Compounds useful as kinase inhibitors

Abstract

The present invention relates to novel compounds useful as kinase inhibitors. The compounds of the present invention are tyrosine kinase inhibitors. In particular, the compounds of the present invention are useful as inhibitors of Bruton's tyrosine kinase (BTK). The present invention also contemplates the use of these compounds in the treatment of conditions that can be treated by inhibiting Bruton's tyrosine kinase, such as cancer, lymphoma, leukemia and immune diseases.

Description

[0001] This application is a divisional application of the invention patent application with application date of December 16, 2016, application number 201680073031.7, and name “Compounds useful as kinase inhibitors”. Technical Field

[0002] The present invention relates to compounds. More specifically, the present invention relates to compounds useful as kinase inhibitors, as well as methods for preparing the compounds and uses of the compounds. Specifically, the present invention relates to inhibitors of Bruton's tyrosine kinase (BTK). Background Art

[0003] Kinases are a class of enzymes that control the transfer of a phosphate group from a phosphate donor group, such as ATP, to a specific substrate. Protein kinases are a large subset of kinases that play a central role in regulating various cellular signaling and processes, and BTK is one such protein kinase.

[0004] BTK is a member of the Src-related Tec family of cytoplasmic tyrosine kinases. BTK plays a key role in the B cell receptor (BCR) signaling pathway in B cells, which is required for B cell development, activation, and survival. Consequently, BTK inhibitors have been developed with the goal of treating B cell malignancies that rely on BCR signaling, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) (Buggy 2012). BTK is also expressed in specific myeloid cells, including monocytes / macrophages, neutrophils, and mast cells. Within these myeloid cells, BTK has been implicated in immune complex-mediated FcγR and FcεR activation, which is thought to contribute to the pathogenesis of rheumatoid arthritis (RA) (Whang 2014). Furthermore, BTK is required for osteoclast maturation, so inhibition of BTK may prevent RA-associated bone erosion. BTK's critical role in both B cells and myeloid cells has made it an attractive target for the treatment of not only B cell malignancies but also autoimmune diseases.

[0005] Ibrutinib is an irreversible BTK inhibitor approved for the treatment of CLL, mantle cell lymphoma (MCL) and Waldenstrom's macroglobulinemia (WM). Since ibrutinib was first disclosed, there are many patent applications related to structures closely related to ibrutinib, for example, referring to WO 2012 / 158843, WO 2012 / 158764, WO 2011 / 153514, WO2011 / 046964, US 2010 / 0254905, US 2010 / 0144705, US 7718662, WO 2008 / 054827 and WO2008 / 121742.

[0006] Other Btk inhibitors are disclosed in WO 2013 / 010136, US 9090621, WO 2015 / 127310, WO 2015 / 095099 and US 2014 / 221333. Kinase inhibitors are also disclosed in US 6660744, US 2002 / 0156081, US 2003 / 0225098 and WO 01 / 19829.

[0007] Ibrutinib also irreversibly binds to interleukin-2-inducible tyrosine kinase (ITK) (Dubovsky 2013). ITK plays a key role in FcR-stimulated natural killer (NK) cell function, which is required for antibody-dependent NK cell-mediated cytotoxicity (ADCC). ADCC is a mechanism that anti-CD20 antibodies such as rituximab are thought to activate, and ibrutinib has been shown to antagonize this mechanism in vitro (Kohrt 2014). Because rituximab combined with chemotherapy is the current standard of care for B-cell malignancies, a BTK inhibitor with greater selectivity for BTK over ITK is desirable.

[0008] In the clinic, adverse events include atrial fibrillation, diarrhea, rash, arthralgia, and bleeding (IMBRUVICA package insert 2014). Known BTK inhibitors such as ibrutinib are also known to have gastrointestinal side effects, which are believed to be a result of secondary EGFR inhibitory activity. Therefore, there is a need for BTK inhibitors with high BTK inhibition and low EGFR inhibition to reduce or avoid gastrointestinal side effects.

[0009] Irreversible and covalently reversible BTK inhibitors specifically target the cysteine ​​residue C481 within BTK. Primary and secondary resistance have emerged following treatment with ibrutinib. Mutations within BTK, such as C481S, C481Y, C481R, and C481F, have been reported in the literature and clearly interfere with drug binding (Woyach 2014; Maddocks 2015). It is predicted that the incidence of resistance observed will increase over time with clinical use outside of clinical trials (Zhang, 2015).

[0010] Therefore, the object of the present invention is to provide BTK inhibitors with different binding modes, more particularly reversible inhibitors. In addition, the present invention aims to provide BTK inhibitors that have high selectivity for BTK inhibition compared to EGFR and ITK inhibition.

[0011] In addition, certain embodiments of the present invention aim to provide new cancer treatments. Specifically, certain embodiments of the present invention aim to provide compounds that have comparable activity to existing cancer treatments but are also effective against mutations. One aspect of the present invention focuses on providing BTK inhibitors that are effective against the C481 mutation.

[0012] It is an object of certain embodiments of the present invention to provide compounds that exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.

[0013] Another object of certain embodiments of the present invention is to provide a compound having a convenient pharmacokinetic profile and a suitable duration of action after administration. Another object of certain embodiments of the present invention is to provide a compound wherein one or more metabolic fragments of the drug after absorption are GRAS (generally recognized as safe).

[0014] Certain embodiments of the present invention meet some or all of the above objectives. Summary of the Invention

[0015] According to the present invention, compounds as disclosed below are provided. In addition, the present invention provides compounds capable of inhibiting Bruton's tyrosine kinase (BTK) and the use of these compounds in inhibiting BTK. According to the present invention, a method for treating a condition regulated by BTK is provided. The present invention provides compounds for treating a condition regulated by BTK.

[0016] In a first aspect of the present invention, there is provided a compound according to formula (I) or a pharmaceutically acceptable salt thereof:

[0017]

[0018] in,

[0019] A represents a ring selected from the group consisting of unsubstituted or substituted phenyl, pyridine, pyridazine, pyrimidine or pyrazine, wherein when substituted A is replaced by 1 to 4 R 7 When replacing;

[0020] R 1 represents a group selected from the following: C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 2-8 Alkyl ether, -C(O)R A 、C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 3-10 Carbocyclic substituted C 1-8 Alkyl and C substituted by 3 to 10 membered heterocyclic group 1-8Alkyl, wherein each of the above groups is unsubstituted or substituted by 1 to 5 substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-NR A R B 、-CN、=O、-OC(O)R A 、-C(O)R A 、-C(O)OR A 、-NR A C(O)R B 、-C(O)NR A R B 、-NR A S(O)2R B 、-S(O)2NR A R B , benzoyl, 5 or 6 membered heterocyclic aryl, 3 to 6 membered heterocyclic alkyl ring, -OR A Substituted C 1-4 Alkyl and -OR A Substituted C 1-4 Alkoxy, or R 1 A single atom of is substituted twice to form a 3- to 6-membered heterocycloalkyl or cycloalkyl ring;

[0021] R 2 represents a group selected from the group consisting of: -OH, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 to 10 membered heterocyclic group, -OR C Alkyl substituted, C 3-10 Carbocyclic substituted C 1-8 alkyl, alkyl substituted by 3 to 10 membered heterocyclic group, and -NR C R D ;

[0022] R 3 Represents -C(O)NR E R F , by-OR G Substituted C 1-6 Alkyl or C 1-6 alkyl halide;

[0023] R 4a and R 4b is independently selected at each occurrence from: H, C 1-6 Alkyl, C1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl and -OR H Substituted C 1-6 alkyl;

[0024] R 5 Is H or C 1-4 alkyl;

[0025] R 6 is selected from the group consisting of substituted or unsubstituted phenyl or a 5- or 6-membered heteroaryl ring, wherein, when substituted, R 6 Contains 1 to 5 substituents, each of which is independently selected from the group consisting of: halogen, -OR I 、-NR I R J 、-CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl and -OR I Substituted C 1-6 alkyl;

[0026] R 7 Selected from: H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and -OR H Substituted C 1-6 alkyl;

[0027] m is 1 or 2;

[0028] R A and R B is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, phenyl, benzyl or -OR H Substituted C 1-4 alkyl;

[0029] R C 、R D 、R E and R F is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group, unsubstituted C 3-10 Carbocyclic substituted C 1-4 Alkyl, 1 or 2 R H OR H Substituted C 3-10 Carbocyclic substituted C 1-4alkyl, and 3- to 10-membered heterocyclic group;

[0030] R G 、R I and R J is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and -OR H Substituted C 1-4 Alkyl; and

[0031] R H Selected from H or C 1-4 alkyl.

[0032] In one embodiment, A is unsubstituted phenyl, unsubstituted pyridine, substituted by 1 to 4 R 7 Substituted phenyl or 1 to 4 R 7 Substituted pyridines.

[0033] Preferably, A is unsubstituted phenyl, unsubstituted pyridine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted pyrazine or substituted by 1 or 2 R 7 Substituted phenyl.

[0034] In one embodiment, A is unsubstituted phenyl, unsubstituted dihydropyridyl, or substituted by 1 to 4 R 7 (Choose 1 or 2 R 7 In one embodiment, A is unsubstituted phenyl or 1 to 4 R 7 Substituted phenyl.

[0035] As the skilled person will notice from the structure of formula (I), the group "A" is substituted by two groups as shown below (it may also be optionally substituted by 1 to 4 R 7 replace).

[0036]

[0037] The two groups may be para-substituted on A. In other words, the two groups may be 1,4-substituted on A.

[0038] In one embodiment, A may be:

[0039]

[0040] Among them, A 1 、A 2 、A 4 and A 5 0, 1 or 2 of them are independently selected from N, and the rest are CR 7 .

[0041] Thus, the compound according to formula (I) may be a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0042]

[0043] Among them, A 1 、A 2 、A 4 and A 5 0, 1 or 2 of them are independently selected from N, and the rest are CR 7 .

[0044] In an embodiment, A 1 、A 2 , A 4 and A 5 0 or 1 is N, the rest are A 1 、A 2 、A 4 and A 5 0 or 1 is CR 7 , the rest are CH.

[0045] In an embodiment, A 1 、A 4 and A 5 It is CH, A 2 It's CR 7 And R 7 is selected from fluoro, methyl, methoxy or -CH2OH. In an embodiment, A 2 、A 4 and A 5 It is CH, A 1 It's CR 7 And R 7 is selected from H, fluoro, methyl, methoxy or -CH2OH. In an embodiment, A 1 、A 4 and A 5 It is CH, A 2 is N. In an embodiment, A 2 、A 4 and A 5 It is CH, A 1 is N. In an embodiment, A 1 and A 5 It is CH, A 2 and A 4 is N. In an embodiment, A 1 and A 5 It's N, A 2 and A 4 is CH. In an embodiment, A 1 and A 4 It is CH, A2 and A 5 is N. In an embodiment, A 1 and A 2 It is CH, A 4 and A 5 It's N.

[0046] In an embodiment, A 1 and A 5 It is CH, A 2 and A 4 It's CR 7 And R 7 is selected from fluoro, methyl, methoxy or -CH2OH. In an embodiment, A 1 and A 2 It is CH, A 4 and A 5 It's CR 7 And R 7 is selected from fluoro, methyl, methoxy or -CH2OH. In an embodiment, A 2 and A 4 It is CH, A 1 and A 5 It's CR 7 And R 7 is selected from fluoro, methyl, methoxy or -CH2OH. In an embodiment, A 1 and A 4 It is CH, A 2 and A 5 It's CR 7 And R 7 is selected from fluorine, methyl, methoxy or -CH2OH.

[0047] Optionally, R 7 Can be selected from: H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy and -OR H Substituted C 1-6 Preferably, R 7 Can be selected from: H, fluorine, methyl, methoxy and -CH2OH. Preferably, R 7 It's H.

[0048] In an embodiment, A may be selected from:

[0049]

[0050] In an embodiment, A may be selected from:

[0051]

[0052] In an embodiment, A may be selected from:

[0053]

[0054] In a preferred embodiment, A can be selected from:

[0055]

[0056] In an embodiment, R 6 is selected from the group consisting of substituted or unsubstituted phenyl or a 6-membered heteroaryl ring. 6 Selected from the group consisting of phenyl or a 6-membered heteroaryl ring substituted with 1 or 2 (preferably 1) methoxy (-OMe) groups.

[0057] In an embodiment, R 6 is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl.

[0058] Preferably, R 6 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl, wherein R 6 Contains 1, 2 or 3 substituents independently selected at each occurrence from the group consisting of: halogen, -OR I 、-CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl and -OR I Substituted C 1-6 Alkyl, optionally, R I Selected from: H, methyl, ethyl, -CF3, -CH2-OR H and -CH2CH2-OR H Preferably, R I It is H or methyl.

[0059] As will be appreciated by the skilled artisan, based on the description of the structural formula of the compounds of the present invention, R 6 The carbonyl group (-C(=O)-) is connected to the rest of the compound of the present invention. 6 When substituted by 1, 2 or 3 substituents, R 6 By carbonyl (R 6 connected to the rest of the compound) and substituted with 1, 2 or 3 additional substituents. In a preferred embodiment, one of the substituents is adjacent to -C(=O)-. In other words, one of the substituents is substituted in the ortho position of the carbonyl group (-C(=O)-). Preferably, in R 6The substituent of the 1, 2 or 3 substituents substituted thereon is methoxy.

[0060] In an embodiment, R 6 is substituted or unsubstituted: phenyl or pyridyl (preferably substituted). In a particularly preferred embodiment, R 6 is a substituted phenyl group.

[0061] Preferably, R 6 Contains 1, 2 or 3 substituents independently selected at each occurrence from the group consisting of fluoro, chloro, methoxy, ethoxy, isopropoxy, -CN, methyl, ethyl, trifluoromethyl, trifluoroethyl or -OCF3. In an embodiment, R 6 Contains 1 or 2 substituents independently selected at each occurrence from the group consisting of fluoro, methoxy or methyl. Preferably, R 6 Contains one methoxy substituent or two substituents, fluorine and methoxy.

[0062] R 6 A particularly preferred substituent of is methoxy. Thus, in a preferred embodiment, R 6 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl. 6 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl substituted by methoxy.

[0063] R 6 Particularly preferred substituents of are methoxy and fluorine. 6 is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl or thiadiazolyl. 6 Selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl or pyrimidinyl substituted by fluoro and methoxy.

[0064] R 6 It can be methoxyphenyl or fluoromethoxyphenyl. 6 Can be methoxyphenyl. As will be appreciated by those skilled in the art, R 6 The carbonyl group (-C(=O)-) is connected to the rest of the compound of the present invention. 6 When it is methoxyphenyl, R 6 The phenyl group is substituted with a carbonyl group (connecting the phenyl ring to the rest of the compound) and a methoxy group. 6In a preferred embodiment where the methoxyphenyl group is present, the methoxy group is substituted adjacent to the -C(=O)- group. In other words, the methoxy group is substituted in the ortho position relative to the carbonyl group (-C(=O)-). Thus, in one embodiment, the compound according to formula (I) is a compound of formula (IIIa) and (IIIb):

[0065]

[0066] Therefore, in a preferred embodiment, R 6 It is 2-methoxyphenyl-1-yl.

[0067] R 6 Can be fluoromethoxyphenyl. As will be appreciated by those skilled in the art, R 6 The carbonyl group (-C(=O)-) is connected to the rest of the compound of the present invention. 6 When it is fluoromethoxyphenyl, R 6 The phenyl group is substituted with a carbonyl group (connecting the phenyl ring to the rest of the compound), a fluoro group, and a methoxy group. 6 In a preferred embodiment of a fluoromethoxyphenyl group, the methoxy group is substituted adjacent to -C(=O)- and the fluoro group is substituted opposite to the methoxy group. In other words, the methoxy group is substituted in the ortho position of the carbonyl group (-C(=O)-) and the fluoro group is attached in the para position to the methoxy group. Thus, in one embodiment, the compound according to formula (I) is a compound of formula (IIIc) and (IIId):

[0068]

[0069] Therefore, in a preferred embodiment, R 6 It is 5-fluoro-2-methoxyphenyl-1-yl.

[0070] In an embodiment, R 6 It is 2-methoxyphenyl-1-yl or 5-fluoro-2-methoxyphenyl-1-yl.

[0071] R 5 It can be H or methyl. Preferably, R 5 It’s H.

[0072] R 4a and R 4b can be independently selected at each occurrence from: H, C 1-6 Alkyl, C 3-6 Cycloalkyl and -OR H Substituted C 1-6 Alkyl. Optionally, R 4a and R 4b can be independently selected at each occurrence from: H, methyl, ethyl, cyclopropyl or -CH2OH. Optionally, R 4aIt's H, R 4b Can be selected from: H, methyl, ethyl, cyclopropyl or -CH2OH. Optionally, R 4a It's H, R 4b is selected from: H, methyl or -CH2OH. Preferably, R 4a It's H, R 4b It’s H.

[0073] In an embodiment, m is 1.

[0074] In an embodiment, m is 1, R 4a and R 4b is H. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 is H. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 is fluoromethoxyphenyl or methoxyphenyl. In an embodiment, m is 1, R 4a and R 4b is H, and A is unsubstituted phenyl or replaced by an R 7 In one embodiment, m is 1, R 4a and R 4b It's H, R 5 is H, and A is unsubstituted phenyl or replaced by an R 7 In one embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 is fluoromethoxyphenyl or methoxyphenyl, and A is unsubstituted phenyl or is replaced by one R 7 Substituted phenyl. R 7 It can be selected from: fluorine, methyl, methoxy and -CH2OH.

[0075] In an embodiment, m is 1, R 4a and R 4b is H. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 is H. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 In one embodiment, m is 1, R 4a and R 4b is H, and A is unsubstituted phenyl or replaced by an R 7In one embodiment, m is 1, R 4a and R 4b It's H, R 5 is H, and A is unsubstituted phenyl or replaced by an R 7 In one embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 is methoxyphenyl, and A is unsubstituted phenyl or replaced by one R 7 Substituted phenyl. R 7 It can be selected from: fluorine, methyl, methoxy and -CH2OH.

[0076] In an embodiment, R 3 Represents -C(O)NR E R F Preferably, R 3 It represents -C(O)NHMe or -C(O)NH2.

[0077] In an embodiment, the compound according to formula (I) may be a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0078]

[0079] In an embodiment, R 2 represents a group selected from the following: halogen, C 1-8 Alkyl, C 1-8 Haloalkyl and -NR C R D Preferably, R 2 Represents Cl, CHF2, CF3, NH2, NHPh, NHMe, NHEt and NH i- Pr.

[0080] In an embodiment, the compound according to formula (I) may be a compound of formula (IVa), (IVb), (IVc) or (IVd), or a pharmaceutically acceptable salt thereof:

[0081]

[0082] Additionally or alternatively, in an embodiment, the compound according to formula (I) may be a compound of formula (IVe) or (IVf) or a pharmaceutically acceptable salt thereof:

[0083]

[0084] In one embodiment, R C and R D is independently selected at each occurrence from: H, C1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (optional C 3-6 carbocyclyl or phenyl), 3 to 10 membered heterocyclyl (optionally 3 to 6 membered heterocyclyl). Preferably, R C and R D are independently selected from the group consisting of: H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl. C It's H, R D Selected from: H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl and sec-butyl.

[0085] In one embodiment, R C and R D is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (optional C 3-6 carbocyclic group), 3 to 10-membered heterocyclic group (optionally 3 to 6-membered heterocyclic group). Preferably, R C and R D are independently selected from the group consisting of: H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl and sec-butyl. C and R D It’s H.

[0086] In an embodiment, R E and R F is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (optional C 3-6 carbocyclyl), 3 to 10 membered heterocyclyl (optionally 3 to 6 membered heterocyclyl). In an embodiment, R E and R F is independently selected at each occurrence from: H, C 1-4 Alkyl (preferably R E and R F is independently selected at each occurrence from: H, methyl, and ethyl). In an embodiment, R E and R F It's H.

[0087] In an embodiment, R C 、R D 、R E and R F It’s H.

[0088] In an embodiment, the compound according to formula (I) may be a compound of formula (Va) and (Vb) or a pharmaceutically acceptable salt thereof:

[0089]

[0090] R 2 represents a group selected from the group consisting of: -OH, halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 1-8 Alkoxy, C 3-10 Cycloalkyl, C 6-10 Aryl, 3 to 10 membered heterocyclic group, -OR C Substituted C 1-8 Alkyl, C 3-10 Carbocyclic substituted C 1-8 Alkyl, C substituted by 3 to 10 membered heterocyclic group 1-8 Alkyl, and -NR C R D .

[0091] In an embodiment, R 2 represents a group selected from the following: halogen, C 1-8 Alkyl or -NR C R D , where R C and R D is independently selected at each occurrence from: H or C 1-4 alkyl.

[0092] In some embodiments, R 2 represents a group selected from the group consisting of fluorine, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, morpholinyl, -CH2OH and -NR C R D , where R C and R D is independently selected at each occurrence from the group consisting of: H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

[0093] Preferably, R 2 It is NH2 or Me.

[0094] In an embodiment, R 3 Represents -C(O)NR E R F , by-OR G Substituted C 1-6 Alkyl, or C 1-6 haloalkyl, optionally wherein R E and R F is independently selected at each occurrence from: H or C 1-4Alkyl (preferably R E and R F is independently selected at each occurrence from: H, methyl and ethyl, R G Select from: H or C 1-4 alkyl).

[0095] In an embodiment, R E and R F One of them is H and the other is selected from

[0096] In an embodiment, R 3 represents -C(O)NH2, -C(O)NHMe, -CH2OH, CH(OH)CH3, -CF3 or -CHF2.

[0097] Preferably, R 3 Represents -C(O)NH2.

[0098] In an embodiment, R 2 is NH2 or Me, R 3 In a particularly preferred embodiment, R 2 is NH2, R 3 It is -C(O)NH2.

[0099] In an embodiment, m is 1, R 4a and R 4b It's H, R 2 is NH2, R 3 is -C(O)NH2. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 2 is NH2, R 3 is -C(O)NH2. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 is fluoromethoxyphenyl or methoxyphenyl, R 2 is NH2, R 3 is -C(O)NH2. In an embodiment, m is 1, R 4a and R 4b It's H, R 5 It's H, R 6 is methoxyphenyl, R 2 is NH2, R 3 It is -C(O)NH2.

[0100] R 1 represents a group selected from the following: C 1-8 Alkyl, C1-8 Halogenated alkyl, C 2-8 Alkyl ether, -C(O)R A 、C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 3-10 Carbocyclic substituted C 1-8 Alkyl and C substituted by 3 to 10 membered heterocyclic group 1-8 Alkyl, wherein the above groups are unsubstituted or substituted by 1 to 5 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-CN、=O、-C(O)OR A 、-C(O)NR A R B , 3 to 6 membered heterocycloalkyl ring, -OR A 、BE-OR A Substituted C 1-4 Alkoxy; wherein R A and R B Independently selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, benzyl or -OR H Substituted C 1-4 alkyl.

[0101] R 1 represents a group selected from the following: C 1-8 Alkyl, C 1-8 Halogenated alkyl, C 2-8 Alkyl ether, -C(O)R A 、C 3-10 Carbocyclic group, 3 to 10 membered heterocyclic group, C 3-10 Carbocyclic substituted C 1-8 Alkyl and C substituted by 3 to 10 membered heterocyclic group 1-8 Alkyl, wherein the above groups are unsubstituted or substituted by 1 to 5 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-CN、=O、-C(O)OR A 、BE-OR A Substituted C 1-4 Alkyl, -OR A Substituted C 1-4 Alkoxy; wherein R A Selected from: H, C 1-4 Alkyl, C1-4 Halogenated alkyl, benzyl or -OR H Substituted C 1-4 alkyl.

[0102] R 1 represents a group selected from the following: C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkyl ether, -C(O)R A 、C 3-10 Cycloalkyl (preferably C 3-6 Cycloalkyl), C 6-10 Aryl (preferably phenyl or indanyl), 3 to 10 membered heterocycloalkyl (optionally 3 to 6 members), 3 to 10 membered heteroaryl (optionally 3 to 6 members, such as 5 or 6 members), C 3-10 Cycloalkyl (preferably C 3-6 Cycloalkyl) substituted C 1-6 Alkyl, C 6-10 Aryl (preferably phenyl) substituted C 1-6 alkyl, C substituted by 3 to 10 membered heterocycloalkyl (optionally 3 to 6 membered) 1-6 alkyl and C substituted by 3 to 10 membered heteroaryl (optionally 3 to 6 membered, for example 5 or 6 membered) 1-6 Alkyl, wherein the above groups are unsubstituted or substituted by 1 to 5 substituents selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-CN、=O、-C(O)OR A 、-C(O)NR A R B , 3 to 6 membered heterocycloalkyl ring, -OR A Substituted C 1-4 Alkyl, -OR A Substituted C 1-4 Alkoxy, where R A Selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, benzyl or -OR H Substituted C 1-4 alkyl.

[0103] In an embodiment, R 1Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, propyl, hexyl, tert-hexyl, tert-butyl, trifluoroethyl, trifluoropropyl, trifluorobutyl, difluoropropyl, chloropropyl, propyl ether, cyclopropyl, cyclopentenyl, cyclohexyl, indanyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, phenyl, pyridyl, thiazolyl, C substituted by oxetane 1-8 Alkyl (preferably methyl or ethyl), C substituted by morpholine 1-8 Alkyl (preferably methyl or ethyl), C substituted by tetrazole 1-8 Alkyl (preferably methyl or ethyl), C substituted by piperidine 1-8 Alkyl (preferably methyl or ethyl), C substituted by cyclohexyl 1-8 Alkyl (preferably methyl or ethyl), C substituted by cyclopentyl 1-8 Alkyl (preferably methyl or ethyl), C 1-8 Alkyl (preferably methyl or ethyl), C 1-8 Alkyl (preferably methyl or ethyl), C substituted by pyridyl 1-8 Alkyl (preferably methyl or ethyl), C substituted by phenyl 1-8 Alkyl (preferably methyl or ethyl), C substituted by tetrahydrofuran 1-8 Alkyl (preferably methyl or ethyl) and C substituted by cyclopropyl 1-8 Alkyl (preferably methyl or ethyl).

[0104] In an embodiment, R 1 Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C substituted by oxetane 1-8 Alkyl (preferably methyl or ethyl), C substituted by morpholine 1-8 Alkyl (preferably methyl or ethyl), C substituted by tetrazole 1-8 Alkyl (preferably methyl or ethyl), C substituted by piperidine 1-8 Alkyl (preferably methyl or ethyl) and C substituted by cyclohexyl 1-8 Alkyl (preferably methyl or ethyl).

[0105] Preferably, R 1 Substituted by 1 to 5 substituents (optionally 1 to 4) selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-CN、=(O)ORA 、-C(O)NR A R B , 5 or 6 membered heteroaryl, 3 to 6 membered heterocycloalkyl ring, -OR A Substituted C 1-4 Alkyl, -OR A Substituted C 1-4 Alkoxy, or R 1 A single atom of is substituted twice to form a 3- to 6-membered heterocycloalkyl or cycloalkyl ring.

[0106] In an embodiment, R 1 is substituted with 1 to 4 substituents selected from the group consisting of -OH, =O, -OMe, -CN, methyl, ethyl, propyl, isopropyl, tert-butyl, CF3, Cl, F, -OBn, -CO2H, -CO2Me, -CO2Et, -C(O)NH2, -C(O)NHMe, -C(O)NMe2, -C(O)NHOMe, pyridyl, pyrrolidinyl, oxetanyl, tetrahydropyranyl, or tetrahydrofuranyl, or R 1 A single atom of is substituted twice to form oxirane or oxetane.

[0107] Optionally, R 1 Substituted by 1 to 5 substituents (optionally 1 to 3) selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-CN、=O、-C(O)OR A 、BE-OR A Substituted C 1-4 Alkyl, -OR A Substituted C 1-4 In an embodiment, R 1 Substituted with 1 to 3 substituents selected from the group consisting of -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn, or -CO2Et.

[0108] In an embodiment, R 1 Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, propyl ether, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, indanyl, bicyclo[3.1.0]hexyl, oxetane, tetrahydropyranyl, phenyl, pyridyl, C substituted by oxetane 1-8 Alkyl (preferably methyl or ethyl), C substituted by morpholine 1-8 Alkyl (preferably methyl or ethyl), C substituted by tetrazole 1-8Alkyl (preferably methyl or ethyl), C substituted by piperidine 1-8 Alkyl (preferably methyl or ethyl) and C substituted by cyclohexyl 1-8 Alkyl (preferably methyl or ethyl), wherein R 1 Substituted with 1 to 5 substituents selected from the group consisting of -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn, or -CO2Et.

[0109] In an embodiment, R 1 is selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, wherein R 1 Substituted with 1 to 5 substituents selected from the group consisting of -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn, or -CO2Et.

[0110] R 1 Can be selected from:

[0111]

[0112]

[0113]

[0114] R 1 Can be selected from:

[0115]

[0116]

[0117] In an embodiment, R 1 Selected from substituted or unsubstituted: C 3-10 Carbocyclic group, wherein, when substituted R 1 When substituted by 1 to 5 substituents selected from the group consisting of halogen, C 1-4 Alkyl or -OR A , where R A Selected from H or C 1-4 alkyl.

[0118] In some embodiments, R 1 Selected from substituted or unsubstituted: C 3-6 Cycloalkyl or phenyl, wherein when substituted R 1 When substituted by 1 to 5 substituents selected from the group consisting of halogen, C 1-4 Alkyl or -OR A , where R A Selected from H or C 1-4 alkyl.

[0119] In a preferred embodiment, R 1 is selected from substituted or unsubstituted cyclohexyl, phenyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl)ethyl or (tetrahydropyranyl)ethyl. 1 Can be selected from:

[0120]

[0121] In a preferred embodiment, R 1 is selected from substituted or unsubstituted cyclohexyl, phenyl, cyclobutyl, cyclopentyl or bicyclo[3.1.0]hexyl. Preferably, R 1 Can be selected from:

[0122]

[0123] In a preferred embodiment, R 1 is selected from substituted or unsubstituted piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl)ethyl or (tetrahydropyranyl)ethyl. 1 Can be selected from:

[0124]

[0125] In one embodiment, the compound according to formula (I) may be a compound of formula (VIa) and (VIb) or a pharmaceutically acceptable salt thereof:

[0126]

[0127] Alternatively, the compound according to formula (I) may be a compound of formula (VIc) and (VId) or a pharmaceutically acceptable salt thereof:

[0128]

[0129] In one embodiment, the compound according to formula (I) may be a compound of formula (VIIa) and (VIIb) or a pharmaceutically acceptable salt thereof:

[0130]

[0131] Alternatively, the compound according to formula (I) may be a compound of formula (VIIc) and (VIId) or a pharmaceutically acceptable salt thereof:

[0132]

[0133] In one embodiment, the compound according to formula (I) may be a compound of formula (VIIIa) and (VIIIb) or a pharmaceutically acceptable salt thereof:

[0134]

[0135] Alternatively, the compound according to formula (I) may be a compound of formula (VIIIc) and (VIIId) or a pharmaceutically acceptable salt thereof:

[0136]

[0137] In one embodiment, the compound according to formula (I) may be a compound of formula (IXa) and (IXb) or a pharmaceutically acceptable salt thereof:

[0138]

[0139] Alternatively, the compound according to formula (I) may be a compound of formula (IXc) and (IXd) or a pharmaceutically acceptable salt thereof:

[0140]

[0141] For compounds of formula (VIa), (VIIa), (VIIIa), (IXa), (VIc), (VIIc), (VIIIc) and (IXc), R 7 As defined elsewhere herein, preferably R 7 It can be selected from: H, fluorine, methyl, methoxy and -CH2OH.

[0142] In a particularly preferred embodiment of the present invention, R 1 yes Thus, the compound according to formula (I) may be a compound of formula (X) or a pharmaceutically acceptable salt thereof:

[0143]

[0144] Among them, R 1A Selected from C 1-2 Alkyl or C 1-2 Haloalkyl, R 1B Selected from unsubstituted C 1-4 Alkyl, C 1-4 Haloalkyl, C substituted by OH 1-4 Alkyl, C substituted by OMe 1-4 alkyl, 5- or 6-membered heteroaryl, 3- to 6-membered heterocycloalkyl ring, phenyl or C 3-10 carbocyclic group (e.g., a 3- to 10-membered cycloalkyl ring). 1A It is C 1-2 When alkyl, then R1B Not unsubstituted C 1-4 alkyl.

[0145] Preferably, R 1A is selected from methyl, difluoromethyl or trifluoromethyl, R 1B is selected from methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH2OH, -CH2CH2OH, -CH2OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; provided that when R 1A If it is not a methyl group, then R 1B is not methyl, ethyl or propyl. In an embodiment, R 1A It is trifluoromethyl.

[0146] Preferred R 1A is selected from methyl or trifluoromethyl, R 1B is selected from methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH2OH, -CH2OMe, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclobutyl, cyclopentyl or cyclohexyl; provided that when R 1A If it is not a methyl group, then R 1B is not methyl, ethyl or propyl. In an embodiment, R 1A It is trifluoromethyl.

[0147] The compound according to formula (I) may be a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0148]

[0149] Among them A 1 、A 2 、A 4 and A 5 0, 1 or 2 of them are independently selected from N, and the rest are CR 7 .

[0150] In one embodiment, the compound according to formula (I) is a compound of formula (XIIa), (XIIb), (XIIc) and (XIId):

[0151]

[0152] In an embodiment, the compound according to formula (I) is a compound of formula (XIIIa), (XIIIb), (XIIIc), (XIIId), (XIIIe) and (XIIIf), or a pharmaceutically acceptable salt thereof:

[0153]

[0154] In one embodiment, the compound according to formula (I) may be a compound of formula (XIVa), (XIVb), (XIVc) and (XIVd) or a pharmaceutically acceptable salt thereof:

[0155]

[0156] In one embodiment, the compound according to formula (I) may be a compound of formula (XVa), (XVb), (XVc) and (XVd) or a pharmaceutically acceptable salt thereof:

[0157]

[0158] In the compounds of formula (XVa), (XVb), (XVc) and (XVd), R C and R D can be H. In the compounds of formula (XVa), (XVb), (XVc) and (XVd), R E and R F Can be H. In the compounds of formula (XVa), (XVb), (XVc) and (XVd), R C and R D Can be H, R E and R F It can be H.

[0159] In one embodiment, the compound according to formula (I) may be a compound of formula (XVa), (XVb), (XVc) and (XVd) or a pharmaceutically acceptable salt thereof:

[0160]

[0161] In an embodiment of the compounds of Formula (XVIa), (XVIb), (XVIc) and (XVId), A 1 、A 2 、A 4 and A 5 It is CH, or A 1 、A 4 and A 5 It is CH, A 2 It is CH, or A 2 、A 4 and A 5 It is CH, A 1 It's CF.

[0162] In an embodiment of the compounds of Formula (XVIa), (XVIb), (XVIc) and (XVId), R 2 Indicates -NR C R D , R3 Represents -C(O)NR E R F . Optionally, R C and R D It's H, R E and R F It’s H.

[0163] The compound represented by formula (X) (ie, wherein R 1 -CHR 1A R 1B ) species are active species.

[0164] Preferred compounds of the present invention include:

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182] The compound according to formula (I) may be a compound selected from the group consisting of:

[0183]

[0184] The compounds according to formula (I) may also be selected from:

[0185]

[0186]

[0187]

[0188]

[0189] Some of the above-mentioned compounds have one or more chiral centers, such as one or two chiral centers. All enantiomers and diastereomers of the above-mentioned compounds are contemplated by the present invention. Certain chiral centers are indicated by the * symbol on the above-mentioned compounds. In addition to those compounds indicated by *, compounds may have chiral centers. In one embodiment, the compounds of the present invention have an (R)-configuration at a stereocenter. In another embodiment, the compounds of the present invention have an (S)-configuration at a stereocenter. When a compound has two stereocenters, the stereocenters may have an (R), (R) configuration, a (S), (R) configuration, a (R), (S) configuration, or a (S), (S) configuration. The present invention also contemplates racemic mixtures of these compounds.

[0190] The compound of formula (I) may be a compound selected from the following:

[0191]

[0192]

[0193]

[0194] Any compounds described in the examples also form part of the present invention. This includes compounds falling within the scope of formula (I) and, on the other hand, any and all novel intermediates in the synthesis of compounds of formula (I).

[0195] Less preferred compounds of formula (I) are given below. In certain embodiments, the compounds shown below do not form part of the present invention.

[0196]

[0197] In another aspect of the present invention, there is provided a compound of any formula disclosed herein for use as a medicament.

[0198] In another aspect, compounds of any formula herein are used to treat conditions that are modulated by Bruton's tyrosine kinase (BTK). Conditions that are modulated by BTK are generally conditions that can be treated by inhibiting BTK using the compounds of the present invention. Compounds of any formula disclosed herein can be used to treat conditions that can be treated by inhibiting Bruton's tyrosine kinase (BTK).

[0199] BTK inhibition is a novel approach for treating many different human diseases associated with inappropriate activation of B cells, including B cell proliferative disorders, B cell malignancies, immune diseases such as autoimmune diseases, heteroimmune diseases, and inflammatory disorders or fibrosis. In particular, BTK inhibition is a novel approach for treating many different human diseases associated with inappropriate activation of B cells, including B cell malignancies, immune diseases such as autoimmune diseases, and inflammatory disorders.

[0200] In an embodiment, the condition treatable by inhibiting BTK can be selected from the group consisting of cancer, lymphoma, leukemia, autoimmune disease, inflammatory disease, heteroimmune disease or fibrosis. Specific conditions treatable by inhibiting BTK can be selected from the group consisting of B cell malignancies, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, follicular lymphoma, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mediastinal (thymic) large B cell lymphoma , intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes mellitus, myasthenia gravis, Hashimoto's thyroiditis, O'Donnell's syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, multiple sclerosis, multiple sclerosis, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune lytic Hemorrhagic anemia, Wegener's granulomatosis, psoriasis, alopecia areata, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, scleroderma, vulvodynia, graft-versus-host disease, transplantation, blood transfusion, allergy, allergic reaction, type I hypersensitivity reaction, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, oophoritis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis , pharyngitis, pleurisy, phlebitis, pneumonia, lung disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vasculitis, vulvitis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), uncommon interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver, steatosis (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct damage, bile fibrosis, cholestasis, or bile duct disease.In some embodiments, liver fibrosis or hepatic fibrosis includes, but is not limited to, liver fibrosis associated with alcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B, or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), renal disease associated with injury / fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy associated with chronic kidney disease (CKD), chronic progressive renal disease, and renal fibrosis. (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy damage, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory conditions such as Barrett's esophagus and chronic gastritis and / or fibrosis associated with hindgut inflammatory conditions such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma.

[0201] B cell malignancies, B cell lymphomas, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, chronic lymphocytic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, cytoblastoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia and lymphomatoid granulomatosis are examples of cancers, lymphomas and leukemias treatable by BTK inhibition.

[0202] B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer and bone metastases are examples of cancers, lymphomas and leukemias treatable by BTK inhibition.

[0203] Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, regeneration Atrophic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behcet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma and vulvodynia, asthma, appendix Inflammation, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, colitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, inflammatory enteritis, suppurative inflammation, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, Pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergy, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis are examples of immune diseases treatable by BTK inhibition.

[0204] Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis Myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis are examples of inflammatory disorders treatable by BTK inhibition.

[0205] Lupus and Sjögren's syndromes, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, endometriosis, interstitial cystitis, neuromyotonia, scleroderma, and vulvodynia are examples of autoimmune diseases treatable by BTK inhibition.

[0206] Graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergic reactions, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis are examples of xenoimmune diseases treatable by BTK inhibition.

[0207] Pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), bronchiolitis obliterans, bronchiectasis, fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct damage, bile fibrosis, cholestasis, or bile duct disease. In some embodiments, liver fibrosis or hepatic fibrosis includes, but is not limited to, liver fibrosis associated with alcoholism, viral infection, such as hepatitis (e.g., hepatitis C, hepatitis B or C), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), renal fibrosis (e.g., chronic renal fibrosis), renal disease associated with injury / fibrosis (e.g., chronic kidney disease associated with diabetes (e.g., diabetic nephropathy)), lupus, nephrosclerosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), nephrotic syndrome. Tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy damage, HIV-associated nephropathy, or fibrosis associated with exposure to toxins, irritants or chemotherapeutic agents, fibrosis associated with scleroderma; radiation-induced intestinal fibrosis; fibrosis associated with foregut inflammatory conditions such as Barrett's esophagus and chronic gastritis and / or fibrosis associated with hindgut inflammatory conditions such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity and neovascular glaucoma are examples of fibrosis treatable by BTK inhibition.

[0208] Arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, and lupus are examples of immune diseases treatable by BTK inhibition. Arthritis is an example of an inflammatory disease treatable by BTK inhibition. Lupus and Sjögren's syndrome are examples of autoimmune diseases treatable by BTK inhibition.

[0209] Any of the conditions disclosed above as treatable by BTK inhibition may be treated by a compound of the invention, or may be treated in a method comprising administering a compound of the invention, or may be treated by a medicament manufactured through use of a compound of the invention.

[0210] In an embodiment, the compounds of the present invention can be used for treating: cancer, lymphoma, leukemia, immune diseases, autoimmune diseases and inflammatory conditions. The compounds of this invention can be used for treating the following specific conditions selected from: B cell malignancies, B cell lymphoma, diffuse large B cell lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastasis, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjogren's syndrome and lupus. The compound can also be used for treating the conditions relevant to renal transplantation.

[0211] In one embodiment, the compounds of the invention can be used to treat a specific condition selected from the group consisting of, for example, B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B-cell non-Hodgkin's lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, lupus, and arthritis.

[0212] In one aspect of the present invention, there is provided a method of treating a condition modulated by Bruton's tyrosine kinase, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the present invention.

[0213] The method of treatment may be a method of treating a condition treatable by inhibition of Bruton's tyrosine kinase.

[0214] The present invention also provides a method for treating a condition selected from the group consisting of cancer, lymphoma, leukemia, immune diseases, autoimmune diseases, and inflammatory conditions, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of the present invention. The present invention also provides a method for treating a specific condition selected from the group consisting of B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemias, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphomas, follicular lymphomas, hairy cell leukemia B-cell non-Hodgkin's lymphomas, Waldenstrom's macroglobulinemia, multiple myeloma, bone cancer, bone metastases, arthritis, multiple sclerosis osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, Sjögren's syndrome, and lupus, wherein the method comprises administering to a patient in need thereof a therapeutic amount of a compound of any formula disclosed herein. The method can also treat conditions associated with kidney transplantation.

[0215] In one embodiment, the method can be used to treat a specific condition selected from the group consisting of: B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphoma, follicular lymphoma, hairy cell leukemia B cell non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, multiple myeloma, arthritis, and lupus.

[0216] In another aspect of the present invention, a pharmaceutical composition is provided, wherein the composition comprises a compound of the present invention and a pharmaceutically acceptable excipient.

[0217] In one embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent as described below. DETAILED DESCRIPTION

[0218] The following are definitions of terms used in this application. Any terms not defined herein have their normal meaning as would be understood by a skilled person.

[0219] The term "halo" refers to one of the halogens of Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0220] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-8 Alkyl" or "C 1-6 "Alkyl" means a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms or 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Alkylene can likewise be straight or branched and can have two positions of attachment to the rest of the molecule. Furthermore, an alkylene can, for example, correspond to one of those alkyl groups listed in this paragraph. Alkyl and alkylene groups can be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents of alkyl groups can be halogens, for example fluorine, chlorine, bromine and iodine, OH, =O or C 1-6 Alkoxy.

[0221] The term "alkoxy" refers to an alkyl group attached to a molecule through an oxygen. This includes moieties where the alkyl portion can be straight or branched. For example, the term "C 1-6"Alkoxy" refers to an alkyl group attached to the molecule via an oxygen containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Thus, alkoxy can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexyl. The alkyl portion of the alkoxy group can be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Alkyl substituents can be halogens such as fluorine, chlorine, bromine and iodine, OH, C 1-6 Alkoxy.

[0222] The term "alkyl ether" refers to a straight or branched alkyl chain interrupted by a single oxygen atom to provide an ether. For example, the term "C 2-6 Alkyl ether" or "C 2-4 "Alkyl ether" refers to a straight or branched hydrocarbon chain containing 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms with a single oxygen atom within the chain, for example, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3 or -(CH2)2O(CH2)2CH3.

[0223] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom such as fluorine, chlorine, bromine and iodine, selected independently at each occurrence. The halogen atom may be present at any position on the hydrocarbon chain. For example, "C 1-6 "Haloalkyl" refers to a hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted by at least one halogen atom, for example chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl such as 1-chloromethyl and 2-chloroethyl, trichloroethyl such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0224] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C 2-6 "Alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond having 2, 3, 4, 5 or 6 carbon atoms. The double bond can exist as E or Z isomers. The double bond can be located at any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkenyl" may include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0225] The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond. For example, the term "C 2-6"Alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond having 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be located at any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkynyl" may include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0226] The term "heteroalkyl" refers to a branched or straight hydrocarbon chain in which at least one heteroatom selected from N, O and S is located between any carbons in the chain or at the end of the chain. 1-6 "Heteroalkyl" refers to a branched or straight hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, and at least one heteroatom selected from N, O and S is located between any carbon in the chain or at the end of the chain. For example, the hydrocarbon chain can contain one or two heteroatoms. 1-6 A heteroalkyl group can be bonded to the rest of the molecule through a carbon or heteroatom. For example, a "C 1-6 "Heteroalkyl" can be C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 O-alkyl.

[0227] The term "carbocycle" refers to a saturated or unsaturated carbon-containing ring system. A "carbocycle" system can be a monocyclic ring or a fused polycyclic ring system, such as a bicyclic or tricyclic ring. A "carbocycle" moiety can contain 3 to 14 carbon atoms, such as 3 to 8 carbon atoms in a monocyclic ring system and 7 to 14 carbon atoms in a polycyclic ring system. "Carbocycle" includes cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems, and fused ring systems including aromatic moieties.

[0228] The term "heterocycle" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocycle" system can contain 1, 2, 3 or 4 heteroatoms, for example 1 or 2. A "heterocycle" system can be a monocyclic or fused polycyclic system, for example a bicyclic or tricyclic system. A "heterocycle" moiety can contain 3 to 14 carbon atoms, for example 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. A "heterocycle" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, a heterocyclic group can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

[0229] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. A "cycloalkyl" group can be represented by a "C" containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 3-10The ring system may be a monocyclic, bicyclic or tricyclic ring system. For example, "cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclohexyl, cycloheptyl and cyclooctyl.

[0230] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. "Cycloalkenyl" can be represented by "C 3-10 Cycloalkenyl". "C 3-10 A "cycloalkenyl" group is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The ring may contain more than one double bond, provided that the ring system is not aromatic. The ring system may be a monocyclic, bicyclic or tricyclic ring system. For example, a "cycloalkenyl" group may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl and cyclohexadienyl.

[0231] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system having at least one heteroatom selected from N, O and S in the ring. "Heterocycloalkyl" can be represented by "C 3-10 Heterocycloalkyl". "C 3-10 A "heterocycloalkyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there can be 1, 2 or 3 heteroatoms, optionally 1 or 2. A "heterocycloalkyl" group can also be represented as a "3- to 10-membered heterocycloalkyl," which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. The ring system can be a monocyclic, bicyclic or tricyclic ring system. When the ring system is bicyclic, one of the rings can be aromatic, such as in indane. "Heterocycloalkyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkyl" can have one or more, for example, one or two, bonds to the rest of the molecule: these bonds can be through any atom in the ring. For example, "heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and indane.

[0232] The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system which is not aromatic and has at least one heteroatom selected from N, O and S in the ring. "Heterocycloalkenyl" can be represented by "C 3-10 Heterocycloalkenyl". "C 3-10"Heterocycloalkenyl" is a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "Heterocycloalkenyl" may also be represented by "3- to 10-membered heterocycloalkenyl", which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one of which is a heteroatom. The ring system may be a monocyclic or bicyclic or tricyclic ring system. When the ring system is bicyclic, one of the rings may be aromatic, such as in dihydroindole and dihydrobenzofuran. "Heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkenyl" may have one or more, for example one or two, bonds to the rest of the molecule: these bonds may be through any atom in the ring. For example, "C 3-8 The "heterocycloalkenyl" group may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene and dihydroindole.

[0233] The term "aromatic" when applied to a substituent as a whole refers to a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated π system within the ring or ring system, wherein all atoms contributing to the conjugated π system are in the same plane.

[0234] The term "aryl" refers to an aromatic hydrocarbon ring system. This ring system has 4n+2 electrons in a conjugated π system within the ring, where all atoms contributing to the conjugated π system are in the same plane. The ring system can be monocyclic, bicyclic, or tricyclic. For example, "aryl" can include phenyl and naphthyl. Aryl systems themselves can be substituted with other groups.

[0235] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S, either within a single ring or within a fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, wherein all atoms contributing to the conjugated π system are in the same plane. The ring system can be monocyclic, bicyclic, or tricyclic. For example, "heteroaryl" can include imidazole, thiophene, furan, thianthracene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0236] The term "alkaryl" refers to a C 1-4 Alkyl-bonded aryl as defined above, wherein C 1-4 The alkyl group provides the link to the rest of the molecule.

[0237] The term "alkyl heteroaryl" refers to a C 1-4 Alkyl-bonded heteroaryl groups as defined above, wherein the alkyl group provides the link to the rest of the molecule.

[0238] The term "halogen" herein includes reference to F, Cl, Br, and I. Halogen may be Cl. Halogen may be F.

[0239] by" " indicates that the bond is connected to another atom not shown in the structure. A bond that terminates within a cyclic structure and does not terminate at an atom of the cyclic structure indicates that the bond can be connected to any atom in the cyclic structure as long as the valence state allows.

[0240] When a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valence requirements. The moiety may be substituted with one or more substituents, for example 1, 2, 3 or 4 substituents; optionally 1 or 2 substituents are present on the moiety. When there are two or more substituents, the substituents may be the same or different. The substituents may be selected from: OH, NHR 9 , amidino, guanidine, hydroxyguanidine, carbamimidoyl, isothiourea, urea, sulfhydryl, C(O)H, acyl, acyloxy, carboxyl, sulfo, sulfamoyl, carbamoyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, C 2-6 Alkenyl, C 2-6 When the group to be substituted is an alkyl group, the substituent may be =O. When a moiety is substituted with two or more substituents and the two substituents are adjacent, the adjacent substituents may form a C 4-8 Ring, where C 4-8 The ring is a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7 or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring having 4, 5, 6, 7 or 8 carbon atoms and 1, 2 or 3 heteroatoms.

[0241] If chemically possible, cyclic substituents may be substituted on the radical to form a spirocycle.

[0242] Substituents are present only at positions where they are chemically possible, and one skilled in the art will be able to determine (experimentally or theoretically) without undue effort which substitutions are chemically feasible and which are not.

[0243] Ortho, meta, and para substitution are well understood terms in the art. For the sake of clarity, "ortho" substitution is a substitution pattern in which the adjacent carbon has a substituent, whether a simple group, such as the fluoro group in the examples below, or another part of the molecule, such as the one indicated by " " is indicated by a key ending in ".

[0244]

[0245] "Meta" substitution is a substitution pattern in which two substituents are on carbon atoms separated by one carbon, i.e., with a single carbon atom between the substituted carbon atoms. In other words, there is one substituent on an atom that is two atoms away from the atom bearing another substituent. For example, the following groups are meta-substituted.

[0246]

[0247] "Para" substitution is a substitution pattern in which two substituents are placed on carbon atoms two carbons apart, i.e., with two carbon atoms between the substituted carbon atoms. In other words, there is a substituent on an atom three times the size of the atom bearing the other substituent. For example, the following groups are para-substituted.

[0248]

[0249] "Acyl" refers to an organic radical derived from an organic acid, for example, by removal of a hydroxyl group, such as a radical having the formula RC(O)-, where R can be selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl, phenyl, benzyl or phenethyl, for example, R is H or C 1-3 Alkyl. In one embodiment, the acyl group is an alkyl-carbonyl group. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl, and butyryl. A specific acyl group is acetyl.

[0250] In embodiments where a single enantiomer of a compound of the invention is present, the compound of the invention may have an enantiomeric purity of at least about 90% enantiomeric excess (ee), at least about 95% enantiomeric excess (ee), at least about 98% enantiomeric excess (ee), at least about 99% enantiomeric excess (ee), or 100% enantiomeric excess (ee). In embodiments where a mixture of enantiomers of a compound of the invention is present, the compound of the invention may be a racemic mixture or any other mixture of enantiomers, for example, the compound of the invention may have an enantiomeric purity of at least about 50% enantiomeric excess (ee), at least about 60% enantiomeric excess (ee), at least about 70% enantiomeric excess (ee), at least about 80% enantiomeric excess (ee), at least about 90% enantiomeric excess (ee), or at least about 95% enantiomeric excess (ee).

[0251] Throughout the specification, the disclosure of the compound also includes its pharmaceutically acceptable salts, solvates and stereoisomers. When the compound has a stereocenter, the present invention contemplates both (R) and (S) stereoisomers, and the application completes equivalent mixtures or racemic mixtures of stereoisomers. When the compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers can produce diastereomeric mixtures or single diastereoisomers. The compound of the present invention can exist as a single stereoisomer, or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, and diastereomeric mixtures. In the case where the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those disclosed above. When the compound is a single stereoisomer, the compound can still contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have a 100% enantiomeric excess (ee) or diastereomeric excess (de), but may have an ee or de of about at least 85%.

[0252] The present invention contemplates pharmaceutically acceptable salts of the compounds of formula (I). These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compounds.

[0253] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 1,5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, toluenesulfonate, and trifluoroacetate.

[0254] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0255] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of the following three methods:

[0256] (i) by reacting a compound of formula (I) with a desired acid or base;

[0257] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I), or by ring-opening a suitable cyclic precursor (e.g. a lactone or lactam) using the required acid or base; or

[0258] (iii) by converting one salt of a compound of formula (I) into another by reaction with a suitable acid or base or with the aid of a suitable ion exchange column.

[0259] All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization in the resulting salt can range from fully ionized to almost non-ionized.

[0260] The compounds of the present invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0261] Included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein, in contrast to the above-described solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0262] Hereinafter, all references to compounds of any formula include references to salts, solvates and complexes thereof, and to solvates and complexes of salts thereof.

[0263] Compounds of the present invention include compounds of the various formulae defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers (including optical, geometric and tautomers) thereof as defined below, and isotopic labels of the present invention.

[0264] Prior to purification, depending on the synthetic procedure used, the compounds of the present invention may exist as mixtures of enantiomers. Enantiomers can be separated by conventional techniques known in the art. Therefore, the present invention encompasses individual enantiomers and mixtures thereof.

[0265] For some steps of the method for preparing formula (I) compound, it may be necessary to protect the potential reactive functional groups that do not wish to react, and subsequently cut off the protecting group. In this case, any compatible protected free radical can be used. Particularly, the method for protection and deprotection can be used, such as those described by TWGREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or PJKocienski (Protecting groups, Georg Thieme Verlag, 1994). The preparation of the new starting material used in all the above-mentioned reactions and the aforementioned method is conventional, and the reagent and reaction conditions suitable for its performance or preparation and the method for separating the desired product are well-known to those skilled in the art under reference precedent and the example and preparation of this aspect.

[0266] Additionally, the compounds of the present invention and the intermediates used in their preparation can be purified according to various well-known methods such as crystallization or chromatography.

[0267] The methods of treatment or compounds for treating cancer, lymphoma, leukemia or immune disorders as defined above may be applied as sole therapy or in combination therapy with another active agent.

[0268] Therapeutic methods or compounds for treating cancer, lymphoma or leukemia may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more of the following classes of anti-tumor agents:

[0269] (i) antiproliferative / antineoplastic drugs and their combinations (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, bendamustine, melphalan, chlorambucil, phenobarbital, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytarabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and bromocycline inhibitors); proteasome inhibitors such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin);

[0270] (ii) translation errors Cytostatics such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodixanol), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorozole, and exemestane), and 5α-reductase inhibitors such as finasteride;

[0271] (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;

[0272] (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (such as EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-yl)amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; protein regulators that regulate apoptosis (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, such as sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[0273] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin) TM ); thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

[0274] (vi) gene therapy approaches, including, for example, methods to replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2;

[0275] (vii) Immunotherapy, including, for example, antibody therapy such as alemtuzumab, rituximab, ibritumomab and ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors such as IRAK4 inhibitors; cancer vaccines including prophylactic and therapeutic vaccines such as HPV vaccines, for example, Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); and toll-like receptor modulators, for example, TLR-7 or TLR-9 agonists; and

[0276] (viii) Cytotoxic agents such as fludara, cladribine, pentostatin TM );

[0277] (ix) Steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, clomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone propionate, clopredniol, cortisone, cortisone acetate, Cortisol, deoxycorticosterone, diomethasone, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone sodium isonicotinate, diflucorticosterone, flucloxatone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide Acetate, fluocortol butyl, fludrocortisone, fluocortolone, fluocortolone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone acepro, hydrocortisone valerate, icomethasone, icomethasone acetonide, prednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone acetonide, and pharmaceutically acceptable derivatives thereof. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0278] (x) Targeted therapies, such as PI3Kd inhibitors, such as idelalisib and perifosine.

[0279] The method of treatment or the compound for treating an immune disease may include other active agents in addition to the compounds of the present invention. The additional active agent may be one or more active agents for treating a condition treatable by the compound of formula (I) and the additional active agent. The additional active agent may include one or more of the following active agents:

[0280] (i) steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, such as alclomethasone, clomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone propionate, cloprednisolone, cortisone, cortisone acetate, cortisol, deoxycorticosterone, diomethasone, desoximetasone, dexamethasone sodium phosphate, dexamethasone sodium isonicotinate, diflucorticosterone, flucloxatone, flumethasone, flunisolide, fluocinolone aceton ... Corticosteroid acetate, fluocortol butylate, fludrocortisone, fluocortolone, fluocortolone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone acepromazine, hydrocortisone valerate, icomethasone, icomethasone acetonide, prednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone acetonide, and pharmaceutically acceptable derivatives thereof. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0281] (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylacridine);

[0282] (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs;

[0283] (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, bromotropium, tetraoxaprine, elaprix, pemetrexed, raltitrexed, and pralatrexate; and

[0284] (v) Immunosuppressants, for example, cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (for example, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, such as sulfhydryl-containing agents (for example, captopril, zofenopril), dicarboxylate-containing agents (for example, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (for example, fosinopril).

[0285] Such combination treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0286] According to another aspect of the present invention, there is provided a pharmaceutical product comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and an additional active agent. The additional active agent may be an anti-tumor agent as defined above for combined treatment of a condition regulated by BTK.

[0287] According to another aspect of the present invention, there is provided a method for treating a condition modulated by BTK, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an additional anti-tumor agent as defined above simultaneously, sequentially or separately.

[0288] According to another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with another anti-tumor agent as defined above in the treatment of a condition modulated by BTK.

[0289] According to another aspect of the present invention, there is provided the use of a compound of formula (I) in combination with an antitumor agent as described above. The compound of formula (I) can be used simultaneously, sequentially or separately with another antitumor agent. The use can be used in a single combination product comprising a compound of formula (I) and an antitumor agent.

[0290] According to another aspect, a method of providing a combination product is provided, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an antineoplastic agent as defined above. The method may comprise combining the compound of formula (I) and the antineoplastic agent in a single dosage form. Alternatively, the method may comprise providing the antineoplastic agent as a separate dosage form.

[0291] According to another aspect, a method of providing a combination product is provided, wherein the method comprises providing a compound of formula (I) simultaneously, sequentially or separately with an antineoplastic agent as defined above. The method may comprise combining the compound of formula (I) and the antineoplastic agent in a single dosage form. Alternatively, the method may comprise providing the antineoplastic agent as a separate dosage form.

[0292] The above-mentioned condition modulated by BTK can be cancer, leukemia or cancer. More specifically, the condition modulated by BTK can be selected from: B cell malignancies, B cell lymphomas, diffuse large B cell lymphomas, chronic lymphocytic leukemias, non-Hodgkin's lymphomas such as ABC-DLBCL, mantle cell lymphomas, follicular lymphomas, hairy cell leukemia B cell non-Hodgkin's lymphomas, Waldenstrom's macroglobulinemia and multiple myeloma.

[0293] The compounds of the present invention may exist in single crystal form or in a crystalline mixture, or they may be amorphous. Therefore, the compounds of the present invention for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained as solid fillers, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[0294] For the above-mentioned compounds of the present invention, the dosage applied will of course vary with the compound used, the mode of administration, the desired treatment and the disease in question. For example, if the compounds of the present invention are administered orally, the daily dosage of the compounds of the present invention may be in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0295] The compounds of the present invention or their pharmaceutically acceptable salts can be used alone, but are generally administered in the form of a pharmaceutical composition in which the compounds of the present invention or their pharmaceutically acceptable salts are combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0296] Depending on the mode of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05 to 99 weight % (by weight) of the compound of the present invention, more preferably 0.05-80 weight % of the compound of the present invention, still more preferably 0.10-70 weight % of the compound of the present invention, even more preferably 0.10-50 weight % of the compound of the present invention, all weight percentages being based on the total composition.

[0297] The pharmaceutical compositions can be administered topically (e.g., to the skin) in the form of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration in the form of tablets, capsules, syrups, powders, or granules; or parenterally in the form of sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of aerosols.

[0298] For oral administration, the compounds of the present invention can be mixed with an adjuvant or carrier, such as lactose, sucrose, sorbitol, mannitol; starch, such as potato starch, corn starch or pullulan; cellulose derivatives; binders, such as gelatin or polyvinyl pyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, wax and paraffin, and then compressed into tablets. If coated tablets are required, the core prepared as described above can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent.

[0299] In order to prepare soft gelatin capsules, the compound of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules can contain compound particles using the above-mentioned tablet excipients. Liquid or semisolid preparations of the compound of the present invention can also be filled into hard gelatin capsules. Liquid preparations for oral administration can be in the form of syrups or suspensions, for example, solutions containing the compound of the present invention, the rest being mixtures of sugar and ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations can contain colorants, flavorings, sweeteners (e.g., saccharin), preservatives and / or carboxymethyl cellulose as thickeners or other excipients known to those skilled in the art.

[0300] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0301] According to well-known pharmaceutical principles, the size of the dose of the compounds of the present invention for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0302] It is estimated that the dosage level, dosage frequency and treatment duration of the compounds of this invention depend on the clinical indications, age and comorbidity of preparation and patient.For most clinical indications, it is estimated that the standard duration for treatment with the compounds of this invention varies between 1 day and 7 days.In the case of recurrent infection or infection related to tissue or implant material (including bone / joint, respiratory tract, endocardium and tooth tissue) with poor blood supply, it may be necessary to extend the duration for treatment to exceed 7 days.

[0303] Examples and Synthesis

[0304] As used herein, the following terms have the meanings given: “Boc” means tert-butoxycarbonyl; “DCM” means dichloromethane; “DIPEA” means N,N-diisopropylethylamine; “EtOAc” means ethyl acetate; “LCMS” means liquid chromatography / mass spectrometry; “MIM” means monoisotopic mass; “min” means minute; “DMF” means N,N-dimethylformamide; “Pet. Ether” means petroleum ether; “TLC” means thin layer chromatography; “Rf” means retention factor; “RT” means RT; “SCX” means strong cation exchange; “TEA” means triethylamine; “TFA” means trifluoroacetic acid; “THF” means tetrahydrofuran; and “TBME” means tert-butyl methyl ether.

[0305] Unless otherwise stated, solvents, reagents and starting materials were purchased from commercial suppliers and used as received.Unless otherwise stated, all reactions were performed at room temperature.

[0306] Compound identity and purity were confirmed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2 #LCA081). The diode array detector wavelength was 254 nM, and the MS was in positive and negative electrospray modes (m / z: 150-800). A 2 μL aliquot was injected sequentially onto a guard column (0.2 μm x 2 mm filter) and a UPLC column (C18, 50 x 2.1 mm, <2 μm) maintained at 40°C. The sample was eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient listed in Table 1 below. Retention times (RT) are reported in minutes.

[0307] Table 1

[0308]

[0309]

[0310] Compound identity was also confirmed by LCMS UV using a Waters Alliance 2695 Micromass ZQ (K98SM4512M-LAA434). The diode array detector wavelength was 254 nM, and the MS was in positive and negative electrospray modes (m / z: 150-650). A 10 μL aliquot was injected onto an HPLC column (C18, 75×4.6 mm, 2.5 μm) at RT controlled at 19°C. The sample was eluted at a flow rate of 0.9 mL / min using a mobile phase system consisting of A (95:5 (v / v) water:acetonitrile containing 0.1% (v / v) formic acid) and B (95:5 (v / v) acetonitrile:water containing 0.1% (v / v) formic acid) according to the gradient listed in Table 2 below. Retention times (RT) are reported in minutes.

[0311] Table 2

[0312]

[0313]

[0314] Compound identity was also confirmed by analytical supercritical fluid chromatography (SFC) using an Agilent 1260 analytical SFC (SFC-A). A 10 μL aliquot was injected onto an HPLC column (C18, 75×4.6 mm, 2.5 μm) at RT controlled at 19° C. The sample was eluted at a flow rate of 3 mL / min using a mobile phase system consisting of A: CO 2 and B: methanol (0.05% DEA, v / v) with a gradient of phase B from 5% to 40% over 3.6 min.

[0315] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds were measured on silica thin layer chromatography (TLC) plates.

[0316] Compound purification was performed by silica gel flash column chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass spectrometer in positive and negative electrospray mode (m / z: 150-800) with a Waters 2489 UV / Vis detector. The mobile phase system consisted of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient listed in Table 3 below, and the mobile phase system was HPLC-MS / MS. TM The sample was eluted on a preparative C18 5 μM OBD 19x100 mm column at a flow rate of 20 mL / min.

[0317] Table 3

[0318] Time (minutes) ％A ％B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

[0319] Compound purification was also performed by preparative supercritical fluid chromatography (SFC). SFC purification was performed using a Waters 80Q preparative SFC (SFC-B). A mobile phase system consisting of A: CO2 and B: methanol (0.1% NH3H2O) was used under isocratic elution (25% B phase) on a ChiralPak OJ-H column, 250×30 mm ID, at a flow rate of 50 g / min for 5 μm particle size.

[0320] Chemical names in this document were generated using mol2nam-Structure to Name Conversion performed by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesized according to literature procedures.

[0321] General solution

[0322] The compounds of the present invention can be prepared by following either General Scheme 1 or General Scheme 2, as shown below.

[0323] General Solution 1

[0324]

[0325] In one aspect of the present invention, there is provided a compound of formula (A):

[0326]

[0327] Among them, R 6 As defined elsewhere herein, optionally wherein R 6 is substituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl ring, wherein, when substituted, R 6 Contains 1 to 5 substituents independently selected at each occurrence from the group consisting of halogen, -OR I 、-NR I R J 、-CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl and -OR I Substituted C 1-6 alkyl;

[0328] Y is a halogen group, such as fluorine; and

[0329] Z is a metal ion, for example a Group 1 metal such as potassium or sodium.

[0330] In the above aspects of the present invention, R 6Preferably substituted with methoxy and 0 to 4 additional substituents independently selected at each occurrence from: halogen, -OR I 、-NR I R J 、-CN、C 1-6 Alkyl, C 1-6 Halogenated alkyl and -OR I Substituted C 1-6 alkyl.

[0331] In a preferred embodiment, the compound according to formula (A) is a compound according to formula (B) or (C):

[0332]

[0333] General Solution 2

[0334]

[0335] General Solution 3

[0336]

[0337] General Procedures

[0338] General Procedure A

[0339] Under a nitrogen atmosphere, to a suspension of [4-(aminomethyl)phenyl]borate hydrochloride (1.1 equiv.) and anhydrous THF (0.49 M) containing the corresponding benzoic acid (1.0 equiv.) were added N,N-diisopropylethylamine (5.0 equiv.) and propylphosphonic anhydride solution (50 wt. % in EtOAc) (1.5 equiv.) in sequence. The reaction mixture was heated at reflux for 14 h at 70 ° C and stirred. The mixture was diluted with water and DCM, and then separated. The aqueous layer was extracted with DCM (× 2). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the desired boronic acid. No further purification was attempted, and the product was used directly in the next step.

[0340] General Procedure B

[0341] To a suspension of [4-(aminomethyl)phenyl]borate hydrochloride (1.0 equiv) and DIPEA (3.0 equiv) in anhydrous THF (0.2 M) under a nitrogen atmosphere was added a solution of the corresponding benzoyl chloride derivative (1.1 equiv) in anhydrous THF (0.2 M). The reaction mixture was stirred at room temperature for 16 h, quenched with saturated aqueous ammonium chloride, and then extracted into ethyl acetate (×3). The combined organics were washed with brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure to give the desired boronic acid derivative. No further purification was attempted, and the product was used directly in the next step.

[0342] General Program C

[0343] A mixture of halogen (1.0 equiv), boronic acid or pinacol ester (1.5 equiv) and potassium carbonate (2.0 equiv) in 1,4-dioxane and water (3:1, 0.1 M) was degassed by bubbling nitrogen through it for 25 minutes. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.05 equiv) was added and the mixture was degassed again by bubbling nitrogen through it for 30 minutes. The mixture was then heated at 120°C for 14 hours. The reaction mixture was filtered. The filter cake was rinsed with DCM. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (×2). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure to obtain a dark solid. Further purification by silica gel flash column chromatography gave the desired compound.

[0344] General Program D

[0345] A mixture of halogen (1.0 eq.), boronic acid or pinacol ester (1.5 eq.) and potassium carbonate (2.0 eq.) in 1,4-dioxane and water (3:1, 0.1 M) was degassed by bubbling nitrogen through it for 15 minutes. 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane complex (0.05 eq.) was added and the mixture was degassed again by bubbling nitrogen through it for 15 minutes. The mixture was then heated at 120-140°C under microwave irradiation for 60-90 minutes. The reaction mixture was purified by SCX SPE column and used as such or purified using the following procedure unless stated to use crude. By The mixture was filtered through a pad of Celite®. The filter cake was rinsed with DCM. Water was added to the filtrate and the layers were separated. The aqueous layer was extracted with DCM (×2). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure to obtain a dark solid. Further purification by flash column chromatography gave the desired compound.

[0346] General Program E

[0347] To a solution of the ketone (1.0 eq) in MeOH (0.2 M) was added the corresponding hydrazine (1.05 eq) and the reaction was stirred at room temperature for 15 h. The volatiles were removed under reduced pressure to afford the crude Boc-hydrazone derivative.

[0348] General Program F

[0349] A solution of the Boc-hydrazone derivative (1.00 equiv) in methanol was treated with 10% palladium on carbon (0.02 equiv), acetic acid (0.01 equiv) and purged with H2. The solution was stirred under H2 (1 atm) overnight and then purified by The filtrate was concentrated under reduced pressure to afford the corresponding Boc-protected hydrazine.

[0350] General Program G

[0351] To a solution of Boc-protected hydrazine (1.0 equiv) in MeOH (0.5 M) was added 4N HCl in 1,4-dioxane (8.0 equiv) and the reaction was stirred at room temperature for 5 h. Diethyl ether was added to form a precipitate, which was collected by filtration to provide the desired hydrazine intermediate. Alternatively, the mixture was concentrated under reduced pressure and used as is.

[0352] General Program H

[0353] To a solution of 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.0 equiv) and TEA (3.0 equiv) in EtOH (0.6 M) was added the corresponding hydrazine derivative (1.2 equiv), followed by stirring at 100° C. for 2-14 h. Volatiles were removed under reduced pressure. Saturated aqueous ammonium chloride and ethyl acetate were added to the residue, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Further purification by silica gel flash column chromatography afforded the desired compound.

[0354] General Procedure I

[0355] To a stirred solution of alcohol (1.0 eq) in DCM (0.9 M) cooled at 0°C under a nitrogen atmosphere was added triethylamine (1.1 eq). The resulting solution was stirred for 10 minutes, then methanesulfonyl chloride (1.1 eq) was added dropwise. The reaction mixture was stirred at 0°C for 1 h, quenched with water, and extracted with DCM (×2). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the desired mesylated product.

[0356] General Program J

[0357] Hydrochloric acid (1 M, 3.0 equiv) was added to a suspension of the 1,3-dioxolane derivative (1.0 equiv) in THF (1 M) cooled at 0°C. The reaction mixture was allowed to return to room temperature and stirred for 14 h. The mixture was then carefully basified with saturated sodium carbonate solution, and the aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to yield the crude carbonyl.

[0358] General Program K

[0359] A mixture of a halogen derivative (1.0 equiv), Molander salt (1.0 equiv), cesium carbonate (3.0 equiv) and XPhos (0.1 equiv) in THF and water (10:1, 0.06 M) was degassed by bubbling nitrogen therein for 15 minutes. Palladium acetate (0.05 equiv) was then added and the mixture was degassed again by bubbling nitrogen therein for 5 minutes. The mixture was then heated to 85°C for 16 hours and then heated to 40°C for 16 hours. Filter. Rinse the filter cake with DCM. Add water to the filtrate and separate the layers. Extract the aqueous layer with DCM (×2). The combined organic extracts are filtered through a phase separator and then concentrated under reduced pressure. Further purification by silica gel flash column chromatography affords the desired compound.

[0360] General Program L

[0361] To a solution of the nitrile derivative (1.0 equivalent) in EtOH / water (2:1, 0.8 M) was added hydrogenated (dimethylphosphinate kP) [hydrogen bis(dimethylphosphino-kP)] platinum (II) (0.07 g, 0.163 mmol). The mixture was heated at 80 ° C overnight and then concentrated under reduced pressure. The residue was then partitioned between DCM and water. The aqueous layer was extracted with DCM (× 3). The combined organic extracts were filtered through a phase separator and then concentrated under reduced pressure to give the desired crude amide.

[0362] General Program M

[0363] To the nitrile derivative (1 equivalent) was added a solution of sulfuric acid (10 equivalents) and trifluoroacetic acid (40 equivalents), and the reaction mixture was heated to 55°C for 5 h. Once cooled, the mixture was poured into an ice-water mixture, carefully neutralized with sodium bicarbonate, and then extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Further purification by silica gel flash column chromatography afforded the desired amide.

[0364] General Program N

[0365] Cesium carbonate (1.5 equiv) is added to a mixture of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (1 equiv) and a halide derivative (1.2 equiv) in DMF (0.1 M). The reaction mixture is heated to 80° C. for 1.5 h and then concentrated under reduced pressure. Further purification by silica gel flash column chromatography or mass-directed semi-preparative HPLC affords the desired product.

[0366] General Program O

[0367] Under a nitrogen atmosphere and 0°C, a solution of borane tetrahydrofuran complex (BH3-THF, 1.0M in THF, 2 equivalents) was added to a solution of hydrazone (1 equivalent) in THF. The reaction mixture was returned to RT, stirred for 14 hours, and then quenched with methanol (1 mL) and water. The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic glass frit and concentrated under reduced pressure. Dioxane containing hydrogen chloride (4M, 10 equivalents) was added to the residue, and the mixture was stirred at room temperature for 14 hours. The mixture was then concentrated under reduced pressure and the residue was dissolved in ethanol (0.2M). 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.5-1.0 equivalents) and TEA (5 equivalents) were added, and the reactants were stirred at room temperature for 14 hours. The volatiles were removed under reduced pressure. Water and DCM were added to the residue and the layers were separated. The aqueous layer was extracted with DCM (×2). The combined organic extracts were filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification by silica gel flash column chromatography gave the desired product.

[0368] General Program P

[0369] Under nitrogen, 1M borane THF complex (5.0 equivalents) was added dropwise to a stirred solution of anhydrous THF (0.10 M) containing the nitrile derivative (1.0 equivalent). The reaction mixture was then heated at reflux for 4 h before cooling to room temperature. Methanol was carefully added dropwise until gas evolution ceased. The solvent was removed under reduced pressure, and the residue was dissolved in methanol and treated with concentrated aqueous HCl. The resulting mixture was heated at reflux for 10 minutes and then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was carefully treated with an excess of aqueous sodium bicarbonate. The resulting suspension was extracted with ethyl acetate, and the organic layer was dried, filtered, and evaporated under reduced pressure to obtain the corresponding amine.

[0370] General Program Q

[0371] DMF (0.5M) solution containing acid (1.1 equivalents) and 1-hydroxybenzotriazole hydrate (1.1 equivalents) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.1 equivalents) was stirred at room temperature for 30 minutes, then processed with corresponding amine (1.0 equivalents), and subsequently processed with triethylamine (5.0 equivalents). The reaction mixture was then stirred at room temperature for 18h, poured into salt water and extracted with ethyl acetate. The organic layer was washed with 0.2M HCl aqueous solution and salt water. The organic layer was then dried, filtered, and the solvent was evaporated under reduced pressure to obtain the required crude amide.

[0372] General Program R

[0373] To a nitrogen-degassed solution of potassium acetate (3.0 equiv), bis(pinacolato)diboron (1.5 equiv) and a halide derivative (1.0 equiv) in 1,4-dioxane (0.12 M) was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.05 equiv). The reaction mixture was then degassed with nitrogen for another 5 minutes and then stirred at 90°C until the reaction was complete. Once cooled, the mixture was passed through Filter. Add water to the filtrate and separate the layers. Extract the aqueous layer with ethyl acetate (×3). Wash the combined organic layers with brine, dry over sodium sulfate, filter, and remove all volatiles under reduced pressure. The resulting residue can be used crude or further purified by silica gel flash column chromatography to obtain the desired pinacol ester.

[0374] General Program S

[0375] To a solution of benzoyl hydrazide (1 eq) in toluene (0.5 M) was added the ketone (1.5 eq). The reaction mixture was heated to 110°C for 10-18 h and then cooled to room temperature. The reaction mixture was poured into water and then filtered. The solid was washed with water and further dried to obtain the desired crude hydrazone.

[0376] General Program T

[0377] To a solution of hydrazone (1 equivalent) in THF (0.2-0.4 M) cooled at 0°C is added borane-THF (1 M, 2 equivalents). The reaction is allowed to return to room temperature and stirred for 3-14 hours. The mixture is then cooled to 0°C, quenched with MeOH and allowed to return to room temperature. The mixture is then concentrated under reduced pressure and the residue is triturated with a suitable solvent (Pet.Ether, Et2O or EtOAc) to give the desired hydrazine or purified by flash column chromatography on silica gel.

[0378] Universal Program U

[0379] To a solution of benzoyl hydrazide (1 eq) in MeOH (0.7 M) was added 37% aqueous hydrogen chloride solution (16 eq). The mixture was heated at 80 ° C for 16 h, cooled to room temperature and concentrated under reduced pressure. EtOAc was added, the precipitate was filtered and washed twice with EtOAc to give the crude hydrazine salt.

[0380] Universal Program W

[0381] To a solution of toluene (0.5 M) and THF (0.5 M) containing malononitrile (1 eq) was added the corresponding benzoyl chloride (1 eq). The reaction mixture was cooled to -10 ° C and then N, N-diisopropylethylamine (2 eq) was added dropwise while maintaining the internal temperature below -10 ° C. Once the addition was complete, the reaction mixture was stirred at room temperature for 14 h and diluted with EtOAc. The layers were separated. The organic layer was washed with 1 M HCl and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the desired compound.

[0382] General Program X

[0383] At room temperature, sodium carbonate (2 equivalents) is added to a solution of 1,4-dioxane (0.5M) containing dinitrile (1 equivalent). The reaction is stirred for 10 minutes, and then dimethyl sulfate (1.25 equivalents) is added dropwise. Once the addition is complete, the reactant is heated to reflux for 14h, cooled and concentrated under reduced pressure. Water is added to the crude residue, and the mixture is extracted with EtOAc. The combined organic matter is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified by flash column chromatography to obtain the desired compound.

[0384] General Program Y

[0385] Allyltrimethylsilane (1.5 equivalents) and boron trifluoride diethyl etherate (1.5 equivalents) were added to a stirred solution of DCE (0.5 M) containing an olefin (1.0 equivalent). The resulting solution was heated to reflux for 5 minutes. The solvent was then removed under reduced pressure, and the mixture was dissolved in DMF (0.5 M). Trimethyl(trifluoromethyl)silane (2.0 equivalents) and sodium acetate (4.0 equivalents) were then added sequentially. The reaction mixture was stirred at room temperature for 2 hours, quenched with a saturated Na2CO3 solution and diluted with water. The aqueous solution was then extracted with ether (×2), dried over a hydrophobic frit, and concentrated under reduced pressure to give the desired derivative.

[0386] [4-[[(2-Methoxybenzoyl)amino]methyl]phenyl]boronic acid

[0387] Following general procedure A, 2-methoxybenzoic acid (13.32 mL, 89.45 mmol) and [4-(aminomethyl)phenyl]borate hydrochloride (15.24 g, 81.32 mmol) provided the title compound (20.70 g, 72.61 mmol, 89% yield) as an off-white solid.

[0388] UPLC-MS(ES + , short acidic): 1.31 min, m / z 286.1 [M+H] +

[0389] N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0390] Following general procedure C, 5-amino-3-bromo-1H-pyrazol-4-carbonitrile (6.04 g, 32.32 mmol) and [4-[[(2-methoxybenzoyl)amino]methyl]phenyl]boronic acid (purified by flash column chromatography eluting with 0-10% MeOH in DCM) gave N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (6.45 g, 18.57 mmol, 57% yield) as a light brown solid.

[0391] UPLC-MS(ES + , short acidic): 1.42 min, m / z 348.2 [M+H] +

[0392] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroacetyl) Pyrazole-4-carboxamide

[0393] To a degassed solution of N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (6.25 g, 17.99 mmol) was added sulfuric acid (9.59 mL, 179.92 mmol) and trifluoroacetic acid (55.3 mL, 719.68 mmol). The reaction mixture was heated to 55° C. for 5 hours. The reaction mixture was poured into an ice-water mixture, carefully neutralized with sodium bicarbonate, and then extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM gave 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (5.00 g, 13.68 mmol, 76% yield) and 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroacetyl)pyrazole-4-carboxamide (0.37 g, 0.80 mmol, 4% yield) as white solids.

[0394] UPLC-MS(ES + , short acidic): 1.26 min, m / z 366.2 [M+H] +

[0395] UPLC-MS(ES + , short acidic): 1.63 min, m / z 462.1 [M+H] +

[0396] UPLC-MS(ES + , long acidic): 3.31 min, m / z 462.2 [M+H]+

[0397] Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane

[0398] A toluene solution of potassium bis(trimethylsilyl)amide (0.5M, 23.8mL, 11.9mmol) was added dropwise to a solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5g, 11.3mmol) in anhydrous THF (25mL). After stirring at -78°C for 25 minutes, the mixture was allowed to warm to room temperature and anhydrous methanol (1.3mL, 32.1mmol) was added. After 1 hour, 2-methoxybenzoyl chloride (3.4mL, 22.6mmol) was slowly added and the mixture was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated under vacuum. The obtained residue was diluted with methanol (25mL) and then saturated aqueous potassium bifluoride solution (3.5g, 45.3mmol) was added. After stirring overnight, the mixture was concentrated under reduced pressure. The resulting residue was washed with hot acetone (×4). The acetone phase was filtered and the filtrate was concentrated under reduced pressure until almost all of the acetone disappeared. Et2O was then added and the product precipitated and collected to give potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.50 g, 5.53 mmol, 49% yield) as a white solid.

[0399] UPLC-MS(ES + , short acidic): 1.03 min, m / z 232.1 [MK] +

[0400] 2-[(4-Bromophenyl)-hydroxy-methylene]malononitrile

[0401] To a solution of 4-bromobenzoyl chloride (7.00 g, 31.9 mmol) and malononitrile (2.32 g, 35.1 mmol) in toluene (40 mL) and THF (8.6 mL) cooled to -10°C under a nitrogen atmosphere was added a solution of N,N-diisopropylethylamine (11.11 mL, 63.8 mmol) in toluene (30 mL) while maintaining the internal temperature at -10°C. Once the addition was complete, the reaction mixture was stirred at 0°C for 1 hour and then at room temperature for 18 hours. Hydrochloric acid (1 M) was added and the reaction mixture was layered with EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with HCl (1 M), brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to give 2-[(4-bromophenyl)-hydroxy-methylene]malononitrile (7.72 g, 31.0 mmol, 97% yield) as a light brown solid.

[0402] 1H NMR (400MHz, DMSO-d6, δ): 7.58 (dt, J = 8.7, 2.1 Hz, 2H), 7.52 (dt, J = 8.8, 2.1 Hz, 2H).

[0403] 2-[(4-Bromophenyl)-hydroxy-methylene]malononitrile

[0404] Under nitrogen, 4-bromobenzoyl chloride (200 g, 911 mmol), toluene (1000 mL), THF (200 mL), and malononitrile (63 mL, 1003 mmol) were added to a 2 L reactor equipped with a thermometer. The reaction mixture was cooled to -10 ° C, and then N, N-diisopropylethylamine (318 mL, 1823 mmol) was added dropwise to the reaction mixture, maintaining the internal temperature below -10 ° C (coolant at -20 ° C) for more than 45 minutes. Once the addition was complete, the jacket was adjusted to 0 ° C for 2 hours, then 25 ° C for 2 hours. The reaction mixture was transferred to a 7 L separatory funnel, and the reactor was washed with 1 M HCl aqueous solution (1.5 L) and EtOAc (1.5 L) in sequence, and each was transferred to a separatory funnel. The layers were separated, and the organic layer was washed with 1 M HCl aqueous solution (250 mL) and brine (250 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a slurry. The product of 2-[(4-bromophenyl)-hydroxy-methylene] malononitrile (210g, 843mmol, 93% yield) was obtained by slurrying and filtering with petroleum ether (500mL). The solid was washed with cold petroleum ether (100mL) to obtain the crude 2-[(4-bromophenyl)-hydroxy-methylene] malononitrile (232g) of the product after air drying. The material was slurried and filtered with a minimum of cold ethyl acetate, washed with a minimum of ethyl acetate and ether, to obtain 2-[(4-bromophenyl)-hydroxy-methylene] malononitrile (210g, 843mmol, 93% yield), which was a light yellow solid.

[0405] 2-[(4-Bromophenyl)-methoxy-methylene]malononitrile

[0406] 2-[(4-bromophenyl)-hydroxy-methylene] malononitrile (7.00g, 28.11mmol) in THF (17mL) solution was added dropwise to a suspension of sodium hydride (1.24g, 30.92mmol) in THF (20mL), cooled to 0°C. After stirring at 0°C for 30 minutes, dimethyl sulfate (7.98mL, 84.32mmol) was added and the reaction mixture was heated to 80°C and stirred for 14 hours. The mixture was cooled to RT, quenched with saturated ammonium chloride solution and extracted with EtOAc. The organic layer combined was dried over sodium sulfate and concentrated under reduced pressure. Further purified by flash column chromatography on silica gel, eluted with a heptane solution of 20-80% DCM to give 2-[(4-bromophenyl)-methoxy-methylene] malononitrile (3.58g, 13.61mmol, 48% yield), as a white crystalline solid.

[0407] UPLC-MS(ES + , short acidic): 1.76 min, m / z 263.4 [M] +

[0408] 2-[(4-Bromophenyl)-methoxy-methylene]malononitrile

[0409] At room temperature, sodium carbonate (179g, 1686mmol) was added to a solution of 2-[(4-bromophenyl)-hydroxy-methylene] malononitrile (210g, 843mmol) in 1,4-dioxane (1500mL). The mixture was stirred for 10 minutes, and then dimethyl sulfate (100mL, 1054mmol) was added dropwise over 10 minutes. The reaction mixture was then heated to reflux for 2 hours, cooled and layered between water (1.5L) and DCM (1.5L). The aqueous layer was then extracted with DCM (1L), and the combined organic extracts were then washed with water (500mL) and brine (500mL), dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain an orange solid. Further purification by flash column chromatography on silica gel eluting with 50-100% DCM in petroleum ether followed by 25% ethyl acetate in DCM gave a light orange solid which was then slurried with petroleum ether (500 mL) and filtered to give 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (153 g, 582 mmol, 69% yield) as an off-white solid.

[0410] 5-Fluoro-2-methoxy-benzoyl chloride

[0411] At RT, oxalyl chloride (124mL, 1469mmol) is joined in DCM (1750mL) stirred suspension of 5-fluoro-2-methoxybenzoic acid (125g, 735mmol) and DMF (2.7g, 37mmol).Then reaction mixture is at room temperature stirred 16 hours, concentrated under reduced pressure, to obtain rough 5-fluoro-2-methoxy-benzoyl chloride (138g, 732mmol, assuming quantitative yield), is yellow oil, its rapid crystallization.

[0412] UPLC-MS(ES + , short acidic): 1.46 min, m / z: 1.46 min [M+H] + (Methyl ester adduct)

[0413] Potassium trifluoro-[[(5-fluoro-2-methoxybenzoyl)amino]methyl]borane

[0414] A 0.7 M solution of potassium bis(trimethylsilyl)amide in toluene (174 mL, 770 mmol) was added dropwise to a solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (170 g, 770 mmol) in anhydrous THF (1200 mL). After stirring at -78°C for 25 minutes, the mixture was stirred at 0°C for another 10 minutes and then at room temperature for 30 minutes. Anhydrous methanol (99 g, 3078 mmol) was added at room temperature and a precipitate formed. The mixture was stirred at room temperature for another hour, and then the reaction mixture was concentrated under reduced pressure while maintaining the water bath at 30°C. The mixture was co-evaporated with THF (2×250 mL). The residue was dissolved in anhydrous THF (750 mL), and then a solution of 5-fluoro-2-methoxy-benzoyl chloride (138 g, 731 mol) in THF (250 mL) was slowly added. The reaction mixture was then stirred at room temperature for 14 hours and then concentrated under reduced pressure. The resulting residue was dissolved in ice-cold MeOH (1000 mL), and the mixture was then cooled to 0° C. before adding saturated potassium bifluoride solution (264 g, 3386 mmol in water (600 mL)). The reaction mixture was warmed to room temperature and stirred for 15 hours, then concentrated under reduced pressure. The residue was azeotroped twice with toluene (3×500 mL) to remove water. The residue was then washed with cold TBME and filtered. The white solid was washed with cold acetone (750 mL) and then washed with a hot acetone solution (3×2000 mL) containing 25% MeOH. The filtrate was concentrated under reduced pressure. Once most of the solvent was removed, TBME (500 mL) was added, and the obtained white solid was filtered out and washed with cold TBME to obtain trifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]borane potassium (198 g, 411 mmol, 53% yield).

[0415] 1 H NMR(400MHz,DMSO-d6,):7.80-7.71(m,1H),7.64(dd,J=9.8,3.4Hz,1H),7.3 1-7.25(m,1H),7.16(dd,J=9.2,4.4Hz,1H),3.88(s,3H),2.17-2.09(m,2H).

[0416] 4-Bromo-2,6-difluoro-benzoyl chloride

[0417] To a suspension of 4-bromo-2,6-difluorobenzoic acid (2 g, 8.44 mmol) in DCM (30 mL) was added oxalyl chloride (0.80 mL, 9.28 mmol) and DMF (0.1 mL, 1.30 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours and cooled to 0° C. More oxalyl chloride (0.79 mL, 9.28 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to give 4-bromo-2,6-difluoro-benzoyl chloride (1.58 g, 6.19 mmol, 73% yield).

[0418] UPLC-MS: (ES + , short acidic): 1.74 min, m / z 250.9 [M] + (Methyl ester adduct)

[0419] 2-[(4-Bromo-2,6-difluoro-phenyl)-hydroxy-methylene]malononitrile

[0420] General Procedure W was followed from malononitrile (450 mg, 6.80 mmol) and 4-bromo-2,6-difluoro-benzoyl chloride (1.58 g, 6.19 mmol) to afford 2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]malononitrile (2 g, 7.05 mmol, assumed quantitative yield) as a thick yellow oil.

[0421] UPLC-MS: (ES + , short acidic): 1.13 min, m / z 286.7 [M+2] +

[0422] 2-[(4-Bromo-2,6-difluoro-phenyl)-methoxy-methylene]malononitrile

[0423] Following General Procedure X, 2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.01 g, 7.05 mmol) was purified by flash column chromatography on silica gel eluting with 20-80% DCM in heptane to afford 2-[(4-bromo-2,6-difluoro-phenyl)-methoxy-methylene]malononitrile (1.48 g, 4.95 mmol, 70% yield) as a white solid.

[0424] UPLC-MS: (ES + , short acidic): 1.69 min, m / z 300.9 [M+2] +

[0425] 2-[(4-Chloro-3,5-difluoro-phenyl)-hydroxy-methylene]malononitrile

[0426] General procedure W and 4-chloro-3,5-difluorobenzoyl chloride (2.00 g, 9.48 mmol) gave 2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.48 g, 10.31 mmol, assumed quantitative yield) as a brown thick oil.

[0427] UPLC-MS: (ES - , short acidic): 1.34 min, m / z 238.8 [MH] -

[0428] 2-[(4-Chloro-3,5-difluoro-phenyl)-methoxy-methylene]malononitrile

[0429] Following General Procedure X, 2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.48 g, 10.31 mmol) was purified by flash column chromatography on silica gel eluting with 20-80% DCM in heptane to afford 2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]malononitrile (1.68 g, 6.60 mmol, 64% yield) as a light yellow solid.

[0430] UPLC-MS: (ES + , short acidic): 1.70 min, m / z 254.9 [M+H] +

[0431] 2-[(4-Chloro-2,5-difluoro-phenyl)-hydroxy-methylene]malononitrile

[0432] General Procedure W and 4-chloro-2,5-difluorobenzoyl chloride (2.00 g, 9.48 mmol) gave 2-[(4-chloro-2,5-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.66 g, 11.06 mmol, assumed quantitative yield) as a beige solid.

[0433] UPLC-MS: (ES - , short acidic): 1.11 min, m / z 238.8 [MH] -

[0434] 2-[(4-Chloro-2,5-difluoro-phenyl)-methoxy-methylene]malononitrile

[0435] Following General Procedure X, 2-[(4-chloro-2,5-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.66 g, 11.06 mmol) was purified by flash column chromatography on silica gel eluting with 20-80% DCM in heptane to afford 2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]malononitrile (1.64 g, 6.44 mmol, 58% yield) as a light yellow oil.

[0436] UPLC-MS: (ES + , short acidic): 1.67 min, m / z 254.9 [M+H] +

[0437] 4-Chloro-2,3-difluoro-benzoyl chloride

[0438] To a suspension of 4-bromo-2,6-difluorobenzoic acid (2.00 g, 8.44 mmol) in DCM (30 mL) was added oxalyl chloride (0.80 mL, 9.28 mmol) and DMF (0.1 mL, 1.30 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 hours and cooled to 0° C. More oxalyl chloride (0.80 mL, 9.28 mmol) was added and the reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure to give 4-chloro-2,3-difluoro-benzoyl chloride (2.19 g, 10.38 mmol, assumed quantitative yield).

[0439] UPLC-MS: (ES + , short acidic): 1.74 min, m / z 206.8 [M] + (Methyl ester adduct)

[0440] 2-[(4-Chloro-2,3-difluoro-phenyl)-methoxy-methylene]malononitrile

[0441] Malononitrile (750 mg, 11.42 mmol) and 4-chloro-2,3-difluoro-benzoyl chloride (2.19 g, 10.38 mmol) were used to give crude 2-[(4-chloro-2,3-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.61 g, 10.85 mmol, assumed quantitative yield) as a brown solid following General Procedure W. Purification by flash column chromatography on silica gel following General Procedure X, eluting with 20-80% DCM in heptane, gave 2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]malononitrile (1.6 g, 6.40 mmol, 59% yield) as an off-white solid.

[0442] UPLC-MS: (ES + , short acidic): 1.70 min, m / z 254.9 [M+H] +

[0443] Example 1: 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0444]

[0445] 5-Amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

[0446] General Procedure H, 2-[(4-Bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) and cyclopentylhydrazine hydrochloride (0.91 mmol) were reacted to give the title compound (0.83 mmol). UPLC-MS (ES + , short acidic): 2.17 min, m / z 333.2 [M+2] +

[0447] N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0448] General Procedure K, 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.45 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) were reacted to give the title compound (0.36 mmol) as a yellow solid. UPLC-MS (ES + , short acidic): 1.87 min, m / z 416.2 [M+H] +

[0449] 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0450] General Procedure M, N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.36 mmol) was reacted to give the title compound (0.23 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.58 min, m / z 434.2 [M+H] + UPLC-MS(ES + , long acidic): 3.59 min, m / z 434.2 [M+H] +

[0451] 1 H NMR (400 MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 1H), 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.51-7.37 (m, 5H), 7.17-7.13 (m, 1H), 7.03 (td, J = 7.5, 1.0 Hz, 1H), 6.31 (s, 2H), 4.60 (quintet, J = 7.3 Hz, 1H), 4.54 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 2.02-1.86 (m, 4H), 1.83-1.72 (m, 2H), 1.65-1.51 (m, 2H).

[0452] The compound of Example 1 can also be prepared by the following method.

[0453] 5-Amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

[0454] A solution of 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (72.2 mmol), cyclopentylhydrazine dihydrochloride (72.2 mmol), and trimethylamine (288.9 mmol) in EtOH (400 mL) was refluxed for 1.5 hours. The reaction mixture was heated at reflux for 1.5 hours, cooled, and concentrated under reduced pressure. Workup and purification afforded the title compound (51.9 mmol) as a light yellow solid.

[0455] N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0456] Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (36.2 mmol), palladium(II) acetate (1.27 mmol), cesium carbonate (108.7 mmol) and 5-amino-3-(4-bromophenyl)-cyclopentyl-pyrazole-4-carbonitrile (36.2 mmol) were suspended in THF (250 mL) and water (75 mL). The orange reaction mixture was degassed under vacuum and flushed with nitrogen three times. 2-Biscyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.54 mmol) was added and the mixture was heated at reflux for 4 hours. Filtration, workup and concentration gave the title compound (32.01 mmol) as a light orange solid.

[0457] 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0458] After heating to 55° C. for 3 hours, a mixture of N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (32.0 mmol), sulfuric acid (320.1 mmol), and trifluoroacetic acid (800.3 mmol) was cooled and then carefully added to an ice-cold solution of sodium bicarbonate (1921 mmol) in water (750 mL) with vigorous stirring. A mixture of heptane / EtOAc (100 mL, 1:1) was added and the mixture was filtered. The solid was suspended in 10% MeOH / DCM (750 mL) and water (100 mL). After workup and crystallization from EtOAc and MeOH (200 mL), the title product (13.15 mmol) was obtained as an off-white solid.

[0459] Example 2: 5-amino-1-[(1R*,2R*)-2-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0460]

[0461] 5-Amino-3-(4-bromophenyl)-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazole-4-carbonitrile

[0462] General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and (1R*,2R*)-2-hydrazinocyclopentanol (0.38 mmol) were reacted to give the title compound (0.38 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.82 min, m / z 349.1 [M+2] +

[0463] N-[[4-[5-amino-4-cyano-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazol-3-yl]phenyl]methyl]- 2-Methoxy-benzamide

[0464] Following General Procedure C, 5-amino-3-(4-bromophenyl)-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazole-4-carbonitrile (0.12 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.13 mmol) gave the title compound (0.11 mmol) as a white powder. UPLC-MS (ES + , short acidic): 1.60 min, m / z 432.2 [M+H] +

[0465] 5-amino-1-[(1R*,2R*)-2-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[0466] Following General Procedure L and using N-[[4-[5-amino-4-cyano-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.10 mmol), the title compound (0.05 mmol, 49% yield) was obtained as a white powder. UPLC-MS (ES + , short acidic): 1.44 min, m / z 450.3 [M+H] + UPLC-MS(ES + , long acidic): 3.16 min, m / z 450.3 [M+H] +

[0467] 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=5.9Hz, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.52-7.38(m,5H),7.18-7.14(m,1H),7.04(td,J=7.5,1.0Hz,1H),6.26(s,2H ),5.03(d,J=4.6Hz,1H),4.55(d,J=6.1Hz,2H),4.36-4.24(m,2H),3.90(s,3H ),2.11-2.00(m,1H),2.00-1.85(m,2H),1.79-1.67(m,2H),1.60-1.48(m,1H).

[0468] Example 3: 5-amino-1-tert-butyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0469]

[0470] 5-Amino-3-(4-bromophenyl)-1-tert-butyl-pyrazole-4-carbonitrile

[0471] General Procedure H, 2-[(4-Bromophenyl)-methoxy-methylene]malononitrile (0.57 mmol) and tert-butylhydrazine hydrochloride (0.86 mmol) gave the title compound (0.52 mmol) as a light yellow solid after purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM. UPLC-MS (ES + , short acidic): 2.21 min, m / z 321.0 [M+2] +

[0472] N-[[4-(5-Amino-1-tert-butyl-4-cyano-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0473] General Procedure K: 5-amino-3-(4-bromophenyl)-1-tert-butyl-pyrazole-4-carbonitrile (0.22 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.24 mmol) were used to give the title compound (0.21 mmol, 98% yield) as a yellow solid after flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.90 min, m / z 404.2 [M+H] +

[0474] 5-amino-1-tert-butyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0475] Following General Procedure L, the title compound (0.03 mmol) was obtained as a light yellow solid after purification by flash column chromatography on silica gel with N-[[4-(5-amino-1-tert-butyl-4-cyano-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.74 mmol). UPLC-MS (ES + , short acidic): 1.61 min, m / z 422.3 [M+H] + UPLC-MS(ES + , long acidic): 3.57 min, m / z 422.3 [M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.1Hz, 1H), 7.75 (dd, J=7.7, 1.8Hz, 1H), 7.50-7.37 (m, 5H), 7.17- 7.13(m,1H),7.03(td,J=7.5,1.1Hz,1H),6.28(s,2H),4.54(d,J=6.1Hz,2H),3.90(s,3H),1.56(s,9H).

[0477] Example 4: 5-amino-1-(3-bicyclo[3.1.0]hexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0478]

[0479] Bicyclo[3.1.0]hexan-3-one

[0480] To a solution of pyridine (1.68 mmol) and pyridinium chlorochromate (7.64 mmol) in DCM (6 mL) cooled to 0° C. was added cis-bicyclo[3.1.0]hexan-3-ol (5.09 mmol) dropwise. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with diethyl ether and the black residue was washed with more diethyl ether (×3). The combined organics were then passed through a pad of florisil and the solvent removed under reduced pressure to give the title compound as a crude yellow oil. 1 H NMR (400MHz, CDCl3, δ): 2.64-2.54(m,2H), 2.20-2.12(m,2H), 1.57-1.50(m,2H), 0.94-0.86(m,1H), -0.03--0.08(m,1H).

[0481] tert-Butyl N-(3-bicyclo[3.1.0]hexylideneamino)carbamate

[0482] A mixture of bicyclo [3.1.0] hexan-3-one (5.58 mmol) and tert-butyl carbazate (5.58 mmol) in methanol (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure. The reaction mixture was quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic extracts were filtered through a hydrophobic glass frit and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluted with a heptane solution of 0-100% EtOAc to obtain the title compound (2.84 mmol) as a clear oil. 1 H NMR (400MHz, CDCl3, δ): 2.85-2.77(m,1H), 2.63-2.56(m,1H), 2.39-2.35(m,2H), 1.52-1.35(m,12H), 0.74-0.66(m,1H), -0.13--0.18(m,1H).

[0483] 3-Bicyclo[3.1.0]hexylhydrazine; 2,2,2-trifluoroacetic acid

[0484] Sodium cyanoborohydride (4.71mmol) is added in batches to acetic acid (7mL) and water (7mL) stirred solution of N-(3-bicyclo [3.1.0] hexylidene amino) tert-butyl carbamate (4.76mmol).Gained mixture is stirred at room temperature for 2 hours, neutralized by adding 1M NaOH (aqueous solution), then extracted with DCM (× 2).The organic extract merged is washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated to dryness, to obtain crude N-(3-bicyclo [3.1.0] hexylamino) tert-butyl carbamate (4.71mmol), for clear oily matter.The crude product is dissolved in DCM (4.5mL).In trifluoroacetic acid (58.77mmol), DCM (4.5mL) stirred solution of N-(3-bicyclo [3.1.0] hexylamino) tert-butyl carbamate (4.71mmol) is added dropwise. The resulting solution was stirred for 2 hours and then concentrated under reduced pressure to give the crude title compound (4.42 mmol) as a clear oil.

[0485] 1 H NMR (400MHz, CDCl3, δ): 3.88-3.78 (m, 1H), 2.43-2.31 (m, 2H), 1.74 (dd, J = 14.9, 4.9Hz, 2H), 1.40-1.24 (m, 2H), 0.83-0.75 (m, 1H), 0.17-0.11 (m, 1H).

[0486] 5-Amino-1-(3-bicyclo[3.1.0]hexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile

[0487] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.78 mmol) and 3-bicyclo[3.1.0]hexylhydrazine; 2,2,2-trifluoroacetic acid (1.17 mmol) afforded the title compound (0.21 mmol) as a colorless oil. UPLC-MS (ES + , short acidic): 2.15 min, m / z 345.1 [M+2] +

[0488] N-[[4-[5-amino-1-(3-bicyclo[3.1.0]hexyl)-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methyl Oxy-benzamide

[0489] General Procedure K, 5-amino-1-(3-bicyclo[3.1.0]hexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile (0.21 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.21 mmol) gave the title compound (0.23 mmol). UPLC-MS (ES + , short acidic): 1.86 min, m / z 428.2 [M+H] +

[0490] 5-amino-1-(3-bicyclo[3.1.0]hexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl] Pyrazole-4-carboxamide

[0491] General Procedure L: N-[[4-[5-amino-1-(3-bicyclo[3.1.0]hexyl)-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.21 mmol) afforded the title compound (0.04 mmol) after purification by mass-directed semi-preparative HPLC. UPLC-MS (ES + , short acidic): 1.68 min, m / z 446.2 [M+H] + UPLC-MS(ES + , long acidic): 3.72 min, m / z 446.3 [M+H] +

[0492] 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.2Hz, 1H), 7.77 (dd, J=7.7, 1.8Hz, 1H), 7.54 -7.38(m,5H),7.16(dd,J=8.4,0.7Hz,1H),7.04(td,J=7.5,1.0Hz,1H),6.29(s,2H) ,5.01-4.83(m,1H),4.55(d,J=6.1Hz,2H),3.91(s,3H),2.46-2.36(m,2H),1.92(d d,J=13.8,4.8Hz,2H),1.35-1.27(m,2H),0.81(q,J=4.1Hz,1H),0.66-0.54(m,1H).

[0493] Example 5: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methylcyclopentyl)pyrazole-4-carboxamide

[0494]

[0495] tert-Butyl N-[(3-methylcyclopent-2-en-1-ylidene)amino]carbamate

[0496] To a solution of 3-methyl-2-cyclopenten-1-one (10.40 mmol) in methanol (59.4 mL) was added tert-butyl carbazate (10.92 mmol) and the reaction was stirred at room temperature for 16 hours. The volatiles were removed under reduced pressure to give the title compound (12.18 mmol). 1 H NMR (400MHz, DMSO-d6, δ): 5.98-5.93 (m, 1H), 3.26-3.05 (br s, 1H), 2.62-2.57 (m, 2H), 2.44-2.41 (m, 2H), 2.15 (s, 3H), 1.47 (s, 9H).

[0497] (3-Methylcyclopentyl)hydrazine

[0498] To a solution of tert-butyl N-[-(3-methylcyclopent-2-ene-1-ylidene)amino]carbamate (10.40 mmol) in THF / MeOH (21 mL, 1:1) was added sodium cyanoborohydride (12.50 mmol) in portions. The reaction was heated to reflux under a nitrogen atmosphere for 10 minutes and then cooled to room temperature. Hydrogen chloride (30.00 mmol) was added and the reaction mixture was heated to reflux for 3 hours, cooled to room temperature and stirred for 16 hours. The reaction was filtered to remove inorganic insolubles and the filtrate was concentrated under reduced pressure and azeotroped with toluene (×3). The residue was dissolved in hot isopropanol, cooled to RT, diluted with ether, and then cooled to 0°C. The precipitate was filtered and the filtrate was concentrated in vacuo to give the title compound (6.50 mmol). 1 H NMR (400 MHz, DMSO-d6, δ, mixture of diastereomers): 3.83-3.62 and 3.56-3.38 (m, 1H), 3.10-2.99 and 2.78-2.68 (m, 2H), 2.26-2.01 (m, 2H), 2.00-1.57 (m, 5H), 1.40-1.02 (m, 1H), 0.99 and 0.93 (d, J = 6.5 Hz, 3H).

[0499] 5-Amino-3-(4-bromophenyl)-1-(3-methylcyclopentyl)pyrazole-4-carbonitrile

[0500] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-2% MeOH in DCM was followed by the reaction of 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and (3-methylcyclopentyl)hydrazine (0.38 mmol) to afford the title compound. UPLC-MS (ES + , short acidic): 2.26 minutes, m / z 345.1 [M] +

[0501] N-[[4-[5-amino-4-cyano-1-(3-methylcyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzene Formamide

[0502] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(3-methylcyclopentyl)pyrazole-4-carbonitrile (0.08 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.08 mmol) were used to give the title compound (0.05 mmol) after purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 2.03 min, m / z 430.2 [M+H] +

[0503] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-methylcyclopentyl)pyrazole- 4-Formamide

[0504] General Procedure L: N-[[4-[5-amino-4-cyano-1-(3-methylcyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.08 mmol) afforded the title compound (0.01 mmol) after purification by mass-directed semi-preparative HPLC. UPLC-MS (ES + , short acidic): 1.73 min, m / z 448.3 [M+H] + UPLC-MS(ES + , long acidic): 3.86 min, m / z 448.3 [M+H] +

[0505] 1 H NMR (400 MHz, DMSO-d6, δ) (diastereoisomer mixture): 8.74 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.53-7.38 (m, 5H), 7.16 (d, J = 7.8 Hz, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.31 (s, 2H), 4.79-4.58 (m, 1H), 4.55 (d, J =6.0Hz,2H),3.91(s,3H),2.30-2.21(m,0.5H),2.17-2.05(m,1.5H),2.01-1.92(m,2.5H),1.85-1.75 (m,0.5H),1.64-1.51(m,1H),1.44-1.33(m,0.5H),1.21-1.11(m,0.5H),1.02(dd,J=21.0,6.6Hz,3H).

[0506] Example 6: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carboxamide

[0507]

[0508] 5-Amino-3-(4-bromophenyl)-1-[5-(trifluoromethyl)-2-pyridinyl]pyrazole-4-carbonitrile

[0509] Following General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (80 mg, 0.30 mmol) and 5-(trifluoromethyl)pyridin-2-ylhydrazine (0.30 mmol) gave the title compound as an off-white solid. UPLC-MS (ES + , short acidic): 2.27 minutes, m / z 408.1 [M] +

[0510] N-[[4-[5-amino-4-cyano-1-[5-(trifluoromethyl)-2-pyridinyl]pyrazol-3-yl]phenyl]methyl]-2- Methoxybenzamide

[0511] General Procedure K, 5-amino-3-(4-bromophenyl)-1-[5-(trifluoromethyl)-2-pyridinyl]pyrazole-4-carbonitrile (0.10 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.12 mmol) gave the title compound (0.06 mmol) as a white powder. UPLC-MS (ES + , short acidic): 2.03 min, m / z 493.3 [M+H] +

[0512] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[5-(trifluoromethyl)-2-pyridine [pyridyl]pyrazole-4-carboxamide

[0513] General Procedure L, N-[[4-[5-amino-4-cyano-1-[5-(trifluoromethyl)-2-pyridinyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.06 mmol) was used to give the title compound (0.03 mmol) as a white powder. UPLC-MS (ES + , short acidic): 1.85 min, m / z 511.3 [M+H] + UPLC-MS(ES + , long acidic): 4.19 minutes, m / z 511.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.90-8.86 (m, 1H), 8.79 (t, J = 6.1Hz, 1H), 8.38 (dd, J = 8.9, 2.3Hz, 1H), 8.05 (d, J = 8.8Hz, 1H), 7.83-7.7 4(m,3H),7.60(d,J=8.1Hz,2H),7.53-7.45(m,3H),7.17(d,J=8.3Hz,1H),7.09-7.02(m,1H),4.59(d,J=6.0Hz,2H),3.92(s,3H).

[0514] Example 7: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(methoxymethoxy)ethyl]pyrazole-4-carboxamide

[0515]

[0516] General Procedure N, 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.26 mmol) and 1-bromo-2-(methoxymethoxy)ethane (0.39 mmol) gave the title compound (0.03 mmol) after purification by mass-directed semi-preparative HPLC (Intermediate Methods). UPLC-MS (ES + , short acidic): 1.42 min, m / z 454.2 [M+H] + UPLC-MS(ES + , long acidic): 3.10 min, m / z 454.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 7.75 (dd, J=7.7, 1.8Hz, 1H), 7.51-7.38 (m, 5H), 7.18-7.13 (m, 1H), 7.04 (td ,J=7.5,1.0Hz,1H),6.30(s,2H),4.57-4.52(m,4H),4.10(t,J=5.7Hz,2H),3.90(s,3H),3.77(t,J=5.7Hz,2H),3.19(s,3H).

[0517] Example 8: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[(3-methyloxetan-3-yl)methyl]pyrazole-4-carboxamide

[0518]

[0519] General Procedure N, 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.25 mmol) and 3-(chloromethyl)methyloxetane (0.38 mmol) gave the title compound (0.07 mmol) after purification by mass-directed semi-preparative HPLC. UPLC-MS (ES + , short acidic): 1.42 min, m / z 450.2 [M+H] + UPLC-MS(ES + , long acidic): 3.11 min, m / z 450.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 1H), 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.51-7.38 (m, 5H), 7.17-7.13 (m, 1H), 7.04 (td, J = 7.5, 1.5Hz,1H),6.41(s,2H),4.63(d,J=5.9Hz,2H),4.54(d,J=6.1Hz,2H),4.20(d,J=5.9Hz,2H),4.09(s,2H),3.90(s,3H),1.24(s,3H).

[0520] Example 9: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-morpholinoethyl)pyrazole-4-carboxamide

[0521]

[0522] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-morpholinoethyl)pyrazole- 4-Formamide

[0523] General Procedure N: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.27 mmol) and N-chloroethylmorpholine hydrochloride (0.41 mmol) were used to give the title compound (0.04 mmol) after purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.20 min, m / z 479.3 [M+H] + UPLC-MS(ES + , long acidic): 2.51 min, m / z 479.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.53-7.37 (m, 5H), 7.16 (d, J = 8.2 Hz, 1H), 7.05 (td, J = 7.5, 1. 0Hz,1H),6.40(s,2H),4.55(d,J=6.1Hz,2H),4.04(t,J=6.7Hz,2H),3.90(s,3H),3.60-3.56(m,4H),2.69-2.65(m,2H),2.47-2.44(m,4H).

[0524] Example 10: 5-amino-1-(3,3-dimethyl-2-oxo-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0525]

[0526] 5-amino-1-(3,3-dimethyl-2-oxo-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[0527] General Procedure N: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.24 mmol) and 1-bromo-3,3-dimethylbutan-2-one (0.36 mmol) were used to give the title compound (0.03 mmol) after purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.55 min, m / z 464.3 [M+H] + UPLC-MS(ES + , long acidic): 3.49 min, m / z 464.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.53-7.37 (m, 5H), 7.17 (d, J = 8.2 Hz, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 1H), 6.27 (s, 2H), 5.12 (s, 2H), 4.55 (d, J = 6.1Hz, 2H), 3.90 (s, 3H), 1.18 (s, 9H).

[0528] Example 11: 5-amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0529]

[0530] 5-amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4- Formamide

[0531] General Procedure N: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.25 mmol) and 3-bromopropionitrile (0.37 mmol) gave the title compound (0.07 mmol) after purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM.

[0532] UPLC-MS(ES + , short acidic): 1.37 min, m / z 419.2 [M+H] + UPLC-MS(ES + , long acidic): 3.02 min, m / z 419.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.53-7.37 (m, 5H), 7.16 (d, J=7.7Hz, 1H), 7 .04(td,J=7.5,1.0Hz,1H),6.49(s,2H),4.56(d,J=6.1Hz,2H),4.22(t,J=6.7Hz,2H),3.90(s,3H),2.97(t,J=6.7Hz,2H).

[0533] Example 12: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclohexyl)pyrazole-4-carboxamide

[0534]

[0535] A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.82 mmol) in MeCN (0.5 mL) was slowly added to a solution of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.27 mmol) in MeCN (2 mL). The reaction was stirred at room temperature for 15 minutes, and then cyclohex-2-enone (0.55 mmol) was added. The reaction mixture was stirred for 16 hours. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated in vacuo. Purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM gave the title compound (0.15 mmol) as a light brown solid. UPLC-MS (ES + , short acidic): 1.42 min, m / z 462.2 [M+H] + UPLC-MS(ES + , long acidic): 3.00 min, m / z 462.3 [M+H] + .

[0536] 1H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.2Hz, 1H), 7.75 (dd, J=7.7, 1.8Hz, 1H), 7.51-7.45 (m, 3H),7.42-7.37(m,2H),7.17-7.13(m,1H),7.04(td,J=7.6,1.0Hz,1H),6.38(d,J=1.8Hz,1H ),6.09(s,1H),4.54(d,J=6.2Hz,2H),4.53-4.49(m,1H),3.89(s,3H),2.13-2.05(m,1H),2. 01-1.95(m,1H),1.89-1.79(m,2H),1.78-1.68(m,1H),1.67-1.54(m,2H)1.29-1.06(m,1H).

[0537] Example 13: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide

[0538]

[0539] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole- 4-Formamide

[0540] To a mixture of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-indol-7-ol (0.27 mmol) and 2-cyclopentenone (0.33 mmol) in MeCN (0.54 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mmol). The reaction mixture was stirred at RT for 2 days and then concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-3.5% MeOH in DCM and then by reverse phase chromatography eluting with 20-40% MeCN in water with 0.1% formic acid additive to give the title compound (0.04 mmol, 14% yield) as an off-white solid. UPLC-MS (ES + , short acidic): 1.44 min, m / z 448.2 [M+H] + .

[0541] UPLC-MS(ES + , long acidic): 3.09 min, m / z 448.2 [M+H] + .

[0542] 1H NMR (400MHz, DMSO-d6, δ): 8.76-8.69 (m, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J=8.2Hz, 1H), 7.07-7.00 (m, 1H), 6.42 (s, 2H), 5.05-4.95 (m, 1H), 4.54 (d, J = 6.1Hz, 2H), 3.90 (s, 3H), 2.73-2.61 (m, 1H), 2.60-2.30 (m, 3H), 2.27-2.11 (m, 2H).

[0543] Example 14: 5-amino-1-(2-hydroxy-3,3-dimethyl-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0544]

[0545] 5-amino-1-(2-hydroxy-3,3-dimethyl-butyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[0546] A solution of 5-amino-1-(3,3-dimethyl-2-oxobutyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (0.07 mmol) in MeOH (1 mL) was added dropwise to a solution of sodium borohydride (0.07 mmol) in MeOH (1 mL) at 0°C. The reaction mixture was stirred for 30 minutes and then diluted with DCM. Saturated aqueous Na2CO3 solution was then added and the mixture was extracted with DCM (×3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM to give the title compound (0.03 mmol). UPLC-MS (ES + , short acidic): 1.62 min, m / z 466.3 [M+H] + UPLC-MS(ES + , long acidic): 3.49 minutes, m / z 466.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.8Hz, 1H), 7.38-7.54(m,5H),7.16(d,J=8.1Hz,1H),7.05(td,J=7.5,0.9Hz,1H),6.10(s ,2H),5.10(d,J=5.9Hz,1H),4.56(d,J=6.1Hz,2H),3.99(dd,J=14.3,1.7Hz,1 H), 3.91 (s, 3H), 3.78 (dd, J = 14.2, 9.5Hz, 1H), 3.47-3.59 (m, 1H), 0.92 (s, 9H).

[0547] Example 15: 5-amino-1-(2,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0548]

[0549] 5-Amino-3-(4-bromophenyl)-1-(2,4-difluorophenyl)pyrazole-4-carbonitrile

[0550] General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.30 mmol) and 2,4-difluorophenylhydrazine hydrochloride (0.30 mmol) afforded the title compound (0.22 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.99 min, m / z 375.1 [M] +

[0551] N-[[4-[5-amino-4-cyano-1-(2,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzene Formamide

[0552] General Procedure K, 5-amino-3-(4-bromophenyl)-1-(2,4-difluorophenyl)pyrazole-4-carbonitrile (0.11 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) gave the title compound (0.10 mmol) as a white powder. UPLC-MS (ES + , short acidic): 1.73 min, m / z 460.2 [M+H] +

[0553] 5-amino-1-(2,4-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 4-Formamide

[0554] General Procedure L, N-[[4-[5-amino-4-cyano-1-(2,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.10 mmol) gave the title compound (0.05 mmol) as an off-white powder.

[0555] UPLC-MS(ES + , short acidic): 1.57 min, m / z 478.2 [M+H] + UPLC-MS(ES + , long acidic): 3.58 min, m / z 478.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.69-7.60 (m, 1H), 7.60-7.40 (m, 6 H),7.32-7.23(m,1H),7.16(d,J=8.3Hz,1H),7.08-7.01(m,1H),6.46(s,2H),4.57(d,J=6.1Hz,2H),3.90(s,3H).

[0556] Example 16: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide

[0557]

[0558] 5-Amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbonitrile

[0559] General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and [3-(trifluoromethyl)phenyl]hydrazine hydrochloride (0.38 mmol) afforded the title compound (0.31 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 2.18 minutes, m / z 407.1 [M] +

[0560] 5-Amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide

[0561] General Procedure Nitrile hydrolysis with 5-amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carbonitrile (0.12 mmol) gave the crude title compound (0.12 mmol) as a clear oil. UPLC-MS (ES + , short acidic): 1.93 min, m / z 425.0 [M]+

[0562] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[3-(trifluoromethyl)phenyl] Pyrazole-4-carboxamide

[0563] General Procedure K, 5-amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxamide (0.12 mmol) and sodium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borohydride (0.18 mmol) gave the title compound (0.08 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 1.79 min, m / z 510.3 [M+H] + UPLC-MS(ES + , long acidic): 4.06 min, m / z 510.6 [M+H] + . 1 H NMR(400MHz,DMSO-d6,δ):8.77(t,J=6.1Hz,1H),8.02-7.92(m,2H),7.83-7.73(m,3H),7.57(d,J=8.1Hz,2H), 7.53-7.43(m,3H),7.16(d,J=7.2Hz,1H),7.08-7.02(m,1H),6.65(s,2H),4.58(d,J=6.1Hz,2H),3.91(s,3H).

[0564] Example 17: 5-amino-1-(cyclohexylmethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0565]

[0566] General Procedure N, 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.26 mmol) and (bromomethyl)cyclohexane (0.39 mmol) gave the title compound (0.04 mmol) after purification by mass-directed semi-preparative HPLC. UPLC-MS (ES + , short acidic): 1.71 min, m / z 462.3 [M+H] + UPLC-MS(ES + , long acidic): 3.88 min, m / z 462.3 [M+H] + . 1H NMR(400MHz,DMSO-d6,δ):8.74(t,J=6.1Hz,1H),7.76(dd,J=7.7,1.8Hz,1H),7.51-7.38(m,5H),7.18-7.14(m,1H),7.04(td,J=7.5,1.0Hz,1H),6 .31(s,2H),4.55(d,J=6.1Hz,2H),3.90(s,3H),3.75(d,J=7.2Hz,2H),1. 88-1.75(m,1H),1.73-1.53(m,5H),1.27-1.09(m,3H),1.06-0.91(m,2H).

[0567] Example 18: 5-amino-1-cyclohexyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0568]

[0569] 5-Amino-3-(4-bromophenyl)-1-cyclohexyl-pyrazole-4-carbonitrile

[0570] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM followed by the reaction of 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) and cyclohexylhydrazine hydrochloride (0.91 mmol) afforded the title compound (0.65 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 2.11 min, m / z 347.1 [M+2] + .

[0571] N-[[4-(5-Amino-4-cyano-1-cyclohexyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0572] General Procedure K: Purification by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-cyclohexyl-pyrazole-4-carbonitrile (0.64 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.70 mmol) afforded the title compound (0.59 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.81 min, m / z 430.3 [M+H] + .

[0573] 5-amino-1-cyclohexyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0574] General Procedure M: N-[[4-(5-amino-4-cyano-1-cyclohexyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.58 mmol) was purified by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM to afford the title compound (0.32 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.59 min, m / z 448.3 [M+H] + UPLC-MS(ES + , long acidic): 3.63 min, m / z 448.3 [M+H] + .

[0575] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.6, 1.7Hz, 1H), 7.52-7.38 (m, 5H), 7.19-7.14 (m, 1H), 7.04 (td, J=7.6,0.9Hz,1H),6.32(s,2H),4.55(d,J=6.1Hz,2H),4.12-4.03(m,1H),3.90(s,3H),1.76-1.60(m,8H),1.45-1.29(m,2H).

[0576] Example 19: 5-amino-1-isopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0577]

[0578] 5-Amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carbonitrile

[0579] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-2% MeOH in DCM followed by 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and isopropylhydrazine (0.46 mmol) afforded the title compound (0.27 mmol) as a light yellow solid. UPLC-MS (ES+, short acidic): 1.96 min, m / z 307.1 [M+2] + .

[0580] N-[[4-(5-Amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0581] General Procedure K: Purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-isopropyl-pyrazole-4-carbonitrile (0.27 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.27 mmol) afforded the title compound (0.19 mmol) as a yellow solid. UPLC-MS (ESI) + , short acidic): 1.73 min, m / z 390.2 [M+H] + .

[0582] 5-amino-1-isopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0583] General Procedure M: N-[[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.19 mmol) was purified by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM to afford the title compound (0.10 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.46 min, m / z 408.3 [M+H] + UPLC-MS(ES + , long acidic): 3.23 minutes, m / z 408.3 [M+H] + .

[0584] 1 H NMR (400 MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 1H), 7.75 (dd, J = 7.7, 1.8 Hz, 1H), 7.50-7.38 (m, 5H), 7.18-7.13 (m, 1H), 7.04 (td, J = 7.5, 0.9 Hz, 1H), 6.31 (s, 2H), 4.54 (d, J = 6.1 Hz, 2H), 4.47 (quintet, J = 6.6 Hz, 1H), 3.90 (s, 3H), 1.33 (d, J = 6.6 Hz, 6H).

[0585] Example 20: 5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0586]

[0587] 5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[0588] Sodium borohydride (0.20 mmol) was added to a solution of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide (0.18 mmol) in methanol (1 mL) and cooled to 0°C. The reaction mixture was then stirred at room temperature for 30 minutes, quenched with saturated ammonium chloride solution and the layers separated. The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic glass frit and concentrated under reduced pressure. Further purification by reverse phase chromatography eluting with 20-40% MeCN in water with 0.1% formic acid additive gave the title compound (0.08 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.38 min, m / z 450.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.5, 1.8Hz, 1H), 7.55 -7.38(m,5H),7.16(d,J=8.3Hz,1H),7.07-7.01(m,1H),6.40(s,2H),5.07(d,J=5. 7Hz,1H),4.65(quintet, J=7.7Hz,1H),4.55(d, J=6.1Hz,2H),4.18-4.09(m,1H),3.91(s,3H),2.32-2.21(m,1H),2.08-1.92(m,2H),1.92-1.83(m,1H),1.82-1.62(m,2H).

[0589] Example 21: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxamide

[0590]

[0591] 5-Amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile

[0592] Further purification by flash column chromatography on silica gel following General Procedure H, eluting with 0-10% MeOH in DCM, with 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and 2,2,2-trifluoroethylhydrazine (70 wt% in water, 0.46 mmol) afforded the title compound (0.27 mmol) as a light yellow solid. LC-MS (ES) + , Method 1): 5.80 min, m / z 345.0 [M] + .

[0593] N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy- Benzamide

[0594] Further purification by flash column chromatography on silica gel following General Procedure K, eluting with 10-100% EtOAc in heptane, with 5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carbonitrile (0.29 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.38 mmol) afforded the title compound (0.17 mmol) as an off-white solid. LC-MS (ES) + , method 1): 5.01 min, m / z 430.2 [M+H] + .

[0595] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidone oxazole-4-carboxamide

[0596] General Procedure L: N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.16 mmol) was further purified by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane to afford the title compound (0.08 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.54 min, m / z 448.2 [M+H] + UPLC-MS(ES + , long acidic): 3.22 minutes, m / z 448.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.0Hz, 1H), 7.76 (dd, J=7.7, 1.8Hz, 1H), 7.52-7.40 (m, 5H), 7.16 (d, J=8.1Hz,1H),7.07-7.02(m,1H),6.68(s,2H),4.95(q,J=9.0Hz,2H),4.56(d,J=6.1Hz,2H),3.91(s,3H).

[0597] Example 22: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-phenyl-pyrazole-4-carboxamide

[0598]

[0599] 5-Amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile

[0600] General Procedure H. Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM was followed by the reaction of 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.35 mmol) and phenylhydrazine (0.42 mmol) to afford 5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile (0.28 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 2.04 min, m / z 339.1 [M] + .

[0601] N-[[4-(5-Amino-4-cyano-1-phenyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0602] Further purification by flash column chromatography on silica gel following General Procedure K, eluting with 10-100% EtOAc in heptane, with 5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carbonitrile (0.12 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) afforded the title compound (0.09 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.77 min, m / z 424.1 [M+H] + .

[0603] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-phenyl-pyrazole-4-carboxamide

[0604] General Procedure L: N-[[4-(5-amino-4-cyano-1-phenyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.07 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.05 mmol) as a white solid. LC-MS (ES) + , method 1): 4.53 min, m / z 442.2 [M+H] + UPLC-MS(ES + , long acidic): 3.39 min, m / z 442.2 [M+H] + .

[0605] 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.6, 2.0Hz, 1H), 7.65-7.60 (m, 2H), 7.59- 7.38(m,8H),7.16(d,J=8.1Hz,1H),7.08-7.02(m,1H),6.49(s,2H),4.58(d,J=6.1Hz,2H),3.91(s,3H).

[0606] Example 23: 5-amino-1-[(1R)-indan-1-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0607]

[0608] N-[[4-[5-amino-4-cyano-1-[(1R)-indan-1-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy- Benzamide

[0609] A suspension of N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (100 mg, 0.29 mmol), (S)-(+)-1-indanol (0.49 mmol) and triphenylphosphine (0.49 mmol) in anhydrous THF (2 mL) was cooled to 0 ° C. Diisopropyl azodicarboxylate (0.49 mmol) was added dropwise over 5 minutes, and the reaction mixture was returned to room temperature over 30 minutes and then stirred for 16 hours. The reaction mixture was concentrated in vacuo. Further purification by SPE SCX column eluted with MeOH gave the title compound (0.17 mmol). UPLC-MS (ES + , short acidic): 1.90 min, m / z 464.3 [M+H] + .

[0610] 5-amino-1-[(1R)-indan-1-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrrolidone oxazole-4-carboxamide

[0611] General Procedure L: N-[[4-[5-amino-4-cyano-1-[(1R)-indan-1-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.27 mmol) was purified by flash column chromatography on silica gel eluting with 0-5% MeOH in DCM to afford the title compound (0.03 mmol). UPLC-MS (ESI) + , short acidic): 1.74 min, m / z 482.3 [M+H] + UPLC-MS(ES + , long acidic): 3.77 min, m / z 482.3 [M+H] + .

[0612] 1H NMR (400MHz, DMSO-d6, δ): 8.70 (t, J=6.1Hz, 1H), 7.74 (dd, J=7.6, 1.7Hz, 1H), 7.5 2-7.43(m,1H),7.41-7.34(m,4H),7.30(d,J=7.4Hz,1H),7.24(t,J=7.1Hz,1H),7. 20-7.11(m,2H),7.09-6.98(m,2H),6.56(s,2H),5.91(t,J=7.5Hz,1H),4.52(d,J= 6.0Hz,2H),3.88(s,3H),3.21-3.06(m,1H),2.97-2.84(m,1H),2.49-2.38(m,2H).

[0613] Example 24: 1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide

[0614]

[0615] 2-(4-bromobenzoyl)-3-oxo-butyric acid methyl ester

[0616] Under N2, methylmagnesium bromide solution (2.2M in THF, 9.27mmol) was added to a solution of methyl acetoacetate (9.27mmol) in THF (44mL) at 0°C, and then stirred at 0°C for 30 minutes. 4-Bromobenzoyl chloride (9.27mmol) was then added, and then stirred at RT for 16 hours. Afterwards, it was quenched with saturated ammonium chloride solution. The aqueous layer was then extracted with DCM (×3), the organics were combined, filtered through a hydrophobic glass frit, and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel, eluting with 0-15% EtOAc in heptane, gave the title compound (4.99mmol) as a clear oil. UPLC-MS (ES + , short acidic): 1.88 min, m / z 299.0 [M] + .

[0617] 3-(4-Bromophenyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester

[0618] A solution of hydrazine hydrate (55-60% in water, 3.99 mmol) was added to a solution of methyl 2-(4-bromobenzoyl)-3-oxo-butyrate (4.99 mmol) in acetic acid (20 mL). Afterwards, the mixture was stirred at RT for 72 hours, and then all volatiles were removed under reduced pressure. Afterwards, the residue was basified with saturated sodium carbonate solution. The aqueous layer was then extracted with DCM (× 3), and the extracts were combined and filtered through a hydrophobic glass frit. Afterwards, the title compound (4.21 mmol) was purified by flash column chromatography on silica gel eluting with 0-6% MeOH in DCM to give the title compound as a clear oil. UPLC-MS (ES + , short acidic): 1.60 min, m / z 296.9 [M+2] + .

[0619] 3-(4-Bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid methyl ester

[0620] Cesium carbonate (3.00 mmol) was added to a solution of bromocyclopentane (2.40 mmol) and 3-(4-bromophenyl)-5-methyl-pyrazole-4-carboxylic acid methyl ester (1.20 mmol) in DMF (2.5 mL). Afterwards, it was stirred at 75 ° C for 45 minutes, and then all volatiles were removed under reduced pressure. The residue was then suspended in EtOAc (50 mL). Afterwards, the organic layer was washed with water (×2) and saturated brine solution (×1). The organic layer was then dried over sodium sulfate, filtered and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel eluted with 0-40% EtOAc in heptane gave the title compound (0.87 mmol) as a clear oil. UPLC-MS (ES + , short acidic): 2.27 min, m / z 365.1 [M+2] + .

[0621] 3-(4-Bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid

[0622] Lithium hydroxide (2.75 mmol) was added to a solution of 3-(4-bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid methyl ester (0.28 mmol) in 1,4-dioxane (0.75 mL) and water (0.75 mL). Afterwards, the mixture was stirred at 80 ° C for 16 hours and then at 100 ° C for 16 hours. After the reaction mixture was cooled back to RT, the reaction mixture was acidified to pH 3 with hydrochloric acid (1 M). It was then extracted with DCM (× 3), filtered through a hydrophobic glass frit, and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel eluted with 0-20% EtOAc in heptane gave the title compound (0.28 mmol) as a white solid. UPLC-MS (ES + , short acidic): 2.00 min, m / z 351.1 [M+2]+ .

[0623] 3-(4-Bromophenyl)-1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazole-4-carboxamide

[0624] Under N2, 3-(4-bromophenyl)-1-cyclopentyl-5-methyl-pyrazole-4-carboxylic acid (0.28mmol), 2,4-dimethoxybenzylamine (0.33mmol) and triethylamine (0.41mmol) were suspended in THF (1.4mL). After the reaction mixture was stirred at room temperature for 5 minutes, a solution of propylphosphonic anhydride (50% by weight in EtOAc, 0.41mmol) was added, and the reaction was stirred at room temperature for 72 hours. 2,4-dimethoxybenzylamine (0.33mmol), triethylamine (0.41mmol) and a solution of propylphosphonic anhydride (50% by weight in EtOAc, 0.41mmol) were then added. The reactants were then stirred at room temperature for 16 hours. Saturated ammonium chloride solution (10mL) and water (10mL) were then added. Afterwards, the aqueous layer was extracted with DCM (×3). The organic extracts were combined, filtered through a hydrophobic glass frit, and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-50% EtOAc in heptane followed by reverse phase chromatography eluting with 30-70% MeCN in water containing 0.1% formic acid afforded the title compound (0.07 mmol) as a white solid. UPLC-MS (ES + , short acidic): 2.18 min, m / z 500.2 [M+2] + .

[0625] 1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl phenyl]-5-methyl-pyrazole-4-carboxamide

[0626] Following General Procedure K, 3-(4-bromophenyl)-1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-5-methyl-pyrazole-4-carboxamide (0.07 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borate were used to afford the title compound (0.05 mmol) as a white solid after purification by flash column chromatography on silica gel eluting with 0-2.5% MeOH in DCM, followed by reverse phase chromatography eluting with 20-70% MeCN in water containing 0.1% formic acid. UPLC-MS (ESI) + , short acidic): 2.04 min, m / z 583.4 [M+H] + .

[0627] 1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxylate amine

[0628] Trifluoroacetic acid (0.04 mmol) was added to a solution of 1-cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methyl-pyrazole-4-carboxamide (0.04 mmol) in DCM (0.4 mL) at 0°C and the reaction mixture was stirred at room temperature for 48 hours. Additional trifluoroacetic acid (0.04 mmol) was then added every 24 hours for 3 days while the reaction mixture was stirred at room temperature. The reaction mixture was then basified with saturated sodium carbonate solution. The layers were separated and the aqueous layer was extracted with DCM (×3), combined, filtered through a hydrophobic frit and concentrated under reduced pressure. Further purification was achieved by flash column chromatography on silica gel eluting with 0-6% MeOH in DCM followed by reverse phase chromatography eluting with 20-70% MeCN in water with 0.1% formic acid additive to afford the title compound (0.02 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.62 min, m / z 433.2 [M+H] + UPLC-MS(ES + , long acidic): 3.70 min, m / z 433.2 [M+H] + .

[0629] 1 H NMR (400MHz, DMSO-d6, δ): 8.70 (t, J=6.0Hz, 1H), 7.75 (dd, J=7.6, 1.8Hz, 1H), 7.60 ( d,J=8.2Hz,2H),7.51-7.45(m,1H),7.34(d,J=8.2Hz,2H),7.24-7.17(m,2H),7.16( d, J = 8.3 Hz, 1H), 7.08-7.01 (m, 1H), 4.71 (quintet, J = 7.3 Hz, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.37 (s, 3H), 2.11-1.91 (m, 4H), 1.91-1.80 (m, 2H), 1.71-1.55 (m, 2H).

[0630] Example 25: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(1H-tetrazol-5-yl)ethyl]pyrazole-4-carboxamide

[0631]

[0632] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-(1H-tetrazol-5-yl)ethyl 1,2-Dimethylpyrazole-4-carboxamide

[0633] To a solution of 5-amino-1-(2-cyanoethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (0.27 mmol) in DMF (2 mL) was added sodium azide (0.28 mmol) and ammonium chloride (0.30 mmol). The reaction mixture was heated to 110° C. for 16 hours. Additional sodium azide (0.28 mmol) and ammonium chloride (0.30 mmol) were added and the mixture was heated to 110° C. for 16 hours, cooled to room temperature and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-20% MeOH in DCM to give the title compound (0.02 mmol). UPLC-MS (ESI) + , short acidic): 1.22 min, m / z 462.2 [M+H] + UPLC-MS(ES + , long acidic): 2.70 min, m / z 462.2 [M+H] + .

[0634] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 8.32 (br s,1H),7.76(dd,J=7.6,1.9Hz,1H),7.45-7.52(m,1H),7.44-7.38(m,4H),7.16(d,J=7.7Hz,1H),7.04(td,J=7 .5,1.0Hz,1H),6.48(s,2H),4.55(d,J=6.2Hz,2H),4.33(t,J=7.1Hz,2H),3.90(s,3H),3.27(t,J=7.2Hz,2H).

[0635] Example 26: 5-amino-1-(4,4-dimethylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0636]

[0637] tert-Butyl N-[(4,4-dimethylcyclohexylidene)amino]carbamate

[0638] General procedure E and 4,4-dimethylcyclohexanone (0.79 mmol) gave the title compound (0.78 mmol) as an off-white powder. 1 H NMR (400MHz, CDCl3, δ): 7.49 (br s, 1H), 2.45-2.39 (m, 2H), 2.26-2.20 (m, 2H), 1.55-1.44 (m, 13H), 1.02 (s, 6H).

[0639] 5-Amino-3-(4-bromophenyl)-1-(4,4-dimethylcyclohexyl)pyrazole-4-carbonitrile

[0640] General Procedure O, tert-butyl N-[(4,4-dimethylcyclohexylidene)amino]carbamate (0.78 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) gave the title compound (0.36 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 2.33 min, m / z 375.1 [M+2] + .

[0641] N-[[4-[5-amino-4-cyano-1-(4,4-dimethylcyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy Benzamide

[0642] General Procedure K, 5-amino-3-(4-bromophenyl)-1-(4,4-dimethylcyclohexyl)pyrazole-4-carbonitrile (0.13 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.15 mmol) gave the title compound (0.13 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 1.99 min, m / z 458.3 [M+H] + .

[0643] 5-amino-1-(4,4-dimethylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl] Pyrazole-4-carboxamide

[0644] General Procedure M: N-[[4-[5-amino-4-cyano-1-(4,4-dimethylcyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.07 mmol) was further purified by reverse phase chromatography eluting with 20-60% MeCN in water with 0.1% formic acid additive to afford the title compound (0.02 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.74 min, m / z 476.3 [M+H] + UPLC-MS(ES + , long acidic): 4.04 min, m / z 476.3 [M+H] + . 1HNMR(400MHz,DMSO-d6,δ):8.74(t,J=6.1Hz,1H),7.76(dd,J=7.6,1.8Hz,1H),7.52-7.38(m,5H),7.16(d,J=8.3Hz,1H),7.08-7.01(m,1H),6.31(s, 2H),4.55(d,J=6.1Hz,2H),4.10-3.98(m,1H),3.91(s,3H),2.00-1.86(m, 2H),1.71-1.60(m,2H),1.52-1.42(m,2H),1.42-1.29(m,2H),0.95(s,6H).

[0645] Example 27: 5-amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0646]

[0647] 8-Methyl-1,4-dioxaspiro[4.5]decan-8-ol

[0648] Methylmagnesium bromide (2.2M in diethyl ether, 2.82mmol) solution was added to a THF (5mL) solution of 1,4-cyclohexanedione monovinyl acetal (2.56mmol) and cooled to 0°C. The reaction mixture was stirred at RT for 2h and then quenched with saturated aqueous ammonium chloride solution. The layers were layered between DCM (20mL) and water (20mL). The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a phase separator and concentrated under reduced pressure to give the title compound (2.50mmol) as a clear oil. 1 HNMR (400MHz, CDCl3, δ): 4.02-3.91 (m, 4H), 1.96-1.84 (m, 2H), 1.78-1.65 (m, 4H), 1.65-1.56 (m, 2H), 1.29 (s, 3H), 1.15 (s, 1H).

[0649] 4-Hydroxy-4-methyl-cyclohexanone

[0650] General Procedure J was followed using a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (2.50 mmol) in THF (2.5 mL) to give the crude title compound (2.50 mmol) as a brown oil. 1H NMR (400MHz, CDCl3, δ): 2.71-2.59(m,2H), 2.23-2.12(m,2H), 1.96-1.86(m,2H), 1.85-1.73(m,2H), 1.31(s,3H), 1.23(s,1H).

[0651] tert-Butyl N-[(4-hydroxy-4-methylcyclohexylidene)amino]carbamate

[0652] Following general procedure E, 4-hydroxy-4-methyl-cyclohexanone (2.50 mmol) gave the title compound (1.36 mmol) as a clear oil. UPLC-MS (ES + , short acidic): 1.21 min, m / z 243.1 [M+H] + .

[0653] 5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile

[0654] Following General Procedure O, tert-butyl N-[(4-hydroxy-4-methyl-cyclohexylidene)amino]carbamate (0.83 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.68 mmol) were purified by flash column chromatography eluting with 55% EtOAc in heptane and then 0-8% MeOH in DCM to afford the title compound as an off-white powder (isomer 1, 0.43 mmol) and an off-white solid (isomer 2, 0.09 mmol). UPLC-MS (ESI) + , short acidic; isomer 1): 1.65 minutes, m / z 375.0 [M] + UPLC-MS(ES + , short acidic; isomer 2): 1.72 minutes, m / z 375.1 [M] + .

[0655] 5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide

[0656] Following General Procedure L, 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile (Isomer 1) (50 mg, 0.13 mmol) gave 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide (44 mg, 0.11 mmol, 84%) as an off-white powder. UPLC-MS (ESI) + , short acidic): 1.35 min, m / z 394.9 [M+2] + .

[0657] 5-amino-1-(4-hydroxy-4-methylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]benzene 1,2-Dimethylpyrazole-4-carboxamide

[0658] General Procedure K, 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide (0.11 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.12 mmol) gave the title compound (0.09 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 1.33 min, m / z 478.5 [M+H] + UPLC-MS(ES + , long acidic): 2.98 min, m / z 478.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.7Hz, 1H) ,7.52-7.37(m,5H),7.16(d,J=8.3Hz,1H),7.08-7.01(m,1H),6.29(s,2H),4. 55(d,J=6.2Hz,2H),4.12(s,1H),4.08-3.97(m,1H),3.91(s,3H),2.24-2.07( m,2H),1.70-1.60(m,2H),1.60-1.50(m,2H),1.50-1.37(m,2H),1.15(s,3H).

[0659] Example 28: 5-amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0660]

[0661] 8-Benzyloxy-1,4-dioxaspiro[4.5]decane

[0662] Under N2, sodium hydride (60% dispersion in mineral oil, 1.90 mmol) was added to a solution of 1,4-dioxaspiro[4.5]dec-8-ol (1.26 mmol) in THF (2.4 mL) and cooled to 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then benzyl bromide (1.90 mmol) was added. The mixture was stirred at RT overnight, quenched with saturated ammonium chloride solution and separated. The aqueous layer was extracted with DCM (× 3). The combined organic extracts were filtered through a hydrophobic glass frit and concentrated under reduced pressure. Further purification by flash column chromatography on silica gel, eluting with 30% EtOAc in heptane, gave the title compound (0.81 mmol) as a clear oil. UPLC-MS (ES +, short acidic): 1.76 min, m / z 249.0 [M+H] + .

[0663] 4-Benzyloxycyclohexanone

[0664] General Procedure J, 8-benzyloxy-1,4-dioxaspiro[4.5]decane (0.81 mmol) gave the crude title compound (0.81 mmol) as a clear oil. 1 H NMR(400MHz, CDCl3, δ):7.44-7.29(m,5H),4.63(s,2H),3.88-3.82(m,1H), 2.71-2.60(m,2H),2.35-2.25(m,2H),2.24-2.12(m,2H),2.05-1.94(m,2H).

[0665] tert-Butyl N-[(4-benzyloxycyclohexylidene)amino]carbamate

[0666] Following General Procedure E, 4-benzyloxycyclohexanone (0.81 mmol) gave the title compound (0.81 mmol) as a clear oil. UPLC-MS (ES + , short acidic): 1.74 min, m / z 319.2 [M+H] + .

[0667] 5-Amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile

[0668] Following General Procedure O, tert-butyl N-[(4-benzyloxycyclohexylidene)amino]carbamate (0.81 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.68 mmol) gave the title compound (0.68 mmol) as an off-white powder. UPLC-MS (ES + , short acidic, cis / trans mixture): 2.18 min and 2.20 min, m / z 453.1 [M+2] + .

[0669] 5-Amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxamide

[0670] General Procedure L, 5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carbonitrile (0.13 mmol) afforded the title compound (0.13 mmol) as a clear oil. UPLC-MS (ES + , short acidic, cis / trans mixture): 1.91 min, m / z 471.0 [M+2] + .

[0671] 5-amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrrolidone oxazole-4-carboxamide

[0672] General Procedure K was followed with 5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxamide (0.13 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.15 mmol) to afford the title compound as a mixture of diastereoisomers (0.12 mmol) as a white powder. UPLC-MS (ES + , short acidic): 1.73 min, m / z 554.5 [M+H] + , 1.77 min, m / z 554.2 [M+H] + UPLC-MS(ES + , long acidic): 4.02 min, m / z 554.3 [M+H] + , 4.11 min, m / z 554.3 [M+H] + .

[0673] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=5.9Hz, 1H), 7.76 (dd, J=7.6, 1.6Hz, 1H), 7.53-7.31 (m,9H),7.31-7.23(m,1H),7.16(d,J=8.4Hz,1H),7.08-7.01(m,1H),6.34(s,1H),6.32( s,1H),4.59-4.46(m,4H),4.20-4.06(m,1H),3.90(s,3H),3.69-3.62(m,0.5),3.46-3.3 5(m,0.5H),2.20-1.94(m,3H),1.93-1.73(m,2H),1.68-1.46(m,2H),1.46-1.25(m,1H).

[0674] Example 29: 5-amino-1-cyclopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0675]

[0676] 5-Amino-3-(4-bromophenyl)-1-cyclopropyl-pyrazole-4-carbonitrile

[0677] Further purification by flash column chromatography on silica gel following General Procedure H, eluting with 0-10% MeOH in DCM, was carried out using 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.46 mmol) and cyclopropylhydrazine hydrochloride (0.55 mmol) to afford the title compound (0.34 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.73 min, m / z 303.0 [M] + .

[0678] N-[[4-(5-Amino-4-cyano-1-cyclopropylpyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0679] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by 5-amino-3-(4-bromophenyl)-1-cyclopropyl-pyrazole-4-carbonitrile (0.32 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) afforded the title compound (0.34 mmol) as a crude brown solid. UPLC-MS (ESI) + , short acidic): 1.51 min, m / z 388.2 [M+H] + .

[0680] 5-amino-1-cyclopropyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0681] General Procedure L: N-[[4-(5-amino-4-cyano-1-cyclopropylpyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.32 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.15 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.32 min, m / z 406.2 [M+H] + UPLC-MS(ES + , long acidic): 2.95 min, m / z 406.3 [M+H] + .

[0682] 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.0Hz, 1H), 7.76 (dd, J=7.7, 1.3Hz, 1H), 7.53-7.34 (m, 5H), 7.16 (d, J=8.3H z,1H),7.06-7.03(m,1H),6.33(s,2H),4.55(d,J=6.1Hz,2H),3.90(s,3H),3.32-3.24(m,1H),1.04-0.92(m,4H).

[0683] Example 30: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-methyl-pyrazole-4-carboxamide

[0684]

[0685] 5-Amino-3-(4-bromophenyl)-1-methylpyrazole-4-carbonitrile

[0686] Further purification by flash column chromatography on silica gel following General Procedure H, eluting with 0-10% MeOH in DCM, with 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.14 mmol) and methylhydrazine (1.37 mmol) afforded an inseparable mixture of regioisomers of the title compound (0.47 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.57 min and 1.67 min, m / z 277.0 [M] + .

[0687] N-[[4-(5-Amino-4-cyano-1-methyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0688] General Procedure K. A mixture of 5-amino-3-(4-bromophenyl)-1-methyl-pyrazole-4-carbonitrile and 3-amino-5-(4-bromophenyl)-1-methyl-pyrazole-4-carbonitrile (0.43 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.37 mmol) was further purified by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane to afford the title compound (0.11 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.54 min, m / z 362.2 [M+H] + .

[0689] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-methylpyrazole-4-carboxamide

[0690] General Procedure L: N-[[4-(5-amino-4-cyano-1-methyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.09 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.05 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.24 min, m / z 380.2 [M+H] + UPLC-MS(ES + , long acidic): 2.76 min, m / z 380.2 [M+H] + .

[0691] 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.2Hz, 1H), 7.76 (dd, J=7.8, 1.7Hz, 1H), 7.51-7.39 (m, 5H), 7.16 ( dd,J=8.4,0.9Hz,1H),7.07-7.03(m,1H),6.28(s,2H),4.55(d,J=6.2Hz,2H),3.90(s,3H),3.56(s,3H).

[0692] Example 31: 5-amino-1-(2-hydroxyethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0693]

[0694] 5-Amino-3-(4-bromophenyl)-1-(2-hydroxyethyl)pyrazole-4-carbonitrile

[0695] General Procedure H: Purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane followed by 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.14 mmol) and 2-hydroxyethylhydrazine (1.37 mmol) afforded the title compound (0.40 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.60 min, m / z 307.0 [M] + .

[0696] N-[[4-[5-amino-4-cyano-1-(2-hydroxyethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0697] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-(2-hydroxyethyl)pyrazole-4-carbonitrile (0.35 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.49 mmol) afforded the title compound (0.22 mmol) as a light brown solid. UPLC-MS (ESI) + , short acidic): 1.36 min, m / z 392.1 [M+H] + .

[0698] 5-amino-1-(2-hydroxyethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid Amide

[0699] General Procedure L: N-[[4-[5-amino-4-cyano-1-(2-hydroxyethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.21 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.09 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.20 min, m / z 410.2 [M+H] + UPLC-MS(ES + , long acidic): 2.66 min, m / z 410.2 [M+H] + .

[0700] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.2Hz, 1H), 7.76 (dd, J=7.8, 1.7Hz, 1H), 7.52-7.39 (m, 5H), 7.16 (m, 1H), 7.05 (m, 1H), 6.21 (s, 2H), 5.00-4.94 (m, 1H), 4.56 (d, J = 6.2Hz, 2H), 3.98 (t, J = 5.9Hz, 2H), 3.90 (s, 3H), 3.71 (q, J = 5.71Hz, 2H).

[0701] Example 32: 5-amino-1-(3-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0702]

[0703] 5-Amino-3-(4-bromophenyl)-1-(3-fluorophenyl)pyrazole-4-carbonitrile

[0704] General Procedure H: (3-Fluorophenyl)hydrazine chloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.57 mmol) were used to give the title compound (0.22 mmol, 38% yield) as a light brown solid after further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.97 min, m / z 357.1 [M] + .

[0705] N-[[4-[5-amino-4-cyano-1-(3-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0706] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by the reaction of 5-amino-3-(4-bromophenyl)-1-(3-fluorophenyl)pyrazole-4-carbonitrile (0.22 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) afforded the title compound (0.05 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.71 min, m / z 442.2 [M+H] + .

[0707] 5-amino-1-(3-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid Amide

[0708] General Procedure L: N-[[4-[5-amino-4-cyano-1-(3-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.05 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.03 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.54 min, m / z 460.2 [M+H] + UPLC-MS(ES + , long acidic): 3.52 minutes, m / z 460.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6,δ):8.77(t,J=6.1Hz,1H),7.76(dd,J=7.5,1.6Hz,1H),7.62-7.55(m,3H),7.52-7.45(m,5H),7 .26(t,J=8.6Hz,1H),7.16(d,J=8.2Hz,1H),7.05(t,J=7.58Hz,1H),6.62(s,2H),4.57(d,J=6.1Hz,2H),3.91(s,3H).

[0709] Example 33: 5-amino-1-(4-hydroxy-4-methyl-cyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0710]

[0711] 5-Amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide

[0712] Following General Procedure L, 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carbonitrile (Isomer 2) (0.09 mmol) was used to give the crude title compound (0.09 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 1.38 min, m / z 395.1 [M+2] + .

[0713] 5-amino-1-(4-hydroxy-4-methylcyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]benzene 1,2-Dimethylpyrazole-4-carboxamide

[0714] General Procedure K, 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide (0.09 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.09 mmol) gave the title compound (0.04 mmol) as an off-white powder. UPLC-MS (ES + , short acidic): 1.30 min, m / z 478.3 [M+H] + UPLC-MS(ES + , long acidic): 2.94 min, m / z 478.3 [M+H] + .

[0715] 1 H NMR (400MHz, DMSO-d6, δ): 8.74(t,J=6.0Hz,1H),7.76(dd,J=7.6,1.7Hz,1H),7.52-7.37(m,5H),7.16(d,J=8.3Hz,1H),7.08-7.00(m,1H),6.33( s,2H),4.55(d,J=6.0Hz,2H),4.42(s,1H),4.18-4.05(m,1H),3.90(s,3H ),1.92-1.71(m,4H),1.70-1.60(m,2H),1.60-1.48(m,2H),1.17(s,3H).

[0716] Examples 34a (Isomer 1) and 34b (Isomer 2): 5-amino-1-(4-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0717]

[0718] 5-amino-1-(4-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 4-Formamide

[0719] To a solution of 5-amino-1-(4-benzyloxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (0.13 mmol) in MeOH (1.3 mL) and ammonium formate (0.40 mmol) was added palladium (10 wt% on carbon powder, dried). The reaction mixture was stirred at 60° C. for 2 hours, then ammonium formate (1.34 mmol) was added, and the mixture was stirred at 60° C. for 1 hour. Acetic acid (0.5 mL) was added, and the reaction mixture was stirred at 60° C. for another 14 hours, cooled to room temperature, and filtered by The plug was filtered. The plug was washed with DCM and the filtrate was concentrated under reduced pressure. The residue was alkalized with saturated sodium bicarbonate solution and extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic glass frit and concentrated under reduced pressure. Further purification was performed by silica gel flash column chromatography, eluting with 0-10% MeOH in DCM to give the title compound (isomer 1, 0.02 mmol) as a white solid and the title compound (isomer 2, 0.09 mmol) as a brown solid.

[0720] UPLC-MS(ES + , short acidic; isomer 1): 1.27 minutes, m / z 464.3 [M+H] + UPLC-MS(ES + , long acidic; isomer 1): 2.84 minutes, m / z 464.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ) (Isomer 1): 8.74 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.6, 1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J = 8.3 Hz, 1H), 7.08-7.00 (m, 1H), 6.30 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.40 (d, J = 2.6 Hz, 1H), 4.13-4.02 (m, 1H), 3.90 (s, 3H), 3.86 (br s, 1H), 2.23-2.07 (m, 2H), 1.84-1.72 (m, 2H), 1.61-1.47 (m, 4H).

[0721] UPLC-MS(ES + , short acidic; isomer 2): 1.26 minutes, m / z 464.3 [M+H] + UPLC-MS(ES + , long acidic; isomer 2): 2.82 minutes, m / z 464.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6, δ) (isomer 2): 8.74 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.7 Hz, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J = 8.3 Hz, 1H), 7.08-7.00 (m, 1H), 6.33 (s, 2H), 4.63 (d, J = 4.5 Hz, 1H), 4.55 (d, J = 6.1 Hz, 2H), 4.13-4.01 (m, 1H), 3.90 (s, 3H), 3.51-3.39 (m, 1H), 1.96-1.86 (m, 2H), 1.86-1.74 (m, 4H), 1.39-1.25 (m, 2H).

[0722] Example 35: 5-amino-1-cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0723]

[0724] tert-Butyl N-(cyclobutyleneamino)carbamate

[0725] To a solution of cyclobutanone (2.0 mmol) in heptane (2 mL) was added tert-butyl carbazate (2.2 mmol) and the reaction was heated to reflux and stirred for 2 hours. The volatiles were removed under reduced pressure to afford the title compound (2.0 mmol, 100% yield) as a white solid. UPLC-MS (ES + , short acidic): 1.61 min, m / z 185.0 [M+H] + .

[0726] Cyclobutylhydrazine hydrochloride

[0727] N-(cyclobutylene amino) t-butyl carbamate (0.27mmol) is dissolved in THF (5mL) and dimethyl sulfide borane (0.46mmol) is added.The reaction is stirred at room temperature for 1 hour.When TLC shows that starting material consumes, solvent is removed in vacuo.Residue is dissolved in hydrogen chloride-methanol solution (7.6mL), reactant is heated to reflux and stirred overnight.Evaporating solvent obtains title compound (0.27mmol), is light yellow jelly, and it is used without any further purification. 1 H NMR (400MHz, DMSO-d6, δ): 3.66-3.54(m,1H), 2.16-1.97(m,4H), 1.83-1.64(m,2H).

[0728] 5-Amino-3-(4-bromophenyl)-1-cyclobutyl-pyrazole-4-carbonitrile

[0729] General Procedure H: Purification by flash column chromatography on silica gel eluting with 20-80% EtOAc in heptane followed by cyclobutylhydrazine hydrochloride (0.25 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.21 mmol) afforded the title compound (0.14 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.95 min, m / z 317.0 [M] + .

[0730] N-[[4-(5-Amino-4-cyano-1-cyclobutyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide

[0731] Following General Procedure K, 5-amino-3-(4-bromophenyl)-1-cyclobutyl-pyrazole-4-carbonitrile (0.14 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) gave the title compound (0.13 mmol) as a white powder. UPLC-MS (ES+, short acidic): 1.67 min, m / z 402.2 [M+H] + .

[0732] 5-amino-1-cyclobutyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0733] General Procedure L, N-[[4-(5-amino-4-cyano-1-cyclobutyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.05 mmol) afforded the title compound as a white powder. UPLC-MS (ES + , short acidic): 1.46 min, m / z 420.3 [M+H] + UPLC-MS(ES + , long acidic): 3.29 minutes, m / z 420.2 [M+H] + .

[0734] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.2Hz, 1H), 7.76 (dd, J=7.9, 2.2Hz, 1H), 7.50-7.41 (m, 5H), 7.16 (d, J=8.3Hz, 1H), 7.04 (t,J=7.5Hz,1H),6.30(s,2H),4.81-4.73(m,1H),4.55(d,J=6.0Hz,2H),3.91(s,3H),2.33-2.26(m,4H),1.78-1.69(m,2H).

[0735] Example 36: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole-4-carboxamide

[0736]

[0737] tert-Butyl N-tetrahydrofuran-3-ylideneamino]carbamate

[0738] To a solution of dihydro(3(2H)-furanone (1.95 mmol) in ethanol (2 mL) was added tert-butyl carbazate (2.35 mmol). The reaction was heated to reflux and stirred overnight. The volatiles were removed under reduced pressure to give the title compound (1.95 mmol) as a white solid. 1 H NMR (400 MHz, CDCl3, δ, mixture of isomers): 7.25 (s, 0.75 H), 7.12 (s, 0.25 H), 4.34 (t, J = 1.2 Hz, 1.5 H), 4.24 (t, J = 1.2 Hz, 0.5 H), 4.12 (t, J = 6.9 Hz, 1.5 H), 4.02 (t, J = 6.9 Hz, 0.5 H), 2.78 (td, J = 6.9, 1.2 Hz, 0.5 H), 2.48 (td, J = 6.9, 1.2 Hz, 1.5 H), 1.54 (s, 7.5 H), 1.53 (s, 1.5 H).

[0739] Tetrahydrofuran-3-ylhydrazine hydrochloride

[0740] N-[tetrahydrofuran-3-ylideneamino] t-butyl carbamate (0.25mmol) is dissolved in THF (5mL) and dimethyl sulfide borane (0.42mmol) is added.The reaction is stirred at room temperature for 1 hour until TLC shows that starting material is completely consumed.Desolvent is removed in vacuo.Residue is dissolved in MeOH solution (1.25M, 6.99mL) of hydrogen chloride, and reactant is heated to reflux and stirred overnight.Evaporating solvent obtains title compound (0.25mmol), is light yellow jelly, and it is used without any further purification. 1 H NMR (400MHz, DMSO-d6, δ): 3.86-3.59 (m, 6H), 2.11-1.96 (m, 1H), 1.95-1.84 (m, 1H).

[0741] 5-Amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile

[0742] General Procedure H: Purification by flash column chromatography on silica gel eluting with 20-80% EtOAc in heptane followed by the reaction of tetrahydrofuran-3-ylhydrazine (0.23 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile afforded the title compound (0.09 mmol) as a light brown solid. UPLC-MS (ESI) + , short acidic): 1.71 min, m / z 333.1 [M] + .

[0743] N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzene Formamide

[0744] General Procedure K, 5-amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazole-4-carbonitrile (0.10 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.14 mmol) gave the title compound (0.06 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.51 min, 418.2 m / z [M+H] + .

[0745] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydrofuran-3-yl-pyrazole- 4-Formamide

[0746] General Procedure L, N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.06 mmol) gave the title compound (0.03 mmol) as a white powder. UPLC-MS (ES + , short acidic): 1.32 min, m / z 458.2 [M+Na] + UPLC-MS(ES + , long acidic): 2.95 min, m / z 436.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=5.8Hz, 1H), 7.75 (dd, J=7.4, 1.8Hz, 1H), 7.50-7.40 (m, 5H), 7.16 (d, J=7.7Hz, 1H), 7.04 (td, J=7.5, 1.0Hz,1H),6.40(s,2H),4.97-4.90(m,1H),4.55(d,J=6.0Hz,2H),4.00-3.94(m,2H),3.90(s,3H),3.83-3.78(m,2H),2.28-2.24(m,2H).

[0747] Example 37: 5-amino-1-[(1S*,3S*)-3-chlorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0748]

[0749] 5-Amino-1-[(1S*,3S*)-3-chlorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]benzene 1,2-Dimethylpyrazole-4-carboxamide

[0750] Thionyl chloride (0.67 mmol) was added to a solution of 5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (0.22 mmol) in DCM (3 mL) and cooled to 0°C. The reaction was allowed to warm to room temperature and stirred at this temperature for 48 hours. The mixture was then concentrated and the resulting residue was purified by reverse phase chromatography eluting with 30-80% MeCN in water with 0.1% formic acid additive to give the title compound (0.07 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.58 minutes, m / z 468.1 [M] + UPLC-MS(ES + , long acidic): 3.62 minutes, m / z 468.1[M] + .

[0751] 1 H NMR (400MHz, CDCl3, δ): 8.29-8.20 (m, 2H), 7.56-7.42 (m, 5H), 7.15-7.11 (m, 1H), 6.99 (d, J = 8.2Hz, 1H), 5.46 (br.s, 2H), 5.15 (br.s ,2H)4.80-4.70(m,3H),4.68-4.63(m,1H),3.95(s,3H),2.77-2.67(m,1H),2.55-2.37(m,3H),2.23-2.11(m,1H),2.11-2.01(m,1H).

[0752] Example 38: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3R)-3-piperidinyl]methyl]pyrazole-4-carboxamide

[0753]

[0754] tert-Butyl (3R)-3-(Hydroxymethyl)piperidine-1-carboxylate

[0755] At RT, borane-tetrahydrofuran (1: 1, 2.62mmol) was added dropwise to a stirred solution of (3R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.87mmol) in anhydrous THF (10mL). The reaction was stirred for 4 hours, quenched with saturated NH4Cl solution (2mL) and separated. The aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purified by flash column chromatography on silica gel, eluted with a heptane solution of 0-100% EtOAc to give the title compound (0.84mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6,δ):4.52-4.46(m,1H),4.01-3.86(m,1H),3.83-3.75(m,1H),3.30-3.26(m,1H),3.22-3.16(m,1H),2. 75-2.63(m,1H),1.70-1.62(m,1H),1.61-1.53(m,1H),1.50-1.40(m,1H),1.38(s,9H),1.36-1.21(m,2H),1.13-1.01(m,1H).

[0756] tert-Butyl (3R)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate

[0757] General Procedure I: Purification by flash column chromatography on silica gel eluting with 0-50% EtOAc in heptane followed by the reaction of tert-butyl (3R)-3-(hydroxymethyl)piperidine-1-carboxylate (0.84 mmol) and methanesulfonyl chloride (0.88 mmol) afforded the title compound (0.58 mmol) as a colorless oil. UPLC-MS (ES + , short acidic): 1.71 min, m / z 316.1 [M+Na] + .

[0758] (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl] tert-Butyl]pyrazol-1-yl]methyl]piperidine-1-carboxylate

[0759] General Procedure N: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.29 mmol) and (3R)-tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (0.58 mmol) gave the title compound (0.19 mmol) and (3R)-tert-butyl 3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylate as a mixture of regioisomers after purification by silica gel flash column chromatography. UPLC-MS (ESI) +, short acidic): 1.58 and 1.60 min, m / z 563.3 [M+H] + .

[0760] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3R)-3-piperidinyl]methane 1,2-Dimethylpyrazole-4-carboxamide

[0761] A mixture of regioisomers of tert-butyl (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidine-1-carboxylate (0.19 mmol) and tert-butyl (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]piperidin-1-yl]methyl]piperidine-1-carboxylate was dissolved in DCM (5 mL) and trifluoroacetic acid (4.7 mmol) was added. The reaction was stirred at RT overnight. The solvent was removed in vacuo. The residue was dissolved in MeOH and passed through an SPE SCX column, eluting with 0-100% 1N ammonia in MeOH. Further purification by mass-directed semi-preparative HPLC gave the title compound (0.02 mmol). UPLC-MS (ESI) + , short acidic): 1.10 min, m / z 463.2 [M+H] + UPLC-MS(ES + , long acidic): 2.41 min, m / z 463.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.0Hz, 1H), 8.38 (s, 2H), 7.76 (dd, J=7.4, 1.5Hz ,1H),7.51-7.40(m,5H),7.16(d,J=8.6Hz,1H),7.04(t,J=7.5Hz,1H),6.37(s,2H),4. 55(d,J=6.0Hz,2H),3.90(s,3H),3.83(d,J=7.1Hz,2H),2.95-2.88(m,2H),2.43-2.3 8(m,1H),2.09-1.99(m,1H),1.70-1.64(m,2H),1.46-1.36(m,1H),1.24-1.15(m,1H).

[0762] Example 39: 5-amino-1-(2-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0763]

[0764] 5-Amino-3-(4-bromophenyl)-1-(2-fluorophenyl)pyrazole-4-carbonitrile

[0765] General Procedure H: (2-Fluorophenyl)hydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.57 mmol) were used to give the title compound (0.29 mmol) as a brown solid after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.88 min, m / z 357.1[M] + .

[0766] N-[[4-[5-amino-4-cyano-1-(2-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0767] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane with 5-amino-3-(4-bromophenyl)-1-(2-fluorophenyl)pyrazole-4-carbonitrile (0.29 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.40 mmol) afforded the title compound (0.23 mmol) as a red solid. UPLC-MS (ES+, short acidic): 1.62 min, m / z 442.1 [M+H] + .

[0768] 5-amino-1-(2-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid Amide

[0769] General Procedure L: N-[[4-[5-amino-4-cyano-1-(2-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.23 mmol) was further purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.02 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.46 min, m / z 460.2 [M+H] + UPLC-MS(ES + , long acidic): 3.32 minutes, m / z 460.2 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.60-7.53 (m, 4H), 7.50-7.43 (m, 4H), 7 .38(t,J=7.75Hz,1H),7.16(d,J=8.4Hz,1H),7.05(t,J=7.4Hz,1H),6.42(s,2H),4.57(d,J=6.0Hz,2H),3.91(s,3H).

[0770] Example 40: Ethyl 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate

[0771]

[0772] Ethyl 4-(tert-Butoxycarbonylhydrazono)cyclohexanecarboxylate

[0773] General Procedure E, ethyl 4-oxocyclohexanecarboxylate (3.14 mmol) afforded the title compound (2.96 mmol) as a clear oil. UPLC-MS (ES + , short acidic): 1.52 min, m / z 285.1 [M+H] + .

[0774] 4-[5-Amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylic acid ethyl ester

[0775] General Procedure O, ethyl 4-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate (1.93 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.63 mmol) gave the title compound (1.56 mmol, cis / trans isomer mixture) as a white powder. UPLC-MS (ES + , short acidic): 2.00 min, m / z 419.1 [M+2] + , 2.06 min, m / z 419.1[M+2] + .

[0776] 4-[5-Amino-3-(4-bromophenyl)-4-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylic acid ethyl ester

[0777] General Procedure L, 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylic acid ethyl ester (0.91 mmol) afforded the title compound (0.91 mmol, cis / trans isomer mixture) as an off-white powder. UPLC-MS (ES + , short acidic): 1.70 min, m / z 437.1 [M+2] +, 1.72 min, m / z 437.1[M+2] + .

[0778] 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 1-Methyl]cyclohexanecarboxylic acid ethyl ester

[0779] General Procedure K, potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.00 mmol) and ethyl 4-[5-amino-3-(4-bromophenyl)-4-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylate (0.91 mmol) afforded the title compound (0.68 mmol, cis / trans isomer mixture) as a white powder. UPLC-MS (ES + , short acidic): 1.57 min, m / z 520.3 [M+H] + , 1.59 min, m / z 520.3 [M+H ]+ UPLC-MS(ES + , long acidic): 3.63 min, m / z 520.3 [M+H] + , 3.67 min, m / z 520.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6,δ)8.73(t,J=6.1Hz,1H),7.79-7.73(m,1H),7.52-7.3 8(m,5H),7.16(d,J=8.4Hz,1H),7.08-7.00(m,1H),6.35(s,0.8H),6.33(s,1. 2H),4.55(d,J=6.1Hz,2H),4.18-4.03(m,3H),3.90(s,3H),2.73-2.29(m,1H) ,2.22-2.11(m,1H),2.06-1.95(m,1H),1.92-1.42(m,6H),1.23-1.15(m,3H).

[0780] Example 41: 5-amino-1-[(1S*,3S*)-3-fluorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0781]

[0782] 5-Amino-1-[(1S*,3S*)-3-fluorocyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]benzene 1,2-Dimethylpyrazole-4-carboxamide

[0783] (Diethylamino)sulfur trifluoride (0.96 mmol) was added dropwise to a solution of 5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (0.24 mmol) in DCM (2 mL) and cooled to -20°C. The reaction mixture was allowed to return to room temperature and then stirred for an additional 2 hours. The mixture was diluted with DCM and then quenched with saturated aqueous NaHCO3. The aqueous layer was extracted with DCM. The organic layers were combined, filtered through a hydrophobic frit and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. Further purification by reverse phase chromatography eluting with 30-80% MeCN with 0.1% formic acid additive gave the title compound (0.02 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.49 min, m / z 452.1 [M+H] + UPLC-MS(ES + , long acidic): 3.39 min, m / z 452.3 [M+H] + .

[0784] 1 H NMR (400MHz, DMSO-d6, δ): 8.72(t,J=6.1Hz,1H),7.74(dd,J=1.8,7.7,1H),7.50-7.37(m,5H),7.14(d,J=8Hz,1H),7.03(td,J=1.0,7.5Hz,1H),6.39(br s,2H),5.32(d,J=53.6Hz,1H),4.94-4.83(m,1H),4.53(d,J=6.1Hz,2H),3.89(s,3H),2.31-1.79(m,6H).

[0785] Example 42: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidinyl]methyl]pyrazole-4-carboxamide

[0786]

[0787] tert-Butyl (3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate

[0788] Purification by flash column chromatography on silica gel eluting with 0-50% EtOAc in heptane followed by the reaction of tert-butyl (3S)-3-(hydroxymethyl)piperidine-1-carboxylate (0.82 mmol) and methanesulfonyl chloride (0.86 mmol) afforded the title compound (0.72 mmol) as a colorless oil. UPLC-MS (ES +, short acidic): 1.71 min, m / z 316.1 [M+Na] + .

[0789] (3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl] tert-Butyl]pyrazol-1-yl]methyl]piperidine-1-carboxylate

[0790] General Procedure N: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.23 mmol) and tert-butyl (3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (0.47 mmol) afforded the title compound and tert-butyl (3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidine-1-carboxylate (0.13 mmol) as a beige solid mixture of regioisomers after purification by silica gel flash column chromatography. UPLC-MS (ESI) + , short acidic): 1.59 and 1.60 min, m / z 563.3 [M+H] + .

[0791] 3-amino-5-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidinyl]methane 1-[[(3S)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3- [piperidinyl]methyl]pyrazole-4-carboxamide

[0792] By (3S) -3- [[5- amino -4- formamyl -3- [4- [[(2- methoxybenzoyl) amino] methyl] phenyl] pyrazol-1-yl] methyl] piperidine -1- acid tert-butyl ester and (3S) -3- [[5- amino -4- formamyl -3- [4- [[(2- methoxybenzoyl) amino] methyl] phenyl] pyrazol-2-yl] methyl] piperidine -1- acid tert-butyl ester (0.13mmol) is dissolved in DCM (5mL) and trifluoroacetic acid (3.3mmol) is added. The reaction is stirred at RT overnight. The solvent is removed under reduced pressure. The residue is dissolved in MeOH and passed through an SPE SCX column, eluted with a 0-100% 1M ammonia solution in MeOH. The regioisomer mixture was then purified by mass-directed semi-preparative HPLC to give 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3S)-3-piperidinyl]methyl]pyrazole-4-carboxamide (0.01 mmol). UPLC-MS (ES + , short acidic): 1.09 min, m / z 463.2 [M+H] + UPLC-MS(ES + , long acidic): 2.41 min, m / z 463.3 [M+H] + .

[0793] 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 5.8 Hz, 1H), 8.42 (s, 2H), 7.75 (dd, J = 7.5, 1.5H z,1H),7.50-7.40(m,5H),7.16(d,J=8.2Hz,1H),7.06-7.03(m,1H),6.36(s,2H),4.5 5(d,J=5.8Hz,2H),3.90(s,3H),3.82(d,J=7.1Hz,2H),2.91-2.86(m,2H),2.40-2.38 (m,2H),2.03-1.99(m,1H),1.69-1.62(m,2H),1.40-1.34(m,1H),1.21-1.15(m,1H).

[0794] Example 43: 5-amino-1-(4-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0795]

[0796] 5-Amino-3-(4-bromophenyl)-1-(4-fluorophenyl)pyrazole-4-carbonitrile

[0797] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by the reaction of 4-(fluorophenyl)hydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile afforded the title compound (0.41 mmol) as a light brown solid. UPLC-MS (ESI) + , short acidic): 1.94 min, m / z 359.0 [M+2] + .

[0798] N-[[4-[5-amino-4-cyano-1-(4-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0799] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(4-fluorophenyl)pyrazole-4-carbonitrile (0.41 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.57 mmol) were used to give the title compound (0.38 mmol) as a brown solid after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.69 min, m / z 442.2 [M+H] + .

[0800] 5-amino-1-(4-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid Amide

[0801] General Procedure M: N-[[4-[5-amino-4-cyano-1-(4-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.33 mmol) gave the title compound (0.03 mmol) as a white solid after further purification by mass-directed semi-preparative HPLC. UPLC-MS (ESI) + , short acidic): 1.52 min, m / z 460.2 [M+H] + UPLC-MS(ES + , long acidic): 3.45 minutes, m / z 460.3 [M+H] + .

[0802] 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J=6.1Hz, 1H), 7.77 (dd, J=7.7, 1.7Hz, 1H), 7.66-7.63 (m, 2H), 7.56-7.54 (m, 2H), 7.5 1-7.44(m,3H),7.41(m,2H),7.16(d,J=8.1Hz,1H),7.07-7.03(m,1H),6.47(s,2H),4.57(d,J=6.1Hz,2H),3.91(s,3H).

[0803] Example 44: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(p-tolyl) Pyrazole-4-carboxamide

[0804]

[0805] 5-Amino-3-(4-bromophenyl)-1-(p-tolyl)pyrazole-4-carbonitrile

[0806] General Procedure H. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by the reaction of p-tolylhydrazine hydrochloride (0.34 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile afforded the title compound (0.29 mmol) as an orange solid. UPLC-MS (ES + , short acidic): 2.00 min, m / z 353.0 [M] + .

[0807] N-[[4-[5-amino-4-cyano-1-(p-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0808] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by the reaction of potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) and 5-amino-3-(4-bromophenyl)-1-(p-tolyl)pyrazole-4-carbonitrile (0.21 mmol) afforded the title compound (0.09 mmol) as a light brown solid. UPLC-MS (ESI) + , short acidic): 1.75 min, m / z 438.3 [M+H] + .

[0809] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(p-tolyl)pyrazole-4-carboxylic acid Amide

[0810] General Procedure M with further purification by preparative HPLC gave N-[[4-[5-amino-4-cyano-1-(p-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.09 mmol) to afford the title compound (0.01 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.57 min, m / z 456.3 [M+H] + UPLC-MS(ES + , long acidic): 3.59 minutes, m / z 456.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J=5.9Hz, 1H), 7.77 (dd, J=7.7, 1.8Hz, 1H), 7.55-7.53 (m, 2H), 7.51-7.44 (m, 5H), 7.3 4-7.33(m,2H),7.16(d,J=8.6Hz,1H),7.07-7.03(m,1H),6.41(s,2H),4.56(d,J=6.2Hz,2H),3.91(s,3H),2.38(s,3H).

[0811] Example 45: 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]benzene 1-Yl]pyrazol-1-yl]benzoic acid methyl ester

[0812]

[0813] 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]benzoic acid methyl ester

[0814] Further purification by flash column chromatography on silica gel following General Procedure H, eluting with 0-100% EtOAc in heptane, was carried out using methyl 4-chlorobenzoate (0.55 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.46 mmol) to afford the title compound (0.27 mmol) as an orange solid. UPLC-MS (ESI) + , short acidic): 1.96 min, m / z 397.1 [M] + .

[0815] 4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzene Methyl formate

[0816] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptanes was followed by the reaction of 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]benzoic acid methyl ester (0.27 mmol) and trifluoro-[[(2-methoxybenzoyl)amino]methyl] to afford the title compound (0.20 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.70 min, 482.3 m / z [M+H] + .

[0817] 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 1-Methyl]benzoic acid methyl ester

[0818] General Procedure M with further purification by mass-directed preparative HPLC gave methyl 4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate (0.20 mmol) to afford the title compound (0.01 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.53 min, m / z 500.3 [M+H] + UPLC-MS(ES + , long acidic): 3.52 min, m / z 500.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J = 6.3Hz, 1H), 8.10 (d, J = 8.5Hz, 2H), 7.83 (d, J = 8.5Hz, 2H), 7.76 (dd, J = 7.7, 1.7Hz, 1H), 7.57 (d, J = 8 .4Hz,2H),7.50-7.45(m,3H),7.16(d,J=8.4Hz,1H),7.04(t,J=7.4Hz,1H),6.7(s,2H),4.58(d,J=6.0Hz,2H),3.90(s,3H),3.89(s,3H).

[0819] Example 46: 5-amino-1-[(1S*,3S*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0820]

[0821] [(1S*)-3-[(1S*)-5-Amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclopentyl]2,2-dimethylpropanoate

[0822] To a solution of 5-amino-1-[(1S*,3R*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (160 mg, 0.36 mmol) in THF (1.8 mL) was added triphenylphosphine (0.71 mmol) and trimethylacetic acid (0.53 mmol) and cooled to 0°C. Diisopropyl azodicarboxylate (0.71 mmol) was then added and the mixture was stirred at this temperature for 15 minutes, then allowed to warm to room temperature and stirred at this temperature for 48 hours. The reaction was concentrated and then purified by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane to give the title compound (0.18 mmol). UPLC-MS (ES) + , short acidic): 1.73 min, 534.3 m / z [M+H] + .

[0823] 5-amino-1-[(1S*,3S*)-3-hydroxycyclopentyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[0824] To a solution of dimethyl [(1S*,3S*)-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclopentyl]2,2-propanoate (0.22 mmol) in THF (1 mL) was added lithium hydroxide (1.79 mmol). The reaction mixture was then heated to 80°C for 4 days, cooled and diluted with DCM and separated into layers with water. The mixture was passed through a phase separator and the aqueous layer was extracted several times with DCM. The organic layers were combined and concentrated. The resulting residue was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to give the title compound (0.05 mmol, 23% yield) as a white solid. UPLC-MS (ES + , short acidic): 1.28 min, m / z 450.3 [M+H] + UPLC-MS(ES + , long acidic): 2.86 min, m / z 450.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6,δ):8.72(t,J=6.1Hz,1H),7.74(dd,J=1.8,7.6Hz,1H),7.50-7.45(m,1H),7 .43(d,J=8.3Hz,2H),7.39(d,J=8.3Hz,2H),7.15(d,J=8.5Hz,1H),7.03(td,J=1.0,7.5Hz,1H),6.3 3(br.s,2H),4.82(quintet, J=8.1,15.3Hz,1H),4.62(d, J=3.4Hz,1H),4.54(d, J=6.1Hz,2H),4.35-4.28(m,1H),3.89(s,3H),2.21-2.06(m,2H),2.04-1.86(m,2H),1.85-1.74(m,1H),1.58-1.48(m,1H).

[0825] Example 47: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(o-tolyl) Pyrazole-4-carboxamide

[0826]

[0827] 5-Amino-3-(4-bromophenyl)-1-(o-tolyl)pyrazole-4-carbonitrile

[0828] Further purification by flash column chromatography on silica gel following General Procedure H, eluting with 0-100% EtOAc in heptane, followed by o-tolylhydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile, afforded the title compound (0.53 mmol) as an orange solid. UPLC-MS (ES+ , short acidic): 1.94 min, m / z 355.0 [M+2] + .

[0829] N-[[4-[5-amino-4-cyano-1-(o-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0830] General Procedure K. Further purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane followed by the reaction of potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) and 5-amino-3-(4-bromophenyl)-1-(o-tolyl)pyrazole-4-carbonitrile (0.21 mmol) afforded the title compound (0.19 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.69 min, m / z 438.3 [M+H] + .

[0831] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(o-tolyl)pyrazole-4-carboxylate Amide

[0832] General Procedure M: Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM gave N-[[4-[5-amino-4-cyano-1-(o-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.19 mmol) to afford the title compound (0.06 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.50 min, m / z 456.3 [M+H] + UPLC-MS(ES + , long acidic): 3.42 minutes, m / z 456.3 [M+H] + .

[0833] 1 H NMR (400MHz, DMSO-d6, δ): 8.81 (t, J=6.0Hz, 1H), 7.82 (dd, J=7.4, 1.7Hz, 1H), 7.60-7.58 (m, 2H), 7.56-7.49 (m, 5H), 7.45 -7.40(m,2H),7.21(d,J=8.2Hz,1H),7.10(t,J=7.3Hz,1H),6.21(s,2H),4.62(d,J=6.0Hz,2H),3.96(s,3H),2.19(s,3H).

[0834] Example 48: 5-amino-1-(3-hydroxycyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0835]

[0836] Sodium borohydride (836 mg, 22.10 mmol) was added to a solution of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclohexyl)pyrazole-4-carboxamide (0.44 mmol) in MeOH (15 mL) and cooled to 0°C. The reaction was allowed to return to room temperature once gas evolution ceased, and then heated to 60°C for 14 hours. The reaction was cooled back to 0°C and more sodium borohydride (22.1 mmol) was added and the reaction was heated to 60°C again. The mixture was then cooled and quenched with ammonium chloride and then extracted with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give the title compound (0.09 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.30 min, m / z 464.3 [M+H] + UPLC-MS(ES + , long acidic): 2.90 min, m / z 464.3 [M+H] + .

[0837] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.0Hz, 1H), 7.75 (dd, J=7.5, 1.8Hz, 1H), 7.51-7.37 (m, 5H), 7.17-7.13(m,1H),7.04(td,J=7.6,0.9Hz,1H),6.32(s,2H),4.70(d,J=4.9Hz,1H),4.54(d,J=6. 0Hz,2H),4.17-4.06(m,1H),3.90(s,3H),3.56-3.45(m,1H),2.05-1.96(m,1H),1.88-1.80(m,1H ),1.79-1.71(m,2H),1.71-1.61(m,1H),1.61-1.51(m,1H),1.39-1.21(m,1H),1.15-1.01(m,1H).

[0838] Example 49: 5-amino-1-[4-(hydroxymethyl)phenyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0839]

[0840] To a solution of 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoic acid (0.05mmol) in THF (3mL) was added borane-dimethyl sulfide (0.24mmol). The reaction mixture was stirred at RT for 5h, quenched by the addition of saturated ammonium chloride solution (1mL) and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by mass-guided semi-preparative HPLC to give the title compound (0.01mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.31 min, m / z 472.3 [M+H] + UPLC-MS(ES + , long acidic): 2.95 min, m / z 472.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J = 6.0 Hz, 1H), 7.78-7.72 (m, 1H), 7.59-7.51 (m, 4H), 7.51-7.41 (m, 5H) ),7.18-7.13(m,1H),7.06-7.01(m,1H),6.44(s,2H),5.35-5.27(m,1H),4.60-4.52(m,4H),3.90(s,3H).

[0841] Example 50: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(m-tolyl)pyrazole-4-carboxamide

[0842]

[0843] 5-Amino-3-(4-bromophenyl)-1-(m-tolyl)pyrazole-4-carbonitrile

[0844] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane from 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.29 mmol) and m-tolylhydrazine (0.34 mmol) afforded the title compound (0.21 mmol) as an orange solid. UPLC-MS (ES + , short acidic): 2.02 minutes, m / z 353.0 [M] + .

[0845] N-[[4-[5-amino-4-cyano-1-(m-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0846] General Procedure K: Purification by flash column chromatography on silica gel eluting with 10-100% EtOAc in heptane followed by potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.39 mmol) and 5-amino-3-(4-bromophenyl)-1-(m-tolyl)pyrazole-4-carbonitrile afforded the title compound (0.19 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.76 min, m / z 438.3 [M+H] + .

[0847] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(m-tolyl)pyrazole-4-carboxylic acid Amide

[0848] General Procedure M: N-[[4-[5-amino-4-cyano-1-(m-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.19 mmol) was used to give the title compound (0.02 mmol) after purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. UPLC-MS (ES + , short acidic): 1.57 min, m / z 456.3 [M+H] + UPLC-MS(ES + , long acidic): 3.59 minutes, m / z 456.3 [M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.2Hz, 1H), 7.75 (dd, J=7.6, 1.7Hz, 1H), 7.57-7.52 (m, 2H), 7.51-7.37 (m, 6H), 7 .24-7.19(m,1H),7.18-7.13(m,1H),7.07-7.01(m,1H),6.46(s,2H),4.56(d,J=6.2Hz,2H),3.90(s,3H),2.39(s,3H).

[0850] Example 51: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-pyridyl)pyrazole-4-carboxamide

[0851]

[0852] 5-Amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carbonitrile

[0853] General Procedure H, without triethylamine, was used with 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.42 mmol) and 3-pyridylhydrazine (0.46 mmol) to give the title compound (0.42 mmol) as a white solid. LC-MS (ES + , short acidic): 5.21 min, m / z 339.9 [M] + .

[0854] N-[[4-[5-amino-4-cyano-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0855] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carbonitrile (0.42 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.46 mmol) were used to give the title compound (0.30 mmol) as an off-white solid after flash column chromatography on silica gel eluting with 0-5% MeOH in DCM. LC-MS (ESI) + , short acidic): 4.44 min, m / z 425.1 [M+H] + .

[0856] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-pyridyl)pyrazole-4-carboxylate Amide

[0857] General Procedure M: N-[[4-[5-amino-4-cyano-1-(3-pyridinyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.14 mmol) was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.10 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.29 min, m / z 443.4 [M+H] + UPLC-MS(ES + , long acidic): 2.86 min, m / z 443.1 [M+H] + .

[0858] 1H NMR(400MHz,DMSO-d6,δ):8.86(d,J=2.5Hz,1H),8.76(t,J=6.2Hz,1H),8.60(dd,J=4.9,1.6Hz,1H),8.06-8.03(m,1H),7 .75(dd,J=7.7,1.8Hz,1H),7.60-7.54(m,3H),7.50-7.44(m,3H),7.17-7.14(m,1H)7.03(td,J=7.7,1.1Hz,1H),6.63(br s, 2H), 4.56 (d, J = 6.1Hz, 2H), 3.90 (s, 3H).

[0859] Example 52: 5-amino-1-indan-2-yl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0860]

[0861] tert-Butyl N-(indan-2-ylideneamino)carbamate

[0862] General procedure E, 2-indanone (1.14 mmol) and tert-butyl carbazate (1.36 mmol) gave the title compound (0.89 mmol) as a light yellow solid after purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane. 1 H NMR (400MHz, DMSO-d6, δ): 9.54 (s, 1H), 7.31-7.26 (m, 2H), 7.23-7.20 (m, 2H), 3.72 (s, 2H), 3.69 (s, 2H), 1.47 (s, 9H).

[0863] Indan-2-ylhydrazine hydrochloride

[0864] Tert-butyl N-(indan-2-ylideneamino)carbamate (0.89 mmol) was dissolved in THF (5 mL) and a borane dimethyl sulfide complex solution (2 M in THF, 1.52 mmol) was added. The reaction was stirred at room temperature for 2 hours until TLC showed complete consumption of the starting material. The reaction was quenched with a saturated aqueous NH4Cl solution and the layers were separated. The aqueous layer was extracted with DCM, the combined organic extracts were dried over sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in hydrogen chloride solution (1.25 M in MeOH, 9.04 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure to give crude indan-2-ylhydrazine hydrochloride (0.89 mmol). UPLC-MS: (ESI): + , short acidic): 0.83 min, m / z 149.0 [M-HCl+H]+ .

[0865] 5-Amino-3-(4-bromophenyl)-1-indan-2-yl-pyrazole-4-carbonitrile

[0866] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane followed by 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.68 mmol) and indan-2-ylhydrazine hydrochloride (0.82 mmol) afforded the title compound (0.45 mol) as an orange solid. UPLC-MS: (ESI) + , short acidic): 2.09 min, m / z 381.1 [M+2] + .

[0867] N-[[4-(5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzoyl amine

[0868] General Procedure K: 5-amino-3-(4-bromophenyl)-1-indan-2-yl-pyrazole-4-carbonitrile (0.45 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.63 mmol) gave the title compound benzamide (0.34 mol) as an off-white solid after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. 1 HNMR (400MHz, CDCl3, δ): 8.27 (dd, J=7.8, 1.8Hz, 1H), 8.24-8.19 (m, 1H), 7.91- 7.89(m,2H),7.50-7.47(m,1H),7.44-7.41(m,2H),7.28-7.25(m,4H),7.14-7. 10(m,1H),7.01-6.99(m,1H),5.09-5.01(m,1H),4.73(d,J=5.6Hz,2H),4.27(s ,2H),3.95(s,3H),3.61(dd,J=16.1,7.1Hz,2H),3.45(dd,J=16.4,8.7Hz,2H).

[0869] 5-amino-1-indan-2-yl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylate Amide

[0870] General Procedure L: N-[[4-(5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.11 mmol) was purified by flash column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (0.03 mmol) as a white solid. UPLC-MS (ESI) +, short acidic): 1.65 min, m / z 482.1 [M+H] + UPLC-MS(ES + , long acidic): 3.85 min, m / z 482.1 [M+H] + .

[0871] 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J=6.0Hz, 1H), 7.74 (dd, J=6.2, 1.7Hz, 1H), 7.50-7.38 (m, 5H), 7.25-7.23 (m, 2H), 7.19 -7.14(m,3H),7.05-7.01(m,1H),6.45(s,2H),5.23-5.15(m,1H),4.53(d,J=6.0Hz,2H),3.89(s,3H),3.39-3.28(m,4H).

[0872] Example 53: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-pyridyl)pyrazole-4-carboxamide

[0873]

[0874] 5-Amino-3-(4-bromophenyl)-1-(2-pyridyl)pyrazole-4-carbonitrile

[0875] General Procedure H, without triethylamine, used 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.24 mmol) and 2-hydrazinopyridine (1.36 mmol) to give the crude title compound (1.24 mmol, assumed quantitative) as a white solid. UPLC-MS (ES + , short acidic): 2.03 min, m / z 340.1 [M] + .

[0876] N-[[4-[5-amino-4-cyano-1-(2-pyridinyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0877] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(2-pyridyl)pyrazole-4-carbonitrile (0.44 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.48 mmol) were used to give the title compound (0.31 mmol, 70% yield) as an off-white solid after flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.77 min, m / z 425.1 [M+H] + .

[0878] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-pyridyl)pyrazole-4-carboxylate Amide

[0879] General Procedure M: N-[[4-[5-amino-4-cyano-1-(2-pyridinyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.31 mmol) was used to give the title compound (0.10 mmol) as a white solid after flash column chromatography on silica gel eluting with 0-10% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.60 min, m / z 443.1 [M+H] + UPLC-MS(ES + , long acidic): 3.67 min, m / z 443.1 [M+H] + .

[0880] 1 H NMR (400MHz, DMSO-d6, δ): 8.77 (t, J=6.3Hz, 1H), 8.49-8.47 (m, 1H), 8.01-7.96 (m, 1H), 7.88-7.86 (m, 1H), 7.76 (dd, J=7.7, 1.9Hz, 1H), 7.69 (br s,2H),7.59-7.56(m,2H),7.51-7.46(m,3H),7.34-7.31(m,1H),7.17-7.1 5(m,1H),7.04(td,J=7.6,0.8Hz,1H),4.58(d,J=6.0Hz,2H),3.91(s,3H).

[0881] Example 54: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-pyridyl)pyrazole-4-carboxamide

[0882]

[0883] 5-Amino-3-(4-bromophenyl)-1-(4-pyridyl)pyrazole-4-carbonitrile

[0884] Following General Procedure H without triethylamine, 4-pyridylhydrazine (1.44 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.31 mmol) gave the crude title compound (1.31 mmol) as a white solid. LC-MS (ES) + , short acidic): 4.66 min, m / z 341.9 [M+2] + .

[0885] N-[[4-[5-amino-4-cyano-1-(4-pyridinyl)pyrazol-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0886] General Procedure K: Purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-(4-pyridyl)pyrazole-4-carbonitrile (0.44 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.48 mmol) afforded the title compound (0.36 mmol) as an off-white solid. UPLC-MS (ESI) + , short acidic): 1.37 min, m / z 425.1 [M+H] + .

[0887] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-pyridyl)pyrazole-4-carboxylate Amide

[0888] General Procedure M: N-[[4-[5-amino-4-cyano-1-(4-pyridinyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.36 mmol) was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.13 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.19 min, m / z 443.1 [M+H] + UPLC-MS(ES + , long acidic): 2.67 min, m / z 443.1 [M+H] + .

[0889] 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J = 6.2 Hz, 1H), 8.69-8.67 (m, 2H), 7.75 (dd, J = 7.6, 1.8 Hz, 1H), 7.73-7. 71(m,2H),7.58-7.55(m,2H),7.50-7.45(m,3H),7.17-7.14(m,1H),7.03(td,J=7.6,1.0Hz,1H),6.81(br s, 2H), 4.57 (d, J = 6.0Hz, 2H), 3.90 (s, 3H).

[0890] Example 55: Ethyl 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (Isomer 1)

[0891]

[0892] Ethyl 3-(tert-Butoxycarbonylhydrazono)cyclohexanecarboxylate

[0893] General Procedure E, ethyl 3-oxocyclohexanecarboxylate (5.04 mmol) and tert-butyl carbazate (5.30 mmol) were stirred at room temperature for 3 hours. The reaction mixture was quenched with MeOH and then concentrated under reduced pressure. The residue was diluted with DCM and washed with saturated NH4Cl aqueous solution. The organic layer was passed through a phase separator and concentrated under reduced pressure to give the crude title compound (3.77 mmol). UPLC-MS (ESI) + , short acidic): 1.55 min, m / z 285.1 [M+H] + .

[0894] 3-[5-Amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylic acid ethyl ester

[0895] General Procedure O: Ethyl 3-(tert-butoxycarbonylhydrazono)cyclohexanecarboxylate (3.77 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile afforded the title compound (Isomer 1, 1.47 mmol) and the title compound (Isomer 2, 1.21 mmol) after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ES) + , short acidic, isomer 1): 2.05 min, m / z 419.1 [M+2] + UPLC-MS(ES + , short acidic, isomer 2): 2.11 min, m / z 419.1 [M+2] + .

[0896] 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexane Ethyl hexanecarboxylate (isomer 1)

[0897] General Procedure K, potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.11 mmol) and 3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylic acid methyl ester (Isomer 1, 0.72 mmol) were stirred at 80° C. for 16 hours. The reaction mixture was washed with water. The solution was diluted with water and extracted with DCM (×3). The combined organic layers were passed through a phase separator and concentrated under reduced pressure to give the crude title compound (isomer 1, 0.72 mmol). UPLC-MS (ES + , short acidic): 1.83 min, m / z 502.3 [M+H] + .

[0898] 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 1-[1-methyl]cyclohexanecarboxylic acid ethyl ester (isomer 1)

[0899] General Procedure L: Ethyl 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (Isomer 1, 0.30 mmol) was purified by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane to afford the title compound (Isomer 1, 0.03 mmol, 10%). UPLC-MS (ESI) + , short acidic): 1.63 min, m / z 520.4 [M+H] + UPLC-MS(ES + , long acidic): 3.76 min, m / z 520.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6,δ):8.73(t,J=6.1Hz,1H),7.75(dd,J=7.7,1.8Hz,1H ),7.51-7.39(m,5H),7.17-7.15(m,1H),7.04(td,J=7.6,1.0Hz,1H),6.27(br s,2H),4.55(d,J=6.2Hz,2H),4.34-4.25(m,1H),4.15-4.09(m,2H),3.90(s,3H) ,3.01-2.94(m,1H),2.11-2.04(m,2H),1.93-1.43(m,6H),1.22(t,J=6.9Hz,3H).

[0900] Example 56: 5-anilino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0901]

[0902] 5-anilino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile

[0903] To a solution of 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.15 mmol), phenylboronic acid (0.30 mmol) and copper(II) acetate (0.15 mmol) in DCM (1 mL) was added triethylamine (0.30 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 20-60% EtOAc in heptane gave the title compound (0.10 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 2.30 min, m / z 407.0 [M] + .

[0904] N-[[4-(5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxybenzoyl amine

[0905] General Procedure K: 5-anilino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.10 mmol) was purified by flash column chromatography on silica gel eluting with 20-80% EtOAc in heptane to afford the title compound (0.09 mmol) as a white powder. UPLC-MS (ES + , short acidic): 2.04 min, m / z 492.1 [M+H] + .

[0906] 5-anilino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylate amine

[0907] General Procedure L: N-[[4-(5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.09 mmol) was purified by flash column chromatography on silica gel eluting with 0-3% MeOH in DCM to afford the title compound (0.07 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.88 min, m / z 510.2 [M+H] + UPLC-MS(ES + , long acidic): 4.47 min, m / z 510.2 [M+H] + .

[0908] 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J = 6.0 Hz, 1H), 7.83 (s, 1H), 7.76 (dd, J = 7.6, 1. 7Hz,1H),7.67(d,J=8.2Hz,2H),7.52-7.44(m,1H),7.35(d,J=8.2Hz,2H),7.22-7. 09(m,4H),7.08-6.95(m,2H),6.80-6.72(m,1H),6.61(d,J=7.7Hz,2H),4.67-4.57 (m,1H),4.53(d,J=6.0Hz,2H),3.91(s,3H),2.01-1.76(m,6H),1.63-1.48(m,2H).

[0909] Example 57: 5-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (Isomer 1, Example 57a, and Isomer 2, Example 57b)

[0910]

[0911] 5-amino-1-[4-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0912] A solution of propylphosphonic anhydride (50% by weight in EtOAc, 0.14 mmol) was added to a solution of dimethylamine (2M in THF, 0.92 mmol), N,N-diisopropylethylamine (0.27 mmol) and 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylic acid (0.09 mmol) in THF (0.50 mL). The reaction mixture was heated to 40° C. and stirred for 16 hours. Additional dimethylamine (2M in THF, 0.92 mmol), N,N-diisopropylethylamine (0.27 mmol) and propylphosphonic anhydride (50% by weight in EtOAc, 0.14 mmol) were added sequentially, and the reaction mixture was continued at 40° C. for 48 hours and then cooled to room temperature. The reaction mixture was layered between water and DCM. The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic frit and all volatiles were removed under reduced pressure. Further purification was performed by flash column chromatography on silica gel eluting with 0-8% MeOH in DCM to afford the title compound (isomer 1: 0.04 mmol, 42% yield) and the title compound (isomer 2: 0.02 mmol) as white solids. UPLC-MS (ES + , short acidic; isomer 1): 1.40 min, m / z 519.3 [M+H] + UPLC-MS(ES + , long acidic; isomer 1): 3.71 min, m / z 519.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ, isomer 1): 8.73 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.7, 1.7 Hz, 1H), 7.52-7.38 (m, 5H), 7.16 (d, J = 8.4 Hz, 1H), 7.08-7.01 (m, 1H), 6.30 (s, 2H), 4.55 (d, J =6.0Hz,2H),4.21-4.10(m,1H),3.91(s,3H),3.00(s,3H),2.90-2.82(m,1H),2.80( s,3H),2.22-2.08(m,2H),2.03-1.90(m,2H),1.74-1.64(m,2H),1.64-1.53(m,2H).

[0913] UPLC-MS(ES + , short acidic; isomer 2): 1.37 min, m / z 519.2 [M+H] + UPLC-MS(ES + , long acidic; isomer 2): 3.67 minutes, m / z 519.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ, Isomer 2): 8.74 (t, J = 6.1 Hz, 1H), 7.78-7.73 (m, 1H), 7.52-7.37 (m, 5H), 7.16 (d, J = 9.0 Hz, 1H), 7.08-7.01 (m, 1H), 6.35 (s, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.20-4.06 (m, 1H), 3.90 (s, 3H), 3.03 (s, 3H), 2.81 (s, 3H), 2.73-2.61 (m, 1H), 1.96-1.82 (m, 4H), 1.82-1.73 (m, 2H), 1.62-1.44 (m, 2H).

[0914] Example 58: Ethyl 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (Isomer 2)

[0915]

[0916] 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexane Ethyl hexanecarboxylate (isomer 2)

[0917] General Procedure K, ethyl 3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazol-1-yl]cyclohexanecarboxylate (Isomer 2, 0.72 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.11 mmol) gave the crude title compound (Isomer 2, 0.72 mmol, assumed quantitative yield). UPLC-MS (ES + , short acidic): 1.78 min, m / z 502.3 [M+H] + .

[0918] 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 1-[1-yl]cyclohexanecarboxylic acid ethyl ester (isomer 2)

[0919] General Procedure L: Ethyl 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (Isomer 2, 0.30 mmol) was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (Isomer 2, 0.02 mmol, 6% yield). UPLC-MS (ESI) + , short acidic): 1.78 min, m / z 520.2 [M+H] + UPLC-MS(ES + , long acidic): 4.23 minutes, m / z 520.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6,δ):8.74(t,J=6.1Hz,1H),7.75(dd,J=7.7,1.8Hz,1H ),7.52-7.38(m,5H),7.17-7.15(m,1H),7.04(td,J=7.5,0.7Hz,1H),6.35(br s,2H),4.55(d,J=6.1Hz,2H),4.23-4.12(m,1H),4.11-4.02(m,2H),3.90(s,3H),2.49-2.43(m,1H) ,2.08-1.99(m,1H),1.94-1.66(m,5H),1.51-1.36(m,1H),1.35-1.21(m,1H),1.17(t,J=7.0Hz,3H).

[0920] Example 59: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxoindan-1-yl)pyrazole-4-carboxamide

[0921]

[0922] tert-Butyl N-[(3-oxoindane-1-ylidene)amino]carbamate

[0923] General Procedure E provided 1,3-indandione (1.37 mmol) and tert-butyl carbazate (1.44 mmol) as a yellow solid after purification by flash column chromatography on silica gel eluting with 10-50% EtOAc in heptane. 1H NMR (400MHz, DMSO-d6, δ): 10.19 (s, 1H), 7.90-7.88 (m, 1H), 7.81-7.76 (m, 1H), 7.63-7.59 (m, 1H), 7.63-7.59 (m, 1H), 3.41 (s, 2H), 1.50 (s, 9H).

[0924] tert-Butyl N-[(3-oxoindan-1-yl)amino]carbamate

[0925] General Procedure F, using tert-butyl N-[(3-oxoindane-1-ylidene)amino]carbamate (0.75 mmol) gave the crude title compound (0.57 mmol) as a colorless oil. UPLC-MS (ES + , short acidic): 1.41 min, m / z 285.1 [M+Na] + .

[0926] [(3-Oxoindane-1-yl)amino]ammonium; 2,2,2-trifluoroacetate

[0927] To a solution of tert-butyl N-[(3-oxoindan-1-yl)amino]carbamate (0.57 mmol) in DCM (5 mL) was added TFA (60 mmol). The reaction mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give the crude title compound (0.57 mmol). 1 H NMR (400MHz, DMSO-d6, δ): 7.89-7.35 (m, 4H), 5.21-5.10 (m, 1H), 3.19-3.05 (m, 1H), 2.88-2.75 (m, 1H).

[0928] 5-Amino-3-(4-bromophenyl)-1-(3-oxoindan-1-yl)pyrazole-4-carbonitrile

[0929] Following General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.46 mmol) and [(3-oxoindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.10 mmol) were purified by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane to afford the title compound (0.10 mmol) as an orange solid. UPLC-MS (ESI) + , short acidic): 1.84 min, m / z 394.9 [M+2] + .

[0930] N-[[4-[5-amino-4-cyano-1-(3-oxoindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy Benzamide

[0931] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(3-oxoindan-1-yl)pyrazole-4-carbonitrile (0.1 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.13 mmol) were used to give the title compound (0.03 mmol) as a brown solid after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.63 min, m / z 478.1 [M+H] + .

[0932] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxoindan-1-yl)pyrrolidone oxazole-4-carboxamide

[0933] General Procedure L: N-[[4-[5-amino-4-cyano-1-(3-oxoindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.03 mmol) gave the title compound (0.02 mmol) as a beige solid after purification by mass-directed semi-preparative HPLC. UPLC-CMS (ES + , short acidic): 1.47 min, m / z 496.1 [M+H] + UPLC-MS(ES + , long acidic): 3.74 min, m / z 496.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.69 (t, J=6.0Hz, 1H), 7.75-7.71 (m, 3H), 7.56 (t ,J=7.8Hz,1H),7.49-7.47(m,2H),7.34(s,4H),7.14(d,J=6.0Hz,1H),7.05 -7.00(m,1H),6.72(s,2H),6.20(dd,J=7.7,3.5Hz,1H),4.50(d,J=6.1Hz,2 H), 3.87 (s, 3H), 3.25 (dd, J = 18.5, 7.6Hz, 1H), 3.03 (dd, J = 18.6, 3.4Hz, 1H).

[0934] Example 60: 1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4-carboxamide

[0935]

[0936] 3-(4-Bromophenyl)-1-cyclopentyl-5-(methyleneamino)pyrazole-4-carbonitrile

[0937] To a solution of 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30mmol) in MeOH (3mL) was added paraformaldehyde (0.91mmol) and sodium methoxide (25% by weight in MeOH, 1.81mmol). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and then layered between DCM and water. The aqueous layer was extracted with DCM (×3), and the combined organic layers were passed through a hydrophobic glass frit and concentrated under reduced pressure to give the crude title compound (0.30mmol). UPLC-MS (ES + , short acidic): 2.09 min, m / z 377.0 [M+MeOH+2] + .

[0938] 3-(4-Bromophenyl)-1-cyclopentyl-5-(methylamino)pyrazole-4-carbonitrile

[0939] To a solution of 3-(4-bromophenyl)-1-cyclopentyl-5-(methyleneamino)pyrazole-4-carbonitrile (0.30mmol) in MeOH (3mL) was added sodium borohydride (3.02mmol) at 0°C. The reaction mixture was stirred at room temperature for 72 hours. It was then carefully quenched with saturated NH4Cl aqueous solution. The aqueous layer was then extracted with DCM (×3), and the combined organic layers were passed through a hydrophobic glass frit and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluted with 20-60% EtOAc in heptane gave the title compound (0.20mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 2.14 min, m / z 347.0 [M+2] + .

[0940] N-[[4-[4-Cyano-1-cyclopentyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzyl Amide

[0941] General Procedure K: 3-(4-bromophenyl)-1-cyclopentyl-5-(methylamino)pyrazole-4-carbonitrile (0.20 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.22 mmol) were used to give the title compound (0.11 mmol) as a white solid after purification by silica gel column chromatography eluting with 20-60% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.85 min, m / z 430.1 [M+H] + .

[0942] 1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-(methylamino)pyrazole-4- Formamide

[0943] General Procedure L: N-[[4-[4-Cyano-1-cyclopentyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.11 mmol) was purified by flash column chromatography on silica gel eluting with 0-4% MeOH in DCM and by reverse phase column chromatography eluting with 20-70% MeCN in water containing 1% formic acid to afford the title compound (0.05 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.67 min, m / z 448.1 [M+H] + UPLC-MS(ES + , long acidic): 4.30 min, m / z 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.8Hz, 1H) ,7.54-7.46(m,3H),7.37-7.34(m,2H),7.17-7.15(m,1H),7.07-7.02(m,1H), 5.85-5.81(m,1H),4.73-4.64(m,1H),4.52(d,J=6.0Hz,2H),3.90(s,3H),2. 83(d,J=5.6Hz,3H),2.06-1.89(m,4H),1.89-1.76(m,2H),1.69-1.54(m,2H).

[0944] Example 61: 5-amino-1-(2,5-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0945]

[0946] 5-Amino-3-(4-bromophenyl)-1-(2,5-difluorophenyl)pyrazole-4-carbonitrile

[0947] Following General Procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) and (2,5-difluorophenyl)hydrazine (0.76 mmol) were purified by flash column chromatography on silica gel at RT eluting with 0-60% EtOAc in heptane to afford the title compound (0.24 mmol) as a beige solid. UPLC-MS (ES + , short acidic): 1.92 min, m / z 375.0 [M] + .

[0948] N-[[4-[5-amino-4-cyano-1-(2,5-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzene Formamide

[0949] General Procedure K: Purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-(2,5-difluorophenyl)pyrazole-4-carbonitrile (0.24 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.26 mmol) afforded the title compound (0.24 mmol) as a dark yellow gum. UPLC-MS (ES + , short acidic): 1.68 min, m / z 460.2 [M+H] + .

[0950] 5-amino-1-(2,5-difluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 4-Formamide

[0951] General Procedure M: N-[[4-[5-amino-4-cyano-1-(2,5-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.26 mmol) was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM to afford the title compound (0.03 mmol, 10% yield) as a white solid. UPLC-MS (ESI) + , short acidic): 1.50 min, m / z 478.2 [M+H] + UPLC-MS(ES + , long acidic): 3.42 minutes, m / z 478.3 [M+H] + .

[0952] 1 H NMR (400MHz, DMSO-d6, δ): 8.77 (t, J=6.1Hz, 1H), 7.76 (dd, J=1.8, 7.7Hz, 1H), 7.57-7.41 (m, 8H),7.17-7.15(m,1H),7.07-7.01(m,1H),6.54(s,2H),4.57(d,J=6.1Hz,2H),3.90(s,3H).

[0953] Example 62: 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-3-methyl-phenyl]pyrazole-4-carboxamide

[0954]

[0955] N-[(4-Bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide

[0956] At 0 ° C, a solution of 4-bromo-2-methyl-benzonitrile (5.10 mmol) in THF (30 mL) was added with a solution of borane tetrahydrofuran complex (1M in THF, 15.30 mmol). The solution was stirred at 0 ° C for 30 minutes, then warmed to room temperature and stirred for 18 hours. MeOH was added dropwise to quench the reaction. The volatiles were concentrated under reduced pressure and the residue was layered with an aqueous solution of NaOH (1M) and EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude (4-bromo-2-methyl-phenyl)methylamine, which was then dissolved in THF (20 mL) and N,N-diisopropylethylamine (15.29 mmol) was added. The solution was cooled to 0 ° C, and 2-methoxybenzoyl chloride (5.61 mmol) was added. It was then stirred at 0 ° C for 20 minutes, and the reaction was then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous NH4Cl and worked up and purified (column chromatography, 0-30% EtOAc in heptane) to afford the title compound (2.49 mmol). UPLC-MS (ES + , short acidic): 1.85 min, m / z 336.1 [M+2] + .

[0957] 2-Methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methane Benzamide

[0958] General Procedure R, using N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide, gave the crude title compound (2.49 mmol). UPLC-MS (ES + , short acidic): 1.95 min, m / z 382.2 [M+H] + .

[0959] N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzoyl amine

[0960] General Procedure D: 2-methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]benzamide (2.04 mmol) gave the title compound (0.48 mmol) after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ES + , short acidic): 1.40 min, m / z 362.3 [M+H] + .

[0961] N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy- Benzamide

[0962] Cesium carbonate (0.63 mmol) was added to a solution of N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide (0.48 mmol) and bromocyclopentane (0.53 mmol) in DMF (5 mL). The reaction was heated to 80° C. for 16 hours. The title compound (0.15 mmol) was obtained after workup and purification by flash column chromatography eluting with 0-1% MeOH in DCM. UPLC-MS (ESI) + , short acidic): 1.81 min, m / z 430.1 [M+H] + .

[0963] 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]-3-methyl-phenyl]pyrazole- 4-Formamide

[0964] General Procedure L: N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide (0.15 mmol) was used to give the title compound (0.04 mmol) after purification by flash column chromatography on silica gel eluting with 25-100% EtOAc in heptane. UPLC-MS (ES) + , short acidic): 1.70 min, m / z 448.1 [M+H] + UPLC-MS(ES + , long acidic): 4.04 min, m / z 448.1 [M+H] + .

[0965] 1 H NMR (400MHz, DMSO-d6, δ): 8.61 (t, J=5.8Hz, 1H), 7.73 (dd, J=7.7, 1.7Hz, 1H), 7 .50-7.46(m,1H),7.35(d,J=7.6Hz,1H),7.30-7.23(m,2H),7.15(d,J=8.3Hz,1H ),7.06-7.02(m,1H),6.32(s,2H),4.64-4.56(m,1H),4.50(d,J=5.8Hz,2H),3.8 9(s,3H),2.36(s,3H),2.03-1.84(m,4H),1.84-1.73(m,2H),1.63-1.54(m,2H).

[0966] Example 63: 5-amino-1-(3-hydroxyindan-1-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0967]

[0968] tert-Butyl N-[(3-hydroxyindan-1-yl)amino]carbamate

[0969] Tert-butyl N-[(3-oxoindane-1-ylidene)amino]carbamate (0.58 mmol) was dissolved in THF (5 mL) and a solution of borane dimethyl sulfide complex (2 M in THF, 3.45 mmol) was added. The reaction was stirred at RT for 14 hours. Saturated aqueous NH4Cl solution was added, worked up and concentrated to give the crude title compound (0.57 mmol) as a light orange solid. UPLC-MS (ESI) + , short acidic): 1.57 min, m / z 287.0 [M+Na] + .

[0970] [(3-Hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate

[0971] To a solution of tert-butyl N-[(3-hydroxyindan-1-yl)amino]carbamate (0.57 mmol) in DCM (5 mL) was added trifluoroacetic acid (57 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were concentrated under reduced pressure to give crude [(3-hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.57 mmol). 1 H NMR (400MHz, DMSO-d6, δ): 7.57-7.31(m,4H), 5.04-4.99(m,1H), 2.83-2.78(m,1H), 2.09-1.98(m,1H).

[0972] 5-Amino-3-(4-bromophenyl)-1-(3-hydroxyindan-1-yl)pyrazole-4-carbonitrile

[0973] General Procedure H: Purification by flash column chromatography on silica gel eluting with 0-80% EtOAc in heptane followed by 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.46 mmol) and [(3-hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.55 mmol) afforded the title compound (0.28 mmol) as an orange solid. UPLC-MS (ESI) + , short acidic): 1.87 min, 396.9 [M+2] + .

[0974] N-[[4-[5-amino-4-cyano-1-(3-hydroxyindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy Benzamide

[0975] General Procedure K: 5-amino-3-(4-bromophenyl)-1-(3-hydroxyindan-1-yl)pyrazole-4-carbonitrile (0.28 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.39 mmol) were used to give the title compound (0.25 mmol) as a yellow solid after purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in heptane. UPLC-MS (ESI) + , short acidic): 1.75 min, m / z 480.1 [M+H] + .

[0976] 5-amino-1-(3-hydroxyindan-1-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrrolidone oxazole-4-carboxamide

[0977] General Procedure L: N-[[4-[5-Amino-4-cyano-1-(3-hydroxyindan-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.10 mmol) gave the title compound (0.05 mmol) as a beige solid after purification by mass-directed semi-preparative HPLC. UPL-CMS (ES + , short acidic): 1.60 min, m / z 498.1 [M+H] + UPLC-MS(ES + , long acidic): 3.68 min, m / z 498.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J=6.0Hz, 1H), 7.74 (dd, J=7.7, 1.7Hz, 1H), 7.5 0-7.36(m,6H),7.34-7.30(m,1H),7.27-7.24(m,1H),7.14(d,J=8.3Hz,1H),7.05 -7.00(m,2H),6.58(s,2H),5.76-5.71(m,1H),5.68(d,J=7.4Hz,1H),5.06-5.01( m,1H),4.52(d,J=6.0Hz,2H),3.88(s,3H),2.89-2.82(m,1H),2.41-2.36(m,1H).

[0978] Example 64: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole-4-carboxamide

[0979]

[0980] N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-ylpyrazol-3-yl)phenyl]methyl]-2-methoxy-benzene Formamide

[0981] General Procedure K: Purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by the reaction of 5-amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazole-4-carbonitrile (0.27 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) afforded the title compound (0.19 mmol, 72% yield) as a dark yellow gum. UPLC-MS (ESI) + , short acidic): 1.51 min, m / z 432.3 [M+H] + .

[0982] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-tetrahydropyran-4-yl-pyrazole- 4-Formamide

[0983] General Procedure M: N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.33 mmol) was purified by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM followed by purification on a SPESCX column eluting with MeOH to afford the title compound (0.15 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.56 min, m / z 450.1 [M+H] + UPLC-MS(ES + , long acidic): 3.57 min, m / z 450.1 [M+H] + .

[0984] 1 H NMR (400MHz, DMSO-d6, δ): 8.77 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.50-7.40 (m, 5H), 7.17-7.15 (m, 1H), 7.06-7.02 (m, 1H), 6.38 (s,2H),4.55(d,J=6.0Hz,2H),4.40-4.32(m,1H),3.99-3.95(m,2H),3.90(s,3H),3.46-3.40(m,2H),2.03-1.94(m,2H),1.79-1.76(m,2H).

[0985] Example 65: 5-amino-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0986]

[0987] 8-(Trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol

[0988] Under a nitrogen atmosphere, at 0 ° C, trimethyl (trifluoromethyl) silane (12.8 mmol) was added to a solution of 1,4-cyclohexanedione monovinyl acetal (6.40 mmol) in anhydrous THF (20 mL), followed by tetrabutylammonium fluoride (1.0 M in THF, 13.4 mmol). The reaction mixture was then warmed to 25 ° C and stirred for 2 hours. Saturated aqueous ammonium chloride solution (10 mL) was then added. The reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure. Processing and purification gave the title compound (5.83 mmol) as a light yellow oil. 1 H NMR (400MHz, CDCl3, δ): 4.00-3.92(m,4H), 1.97-1.88(m,4H), 1.83-1.79(m,2H), 1.69-1.67(m,2H).

[0989] 4-Hydroxy-4-(trifluoromethyl)cyclohexanone

[0990] To a solution of 8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decan-8-ol (5.84 mmol) in acetone (29 mL) was added hydrochloric acid (4 M, 8.75 mmol). The reaction mixture was stirred at room temperature for 18 hours and, after workup and purification, the title compound (5.12 mmol) was obtained as a white solid. 1 H NMR (400MHz, DMSO-d6, δ): 6.26 (br s, 1H), 2.62-2.52 (m, 2H), 2.19-2.15 (m, 2H), 2.04-1.92 (m, 2H), 1.79-1.62 (m, 2H).

[0991] tert-Butyl N-[[4-hydroxy-4-(trifluoromethyl)cyclohexylidene]amino]carbamate

[0992] General Procedure E, 4-hydroxy-4-(trifluoromethyl)cyclohexanone (5.12 mmol) afforded the title compound (2.29 mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6,δ):9.60(br s,1H),6.02(br s,1H),2.83-2.79(m,1H),2.42-2.37(m,2H),2.24-2.20(m,1H),1.85-1.79(m,2H),1.70-1.55(m,2H),1.43(s,9H).

[0993] 5-Amino-3-(4-bromophenyl)-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-4-carbonitrile

[0994] General Procedure O, tert-butyl N-[[4-hydroxy-4-(trifluoromethyl)cyclohexylidene]amino]carbamate (2.29 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.89 mmol) afforded the title compound (0.12 mmol) as a yellow solid. UPLC-MS (ES + , short acidic): 1.94 min, m / z 430.9 [M+2] + .

[0995] N-[[4-[5-amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazol-3-yl]phenyl]methane 2-Methoxy-benzamide

[0996] General Procedure K, 5-amino-3-(4-bromophenyl)-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-4-carbonitrile (0.42 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.46 mmol) gave the title compound (0.24 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.82 min, m / z 514.1 [M+H] + .

[0997] 5-amino-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methane 1-[4-[(1-amino-2-methyl-1-phenyl)pyrazole-4-carboxamide]]

[0998] General Procedure L, N-[[4-[5-amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.24 mmol) was used to give the title compound (0.095 mmol) as a light yellow solid. UPLC-MS (ES + , short acidic): 1.68 min, m / z 532.1 [M+H] + UPLC-MS(ES + , long acidic): 3.91 min, m / z 532.1 [M+H] + .

[0999] 1H NMR(400MHz,DMSO-d6,δ):8.73(t,J=6.6Hz,1H),7.75(dd,J=7.7,1.8Hz,1H),7.50-7.39(m,5H),7.16-7.14(m,1H),7.04(td,J=7.5,1.0Hz,1H),6.34(br s,2H),5.86(br s,1H),4.54(d,J=6.0Hz,2H),4.18-4.11(m,1H),3.90(s,3H),2.18-2.07(m,2H),1.85-1.83(m,2H),1.73-1.63(m,4H).

[1000] Example 66: 5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1001]

[1002] tert-Butyl N-(oxetane-3-ylideneamino)carbamate

[1003] Following general procedure E, 3-oxetanone (6.94 mmol) and tert-butyl carbazate (7.29 mmol) gave the title compound (4.51 mmol) as a white solid after washing the crude product with heptane. 1 H NMR (400MHz, DMSO-d6, δ): 10.25 (s, 1H), 5.19-5.15 (m, 4H), 1.43 (s, 9H).

[1004] tert-Butyl N-(oxetan-3-ylamino)carbamate

[1005] Following General Procedure F, tert-butyl N-(oxetan-3-ylideneamino)carbamate (4.40 mmol) gave the title compound (3.84 mmol) as a colorless oil after 2 days. 1 H NMR (400MHz, DMSO-d6, δ): 8.38 (s, 1H), 4.96-4.94 (m, 1H), 4.51 (t, J = 6.8Hz, 2H), 4.37 (t, J = 6.2Hz, 2H), 4.07-3.99 (m, 1H), 1.40 (s, 9H).

[1006] Oxetane-3-ylhydrazine hydrochloride

[1007] Following general procedure G and tert-butyl N-(oxetan-3-ylamino)carbamate (3.84 mmol) provided the title compound (2.88 mmol) as a brown oil.1 H NMR (400MHz, DMSO-d6, δ): 3.81-3.71 (m, 2H), 3.61-3.53 (m, 2H), 3.25-3.19 (m, 1H).

[1008] 5-Amino-3-(4-bromophenyl)-1-[1-(chloromethyl)-2-hydroxy-ethyl]pyrazole-4-carbonitrile

[1009] Following general procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and oxetan-3-ylhydrazine hydrochloride (0.46 mmol) were reacted at 85 °C for 2 h to afford the title compound as a white solid. UPLC-MS (ES + , short acidic): 1.76 min, m / z 357.1 [M+2] + .

[1010] N-[[4-[5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazol-3-yl]phenyl]methyl]- 2-Methoxy-benzamide

[1011] General Procedure K, 5-amino-3-(4-bromophenyl)-1-[1-(chloromethyl)-2-hydroxy-ethyl]pyrazole-4-carbonitrile (0.20 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.28 mmol) gave the title compound (0.13 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.50 min, m / z 440.2 [M] + .

[1012] 5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [phenyl]pyrazole-4-carboxamide

[1013] General Procedure L, N-[[4-[5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.11 mmol) was used to give the title compound (0.03 mmol) as a white solid. UPLC-MS (ES + , short acidic): 1.33 minutes, m / z 458.2 [M] + . 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.6, 1.8 Hz, 1H), 7.51-7.41 (m, 5H), 7.16 (d, J = 8.0 Hz, 1H), 7. 07-7.03(m,1H),6.42(s,2H),5.11(t,J=5.4Hz,1H),4.59-4.52(m,3H),4.02-3.93(m,2H),3.91(s,3H),3.78-3.67(m,2H).

[1014] Example 67: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-methylthiazol-2-yl)pyrazole-4-carboxamide

[1015]

[1016] 5-Amino-3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)pyrazole-4-carbonitrile

[1017] Following general procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) and (4-methylthiazol-2-yl)hydrazine (0.91 mmol) gave the title compound (0.32 mmol) as a yellow solid after purification at 85 °C for 2 h. UPLC-MS (ES + , short acidic): 1.78 min, m / z 362.0 [M+2] + .

[1018] N-[[4-[5-amino-4-cyano-1-(4-methylthiazol-2-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy Benzamide

[1019] Following General Procedure K, 5-amino-3-(4-bromophenyl)-1-(4-methylthiazol-2-yl)pyrazole-4-carbonitrile (86 mg, 0.24 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (100 mg, 0.37 mmol) were used to give the title compound (0.08 mmol) as an orange solid after purification. UPLC-MS (ESI) + , short acidic): 1.64 min, m / z 445.2 [M+H] + .

[1020] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-methylthiazol-2-yl)pyrrolidone oxazole-4-carboxamide

[1021] Following General Procedure M, N-[[4-[5-amino-4-cyano-1-(4-methylthiazol-2-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.05 mmol) was used to give the title compound (0.02 mmol) as a yellow solid after purification. UPLC-MS (ESI) + , short acidic): 1.34 min, m / z 463.1 [M+H] + UPLC-MS(ES + , long acidic): 3.01 min, m / z 463.1 [M+H] + .

[1022] 1 H NMR (400MHz, DMSO-d6, δ): 8.80-8.72 (m, 1H), 7.77 (dd, J = 7.8, 1.9Hz, 1H), 7.52-7.47 (m, 1H), 7.44-7.35 (m, 4H), 7.30-7. 29(m,1H),7.17-7.15(m,1H),6.38-6.35(m,1H),5.97(s,2H),4.59(d,J=6.9Hz,2H),3.91(s,3H),2.14(d,J=1.2Hz,3H).

[1023] Example 68: 5-amino-1-(4,4-difluorocyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1024]

[1025] (4,4-Difluorocyclohexyl)hydrazine hydrochloride

[1026] To a toluene (20 mL) solution of 4,4-difluorocyclohexanol (5.40 mmol) was added triphenylphosphine (8.10 mmol) and di-tert-butyl azodicarboxylate (6.48 mmol), and the reaction mixture was stirred at room temperature under nitrogen for 16 h. The reaction mixture was concentrated. MeOH (30 mL) was added, followed by hydrogen chloride solution (4 M in 1,4-dioxane, 10.8 mL, 43.19 mmol), and the mixture was stirred at room temperature for 14 hours. After filtration, the filtrate was concentrated and EtOAc was added to give the title compound (3.52 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6, δ): 3.11-3.05 (m, 1H), 2.11-1.78 (m, 6H), 1.63-1.53 ​​(m, 2H).

[1027] 5-Amino-3-(4-bromophenyl)-1-(4,4-difluorocyclohexyl)pyrazole-4-carbonitrile

[1028] Following general procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (133 mg, 0.51 mmol) and (4,4-difluorocyclohexyl)hydrazine hydrochloride (113 mg, 0.61 mmol) were reacted at 85 °C for 2 h to afford the title compound (114 mg, 0.30 mmol, 59% yield) as a white solid after purification. UPLC-MS (ESI) + , short acidic): 2.01 min, m / z 383.0 [M+2] + .

[1029] N-[[4-[5-amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy- Benzamide

[1030] Following General Procedure K, after purification, 5-amino-3-(4-bromophenyl)-1-(4,4-difluorocyclohexyl)pyrazole-4-carbonitrile (0.30 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) gave the title compound (0.26 mmol) as an orange solid. UPLC-MS (ESI) + , short acidic): 1.79 min, m / z 466.1 [M+H] + .

[1031] 5-amino-1-(4,4-difluorocyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrrolidone oxazole-4-carboxamide

[1032] Following General Procedure L, N-[[4-[5-amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (160 mg, 0.34 mmol) was used to give the title compound (0.11 mmol) as a white solid after purification. UPLC-MS (ES + , short acidic): 1.71 min, m / z 484.2 [M+H] + UPLC-MS(ES + , long acidic): 4.09 min, m / z 484.1 [M+H] + .

[1033] 1H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.1Hz, 1H), 7.75 (dd, J=7.7, 1.8Hz, 1H), 7.50-7.39 (m, 5H), 7.16-7.14 (m, 1H),7.05-7.01(m,1H),6.36(s,2H),4.54(d,J=6.1Hz,2H),4.34-4.26(m,1H),3.89(s,3H),2.20-1.89(m,8H).

[1034] Example 69: 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-N-methyl-pyrazole-4-carboxamide

[1035]

[1036] 5-Amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid

[1037] A mixture of ethyl 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylate (0.22 mmol), sodium hydroxide (5 M in water, 1 mL, 5.00 mmol) and MeOH (3 mL) in THF (5 mL) was stirred at 80 ° C for 48 hours. The mixture was then cooled and the MeOH was removed under reduced pressure. The residue was neutralized with hydrochloric acid (6 M) at 0 ° C until precipitation was observed. The aqueous layer was then extracted and concentrated to give the crude title compound (0.20 mmol) as a light brown solid. LC-MS (ES) + , short acidic): 4.87 min, m / z 435.2 [M+H] + .

[1038] 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-N-methylpyrazole- 4-Formamide

[1039] Under nitrogen, 5-amino-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxylic acid (30 mg, 0.07 mmol) was dissolved in DMF (3 mL). HATU (34 mg, 0.09 mmol) and N,N-diisopropylethylamine (36 μL, 0.21 mmol) were added at RT. The mixture was stirred for 45 minutes. Methylamine (2 M in THF, 104 μL, 0.21 mmol) was then added and the mixture was stirred for 48 hours. After workup and purification, the title compound (0.04 mmol) was obtained as a white solid. UPLC-MS (ESI) + , short acidic): 1.80 min, m / z 448.2 [M+H] + UPLC-MS(ES+ , long acidic): 4.21 min, m / z 448.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.7, 1.8Hz, 1H ),7.51-7.45(m,3H),7.39-7.37(m,2H),7.17-7.15(m,1H),7.07-7.03(m,1 H),6.18-6.11(m,1H),6.11(s,2H),4.64-4.57(m,1H),4.54(d,J=6.1Hz,2H ), 3.91 (s, 3H), 2.59 (d, J = 4.7Hz, 3H), 2.03-1.76 (m, 6H), 1.64-1.56 (m, 2H).

[1040] Example 70: 5-amino-1-[3-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide (Isomer 1)

[1041]

[1042] Lithium-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrrolidone [1-oxazol-1-yl]cyclohexanecarboxylate (isomer 1)

[1043] A suspension of lithium hydroxide (9 mg, 0.39 mmol) in a solution of ethyl 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-1-carboxylate (Isomer 1, 0.19 mmol) in THF (1.5 mL) and water (0.4 mL) was heated to 60° C. for 16 hours. The reaction was concentrated to give the crude title compound (Isomer 1, 0.19 mmol) which was used immediately in the next step. UPLC-MS (ESI) + , short acidic): 1.60 min, m / z 492.1 [M+H] + .

[1044] 5-amino-1-[3-(dimethylcarbamoyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino] [Methyl]phenyl]pyrazole-4-carboxamide (isomer 1)

[1045] A solution of lithium-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylic acid methyl ester (isomer 1, 95 mg, 0.19 mmol) in THF (2 mL) was stirred with a dimethylamine solution (2 M in THF, 0.05 mL, 0.96 mmol) and a propylphosphonic anhydride solution (50 wt% in EtOAc, 0.34 mL, 0.57 mmol) at room temperature for 48 hours. After workup and purification, the title compound (isomer 1, 0.03 mmol) was obtained. UPLC-MS (ES + , short acidic): 1.67 min, m / z 519.2 [M+H] + UPLC-MS(ES + , long acidic): 3.87 min, m / z 519.2 [M+H] + .

[1046] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.0Hz, 1H), 7.76 (dd, J = 7.6, 1.7Hz, 1H), 7.51-7.38 (m, 5H), 7.16 (d, J = 8.2Hz, 1H), 7.08-7.01 (m, 1H), 6.24 (br s,2H),4.70-4.60(m,1H),4.55(d,J=6.1Hz,2H),3.90(s,3H),3.54-3.42 (m,1H),2.98(s,3H),2.81(s,3H),2.04-1.95(m,1H),1.89-1.51(m,7H).

[1047] Example 71: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carboxamide

[1048]

[1049] tert-Butyl N-(2-oxaspiro[3.5]nonan-7-ylideneamino)carbamate

[1050] General procedure E was followed from 2-oxaspiro[3.5]nonan-7-one (120 mg, 0.86 mmol) and tert-butyl carbazate (136 mg, 1.03 mmol) to give crude tert-butyl N-(2-oxaspiro[3.5]nonan-7-ylideneamino)carbamate (0.86 mmol) as a white solid. 1H NMR (400MHz, DMSO-d6, δ): 9.58 (s, 1H), 4.33 (s, 4H), 2.28-2.25 (m, 2H), 2.16-2.13 (m, 2H), 1.88-1.85 (m, 2H), 1.81-1.78 (m, 2H), 1.43 (s, 9H).

[1051] 5-Amino-3-(4-bromophenyl)-1-(2-oxaspiro[3.5]non-7-yl)pyrazole-4-carbonitrile

[1052] Tert-butyl N-(2-oxaspiro[3.5]non-7-ylamino)carbamate (0.85 mmol) was dissolved in THF (10 mL) and a borane dimethyl sulfide complex solution (2 M in THF, 0.73 mL, 1.45 mmol) was added. The reaction was stirred at room temperature for 2 hours. The volatiles were concentrated and the residue was dissolved in DCM (5 mL), and then TFA (0.88 mL, 4.27 mmol) was added. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was dissolved in EtOH (10 mL). 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.65 mmol) and triethylamine (3.23 mmol) were then added. The reaction mixture was heated to 80 ° C for 3 hours, then cooled to room temperature and concentrated. Purification gave the title compound (0.30 mmol) as a yellow solid. UPLC-MS (ES + , short acidic): 1.96 min, m / z 386.9 [M] + .

[1053] N-[[4-[5-amino-4-cyano-1-(2-oxaspiro[3.5]non-7-yl)pyrazol-3-yl]phenyl]methyl]-2- Methoxybenzamide

[1054] Following General Procedure K, 5-amino-3-(4-bromophenyl)-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazole-4-carbonitrile (0.22 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.31 mmol) were purified to give the title compound (0.21 mmol) as a yellow solid. UPLC-MS (ES + , short acidic): 1.78 min, 472.2 m / z [M+H] + .

[1055] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-oxaspiro[3.5]nonane-7- 4-Methyl)pyrazole-4-carboxamide

[1056] General Procedure L, after purification, N-[[4-[5-amino-4-cyano-1-(2-oxaspiro[3.5]nonan-7-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.24 mmol) gave the title compound (0.06 mmol) as a beige solid. UPLC-MS (ES + , short acidic): 1.65 min, m / z 490.2 [M+H] + UPLC-MS(ES + , long acidic): 3.89 min, m / z 490.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J=6.1Hz, 1H), 7.75 (dd, J=7.6, 1.8Hz, 1H) ,7.51-7.46(m,1H),7.44-7.39(m,4H),7.18-7.13(m,1H),7.06-7.02(m,1H) ,6.34(s,2H),4.54(d,J=6.7Hz,2H),4.36(s,2H),4.26(s,2H),4.11-4.00(m ,1H),3.90(s,3H),2.21-2.11(m,2H),1.79-1.62(m,4H),1.61-1.49(m,2H).

[1057] Example 72: 1-cyclopentyl-5-(isopropylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1058]

[1059] 3-(4-Bromophenyl)-1-cyclopentyl-5-(isopropylamino)pyrazole-4-carbonitrile

[1060] A mixture of 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30 mmol), cesium carbonate (0.91 mmol) and 2-bromopropane (0.72 mmol) in DMF (10 mL) was heated to 50° C. for 16 hours. After workup and purification, the title compound (0.13 mmol) was obtained as a brown solid. UPLC-MS: (ESI): + , short acidic): 2.45 min, m / z 375.0 [M+2] + .

[1061] N-[[4-[4-Cyano-1-cyclopentyl-5-(isopropylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzene Formamide

[1062] General Procedure K, after purification, 3-(4-bromophenyl)-1-cyclopentyl-5-(isopropylamino)pyrazole-4-carbonitrile (0.13 mol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.18 mmol) gave the title compound (0.12 mmol) as a light brown solid. UPLC-MS: (ESI) + , short acidic): 2.18 min, m / z 458.2 [M+H] +.

[1063] 1-cyclopentyl-5-(isopropylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 4-Formamide

[1064] General Procedure L, after purification, N-[[4-[4-cyano-1-cyclopentyl-5-(isopropylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.12 mmol) gave the title compound (0.05 mmol) as a white solid. UPLC-MS: (ES + , long acidic): 4.99 min, m / z 476.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J=6.4Hz, 1H), 7.76 (dd, J=8.0, 2.0Hz, 1H), 7.54 ( d,J=8.4Hz,2H),7.51-7.46(m,1H),7.36(d,J=8.4Hz,2H),7.17-7.15(m,1H),7.07-7 .01(m,1H),5.29(d,J=9.2Hz,1H),4.78-4.70(m,1H),4.53(d,J=6.0Hz,2H),3.90(s, 3H), 3.48-3.36 (m, 1H), 2.06-1.79 (m, 6H), 1.69-1.59 (m, 2H), 1.11 (d, J = 6.4Hz, 6H).

[1065] Example 73: 1-cyclopentyl-5-(ethylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1066]

[1067] 3-(4-Bromophenyl)-1-cyclopentyl-5-(ethylamino)pyrazole-4-carbonitrile

[1068] A mixture of 5-amino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carbonitrile (0.30 mmol) and cesium carbonate (295 mg, 0.91 mmol) and iodoethane (0.36 mmol) in DMF (5 mL) was stirred at RT for 14 h. After workup and purification, the title compound (0.15 mmol) was obtained as an off-white solid. UPLC-MS: (ESI + , short acidic): 2.33 min, m / z 361.0 [M+2] + .

[1069] N-[[4-[4-Cyano-1-cyclopentyl-5-(ethylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzyl Amide

[1070] General Procedure K, after purification, 3-(4-bromophenyl)-1-cyclopentyl-5-(ethylamino)pyrazole-4-carbonitrile (0.15 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.22 mmol) gave the title compound (0.14 mmol) as an off-white solid. UPLC-MS: (ES + , short acidic): 2.11 min, m / z 444.2 [M+H] + .

[1071] 1-cyclopentyl-5-(ethylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4- Formamide

[1072] General Procedure L, after purification, N-[[4-[4-cyano-1-cyclopentyl-5-(ethylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.14 mmol) gave the title compound (0.06 mmol) as a white solid. UPLC-MS (ES + , long acidic): 4.84 min, m / z 462.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J=6.3Hz, 1H), 7.75 (dd, J=7.6, 1.8Hz, 1H), 7.53 ( d,J=8.3Hz,2H),7.51-7.46(m,1H),7.36(d,J=8.4Hz,2H),7.17-7.15(m,1H),7.06-7 .00(m,1H),5.63(t,J=6.4Hz,1H),4.74-4.68(m,1H),4.53(d,J=6.1Hz,2H),3.90(s, 3H),3.18-3.11(m,2H),2.04-1.78(m,6H),1.66-1.57(m,2H),1.12(t,J=7.1Hz,3H).

[1073] Example 74: Example 78: 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylic acid

[1074]

[1075] 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 1-Methyl]cyclohexanecarboxylic acid

[1076] Lithium hydroxide (6.16 mmol) was added to a solution of ethyl 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (0.62 mmol) in THF (3 mL) and water (1 mL). The reaction mixture was stirred at 50° C. for 16 hours and then cooled to room temperature. The reaction mixture was acidified to ~pH 2 with hydrochloric acid (1 M). Workup and purification gave an inseparable mixture of the cis and trans title compounds (0.39 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.32 min, m / z 492.3 [M+H] + UPLC-MS(ES + , long acidic): 3.67 min, m / z 492.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ, cis / trans mixture): 12.1 (br s, 1H), 8.73 (t, J = 5.9 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 1H), 7.52-7.38 (m, 5H), 7.16 (d, J = 8.3 Hz, 1H), 7.08-7.01 (m, 1H), 6.40-6.25 (m, 2H), 4.55 (d, J = 6.0 Hz, 2H), 4.17-4.04 (m, 1H), 3.90 (s, 3H), 2.64-2.10 (m, 1H), 2.07-1.94 (m, 2H), 1.93-1.39 (m, 6H).

[1077] Example 75: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[4-(methoxycarbamoyl)cyclohexyl]pyrazole-4-carboxamide

[1078]

[1079] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[4-(methoxybenzoyl)amino]methyl]phenyl] [4-[(1-[(1-[(4-( ...

[1080] A solution of propylphosphonic anhydride (50 wt% in EtOAc, 0.27 mmol), N,N-diisopropylethylamine (0.92 mmol), methoxyamine hydrochloride (0.22 mmol) and 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylic acid (0.18 mmol) in THF (1 mL) was stirred at 80° C. for 16 hours and cooled to room temperature. Workup and purification gave the title compound (0.03 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.53 min, m / z 521.2 [M+H] + UPLC-MS(ES + , long acidic): 3.58 min, m / z 521.2 [M+H] + .

[1081] Example 76: 5-amino-1-cyclopentyl-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1082]

[1083] (4-Bromo-2-fluoro-phenyl)methanamine

[1084] A solution of 4-bromo-2-fluorobenzonitrile (5.00mmol) in THF (30mL) is cooled to 0°C. Borane tetrahydrofuran complex solution (1M in THF, 15.0mL) is added dropwise. The solution is stirred at 0°C for 20 minutes, then warmed to room temperature and stirred for 16 hours. MeOH (30mL) is added dropwise and the solution is concentrated under reduced pressure. Residue is layered between the NaOH aqueous solution (1M) and EtOAc. The organic layer is processed to obtain the title compound (5.00mmol), which is a yellow oil. 1 H NMR (400MHz, CDCl3, δ): 7.42-7.27 (m, 1H), 7.25-7.16 (m, 2H), 3.65 (t, J = 6.6Hz, 2H).

[1085] N-[(4-Bromo-2-fluoro-phenyl)methyl]-5-fluoro-2-methoxy-benzamide

[1086] A solution of (4-bromo-2-fluoro-phenyl)methanamine (5.00 mmol) in THF (8 mL) was added dropwise to a mixture of 5-fluoro-2-methoxybenzoic acid (1.03 g, 6.04 mmol), N,N-diisopropylethylamine (5.22 mL, 30.0 mmol) and propylphosphonic anhydride solution (50 wt% in EtOAc, 4.46 mL, 7.50 mmol) in THF (17 mL). The reaction was heated at 80°C for 4 hours. Work-up and concentration gave the title compound (3.18 mmol). UPLC-MS (ES) + , short acidic): 1.98 min, m / z 357.9 [M+2] + .

[1087] 5-Fluoro-N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methyl Oxy-benzamide

[1088] General Procedure R, after purification, N-[(4-bromo-2-fluoro-phenyl)methyl]-5-fluoro-2-methoxy-benzamide (3.34 mmol) gave the title compound (3.30 mmol). UPLC-MS (ES + , short acidic): 2.14 min, m / z 404.0 [M+H] + .

[1089] N-[[4-(5-Amino-4-cyano-1H-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzyl Amide

[1090] General Procedure D, after purification, 5-fluoro-N-[[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]-2-methoxy-benzamide (1.65 mmol) and 5-amino-3-bromo-1H-pyrazole-4-carbonitrile (1.34 mmol) gave the title compound (0.78 mmol). UPLC-MS (ES + , short acidic): 1.67 min, m / z 384.0 [M+H] + .

[1091] N-[[4-(5-Amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy Benzamide

[1092] A solution of cesium carbonate (1.64 mmol), N-[[4-(5-amino-4-cyano-1H-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide (1.27 mmol) and bromocyclopentane (1.39 mmol) in DMF (10 mL) was heated to 80° C. for 18 hours. Workup and purification afforded the title compound (0.21 mmol). UPLC-MS (ES +, short acidic): 2.04 min, m / z 452.1 [M+H] + .

[1093] 5-amino-1-cyclopentyl-3-[3-fluoro-4-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]phenyl]pyrrolidone oxazole-4-carboxamide

[1094] General Procedure L, after purification, N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-fluoro-phenyl]methyl]-5-fluoro-2-methoxy-benzamide (0.11 mmol) gave the title compound (0.07 mmol). UPLC-MS (ES + , short acidic): 1.93 min, m / z 470.1 [M+H] + UPLC-MS(ES + , long acidic): 5.12 min, m / z 470.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6,δ):8.81(t,J=5.9Hz,1H),7.51(dd,J=9.2,3.3Hz,1H),7.46-7.40(m,1H),7.38-7.25(m,3H),7.19(dd,J=9.1,4 .3Hz,1H),6.25(s,2H),4.67-4.58(m,1H),4.56(d,J=5.9Hz,2H),3.90(s,3H),2.03-1.84(m,4H),1.84-1.74(m,2H),1.65-1.54(m,2H).

[1095] Example 77: 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3-yl]pyrazole-4-carboxamide (Isomer 1)

[1096]

[1097] tert-Butyl N-[(2-methyltetrahydrofuran-3-ylidene)amino]carbamate

[1098] A solution of tert-butyl carbazate (11.99 mmol) and 2-methyltetrahydro-3-furanone (9.99 mmol) in EtOH (25 mL) was heated at reflux for 16 hours, cooled and concentrated under reduced pressure. The residue was dissolved in DCM, washed with water and saturated NaHCO solution, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (9.99 mmol) as a white solid. 1HNMR(400MHz, CDCl3, δ):7.22(s,1H),4.39-4.31(m,1H),4.27-4.19(m,1H) ,3.97-3.88(m,1H),2.53-2.46(m,2H),1.54(s,9H),1.44(d,J=6.4Hz,3H).

[1099] (2-Methyltetrahydrofuran-3-yl)hydrazine

[1100] General Procedures T and U tert-butyl N-[(2-methyltetrahydrofuran-3-ylidene)amino]carbamate (9.99 mmol) gave (2-methyltetrahydrofuran-3-yl)hydrazine (9.33 mmol) after purification by SPE SCX column eluting with 1M NH3 in MeOH. 1 H NMR (400MHz, CDCl3, δ): 4.03-3.66(m,3H), 3.31-3.24(m,1H), 2.18-2.05(m,1H), 1.95-1.85(m,1H), 1.30-1.22(m,3H).

[1101] 5-amino-3-(4-bromophenyl)-1-(2-methyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile

[1102] General Procedure H, after purification, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.90 mmol) and (2-methyltetrahydrofuran-3-yl)hydrazine (2.28 mmol) gave the title compound (600 mg, 1.73 mmol, 91% yield) as inseparable diastereomers. UPLC-MS (ES + , short acidic, diastereoisomer mixture): 2.02 min, m / z 349.0 [M+2] + and 2.07 min, m / z 349.0 [M+2] + .

[1103] N-[[4-[5-amino-4-cyano-1-[2-methyltetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methyl Oxy-benzamide

[1104] General Procedure K, after purification, 5-amino-3-(4-bromophenyl)-1-(2-methyltetrahydrofuran-3-yl)pyrazole-4-carbonitrile (0.86 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane gave the title compound (Isomer 1, 0.17 mmol) and (Isomer 2, 0.32 mmol). UPLC-MS (ES + , short acidic, isomer 1): 1.98 min, m / z 432.1 [M+H] + UPLC-MS(ES +, short acidic, isomer 2): 1.96 min, m / z 432.1 [M+H] + .

[1105] 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[2-methyltetrahydrofuran-3- 1-[4-[ ...pyrazole]]]-4-carboxamide (isomer 1)

[1106] Following General Procedure L, N-[[4-[5-amino-4-cyano-1-[2-methyltetrahydrofuran-3-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (Isomer 1, 0.17 mmol) was used to give the title compound (Isomer 1, 0.09 mmol) after purification. UPLC-MS (ES + , short acidic): 2.03 min, m / z 450.1 [M+H] + UPLC-MS(ES + , long acidic): 4.49 min, m / z 450.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74(t,J=6.3Hz,1H),7.75(dd,J=7.6,1.7Hz,1H),7.51-7.38(m,5H),7.15(d,J=8.5Hz,1H),7.08-7.00(m,1H),6.43( brs,2H),4.55(d,J=5.9Hz,2H),4.51-4.44(m,1H),4.08-4.02(m,1H),3 .95-3.90(m,2H),3.90(s,3H),2.38-2.18(m,2H),1.21(d,J=6.2Hz,3H).

[1107] Example 78: 5-Chloro-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[1108]

[1109] 3-(4-Bromophenyl)-1H-pyrazol-5-ol

[1110] A solution of ethyl 3-(4-bromophenyl)-3-oxopropanoate (12.2 mmol) in EtOH (20 mL) and hydrazine hydrate solution (55-60% in water, 12.2 mmol) was stirred at RT for 40 minutes. The reaction mixture was then heated at reflux for 1 hour, then cooled to RT and concentrated under reduced pressure to give the crude title compound (12.2 mmol) as a white solid. UPLC-MS (ESI) + , short acidic): 1.57 min, m / z 240.6 [M+2] + .

[1111] 3-(4-Bromophenyl)-5-chloro-1H-pyrazole-4-carbaldehyde

[1112] Under nitrogen, anhydrous DMF (1.0 mL) was slowly added to phosphorus oxychloride (29.3 mmol) at 0°C. The reaction mixture was then warmed to room temperature and stirred for 5 minutes, and then 3-(4-bromophenyl)-1H-pyrazole-5-ol (4.18 mmol) was added to the reaction mixture at 0°C. After completion of the addition, the reaction mixture was heated at 85°C for 24 hours. The reaction mixture was cooled to room temperature, quenched with saturated potassium carbonate solution (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification gave the title compound (2.31 mmol) as an off-white solid. UPLC-MS (ES + , short acidic): 1.99 min, m / z 286.8 [M+H] + .

[1113] 3-(4-Bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde

[1114] General Procedure N, after purification, 3-(4-bromophenyl)-5-chloro-1H-pyrazole-4-carbaldehyde (2.31 mmol), cesium carbonate (4.62 mmol) and bromocyclopentane (3.47 mmol) gave the title compound (1.35 mmol) as a white solid. UPLC-MS (ES + , short acidic): 2.49 min, m / z 354.9 [M+H] + .

[1115] 3-(4-Bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carboxylic acid

[1116] To a suspension of 3-(4-bromophenyl)-5-chloro-1-cyclopentyl-pyrazole-4-carbaldehyde (0.46 mmol) in water (5 mL) was added potassium permanganate (0.91 mmol) at RT. The reaction mixture was heated at 100° C. for 18 hours, then cooled to RT and stirred by The mixture was filtered and washed with water and EtOAc. The two lay...

Claims

1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof: in, R 1 Can be selected from: R 2 represents a group selected from the following: halogen, C 1-8 Alkyl, C 1-8 Haloalkyl or -NR C R D , where R C and R D is independently selected at each occurrence from: H or C 1-4 alkyl; R 3 represents -C(O)NH2 or -C(O)NHMe; R 4a and R 4b It is H; R 5 It is H; R 6 is methoxyphenyl or methoxyfluorophenyl; A is unsubstituted phenyl or substituted by one or two R 7 Substituted phenyl, optionally, wherein R 7 is selected from the group consisting of: fluoro, methyl, methoxy, and -CH2OH; and m is 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IXa, IXb, IXc or IXd:

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IXd:

4. A pharmaceutical composition, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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