Compounds that can be used 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 filed on December 16, 2016, with application number 201680073031.7 and entitled "A compound that can be used as a kinase inhibitor". Technical Field

[0002] This invention relates to compounds. More specifically, this invention relates to compounds that can be used as kinase inhibitors, methods for preparing the compounds, and uses of the compounds. Specifically, this invention relates to inhibitors of Bruton's tyrosine kinase (BTK). Background Technology

[0003] Kinases are a class of enzymes that control the transfer of phosphate groups from phosphate donor groups, such as ATP, to specific substrates. 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-associated Tec family of cytoplasmic tyrosine kinases. BTK plays a crucial role in the B-cell receptor (BCR) signaling pathway on B cells, which is essential for B-cell development, activation, and survival. Therefore, BTK inhibitors have been developed to treat B-cell malignancies dependent on BCR signaling, such as chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL) (Buggy 2012). BTK is also expressed in specific bone marrow cells, including monocytes / macrophages, neutrophils, and mast cells. In these bone marrow cells, BTK has been identified 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 essential for osteoclast maturation, so inhibiting BTK can prevent RA-related bone erosion. The crucial role of BTK in both B cells and bone marrow cells has made BTK an attractive target for treating 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 Waldenström macroglobulinemia (WM). Since ibrutinib was first disclosed, numerous patent applications have been filed concerning structures closely related to ibrutinib, such as WO 2012 / 158843, WO 2012 / 158764, WO 2011 / 153514, WO 2011 / 046964, US, US 2010 / 0144705, US 7718662, WO 2008 / 054827, and WO 2008 / 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, US2003 / 0225098, and WO 01 / 19829.

[0007] Ibrutinib also irreversibly binds to interleukin-2-inducible tyrosine kinase (ITK) (Dubovsky 2013). ITK plays a crucial 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 is believed to be activated by anti-CD20 antibodies such as rituximab, and ibrutinib has been shown to antagonize this mechanism in vitro (Kohrt 2014). Since rituximab combined with chemotherapy is currently the standard of care for B-cell malignancies, there is a desire for a BTK inhibitor with higher selectivity for BTK than ITK.

[0008] In clinical practice, adverse events include atrial fibrillation, diarrhea, rash, arthralgia, and bleeding (IMBRUVICA encapsulated insert 2014). Known BTK inhibitors, such as ibrutinib, are also thought to have gastrointestinal side effects, which are attributed to secondary EGFR inhibitory activity. Therefore, BTK inhibitors with high BTK inhibition and low EGFR inhibition are needed 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 ibrutinib treatment. Mutations in BTK such as C481S, C481Y, C481R, and C481F have been reported in the literature and have clearly interfered with drug binding (Woyach 2014; Maddocks 2015). It is predicted that the observed incidence of resistance will increase over time with clinical use outside of clinical trials (Zhang, 2015).

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

[0011] Furthermore, some embodiments of the present invention aim to provide novel cancer treatments. Specifically, some embodiments of the present invention aim to provide compounds with activity comparable to existing cancer treatments but also effective against mutations. One aspect of the present invention focuses on providing BTK inhibitors that are effective against C481 mutations.

[0012] The purpose of certain embodiments of the present invention is to provide compounds that exhibit reduced cytotoxicity compared to prior art compounds and existing therapies.

[0013] Another object of certain embodiments of the present invention is to provide compounds that have convenient pharmacokinetic characteristics and a suitable duration of action after administration. Another object of certain embodiments of the present invention is to provide compounds in which one or more metabolic fragments of the drug are GRAS (Generally Recognized As Safe) after absorption.

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

[0015] According to the present invention, compounds disclosed below are provided. Furthermore, 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 BTK-regulated conditions is provided. The present invention provides compounds for treating BTK-regulated conditions.

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

[0017]

[0018] in,

[0019] A represents a ring selected from the following unsubstituted or substituted rings: phenyl, pyridine, pyridazine, pyrimidine, or pyrazine, wherein when the substituted A is surrounded by 1 to 4 R... 7 When replacing;

[0020] R 1 It indicates that the group is selected from the following: C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 2-8 Alkyl ethers, -C(O)R A C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, and C-shaped groups 3-10 C substituted with carbocyclic group 1-8 Alkyl groups and C groups substituted with 3 to 10-membered heterocyclic groups 1-8Alkyl groups, wherein the aforementioned groups are unsubstituted or substituted by 1 to 5 independent substituents selected from the following: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -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 Replacement C 1-4 Alkyl and -OR A Replacement C 1-4 alkoxy, or R 1 Individual atoms are substituted twice to form 3- to 6-membered heterocyclic alkyl or cycloalkyl rings;

[0021] R 2 The group is selected from the following: -OH, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 3-10 cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocyclic groups, and -OR C Substituted alkyl groups, C 3-10 C substituted with carbocyclic group 1-8 Alkyl groups, alkyl groups substituted with 3 to 10-membered heterocyclic groups, and -NR C R D ;

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

[0023] R 4a and R 4b Each time it appears, it is independently selected from: H, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl and -OR H Replacement C 1-6 alkyl;

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

[0025] R 6 Selected from the following groups, substituted or unsubstituted: phenyl or 5- or 6-membered heteroaryl rings, wherein, when substituted, R 6 Contains 1 to 5 substituents, each substituent being independently selected from: halogens, -OR I -NR I R J -CN,C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR I Replacement C 1-6 alkyl;

[0026] R 7 Selected from: H, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and -OR H Replacement C 1-6 alkyl;

[0027] m is 1 or 2;

[0028] R A and R B Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, phenyl, benzyl or -OR H Replacement C 1-4 alkyl;

[0029] R C R D R E and R F Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group, unsubstituted C 3-10 C substituted with carbocyclic group 1-4 Alkyl group, with 1 or 2 R groups H or -OR H Replacement C 3-10 C substituted with carbocyclic group1-4 Alkyl groups, and 3 to 10-membered heterocyclic groups;

[0030] R G R I and R J Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and -OR H Replacement C 1-4 Alkyl groups; and

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

[0032] In one embodiment, A is an unsubstituted phenyl, an unsubstituted pyridine, or a compound with 1 to 4 R atoms. 7 Substituted phenyl groups or those with 1 to 4 R groups 7 Substituted pyridine.

[0033] Preferably, A is an unsubstituted phenyl, unsubstituted pyridine, unsubstituted pyridazine, unsubstituted pyrimidine, unsubstituted pyrazine, or is represented by one or two Rs. 7 Substituted phenyl groups.

[0034] In one embodiment, A is an unsubstituted phenyl group, an unsubstituted dihydropyridyl group, or a group with 1 to 4 R groups. 7 (Choose 1 or 2 Rs) 7 A is a substituted phenyl group. In one embodiment, A is an unsubstituted phenyl group or a phenyl group with 1 to 4 R atoms. 7 Substituted phenyl groups.

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

[0036]

[0037] These two groups can be para-substituted at A. In other words, these two groups can be 1,4-substituted at A.

[0038] In one implementation, A can be:

[0039]

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

[0041] Therefore, a compound according to formula (I) can 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 The 0, 1, or 2 in the N are independently selected, and the rest are CR. 7 .

[0044] In the implementation, A 1 A 2 A 4 and A 5 One of them is N (0 or 1), and the rest are A. 1 A 2 A 4 and A 5 0 or 1 is CR 7 The rest are CH.

[0045] In the implementation, A 1 A 4 and A 5 It is CH, A 2 It is CR 7 And R 7 Selected from fluorine, methyl, methoxy, or -CH2OH. In the embodiments, A 2 A 4 and A 5 It is CH, A 1 It is CR 7 And R 7 Selected from H, fluorine, methyl, methoxy, or -CH2OH. In the embodiments, A 1 A 4 and A 5 It is CH, A 2 It is N. In the implementation method, A 2 A 4 and A 5 It is CH, A 1 It is N. In the implementation method, A 1 and A 5 It is CH, A 2 and A 4 It is N. In the implementation method, A 1 and A 5 It is N, A 2 and A 4 It is CH. In the implementation method, A 1 and A4 It is CH, A 2 and A 5 It is N. In the implementation method, A 1 and A 2 It is CH, A 4 and A 5 It is N.

[0046] In the implementation, A 1 and A 5 It is CH, A 2 and A 4 It is CR 7 And R 7 Selected from fluorine, methyl, methoxy, or -CH2OH. In the embodiments, A 1 and A 2 It is CH, A 4 and A 5 It is CR 7 And R 7 Selected from fluorine, methyl, methoxy, or -CH2OH. In the embodiments, A 2 and A 4 It is CH, A 1 and A 5 It is CR 7 And R 7 Selected from fluorine, methyl, methoxy, or -CH2OH. In the embodiments, A 1 and A 4 It is CH, A 2 and A 5 It is CR 7 And R 7 Selected from fluorine, methyl, methoxy or -CH2OH.

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

[0048] In the implementation method, A can be selected from:

[0049]

[0050] In the implementation method, A can be selected from:

[0051]

[0052] In the implementation method, A can be selected from:

[0053]

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

[0055]

[0056] In the implementation, R 6 Selected from the following groups, whether substituted or unsubstituted: phenyl or a 6-membered heteroaryl ring. Preferably, R 6 Selected from the following substituted groups: phenyl or 6-membered heteroaryl rings substituted with 1 or 2 (preferably 1) methoxy (-OMe) groups.

[0057] In the implementation, R 6 The group is selected from the following groups, whether substituted or unsubstituted: phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl.

[0058] Preferably, R 6 The substituted group is selected from the following: phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, furanyl, thiopheneyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, wherein R 6 Contains 1, 2, or 3 substituents that, each time they appear, are independently selected from the following: halogen, -OR I -CN,C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR I Replacement 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 those skilled in the art will recognize, based on the description of the structural formula of the compounds of this invention, R 6 The remaining portion of the compound of the present invention is connected via a carbonyl group (-C(=O)-). When R 6 When substituted by 1, 2 or 3 substituents, R 6 Carbonyl group (R) 6The substituent is attached to the remainder of the compound and substituted with one, two, or three additional substituents. In a preferred embodiment, one of the substituents is substituted 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... 6 The substituent of the 1, 2, or 3 substituents is methoxy.

[0060] In the implementation, R 6 It may be substituted or unsubstituted: phenyl or pyridyl (preferably substituted). In a particularly preferred embodiment, R 6 It is a substituted phenyl group.

[0061] Preferably, R 6 Contains one, two, or three substituents, each time independently selected from the following: fluorine, chlorine, methoxy, ethoxy, isopropoxy, -CN, methyl, ethyl, trifluoromethyl, trifluoroethyl, or -OCF3. In embodiments, R 6 It contains one or two substituents, each selected independently from the following: fluorine, methoxy, or methyl, when each occurrence. Preferably, R 6 It contains one methoxy substituent or two substituents: fluorine and methoxy.

[0062] R 6 A particularly preferred substituent is a methoxy group. Therefore, in a preferred embodiment, R... 6 The group is selected from the following methoxy-substituted groups: phenyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, furanyl, thiopheneyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl. Optionally, R 6 The following groups are selected from those substituted with methoxy groups: phenyl, pyridinyl, pyrazinyl, pyrazinyl, or pyrimidinyl.

[0063] R 6 Particularly preferred substituents are methoxy and fluorine. Therefore, in a preferred embodiment, R... 6 The following groups are selected from those substituted with fluorine and methoxy groups: phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrroleyl, pyrazolyl, imidazolyl, furanyl, thiopheneyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl. Optionally, R 6 The following groups are selected from those substituted with fluorine and methoxy: phenyl, pyridinyl, pyrazinyl, pyrazinyl or pyrimidinyl.

[0064] R 6 It can be methoxyphenyl or fluoromethoxyphenyl. R 6 It can be methoxyphenyl. As those skilled in the art will recognize, R 6The remaining portion of the compound of the present invention is connected via a carbonyl group (-C(=O)-). When R 6 When it is methoxyphenyl, R 6 The phenyl group is replaced by a carbonyl group (which connects the benzene ring to the rest of the compound) and a methoxy group. In this compound, R... 6 In a preferred embodiment of the methoxyphenyl group, the methoxy group is substituted adjacent to -C(=O)-. In other words, the methoxy group is substituted at the ortho position of the carbonyl group (-C(=O)-). Therefore, in one embodiment, the compound according to formula (I) is a compound of formulas (IIIa) and (IIIb):

[0065]

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

[0067] R 6 It can be fluoromethoxyphenyl. As those skilled in the art will recognize, R 6 The remaining portion of the compound of the present invention is connected via a carbonyl group (-C(=O)-). When R 6 When it is fluoromethoxyphenyl, R 6 The phenyl group is substituted with a carbonyl group (which connects the benzene ring to the rest of the compound), a fluorine group, and a methoxy group. In this compound, R... 6 In a preferred embodiment of the fluoromethoxyphenyl group, the methoxy group is substituted adjacent to -C(=O)- and the fluorine group is substituted opposite to the methoxy group. In other words, the methoxy group is substituted at the ortho position of the carbonyl group (-C(=O)-), and the fluorine group is attached at the para position of the methoxy group. Therefore, in one embodiment, the compound according to formula (I) is a compound of formulas (IIIc) and (IIId):

[0068]

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

[0070] In the implementation, 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 is H.

[0072] R 4a and R 4b Each time it appears, it can be independently selected from: H, C 1-6 Alkyl, C 3-6cycloalkyl and -OR H Replacement C 1-6 Alkyl group. Optionally, R 4a and R 4b It can be independently selected from: H, methyl, ethyl, cyclopropyl, or -CH2OH each time it appears. Optionally, R 4a It is H, R 4b It can be selected from: H, methyl, ethyl, cyclopropyl, or -CH2OH. Optionally, R 4a It is H, R 4b Selected from: H, methyl, or -CH2OH. Preferably, R 4a It is H, R 4b It is H.

[0073] In the implementation, m is 1.

[0074] In the implementation, m is 1, R 4a and R 4b It is H. In the implementation, m is 1, R 4a and R 4b It is H, R 5 It is H. In the implementation, m is 1, R 4a and R 4b It is H, R 5 It is H, R 6 It is fluoromethoxyphenyl or methoxyphenyl. In the embodiments, m is 1, R 4a and R 4b It is H, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl groups. In the embodiments, m is 1, R 4a and R 4b It is H, R 5 It is H, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl groups. In the embodiments, m is 1, R 4a and R 4b It is H, R 5 It is H, R 6 It is a fluoromethoxyphenyl or methoxyphenyl, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl group. R 7 It can be selected from: fluorine, methyl, methoxy and -CH2OH.

[0075] In the implementation, m is 1, R 4a and R 4b It is H. In the implementation, m is 1, R 4a and R 4b It is H, R 5 It is H. In the implementation, m is 1, R 4a and R4b It is H, R 5 It is H, R 6 It is a methoxyphenyl. In the embodiments, m is 1, R is... 4a and R 4b It is H, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl groups. In the embodiments, m is 1, R 4a and R 4b It is H, R 5 It is H, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl groups. In the embodiments, m is 1, R 4a and R 4b It's H, R 5 It is H, R 6 It is a methoxyphenyl, and A is an unsubstituted phenyl or is converted by an R. 7 Substituted phenyl group. R 7 It can be selected from: fluorine, methyl, methoxy and -CH2OH.

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

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

[0078]

[0079] In the implementation, R 2 Indicates a group selected from the following: halogen, C 1-8 Alkyl, C 1-8 Halogenated alkyl groups and -NR C R D Preferably, R 2 This represents Cl, CHF2, CF3, NH2, NHPh, NHMe, NHEt, and NH. i- Pr.

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

[0081]

[0082] Alternatively or additionally, in embodiments, 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 implementation, R C and R D Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (C optional) 3-6 Carbocyclic or phenyl), 3 to 10-membered heterocyclic groups (optionally 3 to 6-membered heterocyclic groups). Preferably, R C and R D Independently selected from: H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl. For example, R C It's H, R D Selected from: H, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl and sec-butyl.

[0085] In one implementation, R C and R D Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (C optional) 3-6 Carbocyclic groups), 3 to 10-membered heterocyclic groups (optionally 3 to 6-membered heterocyclic groups). Preferably, R C and R D Independently selected from: H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl. In a particularly preferred embodiment, R C and R D It is H.

[0086] In the implementation, R E and R F Each time it appears, it is independently selected from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, unsubstituted C 3-10 Carbocyclic group (C optional) 3-6 Carbocyclic groups), 3 to 10-membered heterocyclic groups (optionally 3 to 6-membered heterocyclic groups). In the embodiments, R E and R F Each time it appears, it is independently selected from: H, C 1-4 Alkyl (preferably R) E and R FEach time it appears, it is independently selected from: H, methyl, and ethyl). In the embodiment, R E and R F It's H.

[0087] In the implementation, R C R D R E and R F It is H.

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

[0089]

[0090] R 2 The group is selected from the following: -OH, halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 3-10 cycloalkyl, C 6-10 Aryl, 3- to 10-membered heterocyclic groups, and -OR C Replacement C 1-8 Alkyl, C 3-10 C substituted with carbocyclic group 1-8 Alkyl groups, C-membered groups substituted with 3 to 10-membered heterocyclic groups 1-8 Alkyl and -NR C R D .

[0091] In the implementation, R 2 Indicates a group selected from the following: halogen, C 1-8 Alkyl or -NR C R D , where R C and R D Each time it appears, it is independently selected from: H or C. 1-4 alkyl.

[0092] In some implementations, R 2 The group is selected from the following: fluorine, methyl, ethyl, cyclopropyl, trifluoromethyl, difluoromethyl, morpholino, -CH2OH, and -NR. C R D , where R C and R D Each time it appears, it is independently selected from: H, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, and sec-butyl.

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

[0094] In the implementation, R 3 Represents -C(O)NR E R F , by -OR G Replacement C 1-6 Alkyl, or C 1-6 Haloalkyl, optionally, wherein R E and R F Each time it appears, it is independently selected from: H or C. 1-4 Alkyl (preferably R) E and R F Each time it appears, it is independently selected from: H, methyl, and ethyl, R G Selected from: H or C 1-4 alkyl).

[0095] In the implementation, R E and R F One is H and the other is chosen from.

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

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

[0098] In the implementation, R 2 Is it NH2 or Me, R? 3 It is -C(O)NH2. In a particularly preferred embodiment, R 2 It is NH2, R 3 It is -C(O)NH2.

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

[0100] R 1 It indicates that the group is selected from the following: C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkyl ethers, -C(O)R A C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, and C-shaped groups 3-10 C substituted with carbocyclic group 1-8 Alkyl groups and C groups substituted with 3 to 10-membered heterocyclic groups 1-8 Alkyl groups, wherein the aforementioned 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 ethers, -OR A -CN, =O, -C(O)OR A -C(O)NR A R B 3 to 6-membered heterocyclic alkyl rings, -OR A OR A Replacement C 1-4 Alkoxy; wherein, R A and R B Selected independently from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, benzyl, or -OR H Replacement C 1-4 alkyl.

[0101] R 1 It indicates that the group is selected from the following: C 1-8 Alkyl, C 1-8 Haloalkyl, C 2-8 Alkyl ethers, -C(O)R A C 3-10 Carbocyclic groups, 3- to 10-membered heterocyclic groups, and C-shaped groups 3-10 C substituted with carbocyclic group 1-8 Alkyl groups and C groups substituted with 3 to 10-membered heterocyclic groups 1-8 Alkyl groups, wherein the aforementioned groups are unsubstituted or substituted by 1 to 5 substituents selected from the following: halogen, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -OR A -CN, =O, -C(O)OR A OR A Replacement C 1-4 Alkyl, -OR A Replacement C 1-4 Alkoxy; wherein, R A Selected from: H, C 1-4 Alkyl, C 1-4 Halogenated alkyl, benzyl or -OR H Replacement C 1-4 alkyl.

[0102] R 1 It indicates that the group is selected from the following: C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkyl ethers, -C(O)R A C 3-10 cycloalkyl (preferably C) 3-6 cycloalkyl), C 6-10 Aryl (preferably phenyl or indane), 3 to 10-membered heterocyclic alkyl (optionally 3 to 6-membered), 3 to 10-membered heteroaryl (optionally 3 to 6-membered, e.g., 5 or 6-membered), 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 groups, C groups substituted with 3 to 10-membered heterocyclic alkyl groups (optionally 3 to 6-membered). 1-6 Alkyl groups and C groups substituted with 3 to 10 heteroaryl groups (optionally 3 to 6, e.g., 5 or 6). 1-6 Alkyl groups, 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 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -OR A -CN, =O, -C(O)OR A -C(O)NR A R B 3 to 6-membered heterocyclic alkyl rings, with -OR A Replacement C 1-4 Alkyl, -OR A Replacement C 1-4 alkoxy, wherein R A Selected from: H, C1-4 Alkyl, C 1-4 Halogenated alkyl, benzyl or -OR H Replacement C 1-4 alkyl.

[0103] In the implementation, R 1 Selected 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, pyridinyl, thiazolyl, C substituted with oxetane 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with morpholine 1-8 Alkyl groups (preferably methyl or ethyl), C substituted with tetrazolium 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with piperidine 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with cyclohexyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with cyclopentyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with tetrahydropyranyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with pyrrolidinyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with pyridyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with phenyl groups 1-8 Alkyl groups (preferably methyl or ethyl), C substituted with tetrahydrofuran 1-8 Alkyl groups (preferably methyl or ethyl) and C groups substituted with cyclopropyl groups 1-8 Alkyl (preferably methyl or ethyl).

[0104] In the implementation, 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 with oxetane 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with morpholine 1-8 Alkyl groups (preferably methyl or ethyl), C substituted with tetrazolium 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with piperidine 1-8 Alkyl groups (preferably methyl or ethyl) and C groups substituted with cyclohexyl groups 1-8 Alkyl (preferably methyl or ethyl).

[0105] Preferably, R1 Substituted by 1 to 5 substituents selected from the following (optionally 1 to 4): halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -OR A -CN, =(O)OR A -C(O)NR A R B 5 or 6-membered heteroaryl, 3 to 6-membered heterocyclic alkyl ring, -OR A Replacement C 1-4 Alkyl, -OR A Replacement C 1-4 alkoxy, or R 1 Individual atoms are substituted twice to form 3 to 6-membered heterocyclic alkyl or cycloalkyl rings.

[0106] In the implementation, R 1 Substituted by 1 to 4 substituents selected from the following: -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, oxetyl, tetrahydropyranyl or tetrahydrofuranyl, or R 1 A single atom is substituted twice to form ethylene oxide or oxobutane.

[0107] Optional, R 1 Substituted by 1 to 5 substituents selected from the following (optionally 1 to 3): halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ethers, -OR A -CN, =O, -C(O)OR A 、 By - OR A Replacement C 1-4 Alkyl, -OR A Replacement C 1-4 Alkyl group. In the embodiments, R 1 It is substituted by 1 to 3 substituents selected from the following: -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn or -CO2Et.

[0108] In the implementation, R 1Selected 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 with oxetane 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with morpholine 1-8 Alkyl groups (preferably methyl or ethyl), C substituted with tetrazolium 1-8 Alkyl groups (preferably methyl or ethyl), C groups substituted with piperidine 1-8 Alkyl groups (preferably methyl or ethyl) and C groups substituted with cyclohexyl groups 1-8 Alkyl (preferably methyl or ethyl), wherein R 1 It is substituted by 1 to 5 substituents selected from the following: -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn or -CO2Et.

[0109] In the implementation, R 1 Selected from substituted or unsubstituted: methyl, ethyl, isopropyl, tert-hexyl, tert-butyl, trifluoroethyl, wherein R 1 It is substituted by 1 to 5 substituents selected from the following: -OH, =O, -OMe, -CN, methyl, CF3, Cl, F, -OBn or -CO2Et.

[0110] R 1 You can choose from:

[0111]

[0112]

[0113]

[0114] R 1 You can choose from:

[0115]

[0116]

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

[0118] In some implementations, R1 Selected from substituted or unsubstituted: C 3-6 cycloalkyl or phenyl, wherein, when the substituted R 1 When substituted by 1 to 5 substituents selected from the following: halogens, 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 Selected from substituted or unsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl, bicyclo[3.1.0]hexyl, piperidinyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl)ethyl, or (tetrahydropyranyl)ethyl. Therefore, R 1 You can choose from:

[0120]

[0121] In a preferred embodiment, R 1 Selected from substituted or unsubstituted: cyclohexyl, phenyl, cyclobutyl, cyclopentyl, or bicyclo[3.1.0]hexyl. Preferably, R 1 You can choose from:

[0122]

[0123] In a preferred embodiment, R 1 Selected from substituted or unsubstituted: piperidinyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl)ethyl, or (tetrahydropyranyl)ethyl. Therefore, R 1 You can choose from:

[0124]

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

[0126]

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

[0128]

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

[0130]

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

[0132]

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

[0134]

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

[0136]

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

[0138]

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

[0140]

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

[0142] In a particularly preferred embodiment of the invention, R 1 yes Therefore, a compound according to formula (I) can 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 C1-4 Alkyl, C 1-4 Haloalkyl, C substituted with OH 1-4 Alkyl groups, C substituted with OMe 1-4 Alkyl, 5- or 6-membered heteroaryl, 3- to 6-membered heterocyclic alkyl ring, phenyl or C 3-10 Carbocyclic group (e.g., 3- to 10-membered cycloalkyl ring). The condition is that R... 1A It is C 1-2 When alkyl, then R 1B Not unreplaced C 1-4 alkyl.

[0145] Preferably, R 1A Selected from methyl, difluoromethyl, or trifluoromethyl, R 1B Selected from methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH2OH, -CH2CH2OH, -CH2OMe, pyrrolyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the condition is that R 1A When it is not methyl, then R 1B Not methyl, ethyl, or propyl. In the embodiments, R 1A It is trifluoromethyl.

[0146] Preferred R 1A Selected from methyl or trifluoromethyl, R 1B Selected from methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, trifluoroethyl, -CH2OH, -CH2OMe, pyrrolyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl, phenyl, cyclobutyl, cyclopentyl, or cyclohexyl; the condition is that R 1A When it is not methyl, then R 1B Not methyl, ethyl, or propyl. In the embodiments, R 1A It is trifluoromethyl.

[0147] The compounds according to formula (I) can be compounds of formula (II) or their pharmaceutically acceptable salts:

[0148]

[0149] Where A 1 A 2 A 4 and A 5 The 0, 1, or 2 in the N are independently selected, and the rest are CR. 7 .

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

[0151]

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

[0153]

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

[0155]

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

[0157]

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

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

[0160]

[0161] In the embodiments of compounds of formulas (XVIa), (XVIb), (XVIc), and (XVId), A 1 A 2 A 4 and A 5 It's CH, or A. 1 A 4 and A 5 It is CH, A2 It's CH, or A. 2 A 4 and A 5 It is CH, A 1 It's CF.

[0162] In embodiments of compounds of formulas (XVIa), (XVIb), (XVIc), and (XVId), R 2 Indicates -NR C R D R 3 Represents -C(O)NR E R F Optionally, R C and R D It is H, R E and R F It is H.

[0163] The compound represented by formula (X) (i.e., where R) 1 For -CHR 1A R 1B The types of 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 compounds according to formula (I) can be selected from the following:

[0183]

[0184] Compounds according to formula (I) can also be selected from:

[0185]

[0186]

[0187]

[0188]

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

[0190] The compounds of formula (I) can be selected from the following:

[0191]

[0192]

[0193]

[0194] Any compounds described in the examples also constitute a part of this invention. This includes compounds falling within the scope of formula (I) and any and all novel intermediates synthesized from compounds of formula (I) on the other hand.

[0195] The less preferred compounds of formula (I) are given below. In some embodiments, the compounds shown below are not part of this invention.

[0196]

[0197] In another aspect of the invention, the use of compounds of any form disclosed herein as pharmaceuticals is provided.

[0198] On the other hand, compounds of any kind disclosed herein are used to treat conditions regulated by Bruton's tyrosine kinase (BTK). Conditions regulated by BTK are generally those that can be treated by inhibiting BTK using the compounds of this invention. Compounds of any kind 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 a wide range of human diseases associated with inappropriate activation of B cells, including B-cell proliferative disorders, B-cell malignancies, immune disorders such as autoimmune diseases, xenoimmune diseases, and inflammatory conditions or fibrosis. In particular, BTK inhibition is a novel approach for treating a wide range of human diseases associated with inappropriate activation of B cells, including B-cell malignancies, immune disorders such as autoimmune diseases, and inflammatory conditions.

[0200] In the implementation, the conditions that can be treated by inhibiting BTK can be selected from: cancer, lymphoma, leukemia, autoimmune diseases, inflammatory diseases, xenoimmune diseases, or fibrosis. Specific conditions that can be treated by inhibiting BTK include: 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, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, follicular lymphoma, chronic lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasmacytoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodular marginal zone B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, and primary exudative lymphoma. Burkitt lymphoma / leukemia, lymphomatoid granulomatosis, inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Od's syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpassu's syndrome, multiple sclerosis, multiple sclerosis, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Goyan's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis Generalized alopecia, Bechtel's disease, chronic fatigue, autonomic nervous system disorders, endometriosis, interstitial cystitis, scleroderma, vulvar pain, graft-versus-host disease, transplantation, blood transfusion, allergies, hypersensitivity reactions, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, atopic dermatitis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis. Enterocolitis, epididymitis, 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), common interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrotic alveolitis (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver, steatosis (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, bile fibrosis, cholestasis, or bile duct lesions.In some embodiments, liver fibrosis or liver fibrosis includes, but is not limited to, liver fibrosis associated with alcohol poisoning, viral infections such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, drugs, and environmental toxins), kidney fibrosis (e.g., chronic kidney fibrosis), kidney diseases 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 in humans (CKD), chronic progressive kidney disease (CPN), and tubulointerstitial fibrosis. Ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy, HIV-related 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 lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphomas, follicular lymphomas, hairy cell leukemia, B-cell non-Hodgkin lymphomas, Waldenström macroglobulinemia, multiple myeloma, bone cancer, bone metastases, chronic lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / splenic marginal zone lymphoma, plasmacytic myeloma, plasmacytoma, extranodal marginal zone B-cell lymphoma, cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, Burkitt lymphoma / leukemia, and lymphomatoid granulomatosis are examples of cancers, lymphomas, and leukemias that are treatable through BTK inhibition.

[0202] Examples of B-cell malignancies, B-cell lymphomas, diffuse large B-cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas such as ABC-DLBCL, mantle cell lymphomas, follicular lymphomas, hairy cell leukemia, B-cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, multiple myeloma, bone cancer, and bone metastases that are treatable cancers, lymphomas, and leukemias through 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, Auder's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpassuia syndrome, idiopathic thrombocytopenic purpura, optic neuritis. Scleroderma, primary biliary cirrhosis, Reiter's syndrome, Goran's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia areata, Bechtel's disease, chronic fatigue, autonomic nervous system disorders, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma and vulvar pain, asthma, appendicitis, 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 bowel disease, suppurative inflammation. Examples of immune diseases treatable through BTK inhibition include laryngitis, mastitis, meningitis, myelitis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pulmonary disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, vulvitis, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, hypersensitivity reactions, type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0204] Arthritis, asthma, appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis. Examples of inflammatory conditions that can be treated with BTK inhibition include encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, pulmonary disease, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

[0205] Examples of autoimmune diseases that can be treated with BTK inhibition include lupus and Sjögren's syndrome, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Auder's thyroiditis, Graves' disease, Sjögren's syndrome, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, oculoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpassuia syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Lightell's syndrome, Goyan's arteritis, temporal arteritis, hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia areata, Behcet's disease, chronic fatigue, autonomic dysfunction, endometriosis, interstitial cystitis, neurogenic myotonia, scleroderma, and vulvar pain.

[0206] Examples of xenoimmune diseases that are treatable through BTK inhibition include graft-versus-host disease, transplantation, blood transfusion, allergy, hypersensitivity, type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0207] Pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), common interstitial pneumonia (UIP), interstitial lung disease, cryptogenic fibrotic alveolitis (CFA), obliterative bronchiolitis, bronchiectasis, fatty liver disease, steatosis (e.g., non-alcoholic steatohepatitis (NASH)), cholestatic liver disease (e.g., primary biliary cirrhosis (PBC)), cirrhosis, alcohol-induced liver fibrosis, bile duct injury, biliary fibrosis, cholestasis, or bile duct lesions. In some embodiments, liver fibrosis or liver fibrosis includes, but is not limited to, liver fibrosis associated with alcohol poisoning, viral infections such as hepatitis (e.g., hepatitis C, hepatitis B, or hepatitis 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), nephropathy 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, renal fibrosis (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephritis (PGN), endothelial / thrombotic microangiopathy, HIV-related 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 preterm birth and neovascular glaucoma; and instances of fibrosis that can be treated by BTK inhibition.

[0208] Examples of immune diseases that can be treated with BTK inhibition include arthritis, multiple sclerosis, osteoporosis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, and lupus. Arthritis is an example of an inflammatory disease that can be treated with BTK inhibition. Lupus and Sjögren's syndrome are examples of autoimmune diseases that can be treated with BTK inhibition.

[0209] Any of the conditions that can be treated by BTK inhibition as disclosed above can be treated by the compounds of the present invention, or by a method including the administration of the compounds of the present invention, or by a drug manufactured using the compounds of the present invention.

[0210] In embodiments, the compounds of the present invention can be used to treat: cancer, lymphoma, leukemia, immune diseases, autoimmune diseases, and inflammatory conditions. The compounds of the present invention can be used to treat specific conditions selected from the following: 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, Waldenström 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. The compounds can also be used to treat conditions related to kidney transplantation.

[0211] In one embodiment, the compounds of the present invention can be used to treat specific conditions selected from the following: for example, 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, Waldenström macroglobulinemia, multiple myeloma, lupus, and arthritis.

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

[0213] Treatment methods can include those that treat conditions by inhibiting Bruton's tyrosine kinase.

[0214] The present invention also provides methods for treating conditions selected from the group consisting of cancer, lymphoma, leukemia, immune diseases, autoimmune diseases, and inflammatory diseases, wherein the methods comprise administering a therapeutic amount of the compound of the present invention to a patient in need. The present invention also provides methods for treating specific conditions 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, Waldenström 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 methods comprise administering a therapeutic amount of the compound of any form disclosed herein to a patient in need. The method can also treat conditions related to kidney transplantation.

[0215] In one embodiment, the method can be used to treat specific conditions selected from the following: 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, Waldenström macroglobulinemia, multiple myeloma, arthritis, and lupus.

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

[0217] In one embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. This additional pharmaceutically active agent may be an antitumor agent as described below. Detailed Implementation

[0218] The following are definitions of the terms used in this application. Any terms not defined herein shall have their normal meaning as would be understood by one of skill in the art.

[0219] The term "halogenated" refers to one of the halogens in Group 17 of the periodic table. Specifically, 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-chain or branched hydrocarbon chain. For example, the term "C"... 1-8 Alkyl or C 1-6 "Alkyl" refers to a straight-chain 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, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Alkylenes can also be straight-chain or branched and can have two positions attached to the rest of the molecule. Furthermore, an alkylene can correspond, for example, to one of the alkyl groups listed in this section. Alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for alkyl groups can be halogens, such as fluorine, chlorine, bromine and iodine, OH, =O, or C. 1-6 Alkyl group.

[0221] The term "alkoxy" refers to an alkyl group linked to a molecule by an oxygen atom. This includes the fact that the alkyl moiety can be straight-chain or branched. For example, the term "C 1-6An alkoxy group is defined as an alkyl group linked to a molecule by an oxygen atom, 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. Therefore, an alkoxy group can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and n-hexoxy. The alkyl portion of an alkoxy group can be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents on the alkyl group can be halogens such as fluorine, chlorine, bromine, and iodine, OH, C. 1-6 Alkyl group.

[0222] The term "alkyl ether" refers to a straight-chain 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 in the chain, such as -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OCH2CH3, -CH2O(CH2)2CH3 or -(CH2)2O(CH2)2CH3.

[0223] The term "halogenated alkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, chosen independently each time it appears, such as fluorine, chlorine, bromine, and iodine. The halogen atom can be present at any position on the hydrocarbon chain. For example, "C 1-6 "Halogenated alkyl" refers to a hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms that are substituted with at least one halogen atom, such as chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, and trifluoropropyl.

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

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

[0226] The term "heteroalkyl" refers to a branched or straight-chain 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. For example, the term "C 1-6 "Heteroalkyl" refers to a branched or straight-chain 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 atoms in the chain or at the end of the chain. For example, a hydrocarbon chain may contain one or two heteroatoms. C 1-6 Heteroalkyl groups can be bonded to the rest of the molecule via carbon or heteroatoms. For example, "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 "carbocyclic" refers to a saturated or unsaturated carbon-containing ring system. A "carbocyclic" system can be a monocyclic or fused polycyclic system, such as a bicyclic or tricyclic system. The "carbocyclic" 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. "Carbocyclic" systems include cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems, and fused ring systems that include 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, such as a bicyclic or tricyclic system. The "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. "Heterocycle" encompasses heterocyclic alkyl moieties, heterocyclic alkenyl moieties, and heteroaromatic moieties. For example, the heterocyclic group can be ethylene oxide, aziridine, aziridine butane, oxaziridine butane, tetrahydrofuran, pyrrolidine, imidazoline, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

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

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

[0231] The term "heterocyclic alkyl" refers to a saturated hydrocarbon ring system having at least one heteroatom selected from N, O, and S within the ring. "Heterocyclic alkyl" can be represented as "C 3-10 Heterocyclic alkyl groups. "C" 3-10 "Heterocyclic alkyl" 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, it can have 1, 2, or 3 heteroatoms, optionally 1 or 2. The "heterocyclic alkyl" group can also be expressed as "3- to 10-membered heterocyclic alkyl," which is also a ring system containing 3, 4, 5, 6, 7, 8, 9, or 10 atoms. At least one of them is a heteroatom. The ring system can be monocyclic, bicyclic, or tricyclic. When the ring system is bicyclic, one of the rings can be an aromatic ring, such as in indane. A "heterocyclic alkyl" can be bonded to the rest of the molecule by any carbon atom or heteroatom. A "heterocyclic alkyl" can have one or more, for example, one or two, bonds to the rest of the molecule: these bonds can be any atom in the ring. For example, a "heterocyclic alkyl" can be ethylene oxide, aziridine, aziridine butane, oxaziridine butane, tetrahydrofuran, pyrrolidine, imidazoline, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazoline, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, tetrahydropyran, and indane.

[0232] The term "heterocyclic alkenyl" refers to a non-aromatic unsaturated hydrocarbon ring system having at least one heteroatom selected from N, O, and S within the ring. "Heterocyclic alkenyl" can be represented as "C 3-10 Heterocyclic alkenyl groups. "C" 3-10A "heterocyclic alkenyl" 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. "Heterocyclic alkenyl" can also be expressed as "3- to 10-membered heterocyclic alkenyl," 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 monocyclic, bicyclic, or tricyclic. When the ring system is bicyclic, one ring can be an aromatic ring, such as in dihydroindole and dihydrobenzofuran. A "heterocyclic alkenyl" can be bonded to the rest of the molecule by any carbon atom or heteroatom. A "heterocyclic alkenyl" can have one or more, for example, one or two, bonds to the rest of the molecule: these bonds can be made by any atom in the ring. For example, "C 3-8 "Heterocyclic alkenyl" can be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene, and dihydroindole.

[0233] When applied as a whole to substituents, the term "aromatic" refers to a monocyclic or polycyclic system with 4n+2 electrons in a conjugated π system within a 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 lie in the same plane. The ring system can be monocyclic, bicyclic, or tricyclic. For example, "aryl" can refer to phenyl and naphthyl groups. The aryl system itself 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 within a monocyclic or fused-ring system. This ring or system has 4n+2 electrons in a conjugated π system, 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, "heteroaryl" can be imidazole, thiophene, furan, thiathrone, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0236] The term "alkylaryl" refers to an alkyl group that reacts with C10 to form an alkyl group. 1-4 Alkyl-bonded aryl groups as defined above, wherein C 1-4 Alkyl groups provide the connection to the rest of the molecule.

[0237] The term "alkylaryl" refers to an alkyl group that is related to C. 1-4 Alkyl-bonded heteroaryl groups as defined above, wherein the alkyl group provides the connection to the rest of the molecule.

[0238] The term "halogen" in this document includes those indicating F, Cl, Br, and I. A halogen can be Cl. A halogen can be F.

[0239] by A bond at the end indicates that it is connected to another atom not shown in the structure. A bond that terminates within a ring structure but not at a ring atom indicates that it can be connected to any atom in the ring structure where the valence state allows.

[0240] When a portion is substituted, it can be substituted at any point on the portion, provided that it is chemically possible and meets the atomic valence requirements. The portion can be substituted by one or more substituents, for example, 1, 2, 3, or 4 substituents; optionally, there may be 1 or 2 substituents on the group. When there are two or more substituents, the substituents can be the same or different. Substituents can be selected from: OH, NHR 9 Amino, guanidinyl, hydroxyguanidinyl, formamidinyl, isothiourea, urea, mercapto, C(O)H, acyl, acyloxy, carboxyl, sulfonyl, aminosulfonyl, 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 Alkynyl, aryl, heteroaryl, or alkylaryl. When the group to be substituted is alkyl, the substituent can be =O. When a portion is substituted by two or more substituents and the two substituents are adjacent, the adjacent substituents can form a C10 with the atoms of the substituted portions. 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 can be substituted on the group to form a spirocycle.

[0242] Substituents exist only in their chemically possible positions, and those skilled in the art can determine, without undue effort (experimentally or theoretically), which substitutions are chemically feasible and which are not.

[0243] Ortho, meta, and para substitution are well-understood terms in this art. For the sake of clarity, "ortho" substitution is a substitution pattern in which adjacent carbons have substituents, whether simple groups, such as the fluorine group in the examples below, or other parts of the molecule, such as those composed of... The key at the end indicates this.

[0244]

[0245] Meta-substitution is a substitution pattern in which two substituents are placed on carbon atoms separated from each other by one carbon atom, meaning there is a single carbon atom between the substituted carbon atoms. In other words, there is a substituent on the second atom of the atom containing the other substituent. For example, the following groups are meta-substituted.

[0246]

[0247] "Para" substitution is a substitution pattern in which two substituents are placed on carbons two carbons apart, meaning there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom of the atom containing the other substituent. For example, the following groups are para-substituted.

[0248]

[0249] "Acyl" refers to an organic free radical derived from an organic acid, for example, by removing a hydroxyl group, such as a free 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 group. 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. The specific acyl group is acetyl.

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

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

[0252] This invention contemplates pharmaceutically acceptable salts of compounds of formula (I). These may include acid addition salts and base salts of the compounds. Furthermore, this invention contemplates solvates of these 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 acetates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, phenacetinates, hydrochlorides / chlorides, hydrobromates / bromines, hydroiodates / iodides, hydroxyethanesulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthates, 1,5-naphthalenedisulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, glycosides, stearates, succinates, tartrates, toluenesulfonates, and trifluoroacetates.

[0254] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzylamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, aminobutanetriol, and zinc salts. Hemisalts that form both acids and bases can also be formed, such as hemisulfates and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (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 the compound of formula (I) with the desired acid or base;

[0257] (ii) by removing the acid- or base-instable protecting group from a suitable precursor of a compound of formula (I), or by using the desired acid or base to open a suitable cyclic precursor (e.g., a lactone or lactam); or

[0258] (iii) By converting one salt of a compound of formula (I) into another, which is carried out by reacting with a suitable acid or base or by means of a suitable ion exchange column.

[0259] All three reactions typically take place in solution. The resulting salt can precipitate and be 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 unionized.

[0260] The compounds of this invention can exist in both non-solventized and solvated forms. The term "solvent" is used herein to describe a molecular complex comprising a compound of this 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] Complexes such as cage-like structures and drug-body inclusion complexes are included within the scope of this invention, wherein, unlike the solvates described above, the drug and the body 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's JPharm Sci, 64(8), 1269-1288 (August 1975).

[0262] In the following text, all references to compounds of any kind include those relating to their salts, solvates, and complexes, and those relating to the solvates and complexes of their salts.

[0263] The compounds of the present invention include compounds of the plurality of formulas defined herein, including all their polymorphs and crystal habits as defined below, their prodrugs and isomers (including optical, geometric and tautomers), and the 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 isolated using conventional techniques known in the art. Therefore, the present invention covers individual enantiomers and mixtures thereof.

[0265] For some steps in the method for preparing compounds of formula (I), it may be necessary to protect potentially reactive functional groups that are not desired to react, and subsequently cleave the protecting group. In this case, any compatible protecting radical can be used. In particular, methods of protection and deprotection, such as those described by TWGREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or PJ Kocienski (Protecting Groups, Georg Thieme Verlag, 1994), can be used. The preparation of novel starting materials used in all the above reactions and methods is conventional, and the reagents and reaction conditions suitable for their performance or preparation, as well as the methods for isolating the desired products, are well known to those skilled in the art in the precedents mentioned in the references and in the examples and preparations therein.

[0266] Furthermore, 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] Treatment methods or compounds used to treat cancers, lymphomas, leukemias, or immune diseases as defined above can be used as a standalone therapy or in combination with other active agents.

[0268] Treatment methods or compounds used to treat cancer, lymphoma, or leukemia may involve conventional surgery, radiotherapy, or chemotherapy in addition to the compounds of this invention. Such chemotherapy may include one or more antitumor agents from the following classes:

[0269] (i) Antiproliferative / antitumor drugs and combinations thereof (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustine, melphalan, chlorambucil, phenobarbital, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolate agents, such as fluoropyrimidines like fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytarabine, and hydroxyurea); antibiotics (e.g., anthracyclines like doxorubicin, bleomycin, doxorubicin, doxorubicin, epirubicin, idarubicin, mitomycin-C, actinomycin, and scintillans); antimitotic agents (e.g., vinca alkaloids like vincristine, vinblastine, vinorelbine, and vinorelbine, and taxanes like paclitaxel and doxorubicin, and boroxetine kinase inhibitors); Proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (such as epipodophyllotoxins like etoposide and teniposide, acridine, topotecan, mitoxantrone, and camptothecin);

[0270] (ii) Errors in translation: cell growth inhibitors such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodixafen), anti-androgens (e.g., bicalutamide, flutamide, nilumid, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, voroxazole, and exemestane), and 5α-reductase inhibitors such as finasteride;

[0271] (iii) Anti-invasive agents, such as dasatinib and posutinib (SKI-606), and metalloproteinase inhibitors, urokinase plasminogen activator receptor function inhibitors 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]. TMAnti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, and 6-acryloylamino-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-yl)amine (CI1033), erbB2 Tyrosine kinase inhibitors (e.g., lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin-like 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 farnesyltransferase inhibitors, such as sorafenib, telbifab, and lonafab), inhibitors of cell signaling via 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 (VEGF) [e.g., the anti-VEGF antibody bevacizumab (Avastin)]. TM Thalidomide; Lenalidomide; and VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalani, sunitinib, axitinib, and pazopanib;

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

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

[0276] (viii) Cytotoxic agents, such as fludarabine, cladribine, and pentostatin. TM );

[0277] (ix) Steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, such as aclomethasone, clomethasone dipropionate, aldosterone, aninonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone propionate, chlorprednisolone, cortisone, cortisone acetate, cortisol, deoxycorticosterone, diometasone, desoxymethasone, dexamethasone sodium phosphate, dexamethasone isonicotinic acid sodium, difluorocorticosterone, fluclomethasone, flumethasone, flunisolone, fluocinolone acetonide, fluocinolone acetate, fluocinolone acetonide, fluocinolone butyl ester, fludrocortisone, fluocinolone acetate, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetate. Hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone acetopropionic acid, hydrocortisone valerate, icotinamide, acetobutylexetine, prednisone, methylprednisolone, mometasone / peramisone, mometasone furoate monohydrate, prednicarbamate, prednisolone, prednisone, tecortisone, tecortisone pitavaspinate, triamcinolone, triamcinolone acetonide, triamcinolone acetonide, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more types of steroids mentioned in this paragraph;

[0278] (x) Targeted therapy, such as PI3Kd inhibitors, such as ederaris and perifoxine.

[0279] Treatment methods or compounds for treating immune diseases may include other active agents in addition to the compounds of this invention. These additional active agents may be one or more active agents for treating conditions treatable by the compound of formula (I) and the additional active agents. The additional active agents may include one or more of the following active agents:

[0280] (i) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, such as aclomethasone, clomethasone dipropionate, aldosterone, aninonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasone propionate, chlorprednisolone, cortisone, cortisone acetate, cortisol, deoxycorticosterone, diometasone, desoxymethasone, dexamethasone sodium phosphate, dexamethasone isonicotinic acid sodium, difluorocorticosterone, fluclomethasone, flumethasone, flunisolone, fluocinolone acetonide, fluocinolone acetate, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, fluocinolone acetonide, Hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone ketone butyrate, hydrocortisone acetopropionic acid, hydrocortisone valerate, icotinamide, acetobutylexetine, prednisone, methylprednisolone, mometasone / peramisone, mometasone furoate monohydrate, prednicarbamate, prednisolone, prednisone, tecortisone, tecortisone pitavaspinate, triamcinolone, triamcinolone acetonide, triamcinolone acetonide, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more types of steroids mentioned in this paragraph;

[0281] (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), cetuzumab (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT2A agonists (e.g., 2,5-dimethoxy-4-iodophenylamphenicol, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethyl acridine);

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

[0283] (iv) Dihydrofolate reductase inhibitors / antifolate agents, such as methotrexate, trimethoprim, brotropium bromide, alloxan, ellapril, pemetrexed, raltitrexed, and pralatrexate; and

[0284] (v) Immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, such as thiol-containing agents (e.g., captopril, zolfenpril), dicarboxylic acid ester-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zolfenpril, quindopril), and phosphate-containing agents (e.g., fosinopril).

[0285] This combination therapy can be achieved by administering the individual therapeutic components simultaneously, sequentially, or separately. Such combination products use the compounds of the invention within the therapeutically effective dosage range described above, and other pharmaceutically active agents within their approved dosage ranges.

[0286] According to another aspect of the invention, a pharmaceutical product is provided 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 antitumor agent as defined above for combination therapy of conditions regulated by BTK.

[0287] According to another aspect of the invention, a method for treating a condition regulated by BTK is provided, comprising administering, simultaneously, sequentially or separately, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and additional antitumor agents as defined above, to a patient in need.

[0288] According to another aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use simultaneously, sequentially, or separately with other antitumor agents as defined above for treating conditions modulated by BTK.

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

[0290] According to another aspect, a method for providing a combined product is provided, wherein the method includes providing a compound of formula (I) simultaneously, sequentially, or separately from an antitumor agent as defined above. The method may include combining the compound of formula (I) and the antitumor agent in a single dosage form. Alternatively, the method may include providing the antitumor agent as a separate dosage form.

[0291] According to another aspect, a method for providing a combined product is provided, wherein the method includes providing a compound of formula (I) simultaneously, sequentially, or separately from an antitumor agent as defined above. The method may include combining the compound of formula (I) and the antitumor agent in a single dosage form. Alternatively, the method may include providing the antitumor agent as a separate dosage form.

[0292] The conditions regulated by BTK mentioned above can be cancer, leukemia, or other cancer-related conditions. More specifically, conditions regulated by BTK can be selected from: 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, Waldenström macroglobulinemia, and multiple myeloma.

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

[0294] The dosage of the compounds of the present invention will naturally vary depending on the compound used, the mode of administration, the desired treatment, and the disease described. For example, if the compounds of the present invention are administered orally, the daily dose 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 pharmaceutically acceptable salts thereof may be used alone, but are generally administered in the form of pharmaceutical compositions in combination with pharmaceutically acceptable adjuvants, diluents or carriers. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988.

[0296] Depending on the administration method 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% by weight of the compound of the present invention, more preferably 0.05 to 80% by weight, even more preferably 0.10 to 70% by weight, and even more preferably 0.10 to 50% by weight, all weight percentages being based on the total composition.

[0297] The pharmaceutical composition may be applied topically (e.g., to the skin) in the form of cream, gel, lotion, solution, suspension or systemic preparation, for example, by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of a suppository; or by inhalation in the form of an aerosol.

[0298] For oral administration, the compounds of the present invention can be mixed with adjuvants or carriers, such as lactose, sucrose, sorbitol, mannitol; starches, such as potato starch, corn starch, or amylopectin; cellulose derivatives; binders, such as gelatin or polyvinylpyrrolidone; and / or lubricants, such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, 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 may 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] To prepare soft gelatin capsules, the compounds of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain particles of the compounds using the above-described tablet excipients. Liquid or semi-solid formulations of the compounds of the present invention may also be filled into hard gelatin capsules. Liquid formulations for oral administration may be in the form of syrups or suspensions, such as solutions containing the compounds of the present invention, with the remainder being a mixture of sugar and ethanol, water, glycerol, and propylene glycol. Optionally, such liquid formulations may contain colorants, flavoring agents, 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 this invention can be administered as sterile aqueous or oily solutions.

[0301] Based on well-known pharmacological principles, the dosage 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] The dosage level, frequency of dosing, and duration of treatment of the compounds of this invention are expected to depend on the formulation and the patient's clinical indication, age, and comorbidities. For most clinical indications, the standard duration of treatment with the compounds of this invention is expected to vary between 1 and 7 days. In cases of recurrent infection or infection associated with poorly vascularized tissues or implanted materials (including bone / joint, respiratory tract, endocardium, and dental tissues), it may be necessary to extend the duration of treatment beyond 7 days.

[0303] Examples and Synthesis

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

[0305] Unless otherwise specified, solvents, reagents, and starting materials should be purchased from commercial suppliers and used as is. Unless otherwise specified, all reactions should be carried out at room temperature.

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

[0307] Table 1

[0308]

[0309]

[0310] Compound identification was also performed using a Waters Alliance 2695 micromass ZQ (K98SM4 512M-LAA434) via LCMS UV. A diode array detector was used at 254 nm, and the MS was operated in both positive and negative electrospray modes (m / z: 150–650). 10 μL aliquots were injected onto an HPLC column (C18, 75 × 4.6 mm, 2.5 μm) at RT controlled at 19 °C. Samples were eluted at a flow rate of 0.9 mL / min using mobile phases 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). Retention times (RT) are reported in minutes.

[0311] Table 2

[0312]

[0313]

[0314] Compound identification was also performed using analytical supercritical fluid chromatography (SFC) with an Agilent 1260 analytical SFC (SFC-A). 10 μL aliquots were injected onto an HPLC column (C18, 75 × 4.6 mm, 2.5 μm) at RT controlled at 19 °C. The samples were eluted using a mobile phase consisting of A: CO2 and B: methanol (0.05% DEA, V / V) at a flow rate of 3 mL / min to allow the gradient of phase B to dilute from 5% to 40% within 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 rapid column chromatography or preparative LCMS. LCMS purification was performed using a Waters 2489 UV / Vis detector in both positive and negative electrospray ionization modes (m / z: 150-800) with a Waters 3100 mass spectrometer detector. According to the gradients listed in Table 3 below, a mobile phase system consisting of A (0.1% (v / v) aqueous formic acid) and B (0.1% (v / v) acetonitrile formic acid solution) was used in XBridge chromatography. TM Samples were prepared and eluted at a flow rate of 20 mL / min on a C185 μM OBD 19 x 100 mm column.

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

[0320] The chemical names in this document were generated using mol₂nam-Structure to Name Conversion performed with OpenEye Scientific Software. Raw 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 one of the general schemes shown below, namely, general scheme 1 or general scheme 2.

[0323] General Solution 1

[0324]

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

[0326]

[0327] Among them, R 6 As defined elsewhere in this document, optionally where R 6 It is a substituted phenyl or a substituted or unsubstituted 5- or 6-membered heteroaryl ring, wherein, when substituted, R 6 Contains 1 to 5 substituents, each selected independently from the following groups: halogen, -OR I -NR I R J -CN,C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR I Replacement C 1-6 alkyl;

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

[0329] Z is a metal ion, such as a group 1 metal like potassium or sodium.

[0330] In the above aspects of the invention, R 6Preferably substituted with a methoxy group and 0 to 4 other substituents, each substituent being independently selected from: halogen, -OR I -NR I R J -CN,C 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR I Replacement 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 Program

[0338] General Program A

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

[0340] General Program B

[0341] Under a nitrogen atmosphere, an anhydrous THF (0.2 M) solution containing the corresponding benzoyl chloride derivative (1.1 equivalent) was added to a suspension of [4-(aminomethyl)phenyl]borate acid salt (1.0 equivalent) and anhydrous THF (0.2 M) containing DIPEA (3.0 equivalent). The reaction mixture was stirred at room temperature for 16 h, quenched with a saturated aqueous ammonium chloride solution, and then extracted into ethyl acetate (×3). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and then concentrated under reduced pressure to give the desired boric 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 equivalent), boric acid or pinacol ester (1.5 equivalent), and potassium carbonate (2.0 equivalent) in 1,4-dioxane and water (3:1, 0.1 M) was degassed by bubbling nitrogen into it for 25 minutes. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.05 equivalent) was added, and the mixture was degassed again by bubbling nitrogen into it for 30 minutes. The mixture was then heated at 120°C for 14 hours. Filter the reaction mixture. Wash the filter cake with DCM. Add water to the filtrate and allow the layers to separate. Extract the aqueous layer with DCM (×2). Filter the combined organic extracts through a phase separator and then concentrate under reduced pressure to give a dark solid. Further purification by silica gel rapid column chromatography yields the desired compound.

[0344] General Program D

[0345] A mixture of halogen (1.0 equivalent), boric acid or pinacol ester (1.5 equivalent), and potassium carbonate (2.0 equivalent) in 1,4-dioxane and water (3:1, 0.1 M) was degassed by bubbling nitrogen into it for 15 minutes. A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.05 equivalent) was added, and the mixture was degassed again by bubbling nitrogen into it for 15 minutes. The mixture was then heated at 120–140 °C for 60–90 minutes under microwave irradiation. The reaction mixture was purified by an SCXSPE column and used as is, or purified using the following procedure unless a crude product is declared. Filter the mixture using a pad filter. Rinse the filter cake with DCM. Add water to the filtrate and allow it to separate into layers. Extract the aqueous layer with DCM (×2). Filter the combined organic extracts through a phase separator and then concentrate under reduced pressure to give a dark solid. Further purification by rapid column chromatography yields the desired compound.

[0346] General Program E

[0347] The corresponding amount of hydrazine (1.05 equivalents) was added to a MeOH (0.2 M) solution containing ketone (1.0 equivalents), and the reaction was stirred at room temperature for 15 h. The volatiles were removed under reduced pressure to provide crude Boc-hydrazone derivatives.

[0348] General Program F

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

[0350] General program G

[0351] Add 1,4-dioxane (8.0 equivalents) containing 4N HCl to a MeOH (0.5 M) solution containing Boc-protected hydrazine (1.0 equivalents), and stir the reaction at room temperature for 5 h. Add diethyl ether to form a precipitate, which is collected by filtration to obtain the desired hydrazine intermediate. Alternatively, concentrate the mixture under reduced pressure and use it as is.

[0352] General Program H

[0353] To an EtOH (0.6 M) solution containing 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (1.0 equivalent) and TEA (3.0 equivalent), the corresponding hydrazine derivative (1.2 equivalent) was added, and the mixture was stirred at 100 °C for 2–14 h. Volatile substances were removed under reduced pressure. The residue was then treated with a saturated aqueous solution of ammonium chloride and ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Further purification by silica gel column chromatography yielded the desired compound.

[0354] General Program I

[0355] Triethylamine (1.1 equivalents) was added to a stirred solution of DCM (0.9 M) containing alcohol (1.0 equivalents) cooled under a nitrogen atmosphere at 0 °C. The resulting solution was stirred for 10 min, and then methanesulfonyl chloride (1.1 equivalents) 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 methanesulfonated product.

[0356] General Program J

[0357] Hydrochloric acid (1M, 3.0 equivalents) was added to a THF (1M) suspension containing a 1,3-dioxolane derivative (1.0 equivalent) cooled at 0°C. The reaction mixture was brought back to room temperature and stirred for 14 h. The mixture was then carefully alkalized with a 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 give crude carbonyl.

[0358] General Program K

[0359] A mixture of a halogen derivative (1.0 equivalent), Molander salt (1.0 equivalent), cesium carbonate (3.0 equivalent), and XPhos (0.1 equivalent) in THF and water (10:1, 0.06 M) was degassed by bubbling nitrogen into it for 15 minutes. Palladium acetate (0.05 equivalent) was then added, and the mixture was degassed again by bubbling nitrogen into it for 5 minutes. The mixture was then heated to 85°C for 16 hours. Filtration. The filter cake was washed with DCM. Water was added to the filtrate and the layers 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. Further purification was performed by silica gel rapid column chromatography to obtain the desired compound.

[0360] General Program L

[0361] Hydrogenated (dimethylphosphonic acid kP) [hydrobis(dimethylphosphono-kP)]platinum(II) (0.07 g, 0.163 mmol) was added to an EtOH / water (2:1, 0.8 M) solution containing a nitrile derivative (1.0 equivalent). The mixture was heated overnight at 80 °C and then concentrated under reduced pressure. The residue was then separated into layers 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 obtain the desired crude amide.

[0362] General Program M

[0363] A solution of sulfuric acid (10 equivalents) and trifluoroacetic acid (40 equivalents) was added to a nitrile derivative (1 equivalent), 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 rapid column chromatography yielded the desired amide.

[0364] General Program N

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

[0366] General Program O

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

[0368] General program P

[0369] Under nitrogen atmosphere, 1 M borane-THF complex (5.0 equivalents) was added dropwise to a stirred solution of anhydrous THF (0.10 M) containing a nitrile derivative (1.0 equivalent). The reaction mixture was then refluxed for 4 h before cooling to room temperature. Methanol was carefully added dropwise until gas escaping 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 refluxed for 10 min and then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was carefully treated with excess aqueous sodium bicarbonate. The resulting suspension was extracted with ethyl acetate, the organic layer was dried, filtered, and evaporated under reduced pressure to give the corresponding amine.

[0370] General Program Q

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

[0372] General Program R

[0373] A 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (0.05 equivalents) was added to a nitrogen-degassed solution of 1,4-dioxane (0.12 M) containing potassium acetate (3.0 equivalents), di(pinacolyl)diboron (1.5 equivalents), and a halide derivative (1.0 equivalents). The reaction mixture was then degassed with nitrogen for 5 minutes, and then stirred at 90°C until the reaction was complete. Once cooled, the mixture was passed through... Filtration. 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 with sodium sulfate, filter, and remove all volatiles under reduced pressure. Use the resulting residue as a crude product, or further purify by silica gel rapid column chromatography to obtain the desired pinacol ester.

[0374] General Program S

[0375] Add ketone (1.5 equivalents) to a toluene (0.5 M) solution containing benzoyl hydrazine (1 equivalent). Heat the reaction mixture to 110 °C for 10–18 h, then cool to room temperature. Pour the reaction mixture into water and filter. Wash the solid with water and further dry to obtain the desired crude hydrazone.

[0376] General Program T

[0377] Add borane-THF (1M, 2 equivalents) to a THF solution containing hydrazone (1 equivalent) cooled at 0°C. Allow the reaction to return to room temperature and stir for 3–14 h. Then cool the mixture to 0°C, quench it with MeOH, and allow it to return to room temperature. Concentrate the mixture under reduced pressure and crush the residue with a suitable solvent (Pet. Ether, Et2O, or EtOAc) to obtain the desired hydrazine or purify it by rapid silica gel column chromatography.

[0378] General Program U

[0379] Add 37% aqueous hydrogen chloride solution (16 equivalents) to a MeOH (0.7 M) solution containing benzoyl hydrazine (1 equivalent). Heat the mixture at 80 °C for 16 h, cool to room temperature, and concentrate under reduced pressure. Add EtOAc, filter the precipitate, and wash twice with EtOAc to obtain crude hydrazine salt.

[0380] General Program W

[0381] Add the corresponding benzoyl chloride (1 equivalent) to a solution of toluene (0.5 M) and THF (0.5 M) containing malononitrile (1 equivalent). Cool the reaction mixture to -10 °C, and then add N,N-diisopropylethylamine (2 equivalents) dropwise while maintaining the internal temperature below -10 °C. Once the addition is complete, stir the reaction mixture at room temperature for 14 h and dilute with EtOAc. Separate the layers. Wash the organic layer successively with 1 M HCl and brine, dry with sodium sulfate, filter, and concentrate under reduced pressure to obtain the desired compound.

[0382] General Program X

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

[0384] General Program Y

[0385] Allyltrimethylsilane (1.5 equivalents) and diethyl boron trifluoride ether (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 under 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 saturated Na₂CO₃ solution, and diluted with water. The aqueous solution was then extracted with diethyl ether (×2), dried over a hydrophobic glass frit, and concentrated under reduced pressure to obtain the desired derivative.

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

[0387] Following general procedure A, the title compound (20.70 g, 72.61 mmol, 89.45 mmol) was obtained as a grayish-white solid from 2-methoxybenzoic acid (13.32 mL, 89.45 mmol) and [4-(aminomethyl)phenyl]borate salt (15.24 g, 81.32 mmol).

[0388] UPLC-MS(ES + (Short acidic): 1.31 minutes, 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, N-[[4-(5-amino-4-cyano-1H-pyrazol-4-carboxynitrile, 6.04 g, 32.32 mmol]-2-methoxy-benzamide (6.45 g, 18.57 mmol, 57% yield) was obtained as a pale brown solid by reacting 5-amino-3-bromo-1H-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (6.45 g, 18.57 mmol, 57% yield) with 5-amino-3-bromo-1H-pyrazol-3-yl)phenyl]methyl]methyl]-2-methoxy-benzamide (6.45 g, 18.57 mmol, 57% yield) with (purified by rapid column chromatography and eluted with 0-10% MeOH in DCM solution).

[0391] UPLC-MS(ES + (Short acidic): 1.42 minutes, 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] Sulfuric acid (9.59 mL, 179.92 mmol) and trifluoroacetic acid (55.3 mL, 719.68 mmol) were added 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). 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 (x3). The combined organic extracts were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Further purification by silica gel rapid column chromatography, followed by elution with 0-10% MeOH in DCM solution, yielded 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 minutes, m / z 366.2 [M+H] +

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

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

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

[0398] A toluene solution of potassium di(trimethylsilyl)amine (0.5 M, 23.8 mL, 11.9 mmol) was added dropwise to an anhydrous THF solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (2.5 g, 11.3 mmol) (25 mL). After stirring at -78 °C for 25 min, the mixture was warmed to room temperature and anhydrous methanol (1.3 mL, 32.1 mmol) was added. After 1 hour, 2-methoxybenzoyl chloride (3.4 mL, 22.6 mmol) was slowly added and the mixture was stirred overnight. The resulting suspension was filtered, and the filtrate was concentrated under vacuum. The residue was diluted with methanol (25 mL) and then a saturated aqueous solution of potassium hydrogen fluoride (3.5 g, 45.3 mmol) 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 the acetone disappeared. Et₂O was then added, and the product was precipitated and collected. Potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.50 g, 5.53 mmol, 49% yield) was given as a white solid.

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

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

[0401] A solution of N,N-diisopropylethylamine (11.11 mL, 63.8 mmol) in toluene (30 mL) was added dropwise to a solution of 4-bromobenzoyl chloride (7.00 g, 31.9 mmol) and malononitrile (2.32 g, 35.1 mmol) cooled to -10 °C in toluene (40 mL) and THF (8.6 mL) under a nitrogen atmosphere, 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 stirred at room temperature for 18 hours. Hydrochloric acid (1 M) was added, and the reaction mixture was separated into layers using EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with HCl (1 M) and 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 atmosphere, 200 g (911 mmol) of 4-bromobenzoyl chloride, 1000 mL of toluene, 200 mL of THF, and 63 mL (1003 mmol) of malononitrile 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 while 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, and then to 25 °C for 2 hours. The reaction mixture was transferred to a 7 L separatory funnel, and the reactor was washed sequentially with 1 M HCl aqueous solution (1.5 L) and EtOAc (1.5 L), each 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 with magnesium sulfate, filtered, and concentrated under reduced pressure to a slurry. The mixture was then slurried with petroleum ether (500 mL) and filtered. The solid was washed with cold petroleum ether (100 mL) and dried in air to give crude 2-[(4-bromophenyl)-hydroxy-methylene]malononitrile (232 g). This substance was slurried with a minimal amount of cold ethyl acetate and filtered, and washed with a minimal amount of ethyl acetate and diethyl ether to give 2-[(4-bromophenyl)-hydroxy-methylene]malononitrile (210 g, 843 mmol, 93% yield) as a pale yellow solid.

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

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

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

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

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

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

[0411] Oxaloyl chloride (124 mL, 1469 mmol) was added to a stirred suspension of 5-fluoro-2-methoxybenzoic acid (125 g, 735 mmol) and DMF (2.7 g, 37 mmol) in DCM (1750 mL) under RT. The reaction mixture was then stirred at room temperature for 16 hours and concentrated under reduced pressure to give crude 5-fluoro-2-methoxybenzoyl chloride (138 g, 732 mmol, assumed quantitative yield) as a yellow oil that rapidly crystallized.

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

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

[0414] A 0.7 M potassium bis(trimethylsilyl)amide solution in toluene (174 mL, 770 mmol) was added dropwise to a solution of 2-(bromomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (170 g, 770 mmol) in anhydrous THF (1200 mL). The mixture was stirred at -78 °C for 25 min, then stirred at 0 °C for 10 min, and finally stirred at room temperature for 30 min. Anhydrous methanol (99 g, 3078 mmol) was added under RT, resulting in a precipitate. The mixture was stirred under RT for 1 h, and then the reaction mixture was concentrated under reduced pressure while maintaining a water bath at 30 °C. The mixture was then evaporated together 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, followed by concentration under reduced pressure. The resulting residue was dissolved in ice-cold MeOH (1000 mL), and the mixture was cooled to 0 °C, then a saturated potassium hydrogen fluoride solution (264 g, 3386 mmol in water (600 mL)) was added. The reaction mixture was warmed to room temperature and stirred for 15 hours, followed by concentration under reduced pressure. The residue was azeotropically reacted 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), followed by washing with hot acetone solution containing 25% MeOH (3 × 2000 mL). The filtrate was concentrated under reduced pressure. Once most of the solvent was removed, TBME (500 mL) was added, and the resulting white solid was filtered off and washed with cold TBME to give potassium trifluoro-[[(5-fluoro-2-methoxy-benzoyl)amino]methyl]borane (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),7.31-7.25(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-difluorobenzoyl chloride

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

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

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

[0420] Following general procedure W, 2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]malonium (2 g, 7.05 mmol, assumed quantitative yield) was obtained from malononitrile (450 mg, 6.80 mmol) and 4-bromo-2,6-difluoro-benzoyl chloride (1.58 g, 6.19 mmol) as a thick yellow oil.

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

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

[0423] Purification was performed by silica gel rapid column chromatography according to general procedure X. After elution with heptane solution of 20-80% DCM, 2-[(4-bromo-2,6-difluoro-phenyl)-hydroxy-methylene]malonium (2.01 g, 7.05 mmol) was obtained to give 2-[(4-bromo-2,6-difluoro-phenyl)-methoxy-methylene]malonium (1.48 g, 4.95 mmol, 70% yield), as a white solid.

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

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

[0426] Following general procedure W, 2-[(4-chloro-3,5-difluorobenzoyl chloride) (2.00 g, 9.48 mmol) was reacted with 4-chloro-3,5-difluorobenzoyl chloride (2.00 g, 9.48 mmol) to give 2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]malonium (2.48 g, 10.31 mmol, assuming quantitative yield), as a brown, viscous oil.

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

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

[0429] Purification was performed by silica gel rapid column chromatography according to general procedure X. After elution with heptane solution of 20-80% DCM, 2-[(4-chloro-3,5-difluoro-phenyl)-hydroxy-methylene]malonium (2.48 g, 10.31 mmol) was obtained to give 2-[(4-chloro-3,5-difluoro-phenyl)-methoxy-methylene]malonium (1.68 g, 6.60 mmol, 64% yield), as a pale yellow solid.

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

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

[0432] Following general procedure W, 2-[(4-chloro-2,5-difluorobenzoyl chloride)-2.00 g, 9.48 mmol] malononitrile (2.66 g, 11.06 mmol, assumed quantitative yield) was obtained from 4-chloro-2,5-difluorobenzoyl chloride (2.00 g, 9.48 mmol) as a beige solid.

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

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

[0435] Purification was performed by silica gel rapid column chromatography according to general procedure X. After elution with heptane solution of 20-80% DCM, 2-[(4-chloro-2,5-difluoro-phenyl)-hydroxy-methylene]malonium (2.66 g, 11.06 mmol) was obtained to give 2-[(4-chloro-2,5-difluoro-phenyl)-methoxy-methylene]malonium (1.64 g, 6.44 mmol, 58% yield), which is a pale yellow oil.

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

[0437] 4-Chloro-2,3-difluorobenzoyl chloride

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

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

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

[0441] Following general procedure W, malononitrile (750 mg, 11.42 mmol) and 4-chloro-2,3-difluoro-benzoyl chloride (2.19 g, 10.38 mmol) were reacted to yield crude 2-[(4-chloro-2,3-difluoro-phenyl)-hydroxy-methylene]malononitrile (2.61 g, 10.85 mmol, assumed quantitative yield), a brown solid. Following general procedure X, the mixture was purified by rapid silica gel column chromatography, eluting with heptane in 20–80% DCM, to give 2-[(4-chloro-2,3-difluoro-phenyl)-methoxy-methylene]malononitrile (1.6 g, 6.40 mmol, 59% yield), a grayish-white solid.

[0442] UPLC-MS: (ES) + (Short acidic): 1.70 minutes, 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-cyclopentylpyrazole-4-carboxynitrile

[0446] Universal procedure H was used to react 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) with cyclopentylhydrazine hydrochloride (0.91 mmol) to give the title compound (0.83 mmol). UPLC-MS (ES) was then used to analyze the reaction. + (Short acidity): 2.17 minutes, m / z 333.2 [M+2] +

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

[0448] Universal procedure K was used to react 5-amino-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile (0.45 mmol) with potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) to give the title compound (0.36 mmol) as a yellow solid. UPLC-MS (ES) + (Short acid): 1.87 minutes, m / z 416.2 [M+H] +

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

[0450] Universal procedure M was used to react N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.36 mmol) to give the title compound (0.23 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.58 minutes, m / z 434.2 [M+H] + UPLC-MS(ES + (Long acidic): 3.59 minutes, m / z 434.2 [M+H] +

[0451] 1 ¹H NMR (400MHz, DMSO-d⁶, δ): 8.73 (t, J = 6.1Hz, 1H), 7.75 (dd, J = 7.7, 1.8Hz, 1H), 7.51–7.37 (m, 5H), 7.17–7.13 (m, 1H), 7.03 (td, J = 7.5, 1.0Hz, 1H), 6.31 (s, 2H), 4.60 (quintet, J = 7.3Hz, 1H), 4.54 (d, J = 6.1Hz, 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-cyclopentylpyrazole-4-carboxynitrile

[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 h. The reaction mixture was heated under reflux for 1.5 h, cooled, and concentrated under reduced pressure. The mixture was then treated and purified to give the title compound (51.9 mmol) as a pale yellow solid.

[0455] N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazole-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-carboxynitrile (36.2 mmol) were suspended in THF (250 mL) and water (75 mL). The orange reaction mixture was degassed under vacuum and washed three times with nitrogen. 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (2.54 mmol) was added, and the mixture was heated under reflux for 4 hours. The mixture was filtered, processed, and concentrated to give 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-pyrazole-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 treatment and crystallization from EtOAc and MeOH (200 mL), the title product (13.15 mmol) was given as a grayish-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-carboxynitrile

[0462] Universal procedure H was used to react 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) with (1R*,2R*)-2-hydrazinocyclopentanol (0.38 mmol) to give the title compound (0.38 mmol) as a white solid. UPLC-MS (ES) was then used to analyze the reaction. + (Short acidic): 1.82 minutes, m / z 349.1 [M+2] +

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

[0464] Following general procedure C, the title compound (0.11 mmol) was obtained as a white powder by reacting 5-amino-3-(4-bromophenyl)-1-[(1R*,2R*)-2-hydroxycyclopentyl]pyrazole-4-carboxynitrile (0.12 mmol) with potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.13 mmol). UPLC-MS (ES) + (Short acidic): 1.60 minutes, m / z 432.2 [M+H] +

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

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

[0467] 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 5.9 Hz, 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-carboxynitrile

[0471] Universal procedure H, after purification by silica gel rapid column chromatography, elution with 0-5% MeOH in DCM solution, followed by reaction of 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.57 mmol) and tert-butylhydrazine hydrochloride (0.86 mmol) to give the title compound (0.52 mmol) as a pale yellow solid. UPLC-MS (ES) + (Short acidity): 2.21 minutes, m / z 321.0 [M+2] +

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

[0473] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-tert-butyl-pyrazole-4-carboxynitrile (0.22 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.24 mmol) were reacted to give the title compound (0.21 mmol, 98% yield) as a yellow solid. UPLC-MS (ES) + (Short acidic): 1.90 minutes, 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 compound was purified by rapid silica gel column chromatography and then reacted with N-[[4-(5-amino-1-tert-butyl-4-cyano-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.74 mmol) to give the title compound (0.03 mmol) as a pale yellow solid. UPLC-MS (ES) + (Short acidic): 1.61 minutes, m / z 422.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.57 minutes, m / z 422.3 [M+H] + .

[0476] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 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] Bicyclic [3.1.0]hexane-3-one

[0480] To a DCM solution of pyridine (1.68 mmol) and pyridinium chlorochromate (7.64 mmol) cooled to 0 °C, cis-bicyclo[3.1.0]hexane-3-ol (5.09 mmol) was added dropwise. The reaction mixture was then heated 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 Florisil pad and the solvent was 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] N-(3-Bicyclo[3.1.0]hexylamino)carbamate tert-butyl ester

[0482] A mixture of bicyclo[3.1.0]hexane-3-one (5.58 mmol) and tert-butyl hydrazinocarbamate (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 buffer and then concentrated under reduced pressure. The resulting residue was purified by rapid silica gel column chromatography, eluting with a heptane solution of 0–100% EtOAc to give 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 (4.71 mmol) was added in portions to a stirred solution of N-(3-bicyclo[3.1.0]hexylamino)carbamate (4.76 mmol) in acetic acid (7 mL) and water (7 mL). The resulting mixture was stirred at room temperature for 2 hours, neutralized by adding 1 M NaOH (aqueous solution), and then extracted with DCM (× 2). The combined organic extracts were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered, and concentrated to dryness to give crude N-(3-bicyclo[3.1.0]hexylamino)carbamate (4.71 mmol) as a clear oil. The crude product was dissolved in DCM (4.5 mL). A stirred solution of N-(3-bicyclo[3.1.0]hexylamino)carbamate (4.71 mmol) in DCM (4.5 mL) was added dropwise to trifluoroacetic acid (58.77 mmol). The resulting solution was stirred for 2 hours and then concentrated under reduced pressure to obtain crude title compound (4.42 mmol), which was 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-carboxynitrile

[0487] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 0-100% EtOAc in heptane, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.78 mmol) and 3-bicyclo[3.1.0]hexylhydrazine; 2,2,2-trifluoroacetic acid (1.17 mmol) were added to give the title compound (0.21 mmol) as a colorless oil. UPLC-MS (ES) was then used. + (Short acidic): 2.15 minutes, m / z 345.1 [M+2] +

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

[0489] Universal procedure K was used to prepare the title compound (0.23 mmol) with 5-amino-1-(3-bicyclo[3.1.0]hexyl)-3-(4-bromophenyl)pyrazole-4-carboxynitrile (0.21 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.21 mmol). UPLC-MS (ES) + (Short acidic): 1.86 minutes, 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] Following general procedure L, N-[[4-[5-amino-1-(3-bicyclo[3.1.0]hexyl)-4-cyano-pyrazole-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.21 mmol) was purified by quality-guided semi-preparative HPLC to give the title compound (0.04 mmol). UPLC-MS (ES) was then used to further refine the compound. + (Short acidic): 1.68 minutes, m / z 446.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.72 minutes, 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, 1.0 Hz,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(dd,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] N-[(3-methylcyclopent-2-en-1-yl)amino]tert-butyl carbamate

[0496] To a methanol (59.4 mL) solution of 10.40 mmol of 3-methyl-2-cyclopenten-1-one, tert-butyl hydrazinoate (10.92 mmol) was added, 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 (brs, 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] Sodium cyanoborohydride (12.50 mmol) was added fractionally to a THF / MeOH solution of N-[-(3-methylcyclopent-2-en-1-yl)amino]carbamate (10.40 mmol) in 21 mL of THF / MeOH (1:1). The reaction mixture was heated to reflux for 10 min under a nitrogen atmosphere and then cooled to room temperature. Hydrogen chloride (30.00 mmol) was added, and the reaction mixture was heated to reflux for 3 h, cooled to room temperature, and stirred for 16 h. The reactants were filtered to remove inorganic insolubles, and the filtrate was concentrated under reduced pressure and azeotropically treated with toluene (×3). The residue was dissolved in hot isopropanol, cooled to RT, diluted with diethyl ether, and then cooled to 0 °C. The precipitate was filtered, and the filtrate was concentrated under vacuum to give the title compound (6.50 mmol). 1 ¹H NMR (400MHz, DMSO-d6, δ, diastereomer mixture): 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 = 6.5Hz, 3H).

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

[0500] Purification was performed using general procedure H via rapid silica gel column chromatography, eluting with 0–2% MeOH in DCM solution, followed by 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.38 mmol) and (3-methylcyclopentyl)hydrazine (0.38 mmol) to give the title compound. UPLC-MS (ES) + (Short acidity): 2.26 minutes, m / z 345.1 [M] +

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

[0502] Universal procedure K, purified by silica gel rapid column chromatography, eluted with 0-10% MeOH in DCM solution, followed by reaction of 5-amino-3-(4-bromophenyl)-1-(3-methylcyclopentyl)pyrazole-4-carboxynitrile (0.08 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.08 mmol) to give the title compound (0.05 mmol). UPLC-MS (ES) + (Short acidic): 2.03 minutes, m / z 430.2 [M+H] +

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

[0504] Following general procedure L, N-[[4-[5-amino-4-cyano-1-(3-methylcyclopentyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.08 mmol) was purified by quality-guided semi-preparative HPLC to give the title compound (0.01 mmol). UPLC-MS (ES) + (Short acid): 1.73 minutes, m / z 448.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.86 minutes, m / z 448.3 [M+H] +

[0505] 1 ¹H NMR (400MHz, DMSO-d⁶, δ) (diastereomeric 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 = 6.0 Hz, 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-pyridyl]pyrazole-4-carboxynitrile

[0509] The title compound was obtained as a grayish-white solid by reacting 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (80 mg, 0.30 mmol) and 5-(trifluoromethyl)pyridin-2-ylhydrazine (0.30 mmol) according to general procedure H. UPLC-MS (ES) + (Short acidic): 2.27 minutes, m / z 408.1 [M] +

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

[0511] Universal procedure K was used with 5-amino-3-(4-bromophenyl)-1-[5-(trifluoromethyl)-2-pyridyl]pyrazole-4-carboxynitrile (0.10 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.12 mmol) to give the title compound (0.06 mmol) as a white powder. UPLC-MS (ES) + (Short acidic): 2.03 minutes, m / z 493.3 [M+H] +

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

[0513] Universal procedure L, with N-[[4-[5-amino-4-cyano-1-[5-(trifluoromethyl)-2-pyridyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.06 mmol), yielded the title compound (0.03 mmol) as a white powder. UPLC-MS (ES) + (Short acidic): 1.85 minutes, 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),7.83-7.74(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] Following 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) were purified by quality-guided semi-preparative HPLC (intermediate method) to give the title compound (0.03 mmol). UPLC-MS (ES) was then used to further refine the compound. + (Short acidic): 1.42 minutes, m / z 454.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.10 minutes, 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-methyloxetane-3-yl)methyl]pyrazole-4-carboxamide

[0518]

[0519] Following 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) were purified by quality-guided semi-preparative HPLC to give the title compound (0.07 mmol). UPLC-MS (ES) + (Short acidic): 1.42 minutes, m / z 450.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.11 minutes, 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, 1.5 Hz,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] The general procedure N was purified by silica gel rapid column chromatography, eluting with 0–5% MeOH in DCM solution, yielding the title compound (0.04 mmol) to 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.27 mmol) and N-chloroethylmorpholine hydrochloride (0.41 mmol). UPLC-MS (ES) was then used to further purify the compound. + (Short acidic): 1.20 minutes, m / z 479.3 [M+H] + UPLC-MS(ES) + (Long acidic): 2.51 minutes, m / z 479.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.0Hz, 1H), 7.76 (dd, J = 7.7, 1.8Hz, 1H), 7.53-7.37 (m, 5H), 7.16 (d, J = 8.2Hz, 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] [Phenylene]pyrazole-4-carboxamide

[0527] Universal procedure N, purified by silica gel rapid column chromatography, eluted with 0-5% MeOH in DCM solution, yielded the title compound (0.03 mmol) after the reaction of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.24 mmol) and 1-bromo-3,3-dimethylbut-2-one (0.36 mmol). UPLC-MS (ES) + (Short acidic): 1.55 minutes, m / z 464.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.49 minutes, m / z 464.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.1Hz, 1H), 7.76 (dd, J = 7.6, 1.8Hz, 1H), 7.53-7.37 (m, 5H), 7.17 (d, J = 8.2Hz, 1H), 7.04(td,J=7.5,1.0Hz,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] The general procedure N was used to purify the compound by rapid silica gel column chromatography, followed by elution with 0-5% MeOH in DCM solution, resulting in 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.25 mmol) and 3-bromopropionitrile (0.37 mmol) to give the title compound (0.07 mmol).

[0532] UPLC-MS(ES + (Short acidic): 1.37 minutes, m / z 419.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.02 minutes, 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 0.82 mmol of 1,8-diazabicyclo[5.4.0]undec-7-ene in MeCN (0.5 mL) was slowly added to a solution of 0.27 mmol of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide in MeCN (2 mL). The reaction was stirred at room temperature for 15 min, and then cyclohexyl-2-enone (0.55 mmol) was added. The reaction mixture was stirred for 16 h. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and evaporated under vacuum. Purification was performed by silica gel column chromatography, eluting with 0–5% MeOH in DCM solution, to give the title compound (0.15 mmol) as a light brown solid. UPLC-MS (ES) + (Short acidic): 1.42 minutes, m / z 462.2 [M+H] + UPLC-MS (ES) + (Long acidic): 3.00 minutes, 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-indole-7-ol (0.27 mmol) and 2-cyclopentenone (0.33 mmol) in MeCN (0.54 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mmol) was added. The reaction mixture was stirred at RT for 2 days, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with 0–3.5% MeOH in DCM solution, followed by reversed-phase chromatography, eluting with 20–40% MeCN in an aqueous solution containing 0.1% formic acid additive, to give the title compound (0.04 mmol, 14% yield) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.44 minutes, m / z 448.2 [M+H] + .

[0541] UPLC-MS(ES + (Long acidic): 3.09 minutes, 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] [Phenylene]pyrazole-4-carboxamide

[0546] At 0 °C, 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). The reaction mixture was stirred for 30 min and then diluted with DCM. A saturated aqueous solution of Na₂CO₃ 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 silica gel rapid column chromatography, eluting with 0–5% MeOH in DCM solution to give the title compound (0.03 mmol). UPLC-MS (ES) + (Short acidic): 1.62 minutes, 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 = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.38-7.54 (m, 5H), 7.16 (d, J = 8.1 Hz, 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,1H),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-carboxynitrile

[0550] Universal procedure H, with 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.30 mmol) and 2,4-difluorophenylhydrazine hydrochloride (0.30 mmol), yielded the title compound (0.22 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.99 minutes, 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] Universal procedure K was used with 5-amino-3-(4-bromophenyl)-1-(2,4-difluorophenyl)pyrazole-4-carboxynitrile (0.11 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) to give the title compound (0.10 mmol) as a white powder. UPLC-MS (ES) + (Short acidic): 1.73 minutes, m / z 460.2 [M+H] +

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

[0554] Universal procedure L, using N-[[4-[5-amino-4-cyano-1-(2,4-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.10 mmol), yielded the title compound (0.05 mmol) as a grayish-white powder.

[0555] UPLC-MS(ES + (Short acidic): 1.57 minutes, m / z 478.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.58 minutes, 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, 6H), 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-carboxynitrile

[0559] Universal procedure H, with 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and [3-(trifluoromethyl)phenyl]hydrazine hydrochloride (0.38 mmol), yielded the title compound (0.31 mmol) as a grayish-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] Universally programmed hydrolysis of the nitrile yielded crude title compound (0.12 mmol) as a clear oil via hydrolysis with 5-amino-3-(4-bromophenyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxynitrile (0.12 mmol). UPLC-MS (ES) + (Short acidity): 1.93 minutes, m / z 425.0 [M]+

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

[0563] The 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) yielded the title compound (0.08 mmol) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.79 minutes, m / z 510.3 [M+H] + UPLC-MS(ES) + (Long acidic): 4.06 minutes, 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] Following 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) were purified by quality-guided semi-preparative HPLC to give the title compound (0.04 mmol). UPLC-MS (ES) + (Short acidic): 1.71 minutes, m / z 462.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.88 minutes, m / z 462.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.51-7.38 (m, 5H), 7.18-7.14 (m, 1H), 7.04 (td, J = 7.5, 1.0 Hz, 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-cyclohexylpyrazole-4-carboxynitrile

[0570] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 0–5% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.76 mmol) and cyclohexylhydrazine hydrochloride (0.91 mmol) were reacted to give the title compound (0.65 mmol) as a white solid. UPLC-MS (ES) was then used. + (Short acidic): 2.11 minutes, m / z 347.1 [M+2] + .

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

[0572] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0–5% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-cyclohexyl-pyrazole-4-carboxynitrile (0.64 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.70 mmol) were reacted to give the title compound (0.59 mmol) as a white solid. UPLC-MS (ES) was then performed. + (Short acidic): 1.81 minutes, m / z 430.3 [M+H] + .

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

[0574] The general procedure M was used for purification by rapid silica gel column chromatography. After elution with 0-5% MeOH in DCM solution, N-[[4-(5-amino-4-cyano-1-cyclohexyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.58 mmol) was eluted to give the title compound (0.32 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.59 minutes, m / z 448.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.63 minutes, m / z 448.3 [M+H] + .

[0575] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 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-carboxynitrile

[0579] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 0–2% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.38 mmol) and isopropylhydrazine (0.46 mmol) were added to give the title compound (0.27 mmol) as a pale yellow solid. UPLC-MS (ES+, short acid): 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] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-isopropylpyrazole-4-carboxynitrile (0.27 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.27 mmol) were reacted to give the title compound (0.19 mmol) as a yellow solid. UPLC-MS (ES) + (Short acidic): 1.73 minutes, m / z 390.2 [M+H] + .

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

[0583] The general procedure M was used for purification by rapid silica gel column chromatography. After elution with 0-5% MeOH in DCM solution, N-[[4-(5-amino-4-cyano-1-isopropyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.19 mmol) was eluted to give the title compound (0.10 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidity): 1.46 minutes, m / z 408.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.23 minutes, m / z 408.3 [M+H] + .

[0584] 1 ¹H NMR (400MHz, DMSO-d⁶, δ): 8.73 (t, J = 6.1Hz, 1H), 7.75 (dd, J = 7.7, 1.8Hz, 1H), 7.50–7.38 (m, 5H), 7.18–7.13 (m, 1H), 7.04 (td, J = 7.5, 0.9Hz, 1H), 6.31 (s, 2H), 4.54 (d, J = 6.1Hz, 2H), 4.47 (quintet, J = 6.6Hz, 1H), 3.90 (s, 3H), 1.33 (d, J = 6.6Hz, 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] [Phenylene]pyrazole-4-carboxamide

[0588] Sodium borohydride (0.20 mmol) was added to a methanol (1 mL) solution of 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxocyclopentyl)pyrazole-4-carboxamide (0.18 mmol) and cooled to 0 °C. The reaction mixture was then stirred at room temperature for 30 min, 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 filter and concentrated under reduced pressure. Further purification was achieved by reversed-phase chromatography, eluting with an aqueous solution of 20–40% MeCN containing 0.1% formic acid additive, to give the title compound (0.08 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acid): 1.38 minutes, 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 = 5.7 Hz, 1H), 4.65 (quintet, J = 7.7 Hz, 1H), 4.55 (d, J = 6.1 Hz, 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-carboxynitrile

[0592] Further purification was performed by silica gel rapid column chromatography following the general procedure H. After elution with 0–10% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.38 mmol) and 2,2,2-trifluoroethylhydrazine (70 wt% in water, 0.46 mmol) were reacted to give the title compound (0.27 mmol) as a pale yellow solid. LC-MS (ES) + Method 1): 5.80 minutes, 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] Following general procedure K, the compound was further purified by silica gel rapid column chromatography. After elution with 10-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)pyrazole-4-carboxynitrile (0.29 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.38 mmol) were reacted to give the title compound (0.17 mmol) as a grayish-white solid. LC-MS (ES) + Method 1): 5.01 minutes, m / z 430.2 [M+H] + .

[0595] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2,2,2-trifluoroethyl)pyridine azole-4-carboxamide

[0596] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 10-100% EtOAc in heptane, N-[[4-[5-amino-4-cyano-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.16 mmol) was eluted to give the title compound (0.08 mmol) as a white solid. UPLC-MS (ES) was then used. + (Short acidic): 1.54 minutes, 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-carboxynitrile

[0600] The general procedure H was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.35 mmol) and phenylhydrazine (0.42 mmol) were reacted to yield 5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carboxynitrile (0.28 mmol), a white solid. UPLC-MS (ES) was then used. + (Short acidic): 2.04 minutes, m / z 339.1 [M] + .

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

[0602] Following general procedure K, further purification was performed by silica gel rapid column chromatography. After elution with 10-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-phenyl-pyrazole-4-carboxynitrile (0.12 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) were reacted to give the title compound (0.09 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acid): 1.77 minutes, m / z 424.1 [M+H] + .

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

[0604] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, N-[[4-(5-amino-4-cyano-1-phenyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.07 mmol) was eluted to give the title compound (0.05 mmol) as a white solid. LC-MS (ES) + Method 1): 4.53 minutes, m / z 442.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.39 minutes, m / z 442.2 [M+H] + .

[0605] 1H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J = 6.1 Hz, 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 allowed to return to room temperature over 30 minutes, followed by stirring for 16 hours. The reaction mixture was concentrated under vacuum. Further purification was performed by column chromatography using SPESCX, eluting with MeOH to give the title compound (0.17 mmol). UPLC-MS (ES) + (Short acidic): 1.90 minutes, m / z 464.3 [M+H] + .

[0610] 5-Amino-1-[(1R)-indan-1-yl]-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyridine azole-4-carboxamide

[0611] Universal procedure L, purification by silica gel rapid column chromatography, elution with 0-5% MeOH in DCM solution, yielded the title compound (0.03 mmol) from N-[[4-[5-amino-4-cyano-1-[(1R)-indan-1-yl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.27 mmol). UPLC-MS (ES) + (Short acidic): 1.74 minutes, m / z 482.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.77 minutes, m / z 482.3 [M+H]+ .

[0612] 1 H NMR (400MHz, DMSO-d6, δ): 8.70 (t, J = 6.1 Hz, 1H), 7.74 (dd, J = 7.6, 1.7Hz,1H),7.52-7.43(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-methylpyrazole-4-carboxamide

[0614]

[0615] Methyl 2-(4-bromobenzoyl)-3-oxo-butyrate

[0616] Under N2 conditions, a solution of methyl magnesium bromide (2.2 M in THF, 9.27 mmol) was added to a solution of methyl acetoacetate (9.27 mmol) in THF (44 mL) at 0 °C, and the mixture was stirred at 0 °C for 30 min. Then, 4-bromobenzoyl chloride (9.27 mmol) was added, and the mixture was stirred at RT for 16 h. The mixture was then quenched with saturated ammonium chloride solution. The aqueous layer was then extracted with DCM (×3), the organic matter was combined, filtered through a hydrophobic glass filter, and all volatiles were removed under reduced pressure. Purification was performed by silica gel rapid column chromatography, eluting with 0–15% EtOAc in heptane, to give the title compound (4.99 mmol) as a clear oil. UPLC-MS (ES) + (Short acidity): 1.88 minutes, m / z 299.0 [M] + .

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

[0618] A hydrazine hydrate solution (55-60% aqueous solution, 3.99 mmol) was added to a solution of methyl 2-(4-bromobenzoyl)-3-oxo-butyrate (4.99 mmol) in acetic acid (20 mL). The mixture was then stirred at RT for 72 hours, followed by vacuum to remove all volatiles. The residue was then alkalized 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 buffer. Purification was then performed by silica gel column chromatography, eluting with 0-6% MeOH in DCM solution, to give the title compound (4.21 mmol) as a clear oil. UPLC-MS (ES) + (Short acidic): 1.60 minutes, 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 methyl 3-(4-bromophenyl)-5-methylpyrazole-4-carboxylate (1.20 mmol) in DMF (2.5 mL). The mixture was then stirred at 75 °C for 45 min, followed by vacuum removal of all volatiles. The residue was then suspended in EtOAc (50 mL). The organic layer was then washed with water (×2) and saturated brine (×1). The organic layer was then dried over sodium sulfate, filtered, and vacuum removed of all volatiles. Purification was performed by silica gel column chromatography, eluting with 0–40% EtOAc in heptane to give the title compound (0.87 mmol) as a clear oil. UPLC-MS (ES) + (Short acidic): 2.27 minutes, m / z 365.1 [M+2] + .

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

[0622] Lithium hydroxide (2.75 mmol) was added to a solution of methyl 3-(4-bromophenyl)-1-cyclopentyl-5-methylpyrazole-4-carboxylate (0.28 mmol) in 1,4-dioxane (0.75 mL) and water (0.75 mL). The mixture was then stirred at 80 °C for 16 h, followed by stirring at 100 °C for 16 h. After cooling the reaction mixture back to RT, the mixture was acidified to pH 3 with hydrochloric acid (1 M). Extraction was then performed using DCM (×3), filtered through a hydrophobic glass buffer, and all volatiles were removed under reduced pressure. Purification was achieved by silica gel rapid column chromatography, eluting with 0–20% EtOAc in heptane to give the title compound (0.28 mmol) as a white solid. UPLC-MS (ES) +(Short acidic): 2.00 minutes, m / z 351.1 [M+2] + .

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

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

[0625] 1-Cyclopentyl-N-[(2,4-dimethoxyphenyl)methyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [By]-5-methylpyrazole-4-carboxamide

[0626] Purification was performed according to general procedure K by rapid silica gel column chromatography, eluting with 0-2.5% MeOH in DCM solution, followed by reversed-phase chromatography, eluting with 20-70% MeCN in an aqueous solution containing 0.1% formic acid. 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 gave the title compound (0.05 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 2.04 minutes, m / z 583.4 [M+H] + .

[0627] 1-Cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-5-methylpyrazole-4-carboxyl amine

[0628] At 0 °C, 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-methylpyrazole-4-carboxamide (0.04 mmol) in DCM (0.4 mL), 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 alkalized with saturated sodium carbonate solution. The layers were separated, and the aqueous layer was extracted with DCM (×3), combined, filtered through a hydrophobic glass buffer, and concentrated under reduced pressure. Further purification was performed by silica gel rapid column chromatography, eluting with a DCM solution of 0–6% MeOH, followed by reversed-phase chromatography, eluting with an aqueous solution of 20–70% MeCN containing 0.1% formic acid additive, to give the title compound (0.02 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.62 minutes, m / z 433.2 [M+H] + UPLC-MS (ES) + (Long acidic): 3.70 minutes, m / z 433.2 [M+H] + .

[0629] 1 ¹H 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 = 8.3Hz, 1H), 7.08–7.01 (m, 1H), 4.71 (quintet, J = 7.3Hz). Hz,1H),4.51(d,J=6.0Hz,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] [Pyrazole-4-carboxamide]

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

[0634] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 8.32 (brs, 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] N-[(4,4-dimethylcyclohexyl)amino]tert-butyl carbamate

[0638] Following general procedure E, the title compound (0.78 mmol) was obtained as a grayish-white powder by reacting 0.79 mmol of 4,4-dimethylcyclohexanone. 1H NMR (400MHz, CDCl3, δ): 7.49 (brs, 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-carboxynitrile

[0640] Universal procedure O, using N-[(4,4-dimethylcyclohexylene)amino]tert-butyl carbamate (0.78 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol), yielded the title compound (0.36 mmol) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 2.33 minutes, m / z 375.1 [M+2] + .

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

[0642] Universal procedure K was used with 5-amino-3-(4-bromophenyl)-1-(4,4-dimethylcyclohexyl)pyrazole-4-carboxynitrile (0.13 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.15 mmol) to give the title compound (0.13 mmol) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.99 minutes, m / z 458.3 [M+H] + .

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

[0644] The general procedure M was used for further purification by reversed-phase chromatography, eluting with an aqueous solution of 20-60% MeCN containing 0.1% formic acid additive, followed by N-[[4-[5-amino-4-cyano-1-(4,4-dimethylcyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.07 mmol) to give the title compound (0.02 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.74 minutes, m / z 476.3 [M+H] + UPLC-MS (ES) + (Long acidic): 4.04 minutes, m / z 476.3 [M+H] + . 1H NMR (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]dec-8-ol

[0648] A solution of methyl magnesium bromide (2.2 M in diethyl ether, 2.82 mmol) was added to a solution of 1,4-cyclohexanedione monovinyl acetal (2.56 mmol) in THF (5 mL), and the mixture was cooled to 0 °C. The reaction mixture was stirred at RT for 2 h, and then quenched with a saturated aqueous ammonium chloride solution. The layers were separated between DCM (20 mL) and water (20 mL). 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 (2.50 mmol) as a clear oil. 1 H NMR (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] According to general procedure J, crude title compound (2.50 mmol) was obtained as a brown oil by using a solution of 2.50 mmol of 8-methyl-1,4-dioxaspiro[4.5]dec-8-ol in THF (2.5 mL). 1H NMR (400 MHz, 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] N-[(4-hydroxy-4-methylcyclohexyl)amino]tert-butyl carbamate

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

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

[0654] Purification was performed according to general procedure O by rapid column chromatography, eluting with 55% EtOAc in heptane, followed by elution with 0-8% MeOH in DCM solution, and then reacting N-[(4-hydroxy-4-methyl-cyclohexyl)amino]carbamate tert-butyl ester (0.83 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.68 mmol) to give the title compound as a grayish-white powder (isomer 1, 0.43 mmol) and the title compound as a grayish-white solid (isomer 2, 0.09 mmol). UPLC-MS (ES) + Short acidity; isomer 1): 1.65 min, m / z 375.0 [M] + UPLC-MS(ES) + Short acidity; isomer 2): 1.72 min, 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-carboxynitrile (isomer 1) (50 mg, 0.13 mmol) was reacted with 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxamide (44 mg, 0.11 mmol, 84%) to obtain a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.35 minutes, m / z 394.9 [M+2] + .

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

[0658] Universal procedure K, with 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), yielded the title compound (0.09 mmol) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.33 minutes, m / z 478.5 [M+H] + UPLC-MS(ES) + (Long acidic): 2.98 minutes, m / z 478.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 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=8.3Hz,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% dispersed in mineral oil, 1.90 mmol) was added to a solution of 1,4-dioxane[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 min, and then benzyl bromide (1.90 mmol) was added. The mixture was stirred overnight at RT, quenched with saturated ammonium chloride solution, and separated into layers. The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic glass buffer and concentrated under reduced pressure. Further purification was achieved by silica gel rapid column chromatography, eluting with 30% EtOAc in heptane solution to give the title compound (0.81 mmol) as a clear oil. UPLC-MS (ES)+ (Short acidic): 1.76 minutes, m / z 249.0 [M+H] + .

[0663] 4-Benzyloxycyclohexanone

[0664] General procedure J, using 8-benzyloxy-1,4-dioxaspiro[4.5]decane (0.81 mmol), yielded 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] N-[(4-benzyloxycyclohexyl)amino]tert-butyl carbamate

[0666] Following general procedure E, the title compound (0.81 mmol) was obtained with 4-benzyloxycyclohexanone (0.81 mmol) as a clear oil. UPLC-MS (ES) + (Short acidic): 1.74 minutes, m / z 319.2 [M+H] + .

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

[0668] Following general procedure O, N-[(4-benzyloxycyclohexyl)amino]carbamate tert-butyl ester (0.81 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.68 mmol) were reacted to yield the title compound (0.68 mmol), as a grayish-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] Universal procedure L, with 5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxynitrile (0.13 mmol), yielded 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]pyridine azole-4-carboxamide

[0672] Following general procedure K, the title compound was obtained as a mixture of diastereomers (0.12 mmol) of potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane, using 0.13 mmol of 5-amino-1-(4-benzyloxycyclohexyl)-3-(4-bromophenyl)pyrazole-4-carboxamide and 0.15 mmol of potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane, as a white powder. UPLC-MS (ES) + (Short acid): 1.73 minutes, m / z 554.5 [M+H] + 1.77 minutes, m / z 554.2 [M+H] + UPLC-MS (ES) + (Long acidic): 4.02 minutes, m / z 554.3 [M+H] + 4.11 minutes, m / z 554.3 [M+H] + .

[0673] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 5.9 Hz, 1H), 7.76 (dd, J = 7.6, 1.6 Hz, 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),3.46-3.35(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-carboxynitrile

[0677] Following the general procedure H, further purification was performed by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.46 mmol) and cyclopropylhydrazine hydrochloride (0.55 mmol) were reacted to give the title compound (0.34 mmol) as a white solid. UPLC-MS (ES) + (Short acidity): 1.73 minutes, m / z 303.0 [M] + .

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

[0679] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-cyclopropylpyrazole-4-carboxynitrile (0.32 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) were reacted to give the title compound (0.34 mmol) as a crude brown solid. UPLC-MS (ES) was then used to further purify the compound. + (Short acidic): 1.51 minutes, m / z 388.2 [M+H] + .

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

[0681] Universal procedure L, further purification by silica gel rapid column chromatography, eluting with 0-10% MeOH in DCM solution, yielded the title compound (0.15 mmol) as a white solid to N-[[4-(5-amino-4-cyano-1-cyclopropylpyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.32 mmol). UPLC-MS (ES) + (Short acidic): 1.32 minutes, m / z 406.2 [M+H] + UPLC-MS(ES) + (Long acidic): 2.95 minutes, m / z 406.3 [M+H] + .

[0682] 1H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J = 6.0 Hz, 1H), 7.76 (dd, J = 7.7, 1.3Hz,1H),7.53-7.34(m,5H),7.16(d,J=8.3Hz,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-carboxynitrile

[0686] Further purification was performed by silica gel rapid column chromatography following general procedure H. After elution with 0–10% MeOH in DCM solution, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (1.14 mmol) and methylhydrazine (1.37 mmol) were reacted to yield an inseparable mixture of regioisomers of the title compound (0.47 mmol), as a white solid. UPLC-MS (ES) + (Short acidity): 1.57 min and 1.67 min, m / z 277.0 [M] + .

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

[0688] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with a heptane solution of 10–100% EtOAc, a mixture of 5-amino-3-(4-bromophenyl)-1-methylpyrazol-4-carboxynitrile and 3-amino-5-(4-bromophenyl)-1-methylpyrazol-4-carboxynitrile (0.43 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.37 mmol) gave the title compound (0.11 mmol) as a white solid. UPLC-MS (ES) + (Short acid): 1.54 minutes, m / z 362.2 [M+H] + .

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

[0690] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, N-[[4-(5-amino-4-cyano-1-methyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.09 mmol) was eluted to give the title compound (0.05 mmol) as a white solid. UPLC-MS (ES) + (Short acid): 1.24 minutes, m / z 380.2 [M+H] + UPLC-MS(ES) + (Long acidic): 2.76 minutes, 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-carboxynitrile

[0695] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 10-100% EtOAc in heptane, followed by reaction with 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (1.14 mmol) and 2-hydroxyethylhydrazine (1.37 mmol), the title compound (0.40 mmol) was obtained as a white solid. UPLC-MS (ES) + (Short acidic): 1.60 minutes, m / z 307.0 [M] + .

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

[0697] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-(2-hydroxyethyl)pyrazole-4-carboxynitrile (0.35 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.49 mmol) were reacted to give the title compound (0.22 mmol) as a light brown solid. UPLC-MS (ES) + (Short acidic): 1.36 minutes, m / z 392.1 [M+H] + .

[0698] 5-Amino-1-(2-hydroxyethyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-methyl amide

[0699] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(2-hydroxyethyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.21 mmol) was eluted to give the title compound (0.09 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.20 minutes, m / z 410.2 [M+H] + UPLC-MS(ES) + (Long acidic): 2.66 minutes, m / z 410.2 [M+H] + .

[0700] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.2 Hz, 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-carboxynitrile

[0704] The compound was further purified by silica gel rapid column chromatography using general procedure H, eluting with 0-100% EtOAc in heptane, followed by reaction with (3-fluorophenyl)hydrazine chloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonium (0.57 mmol) to give the title compound (0.22 mmol, 38% yield) as a light brown solid. UPLC-MS (ES) + (Short acidic): 1.97 minutes, m / z 357.1 [M] + .

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

[0706] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-(3-fluorophenyl)pyrazole-4-carboxynitrile (0.22 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) were applied to give the title compound (0.05 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.71 minutes, m / z 442.2 [M+H] + .

[0707] 5-Amino-1-(3-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-methyl amide

[0708] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(3-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.05 mmol) was eluted to give the title compound (0.03 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.54 minutes, m / z 460.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.52 minutes, m / z 460.2 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.77 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.5, 1.6 Hz, 1H), 7.62-7.55 (m, 3H), 7.52-7.45 (m, 5H), 7.26 (t, J = 8.6 Hz, 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, crude title compound (0.09 mmol) was obtained as a grayish-white powder by reacting 5-amino-3-(4-bromophenyl)-1-(4-hydroxy-4-methyl-cyclohexyl)pyrazole-4-carboxynitrile (isomer 2) (0.09 mmol). UPLC-MS (ES) + (Short acidic): 1.38 minutes, m / z 395.1 [M+2] + .

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

[0714] Universal procedure K, using 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), yielded the title compound (0.04 mmol) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.30 minutes, m / z 478.3 [M+H] + UPLC-MS(ES) + (Long acidic): 2.94 minutes, m / z 478.3 [M+H] + .

[0715] 1H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J = 6.0 Hz, 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,2 H),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] Palladium (10 wt% on carbon powder, dried) was added 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). 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. The mixture was cooled to room temperature and then... Filter the solution using a stopper. Wash the stopper with DCM and concentrate the filtrate under reduced pressure. Alkalize the residue with saturated sodium bicarbonate solution and extract with DCM (×3). Filter the combined organic extracts through a hydrophobic glass buffer and concentrate under reduced pressure. Further purification was achieved by silica gel column chromatography, eluting with 0–10% MeOH in DCM solution 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 acidity; isomer 1): 1.27 min, m / z 464.3 [M+H] + UPLC-MS (ES) + , long acidity; isomer 1): 2.84 min, m / z 464.3 [M+H]+ . 1 ¹H NMR (400MHz, 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 (brs, 1H), 2.23–2.07 (m, 2H), 1.84–1.72 (m, 2H), 1.61–1.47 (m, 4H).

[0721] UPLC-MS(ES + Short acidity; isomer 2): 1.26 min, m / z 464.3 [M+H] + UPLC-MS (ES) + , long acidity; isomer 2): 2.82 min, m / z 464.3 [M+H] + . 1 ¹H NMR (400MHz, 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] N-(cyclobutylene)carbamate tert-butyl ester

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

[0726] Cyclobutylhydrazine hydrochloride

[0727] 0.27 mmol of N-(cyclobutyleneamino)carbamate tert-butyl ester was dissolved in 5 mL of THF and 0.46 mmol of dimethyl sulfide borane was added. The reaction was stirred at room temperature for 1 hour. When TLC showed that the starting material was consumed, the solvent was removed under vacuum. The residue was dissolved in 7.6 mL of hydrogen chloride-methanol solution, and the reaction mixture was heated under reflux and stirred overnight. The solvent was evaporated to give the title compound (0.27 mmol) as a pale yellow gel, which was used without any further purification. 1 HNMR (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-cyclobutylpyrazole-4-carboxynitrile

[0729] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 20–80% EtOAc in heptane, cyclobutylhydrazine hydrochloride (0.25 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.21 mmol) were applied to give the title compound (0.14 mmol) as a white solid. UPLC-MS (ES) was then performed. + (Short acidic): 1.95 minutes, 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, the title compound (0.13 mmol) was obtained as a white powder with potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.19 mmol) using 5-amino-3-(4-bromophenyl)-1-cyclobutylpyrazole-4-carboxynitrile (0.14 mmol). UPLC-MS (ES+, short acid): 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] The title compound was obtained as a white powder using general procedure L with N-[[4-(5-amino-4-cyano-1-cyclobutyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.05 mmol). UPLC-MS (ES) + (Short acidic): 1.46 minutes, 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] [N-Tetrahydrofuran-3-imino]tert-butyl carbamate

[0738] Add tert-butyl hydrazine (2.35 mmol) to a 2 mL ethanol solution of dihydro(3(2H)-furanone (1.95 mmol), heat the reactants under reflux and stir overnight, remove the volatiles under reduced pressure to give the title compound (1.95 mmol) as a white solid. 1¹H NMR (400MHz, CDCl₃, δ, isomer mixture): 7.25 (s, 0.75H), 7.12 (s, 0.25H), 4.34 (t, J = 1.2Hz, 1.5H), 4.24 (t, J = 1.2Hz, 0.5H), 4.12 (t, J = 6.9Hz, 1.5H), 4.02 (t, J = 6.9Hz, 0.5H), 2.78 (td, J = 6.9, 1.2Hz, 0.5H), 2.48 (td, J = 6.9, 1.2Hz, 1.5H), 1.54 (s, 7.5H), 1.53 (s, 1.5H).

[0739] Tetrahydrofuran-3-ylhydrazine hydrochloride

[0740] 0.25 mmol of N-[tetrahydrofuran-3-iminoamino]carbamate tert-butyl ester was dissolved in THF (5 mL) and dimethyl sulfide borane (0.42 mmol) was added. The reaction was stirred at room temperature for 1 hour until TLC showed complete consumption of the starting material. The solvent was removed under vacuum. The residue was dissolved in MeOH solution of hydrogen chloride (1.25 M, 6.99 mL), and the reaction mixture was heated to reflux and stirred overnight. The solvent was evaporated to give the title compound (0.25 mmol) as a pale yellow gel, which was 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-carboxynitrile

[0742] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 20-80% EtOAc in heptane, tetrahydrofuran-3-ylhydrazine (0.23 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile were reacted to give the title compound (0.09 mmol) as a light brown solid. UPLC-MS (ES) + (Short acidic): 1.71 minutes, m / z 333.1 [M] + .

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

[0744] Universal procedure K, with 5-amino-3-(4-bromophenyl)-1-tetrahydrofuran-3-yl-pyrazol-4-carboxynitrile (0.10 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.14 mmol), yielded the title compound (0.06 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.51 minutes, 418.2 m / z [M+H] + .

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

[0746] Universal procedure L, with N-[[4-(5-amino-4-cyano-1-tetrahydrofuran-3-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.06 mmol), yielded the title compound (0.03 mmol) as a white powder. UPLC-MS (ES) + (Short acidic): 1.32 minutes, m / z 458.2 [M+Na] + UPLC-MS(ES) + (Long acidic): 2.95 minutes, 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 [Pyrazole-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 the mixture was cooled to 0 °C. The reaction was then brought to room temperature and stirred at this temperature for 48 hours. The mixture was then concentrated, and the residue was purified by reversed-phase chromatography, eluting with an aqueous solution of 30–80% MeCN containing 0.1% formic acid additive, to give the title compound (0.07 mmol) as a white solid. UPLC-MS (ES) + (Short acidity): 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] (3R)-3-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0755] At RT, borane-tetrahydrofuran (1:1, 2.62 mmol) was added dropwise to an anhydrous THF (10 mL) stirred solution of (3R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (0.87 mmol). The reaction was stirred for 4 h, quenched with saturated NH4Cl solution (2 mL), and the phases were 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 purification was performed by silica gel column chromatography, eluting with 0–100% EtOAc in heptane to give the title compound (0.84 mmol) 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),1.7 0-1.62(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] (3R)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0757] Universal Procedure I, purification by silica gel rapid column chromatography, followed by elution with 0-50% EtOAc in heptane, followed by reaction of (3R)-3-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester (0.84 mmol) and methanesulfonyl chloride (0.88 mmol) to give the title compound (0.58 mmol) as a colorless oil. UPLC-MS (ES) + (Short acidic): 1.71 minutes, 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] Following purification by silica gel rapid column chromatography using general procedure N, 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.29 mmol) and (3R)-3-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (0.58 mmol) yielded the title compound (0.19 mmol) and (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-2-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester, a mixture of regioisomers. UPLC-MS (ES) +(Short acidic): 1.58 and 1.60 minutes, m / z 563.3 [M+H] + .

[0760] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-[[(3R)-3-piperidinyl]methyl [Pyrazole-4-carboxamide]

[0761] A mixture of regioisomers of (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester (0.19 mmol) and (3R)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]piperidin-1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester was dissolved in DCM (5 mL) and trifluoroacetic acid (4.7 mmol) was added. The reaction was stirred overnight at RT. The solvent was removed under vacuum. The residue was dissolved in MeOH and passed through a SPESCX column, eluted with 0-100% 1N ammonia in MeOH solution. Further purification by quality-guided semi-preparative HPLC gave the title compound (0.02 mmol). UPLC-MS (ES) + (Short acidic): 1.10 minutes, m / z 463.2 [M+H] + UPLC-MS(ES) + (Long acidic): 2.41 minutes, m / z 463.3 [M+H] + . 1 HNMR (400MHz, DMSO-d6, δ):8.74(t,J=6.0Hz,1H),8.38(s,2H),7.76(dd,J=7.4,1.5 Hz,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),2.43-2.38(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-carboxynitrile

[0765] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 0-100% EtOAc in heptane, (2-fluorophenyl)hydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.57 mmol) were applied to give the title compound (0.29 mmol) as a brown solid. UPLC-MS (ES) + (Short acidic): 1.88 minutes, m / z 357.1 [M] + .

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

[0767] Universal procedure K, further purification by silica gel rapid column chromatography, eluting with 0-100% EtOAc in heptane, followed by reaction of 5-amino-3-(4-bromophenyl)-1-(2-fluorophenyl)pyrazole-4-carboxynitrile (0.29 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.40 mmol) to give the title compound (0.23 mmol) as a red solid. UPLC-MS (ES+, short acid): 1.62 min, m / z 442.1 [M+H] + .

[0768] 5-Amino-1-(2-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-methyl amide

[0769] The general procedure L was followed by rapid silica gel column chromatography for further purification. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(2-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.23 mmol) was eluted to give the title compound (0.02 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.46 minutes, 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 = 7.75 Hz, 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] 4-(tert-butoxycarbonylhydrazine)cyclohexanecarboxylic acid ethyl ester

[0773] Universal procedure E, with ethyl 4-oxocyclohexanecarboxylate (3.14 mmol), yielded the title compound (2.96 mmol) as a clear oil. UPLC-MS (ES) + (Short acidic): 1.52 minutes, m / z 285.1 [M+H] + .

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

[0775] Universal procedure O, with ethyl 4-(tert-butoxycarbonylhydrazine)cyclohexanecarboxylate (1.93 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.63 mmol), yielded the title compound (1.56 mmol, a mixture of cis / trans isomers) as a white powder. UPLC-MS (ES) + (Short acidity): 2.00 minutes, m / z 419.1 [M+2] + 2.06 minutes, m / z 419.1 [M+2] + .

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

[0777] Universal procedure L, with ethyl 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazole-1-yl]cyclohexanecarboxylate (0.91 mmol), yielded the title compound (0.91 mmol, a mixture of cis / trans isomers) as a grayish-white powder. UPLC-MS (ES) + (Short acidic): 1.70 minutes, m / z 437.1 [M+2]+ 1.72 minutes, m / z 437.1 [M+2] + .

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

[0779] Universal procedure K, using 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), yielded the title compound (0.68 mmol, a mixture of cis / trans isomers) as a white powder. UPLC-MS (ES) + (Short acidic): 1.57 minutes, m / z 520.3 [M+H] + 1.59 minutes, m / z 520.3 [M+H] ]+ UPLC-MS(ES) + (Long acidic): 3.63 minutes, m / z 520.3 [M+H] + 3.67 minutes, 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),7.52-7.38(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 [Pyrazole-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 the mixture was cooled to -20 °C. The reaction mixture was brought back to room temperature and then stirred for 2 hours. The mixture was diluted with DCM and then quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with DCM. The organic layers were combined, filtered through a hydrophobic glass buffer, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with a DCM solution of 0–10% MeOH. Further purification was performed by reversed-phase chromatography, eluting with a solution of 30–80% MeCN containing 0.1% formic acid additive, to give the title compound (0.02 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.49 minutes, m / z 452.1 [M+H] + UPLC-MS(ES) + (Long acidic): 3.39 minutes, m / z 452.3 [M+H] + .

[0784] 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J = 6.1 Hz, 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(brs,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] (3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[0788] Purified by silica gel rapid column chromatography, eluting with 0-50% EtOAc in heptane, followed by the reaction of (3S)-3-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester (0.82 mmol) and methanesulfonyl chloride (0.86 mmol) to give the title compound (0.72 mmol), a colorless oil. UPLC-MS (ES)+ (Short acidic): 1.71 minutes, 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] Following purification by silica gel rapid column chromatography using general procedure N, 5-amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1H-pyrazole-4-carboxamide (0.23 mmol) and (3S)-3-(methanesulfonyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester (0.47 mmol) yielded the title compound and (3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-2-yl]methyl]piperidine-1-carboxylic acid tert-butyl ester (0.13 mmol), a mixture of beige solids of regiomeric isomers. UPLC-MS (ES) + (Short acidic): 1.59 and 1.60 minutes, m / z 563.3 [M+H] + .

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

[0792] (3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester and (3S)-3-[[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-2-yl]methyl]piperidin-1-carboxylic acid tert-butyl ester (0.13 mmol) were dissolved in DCM (5 mL) and trifluoroacetic acid (3.3 mmol) was added. The reaction was stirred overnight at RT. The solvent was removed under reduced pressure. The residue was dissolved in MeOH and passed through a SPESCX column, eluted with 0-100% 1M ammonia in MeOH solution. The regioisomer mixture was then purified by quality-guided 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 minutes, m / z 463.2 [M+H] + UPLC-MS(ES) + (Long acidic): 2.41 minutes, m / z 463.3 [M+H] + .

[0793] 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=5.8Hz, 1H), 8.42 (s, 2H), 7.75 (dd, J=7.5, 1.5Hz, 1H), 7.50-7.40 (m, 5H), 7.16 (d, J=8.2Hz, 1H), 7.06-7.03 (m, 1H),6.36(s,2H),4.55(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-carboxynitrile

[0797] Universal procedure H, rapid silica gel column chromatography purification, elution with 0-100% EtOAc in heptane, followed by 4-(fluorophenyl)hydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile to give the title compound (0.41 mmol) as a light brown solid. UPLC-MS (ES) + (Short acidic): 1.94 minutes, m / z 359.0 [M+2] + .

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

[0799] Universal procedure K, purified by silica gel rapid column chromatography, eluted with 0-100% EtOAc in heptane, followed by reaction of 5-amino-3-(4-bromophenyl)-1-(4-fluorophenyl)pyrazole-4-carboxynitrile (0.41 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.57 mmol) to give the title compound (0.38 mmol) as a brown solid. UPLC-MS (ES) + (Short acidic): 1.69 minutes, m / z 442.2 [M+H] + .

[0800] 5-Amino-1-(4-fluorophenyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-methyl amide

[0801] Following general procedure M, further purification by quality-guided semi-preparative HPLC yielded the title compound (0.03 mmol) as a white solid from N-[[4-[5-amino-4-cyano-1-(4-fluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.33 mmol). UPLC-MS (ES) was then used to further purify the compound. + (Short acidic): 1.52 minutes, 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 = 6.1 Hz, 1H), 7.77 (dd, J = 7.7, 1.7Hz,1H),7.66-7.63(m,2H),7.56-7.54(m,2H),7.51-7.44(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-carboxynitrile

[0806] The compound was further purified by silica gel rapid column chromatography using general procedure H. After elution with 0-100% EtOAc in heptane, p-tolylhydrazine hydrochloride (0.34 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile were reacted to give the title compound (0.29 mmol) as an orange solid. UPLC-MS (ES) + (Short acidic): 2.00 minutes, m / z 353.0 [M] + .

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

[0808] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane potassium (0.30 mmol) and 5-amino-3-(4-bromophenyl)-1-(p-tolyl)pyrazole-4-carboxynitrile (0.21 mmol) were applied to give the title compound (0.09 mmol) as a light brown solid. UPLC-MS (ES) was then performed. + (Short acidic): 1.75 minutes, m / z 438.3 [M+H] + .

[0809] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(p-tolyl)pyrazole-4-methyl amide

[0810] The general procedure M was followed by preparative HPLC purification to obtain the title compound (0.01 mmol) as a grayish-white solid from N-[[4-[5-amino-4-cyano-1-(p-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.09 mmol). UPLC-MS (ES) was then used to further purify the compound. + (Short acidic): 1.57 minutes, m / z 456.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.59 minutes, m / z 456.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ): 8.76 (t, J = 5.9 Hz, 1H), 7.77 (dd, J = 7.7, 1.8 Hz, 1H), 7.55-7.53(m,2H),7.51-7.44(m,5H),7.34-7.33(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 Methyl pyrazole-1-yl]benzoate

[0812]

[0813] Methyl 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazole-1-yl]benzoate

[0814] Further purification was performed by silica gel rapid column chromatography following the general procedure H. After elution with 0-100% EtOAc in heptane, methyl 4-chlorobenzoate (0.55 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.46 mmol) were reacted to give the title compound (0.27 mmol) as an orange solid. UPLC-MS (ES) + (Short acidity): 1.96 minutes, 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] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, methyl 4-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazole-1-yl]benzoate (0.27 mmol) and trifluoro-[[(2-methoxybenzoyl)amino]methyl] gave the title compound (0.20 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.70 minutes, 482.3 m / z [M+H] + .

[0817] 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- methyl 1-yl]benzoate

[0818] General procedure M, followed by quality-guided preparative HPLC purification, yielded methyl 4-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoate (0.20 mmol) to the title compound (0.01 mmol), a grayish-white solid. UPLC-MS (ES) + (Short acid): 1.53 minutes, m / z 500.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.52 minutes, m / z 500.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J = 6.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.5 Hz, 2H), 7.76 (dd, J = 7.7, 1.7 Hz, 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-dimethylpropionate

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

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

[0824] Lithium hydroxide (1.79 mmol) was added to a THF (1 mL) solution of [(1S*,3S*)-3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclopentyl]dimethyl 2,2-propionic acid (0.22 mmol). The reaction mixture was then heated to 80 °C for 4 days, cooled, 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 residue was purified by silica gel column chromatography, 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 acid): 1.28 minutes, m / z 450.3 [M+H] + UPLC-MS(ES) + (Long acidic): 2.86 minutes, m / z 450.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J = 6.1 Hz, 1H), 7.74 (dd, J = 1.8, 7.6 Hz, 1H), 7.50-7.45 (m, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.3 Hz,2H),7.15(d,J=8.5Hz,1H),7.03(td,J=1.0,7.5Hz,1H),6.33(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-carboxynitrile

[0828] Following the general procedure H, further purification was performed by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, o-tolylhydrazine hydrochloride (0.68 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile were reacted to give the title compound (0.53 mmol) as an orange solid. UPLC-MS (ES) + (Short acidic): 1.94 minutes, m / z 355.0 [M+2] + .

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

[0830] The general procedure K was used for further purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane potassium (0.30 mmol) and 5-amino-3-(4-bromophenyl)-1-(o-tolyl)pyrazol-4-carboxynitrile (0.21 mmol) were applied to give the title compound (0.19 mmol) as a white solid. UPLC-MS (ES) was then performed. + (Short acid): 1.69 minutes, m / z 438.3 [M+H] + .

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

[0832] The general procedure M was used for further purification by silica gel rapid column chromatography. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(o-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.19 mmol) gave the title compound (0.06 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.50 minutes, m / z 456.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.42 minutes, m / z 456.3 [M+H] + .

[0833] 1H 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 the mixture was cooled to 0 °C. The reaction was allowed to return to room temperature, and once gas evaporation stopped, it was 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 again to 60 °C. The mixture was then cooled and quenched with ammonium chloride, followed by extraction with EtOAc. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by reversed-phase chromatography to give the title compound (0.09 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.30 minutes, m / z 464.3 [M+H] + UPLC-MS(ES) + (Long acidic): 2.90 minutes, m / z 464.3 [M+H] + .

[0837] 1H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.0 Hz, 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] Borane-dimethyl sulfide (0.24 mmol) was added to a THF (3 mL) solution of 0.05 mmol of 4-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]benzoic acid. The reaction mixture was stirred at RT for 5 h, quenched by the addition of saturated ammonium chloride solution (1 mL), and the layers 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 quality-guided semi-preparative HPLC to give the title compound (0.01 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.31 minutes, m / z 472.3 [M+H] + UPLC-MS(ES) + (Long acidic): 2.95 minutes, m / z 472.3 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.75 (t, J=6.0Hz, 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-carboxynitrile

[0844] Purification was performed using general procedure H, via rapid silica gel column chromatography, eluting with 0-80% EtOAc in heptane solution, followed by 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.29 mmol) and m-tolylhydrazine (0.34 mmol) to give 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)pyrazole-3-yl]phenyl]methyl]-2-methoxybenzoyl amine

[0846] Universal procedure K, purified by silica gel rapid column chromatography, eluted with 10-100% EtOAc in heptane, followed by reaction of potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.39 mmol) and 5-amino-3-(4-bromophenyl)-1-(m-tolyl)pyrazole-4-carboxynitrile to give the title compound (0.19 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.76 minutes, m / z 438.3 [M+H] + .

[0847] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(m-tolyl)pyrazole-4-methyl amide

[0848] Universal procedure M, purification by silica gel rapid column chromatography, elution with 0-10% MeOH in DCM solution, yielded the title compound (0.02 mmol) by N-[[4-[5-amino-4-cyano-1-(m-tolyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.19 mmol). UPLC-MS (ES) + (Short acidic): 1.57 minutes, 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 = 6.2 Hz, 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-carboxynitrile

[0853] Universal procedure H, without triethylamine, yielded the title compound (0.42 mmol) as a white solid using 2-[(4-bromophenyl)-methoxy-methylene]malonium (0.42 mmol) and 3-pyridylhydrazine (0.46 mmol). LC-MS (ES) + (Short acidic): 5.21 minutes, m / z 339.9 [M] + .

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

[0855] The general procedure K was used for purification by rapid silica gel column chromatography. After elution with 0–5% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-(3-pyridyl)pyrazole-4-carboxynitrile (0.42 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.46 mmol) were reacted to give the title compound (0.30 mmol) as a grayish-white solid. LC-MS (ES) + (Short acidic): 4.44 minutes, m / z 425.1 [M+H] + .

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

[0857] The general procedure M was used for purification by rapid silica gel column chromatography. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(3-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.14 mmol) was eluted to give the title compound (0.10 mmol) as a white solid. UPLC-MS (ES) + (Short acid): 1.29 minutes, m / z 443.4 [M+H] + UPLC-MS(ES) + (Long acidic): 2.86 minutes, m / z 443.1 [M+H] + .

[0858] 1 H 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(brs,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] N-(indan-2-imino)carbamate tert-butyl ester

[0862] Universal procedure E, purified by rapid silica gel column chromatography, followed by elution with 0-80% EtOAc in heptane, yielded the title compound (0.89 mmol) from 2-indanone (1.14 mmol) and tert-butyl hydrazinocarbamate (1.36 mmol) as a pale yellow solid. 1 HNMR (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] Indane-2-ylhydrazine hydrochloride

[0864] 0.89 mmol of N-(indan-2-iminoamino)carbamate tert-butyl ester was dissolved in THF (5 mL) and a solution of borane dimethyl sulfide complex (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 saturated NH4Cl aqueous 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: (ES + (Short acid): 0.83 minutes, m / z 149.0 [M-HCl+H] + .

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

[0866] Universal procedure H, purification by silica gel rapid column chromatography, elution with 0-80% EtOAc in heptane, followed by reaction with 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.68 mmol) and indane-2-ylhydrazine hydrochloride (0.82 mmol) to give the title compound (0.45 mol) as an orange solid. UPLC-MS: (ES) + (Short acidic): 2.09 minutes, m / z 381.1 [M+2] + .

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

[0868] The general procedure K was used to purify the compound benzamide (0.34 mol) by rapid silica gel column chromatography. After elution with 0-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-indan-2-ylpyrazol-4-carboxynitrile (0.45 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.63 mmol) were added to give the title compound benzamide (0.34 mol) as a grayish-white solid. 1 HNMR (400MHz, CDCl3, δ): 8.27 (dd, J = 7.8, 1.8 Hz, 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-methyl amide

[0870] Universal procedure L, rapid column chromatography purification, elution with 0-10% MeOH in DCM solution, followed by N-[[4-(5-amino-4-cyano-1-indan-2-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.11 mmol) to give the title compound (0.03 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.65 minutes, m / z 482.1 [M+H] + UPLC-MS(ES) + (Long acidic): 3.85 minutes, m / z 482.1 [M+H] + .

[0871] 1H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J = 6.0 Hz, 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-carboxynitrile

[0875] Universal procedure H, without triethylamine, yielded the crude title compound (1.24 mmol, assumed quantification) as a white solid using 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.24 mmol) and 2-hydrazinopyridine (1.36 mmol). UPLC-MS (ES) + (Short acidic): 2.03 minutes, m / z 340.1 [M] + .

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

[0877] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-(2-pyridyl)pyrazole-4-carboxynitrile (0.44 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.48 mmol) were applied to give the title compound (0.31 mmol, 70% yield) as a grayish-white solid. UPLC-MS (ES) + (Short acid): 1.77 minutes, m / z 425.1 [M+H] + .

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

[0879] Universal procedure M, using rapid silica gel column chromatography, eluted with 0-10% MeOH in DCM solution, yielded the title compound (0.10 mmol) as a white solid by N-[[4-[5-amino-4-cyano-1-(2-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.31 mmol). UPLC-MS (ES) was then used to further refine the reaction. + (Short acidic): 1.60 minutes, m / z 443.1 [M+H] + UPLC-MS(ES) + (Long acidic): 3.67 minutes, 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(brs,2H), 7.59-7.56(m,2H),7.51-7.46(m,3H),7.34-7.31(m,1H),7.17-7.15(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-carboxynitrile

[0884] Following general procedure H, without triethylamine, 4-pyridylhydrazine (1.44 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (1.31 mmol) were reacted to give the crude title compound (1.31 mmol) as a white solid. LC-MS (ES) + (Short acidic): 4.66 minutes, m / z 341.9 [M+2] + .

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

[0886] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0-10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-(4-pyridyl)pyrazole-4-carboxynitrile (0.44 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.48 mmol) were reacted to give the title compound (0.36 mmol) as a grayish-white solid. UPLC-MS (ES) was then performed. + (Short acidic): 1.37 minutes, m / z 425.1 [M+H] + .

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

[0888] The general procedure M was used for purification by rapid silica gel column chromatography. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(4-pyridyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.36 mmol) was eluted to give the title compound (0.13 mmol) as a white solid. UPLC-MS (ES) + (Short acid): 1.19 minutes, m / z 443.1 [M+H] + UPLC-MS(ES) + (Long acidic): 2.67 minutes, m / z 443.1 [M+H] + .

[0889] 1 H NMR (400MHz, DMSO-d6, δ): 8.76 (t, J=6.2Hz, 1H), 8.69-8.67 (m, 2H), 7.75(dd,J=7.6,1.8Hz,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(brs,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] 3-(tert-butoxycarbonylhydrazine)cyclohexanecarboxylic acid ethyl ester

[0893] Ethyl 3-oxocyclohexanecarboxylate (5.04 mmol) and tert-butyl hydrazinocarboxylate (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 aqueous NH4Cl solution. The organic layer was passed through a phase separator and concentrated under reduced pressure to give the title compound (3.77 mmol). UPLC-MS (ES) + (Short acidic): 1.55 minutes, m / z 285.1 [M+H] + .

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

[0895] Universal procedure O, purification by silica gel rapid column chromatography, elution with 0-100% EtOAc in heptane, followed by reaction of ethyl 3-(tert-butoxycarbonylhydrazine)cyclohexanecarboxylate (3.77 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malonitrile to give the title compound (isomer 1, 1.47 mmol) and the title compound (isomer 2, 1.21 mmol). UPLC-MS (ES) + Short acid, isomer 1): 2.05 min, m / z 419.1 [M+2] + UPLC-MS(ES) + Short acidity, 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]cyclo Ethyl hexanecarboxylate (isomer 1)

[0897] Following general procedure K, potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.11 mmol) and methyl 3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazole-1-yl]cyclohexanecarboxylate (isomer 1, 0.72 mmol) were stirred at 80 °C for 16 hours. The reaction mixture was then passed through... The solution was filtered through a filter and washed with DCM. 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 minutes, m / z 502.3 [M+H] + .

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

[0899] Universal procedure L, purification by silica gel rapid column chromatography, elution with 0-100% EtOAc in heptane, followed by ethyl 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (isomer 1, 0.30 mmol) to give the title compound (isomer 1, 0.03 mmol, 10%). UPLC-MS (ES) + (Short acidic): 1.63 minutes, m / z 520.4 [M+H] + UPLC-MS(ES) + (Long acidic): 3.76 minutes, 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(brs,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-Aniline-1-cyclopentyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4-carboxamide

[0901]

[0902] 5-Aniline-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile

[0903] Triethylamine (0.30 mmol) was added to a solution of 5-amino-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile (0.15 mmol), phenylboronic acid (0.30 mmol), and copper(II) acetate (0.15 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure. Purification was performed by silica gel column chromatography, eluting with 20–60% EtOAc in heptane, to give the title compound (0.10 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 2.30 minutes, m / z 407.0 [M] + .

[0904] N-[[4-(5-anilino-4-cyano-1-cyclopentyl-pyrazole-3-yl)phenyl]methyl]-2-methoxy-benzoyl amine

[0905] The general procedure K was used for purification by rapid silica gel column chromatography, eluting with 20-80% EtOAc in heptane, followed by 5-anilino-3-(4-bromophenyl)-1-cyclopentyl-pyrazole-4-carboxynitrile (0.10 mmol) to give the title compound (0.09 mmol) as a white powder. UPLC-MS (ES) + (Short acid): 2.04 minutes, m / z 492.1 [M+H] + .

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

[0907] The general procedure L was used for purification by rapid silica gel column chromatography. After elution with 0-3% MeOH in DCM solution, N-[[4-(5-anilino-4-cyano-1-cyclopentyl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.09 mmol) was eluted to give the title compound (0.07 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.88 minutes, m / z 510.2 [M+H] + UPLC-MS(ES) + (Long acidic): 4.47 minutes, m / z 510.2 [M+H] + .

[0908] 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J = 6.0Hz, 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 = 8.2 Hz,2H),7.22-7.09(m,4H),7.08-6.95(m,2H),6.80-6.72(m,1H),6.61(d,J=7.7 Hz, 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 wt% in EtOAc, 0.14 mmol) was added to a solution of dimethylamine (2 M 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. A further solution of dimethylamine (2 M in THF, 0.92 mmol), N,N-diisopropylethylamine (0.27 mmol), and propylphosphonic anhydride (50 wt% in EtOAc, 0.14 mmol) was added sequentially, and the reaction mixture was maintained at 40 °C for 48 hours, then cooled to room temperature. The reaction mixture was separated into layers between water and DCM. The aqueous layer was extracted with DCM (×3). The combined organic extracts were filtered through a hydrophobic glass filter, and all volatiles were removed under reduced pressure. Further purification was achieved by silica gel rapid column chromatography, eluting with 0–8% MeOH in DCM solution to give 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 acidity; isomer 1): 1.40 min, m / z 519.3 [M+H] + UPLC-MS(ES) + Long acidity; isomer 1): 3.71 min, m / z 519.2 [M+H] + . 1¹H NMR (400MHz, 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 = 6.0 Hz, 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 acidity; isomer 2): 1.37 min, m / z 519.2 [M+H] + UPLC-MS (ES) + , long acidity; isomer 2): 3.67 min, m / z 519.2 [M+H] + . 1 ¹H NMR (400MHz, 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]cyclo Ethyl hexanecarboxylate (isomer 2)

[0917] Universal procedure K was used to prepare the crude title compound (isomeric compound 2, 0.72 mmol, assumed quantitative yield) with ethyl 3-[5-amino-3-(4-bromophenyl)-4-cyano-pyrazole-1-yl]cyclohexane carboxylate (isomeric compound 2, 0.72 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (1.11 mmol). UPLC-MS (ES) + (Short acidic): 1.78 minutes, 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] Universal procedure L, purification by silica gel rapid column chromatography, elution with 0-10% MeOH in DCM solution, followed by ethyl 3-[5-amino-4-cyano-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazol-1-yl]cyclohexanecarboxylate (isomer 2, 0.30 mmol) to give the title compound (isomer 2, 0.02 mmol, 6% yield). UPLC-MS (ES) + (Short acidic): 1.78 minutes, 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(brs,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] N-[(3-oxoindan-1-ylidene)amino]tert-butyl carbamate

[0923] Universal procedure E, purified by rapid silica gel column chromatography, followed by elution with a heptane solution of 10-50% EtOAc, yielded the title compound (0.86 mmol, 62% yield) as a yellow solid after reacting 1,3-indanedione (1.37 mmol) and tert-butyl hydrazinocarbamate (1.44 mmol) with silica gel column chromatography. 1 H 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] N-[(3-oxoindan-1-yl)amino]tert-butyl carbamate

[0925] Universal procedure F, with N-[(3-oxoindan-1-ylidene)amino]carbamate tert-butyl ester (0.75 mmol), yielded crude title compound (0.57 mmol) as a colorless oil. UPLC-MS (ES) + (Short acidic): 1.41 minutes, m / z 285.1 [M+Na] + .

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

[0927] TFA (60 mmol) was added to a DCM (5 mL) solution of N-[(3-oxoindan-1-yl)amino]carbamate (0.57 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-carboxynitrile

[0929] Purification was performed according to general procedure H by rapid silica gel column chromatography. After elution with 0-80% EtOAc in heptane, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.46 mmol) and [(3-oxoindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.10 mmol) were reacted to give the title compound (0.10 mmol) as an orange solid. UPLC-MS (ES) +(Short acidic): 1.84 minutes, 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] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-(3-oxoindan-1-yl)pyrazol-4-carboxynitrile (0.1 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.13 mmol) yielded the title compound (0.03 mmol) as a brown solid. UPLC-MS (ES) + (Short acidic): 1.63 minutes, m / z 478.1 [M+H] + .

[0932] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(3-oxoindan-1-yl)pyridine azole-4-carboxamide

[0933] Following 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) was purified by quality-guided semi-preparative HPLC to yield the title compound (0.02 mmol) as a beige solid. UPLC-CMS (ES) + (Short acidic): 1.47 minutes, m / z 496.1 [M+H] + UPLC-MS(ES) + (Long acidic): 3.74 minutes, 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 ,2H),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-carboxynitrile

[0937] To a solution of 0.30 mmol of 5-amino-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile (0.30 mmol) in MeOH (3 mL), oligooxymethylene (0.91 mmol) and sodium methoxide (25 wt% in MeOH, 1.81 mmol) were added. The reaction mixture was heated under reflux for 16 hours. The reaction mixture was cooled to room temperature and then separated into layers 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 (0.30 mmol). UPLC-MS (ES) + (Short acid): 2.09 minutes, m / z 377.0 [M+MeOH+2] + .

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

[0939] Sodium borohydride (3.02 mmol) was added to a solution of 0.30 mmol of 3-(4-bromophenyl)-1-cyclopentyl-5-(methyleneamino)pyrazole-4-carboxynitrile (MeOH) (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was then carefully quenched with a saturated aqueous solution of NH4Cl. The aqueous layer was then extracted with DCM (×3), and the combined organic layers were passed through a hydrophobic glass buffer and concentrated under reduced pressure. Purification was performed by rapid silica gel column chromatography, eluting with a 20–60% EtOAc solution in heptane, to give the title compound (0.20 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 2.14 minutes, m / z 347.0 [M+2] + .

[0940] N-[[4-[4-cyano-1-cyclopentyl-5-(methylamino)pyrazole-3-yl]phenyl]methyl]-2-methoxy-benzyl amide

[0941] The general procedure K was used for purification by silica gel column chromatography, followed by elution with 20-60% EtOAc in heptane, and then 3-(4-bromophenyl)-1-cyclopentyl-5-(methylamino)pyrazole-4-carboxynitrile (0.20 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.22 mmol) to give the title compound (0.11 mmol) as a white solid. UPLC-MS (ES)+ (Short acidic): 1.85 minutes, m / z 430.1 [M+H] + .

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

[0943] The general procedure L was used for purification by rapid silica gel column chromatography, eluting with 0-4% MeOH in DCM solution, and by reversed-phase column chromatography, eluting with 20-70% MeCN in an aqueous solution containing 1% formic acid, followed by N-[[4-[4-cyano-1-cyclopentyl-5-(methylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.11 mmol) to give the title compound (0.05 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.67 minutes, m / z 448.1 [M+H] + UPLC-MS(ES) + (Long acidic): 4.30 minutes, m / z 448.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 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-carboxynitrile

[0947] Purification was performed according to general procedure H at RT by rapid silica gel column chromatography, eluting with 0-60% EtOAc in heptane, followed by reaction of 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.76 mmol) and (2,5-difluorophenyl)hydrazine (0.76 mmol) to give the title compound (0.24 mmol) as a beige solid. UPLC-MS (ES) + (Short acidic): 1.92 minutes, m / z 375.0 [M] + .

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

[0949] Universal procedure K, purified by silica gel rapid column chromatography, eluted with 0-10% MeOH in DCM solution, followed by reaction of 5-amino-3-(4-bromophenyl)-1-(2,5-difluorophenyl)pyrazole-4-carboxynitrile (0.24 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.26 mmol) to give the title compound (0.24 mmol), a deep yellow gel. UPLC-MS (ES) + (Short acidic): 1.68 minutes, m / z 460.2 [M+H] + .

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

[0951] The general procedure M was used for purification by rapid silica gel column chromatography. After elution with 0-10% MeOH in DCM solution, N-[[4-[5-amino-4-cyano-1-(2,5-difluorophenyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.26 mmol) was extracted to give the title compound (0.03 mmol, 10% yield) as a white solid. UPLC-MS (ES) + (Short acidic): 1.50 minutes, m / z 478.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.42 minutes, m / z 478.3 [M+H] + .

[0952] 1H NMR (400MHz, DMSO-d6, δ): 8.77 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 1.8, 7.7 Hz, 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 boranetetrahydrofuran complex (1 M in THF, 15.30 mmol) was added to a THF (30 mL) solution of 5.10 mmol of 4-bromo-2-methylbenzonitrile. The solution was stirred at 0 °C for 30 min, then heated to room temperature and stirred for 18 h. The reaction was quenched by the dropwise addition of MeOH. The volatiles were concentrated under reduced pressure and the residue was separated into layers by aqueous solutions of NaOH (1 M) and EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give crude (4-bromo-2-methylphenyl)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. The mixture was then stirred at 0 °C for 20 min, and the reaction was heated to room temperature and stirred for 16 h. The reaction was quenched with a saturated aqueous NH4Cl solution, treated, and purified (column chromatography, 0-30% EtOAc in heptane solution) to give the title compound (2.49 mmol). UPLC-MS (ES) + (Short acidic): 1.85 minutes, m / z 336.1 [M+2] + .

[0957] 2-Methoxy-N-[[2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]methyl [Benzoamide]

[0958] Universal procedure R was used to obtain the crude title compound (2.49 mmol) with N-[(4-bromo-2-methyl-phenyl)methyl]-2-methoxy-benzamide. UPLC-MS (ES) + (Short acidic): 1.95 minutes, m / z 382.2 [M+H] + .

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

[0960] Universal procedure D, purification by silica gel rapid column chromatography, elution with 0-100% EtOAc in heptane, yielded the title compound (0.48 mmol) from 2-methoxy-N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)phenyl]methyl]benzamide (2.04 mmol). UPLC-MS (ES) + (Short acidic): 1.40 minutes, m / z 362.3 [M+H] + .

[0961] N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazole-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 mixture was heated to 80 °C for 16 hours. After treatment and purification by rapid column chromatography, eluting with 0–1% MeOH in DCM solution, the title compound (0.15 mmol) was given. UPLC-MS (ES) + (Short acidic): 1.81 minutes, m / z 430.1 [M+H] + .

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

[0964] Universal procedure L, purification by silica gel rapid column chromatography, elution with 25-100% EtOAc in heptane, followed by N-[[4-(5-amino-4-cyano-1-cyclopentyl-pyrazol-3-yl)-2-methyl-phenyl]methyl]-2-methoxy-benzamide (0.15 mmol) to give the title compound (0.04 mmol). UPLC-MS (ES) + (Short acidic): 1.70 minutes, m / z 448.1 [M+H] + UPLC-MS(ES) + (Long acidic): 4.04 minutes, m / z 448.1 [M+H] + .

[0965] 1H NMR (400MHz, DMSO-d6, δ): 8.61 (t, J = 5.8 Hz, 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=5.8 Hz,2H),3.89(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] N-[(3-hydroxyindan-1-yl)amino]tert-butyl carbamate

[0969] 0.58 mmol of tert-butyl N-[(3-oxoindan-1-ylidene)amino]carbamate was dissolved in 5 mL of THF and a 3.45 mmol solution of a borane dimethyl sulfide complex (2 M in THF) was added. The reaction was stirred at RT for 14 hours. After treatment and concentration with the addition of saturated NH4Cl aqueous solution, the crude title compound (0.57 mmol) was given as a pale orange solid. UPLC-MS (ES) was performed. + (Short acidic): 1.57 minutes, m / z 287.0 [M+Na] + .

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

[0971] Trifluoroacetic acid (57 mmol) was added to a DCM (5 mL) solution of N-[(3-hydroxyindamino-1-yl)amino]carbamate (0.57 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were concentrated under reduced pressure to give crude [(3-hydroxyindamino-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-carboxynitrile

[0973] Purification was performed using general procedure H via rapid silica gel column chromatography. After elution with 0-80% EtOAc in heptane, 2-[(4-bromophenyl)-methoxy-methylene]malonitrile (0.46 mmol) and [(3-hydroxyindan-1-yl)amino]ammonium; 2,2,2-trifluoroacetate (0.55 mmol) were added to give the title compound (0.28 mmol) as an orange solid. UPLC-MS (ES) was then used to further purify the compound. + (Short acidic): 1.87 minutes, 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] The general procedure K was used for purification by silica gel rapid column chromatography. After elution with 0-100% EtOAc in heptane, 5-amino-3-(4-bromophenyl)-1-(3-hydroxyindan-1-yl)pyrazol-4-carboxynitrile (0.28 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.39 mmol) yielded the title compound (0.25 mmol) as a yellow solid. UPLC-MS (ES) + (Short acidic): 1.75 minutes, m / z 480.1 [M+H] + .

[0976] 5-Amino-1-(3-hydroxyindano-1-yl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyridine azole-4-carboxamide

[0977] Following general procedure L, N-[[4-[5-amino-4-cyano-1-(3-hydroxyindane-1-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.10 mmol) was purified by quality-guided semi-preparative HPLC to yield the title compound (0.05 mmol) as a beige solid. UPL-CMS (ES) + (Short acidic): 1.60 minutes, m / z 498.1 [M+H] + UPLC-MS(ES) + (Long acidic): 3.68 minutes, m / z 498.1 [M+H] + . 1H NMR (400MHz, DMSO-d6, δ): 8.71 (t, J=6.0Hz, 1H), 7.74 (dd, J=7.7, 1.7Hz, 1H),7.50-7.36(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-ylpyrazole-3-yl)phenyl]methyl]-2-methoxy-benzene formamide

[0981] The general procedure K was used for purification by rapid silica gel column chromatography. After elution with 0–10% MeOH in DCM solution, 5-amino-3-(4-bromophenyl)-1-tetrahydropyran-4-yl-pyrazol-4-carboxynitrile (0.27 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.30 mmol) were applied to give the title compound (0.19 mmol, 72% yield) as a deep yellow gel. UPLC-MS (ES) + (Short acidic): 1.51 minutes, m / z 432.3 [M+H] + .

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

[0983] The general procedure M was used for purification by rapid silica gel column chromatography, eluting with 0-10% MeOH in DCM solution, followed by purification with a SPESCX column, eluting with MeOH, to give the title compound (0.15 mmol) as a white solid by elution of N-[[4-(5-amino-4-cyano-1-tetrahydropyran-4-yl-pyrazol-3-yl)phenyl]methyl]-2-methoxy-benzamide (0.33 mmol). UPLC-MS (ES) + (Short acidic): 1.56 minutes, m / z 450.1 [M+H] + UPLC-MS(ES)+ (Long acidic): 3.57 minutes, 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, 1.8Hz,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]decane-8-ol

[0988] Under a nitrogen atmosphere at 0 °C, trimethyl(trifluoromethyl)silane (12.8 mmol) was added to an anhydrous THF (20 mL) solution of 6.40 mmol of 1,4-cyclohexanedione monovinyl acetal, followed by tetrabutylammonium fluoride (1.0 M in THF, 13.4 mmol). The reaction mixture was then heated to 25 °C and stirred for 2 hours. A saturated aqueous solution of ammonium chloride (10 mL) was then added. The reaction mixture was stirred for 10 minutes and then concentrated under reduced pressure. Treatment and purification yielded the title compound (5.83 mmol) as a pale 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] Hydrochloric acid (4 M, 8.75 mmol) was added to a solution of 5.84 mmol of 8-(trifluoromethyl)-1,4-dioxaspiro[4.5]decane-8-ol in 29 mL of acetone. The reaction mixture was stirred at room temperature for 18 hours, treated and purified to give the title compound (5.12 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6, δ): 6.26 (brs, 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] N-[[4-hydroxy-4-(trifluoromethyl)cyclohexyl]amino]tert-butyl carbamate

[0992] Universal procedure E, with 5.12 mmol of 4-hydroxy-4-(trifluoromethyl)cyclohexanone, yielded the title compound (2.29 mmol) as a white solid. 1 H NMR(400MHz,DMSO-d6,δ):9.60(brs,1H),6.02 (brs,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-carboxynitrile

[0994] Universal procedure O was used to react N-[[4-hydroxy-4-(trifluoromethyl)cyclohexylene]amino]carbamate tert-butyl ester (2.29 mmol) and 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.89 mmol) to give the title compound (0.12 mmol) as a yellow solid. UPLC-MS (ES) + (Short acidic): 1.94 minutes, m / z 430.9 [M+2] + .

[0995] N-[[4-[5-amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-3-yl]phenyl]methyl 1,2-methoxy-benzamide

[0996] Universal procedure K, using 5-amino-3-(4-bromophenyl)-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazole-4-carboxynitrile (0.42 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.46 mmol), yielded the title compound (0.24 mmol) as a grayish-white solid. UPLC-MS (ES) + (Short acidic): 1.82 minutes, m / z 514.1 [M+H]+ .

[0997] 5-Amino-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [By]phenyl]pyrazole-4-carboxamide

[0998] Universal procedure L, using N-[[4-[5-amino-4-cyano-1-[4-hydroxy-4-(trifluoromethyl)cyclohexyl]pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.24 mmol), yielded the title compound (0.095 mmol) as a pale yellow solid. UPLC-MS (ES) + (Short acidic): 1.68 minutes, m / z 532.1 [M+H] + UPLC-MS (ES) + (Long acidic): 3.91 minutes, m / z 532.1 [M+H] + .

[0999] 1 H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.6 Hz, 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(brs,2H),5.86(brs,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] N-(oxetane-3-imino) tert-butyl carbamate

[1003] Following general procedure E, the crude product was washed with heptane, followed by the reaction of 3-oxetane (6.94 mmol) and tert-butyl hydrazine (7.29 mmol) to give the title compound (4.51 mmol) as a white solid. 1 H NMR (400MHz, DMSO-d6, δ): 10.25 (s, 1H), 5.19-5.15 (m, 4H), 1.43 (s, 9H).

[1004] N-(oxetane-3-ylamino)tert-butyl carbamate

[1005] Following the general procedure F, after 2 days, N-(oxetane-3-iminoamino)carbamate tert-butyl ester (4.40 mmol) was reacted to give the title compound (3.84 mmol) as a colorless oil. 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] According to general scheme G, the title compound (2.88 mmol) was obtained by reacting N-(oxetane-3-ylamino)carbamate tert-butyl ester (3.84 mmol) with N-(oxetane-3-ylamino)carbamate 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-carboxynitrile

[1009] Following general procedure H, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.38 mmol) and oxetane-3-ylhydrazine hydrochloride (0.46 mmol) were reacted at 85 °C for 2 hours to give the title compound as a white solid. UPLC-MS (ES) + (Short acidic): 1.76 minutes, m / z 357.1 [M+2] + .

[1010] N-[[4-[5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazole-3-yl]phenyl]methyl]- 2-Methoxy-benzamide

[1011] Universal procedure K, using 5-amino-3-(4-bromophenyl)-1-[1-(chloromethyl)-2-hydroxyethyl]pyrazole-4-carboxynitrile (0.20 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.28 mmol), yielded the title compound (0.13 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.50 minutes, m / z 440.2 [M] + .

[1012] 5-Amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-3-[4-[[(2-methoxybenzoyl)amino]methyl] [Phenylene]pyrazole-4-carboxamide

[1013] Universal procedure L, with N-[[4-[5-amino-1-[1-(chloromethyl)-2-hydroxy-ethyl]-4-cyano-pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.11 mmol), yielded the title compound (0.03 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.33 minutes, m / z 458.2 [M] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.74 (t, J=6.1Hz, 1H), 7.76 (dd, J=7.6, 1.8Hz, 1H), 7.51-7.41 (m, 5H),7.16(d,J=8.0Hz,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-methylthiazolyl)pyrazole-4-carboxamide

[1015]

[1016] 5-Amino-3-(4-bromophenyl)-1-(4-methylthiazolyl-2-yl)pyrazole-4-carboxynitrile

[1017] Following general procedure H, after purification, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (0.76 mmol) and (4-methylthiazolyl-2-yl)hydrazine (0.91 mmol) were reacted to give the title compound (0.32 mmol) as a yellow solid at 85 °C for 2 hours. UPLC-MS (ES) + (Short acidic): 1.78 minutes, m / z 362.0 [M+2] + .

[1018] N-[[4-[5-amino-4-cyano-1-(4-methylthiazo-2-yl)pyrazole-3-yl]phenyl]methyl]-2-methoxy Benzamide

[1019] Following general procedure K, after purification, 5-amino-3-(4-bromophenyl)-1-(4-methylthiazolyl-2-yl)pyrazol-4-carboxynitrile (86 mg, 0.24 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (100 mg, 0.37 mmol) were reacted to give the title compound (0.08 mmol) as an orange solid. UPLC-MS (ES) +(Short acidic): 1.64 minutes, m / z 445.2 [M+H] + .

[1020] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(4-methylthiazolyl)pyridine azole-4-carboxamide

[1021] Following general procedure M, after purification, N-[[4-[5-amino-4-cyano-1-(4-methylthiazolyl-2-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.05 mmol) was reacted to give the title compound (0.02 mmol) as a yellow solid. UPLC-MS (ES) + (Short acidic): 1.34 minutes, m / z 463.1 [M+H] + UPLC-MS (ES) + (Long acidic): 3.01 minutes, 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] Triphenylphosphine (8.10 mmol) and di-tert-butyl azodicarbonate (6.48 mmol) were added to a solution of 5.40 mmol of 4,4-difluorocyclohexanol in 20 mL of toluene, 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 a solution of hydrogen chloride (4 M in 1,4-dioxane, 10.8 mL, 43.19 mmol), and the mixture was stirred at room temperature for 14 h. 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-carboxynitrile

[1028] Following general procedure H, after purification at 85 °C for 2 hours, 2-[(4-bromophenyl)-methoxy-methylene]malononitrile (133 mg, 0.51 mmol) and (4,4-difluorocyclohexyl)hydrazine hydrochloride (113 mg, 0.61 mmol) were reacted to give the title compound (114 mg, 0.30 mmol, 59% yield) as a white solid. UPLC-MS (ES) + (Short acidity): 2.01 minutes, m / z 383.0 [M+2] + .

[1029] N-[[4-[5-amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazole-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-carboxynitrile (0.30 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.45 mmol) were reacted to give the title compound (0.26 mmol) as an orange solid. UPLC-MS (ES) + (Short acidic): 1.79 minutes, m / z 466.1 [M+H] + .

[1031] 5-Amino-1-(4,4-difluorocyclohexyl)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyridine azole-4-carboxamide

[1032] Following general procedure L, after purification, N-[[4-[5-amino-4-cyano-1-(4,4-difluorocyclohexyl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (160 mg, 0.34 mmol) was reacted to give the title compound (0.11 mmol) as a white solid. UPLC-MS (ES) + (Short acidic): 1.71 minutes, m / z 484.2 [M+H] + UPLC-MS(ES) + (Long acidic): 4.09 minutes, m / z 484.1 [M+H] + .

[1033] 1H NMR (400MHz, DMSO-d6, δ): 8.73 (t, J = 6.1 Hz, 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 at 0 °C with hydrochloric acid (6 M) until a 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 minutes, 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 atmosphere, 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 min. Then methylamine (2 M in THF, 104 μL, 0.21 mmol) was added and the mixture was stirred for 48 h. After treatment and purification, the title compound (0.04 mmol) was given as a white solid. UPLC-MS (ES) + (Short acidity): 1.80 minutes, m / z 448.2 [M+H] +UPLC-MS(ES) + (Long acidic): 4.21 minutes, m / z 448.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6, δ): 8.72 (t, J = 6.1 Hz, 1H), 7.76 (dd, J = 7.7, 1.8 Hz, 1H), 7.51-7.45 (m, 3H), 7.39-7.37 (m, 2H), 7.17-7.15 (m, 1H), 7.07-7.03(m,1H),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]pyridine [Zol-1-yl]cyclohexane carboxylate (isomer 1)

[1043] A suspension of lithium hydroxide (9 mg, 0.39 mmol) in a solution of 3-[5-amino-4-carbamoyl-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-1-carboxylic acid ethyl ester (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 immediately used in the next step. UPLC-MS (ES) + (Short acidic): 1.60 minutes, 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]cyclohexanecarboxylate (isomer 1, 95 mg, 0.19 mmol) in THF (2 mL) was stirred at room temperature for 48 hours with a solution of dimethylamine (2 M in THF, 0.05 mL, 0.96 mmol) and a solution of propylphosphonic anhydride (50 wt% in EtOAc, 0.34 mL, 0.57 mmol). After treatment and purification, the title compound (isomer 1, 0.03 mmol) was obtained. UPLC-MS (ES) + (Short acidic): 1.67 minutes, m / z 519.2 [M+H] + UPLC-MS(ES) + (Long acidic): 3.87 minutes, 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]non-7-yl)pyrazole-4-carboxamide

[1048]

[1049] N-(2-oxaspiro[3.5]non-7-ylideneamino)carbamate tert-butyl ester

[1050] Following general procedure E, crude N-(2-oxaspiro[3.5]non-7-one (120 mg, 0.86 mmol) N-(2-oxaspiro[3.5]non-7-ylamino)carbamate (0.86 mmol) was obtained as a white solid by reacting 2-oxaspiro[3.5]non-7-ylamino)carbamate (136 mg, 1.03 mmol) with tert-butyl hydrazine carbamate (136 mg, 1.03 mmol). 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)pyrazol-4-carboxynitrile

[1052] 0.85 mmol of N-(2-oxaspiro[3.5]non-7-ylethyleneamino)carbamate tert-butyl ester was dissolved in THF (10 mL), and a solution of borane dimethyl sulfide complex (2 M in THF, 0.73 mL, 1.45 mmol) was added. The reaction mixture 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). Then 0.65 mmol of 2-[(4-bromophenyl)-methoxy-methylene]malonium (3.23 mmol) and triethylamine (3.23 mmol) were 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 minutes, 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]non-7-yl)pyrazol-4-carboxynitrile (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 minutes, 472.2 m / z [M+H] + .

[1055] 5-Amino-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]-1-(2-oxaspiro[3.5]non-7- pyrazole-4-carboxamide

[1056] Following general procedure L, after purification, N-[[4-[5-amino-4-cyano-1-(2-oxaspiro[3.5]non-7-yl)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.24 mmol) was reacted to give the title compound (0.06 mmol) as a beige solid. UPLC-MS (ES) + (Short acidic): 1.65 minutes, m / z 490.2 [M+H] + UPLC-MS (ES) + (Long acidic): 3.89 minutes, 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-carboxynitrile

[1060] A mixture of 5-amino-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile (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 treatment and purification, the title compound (0.13 mmol) was given as a brown solid. UPLC-MS: (ES) + (Short acidic): 2.45 minutes, m / z 375.0 [M+2] + .

[1061] N-[[4-[4-cyano-1-cyclopentyl-5-(isopropylamino)pyrazole-3-yl]phenyl]methyl]-2-methoxy-benzene formamide

[1062] Following general procedure K, after purification, 3-(4-bromophenyl)-1-cyclopentyl-5-(isopropylamino)pyrazole-4-carboxynitrile (0.13 mol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.18 mmol) were reacted to give the title compound (0.12 mmol) as a light brown solid. UPLC-MS: (ES + (Short acid): 2.18 minutes, m / z 458.2 [M+H]+.

[1063] 1-Cyclopentyl-5-(isopropylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole- 4-Formamide

[1064] Following general procedure L, after purification, N-[[4-[4-cyano-1-cyclopentyl-5-(isopropylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.12 mmol) was reacted to give the title compound (0.05 mmol) as a white solid. UPLC-MS: (ES) + (Long acidic): 4.99 minutes, m / z 476.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ): 8.71 (t, J = 6.4 Hz, 1H), 7.76 (dd, J = 8.0, 2.0 Hz, 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-carboxynitrile

[1068] A mixture of 5-amino-3-(4-bromophenyl)-1-cyclopentylpyrazole-4-carboxynitrile (0.30 mmol), cesium carbonate (295 mg, 0.91 mmol), and iodoethane (0.36 mmol) in DMF (5 mL) was stirred at RT for 14 hours. After treatment and purification, the title compound (0.15 mmol) was given as a grayish-white solid. UPLC-MS: (ES) + (Short acidic): 2.33 minutes, m / z 361.0 [M+2] + .

[1069] N-[[4-[4-cyano-1-cyclopentyl-5-(ethylamino)pyrazole-3-yl]phenyl]methyl]-2-methoxy-benzyl amide

[1070] Following universal procedure K, after purification, 3-(4-bromophenyl)-1-cyclopentyl-5-(ethylamino)pyrazole-4-carboxynitrile (0.15 mmol) and potassium trifluoro-[[(2-methoxybenzoyl)amino]methyl]borane (0.22 mmol) were reacted to give the title compound (0.14 mmol), a grayish-white solid. UPLC-MS: (ES) + (Short acidic): 2.11 minutes, m / z 444.2 [M+H] + .

[1071] 1-Cyclopentyl-5-(ethylamino)-3-[4-[[(2-methoxybenzoyl)amino]methyl]phenyl]pyrazole-4- formamide

[1072] Following general procedure L, after purification, N-[[4-[4-cyano-1-cyclopentyl-5-(ethylamino)pyrazol-3-yl]phenyl]methyl]-2-methoxy-benzamide (0.14 mmol) was reacted to give the title compound (0.06 mmol) as a white solid. UPLC-MS (ES) + (Long acidic): 4.84 minutes, m / z 462.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, δ): 8.71 (t, J = 6.3 Hz, 1H), 7.75 (dd, J = 7.6, 1.8 Hz, 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-yl]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). Treatment and purification yielded an inseparable mixture of cis and trans title compounds (0.39 mmol) as white solids. UPLC-MS (ES) + (Short acidic): 1.32 minutes, m / z 492.3 [M+H] + UPLC-MS(ES) + (Long acidic): 3.67 minutes, m / z 492.2 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶, δ, cis / trans mixture): 12.1 (brs, 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-(methoxycarbamoyl] [(cyclohexyl)pyrazole-4-carboxamide] [1080...

Claims

1. A compound according to formula (I) or a pharmaceutically acceptable salt thereof: in, R 1 is substituted or unsubstituted: piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, difluoroisopropyl, trifluoroisopropyl, (cyclopropyl)ethyl or (tetrahydropyranyl)ethyl, wherein each of the foregoing groups, when substituted, is substituted by 1 to 5 substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 2-4 Alkyl ether, -OR A 、-NR A R B 、、=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, 3 to 6 membered heterocycloalkyl 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, wherein R A and R B is independently selected at each occurrence from: H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, phenyl, benzyl or -OR H Substituted C 1-4 Alkyl; R H Select from H or C 1-4 alkyl; 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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