrazol—I—yljazetidine-I—carboxylate #0 N-N O O A e of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-lH-pyrazole (0.990 g, 5.10 mmol), tert—butyl 3-(cyanomethylene)azetidine-l-carboxylate (1.00 g, 5.15 mmol) and l,8-diazabicyclo[5.4.0]undecene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60 0C for 2 h. After cooling, the solvent was removed under reduced re. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product (1.68 g, 84.8%). LCMS cacld. for C15H22BN4O4 (M-55)+: m/z = 333.2; Found: 333.1. 1O Step 3 .' {3-[4-(4, 4, 5, 5-Tetramethyl—I,3,2-di0xab0r0[anyl)-IH-pyrazol—I-yl]azetz'dl'n t0m'trl'le hydrochloride i :BoO NEHCIN. 4.0 N HCl in l,4-dioxane (2.0 mL) was added to on of tert—butyl 3- (cyanomethyl)-3 - [4-(4,4,5 ,5 -tetramethyl-l ,3 ,2-dioxaborolanyl)-1H-pyrazol- l - yl]azetidine-l-carboxylate (1.68 g, 4.33 mmol) in methylene chloride (10 mL). The on mixture was stirred at room temperature overnight, and then concentrated under reduced pressure to afford the desired product as HCl salt which was directly used in the next step reaction without fiarther purification. LCMS cacld. for C14H22BN402 (M+1)+: m/z = 289.2; Found: 289.1.

Step 4.‘ 5-Ch10r0-N-[(IS)-2,2,2-trz'flu0r0-I-methylethyljpyrazinecarb0xamide CIXWNfiN— o N,N—Diisopropylethylamine (l .3 mL, 7.5 mmol) was added to a mixture of 5- chloropyrazinecarboxylic acid (0.40 g, 2.5 mmol), N,N,N',N'—tetramethyl-O-(7- azabenzotriazol-l-yl)uronium hexafluorophosphate (l .0 g, 2.8 mmol) and (2S)—l,l,ltrifluoropropanamine (0.28 g, 2.5 mmol) in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with sat. aqueous NaHCOg, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was d by flash chromatography on a silica gel column with ethyl e in hexanes (0-15%) to afford the d product (0.47 g, 1O 73%). = 254.0; Found: 253.9.

. LCMS cacld. for CgHgClF3N30 (M+l)+: m/z Step 5 .' 5-{3- (CyanomethyU[4-(4, 4, 5, 5-tetramethyl—I, 3, 2-di0xab0rolanyU-IH- pyrazol—I-yl]azetz'dz'n-I-yl}-N-[(IS)-2, 2, 2-trz'flu0r0-I—methylethyljpyrazine carboxamide A e of 5-chloro-N—[(l S)-2,2,2-trifluoro-l-methylethyl]pyrazine carboxamide (254 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)- lH—pyrazol-l-yl]azetidinyl}acetonitrile HCl salt (325 mg, 1.00 mmol) and MN- diisopropylethylamine (401 uL, 2.30 mmol) in l,4-dioxane (5.0 mL) was heated at 100 0C for 2 h. After cooling, the mixture was concentrated under reduced pressure. The e was purified by flash chromatography on a silica gel column g with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.49 g, 97%). LCMS cacld. for szHngF3N703 (M+1)+: m/z = 506.2; Found: 506.1.

Step 6.‘ tert—Butyl 4-br0m0methyl—IH-pyrazole-I—carboxylate yo(Dy—NickN A mixture of 4-bromomethyl-1H—pyrazole (0.2 g, 1 mmol), di-tert— butyldicarbonate (0.30 g, 1.4 mmol), 4-dimethylaminopyridine (0.02 g, 0.1 mmol) and triethylamine (0.26 mL, 1.9 mmol) in acetonitrile (2 mL) was d at rt overnight. The reaction mixture was concentrated, and purified by flash tography on a silica gel column eluting with ethyl e in hexanes (0-15%) to afford the desired product (0.32 g). LCMS cacld. for C5H6BrN202 (M-55)+: m/z = 2050; Found: 204.9.

Step 7.‘ 5-[3- (CyanomethyU (3 '-methyl—IH, I 'H—4, 4 '-bz'pyrazol—I—yUazetidin-I—yU—N- 1O [(1S)-2, 2,2-trl'flu0r0-I-methylethyUpyrazinecarb0xamide trz'fluoroacetate A mixture of 5-{3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)- 1H-pyrazolyl] azetidinyl} -N— [(1 S)-2,2,2-trifiuoro-1 -methylethyl]pyrazine carboxamide (27.0 mg, 0.0533 mmol), tert—butyl4-bromomethyl-1H—pyrazole ylate (15 mg, 0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (3.1 mg, 0.0027 mmol) and sodium carbonate (17.0 mg, 0.160 mmol) in 1,4-dioxane (1.6 mL) and water (0.8 mL) under nitrogen was stirred at 100 CC overnight. The reaction mixture was filtered, and purified by C (pH = 2 conditions) to afford the desired product as TFA salt. 1H NMR (300 MHz, CDgOD) 5 8.73 (d, J: 1.4 Hz, 1H), 8.18 (d, J: 0.6 Hz, 1H), 7.98 (d, J: 1.4 Hz, 1H), 7.91 — 7.79 (m, 2H), 4.84 (m, 1H), 4.81 (d, J: 10.2 Hz, 2H), 4.60 (d, J: 10.2 Hz, 2H), 3.59 (s, 2H), 2.44 (s, 3H), 1.43 (d, J: 7.1 Hz, 3H) ppm.

LCMS cacld. for C20H21F3N90 (M+1)+: m/z = 460.2; Found: 460.0. e 2. 5-[3-(Cyan0methyl)—3-(3'-methyl-1H,1'H—4,4'-bipyrazolyl)azetidin yl]-N—isopr0pylpyrazine—2-carb0xamide trifluoroacetate Step I.‘ 5-Chloro-N-z'sopropylpyrazz’necarb0xamz'de N,N—Diisopropylethylamine (2.6 mL, 15 mmol) was added to a mixture of 5- chloropyrazinecarboxylic acid (0.80 g, 5.0 mmol), benzotriazol-lyloxytris hylamino)phosphonium hexafluorophosphate (2.46 g, 5.56 mmol) and 2- propanamine (0.47 mL, 5.6 mmol) in methylene de (20 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with sat. aqueous NaHCOg, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and trated under reduced pressure.

The residue was purified by flash chromatography on a silica gel column eluting with 1O ethyl acetate in hexanes (0-15%) to afford the desired product. LCMS cacld. for CgH11C1N30(M+1)+:m/z = 2001; Found: 200.1.

Step 2.‘ 5-{3-(Cyan0methyU[4-(4, 4,5, 5-tetramethyl—I,3,2-di0xab0rolanyU-IH- pyrazol—[-yl]azetidin-I-yl}-N-z's0pr0pylpyrazinecarb0xamide A mixture of 5-chloro-N—isopropylpyrazinecarboxamide (200 mg, 1.00 mmol), {3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazolyl]azetidin yl}acetonitrile HCl salt (325 mg, 1.00 mmol, from Example 1, step 3) and MN- ropylethylamine (401 uL, 2.30 mmol) in 1,4-dioxane (5.0 mL) was heated at 100 0C for 2 h. After cooling, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 20-80%) to afford the desired product (0.26 g, 58%). LCMS cacld. for C22H31BN703 (M+1)+: m/z = 4523; Found: 4522.

Step 3 .' 5-[3-(Cyan0methyU(3 '-methyl—IH, I 'H—4,4 '-bz'pyrazol—I—yUazetidin-I—yU—N- isopropylpyrazz’necarb0xamide trz'fluoroacetate A e of tert—butyl 4-bromomethyl-1H—pyrazolecarboxylate (15.7 mg, 0.0600 mmol), 5-{3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1H—pyrazolyl]azetidinyl}-N—isopropylpyrazinecarboxamide (25 .8 mg, 0.0571 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium(II) x with romethane (1:1) (2.3 mg, 0.0028 mmol) and potassium phosphate (0.036 g, 0.17 mmol) in dioxane (0.5 mL) and water (0.2 mL) in a reaction Vial was ed and sealed. The mixture was heated at 110 CC for 3 h. After cooling, the e was diluted with methanol, filtered and purified by RP-HPLC (pH = 2 conditions) to afford the desired product as TFA salt. LCMS cacld. for C20H24N90 (M+l)+: m/z = 406.2; Found: 406. 1.

Example 3. Cyan0methyl)—3-(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidin yl]-N—is0pr0pylbenzamide trifluoroacetate 1O Step I: Ethyl 4-(3-hydr0xyazetz'din-I—yUbenzoate A mixture of ethyl obenzoate (0.841 g, 5.00 mmol, from Aldrich), azetidinol hydrochloride (0.438 g, 4.00 mmol, from Aldrich) and potassium carbonate (1 .38 g, 9.98 mmol) in dimethyl sulfoxide (4 mL) was heated at 180 CC for 2 h. After cooling, the e was diluted with ethyl acetate (50 mL), and washed with water and brine. The c layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-50%) to afford the desired product (0.643, 72.6%). LCMS cacld. for C12H16N03 (M+1)+: m/z = 2221; Found: 222.1.

Step 2: 4-(3-Hydr0xyazetz'din-I—yUbenzoz'c acid A mixture of l-[4-(3-hydroxyazetidin-l-yl)phenyl]methoxyethanone (l .33 g, 6.00 mmol) and lithium hydroxide monohydrate (504 mg, 12.0 mmol) in water (4 mL), methanol (3 mL) and THF (6 mL) was stirred at 40 CC overnight. The mixture was neutralized with 3 N HCl aqueous on (~4 mL) to pH about 7, extracted with ethyl acetate. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to afford the crude product (1.10 g, 94.9%) which was directly used in the next step without further purification. LCMS cacld. for C10H12N03 (M+l)+: m/z = 194.1; Found: 194.1.

Step 3: ydr0xyazetz'dz'n-I-yl)-N-is0pr0pylbenzamide Benzotriazolyloxytris(dimethylamino)phosphonium orophosphate (4.64 g, 10.5 mmol, from Aldrich) was added to a mixture of 4-(3-hydroxyazetidin yl)benzoic acid (1.93 g, 10.0 mmol), 2-propanamine (4.26 mL, 50.0 mmol) and MN- diisopropylethylamine (3.88 g, 30.0 mmol) in dichloromethylene (10 mL). The e was stirred at room temperature for 2 h, and diluted with dichloromethane. The mixture was washed with aqueous NaHC03 and brine, dried over NaZSO4, filtered and 1O concentrated under d pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 0-50%) to afford the desired product (2.21 g, 94.3%). LCMS cacld. for C13H19N202 (M+1)+: m/z = 235.1; Found: 235.1.

Step 4: ropyl—4-(3-0x0azetz'dz'n-I—yUbenzaml'de To a cooled (-78°C) solution of oxalyl chloride (1.05 mL, 12.4 mmol) in romethylene (20 mL) was added dropwise dimethyl sulfoxide (1.71 mL, 24.1 mmol). The e was stirred at -78°C for 10 min. Then a suspension of 4-(3- hydroxyazetidinyl)-N—isopropylbenzamide (1.72 g, 7.34 mmol) in dichloromethylene (20 mL) was added. The mixture was stirred at -78°C for 1 h, and then triethylamine (7.04 mL, 50.5 mmol) was added. The mixture was stirred at -78°C for an additional 1.5 h. The mixture was washed with aq. NaHC03 and brine, dried over NaZSO4, d and concentrated under reduced pressure. The precipitates were washed with ether and collected by filtration to afford the desired product (1.32 g, 77%) which was directly used in the next step without further purification. LCMS cacld. for C13H17N202 (M+l)+: m/z = 233.1; Found: 233.1.

Step 5: 4-[3-(Cyanomethylene)azetz'dz'n-I-yl]-N-is0pr0pylbenzamide To a cooled (at -6 - 0 oC) solution of 1.0 M potassium tert—butoxide in tetrahydrofuran (7.10 mL, 7.10 mmol) was added dropwise a solution of diethyl cyanomethylphosphonate (1.20 mL, 7.43 mmol, from Aldrich) in tetrahydrofuran (10 mL) over a period of 10 min and at -6 to 0 CC. The on was warmed and stirred at room temperature for 1 h. The reaction mixture was cooled at -6 CC again. To the reaction mixture was then added a solution ofN—isopropyl(3-oxoazetidinyl)benzamide (1.30 g, 5.60 mmol) in tetrahydrofuran (10 mL) over a period of 10 min. During this time the temperature of the reaction e was between -5 to 0 oC. The reaction was allowed to warm to room temperature and was stirred for 3 h. The reaction mixture was filtered through a pad of silica gel and washed with ethyl acetate. The filtrate was trated, and the residue was treated with ether. The precipitates formed were collected by 1O filtration to give 0.60 g the desired product. The mother liquid was concentrated under reduced re. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (gradient: 30-80%) to afford the desired product (0.21 g). The total product is 0.81 g (57%). 1H NMR (400 MHz, DMSO-d6) 8 7.91 (d, J: 7.8 Hz, 1H), 7.74 (d, J: 8.7 Hz, 2H), 6.53 (d, J: 8.7 Hz, 2H), 5.88 (p, .1: 2.3 Hz, 1H), 4.77 — 4.67 (m, 2H), 4.62 (dt, J: 5.1, 2.6 Hz, 2H), 4.06 (m, 1H), 1.12 (d, J: 6.6 Hz, 6H) ppm. LCMS cacld. for C15H18N30 (M+1)+: m/z = 256.1; Found: 256.1.

Step 6: 4-{3-(Cyan0methyU[4-(4, 4,5, 5-tetramethyl—I,3,2-di0xab0rolanyU-IH- pyrazol—I—yljazetz'dz'n-I-yl}-N-is0pr0pylbenzamide A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole (2.98 g, 15.3 mmol), 4-[3-(cyanomethylene)azetidinyl]-N—isopropylbenzamide (4.00 g, 15.7 mmol) and 1,8-diazabicyclo[5.4.0]undecene (1.17 g, 7.68 mmol) in isopropyl alcohol (10 mL) was heated at 70 0C for 1 h. The mixture was cooled down to 35 0C. To the suspension was added 30 ml of methyl tert—butyl ether (MTBE), and stirred at room temperature for 1 h. The itates formed was collected by ion, washed with MTBE, and dried under reduced pressure to afford the desired t (6.2 g 89.8%). 1H NMR (400 MHz, DMSO-d6) 5 8.35 (s, 1H), 7.90 (d, J: 7.8 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J: 8.7 Hz, 2H), 6.52 (d, J: 8.7 Hz, 2H), 4.40 (d, J: 8.6 Hz, 2H), 4.20 (d, J: 8.6 Hz, 2H), 4.05 (m, 1H), 3.65 (s, 2H), 1.24 (s, 12H), 1.12 (d, J: 6.6 Hz, 6H) ppm. LCMS cacld. for C24H33BN503 (M+1)+: m/z = 450.3; Found: 450.3.

Step 7.‘ 4-[3- (CyanomethyU (3 '-methyl—IH, 1 74, 4 '-bz'pyrazol—I—yUazetidin-I—yU—N- isopropylbenzamide oroacetate A mixture of tert—butyl 4-bromomethyl-1H—pyrazolecarboxylate (15.7 mg, 0.0600 mmol), 4-{3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1H—pyrazol-1 -yl]azetidinyl}-N—isopropylbenzamide (25 .7 mg, 0.0571 mmol), potassium phosphate (36.4 mg, 0.171 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1 :1) (2.33 mg, 6 mmol) in dioxane (0.5 mL) and water (0.2 mL) in a reaction vial 1O was degassed and sealed. The mixture was heated at 110 0C for 3 h. After cooling, the mixture was diluted with methanol, filtered and d by RP-HPLC (pH = 2 conditions) to afford the desired product as TFA salt. LCMS cacld. for C22H26N7O (M+1)+; m/z = 4042; Found: 404.1.

Example 4. 4-[3-(Cyan0methyl)—3-(3'-methyl-1H,1'H-4,4'-bipyrazol—1-yl)azetidin yl]-2,5-diflu0r0-N—[(1S)-2,2,2-triflu0r0methylethyl]benzamide roacetate - O HN-N Step I .' 2, 4, 5-Trzflu0r0-N-[(IS)-2,2,2-trz'flu0r0-I—methylethyUbenzamide To a solution of 2,4,5-trifluorobenzoic acid (5.00 g, 28.4 mmol) in acetonitrile (50 mL) was added N,N—dimethylformamide (40 uL) ed by addition of oxalyl chloride (3.60 mL, 42.6 mmol). After 90 min, the volatiles were removed under reduced pressure.

The residue was porated with acetonitrile (50 mL). The residue was then ved in methylene chloride (50 mL). This solution was added drop-wise into a cooled (ice bath) mixture of (2S)-1,1,1-trifluoropropanamine hydrochloride (5.52 g, 36.9 mmol) (from Synquest, 98% ee) in toluene (100 mL) and 0.5 M sodium hydroxide aqueous solution (142 mL, 71.0 mmol). After addition, the ice bath was removed, and the reaction was allowed to warm to rt. The on was stirred overnight. The organic layer was separated. The aqueous layer was extracted with methylene de (50 mL). The combined organic layers were washed with 20% brine (75 mL) and water (2 x 75 mL), dried over MgSO4, filtered and concentrated under d pressure to afford the desired product (6.49 g, 84%) which was ly used in the next step without further purification. 1H NMR (300 MHZ, DMSO-d6) 5 9.01 (d, J: 7.6 Hz, 1H), 7.92 — 7.50 (m, 2H), 4.76 (m, 1H), 1.31 (d, J: 7.0 Hz, 3H) ppm. LCMS cacld. for C10H8F6NO (M+1)+: m/z = 272.0; Found: 272.0. 1O Step 2.‘ 2, 5-Dz'flu0r0(3-hydr0xyazetidin-I-yl)-N-[(IS)-2, 2,2-trz'flu0r0-I- methylethyUbenzamide A mixture of 2,4,5-trifiuoro-N—[(1 S)—2,2,2-trifiuoromethylethyl]benzamide (6.39 g, 23.6 mmol), inol hydrochloride (3.19 g, 28.3 mmol) and 1,8- diazabicyclo[5.4.0]undecene (8.81 mL, 58.9 mmol) in acetonitrile (25 mL) was stirred at 80 CC for 2 h. The on mixture was diluted with EtOAc (75 mL) and washed with 1N HCl (50 mL), 1N NaHC03 (60 mL), 20% brine (50 mL) and water (75 mL). The aqueous layers were extracted with EtOAc (100 mL). The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure to yield the desired product (7.59 g, 91.8%). 1H NMR (300 MHz, DMSO-d6) 5 8.38 (dd, J: 8.9, 1.9 Hz, 1H), 7.27 (dd, J: 12.8, 6.5 Hz, 1H), 6.38 (dd, J: 12.3, 7.5 Hz, 1H), 5.71 (d, J: 6.4 Hz,1H), 4.74 (dp, J: 15.3, 7.6 Hz, 1H), 4.62 — 4.46 (m, 1H), 4.30 — 4.15 (m, 2H), 3.71 (m, 2H), 1.29 (d, J: 7.1 Hz, 3H) ppm. LCMS cacld. for C13H14F5N202 : m/z = 325.1; Found: 325.1.

Step 3 .' 2, 5-Dz'flu0r0(3-0x0azetz'dz'n-I-yl)-N-[(IS)-2, 2,2-trz'flu0r0-I - methylethyUbenzamide To a solution of 2,5-difiuoro(3-hydroxyazetidinyl)-N-[(1S)-2,2,2-trifiuoro- 1-methylethyl]benzamide (7.57 g, 23.3 mmol) in methylene chloride (93 mL) was added iodobenzene diacetate (9.40 g, 29.2 mmol) and 2,2,6,6-tetramethylpiperidinyloxy free radical (1.82 g, 11.7 mmol) (TEMPO) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with 0.5N NaHC03 (2x80 mL), 20% brine (100 mL) and water (100 mL). The aqueous layers were extracted with ethyl acetate (75 mL). The organic extracts were combined, dried over MgSO4, d and trated under reduced pressure. The residue was purified by flash chromatography on a silica gel column g with 0% to % ethyl acetate in methylene chloride to afford the crude product which was recrystallized from MTBE (50 mL) and heptane (100 mL) to give the desired product (5.44g, 72%) as colorless solid. 1H NMR (300 MHz, 6) 8 8.52 (d, J = 8.0 Hz, 1H), 7.36 (dd, J: 12.5, 6.5 Hz, 1H), 6.63 (dd, J: 12.1, 7.6 Hz, 1H), 4.90 (d, J: 2.1 Hz, 1O 4H), 4.86 — 4.68 (m, 1H), 1.31 (d, J: 7.1 Hz, 3H) ppm. LCMS cacld. for C13H12F5N202 (M+1)+: m/z = 323.1; Found: 323.0.

Step 4 .' 4-[3- (Cyanomethylene)azetidin-I—yl]-2, 5-dz'flu0r0-N-[(IS)-2, 2,2-trz'flu0r0-I— methylethyUbenzamide l cyanomethylphosphonate (1.95 mL, 11.8 mmol) was added drop-wise to a cooled (ice bath) solution of 1.0 M potassium tert—butoxide in THF (11.8 mL, 11.8 mmol) which was diluted with tetrahydrofuran (12 mL). The bath was removed and the reaction was warmed to room temperature, and stirred for 90 min. The reaction solution was cooled with an ice bath again. The above prepared solution was then added over 12 min to a cooled (ice-bath) solution of 2,5-difiuoro(3-oxoazetidinyl)-N-[(1 S)-2,2,2- trifiuoro-l-methylethyl]benzamide (4.00 g, 12.4 mmol) in tetrahydrofuran (50 mL). The reaction mixture was stirred for 30 min. The ice bath was removed, and the reaction was stirred at room ature overnight, then quenched by the addition of 20% brine (75 mL) and ethyl acetate (75 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash tography on a silica gel column with ethyl acetate in s (0% to 30%) to yield the desired product (2.6g). 1H NMR (400 MHz, DMSO-d6) 8 8.59 — 8.37 (m, 1H), 7.33 (dd, J: 12.5, 6.4 Hz, 1H), 6.59 (dd, J: 12.0, 7.4 Hz, 1H), 5.88 (m, 1H), 4.94 — 4.75 (m, 4H), 4.76 (m, 1H), 1.31 (d, J: 7.1 Hz, 3H) ppm. LCMS cacld. for C15H13F5N30 WO 86706 (M+1)+: m/z = 346.1; Found: 346.1.

Step 5: 4-{3-(Cyan0methyU[4-(4, 4,5, 5-tetramethyl—I,3,2-di0xab0rolanyU-IH- pyrazol—I—yUazetidin-I—yl}-2, u0r0-N-[(IS)-2, 2, 2-trz'flu0r0-I—methylethyUbenzamide A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole (1.00 g, 5.15 mmol), 4-[3-(cyanomethylene)azetidinyl]-2,5-difluoro-N—[(1S)-2,2,2-trifluoro- 1-methylethyl]benzamide (1.78 g, 5.15 mmol) and 1,8-diazabicyclo[5.4.0]undecene (0.31 mL, 2.1 mmol) in acetonitrile (20.2 mL) was heated at 50 CC overnight. After cooling, the solvent was d under reduced pressure. The residue was used in the 1O next step without further purification. LCMS cacld. for C24H28BF5N503 (M+1)+: m/z = 540.2; Found: 540.1.

Step 6: 4-[3-(Cyan0methyU(3 '-methyl—IH, I 'H—4,4 '-bz'pyrazol—I—yUazetidin-I—yU—l5- ro-Nf(IS)-2, 2, 2-trl'flu0r0-I-methylethyl]benzamz'detrzfluoroacetate A mixture of 4-{3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan —pyrazolyl]azetidinyl}-2,5-difluoro-N—[(1S)—2,2,2-trifluoro methylethyl]benzamide (28.8 mg, 0.0533 mmol), tert—butyl 4-bromomethyl-1H— pyrazole-l-carboxxylate (15 mg, 0.059 mmol), tetrakis(triphenylphosphine)palladium(0) (3.1 mg, 0.0027 mmol) and sodium carbonate (17.0 mg, 0.160 mmol) in 1,4-dioxane (1.6 mL) and water (0.8 mL) under nitrogen was stirred at 100 CC overnight. The on mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by RP-HPLC (pH = 2 conditions) to afford the desired product as TFA salt.

LCMS cacld. for C22H21F5N7O (M+1)+: m/z = 494.2; Found: 494.0.

Example 5. 4-[3-(1H,1'H-4,4'-Bipyrazolyl)(cyan0methyl)azetidin-l-yl]-2,5- difluoro-N—[(1S)—2,2,2-triflu0r0-l-methylethyl]benzamide trifluoroacetate I/ F II F N-NH This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 4-bromo-lH—pyrazole and 4-{3- (cyanomethyl)-3 - [4-(4,4,5 ,5 -tetramethyl-l ,3 ,2-dioxaborolanyl)- azol- l - yl] in- l -yl} -2,5 -difluoro-N— [(l S)-2,2,2-trifluoro- l -methylethyl]benzamide. LCMS cacld. for C21H19F5N7O (M+1)+: m/z = 480.2; Found: 480.0.

Example 6. 5-[3-(Cyan0methyl)—3-(3,3'-dimethyl—1H,1'H-4,4'-bipyrazol—1- yl)azetidinyl]-N—isopropylpyrazinecarb0xamide trifluoroacetate $9u x 1O HN-N Step I: tert—Butyl 3-(cyanomethyU[3-methyl—4-(4,4,5,5-tetramethyl—I,3,2- dioxaborolany0-[PI-pyrazol-I—yljazetz'dz'ne-I—carboxylate A mixture of 3-methyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)—lH- pyrazole (1.06 g, 5.10 mmol), tert—butyl 3-(cyanomethylene)azetidine-l-carboxylate (1.00 g, 5.15 mmol) and azabicyclo[5.4.0]undecene (0.38 mL, 2.6 mmol) in acetonitrile (20 mL) was heated at 60 0C for 2 h. After cooling, the solvent was d under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C16H24BN4O4 (M-55)+: m/z = 347.2; Found: 347.1.

Step 2: {3-[3-Methyl—4-(4, 4,5, 5-tetramethyl—I,3,2-di0xab0rolany0-IH-pyrazol—I- yljazetz'dinyl}acetonitrile hydrochloride 4.0 N HCl in dioxane (3 mL) was added to a on of tert—butyl 3- (cyanomethyl)-3 - [3 -methyl(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolanyl)- 1H-pyrazol- 1-yl]azetidinecarboxylate in methylene chloride (10 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under d pressure to afford the crude product as HCl salt. LCMS cacld. for C15H24BN402 (M+1)+: m/z = 303.2; Found: 303.1.

Step 3 .' CyanomethyU[3-methyl—4-(4,4,5,5-tetramethyl—I,3,2-di0xab0rolany0- azol—I—yUazetz'dz'n-I-yl}-N-z's0pr0pylpyrazinecarb0xamide A mixture of methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H- 1O pyrazolyl]azetidinyl}acetonitrile HCl salt (0.43 g, 1.3 mmol), 5-chloro-N— isopropylpyrazinecarboxamide (0.24 g, 1.2 mmol) and N,N—diisopropylethylamine (0.63 mL, 3.6 mmol) in tert—butyl alcohol (12 mL, 120 mmol) was heated at 100 CC for 4 h. After cooling, the solvent was d under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexanes (0-60%) to afford the desired product. LCMS cacld. for C23H33BN703 (M+1)+: m/z = 466.3; Found: 466.2.

Step 4: 5-[3-(Cyan0methyU(3,3 '-dimethyl—IH,I 'H-4,4 '-bz'pyrazol—I—yUazetidin-I—yU—N- isopropylpyrazinecarb0xamide trz'fluoroacetate This compound was prepared using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 4-bromomethyl-1H—pyrazole and 5- {3 -(cyanomethyl)-3 -[3 -methyl(4,4,5 ,5 methyl- 1 ,3 ,2-dioxaborolanyl)- 1H- pyrazolyl]azetidinyl}-N—isopropylpyrazinecarboxamide. LCMS cacld. for C21H26N90 (M+1)+: m/z = 4202; Found: 420.1.

Example 7. Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-diflu0r0-N—[(1S)—2,2,2-triflu0r0methylethyl]benzamide A mixture of 4-{3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)—1H—pyrazolyl]azetidinyl}-2,5-difluoro-N-[(1 S)-2,2,2-trifluoro methylethyl]benzamide (329 mg, 0.610 mmol, from Example 4, step 5), 4-bromo-3,5- dimethyl-lH—pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (320 mg, 3.0 mmol) in 1,4-dioxane (10 mL)/water (5 mL) was purged with nitrogen and d at 110 CC for 1 h. The reaction mixture was d with EtOAc, washed with water and brine, concentrated. The residue was purified first with silica gel (eluting with 0-100% EtOAc/hexanes followed by 10% 1O methanol/dichloromethane), and then by prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired t (30 mg, 9.7%). 1H NMR (500 MHz, DMSO-d6) 8 12.17 (1H, s), 8.45 (1H, d, J: 8.0 Hz), 8.10 (1H, s), 7.70 (1H, s), 7.34 (1H, m), 6.61 (1H, s), 4.77 (1H, m), 4.62 (2H, d, J: 9.0 Hz), 4.39 (1H, d, J: 9.0 Hz), 3.64 (2H, s), 2.22 (6H, s), 1.31 (6H, d, J = 7.0 Hz) ppm. LCMS calculated for F5N7O : m/z = 508.2; Found: 508.0.

Example 8. 5-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl] -N—isopropylpyrazine—2-carb0xamide N: N-— _N> CN \HN’< HN“N A mixture of 5 - {3 -(cyanomethyl)-3 -[4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan- 2-yl)—1H—pyrazolyl]azetidinyl}-N—isopropylpyrazinecarboxamide (256 mg, 0.567 mmol, from Example 2, step 2), 4-bromo-3,5-dimethyl-1H—pyrazole (119 mg, 0.681 2014/038388 mmol), dicyclohexyl(2',4',6'-triisopropylbiphenylyl)phosphine - (2'-aminobiphenyl yl)(chloro)palladium (1:1) (67 mg, 0.085 mmol) and cesium carbonate (550 mg, 1.7 mmol) in 1,4-dioxane (2 mL)/water (1 mL) was purged with nitrogen three times. The reaction was heated to 53 0C for 2 h. The mixture was diluted with EtOAc, washed with brine, concentrated. The resulting reside was purified first on silica gel (eluting with 0- 100% EtOAc/hexanes ed by 10% methanol/dichloromethane), and then by prep- LCMS (XBridge C18 , eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.1 g, 40%). 1H NMR (500 MHz, DMSO-d6) 8 8.64 (1H, d, J: 1.5 Hz), 8.12(1H, s), 8.06 1O (1H, d, J: 8.0 Hz), 7.96 (1H, d, J: 1.0 Hz), 7.71 (1H, s), 4.72 (2H, d, J: 9.5 Hz), 4.49 (1H, d, J: 9.5 Hz), 4.08 (1H, m), 3.68 (2H, s), 2.22 (6H, s), 1.16 (6H, d, J: 6.5 Hz) ppm. LCMS calculated for C21H26N90 (M+H)+: m/z = 420.2; Found: 420.0.

Example 9. 5-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-N-[(1S)-2,2,2-triflu0r0methylethyl]pyrazine—Z-carboxamide trifluoroacetate Step 1. [3-8 ',5 '-Dimethyl—IH,I 'H—4,4 yrazol—I-yl)azetz'dinyl]acet0nitrile hydrochloride A e of tert—butyl 3-(cyanomethyl)[4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1H—pyrazolyl]azetidinecarboxylate (3 81 mg, 0.981 mmol, from Example 1, step 2), 4-bromo-3,5-dimethyl-1H—pyrazole (206 mg, 1.18 mmol), tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.098 mmol) and sodium carbonate (310 mg, 2.9 mmol) in 1,4-dioxane (10 mL) and water (5 mL) was purged with N2 and stirred at 110 CC for 2 h. The reaction mixture was filtered, diluted with EtOAc, then washed with water. The organic layer was concentrated and purified on silica gel (eluting with 0-100% EtOAc/hexanes followed by 0-10% MeOH/dichloromethane) to give tert- butyl 3-(cyanomethyl)-3 -(3',5 '-dimethyl- 1H, 1 'H—4 ,4'-bipyrazolyl)azetidine carboxylate (90 mg, 26%). LCMS ated for C18H25N602 (M+H)+: m/z = 3572; Found: 357.2. This intermediate was treated with 4.0 M hydrogen chloride in dioxane (1.2 mL, 4.9 mmol) in methylene chloride (1 mL) at rt for 2 h. The e was stripped to dryness to give the desired product. LCMS calculated for N6 (M+H)+: m/z = 257.1; Found: 257.1.

Step 2. 5-[3-(CyanomethyU(3 ',5 '-dz'methyl—IH, I 'H-4,4 '-bz'pyrazol—I—yUazetidin-I—yU— )-2, 2, 2-trz'flu0r0-I-methylethyUpyrazinecarb0xamide trz'fluoroacetate A mixture of [3-(3',5'-dimethyl-1H,1'H—4,4'-bipyrazolyl)azetidin yl]acetonitrile hloride (13 mg, 0.039 mmol), 5-chloro-N-[(1S)-2,2,2-trifluoro methylethyl]pyrazinecarboxamide (11 mg, 0.043 mmol, from Example 1, step 4) and N,N—diisopropylethylamine (28 ML, 0.16 mmol) in tert-butyl alcohol (1 mL) was heated at 100°C for 2 h. After cooling, the mixture was diluted with MeOH and purified on prep-LCMS (pH=2 conditions) to give the desired producr as TFA salt (4.1 mg, 22%).

LCMS calculated for C21H23F3N90 (M+H)+: m/z = 4742; Found: 474.0.

Example 10. 5-[3-(Cyanomethyl)(3-methyl-1H,1'H-4,4'-bipyrazolyl)azetidin yl]-N—is0pr0pylpyrazinecarb0xamide trifluoroacetate Step I : tert—Butyl 4-br0m0 -IH-pyrazole-I—carboxylate This compound was prepared by using procedures analogous to those described for the synthesis of Example 1, Step 6 ng from 4-bromo-1H-pyrazole. LCMS ated for C4H4BrN202 (M-55)+: m/z = 191.0; Found: 190.9 Step 2 : 5-[3-(CyanomethyD (3-methyl—IH, 1 74, 4 '-bz'pyrazol—I—yUazetidin-I—yU—N- isopropylpyrazz'necarb0xamide trz'fluoroacetate This compound was prepared as TFA salt by using procedures ous to those described for the synthesis of Example 4, Step 6 starting from tert—butyl 4-bromo-lH- le- l -carboxylate and 5- {3-(cyanomethyl)[3-methyl(4,4,5 ,5-tetramethyl- l ,3 ,2-dioxaborolanyl)- lH-pyrazol- l -yl] azetidin- l -yl} -N—isopropylpyrazine carboxamide. LCMS calculated for C20H24N90 (M+l)+: m/z = 406.2; Found: 406. 1.

Example 11. 5-[3-(Cyan0methyl)—3-(3'-ethyl—1H,1'H-4,4'-bipyrazol—1-yl)azetidin yl]-N—[(1S)-2,2,2-triflu0r0-l-methylethyl]pyrazine—Z-carboxamide roacetate “vb—42H 1O This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 5-{3-(cyanomethyl)[4- (4,4,5 ,5 -tetramethyl-l ,3 ,2-dioxaborolanyl)- l H-pyrazol- l -yl] in- l -yl} -N- [(l S)- 2,2,2-trifluoro-l-methylethyl]pyrazinecarboxamide (Example 1, Step 5) and 4-bromo- 3-ethyl-lH-pyrazole. LCMS calculated for C21H23F3N90 (M+l)+: m/z = 474.2; Found: 474.0. e 12. 4-{3-(Cyan0methyl)—3-[3'-(hydr0xymethyl)—1H,1'H-4,4'-bipyrazol yl] inyl}-2,5-diflu0r0-N—[(1S)—2,2,2-triflu0r0methylethyl]benzamide trifluoroacetate Step I.‘ (4-Br0m0-IH-pyrazol—5-y0methanol Sodium tetrahydroborate (0.13 g, 3.4 mmol) was added to a solution of 4-bromo- lH—pyrazole-S-carbaldehyde (0.30 g, 1.7 mmol, from Maybridge) in tetrahydrofuran (5 mL). The reaction e was stirred at 50 CC for 1 h. The reaction mixture was quenched with saturated aqueous NaHC03, and extracted with ethyl acetate (3 x 20 mL).

The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the crude product which was directly used in the next step reaction without fiarther ation. LCMS ated for rO (M+1)+: m/z = 177.0; Found: 176.9.

Step 2 .' 4-{3-(CyanomethyU[3 '-(hydroxymethyU-IH, 1 74, 4 '-bz'pyrazol—I—yljazetidin-I- yl}-2, 5-dzflu0r0-N-[(IS)-2, 2,2-trz'flu0r0-I—methylethyUbenzamide trz'fluoroacetate 1O This compound was prepared as TFA salt by using procedures analogous to those described for the sis of Example 4, Step 6 starting from cyanomethyl)[4- (4,4,5 ,5 -tetramethyl-1,3 ,2-dioxaborolanyl)-1H—pyrazolyl]azetidinyl}-2,5 - difluoro-N— [(1 S)-2,2,2-trifluoromethylethyl]benzamide and (4-bromo- 1H-pyrazol-3 - yl)methanol. LCMS calculated for C22H21F5N702 (M+1)+: m/z = 510.2; Found: 510.0.

Example 13. 4-{3-(Cyan0methyl)—3-[3-(hydr0xymethyl)—3'-methyl-1H,1'H-4,4'- bipyrazol-l-yl]azetidinyl}-2,5-diflu0r0-N—[(1S)—2,2,2-triflu0r0 methylethyl]benzamide Step I . Ethyl 4-br0m0-I-{3-(cyanomethyU-I-[2, 5-dz'flu0r0({[(IS)-2, 2, 2-trz'flu0r0-I— methylethyUamino}carbonybphenyUazetidinyl}-IH-pyrazolecarb0xylate To a microwave Vial was added isopropyl alcohol (10 mL), ethyl 4-bromo-1H— pyrazolecarboxylate (from ChemBridge) (788 mg, 3.60 mmol), 1,8- diazabicyclo[5.4.0]undecene (48.9 uL, 0.327 mmol) and 4-[3- (cyanomethylene)azetidinyl]-2,5-difluoro-N— [(1 S)—2,2,2-trifluoro methylethyl]benzamide (from Example 4 step 4, 1.13 g, 3.27 mmol). The reaction e was stirred at 80 CC for 2 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified with flash chromatography (eluting with 0- % ethyl e in hexanes) to give the desired product as white foam. 1H NMR (500 MHz, DMSO) 5 8.61 (s, 1H), 8.47 (d, J: 8.7 Hz, 1H), 7.34 (dd, J: 12.5 and 6.3 Hz, 1H), 6.62 (dd, J: 11.9 and 7.3 Hz, 1H), 4.76 (dt, J: 15.5 and 7.8 Hz, 1H), 4.61 (d, J: 9.2 Hz, 2H), 4.39 (d, J: 8.0 Hz, 2H), 4.32 (q, J: 7.1 Hz, 2H), 3.68 (s, 2H), 1.31 (m, 6H) ppm. LCMS calculated for C21H20BrF5N503 (M+H)+: m/z = 564.1; Found: 563.8.

Step 2. Ethyl I—{3-(cyan0methy0-I—[2,5-dzflu0r0({[(IS)-2,2,2-trz'flu0r0-I— 1O methylethyl]amino}carb0nyl)phenyl]azetidinyl}-3 '-methyl—IH, I 'H—4, 4 '-bz'pyrazole carboxylate To a microwave vial were charged with utyl alcohol (1.2 mL), and water (1.2 mL), cesium fluoride (683 mg, 4.50 mmol), ethyl 4-bromo {3-(cyanomethyl) [2,5 -difluoro( { [(1 S)-2,2,2-trifluoromethylethyl]amino}carbonyl)phenyl]azetidin-3 - yl}-1H—pyrazolecarboxylate (725 mg, 1.28 mmol) and 3-methyl(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1H—pyrazole (401 mg, 1.93 mmol), followed by Pd- 127 (49 mg, 0.064 mmol) (from Johnson Mathew). The reaction mixture was heated at 85°C for 48 h. The reaction was cooled to room temperature, diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over Na2S04, trated. The resulting residue was d with flash chromatography (eluting with 30-100% ethyl acetate in hexanes) to give the desired product as an oil.

LCMS calculated for C25H25F5N703 (M+H)+: m/z = 566.2; Found: 566.0.

Step 3. 4-{3-(CyanomethyU[3-(hydroxymethyU-3 '-methyl—IH,I 'H—4,4 '-bz'pyrazol—I— yljazetidin-I-yl}-2, 0r0-N-[(IS)-2, 2,2-trl'flu0r0-I—methylethyUbenzamide To a solution of ethyl 1-{3-(cyanomethyl)[2,5-difluoro({[(1S)-2,2,2- trifluoromethylethyl]amino} carbonyl)phenyl] azetidin-3 -yl} -3 '-methyl-1H 1 'H—4,4'- bipyrazolecarboxylate (35 mg, 0.062 mmol) in THF (0.5 mL) was added 2.0 M lithium tetrahydroborate in THF (0.12 mL, 0.25 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was ed with water slowly. The aqueous layer was extracted with ethyl acetate. The organic layer was concentrated. The resulting residue was purified with prep-LCMS (XBridge C18 , eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. 1H NMR (400 MHZ, CDClg) 5 7.79 — 7.68 (m, 2H), 7.61 (s, 1H), 6.65 (m, 1H), 6.20 (m, 1H), 4.99 — 4.89 (m, 1H), 4.68 (s, 2H), 4.60 (d, J: 8.5 Hz, 2H), 4.45 (dd, J: 8.9 and 2.0 Hz, 2H), 3.38 (s, 2H), 2.34 (s, 3H), 1.41 (d, J: 7.0 Hz, 3H). LCMS calculated for C23H23F5N702 (M+H)+: m/z = 5242; Found: 524.0. e 14. 4-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H—4,4'-bipyrazol 1O yl)azetidinyl]-2,5-diflu0r0-N—[(1S)-2,2,2-triflu0r0methylethyl]benzamide oric acid salt dure 1) To 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl-1H 1 'H-4 ,4'-bipyrazolyl)azetidin yl]-2,5-difluoro-N—[(1S)-2,2,2-trifluoromethylethyl]benzamide (24.8 mg, 0.0489 mmol) was added l (0.3 mL) and the mixture was stirred to form a clear solution.

Phosphoric acid in isopropanol (0.064 mL, 1 M, 0.064 mmol, 1.3 eq.) was added and the mixture was stirred for 2 minutes to form a slurry. This slurry was then stirred uously overnight. This mixture was filtered, and the filter cake washed with methyl tert—butyl ether (MTBE). The filter cake was air-dried to afford the title salt (26.3 mg, 88.9%). The X-ray powder diffraction (XRPD) pattern was determined for the phosphoric acid salt and is shown in Figure 1. A list of 2-theta peaks is provided in Table 2 below.

Table 2 -12.854 -13.577 -14.741 -15.967 WO 86706 16.557 1061 81.6 18.021 299 19.907 87.6 .791 100 21.267 19.1 22.556 168 12.9 23.77 949 73 24.667 55.1 .698 70.2 26.159 33.4 27.392 10.8 28.647 15.3 29.667 19.3 .411 333 25.6 31.213 141 10.9 32.115 6.5 32.893 13.1 33.572 8.4 34.449 8.3 .264 6.3 .741 36.709 13.1 37.381 103 7.9 38.828 4.9 39.443 117 40.559 41.227 43.396 4.7 44.1 n WO 86706 Example 15. 4-[3-(Cyanomethyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide phosphoric acid salt (Procedure 2) To 4- [3 -(cyan0methyl)-3 -(3',5 '-dimethyl-1H 1 'H-4 ,4'-bipyrazolyl)azetidin yl]—2,5-diflu0r0-N—[(1S)-2,2,2-trifiuoromethylethyl]benzamide (24.6 mg, 0.0485 mmol) was added acetonitrile (0.3 mL) and the mixture was stirred to form a clear solution. Phosphoric acid in panol (0.063 mL, 1 M, 0.063 mmol, 1.3 eq.) was added and the mixture was stirred for 2 h to form a slurry, which was then stirred continuously overnight. This mixture was d, and the filter cake washed with MTBE. The filter cake was air-dried to afford the title salt (26.27 mg, 89.5%). The XRPD pattern was determined for the phosphoric acid salt and is shown in Figure 2. A list of 2-theta peaks is provided in Table 3 below.

Table 3 2—Theta- H% 6.884 499 54.1 8.305 n 9.7 11.868 17.9 12.945 32.8 13.685 411 44.6 14.831 125 13.6 16.116 368 40 16.656 818 88.8 17.528 19.9 18.135 278 30.1 .003 91.7 .898 921 100 21.335 19.3 22.409 15.1 22.701 14.6 23.894 77.2 108 11.8 76 $9990.09“w\o\1t\)\loo Example 16. 4-[3-(Cyanomethyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide phosphoric acid salt (Procedure 3) To 4- [3 -(cyan0methy1)-3 -(3',5 thy1-1H 1 'H-4 ,4'-bipyraz01y1)azetidin y1]—2,5-difluoro-N-[(1S)-2,2,2-trifluoromethy1ethy1]benzamide (98.93 mg, 0.195 mmol) was added isopropanol (1.23 mL) and the mixture was stirred to form a clear solution. Phosphoric acid in isopropanol (0.273 mL, 1 M, 0.273 mmol, 1.4 eq.) was added and the mixture stirred for 1 h at 70°C to form a slurry. This slurry was then cooled to room temperature and stirred overnight. This mixture was filtered, and the 2014/038388 filter cake washed with MTBE. The filter cake was air-dried to afford the title salt (109.1 mg, 92.4%). The XRPD pattern was determined for the phosphoric acid salt and is shown in Figure 3. A list of 2-theta peaks is provided in Table 4 below.

Table 4 2—Theta Height H% 6.856 1268 100 8.237 133 10.5 11.765 209 16.5 12.859 343 N \1 13.596 472 37.2 14.74 127 H O .931 403 31.8 16.569 912 \lN 17.425 177 13.9 17.964 18.495 117 $09“ No.) 19.926 876 .783 865 68.2 21.274 197 15.6 22.561 152 ,_. 23.727 634 kl] ON 24.637 370 29.2 .706 443 U.) UI 26.157 290 22.9 27.597 117 28.627 120 $0.0 mo.) 29.682 151 11.9 .389 186 14.6 31.186 103 32.128 55 32.872 995” \le 33.483 72 5.7 Example 17. 4-[3-(Cyanomethyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)-2,2,2-trifluoromethylethyl]benzamide phosphoric acid salt (Procedure 4) Step I. CyanomethyU(3 ',5 '-dimethyl—IH, I 'H-4,4 yrazol—I—yUazetidin-I—yU— 2, 5-dzflu0r0-N-[(IS)-2,2,2-trz'flu0r0-I—methylethyljbenzamide phosphoric acid salt (crude) To a clear on of 4-[3-(cyan0methy1)(3',5'-dimethy1—1H,1'H—4,4'- bipyrazoly1)azetidiny1] -2,5 -difluoro-N—[(1S)—2,2,2-triflu0r0 1O methylethy1]benzamide (405.0 g, 798.1 mmol) in methanol (520.0 mL) and isopropanol (2550.0 mL) at 50 0C was added an aqueous on of 85% phosphoric acid (119.65 g, 1037.8 mmol) in isopropanol (120.0 mL) over 18 minutes to form a slurry. The resulting slurry was stirred at 50 0C for 1 h. n-Heptane (4050.0 mL) was then added to the slurry over 40 min, while maintaining the internal temperature of the slurry between 46 to 53 0C. After the addition of n-heptane, the slurry was gradually cooled to room temperature and stirred at room temperature for 19 h. The solids were then collected by filtration, washed with a mixture of isopropanol and n-heptane (3 : 10 by volume, 2 X 700 mL) followed by n-heptane (3 X 550 mL), and dried under vacuum at room ature to afford crude 4-[3-(cyan0methy1)—3 -(3',5 '-dimethy1— 1H 1 'H-4,4'-bipyraz01— 1 -y1)azetidin y1]-2,5-difluor0-N—[(1S)—2,2,2-trifluor0methy1ethy1]benzamide phosphoric acid salt (434.6 g, 89.9% yield). 2014/038388 Step 2. 4-[3-(CyanomethyU(3 ',5 '-dimethyl—IH, I 'H—4,4 '-bz'pyrazol—I—yUazetidin-I—yU— 2, 5-dl'flu0r0-N-[(IS)-2, 2,2-trz'flu0r0-I-methylethyl]benzamz'de phosphoric acid salt (purified) Into a 22 L round bottom flask equipped with an ad stirring mechanism and a Teflon-coated thermocouple was added 4-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H- 4,4'-bipyrazolyl)azetidinyl]-2,5 -difluoro-N-[( 1 S)—2,2,2-trifluoro methylethyl]benzamide phosphoric acid salt of Step 1 (958.3 g, 1583 mmol) and methanol (MeOH, 9583.0 mL) at room temperature. The ing slurry was heated to 1O 50 0C to give a clear, orange colored solution. The solution was polish filtered, transferred back to the 22 L flask and heated to reflux to distill methanol (4793 g, 6090 mL) over 70 min. Isopropanol (7700 mL) was then added to the flask over 30 min while maintaining the on temperature n 50 to 65 0C. After complete addition of isopropanol, n-heptane (14400 mL) was added portion-wise while maintaining a gentle distillation of the solvent mixture (MeOH, IPA and n-heptane) over 2.5 h. A total of 10818 g (15000 mL) of the solvent mixture was distilled. The resulting slurry was gradually cooled to room temperature, and stirred at room temperature for 17 h. The solids were ted by filtration, washed with a mixture of isopropanol and n-heptane (1 : 5 by volume, 3000 mL) followed by n-heptane (3 x 4000 mL), and dried under vacuum at room temperature to afford the title compound as off-white crystalline powder (925.7 g, 96.6% yield).

The phosphoric acid salt was shown to be a 1:1 salt by 1H NMR and crystallinity was confirmed by XRPD. 1H NMR (400 MHZ, DMSO-d6): 5 9.35 (br. s, 4H), 8.50 (d, J = 8.9 Hz, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.34 (dd, J: 12.5, 6.4 Hz, 1H), 6.61 (dd, J: 12.0, 7.4 Hz, 1H), 4.86 — 4.69 (m, 1H), 4.61 (d, J: 8.9 Hz, 2H), 4.38 (d, J: 8.9 Hz, 2H), 3.64 (s, 2H), 2.21 (s, 6H), 1.30 (d, J: 7.1 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) 5 162.8, 156.7 (d, JCF = 246.5 Hz), 146.9 (d, JCF = 236.1 Hz), 141.6 (dd, JCF = 13.0, 11.7 Hz), 140.3, 138.3, 125.8 (q, JCF = 281.8 Hz), 125.6, 117.2, 116.4 (dd, JCF = 22.3, 4.6 Hz), 115.1, 111.3 (dd, JCF = 15.7, 5.8 Hz), 107.7 102.0 (dd, JCF = 29.5, 4.5 Hz), 62.3, 57.7, 57.7, 45.8 (q, JCF = 30.5 Hz), 27.0, 13.3 (d, JCF = 1.7 Hz), 11.7. C23H22F5N7O (calc. MW 2014/038388 507.46); LCMS: (E1) m/e 508.1 (M+ + H). DSC showed a sharp melting peak at about 227.62°C (onset at 224.45 0C) as shown in Figure 4A. The title compound showed a weight loss ofO. 129% up to 200 °C as shown in Figure 4B. The XRPD pattern was determined for the phosphoric acid salt and is shown in Figure 4C. A list of 2-theta peaks is provided in Table 5 below.

Table 5 135 HWl—‘MNHOMHHN\lQ-bkllOO\l®\l-I>J> 108 H U.) 260 U.) N Example 18. 4-[3-(Cyanomethyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide hydrochloric acid salt (Procedure 1) To 4- [3 -(cyan0methy1)-3 -(3',5 '-dimethy1-1H 1 'H-4 ,4'-bipyraz01y1)azetidin -diflu0r0-N—[(1S)-2,2,2-trifiuoromethy1ethy1]benzamide (97.64 mg, 0.192 mmol) was added 2-butan01 (1.2 mL) and the mixture was stirred for 2 min to afford a clear solution. Hydrochloric acid in isopropanol/isopropylacetate (0.29 mL, 1 M in IPA/IPAc from 3.7 M HC1 in IPAc, 0.29 mmol, 1.5 eq.) was added to give a clear on. This solution was stirred for 6 min to form a slurry. This slurry was then d at room temperature for 5 h. The slurry was then filtered and the filter cake was washed with MTBE. The filter cake was dried under vacuum for 12 h at 45-50°C to afford the title salt (97.8 mg, 93.4%). DSC showed a sharp melting peak at about 213.07°C (onset at 209.22°C) as shown in Figure 5A. The title compound showed a weight loss of 4.635% up to about 210°C as shown in Figure 5B. The XRPD n was determined for the hydrochloric acid salt and is shown in Figure 5C. A list of 2-theta peaks is provided in Table 6 below.

Table 6 2—Theta H% 7.067 38 12.234 289 53 13.716 56.4 14.48 133 24.4 14.784 54 .459 52.9 16.259 33.1 16.609 65.7 17.121 347 63.5 19.486 129 23.5 .439 27 21.259 17.4 22.865 223 40.8 23.857 61.3 24.771 100 .704 37.4 26.496 51.9 27.429 61.1 28.354 194 35.6 28.71 19.3 31.472 12.8 31.84 117 21.4 34.09 21.5 40.551 10.6 41.48 13.8 44.075 9.7 e 19. 4-[3-(Cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide hydrochloric acid salt (Procedure 2) To 4- [3 -(cyan0methyl)-3 -(3',5 '-dimethyl-1H 1 'H-4 ,4'-bipyrazolyl)azetidin yl]—2,5-difluoro-N—[(1S)-2,2,2-trifiuoromethylethyl]benzamide (52.12 mg, 0.103 mmol) was added isopropanol (0.5 mL) and the mixture was stirred for 3 min to form a clear solution. Hydrochloric acid in isopropanol/isopropylacetate (0.144 mL, 1 M in 1O IPA/IPAC from 3.7 M HCl in IPAC, 0.144 mmol, 1.4 eq.) was then added, resulting in a clear solution. This clear solution was stirred for 6-8 minutes to form a slurry. This slurry was then d at room temperature for 5 h. The slurry was then filtered and the filter cake was washed with MTBE. The filter cake was air-dried to afford the title salt (51.2 mg, 91.6%). The XRPD pattern was ined for the hydrochloric acid salt and is shown in Figure 6. A list of 2-theta peaks is provided in Table 7 below.

Table 7 2—Theta- H% 6.967 47.1 12.082 76.8 13.388 202 58 13.71 43.1 14.831 29.1 .438 27.9 16.243 174 50.1 16.634 348 100 16.97 54.2 17.576 21.8 19.672 n 27.5 .758 40.6 21.163 27.1 Example 20. 4-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol tidinyl]-2,5-diflu0r0-N—[(1S)—2,2,2-triflu0r0methylethyl]benzamide hydrobromic acid salt To 4- [3 -(cyanomethyl)-3 -(3',5 '-dimethyl-1H 1 'H-4 ,4'-bipyrazolyl)azetidin yl]-2,5-difluoro-N—[(1S)-2,2,2-trifiuoromethylethyl]benzamide (54.74 mg, 0.108 mmol) was added isopropanol (0.6 mL) and the mixture was stirred for 3 min to give a clear solution. Hydrobromic acid in isopropanol/water (0.151 mL, 1 M IPA/water from 1O 48% HBr in water, 0.144 mmol, 1.4 eq.) was added, resulting in a clear solution, which was then stirred for about 8 minutes to form a slurry. This slurry was stirred at room temperature for 5 h. The slurry was then filtered and the filter cake was washed with MTBE. The filter cake was ied to afford the title salt (53.12 mg, 83.7%). DSC showed a sharp melting peak at about 203.19°C (onset at 199.260C) as shown in Figure 7A. The title nd showed only slight weight loss up to about 100°C as shown in Figure 7B. The XRPD pattern was determined for the hydrobromic acid salt and is shown in Figure 7C. A list of 2-theta peaks is provided in Table 8 below. 2014/038388 Table 8 2—Theta H% 7.007 36.6 12.179 20.1 12.445 116 16.8 13.468 n 12.4 14.377 42.9 .042 9.4 .622 27.6 16.211 140 20.1 17.051 281 40.5 17.407 12.5 18.5 19.583 17.5 .222 308 44.4 21.104 347 50 22.821 376 54.2 23.484 338 48.8 23.663 137 19.8 24.279 19.8 24.889 100 .425 171 24.7 .99 26.62 29.3 27.095 47.6 27.483 116 16.7 28.208 382 55.1 28.572 22.9 29.801 19.3 .33 12.8 31.278 23 31.971 9.5 33.731 17.1 34.608 103 14.8 Example 21. 4-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide sulfuric acid salt (Procedure 1) To 4- [3 -(cyanomethyl)-3 -(3',5'-dimethyl-1H,1'H—4 ,4'-bipyrazolyl)azetidin yl]—2,5-difluoro-N—[(1S)-2,2,2-trifiuoromethylethyl]benzamide (47 mg, 0.103 mmol) was added isopropanol (0.5 mL) and the mixture was stirred for 3 min to give a clear solution. SulfiJric acid in isopropanol (0.5 M in IPA from 98% sulfuric acid, 0.051 mmol, 0.55 eq.) was added, resulting in a clear solution, which was then stirred for 6-8 1O minutes to form a . This slurry was then d at room temperature for 5 h. The slurry was then filtered and the filter cake was washed with MTBE. The filter cake was air-dried to afford the title salt (18.84 mg, 33.6%). DSC showed two endotherms at 136.16 0C and 146.97 0C (onset at 122.15 0C) and a sharp endotherm at 259.16 0C (onset at 255.09 0C) as shown in Figure 8A. The XRPD pattern was determined for the ic acid salt and is shown in Figure 8B. A list of 2-theta peaks is provided in Table 9 below.

Table 9 2014/038388 13.642 56 6.8 .207 -m 17.412 n 7.3 18.978 15.2 19.628 823 100 .002 21.256 212 25.8 24.625 691 .002 n 26.529 15 27.083 174 21.1 28.18 175 21.2 .706 11.1 32.369 6.4 34.766 n 11.6 38.298 38.663 42.485 5.8 Example 22. 4-[3-(Cyan0methyl)—3-(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol yl)azetidinyl]-2,5-difluoro-N—[(1S)—2,2,2-trifluoromethylethyl]benzamide sulfuric acid salt (Procedure 2) To 4- [3 -(cyanomethy1)-3 -(3',5 '-dimethy1-1H 1 'H-4 ,4'-bipyrazoly1)azetidin y1]-2,5-difluoro-N—[(1S)-2,2,2-trifiuoromethy1ethy1]benzamide (27.91 mg, 0.055 mmol) was added isopropanol (0.5 mL) to form a clear solution. Sulfiiric acid in water (1.0 M, 0.06 mmol, 1.09 eq.) was added and the resulting mixture was stirred to form a slurry. This slurry was heated to 60°C and stirred to yield a clear solution. The solution was cooled to room temperature and stirred continuously ght. The resulting mixture was filtered and the filter cake was washed with MTBE. The filter cake was then dried to afford the title salt. The XRPD pattern was determined for the sulfuric acid salt and is shown in Figure 9. A list of a peaks is provided in Table 10 below.

Table 10 4.843 191 22.5 7.313 218 25.8 9.856 116 13.7 12.556 11.2 13.61 14.703 42.6 .261 7.5 16.309 17.3 18.941 17.6 19.611 847 100 .952 13 .3 21.242 241 28.4 21.708 11.8 24.609 73.2 26.513 130 15.3 27.026 126 14.8 28.19 19.7 .659 a 32.346 “ 34.711 38.597 41.082 42.435 Example A: In vitro JAK Kinase Assay Compounds herein were tested for inhibitory ty of JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104. The tic domains of human JAKl (a.a. 837-1142), JAK2 (a.a. 828-1132) and JAK3 (a.a. 781-1124) with an inal His tag were expressed using baculovirus in insect cells and purified. The catalytic actiVity of JAKl, JAK2 or JAK3 was assayed by measuring the phosphorylation of a biotinylated peptide. The phosphorylated peptide was detected by l_iomogenous time resolved fluorescence (HTRF). ICsos of compounds were measured for each kinase in the 40 microL ons that contain the enzyme, ATP 1O and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT, and 0.1 mg/mL (0.01%) BSA. For the 1 mM IC50 measurements, ATP concentration in the reactions was 1 mM. Reactions were carried out at room temperature for 1 hour and then stopped with 20 uL 45 mM EDTA, 300 nM , 6 nM Eu-Py20 in assay buffer (Perkin Elmer, Boston, MA). Binding to the Europium labeled antibody took place for 40 minutes and HTRF signal was measured on a Fusion plate reader n Elmer, Boston, MA). See Table 11 for data related to compounds of the examples.

Table 11. IC50 data for JAK enzyme assay (at 1 mM ATP) *300 nM or less (+); >300 nM to 1000 nM (++); >1000 nM (+++); >700 nM (++++) Example B: Cellular Assays Cancer cell lines dependent on cytokines and hence JAK/STAT signal transduction, for growth, can be plated at 6000 cells per well (96 well plate format) in RPMI 1640, 10% FBS, and 1 nG/mL of appropriate ne. Compounds can be added to the cells in DMSO/media (final concentration 0.2% DMSO) and incubated for 72 hours at 37 oC, 5% C02. The effect of compound on cell viability is assessed using the 1O CellTiter-Glo Luminescent Cell Viability Assay ga) followed by TopCount (Perkin Elmer, Boston, MA) quantitation. Potential off-target effects of compounds are measured in parallel using a non-JAK driven cell line with the same assay readout. All experiments are typically med in duplicate.

The above cell lines can also be used to examine the effects of compounds on phosphorylation of JAK kinases or potential ream substrates such as STAT proteins, Akt, Shp2, or Erk. These ments can be performed following an overnight cytokine starvation, followed by a brief preincubation with compound (2 hours or less) and cytokine stimulation of approximately 1 hour or less. Proteins are then ted from cells and analyzed by techniques familiar to those schooled in the art including Western blotting or ELISAs using antibodies that can differentiate between phosphorylated and total protein. These experiments can utilize normal or cancer cells to investigate the activity of compounds on tumor cell survival biology or on mediators of inflammatory disease. For example, with regards to the latter, cytokines such as IL-6, IL- 12, IL-23, or IFN can be used to stimulate JAK activation resulting in phosphorylation of STAT protein(s) and potentially in transcriptional profiles sed by array or qPCR technology) or production and/or secretion of proteins, such as lL-17. The ability of compounds to inhibit these cytokine mediated effects can be measured using techniques common to those ed in the art.

Compounds herein can also be tested in cellular models designed to evaluate their y and activity against mutant JAKs, for example, the JAK2V617F mutation found in myeloid proliferative disorders. These experiments often utilize ne dependent 1 06 WO 86706 cells of hematological lineage (6.g. BaF/3) into which the wild-type or mutant JAK kinases are ectopically expressed (James, C., et al. Nature 434:1144-1148; Staerk, J et al. JBC 280:41893-41899). Endpoints e the effects of compounds on cell survival, proliferation, and phosphorylated JAK, STAT, Akt, or Erk proteins.

Certain compounds herein can be evaluated for their activity ting T-cell eration. Such as assay can be considered a second cytokine (1.6. JAK) driven proliferation assay and also a simplistic assay of immune suppression or inhibition of immune activation. The following is a brief outline of how such experiments can be med. Peripheral blood mononuclear cells (PBMCs) are prepared from human 1O whole blood samples using Ficoll Hypaque separation method and T-cells (fraction 2000) can be obtained from PBMCs by elutriation. y isolated human T-cells can be maintained in culture medium (RPMI 1640 supplemented with10% fetal bovine serum, 100 U/ml penicillin, 100 ug/ml streptomycin) at a density of 2 x 106 cells/ml at 37 CC for up to 2 days. For IL-2 stimulated cell proliferation analysis, T-cells are first treated with Phytohemagglutinin (PHA) at a final concentration of 10 ug/mL for 72 hours. After washing once with PBS, 6000 cells/well are plated in 96-well plates and treated with compounds at different concentrations in the culture medium in the presence of 100 U/mL human IL-2 ec-Tany TechnoGene; Rehovot, Israel). The plates are incubated at 37 CC for 72h and the proliferation index is assessed using CellTiter-Glo Luminescent reagents following the manufactory suggested protocol (Promega; Madison, WI).

Example C: In vivo anti-tumor efficacy Compounds herein can be evaluated in human tumor xenograft models in immune compromised mice. For e, a tumorigenic variant of the INA-6 cytoma cell line can be used to inoculate SCID mice subcutaneously (Burger, R., et al. Hematol J. 2:42-53, 2001). Tumor bearing animals can then be ized into drug or vehicle treatment groups and different doses of compounds can be administered by any number of the usual routes including oral, i.p., or continuous infilsion using implantable pumps.

Tumor growth is followed over time using calipers. Further, tumor samples can be harvested at any time after the initiation of treatment for analysis as described above (Example B) to evaluate compound effects on JAK activity and downstream signaling pathways. In addition, selectivity of the compound(s) can be assessed using xenograft tumor models that are driven by other know kinases (e.g. Bcr-Abl) such as the K562 tumor model.

Example D: Murine Skin Contact Delayed Hypersensitivity Response Test Compounds herein can also be tested for their eff1cacies (of inhibiting JAK targets) in the T-cell driven murine delayed ensitivity test model. The murine skin 1O contact delayed-type hypersensitivity (DTH) response is considered to be a valid model of clinical t dermatitis, and other T-lymphocyte mediated immune disorders of the skin, such as psoriasis (Immunol Today. 1998 Jan;19(1):37-44). Murine DTH shares le characteristics with psoriasis, including the immune infiltrate, the accompanying increase in inflammatory cytokines, and keratinocyte hyperproliferation. Furthermore, many classes of agents that are efficacious in treating psoriasis in the clinic are also effective tors of the DTH response in mice (Agents s. 1993 Jan;38(1-2):116- 2 1).

On Day 0 and 1, Balb/c mice are sensitized with a l application, to their shaved abdomen with the antigen nitro-fluorobenzene (DNFB). On day 5, ears are measured for thickness using an engineer’s micrometer. This measurement is recorded and used as a baseline. Both of the animals’ ears are then challenged by a topical application of DNFB in a total of 20 uL (10 uL on the internal pinna and 10 uL on the external pinna) at a concentration of 0.2%. -four to seventy-two hours after the challenge, ears are measured again. Treatment with the test compounds is given throughout the sensitization and challenge phases (day -1 to day 7) or prior to and throughout the challenge phase (usually afternoon of day 4 to day 7). Treatment of the test compounds (in different concentration) is administered either systemically or topically (topical ation of the ent to the ears). Efficacies of the test compounds are indicated by a ion in ear swelling comparing to the ion without the treatment. Compounds causing a reduction of 20% or more were considered efficacious. In some experiments, the mice are challenged but not sensitized (negative control).

The inhibitive effect (inhibiting activation of the JAK-STAT pathways) of the test compounds can be confirmed by immunohistochemical analysis. Activation of the JAK- STAT pathway(s) results in the formation and translocation of functional transcription s. Further, the influx of immune cells and the increased proliferation of keratinocytes should also provide unique sion profile changes in the ear that can be investigated and quantified. Formalin fixed and n ed ear sections (harvested after the challenge phase in the DTH model) are subjected to 1O histochemical analysis using an antibody that specifically interacts with phosphorylated STAT3 (clone 58E12, Cell Signaling Technologies). The mouse ears are treated with test nds, vehicle, or dexamethasone (a clinically efficacious treatment for psoriasis), or without any treatment, in the DTH model for comparisons.

Test compounds and the dexamethasone can e similar transcriptional s both qualitatively and quantitatively, and both the test compounds and dexamethasone can reduce the number of infiltrating cells. Both systemically and topical administration of the test compounds can produce inhibitive effects, z'.e., reduction in the number of infiltrating cells and inhibition of the transcriptional changes.

Example E: In vivo anti-inflammatory activity Compounds herein can be evaluated in rodent or non-rodent models designed to replicate a single or x inflammation response. For instance, rodent models of arthritis can be used to evaluate the therapeutic potential of compounds dosed preventatively or therapeutically. These models include but are not limited to mouse or rat collagen-induced arthritis, rat adjuvant-induced tis, and collagen antibody- induced arthritis. Autoimmune diseases ing, but not limited to, multiple sclerosis, type I-diabetes mellitus, uveoretinitis, thyroditis, myasthenia gravis, immunoglobulin nephropathies, myocarditis, airway sensitization a), lupus, or colitis may also be used to evaluate the therapeutic potential of compounds herein. These models are well established in the research community and are familiar to those schooled in the art (Current Protocols in Immunology, Vol 3., Coligan, J.E. et al, Wiley Press.; Methods in Molecular Biology: Vol. 225, Inflammation ols., Winyard, PG. and Willoughby, D.A., Humana Press, 2003.).

Example F: Animal Models for the ent of Dry Eye, Uveitis, and Conjunctivitis Agents may be evaluated in one or more preclinical models of dry eye known to those schooled in the art including, but not limited to, the rabbit avalin A (ConA) lacrimal gland model, the amine mouse model (subcutaneous or transdermal), the Botulinumn mouse lacrimal gland model, or any of a number of spontaneous rodent auto- immune models that result in ocular gland dysfunction (e.g. NOD-SCID, MRL/lpr, or NZB/NZW) (Barabino et al., Experimental Eye Research 2004, 79, 613-621 and Schrader et al., Developmental Opthalmology, Karger 2008, 41, 298-312, each of which is incorporated herein by reference in its entirety). Endpoints in these models may include histopathology of the ocular glands and eye (cornea, etc.) and ly the classic er test or modified versions thereof (Barabino et al.) which measure tear production. Activity may be assessed by dosing via le routes of administration (e. g. systemic or topical) which may begin prior to or after measurable disease exists.

Agents may be evaluated in one or more preclinical models of uveitis known to those schooled in the art. These include, but are not d to, models of experimental autoimmune uveitis (EAU) and endotoxin induced uveitis (EIU). EAU experiements may be performed in the rabbit, rat, or mouse and may involve passive or activate immunization. For ce, any of a number or retinal antigens may be used to sensitize animals to a relevant immunogen after which animals may be challenged y with the same antigen. The EIU model is more acute and involves local or systemic administration of lipopolysaccaride at sublethal doses. Endpoints for both the EIU and EAU models may include fundoscopic exam, histopathology amongst others. These models are reviewed by Smith et al. ology and Cell Biology 1998, 76, 497-512, which is incorporated herein by reference in its entirety). Activity is assessed by dosing via multiple routes of stration (e.g. systemic or topical) which may begin prior to or after measurable disease exists. Some models listed above may also develop scleritis/episcleritis, chorioditis, cyclitis, or iritis and are therefore useful in investigating the potential activity of compounds for the therapeutic ent of these diseases.

Agents may also be evaluated in one or more preclinical models of conjunctivitis known those schooled in the art. These include, but are not limited to, rodent models ing guinea-pig, rat, or mouse. The guinea-pig models include those utilizing active or passive zation and/or immune challenge protocols with antigens such as min or ragweed wed in Groneberg, D.A., et al., y 2003, 58, l 101- 1113, which is orated herein by reference in its entirety). Rat and mouse models 1O are similar in general design to those in the guinea-pig (also reviewed by Groneberg).

Activity may be assessed by dosing via multiple routes of stration (e.g. systemic or topical) which may begin prior to or after measurable disease exists. Endpoints for such studies may include, for example, histological, immunological, biochemical, or molecular is of ocular tissues such as the conjunctiva.

Example G: In vivo protection of bone Compounds may be evaluated in s preclinical models of osteopenia, osteoporosis, or bone resorption known to those schooled in the art. For example, ovariectomized rodents may be used to evaluate the y of compounds to affect signs and markers of bone remodeling and/or density (W.S.S. Jee and W. Yao, J Musculoskel.

Nueron. Interact., 2001, 1(3), 193-207, which is incorporated herein by reference in its entirety). Alternatively, bone density and architecture may be evaluated in control or compound treated rodents in models of therapy (e.g. glucocorticoid) induced osteopenia (Yao, et al. Arthritis and Rheumatism, 2008, 58(6), 3485-3497; and id. 58(l l), 1674- 1686, both of which are incorporated herein by reference in its entirety). In addition, the effects of compounds on bone resorption and density may be evaluable in the rodent models of arthritis discussed above (Example E). Endpoints for all these models may vary but often include histological and radiological assessments as well as immunohisotology and appropriate biochemical markers of bone remodeling.

Example H: $100A9 Transgenic Mouse Model It was previously shown that S100A9 transgenic mice display bone marrow accumulation ofMDSC accompanied by development of progressive multilineage cytopenias and cytological dysplasia similar to MDS. Further, early forced maturation of MDSC by either all-trans-retinoic acid treatment or active immunoreceptor tyrosine- based activation motif—bearing (ITAM-bearing) r protein (DAPl2) interruption of CD33 ing d the hematologic phenotype and ted the disease. This system can be useful to test the effects on JAKl inhibition on MDS-like disease in a preclinical model. J. Clin. Invest., 123(1 l):4595-46ll (2013), Accordingly, a JAKl 1O selective inhibitor is dosed by oral gavage. The compound’s ability to reduce the cytopenias and cytological sia observed in the SI 00A9 transgenic mice is monitored.

Various modifications of the invention, in addition to those described herein, will be apparent to those d in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in the present application, including all , patent applications, and publications, is incorporated herein by reference in its entirety.

Claims (40)

WHAT IS CLAIMED IS:

1. A compound of Formula I: N O Y Cy1 N N N R2 R7 R8 R1 R9 R10 HN N or a ceutically acceptable salt thereof; wherein: Cy1 is phenyl, pyridyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by 1, 2, 3, or 4 groups independently selected from R3, R4, R5, and R6; Y is N or CH; R1 is C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-3 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl-C1-3 alkyl, , phenyl-C1-3 alkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl-C1-3 alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C1-3 alkyl, -OH, -O(C1-3 , -CN, -CF3, -CHF2, - CH2F, -NH2, -NH(C1-3 , -N(C1-3 alkyl)2, -C(=O)N(C1-3 alkyl)2, -C(=O)NH(C1-3 alkyl), -C(=O)NH2, -C(=O)O(C1-3 alkyl), -S(=O)2(C1-3 alkyl), -S(=O)2(C3-6 cycloalkyl), -C(=O)(C3-6 lkyl), and -C(=O)(C1-3 alkyl); R2 is H or C1-3 alkyl; wherein said C1-3 alkyl is optionally substituted by 1, 2, or 3 substituents ndently selected from fluoro, chloro, -OH, 3 alkyl), - CN, -CF3, -CHF2, -CH2F, NH2, -3 alkyl), and -N(C1-3 alkyl)2; or R1 and R2, together with the en atom to which they are attached, form a 4-, 5- or 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, -OH, -O(C1-3 alkyl), -CN, C1-3 alkyl, C1-3 haloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, -CH2CN, and -CH2OH; R3 is H, F, Cl, -CN, C1-3 alkyl, C1-3 fluoroalkyl, -O(C1-3 alkyl), or -O(C1-3 fluoroalkyl); R4 is H, F, Cl, -CN, C1-3 alkyl, C1-3 fluoroalkyl, -O(C1-3 alkyl), or -3 fluoroalkyl); R5 is H, F, Cl, -CN, C1-3 alkyl, C1-3 fluoroalkyl, -O(C1-3 alkyl), or -OC(C1-3 fluoroalkyl); R6 is H, F, Cl, -CN, C1-3 alkyl, C1-3 fluoroalkyl, 3 alkyl), or -OC(C1-3 fluoroalkyl); R7 is H, F, Cl, C1-3 alkyl, C1-3 haloalkyl, -NR17R17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b, or -S(=O)2NR17aR17b, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, -CN, -CF3, - CHF2, -CH2F, -NH2, -NH(CH3), -N(CH3)2, OH, -OCH3, -OCF3, -OCHF2, and - OCH2F; R8 is H, F, Cl, C1-3 alkyl, or C1-3 kyl; R9 is H, F, Cl, C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, -CN, -NH2, -NH(C1-3 alkyl), or -N(C1-3 alkyl)2, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R10 is H, F, Cl, C1-3 alkyl, C1-3 haloalkyl, ropyl, -CN, -NH2, -NH(C1-3 alkyl), or -N(C1-3 alkyl)2, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R17 is C1-6 alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally substituted with 1, 2, 3 or 4 independently selected R27 substituents; R17a is H or C1-3 alkyl; R17b is C1-3 alkyl optionally substituted with 1, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, 3), -N(CH3)2, OH, -OCH3, and -OCF3, , and -OCH2F; and each R27 is independently selected from halo, -OH, NO2, -CN, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, cyano-C1-3 alkyl, HO-C1-3 alkyl, -3 hydroxyalkyl, C1-3 alkoxy-C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, H2N-, (C1-3 alkyl)NH-, (C1-3 2N-, HS-, C1-3 alkyl-S-, C1-3 alkyl-S(=O)-, C1-3 alkyl- S(=O)2-, carbamyl, C1-3 arbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkyl- C(=O)-, C1-4 alkoxy-C(=O)-, C1-3 alkyl-C(=O)O-, C1-3 alkyl-C(=O)NH-, C1-3 alkyl- S(=O)2NH-, H2N-SO2-, C1-3 alkyl-NH-S(=O)2-, (C1-3 alkyl)2N-S(=O)2-, H2NS H-, C1-3 alkyl-NHS(=O)2NH-, (C1-3 alkyl)2N-S(=O)2NH-, H2N-C(=O)NH-, C1-3 alkyl-NHC(=O)NH-, and (C1-3 2N-C(=O)NH-; wherein the compound is not cyanomethyl)(3',5'-dimethyl-1H,1'H- 4,4'-bipyrazolyl)azetidinyl]-2,5-difluoro-N-[(1S)-2,2,2-trifluoro methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

2. The nd of claim 1, having Formula Ia: N W O N N X N R1 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof, wherein: X is N or CR4; and W is N or CR6.

3. The nd of claim 1, having Formula Ia: N W O N N X N R1 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof; wherein: X is N or CR4; W is N or CR6; Y is N or CH; R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-C1-3 alkyl, 4-6 membered heterocycloalkyl, or 4-6 membered heterocycloalkyl-C1-3 alkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, chloro, C1-3 alkyl, -OH, -O(C1-3 alkyl), -CN, -CF3, -CHF2, -CH2F, -NH2, -NH(C1-3 , -N(C1-3 alkyl)2, -C(=O)N(C1-3 alkyl)2, -C(=O)NH(C1-3 alkyl), -C(=O)NH2, -C(=O)O(C1-3 , -S(=O)2(C1-3 alkyl), -S(=O)2(C3-6 cycloalkyl), - C(=O)(C3-6 cycloalkyl), and -C(=O)(C1-3 alkyl); R2 is H or C1-3 alkyl; wherein said C1-3 alkyl is optionally substituted by 1, 2, or 3 substituents independently selected from fluoro, chloro, -OH, -O(C1-3 alkyl), - CN, -CF3, -CHF2, -CH2F, NH2, -NH(C1-3 alkyl), and -N(C1-3 alkyl)2; or R1 and R2, together with the nitrogen atom to which they are attached, form a 4-, 5- or 6-membered heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, -OH, -O(C1-3 alkyl), -CN, C1-3 alkyl, C1-3 haloalkyl, -NH2, -NH(C1-3 alkyl), -N(C1-3 alkyl)2, and -CH2CN; R3 is H, F, Cl, -CN, C1-3 alkyl, -OCF3, -CF3, or -O(C1-3 alkyl); R4 is H, F, Cl, -CN, C1-3 alkyl, or -O(C1-3 alkyl); R5 is H, F, Cl, -CN, C1-3 alkyl, or -O(C1-3 alkyl); R6 is H, F, Cl, -CN, or C1-3 alkyl; R7 is H, F, Cl, C1-3 alkyl, C1-3 haloalkyl, -NR17R17a, -NHC(=O)R17b, -C(=O)NR17aR17b, -NHS(=O)2R17b, or -S(=O)2NR17aR17b, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 substituents selected from F, Cl, -CN, -CF3, - CHF2, -CH2F, -NH2, and OH; R8 is H, F, Cl, C1-3 alkyl, or C1-3 haloalkyl; R9 is H, F, Cl, C1-3 alkyl, C1-3 haloalkyl, cyclopropyl, -CN, -NH2, -NH(C1-3 alkyl), or -N(C1-3 alkyl)2, wherein said C1-3 alkyl is optionally substituted with 1, 2, or 3 tuents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R10 is H, F, Cl, C1-3 alkyl, C1-3 kyl, cyclopropyl, -CN, -NH2, -NH(C1-3 , or -N(C1-3 alkyl)2, wherein said C1-3 alkyl is optionally tuted with 1, 2, or 3 substituents selected from F, chloro, -CN, -CF3, -CHF2, -CH2F, -NH2, and OH; R17 is C1-6 alkyl, phenyl or 5-6 membered heteroaryl, each of which is optionally tuted with 1, 2, 3 or 4 substituents independently ed from R27; R17a is H or C1-3 alkyl; R17b is C1-3 alkyl optionally substituted with 1, 2, or 3 substituents ed from F, , -CN, -CF3, -CHF2, -CH2F, -NH2, and OH and each R27 is independently selected from halo, -OH, NO2, -CN, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, C1-3 haloalkyl, cyano-C1-3 alkyl, HO-C1-3 alkyl, CF3-C1-3 hydroxyalkyl, C1-3 alkoxy-C1-3 alkyl, C3-7 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, H2N-, (C1-3 NH-, (C1-3 alkyl)2N-, HS-, C1-3 alkyl-S-, C1-3 alkyl-S(=O)-, C1-3 alkyl- S(=O)2-, carbamyl, C1-3 alkylcarbamyl, di(C1-3 alkyl)carbamyl, carboxy, C1-3 alkyl- C(=O)-, C1-4 alkoxy-C(=O)-, C1-3 alkyl-C(=O)O-, C1-3 alkyl-C(=O)NH-, C1-3 alkyl- S(=O)2NH-, 2-, C1-3 alkyl-NH-S(=O)2-, (C1-3 alkyl)2N-S(=O)2-, H2N- S(=O)2NH-, C1-3 alkyl-NHS(=O)2NH-, (C1-3 alkyl)2N-S(=O)2NH-, H2N-C(=O)NH-, C1-3 alkyl-NHC(=O)NH-, and (C1-3 alkyl)2N-C(=O)NH-.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or C3-6 cycloalkyl-C1-3 alkyl, wherein said C1-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-3 alkyl, are each optionally substituted with 1, 2, or 3 substituents ndently selected from fluoro, - CF3, and methyl; R2 is H or ; R3 is H, F, or Cl; R4 is H or F; R5 is H or F; R6 is H or F; R7 is H, methyl, ethyl or -; R8 is H or methyl; R9 is H, methyl or ethyl; and R10 is H, methyl, ethyl or HO-CH2-.

5. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is N.

6. The compound of any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

7. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein X is N.

8. The compound of any one of claims 2 to 6, or a pharmaceutically acceptable salt thereof, wherein X is CR4.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4 is H or F.

10. The nd of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein W is N.

11. The compound of any one of claims 2 to 9, or a pharmaceutically acceptable salt thereof, wherein W is CR6.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, n R6 is H, F, or Cl.

13. The compound of claim 11, or a pharmaceutically acceptable salt f, wherein R6 is H or F.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R6 is H.

15. The nd of any one of claims 2 to 14, or a ceutically acceptable salt thereof, wherein R3 is H or F.

16. The compound of any one of claims 2 to 15, or a pharmaceutically acceptable salt thereof, wherein R5 is H or F.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2 is H or methyl.

18. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2 is H.

19. The compound of any one of claims 1 to 18, or a ceutically acceptable salt thereof, wherein R1 is C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or C3-6 cycloalkyl- C1-3 alkyl, wherein said C1-6 alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-C1-3 alkyl, are each optionally substituted with 1, 2, or 3 substituents independently selected from fluoro, -CF3, and methyl.

20. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R1 is pyl, ethyl, 1-methylpropyl, 2,2,2-trifluoro methylethyl, 1-cyclopropylethyl, cyclopropyl, 1-trifluoromethylcyclopropyl, 1- cyclopropyl-2,2,2-trifluoroethyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl.

21. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R1 is isopropyl, ethyl, 1-methylpropyl, or 2,2,2-trifluoro methylethyl.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R7 is H, methyl, ethyl, or -.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R8 is H or methyl.

24. The compound of any one of claims 1 to 22, or a ceutically acceptable salt thereof, n R8 is H.

25. The compound of any one of claims 1 to 24, or a pharmaceutically able salt thereof, wherein R9 is H, methyl or ethyl.

26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R9 is H.

27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R9 is .

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R10 is H, methyl, ethyl, or HO-CH2-.

29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R10 is H.

30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, n R10 is methyl.

31. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R10 is ethyl.

32. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R10 is HO-CH2-.

33. The compound of any one of claims 1-4, 8-9, and 11-32, or a ceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula II: R6 R5 N O N N N R1 R3 R4 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1-4, 8-10, and 15-32, or a pharmaceutically acceptable salt thereof, wherein the nd of Formula I is a compound of a III: R6 R5 N O N N N N R1 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof.

35. The compound of any one of claims 1-4, 7, 10, and 15-32, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I is a compound of Formula IV: N N O N N N N R1 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof.

36. The compound of any one of claims 1-4, 8-9, and 11-32, or a pharmaceutically acceptable salt thereof, n the compound of Formula I is a compound of Formula IIa: R6 R5 N O N N N R1 R3 R4 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof.

37. The compound of any one of claims 1-4, 8-10, and 15-32, or a pharmaceutically able salt thereof, wherein the compound of a I is a compound of having Formula IIIa: R6 R5 N O N N N N R1 R7 R8 R2 R9 R10 HN N IIIa or a pharmaceutically acceptable salt thereof.

38. The compound of any one of claims 1-4, 7, 10, and 15-32, or a pharmaceutically acceptable salt thereof, wherein the nd of Formula I is a compound of Formula IVa: N N O N N N N R1 R7 R8 R2 R9 R10 HN N or a pharmaceutically acceptable salt thereof.

39. The compound of claim 1 selected from: cyanomethyl)(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]-N- [(1S)-2,2,2-trifluoromethylethyl]pyrazinecarboxamide; 5-[3-(cyanomethyl)(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]-N- isopropylpyrazinecarboxamide; 4-[3-(cyanomethyl)(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]-N- isopropylbenzamide; 4-[3-(cyanomethyl)(3'-methyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]- 2,5-difluoro-N-[(1S)-2,2,2-trifluoromethylethyl]benzamide; 4-[3-(1H,1'H-4,4'-Bipyrazolyl)(cyanomethyl)azetidinyl]-2,5-difluoro- N-[(1S)-2,2,2-trifluoromethylethyl]benzamide; 5-[3-(cyanomethyl)(3,3'-dimethyl-1H,1'H-4,4'-bipyrazolyl)azetidin yl]-N-isopropylpyrazinecarboxamide; 5-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'-bipyrazol tidinyl]-N-isopropylpyrazinecarboxamide; 5-[3-(cyanomethyl)(3',5'-dimethyl-1H,1'H-4,4'-bipyrazolyl)azetidin yl]-N-[(1S)-2,2,2-trifluoromethylethyl]pyrazinecarboxamide; 5-[3-(cyanomethyl)(3-methyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]-N- isopropylpyrazinecarboxamide; 5-[3-(cyanomethyl)(3'-ethyl-1H,1'H-4,4'-bipyrazolyl)azetidinyl]-N- [(1S)-2,2,2-trifluoromethylethyl]pyrazinecarboxamide; 4-{3-(cyanomethyl)[3'-(hydroxymethyl)-1H,1'H-4,4'-bipyrazol yl]azetidinyl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoromethylethyl]benzamide; and 4-{3-(cyanomethyl)[3-(hydroxymethyl)-3'-methyl-1H,1'H-4,4'-bipyrazol yl]azetidinyl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoromethylethyl]benzamide; or a pharmaceutically able salt thereof.

40. A composition comprising a compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.