Substituted pyrazolo[1,5-a]pyrimidin-7-amine compounds as CDK inhibitors and their therapeutic uses

Abstract

The present invention relates generally to the field of therapeutic compounds. More specifically, the present invention relates to certain substituted pyrazolo[1,5-a]pyrimidin-7-amine compounds PPA that specifically inhibit cyclin-dependent protein kinases (CDKs), particularly CDK12 and / or CDK13, e.g., selective for CDK12 and / or CDK13 over CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby removing key cofactors required for CDK12 and / or CDK13 activation. This provides additional cellular potency and selectivity. The present invention also relates to methods for inhibiting CDKs, particularly CDK12 and / or CDK13; and to disorders associated with CDKs, particularly CDK12 and / or CDK13, disorders resulting from inappropriate activity of CDKs, particularly CDK12 and / or CDK13, disorders associated with CDK mutations, particularly CDK12 mutations and / or CDK13 mutations, disorders associated with CDK overexpression, particularly CDK12 and / or CDK13 overexpression, disorders associated with pathway activation upstream of CDKs, particularly CDK12 and / or CDK13, The present invention relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds and compositions, both in vitro and in vivo, for treating disorders that are ameliorated by inhibition of CDK12 and / or CDK13, including proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischemia; kidney disease; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis), and disorders caused by dysfunction of translation in cells (including muscular dystrophies). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with additional active agents, such as DNA repair inhibitors, immune checkpoint inhibitors, immune system stimulants, cell cycle checkpoint inhibitors, Her2 blockers, transcription inhibitors, cytotoxic chemotherapeutic agents, and the like.

Description

[Technical Field]

[0001] This application is related to United Kingdom (GB) Patent Application No. 2108572.5, filed June 16, 2021, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention relates generally to the field of therapeutic compounds. More particularly, the present invention relates to certain substituted pyrazolo[1,5-a]pyrimidin-7-amine compounds (referred to herein as "PPA compounds") that specifically inhibit cyclin-dependent protein kinases (CDKs), particularly CDK12 and / or CDK13, and are selective for CDK12 and / or CDK13 over, for example, CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby removing key cofactors required for CDK12 and / or CDK13 activation. This results in increased cellular potency and selectivity. The present invention also relates to methods for inhibiting CDKs, particularly CDK12 and / or CDK13; and to disorders associated with CDKs, particularly CDK12 and / or CDK13, disorders resulting from inappropriate activity of CDKs, particularly CDK12 and / or CDK13, disorders associated with CDK mutations, particularly CDK12 mutations and / or CDK13 mutations, disorders associated with CDK overexpression, particularly CDK12 and / or CDK13 overexpression, disorders associated with pathway activation upstream of CDKs, particularly CDK12 and / or CDK13, The present invention relates to pharmaceutical compositions comprising such compounds, as well as the use of such compounds and compositions, both in vitro and in vivo, for treating disorders ameliorated by inhibition of CDK12 and / or CDK13, including proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischemia; kidney disease; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis), and disorders caused by dysfunction of translation in cells (including muscular dystrophies). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, such as, for example, a DNA repair inhibitor, an immune checkpoint inhibitor, an immune system stimulator, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcription inhibitor, a cytotoxic chemotherapeutic agent, etc. [Background technology]

[0003] Several publications are cited herein in order to more fully describe and disclose the present invention and the state of the art to which it pertains. Each of these references is herein incorporated by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0004] Throughout this specification, including the claims that follow, unless the context otherwise requires, the word "comprise", and variations such as "comprises" and "comprising", will be understood to mean the inclusion of a specified integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers or steps.

[0005] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

[0006] Ranges are often expressed herein as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of the prefix "about," it will be understood that the particular value forms another embodiment.

[0007] This disclosure includes information that may be useful in understanding the present invention. This disclosure is not an admission that any information presented herein is prior art or relevant to the invention claimed herein, or that any publication specifically or implicitly referenced is prior art.

[0008] Cyclin-dependent protein kinases (CDKs) Cyclin-dependent protein kinases (CDKs) are catalytic subunits of a family of 21 serine / threonine protein kinases (see, e.g., Malumbres et al., 2009), some of which control cellular progression through the stages of growth, DNA replication, and mitosis (see, e.g., Pines, 1995; Morgan, 1995). Activation of specific CDKs is required for proper progression through the various stages of the cell cycle and transition to the next stage of the cell cycle.

[0009] Cyclin-dependent kinase 12 (CDK12) and its orthologue 13 (CDK13) belong to the cyclin-dependent kinase (CDK) family of serine / threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Studies have characterized CDK12 and CDK13 as transcriptional CDKs that mediate gene transcription by forming complexes with cyclin K and phosphorylating RNA polymerase II (see, e.g., Li et al., 2016; Greifenberg et al., 2016). The CDK12 / cyclin K and CDK13 / cyclin K complexes phosphorylate RNA Pol II at Ser2 (Ser2p-RNA Pol II), which is thought to be a critical step in the transition from transcription initiation to elongation. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in responses to DNA damage, stress, and heat shock (see, e.g., Blazek et al., 2011; Li et al., 2016). Studies have also shown that CDK12 is involved in mRNA splicing, 3'-end processing, pre-replicative complex assembly, and regulating genome stability (see, e.g., Choi et al., 2020). Genomic alterations in CDK12 have been detected in esophageal, gastric, breast, endometrial, uterine, ovarian, bladder, colorectal, and pancreatic cancers (see, e.g., Gyl et al., 2018). Several studies have pointed to CDK12 inhibition as an effective strategy for inhibiting tumor growth, and synthetic lethal interactions with several pathways related to cancer survival and progression have been described (see, e.g., Johnson et al., 2016; Choi et al., 2019). CDK13 regulates a diverse set of genes relative to CDK12, and CDK13 activity is primarily involved in a growing number of signaling pathways, including tyrosine kinase signaling ( Greifenberg et al., 2016 ).

[0010] Degradation of cyclin K is a characteristic of some, but not all, CDK12 inhibitors (see, e.g., Slabicki et al., 2020; Lv et al., 2020). Upon binding of a degrading inhibitor, CDK12 acts as a surrogate substrate receptor for the CUL4-DDB1 ubiquitin ligase complex, presenting cyclin K for ubiquitination by CRL4, leading to proteasomal degradation. The interaction between CDK12 and DDB1 is driven, in part, by the inhibitor's interaction with DDB1. Therefore, only CDK12 inhibitors that simultaneously occupy the kinase active site and fill the hydrophobic pocket of DDB1 can promote cyclin K degradation. For example, the pan-CDK inhibitor CR8 has been found to cause cyclin K degradation by this mechanism, whereas the CDK12-selective covalent inhibitor THZ-531 did not.

[0011] Degradation of cyclin K can complement direct inhibition of CDK12 and / or 13 in cells. This is advantageous for several reasons. First, degradation can result in enhanced efficacy over kinase inhibition alone, as indicated by increased potency of the molecule in cell killing assays. Increased cellular potency can result in reduced off-target interactions and interactions between the inhibitor and kinases other than CDK12 and / or CDK13. Second, cyclin K is an essential partner for both CDK12 and CDK13 and is required for their activity. Thus, cyclin K degraders cause impairment of the activity of both kinases, even when compounds exhibit differential selectivity between CDK12 and CDK13. Finally, cyclin K has been shown to have a half-life of more than 12 hours in cells (see, e.g., Lei et al., 2018). Thus, degraders can have effects in cells and tumors that may extend beyond the period of exposure to the compound.

[0012] Known compounds Schering Corporation describes certain pyrazolo[1,5-a]pyrimidin-7-amine compounds that are said to act as CDK inhibitors. See, for example, Guzi et al., 2004a, 2004b, 2006, 2007, 2008a, 2008b, 2008c. The following compounds are believed to be listed therein:

[0013] [ka] The 9H-purin-6-amine derivative known as CR8 (or more specifically as (R)-CR8 shown below) is a CDK1 / 2 / 5 / 9 / 12 inhibitor that causes proteosomal-dependent degradation of cyclin K. See, e.g., Slabicki et al., 2020.

[0014] [ka]

[0015] Nam et al. (2019) disclose certain compounds of the following formula (wherein X can be CH, and R 1 can be hydrogen).

[0016] [ka]

[0017] Among the examples presented therein (see, for example, Table 11 on pages 139-183 therein), compounds 1, 47, and 62 are shown below. Any of the examples presented therein can be used in combination with the -Ar group of the compounds described herein. 1 -Ar 2 There are no -Z groups allowed by the group.

[0018] [ka]

[0019] Parratt et al. (2019) describe certain compounds of the following formulas that are said to be useful for treating diseases mediated by excessive or inappropriate CDK2, PDK1 and / or CHK1 activity, including cancer, psoriasis and restenosis. Any of the examples provided therein may be used in combination with the -Ar moiety of the compounds described herein. 1 -Ar 2 There are no -AQ groups allowed by the group.

[0020] [ka]

[0021] (2016) describe certain compounds of the following formula (wherein X can be CH, m can be 1, R6 can be hydrogen, and L2 can be absent) that are purported to be selective transcription CDK inhibitors. None of the examples provided therein are equivalent to the -Ar of the compounds described herein. 1 -Ar 2 There are no -A-L2-B groups allowed by the group.

[0022] [ka]

[0023] Vankayalapati et al. (2020) describe that certain compounds of the following formula, which are said to inhibit CDK7, are useful in the treatment of cancer. In these compounds, R 2 is defined as -C(=O)alkyl, optionally substituted aryl, or optionally substituted alkylaryl (see page 17 thereof), including, for example, benzyl (see pages 19-20 thereof). Any of the examples provided therein may be used in the -Ar of the compounds described herein. 1 -Ar2 R allowed by the group 2 It has no group.

[0024] [ka] Summary of the Invention [Problem to be solved by the invention]

[0025] Potency / selectivity The PPA compounds described herein are highly potent CDK12 and / or CDK13 inhibitors that are also selective for CDK12 and / or CDK13, for example, relative to CDK7.

[0026] In addition to selectively inhibiting CDK12 and / or CDK13, the PPA compounds described herein also act as selective cyclin K degraders, thereby eliminating key signaling mechanisms required for CDK12 and / or CDK13 activation, resulting in additional cellular potency and selectivity.

[0027] One aspect of the present invention pertains to certain substituted pyrazolo[1,5-a]pyrimidin-7-amine compounds (herein referred to as "PPA compounds"), as described herein.

[0028] Another aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising a PPA compound described herein and a pharmaceutically acceptable carrier or diluent.

[0029] Another aspect of the invention relates to a method of preparing a composition (e.g., a pharmaceutical composition), comprising mixing a PPA compound described herein and a pharmaceutically acceptable carrier or diluent.

[0030] Another aspect of the invention relates to a method of inhibiting CDK12 and / or CDK13 function in vitro or in vivo (e.g., in a cell), comprising contacting the cell with an effective amount of a PPA compound described herein.

[0031] Another aspect of the present invention relates to a method for modulating (e.g., inhibiting) cell proliferation (e.g., proliferation of cells), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more thereof, in vitro or in vivo, comprising contacting a cell with an effective amount of a PPA compound described herein.

[0032] Another aspect of the present invention relates to the PPA compounds described herein for use in methods of treatment of the human or animal body by therapy, e.g., for use in methods of treatment of disorders (e.g., diseases) described herein.

[0033] Another aspect of the invention relates to the use of a PPA compound as described herein in the manufacture of a medicament, e.g., for use in a method of treatment, e.g., for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0034] Another aspect of the invention relates to methods of treatment, e.g., methods of treating a disorder (e.g., a disease) described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of a PPA compound described herein, preferably in the form of a pharmaceutical composition.

[0035] In one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, e.g., a DNA repair inhibitor, an immune checkpoint inhibitor, an immune system stimulator, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcription inhibitor, a cytotoxic chemotherapeutic agent, etc., as described herein.

[0036] Another aspect of the present invention relates to kits comprising (a) a PPA compound described herein, preferably supplied as a pharmaceutical composition in a suitable container and / or in suitable packaging, and (b) instructions for use, e.g., written instructions on how to administer the compound.

[0037] Another aspect of the present invention relates to PPA compounds obtainable by the synthetic methods described herein or by methods including the synthetic methods described herein.

[0038] Another aspect of the present invention relates to PPA compounds obtained by the synthetic methods described herein or by a method including the synthetic methods described herein.

[0039] Another aspect of the present invention pertains to novel intermediates, as described herein, that are suitable for use in the synthetic methods described herein.

[0040] Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the synthetic methods described herein.

[0041] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention also relate to other aspects of the invention. [Brief explanation of the drawings]

[0042] [Figure 1] FIG. 1 shows the effects of THZ-531, CR8, PPA-005 and PPA-006 on the degradation of cyclin K in A673 cells, as assessed by Western blotting, and the effect of MLN4924 on cytotoxic potency in A673 cells. DETAILED DESCRIPTION OF THE INVENTION

[0043] compound The present invention relates to certain compounds structurally related to pyrazolo[1,5-a]pyrimidin-7-amine (“PPA”):

[0044] [ka]

[0045] That is, one aspect of the present invention is -L 7 -, -Ar 1 -, -Ar 2 , -X 5 -, -L 5 -, -Cy 5 and -R 3 is as defined herein, or a pharmaceutically acceptable salt or solvate thereof (for convenience, collectively referred to herein as a "PPA" compound):

[0046] [ka]

[0047] -L 7 -Ar 1 -Ar 2 Note that the -NH- group linking the group to the pyrazolo[1,5-a]pyrimidine ring is intended to be unsubstituted.

[0048] Note that the pyrazolo[1,5-a]pyrimidine ring is intended to be unsubstituted at the 2- and 6-positions.

[0049] Some embodiments include: (1) A compound of the following formula:

[0050] [ka] or a pharmaceutically acceptable salt or solvate thereof: (In the formula, -L 7 - is independently -CH2-, -CH(R L7 )- or -C(R L7 )2- and -R L7each independently represents a linear or branched saturated C 1~4 is alkyl, -Ar 1 - is independently phenylene, C6 heteroarylene, or C5 heteroarylene; One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N and optionally substituted by -Ar 2 - is independently phenyl, C6 heteroaryl, or C5 heteroaryl; One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N and optionally substituted by -X 5 - is independently -NH-, -NR X5 -, -O- or a single bond, -R X5 is a linear or branched saturated C 1~4 is alkyl, -L 5 - is independently -CH2-, -CH(R L5 )-, -C(R L5 ) 2- or a single bond, -R L5 each independently represents a linear or branched saturated C 1~4 is alkyl, -Cy 5 are independently -Cy 5A or -Cy 5B and -Cy 5A is a non-aromatic C having at least one nitrogen ring atom 4~10 is heterocyclyl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN and optionally substituted by -Cy 5B is a C having at least one nitrogen ring atom 5~6 is heteroaryl, One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN and optionally substituted by -R 3 independently, -R 3A , -R 3B , -R 3C or -CN, -R 3A is a linear or branched saturated C 1~6 is alkyl, one or more groups -R R3 and optionally substituted by -R 3B is the saturated C 3~6 is cycloalkyl, one or more groups -R R3 and optionally substituted by -R 3C is -F, -Cl, -Br or -I, -R R3 are each independently -F, -OH, or -OMe; -R AR1C are and -R, respectively AR2C are respectively, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -L T -OH, -L T -OR TT , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR TT , -NR TT 2, -R TM , -L T -NH2, -L T -NHR TT , -L T -NRTT 2、-L T -R TM 、 -C(=O)OH、-C(=O)OR TT 、 -OC(=O)R TT 、 -C(=O)NH2、-C(=O)NHR TT 、-C(=O)NR TT 2、-C(=O)R TM 、 -NHC(=O)R TT 、-NR TN C(=O)R TT 、 -NHC(=O)NH2、-NHC(=O)NHR TT 、-NHC(=O)NR TT 2、-NHC(=O)R TM 、 -NR TN C(=O)NH2、-NR TN C(=O)NHR TT 、-NR TN C(=O)NR TT 2、-NR TN C(=O)R TM 、 -NHC(=O)OR TT 、-NR TN C(=O)OR TT 、 -OC(=O)NH2、-OC(=O)NHR TT 、-OC(=O)NR TT 2、-OC(=O)R TM 、 -C(=O)R TT 、 - SR TT 、-S(=O)R TT 、-S(=O)2R TT 、 -S(=O)NH2、-S(=O)NHR TT 、-S(=O)NR TT 2、-S(=O)R TM 、 -S(=O)2NH2、-S(=O)2NHR TT 、-S(=O)2NR TT 2、-S(=O)2R TM 、 -NHS(=O)2R TT , -NR TN S(=O)2R TT , -CN and -NO2 are independently selected from -R AR1N are and -R, respectively AR2N are respectively, -R TT , -L T -OH, -L T -OR TT , -L T -NH2, -L T -NHR TT , -L T -NR TT 2, -L T -R TM , -C(=O)R TT , -C(=O)OR TT , -C(=O)NH2, -C(=O)NHR TT , -C(=O)NR TT 2. -C(=O)R TM , and -S(=O)2R TT are independently selected from During the ceremony, -L T - each independently represents a linear or branched saturated C 1~4 is alkylene, -R TT are each independently -R TT1 , -R TT2 , -L TT -R TT2 , -R TT3 or -L TT -R TT3 and -R TT1 each independently represents a linear or branched saturated C 1~6 Alkyl, -F, -OH and -OR TTT and optionally substituted with one or more groups selected from -RTT2 are saturated C 3~6 cycloalkyl, -F, -R TTT , -OH and -OR TTT and optionally substituted with one or more groups selected from -R TT3 are each independently phenyl or naphthyl, -F, -Cl, -Br, -I, -R TTT , OH, -OR TTT , -OCF3, -NH2, -NHR TTT and -NR TTT Optionally substituted with one or more groups selected from -L TT - each independently represents a linear or branched saturated C 1~4 is alkylene, -R TN are linear or branched saturated C 1~4 alkyl, phenyl or benzyl; -R TM are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; On carbon, -R TMM , -C(=O)R TMM , -S(=O)2R TMM , -F, -NH2, -NHR TMM , -NR TMM 2, -OH and -OR TMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R TMM , -C(=O)R TMM , -C(=O)OR TMM and -S(=O)2R TMM and optionally substituted with a group selected from -R TTT each independently represents a linear or branched saturated C 1~4 alkyl, phenyl or benzyl; -R TMM each independently represents a linear or branched saturated C 1~4 alkyl, phenyl or benzyl; -R Cy5AC are and -R, respectively Cy5BC are respectively, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -L J -OH, -L J -OR JJ , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR JJ , -NR JJ 2, -R JM , -L J -NH2, -L J -NHR JJ , -L J -NR JJ 2, -L J -R JM , -C(=O)OH, -C(=O)OR JJ , -OC(=O)R JJ , -C(=O)NH2, -C(=O)NHR JJ , -C(=O)NR JJ 2. -C(=O)R JM , -NHC(=O)R JJ , -NR JN C(=O)R JJ , -NHC(=O)NH2, -NHC(=O)NHR JJ , -NHC(=O)NR JJ 2. -NHC(=O)R JM , -NR JN C(=O)NH2, -NR JN C(=O)NHR JJ , -NR JN C(=O)NR JJ 2, -NR JN C(=O)R JM , -NHC(=O)OR JJ , -NR JN C(=O)ORJJ , -OC(=O)NH2, -OC(=O)NHR JJ , -OC(=O)NR JJ 2. -OC(=O)R JM , -C(=O)R JJ , -SR JJ , -S(=O)R JJ , -S(=O)2R JJ , -S(=O)NH2, -S(=O)NHR JJ , -S(=O)NR JJ 2. -S(=O)R JM , -S(=O)2NH2, -S(=O)2NHR JJ , -S(=O)2NR JJ 2. -S(=O)2R JM , -NHS(=O)2R JJ , -NR JN S(=O)2R JJ , -CN and -NO2 are independently selected from -R Cy5AN are and -R, respectively Cy5BN are respectively, -R JJ , -L J -OH, -L J -OR JJ , -L J -NH2, -L J -NHR JJ , -L J -NR JJ 2, -L J -R JM , -C(=O)R JJ , -C(=O)OR JJ , -C(=O)NH2, -C(=O)NHR JJ , -C(=O)NR JJ 2. -C(=O)R JM , and -S(=O)2R JJ are independently selected from During the ceremony, -L J - each independently represents a linear or branched saturated C 1~4 is alkylene, -R JJ are each independently -R JJ1 , -R JJ2 , -L JJ -R JJ2 , -R JJ3 or -L JJ -R JJ3 and -R JJ1 each independently represents a linear or branched saturated C 1~6 Alkyl, -F, -OH and -OR JJJ and optionally substituted with one or more groups selected from -R JJ2 are saturated C 3~6 cycloalkyl, -F, -R JJJ , -OH and -OR JJJ and optionally substituted with one or more groups selected from -R JJ3 are each independently phenyl or naphthyl, -F, -Cl, -Br, -I, -R JJJ , OH, -OR JJJ , -OCF3, -NH2, -NHR JJJ and -NR JJJ Optionally substituted with one or more groups selected from -L JJ - each independently represents a linear or branched saturated C 1~4 is alkylene, -R JN are linear or branched saturated C 1~4 alkyl, phenyl or benzyl; -R JM are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; On carbon, -R JMM , -C(=O)R JMM , -S(=O)2RJMM , -F, -NH2, -NHR JMM , -NR JMM 2, -OH and -OR JMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R JMM , -C(=O)R JMM , -C(=O)OR JMM and -S(=O)2R JMM and optionally substituted with a group selected from -R JJJ each independently represents a linear or branched saturated C 1~4 alkyl, phenyl or benzyl; -R JMM each independently represents a linear or branched saturated C 1~4 alkyl, phenyl or benzyl; however, -X 5 - is a single bond, and -L 5 - is a single bond, and -R 3 If is -Br, -Ar 2 is neither oxadiazolyl nor thiadiazolyl Provided that, however, -X 5 - is a single bond, and -L 5 - is a single bond, -Ar 2 is not pyrazolyl (Provided that:

[0051] To avoid misunderstandings, The symbol "C" in the term x~y " is, for example, "C 9~10 Heteroaryl, C 3~7 "Heterocyclyl" and the like refer to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be). For example, pyridyl is an example of a C6 heteroaryl group, and piperidino is an example of a C6 heterocyclyl group.

[0052] The term "heteroaryl" refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, where the aromatic ring is part of an aromatic ring system that has one or more heteroatoms (e.g., optionally N, O, S). For example, pyridyl is an example of a C6 heteroaryl group, and quinolyl is a C 10 are examples of heteroaryl groups.

[0053] The term "heterocyclyl" refers to a group that is attached to the rest of the molecule by an atom that is part of a non-aromatic ring, where the non-aromatic ring is part of a non-aromatic ring system that has one or more heteroatoms (e.g., optionally N, O, S). Unless otherwise specified, "heterocyclyl" includes monocyclic heterocyclyl (e.g., piperidinyl, which is an example of a monocyclic C heterocyclyl), fused heterocyclyl (e.g., fused C 10 Examples of heterocyclyl include decahydroquinolinyl), bridged heterocyclyl (e.g., 6-azabicyclo[3.1.1]heptanyl, an example of a bridged C7 heterocyclyl), and spiroheterocyclyl (7-azaspiro[3.5]nonyl, an example of a spiro C9 heterocyclyl).

[0054] Optional substituents (e.g., "one or more groups -R AR1C In the context of a parent moiety (e.g., "), the phrase "one or more groups" is necessarily constrained by the parent moiety and the number of positions available for substitution on the parent moiety. In some parent moieties (e.g., tetrazolyl), there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five). Unless constrained by the parent moiety, the "one or more groups" may be, for example, 1, 2, 3, 4, etc., but is more preferably 1, 2, or 3, even more preferably 1 or 2, and even more preferably 1.

[0055] The phrase "carbon substituent" is intended to refer to a substituent attached to a carbon ring atom. Similarly, the phrase "secondary nitrogen substituent" is intended to refer to a substituent attached to a nitrogen ring atom that, in the absence of a substituent, is a secondary nitrogen ring atom (i.e., -NH-). Thus, as exemplified below, a pyridyl group can have only a "carbon substituent," while an 1H-pyrrole can have both a "carbon substituent" and a "secondary nitrogen substituent."

[0056] [ka]

[0057] Similarly, as illustrated below, a piperidino group can have only a "carbon substituent," while a piperidino can have both a "carbon substituent" and a "secondary nitrogen substituent."

[0058] [ka]

[0059] Despite having carbon ring atoms, certain groups may not have any carbon ring atoms available for substitution. For example, as illustrated below, a tetrazolyl group may only allow "carbon substituents" or may only allow "secondary nitrogen substituents."

[0060] [ka]

[0061] Unless otherwise indicated, when a compound is shown or described with one or more chiral centers, and two or more stereoisomers are possible, all such stereoisomers are disclosed and included, both individually (e.g., isolated from other stereoisomers) and in admixture (e.g., equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, if a compound has one chiral center, each of the (R) and (S) enantiomers is disclosed and included, both individually (e.g., isolated from other enantiomers) and in admixture (e.g., equimolar or non-equimolar mixtures of two enantiomers). For example, the first carbon atom of the side chain sec-butyl group, —CH(CH3)CH2CH3, is typically chiral, resulting in stereoisomers, e.g., the (R) and (S) enantiomers, each of which is disclosed and included when this carbon is the only chiral center.

[0062] Group-L 7 - (2)-L 7 - is independently -CH2- or -CH(R L7 )-.

[0063] (3)-L 7 The compound according to (1), wherein - is -CH2-.

[0064] Group-R L7 (4)-R L7 A compound according to any one of (1) to (3), wherein each, if present, is independently -Me, -Et, -nPr, or -iPr.

[0065] (5)-R L7 A compound according to any one of (1) to (3), wherein each, if present, is independently -Me or -Et.

[0066] (6)-R L7 A compound according to any one of (1) to (3), wherein each, if present, is -Me.

[0067] Group-X 5 - (7)-X 5 -, independently, -NH-, -NR X5 - or a single bond.

[0068] (8)-X 5 - is independently -NH- or -NR X5 - a compound according to any one of (1) to (6).

[0069] (9)-X 5 The compound according to any one of (1) to (6), wherein - is -NH-.

[0070] (10)-X 5 -Ga-NR X5 - a compound according to any one of (1) to (6).

[0071] (11)-X 5 A compound according to any one of (1) to (6), wherein - is -O-.

[0072] (12)-X 5 A compound according to any one of (1) to (6), wherein - is a single bond.

[0073] Group-L 5 - (13)-L 5 A compound according to any one of (1) to (12), wherein - is independently -CH2- or a single bond.

[0074] (14)-L 5 A compound according to any one of (1) to (12), wherein - is -CH2-.

[0075] (15)-L 5 A compound according to any one of (1) to (12), wherein - is a single bond.

[0076] -X 5- and -L 5 -Some preferred combinations of (16) Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-) Cy 5 -CH2-NR X5 -(i.e., -L 5 - is -CH2-, and -X 5 -Ha-NR X5 -is) Cy 5 -CH2-O- (i.e., -L 5 - is -CH2-, and -X 5 - is -O-) Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) Cy 5 -NR X5 -(i.e., -L 5 - is a single bond, -X 5 -Ha-NR X5 -is) Cy 5 -O- (i.e., -L 5 - is a single bond, -X 5 is -O-), or Cy 5 -(i.e., -L 5 -and-X 5 Each - is a single bond. A compound according to any one of (1) to (6),

[0077] (17) Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5- is -NH-) Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) Cy 5 -O- (i.e., -L 5 - is a single bond, -X 5 is -O-), or Cy 5 -(i.e., -L 5 -and-X 5 Each - is a single bond. A compound according to any one of (1) to (6),

[0078] (18) Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-) Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-, or Cy 5 -O- (i.e., -L 5 - is a single bond, -X 5 is -O-) A compound according to any one of (1) to (6),

[0079] (19) Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-, or Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) A compound according to any one of (1) to (6),

[0080] (20) Cy 5 -L 5 -X 5 -but, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-) A compound according to any one of (1) to (6),

[0081] (21) Cy 5 -L 5 -X 5 -but, Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) A compound according to any one of (1) to (6),

[0082] Group-R X5 (22)-R X5 A compound according to any one of (1) to (21), wherein, if present, is independently -Me, -Et, -nPr, or -iPr.

[0083] (23)-R X5 A compound according to any one of (1) to (21), wherein, if present, is independently -Me or -Et.

[0084] (24)-R X5 A compound according to any one of (1) to (21), wherein, if present, is -Me.

[0085] Group-R L5 (25)-R L5 A compound according to any one of (1) to (24), wherein each, if present, is independently -Me, -Et, -nPr, or -iPr.

[0086] (26)-R L5 A compound according to any one of (1) to (24), wherein each, if present, is independently -Me or -Et.

[0087] (27)-R L5 A compound according to any one of (1) to (24), wherein each, if present, is -Me.

[0088] Group-R 3 (28)-R 3 -Ga-R 3A or -R 3B A compound according to any one of (1) to (27),

[0089] (29)-R 3 -Ga-R 3A A compound according to any one of (1) to (27),

[0090] (30)-R 3 Ga-R 3B A compound according to any one of (1) to (27),

[0091] (31)-R 3 Ga-R 3C - A compound according to any one of (1) to (27).

[0092] (32)-R 3 A compound according to any one of (1) to (27), wherein is -CN.

[0093] Group-R 3A (33)-R 3A If present, linear or branched saturated C 1~6 A compound according to any one of (1) to (32), wherein the compound is alkyl.

[0094] (34)-R 3Ais, if present, independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu or -tBu, n-pentyl, t-pentyl, neo-pentyl, iso-pentyl, sec-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 4-methyl-2-pentyl, 4-methyl-3-pentyl, 2-methyl-2-pentyl, 2-methyl-1-pentyl, 2-methyl-2-pentyl, 3,3-dimethyl-1-butyl, 3,3-dimethyl-2-butyl, 3-methyl-1-pentyl, 3-methyl-2-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl or 2,3-dimethyl-2-butyl.

[0095] (35)-R 3A If present, linear or branched saturated C 1~4 A compound according to any one of (1) to (32), wherein the compound is alkyl.

[0096] (36)-R 3A A compound according to any one of (1) to (32), wherein, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0097] (37)-R 3A A compound according to any one of (1) to (32), wherein, if present, is independently -Me, -Et, -nPr, or -iPr.

[0098] (38)-R 3A A compound according to any one of (1) to (32), wherein, if present, is independently -Et, -nPr, or -iPr.

[0099] (39)-R 3A A compound according to any one of (1) to (32), wherein, if present, is -iPr.

[0100] Group-R 3B (40)-R 3B If exists, the saturated C 3~6 A compound according to any one of (1) to (39), which is cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0101] (41)-R 3B A compound according to any one of (1) to (39), wherein, if present, is independently cyclopropyl or cyclobutyl.

[0102] (42)-R 3B A compound according to any one of (1) to (39), wherein, if present, is cyclopropyl.

[0103] Group-R 3C (43)-R 3C A compound according to any one of (1) to (42), wherein, if present, is independently -F or -Cl.

[0104] (44)-R 3C A compound according to any one of (1) to (42), wherein, if present, is —Cl.

[0105] Group-R R3 (45)-R R3 A compound according to any one of (1) to (44), wherein each, if present, is independently selected from -F and -OH.

[0106] Group - Ar 1 -: Phenylene (46)-Ar 1 - is phenylene and one or more groups -R AR1C A compound according to any one of (1) to (45), optionally substituted by:

[0107] (47)-Ar 1 - is independently 1,4-phenylene, 1,3-phenylene, or 1,2-phenylene, and one or more groups -RAR1C A compound according to any one of (1) to (45), optionally substituted by:

[0108] [ka]

[0109] (48)-Ar 1 - is 1,4-phenylene and one or more groups -R AR1C A compound according to any one of (1) to (45), optionally substituted by:

[0110] (49)-Ar 1 A compound according to any one of (1) to (45), wherein - is 1,4-phenylene.

[0111] Group - Ar 1 -:C6 heteroarylene (50)-Ar 1 - is a C6 heteroarylene and has one or more groups -R AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0112] (51)-Ar 1 is independently pyridine-diyl, pyrimidin-diyl, pyridazine-diyl or pyrazine-diyl, One or more groups -R on the carbon AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0113] Pyridine-di-yl: (52)-Ar 1 - is pyridine-diyl and has one or more groups -R AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0114] (53)-Ar 1is independently pyridine-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl, pyridine-2,6-diyl, pyridine-3,4-diyl or pyridine-3,5-diyl; One or more groups -R on the carbon AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0115] [ka]

[0116] (54)-Ar 1 is independently pyridine-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl or pyridine-3,5-diyl; One or more groups -R on the carbon AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0117] (55)-Ar 1 - is pyridine-2,5-diyl, One or more groups -R on the carbon AR1C A compound according to any one of (1) to (49), optionally substituted by:

[0118] (56)-Ar 1 - is pyridine-2,5-diyl, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 A compound according to any one of (1) to (49), wherein

[0119] [ka]

[0120] (57)-Ar 1 - is pyridine-2,5-diyl, -Ar 2 A compound according to any one of (1) to (49), wherein

[0121] Group - Ar 1 -:C5 heteroarylene (58)-Ar 1 - is C5 heteroarylene; One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N A compound according to any one of (1) to (57), optionally substituted by:

[0122] (59)-Ar 1 - is independently pyrrole-diyl, pyrazole-diyl, imidazole-diyl, triazole-diyl, tetrazole-diyl, furan-diyl, thiofuran-diyl, oxazole-diyl, isoxazole-diyl, thiazol-diyl, isothiazole-diyl, oxadiazol-diyl or thiadiazol-diyl; If present, one or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N A compound according to any one of (1) to (57), optionally substituted by:

[0123] (60)-Ar 1 - is independently pyrrole-diyl, pyrazole-diyl, imidazole-diyl, triazole-diyl, tetraazole-diyl, furan-diyl, thiofuran-diyl, oxazole-diyl, isoxazole-diyl, thiazol-diyl, isothiazole-diyl, If present, one or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1NA compound according to any one of (1) to (57), optionally substituted by:

[0124] (61)-Ar 1 is independently pyrrole-diyl, pyrazole-diyl, imidazole-diyl, oxazole-diyl or isoxazole-diyl, One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N A compound according to any one of (1) to (57), optionally substituted by:

[0125] (62)-Ar 1 - is independently pyrrole-diyl, pyrazole-diyl or imidazole-diyl, One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N A compound according to any one of (1) to (57), optionally substituted by:

[0126] Imidazole-diyl: (63)-Ar 1 - is imidazole-diyl, One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1N A compound according to any one of (1) to (57), optionally substituted by:

[0127] (64)-Ar 1 is independently imidazole-2,4-diyl or imidazole-1,4-diyl, One or more groups -R on the carbon AR1C and optionally substituted by If present, a group -R on the secondary nitrogen AR1NA compound according to any one of (1) to (57), optionally substituted by:

[0128] [ka]

[0129] (65)-Ar 1 - is imidazole-2,4-diyl, One or more groups -R on the carbon AR1C and optionally substituted by -R group on secondary nitrogen AR1N and optionally substituted by -Ar 2 A compound according to any one of (1) to (57), wherein is attached at the 4-position.

[0130] [ka]

[0131] (66)-Ar 1 - is imidazole-2,4-diyl, -Ar 2 A compound according to any one of (1) to (57), wherein is attached at the 4-position.

[0132] (67)-Ar 1 - is imidazole-1,4-diyl, One or more groups -R on the carbon AR1C A compound according to any one of (1) to (57), optionally substituted by:

[0133] (68)-Ar 1 - is imidazole-1,4-diyl, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 A compound according to any one of (1) to (57), wherein is attached at the 1-position.

[0134] [ka]

[0135] (69)-Ar 1 - is imidazole-1,4-diyl, -Ar 2 is bonded at the 1st position, A compound according to any one of (1) to (57).

[0136] Group - Ar 2 : In the case of phenyl (70)-Ar 2 is phenyl, one or more groups -R AR2C A compound according to any one of (1) to (69), optionally substituted by:

[0137] Group - Ar 2 : When C6 heteroaryl (71)-Ar 2 is a C6 heteroaryl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0138] (72)-Ar 2 is independently pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0139] Pyridinyl: (73)-Ar 2 is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl), One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0140] [ka]

[0141] (74)-Ar 2 is pyridin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0142] (75)-Ar 2 is pyridin-2-yl.

[0143] (76)-Ar 2 is pyridin-3-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0144] (77)-Ar 2 is pyridin-4-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0145] Pyrimidinyl: (78)-Ar 2 is pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0146] [ka]

[0147] (79)-Ar 2 is pyrimidin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0148] (80)-Ar 2 is pyrimidin-2-yl.

[0149] (81)-Ar 2 is pyrimidin-3-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0150] (82)-Ar 2 is pyrimidin-4-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0151] Pyridazinyl: (83)-Ar 2 is pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl), One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0152] [ka]

[0153] (84)-Ar 2 is pyridazin-3-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0154] (85)-Ar 2 is pyridazin-4-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0155] Pyrazinyl: (86)-Ar 2 is pyrazinyl (e.g., pyrazin-2-yl), One or more groups -R on the carbon AR2C A compound according to any one of (1) to (70), optionally substituted by:

[0156] [ka]

[0157] Group - Ar 2 : When C5 heteroaryl (87)-Ar 2 is a C5 heteroaryl; One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0158] (88)-Ar 2 are independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiofuranyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; If present, one or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0159] (89)-Ar 2 is independently pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl; One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0160] Pyrrolyl: (90)-Ar 2 is pyrrolyl (e.g., pyrrol-1-yl, 1H-pyrrol-2-yl, or 1H-pyrrol-3-yl), One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0161] [ka] (91)-Ar 2 is pyrrol-1-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0162] (92)-Ar 2 is 1H-pyrrol-2-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0163] (93)-Ar 2 is 1H-pyrrol-3-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2NA compound according to any one of (1) to (86), optionally substituted by:

[0164] Pyrazolyl: (94)-Ar 2 is pyrazolyl (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl); One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0165] [ka]

[0166] (95)-Ar 2 is pyrazol-1-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0167] (96)-Ar 2 is pyrazol-1-yl.

[0168] (97)-Ar 2 is 1H-pyrazol-3-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0169] (98)-Ar 2 is 1H-pyrazol-4-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0170] (99)-Ar 2 is 1H-pyrazol-5-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0171] Imidazolyl: (100)-Ar 2 is imidazolyl (e.g., imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, or 1H-imidazol-5-yl); One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0172] [ka]

[0173] (101)-Ar 2 is imidazol-1-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0174] (102)-Ar 2 is 1H-imidazol-2-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2NA compound according to any one of (1) to (86), optionally substituted by:

[0175] (103)-Ar 2 is 1H-imidazol-4-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0176] (104)-Ar 2 is 1H-imidazol-5-yl, One or more groups -R on the carbon AR2C and optionally substituted by -R group on secondary nitrogen AR2N A compound according to any one of (1) to (86), optionally substituted by:

[0177] Oxazolyl: (105)-Ar 2 is oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl); One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0178] [ka]

[0179] (106)-Ar 2 is oxazol-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0180] (107)-Ar 2 is oxazol-4-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0181] (108)-Ar 2 is oxazol-5-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0182] Thiazolyl: (109)-Ar 2 is thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl); One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0183] [ka]

[0184] (110)-Ar 2 is thiazol-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0185] (111)-Ar 2 is thiazol-2-yl.

[0186] (112)-Ar 2 is thiazol-4-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0187] (113)-Ar 2 is thiazol-5-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (86), optionally substituted by:

[0188] Ar 1 and Ar 2 Some preferred combinations of Pyridinyl-phenyl as Ar 2 -Ar 1 -: (114)-Ar 1 - is phenylene; One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 - is pyridinyl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0189] (115)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 - is pyridinyl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0190] (116)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyridin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0191] (117)-Ar 1- is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyridin-2-yl.

[0192] (118)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyridin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0193] (119)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyridin-2-yl.

[0194] Pyrimidinyl-phenyl as Ar 2 -Ar 1 -: (120)-Ar 1 - is phenylene; One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 - is pyrimidinyl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0195] (121)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 - is pyrimidinyl, One or more groups -R on the carbon AR2CA compound according to any one of (1) to (45), optionally substituted by:

[0196] (122)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyrimidin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0197] (123)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyrimidin-2-yl.

[0198] (124)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyrimidin-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0199] (125)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyrimidin-2-yl.

[0200] Thiazolyl-phenyl as Ar 2 -Ar 1 -: (126) -Ar 1 - is phenylene; One or more groups -R on the carbonAR1C and optionally substituted by -Ar 2 - is thiazolyl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0201] (127)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 - is thiazolyl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0202] (128)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is thiazol-2-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0203] (129)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is thiazol-2-yl.

[0204] (130)-Ar 1 - is 1,4-phenylene, -Ar 2 is thiazol-2-yl, One or more groups -R on the carbon AR2CA compound according to any one of (1) to (45), optionally substituted by:

[0205] (131)-Ar 1 - is 1,4-phenylene, -Ar 2 is thiazol-2-yl.

[0206] Pyrazolyl-phenyl as Ar 2 -Ar 1 -: (132)-Ar 1 - is phenylene; One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyrazolyl, One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (45), optionally substituted by:

[0207] (133)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyrazolyl, One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N A compound according to any one of (1) to (45), optionally substituted by:

[0208] (134)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2is pyrazol-1-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0209] (135)-Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is pyrazol-1-yl.

[0210] (136)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyrazol-1-yl, One or more groups -R on the carbon AR2C A compound according to any one of (1) to (45), optionally substituted by:

[0211] (137)-Ar 1 - is 1,4-phenylene, -Ar 2 is pyrazol-1-yl.

[0212] Substituent -R AR1C and -R AR2C (138)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -L T -OH, -L T -OR TT , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR TT, -NR TT 2, -R TM , -L T -NH2, -L T -NHR TT , -L T -NR TT 2, -L T -R TM , -C(=O)OH, -C(=O)OR TT , -OC(=O)R TT , -C(=O)NH2, -C(=O)NHR TT , -C(=O)NR TT 2. -C(=O)R TM , -NHC(=O)R TT , -NR TN C(=O)R TT , -C(=O)R TT , -S(=O)2R TT , -S(=O)NH2, -S(=O)NHR TT , -S(=O)NR TT 2. -S(=O)R TM , -S(=O)2NH2, -S(=O)2NHR TT , -S(=O)2NR TT 2. -S(=O)2R TM , -NHS(=O)2R TT , -NR TN S(=O)2R TT , -CN and -NO2 A compound according to any one of (1) to (137), independently selected from:

[0213] (139)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -L T -OH, -L T -OR TT , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR TT , -NR TT 2, -R TM , -L T -NH2, -L T -NHR TT , -L T -NR TT 2, -L T -R TM , -C(=O)OH, -C(=O)OR TT , -OC(=O)R TT , -C(=O)NH2, -C(=O)NHR TT , -C(=O)NR TT 2. -C(=O)R TM , -NHC(=O)R TT , -NR TN C(=O)R TT , -C(=O)R TT , -CN and -NO2 A compound according to any one of (1) to (137), independently selected from:

[0214] (140)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -L T -OH, -L T -OR TT , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR TT , -NR TT 2, -RTM , -L T -NH2, -L T -NHR TT , -L T -NR TT 2, -L T -R TM , -CN and -NO2 A compound according to any one of (1) to (137), independently selected from:

[0215] (141)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR TT , -NR TT 2, -R TM , -CN and -NO2 A compound according to any one of (1) to (137), independently selected from:

[0216] (142)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -CF3, -CHF2, -OCF3 and -OCHF2 A compound according to any one of (1) to (137), independently selected from:

[0217] (143)-R AR1C and -R, respectively, if present AR2C respectively, if they exist, -F, -Me, -OMe, -CF3 and -OCF3 A compound according to any one of (1) to (137), independently selected from:

[0218] (144)-R AR1C respectively, if they exist, -F, -Me and -OMe A compound according to any one of (1) to (137), independently selected from:

[0219] Substituent -R AR1N and -R AR2N (145)-R AR1N and -R, respectively, if present AR2N respectively, if they exist, -R TT , -C(=O)R TT , -C(=O)OR TT and -S(=O)2R TT A compound according to any one of (1) to (144), independently selected from:

[0220] (146)-R AR1N and -R, respectively, if present AR2N respectively, if they exist, -R TT , -C(=O)R TT and -C(=O)OR TT A compound according to any one of (1) to (144), independently selected from:

[0221] (147)-R AR1N and -R, respectively, if present AR2N respectively, if they exist, -R TT A compound according to any one of (1) to (144),

[0222] Group-R TT (148)-R TT each, if present, independently, -R TT1, -R TT2 , -R TT3 or -L TT -R TT3 A compound according to any one of (1) to (147),

[0223] (149)-R TT each, if present, independently, -R TT1 , -R TT3 or -L TT -R TT3 A compound according to any one of (1) to (147),

[0224] (150)-R TT If each exists, -R TT1 A compound according to any one of (1) to (147),

[0225] Group-R TT1 (151)-R TT1 each, if present, independently, a linear or branched saturated C 1~6 A compound according to any one of (1) to (150), wherein the compound is alkyl.

[0226] (152)-R TT1 each, if present, independently, a linear or branched saturated C 1~4 Alkyl, -F, -OH and -OR TTT A compound according to any one of (1) to (150), optionally substituted with one or more groups selected from:

[0227] (153)-R TT1 each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (150), wherein the compound is alkyl.

[0228] (154)-R TT1 A compound according to any one of (1) to (150), wherein each, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

[0229] (155)-R TT1 A compound according to any one of (1) to (150), wherein each, if present, is independently -Me, -Et, -nPr, or -iPr.

[0230] (156)-R TT1 A compound according to any one of (1) to (150), wherein each, if present, is -Me.

[0231] Group-R TT2 (157)-R TT2 respectively, if present, saturated C 3~6 Cycloalkyl, -F, -OH and -OR TTT A compound according to any one of (1) to (156), optionally substituted with one or more groups selected from:

[0232] (158)-R TT2 respectively, if present, saturated C 3~6 A compound according to any one of (1) to (156), which is cycloalkyl.

[0233] (159)-R TT2 A compound according to any one of (1) to (156), wherein each, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0234] (160)-R TT2 A compound according to any one of (1) to (156), wherein each, if present, is cyclopropyl.

[0235] Group-R TT3 (161)-R TT3 is phenyl, if present, and -F, -Cl, -Br, -I, -R TTT , OH, -OR TTT , -OCF3, -NH2, -NHR TTT and -NR TTTA compound according to any one of (1) to (160), optionally substituted with one or more groups selected from:

[0236] (162)-R TT3 is phenyl, if present, and -F, -Cl, -Br, -I, -R TTT , OH, -OR TTT A compound according to any one of (1) to (160), optionally substituted with one or more groups selected from -OCF3 and -OCF3.

[0237] (163)-R TT3 is phenyl, if present, and -F, -Cl, -Br, -I and -R TTT A compound according to any one of (1) to (160), optionally substituted with one or more groups selected from:

[0238] (164)-R TT3 A compound according to any one of (1) to (160), wherein each, if present, is phenyl.

[0239] Group-L T - (165)-L T - each, if present, independently, a linear or branched saturated C 1~3 A compound according to any one of (1) to (164), which is alkylene.

[0240] (166)-L T A compound according to any one of (1) to (164), wherein each -, if present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0241] (167)-L T A compound according to any one of (1) to (164), wherein each -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0242] (168)-L T A compound according to any one of (1) to (164), wherein each -, if present, is -CH2-.

[0243] Group-L TT - (169)-L TT - each, if present, independently, a linear or branched saturated C 1~3 A compound according to any one of (1) to (168), which is alkylene.

[0244] (170)-L TT A compound according to any one of (1) to (168), wherein each, if present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0245] (171)-L TT A compound according to any one of (1) to (168), wherein each -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0246] (172)-L TT A compound according to any one of (1) to (168), wherein each -, if present, is -CH2-.

[0247] Group-R TN (173)-R TN each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (172), wherein the compound is alkyl.

[0248] (174)-R TN A compound according to any one of (1) to (172), wherein each, if present, is -Me.

[0249] Group-R TM (175)-R TM each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; -R on carbon TMM , -F, -OH and -OR TMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R TMM , -C(=O)R TMM and -C(=O)OR TMM A compound according to any one of (1) to (174), optionally substituted with a group selected from:

[0250] (176)-R TM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon TMM , -F, -OH and -OR TMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R TMM , -C(=O)R TMM and -C(=O)OR TMM A compound according to any one of (1) to (174), optionally substituted with a group selected from:

[0251] (177)-R TM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon TMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R TMM , -C(=O)R TMM and -C(=O)OR TMM A compound according to any one of (1) to (174), optionally substituted with a group selected from:

[0252] (178)-R TM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon TMM and optionally substituted with one or more groups selected from If present, -R on the secondary nitrogen TMM A compound according to any one of (1) to (174), optionally substituted with a group selected from:

[0253] Group-R TTT (179)-R TTT each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (178), wherein the compound is alkyl.

[0254] (180)-R TTT A compound according to any one of (1) to (178), wherein each, if present, is -Me.

[0255] Group-R TMM (181)-R TMM each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (180), wherein the compound is alkyl.

[0256] (182)-R TMM A compound according to any one of (1) to (180), wherein each, if present, is -Me.

[0257] Group-Cy 5 (183)-Cy 5 -Cy 5A A compound according to any one of (1) to (182),

[0258] (184)-Cy 5 -Cy 5B A compound according to any one of (1) to (182),

[0259] Group-Cy 5A (185)-Cy 5A is, if present, independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, tetrahydropyridinyl, dihydropyridinyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl, 2,7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decanyl, or 3,9-diazaspiro[5.5]undecanyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0260] [ka] TIFF0007806100000030.tif171165

[0261] (186)-Cy 5A If present, non-aromatic C having at least one nitrogen ring atom 4~7 is heterocyclyl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0262] (187)-Cy 5A if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, dihydropyridinyl, azepanyl, diazepanyl, or 6-diazabicyclo[3.1.1]heptanyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0263] (188)-Cy 5A If present, non-aromatic C having at least one nitrogen ring atom 4~6 is heterocyclyl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0264] (189)-Cy 5A if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0265] (190)-Cy 5Ais, if present, independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0266] Azetidinyl: (191)-Cy 5A when present, is azetidinyl (e.g., azetidin-1-yl, azetidin-2-yl, azetidin-3-yl); One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0267] [ka]

[0268] (192)-Cy 5A is azetidin-1-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by A compound according to any one of (1) to (184), optionally substituted on carbon with =O.

[0269] (193)-Cy 5A is azetidin-2-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0270] (194)-Cy 5A is azetidin-3-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0271] Pyrrolidinyl: (195)-Cy 5A when present, is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl); One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0272] [ka]

[0273] (196)-Cy 5A is pyrrolidin-1-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by A compound according to any one of (1) to (184), optionally substituted on carbon with =O.

[0274] (197)-Cy 5A is pyrrolidin-2-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0275] (198)-Cy 5A is pyrrolidin-3-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0276] (199)-Cy 5A A compound according to any one of (1) to (184), which, if present, is pyrrolidin-3-yl.

[0277] (200)-Cy 5A when present, is (3S)-pyrrolidin-3-yl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0278] [ka]

[0279] (201)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is (3S)-pyrrolidin-3-yl.

[0280] Piperidinyl: (202)-Cy 5A when present, is piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl); One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0281] [ka]

[0282] (203)-Cy 5A is piperidin-1-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by A compound according to any one of (1) to (184), optionally substituted on carbon with =O.

[0283] (204)-Cy 5A is piperidin-2-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0284] (205)-Cy 5A is piperidin-3-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0285] (206)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is piperidin-3-yl.

[0286] (207)-Cy 5A when present, is (3S)-piperidin-3-yl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0287] [ka]

[0288] (208)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is (3S)-piperidin-3-yl.

[0289] (209)-Cy 5A is piperidin-4-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0290] (210)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is piperidin-4-yl.

[0291] (211)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is 3-hydroxy-piperidin-4-yl.

[0292] (212)-Cy 5A A compound according to any one of (1) to (184), wherein, if present, is (3R,4R)-3-hydroxy-piperidin-4-yl.

[0293] [ka]

[0294] Piperazinyl: (213)-Cy 5A when present, is piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl); One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0295] [ka]

[0296] (214)-Cy 5A is piperazin-1-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0297] (215)-Cy5A is piperazin-2-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0298] Morpholinyl: (216)-Cy 5A when present, is morpholinyl (e.g., morpholinyl-2-yl, morpholinyl-3-yl, morpholinyl-4-yl); One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0299] [ka]

[0300] (217)-Cy 5A When present, it is morpholinyl-4-yl. One or more groups -R on the carbon Cy5AC and optionally substituted by A compound according to any one of (1) to (184), optionally substituted on carbon with =O.

[0301] (218)-Cy 5A is present, is morpholinyl-3-yl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogenCy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0302] (219)-Cy 5A is morpholinyl-2-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to any one of (1) to (184), optionally substituted by:

[0303] Group-Cy 5B (220)-Cy 5B when present, is independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0304] C5 heteroaryl: (221)-Cy 5B when present, is a C5 heteroaryl having at least one nitrogen ring atom; One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0305] (222)-Cy 5Bwhen present, is independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazole, isoxazole, thiazole, isothiazole, oxadiazolyl, or thiadiazolyl; One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0306] (223)-Cy 5B when present, is independently pyrrolyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, or isothiazole; One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0307] Pyrazolyl: (224)-Cy 5B when present, is pyrazolyl (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl or 1H-pyrazol-5-yl); One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0308] [ka]

[0309] (225)-Cy 5B is 1H-pyrazol-4-yl, when present; One or more groups -R on the carbon Cy5BCand optionally substituted by -R group on secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0310] (226)-Cy 5B is 1H-pyrazol-5-yl, when present; One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN A compound according to any one of (1) to (219), optionally substituted by:

[0311] C6 heteroaryl: (227)-Cy 5B when present, is a C6 heteroaryl having at least one nitrogen ring atom; One or more groups -R on the carbon Cy5BC A compound according to any one of (1) to (219), optionally substituted by:

[0312] (228)-Cy 5B if present, is independently pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; One or more groups -R on the carbon Cy5BC A compound according to any one of (1) to (219), optionally substituted by:

[0313] Pyridinyl: (229)-Cy 5B when present, is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl); One or more groups -R on the carbon Cy5BC A compound according to any one of (1) to (219), optionally substituted by:

[0314] [ka]

[0315] (230)-Cy 5B is pyridin-3-yl, when present; One or more groups -R on the carbon Cy5BC A compound according to any one of (1) to (219), optionally substituted by:

[0316] Substituent -R Cy5AC and -R Cy5BC (231)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -L J -OH, -L J -OR JJ , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR JJ , -NR JJ 2, -R JM , -L J -NH2, -L J -NHR JJ , -L J -NR JJ 2, -L J -R JM , -C(=O)OH, -C(=O)OR JJ , -OC(=O)R JJ , -C(=O)NH2, -C(=O)NHR JJ , -C(=O)NR JJ 2. -C(=O)R JM , -NHC(=O)R JJ , -NR JN C(=O)R JJ , -C(=O)R JJ , -S(=O)2RJJ , -S(=O)NH2, -S(=O)NHR JJ , -S(=O)NR JJ 2. -S(=O)R JM , -S(=O)2NH2, -S(=O)2NHR JJ , -S(=O)2NR JJ 2. -S(=O)2R JM , -NHS(=O)2R JJ , -NR JN S(=O)2R JJ , -CN and -NO2 A compound according to any one of (1) to (230), independently selected from:

[0317] (232)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -L J -OH, -L J -OR JJ , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR JJ , -NR JJ 2, -R JM , -L J -NH2, -L J -NHR JJ , -L J -NR JJ 2, -L J -R JM , -C(=O)OH, -C(=O)OR JJ , -OC(=O)R JJ , -C(=O)NH2, -C(=O)NHR JJ , -C(=O)NR JJ 2. -C(=O)R JM, -NHC(=O)R JJ , -NR JN C(=O)R JJ , -C(=O)R JJ , -CN and -NO2 A compound according to any one of (1) to (230), independently selected from:

[0318] (233)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -L J -OH, -L J -OR JJ , -CF3, -CHF2, -OCF3, -OCHF2, -NH2, -NHR JJ , -NR JJ 2, -R JM , -L J -NH2, -L J -NHR JJ , -L J -NR JJ 2, -L J -R JM , -CN and -NO2 A compound according to any one of (1) to (230), independently selected from:

[0319] (234)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -NH2, -NHR JJ , -NR JJ 2, -R JM, -CN and -NO2 A compound according to any one of (1) to (230), independently selected from:

[0320] (235)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -R JJ , -F, -Cl, -Br, -I, -OH, -OR JJ , -NH2, -NHR JJ , -NR JJ 2 and -R JM A compound according to any one of (1) to (230), independently selected from:

[0321] (236)-R Cy5AC and -R, respectively, if present Cy5BC respectively, if they exist, -F, -Me, -OH, -OMe and -NH2 A compound according to any one of (1) to (230), independently selected from:

[0322] (237)-R Cy5AC A compound according to any one of (1) to (230), wherein each, if present, is —OH.

[0323] (238)-R Cy5BC A compound according to any one of (1) to (230), wherein each, if present, is -Me.

[0324] Substituent -R Cy5AN and -R Cy5BN (239)-R Cy5AN and -R, respectively, if present Cy5BN respectively, if they exist, -R JJ , -C(=O)R JJ , -C(=O)OR JJand -S(=O)2R JJ A compound according to any one of (1) to (238), independently selected from:

[0325] (240)-R Cy5AN and -R, respectively, if present Cy5BN respectively, if they exist, -R JJ , -C(=O)R JJ and -C(=O)OR JJ A compound according to any one of (1) to (238), independently selected from:

[0326] (241)-R Cy5AN and -R, respectively, if present Cy5BN If each exists, -R JJ A compound according to any one of (1) to (238),

[0327] Group-R JJ (242)-R JJ each, if present, independently, -R JJ1 , -R JJ2 , -R JJ3 or -L JJ -R JJ3 A compound according to any one of (1) to (241),

[0328] (243)-R JJ each, if present, independently, -R JJ1 , -R JJ3 or -L JJ -R JJ3 A compound according to any one of (1) to (241),

[0329] (244)-R JJ If each exists, -R JJ1 A compound according to any one of (1) to (241),

[0330] Group-R JJ1 (245)-R JJ1 each, if present, independently, a linear or branched saturated C 1~6 A compound according to any one of (1) to (244), wherein the compound is alkyl.

[0331] (246)-R JJ1 each, if present, independently, a linear or branched saturated C 1~4 Alkyl, -F, -OH and -OR JJJ A compound according to any one of (1) to (244), optionally substituted with one or more groups selected from:

[0332] (247)-R JJ1 each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (244), wherein the compound is alkyl.

[0333] (248)-R JJ1 A compound according to any one of (1) to (244), wherein each, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

[0334] (249)-R JJ1 A compound according to any one of (1) to (244), wherein each, if present, is independently -Me, -Et, -nPr, or -iPr.

[0335] (250)-R JJ1 A compound according to any one of (1) to (244), wherein each, if present, is -Me.

[0336] Group-R JJ2 (251)-R JJ2 respectively, if present, saturated C 3~6 Cycloalkyl, -F, -OH and -OR JJJ A compound according to any one of (1) to (250), optionally substituted with one or more groups selected from:

[0337] (252)-R JJ2 respectively, if present, saturated C 3~6 A compound according to any one of (1) to (250), which is cycloalkyl.

[0338] (253)-R JJ2 A compound according to any one of (1) to (250), wherein each, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0339] (254)-R JJ2 A compound according to any one of (1) to (250), wherein each, if present, is cyclopropyl.

[0340] Group-R JJ3 (255)-R JJ3 is phenyl, if present, and -F, -Cl, -Br, -I, -R JJJ , OH, -OR JJJ , -OCF3, -NH2, -NHR JJJ and -NR JJJ A compound according to any one of (1) to (254), optionally substituted with one or more groups selected from (1) to (255).

[0341] (256)-R JJ3 is phenyl, if present, and -F, -Cl, -Br, -I, -R JJJ , OH, -OR JJJ A compound according to any one of (1) to (254), optionally substituted with one or more groups selected from -OCF3 and -OCF3.

[0342] (257)-R JJ3 is phenyl, if present, and -F, -Cl, -Br, -I and -R JJJ A compound according to any one of (1) to (254), optionally substituted with one or more groups selected from:

[0343] (258)-R JJ3 A compound according to any one of (1) to (254), wherein each, if present, is phenyl.

[0344] Group-L J - (259)-L J -, if present, independently, linear or branched saturated C 1~3 A compound according to any one of (1) to (258), which is alkylene.

[0345] (260)-L J A compound according to any one of (1) to (258), wherein each -, if present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0346] (261)-L J A compound according to any one of (1) to (258), wherein each -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0347] (262)-L J A compound according to any one of (1) to (258), wherein each -, if present, is -CH2-.

[0348] Group-L JJ - (263)-L JJ - each, if present, independently, a linear or branched saturated C 1~3 A compound according to any one of (1) to (262), which is alkylene.

[0349] (264)-L JJA compound according to any one of (1) to (262), wherein each, if present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0350] (265)-L JJ A compound according to any one of (1) to (262), wherein each -, if present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0351] (266)-L JJ A compound according to any one of (1) to (262), wherein each -, if present, is -CH2-.

[0352] Group-R JN (267)-R JN each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (266), wherein the compound is alkyl.

[0353] (268)-R JN A compound according to any one of (1) to (266), wherein each, if present, is -Me.

[0354] Group-R JM (269)-R JM each, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; -R on carbon JMM , -F, -OH and -OR JMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R JMM , -C(=O)R JMM and -C(=O)OR JMMA compound according to any one of (1) to (268), optionally substituted with a group selected from:

[0355] (270)-R JM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon JMM , -F, -OH and -OR JMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R JMM , -C(=O)R JMM and -C(=O)OR JMM A compound according to any one of (1) to (268), optionally substituted with a group selected from:

[0356] (271)-R JM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon JMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R JMM , -C(=O)R JMM and -C(=O)OR JMM A compound according to any one of (1) to (268), optionally substituted with a group selected from:

[0357] (272)-R JM each, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino; -R on carbon JMM and optionally substituted with one or more groups selected from If present, -R on the secondary nitrogen JMM A compound according to any one of (1) to (268), optionally substituted with a group selected from:

[0358] Group-R JJJ (273)-R JJJ each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (272), wherein the compound is alkyl.

[0359] (274)-R JJJ A compound according to any one of (1) to (272), wherein each, if present, is -Me.

[0360] Group-R JMM (275)-R JMM each, if present, independently, a linear or branched saturated C 1~4 A compound according to any one of (1) to (274), wherein the compound is alkyl.

[0361] (276)-R JMM A compound according to any one of (1) to (274), wherein each, if present, is -Me.

[0362] Some preferred combinations (277)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Cy 5 -Cy 5A and -Cy 5A is a non-aromatic C having at least one nitrogen ring atom 4~6 is heterocyclyl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to (1), optionally substituted by:

[0363] (278)-L 7- is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-) Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) Cy 5 -O- (i.e., -L 5 - is a single bond, -X 5 is -O-), or Cy 5 -(i.e., -L 5 -and-X 5 Each - is a single bond. and -Cy 5 -Cy 5A and -Cy 5A is independently azetidinyl, pyrrolidinyl, or piperidinyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to (1), optionally substituted by:

[0364] (279)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar2 is independently pyridinyl, pyrimidinyl, thiazolyl, or pyrazolyl; One or more groups -R on the carbon AR2C and optionally substituted by If present, a group -R on the secondary nitrogen AR2N and optionally substituted by Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-, or Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) and -Cy 5 -Cy 5A and -Cy 5A is independently azetidinyl, pyrrolidinyl, or piperidinyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN A compound according to (1), optionally substituted by:

[0365] (280)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is independently pyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, or pyrazol-1-yl; One or more groups -R on the carbon AR2C and optionally substituted by Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5 - is -NH-, or Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) and -Cy 5 -Cy 5A and -Cy 5A is independently pyrrolidin-3-yl, piperidin-3-yl, or piperidin-4-yl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN A compound according to (1), optionally substituted by:

[0366] (281)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is independently pyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, or pyrazol-1-yl; One or more groups -R on the carbon AR2C and optionally substituted by Cy 5 -L 5 -X 5 - but independently, Cy 5 -CH2-NH- (i.e., -L 5 - is -CH2-, and -X 5- is -NH-, or Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-) and -Cy 5 -Cy 5A and -Cy 5A is independently pyrrolidin-3-yl, piperidin-3-yl, or piperidin-4-yl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN and optionally substituted by -R 3 Ga-R 3B The compound according to (1).

[0367] (282)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, One or more groups -R on the carbon AR1C and optionally substituted by -Ar 2 is independently pyridin-2-yl or pyrimidin-2-yl; One or more groups -R on the carbon AR2C and optionally substituted by Cy 5 -L 5 -X 5 -But Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-), -Cy 5 -Cy 5A and -Cy 5A is piperidin-3-yl, One or more groups -R on the carbon Cy5ACand optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN and optionally substituted by -R 3 Ga-R 3B and -R 3B The compound according to (1), wherein is cyclopropyl.

[0368] (283)-L 7 - is -CH2-, -Ar 1 - is 1,4-phenylene, -Ar 2 is independently pyridin-2-yl or pyrimidin-2-yl; Cy 5 -L 5 -X 5 -But Cy 5 -NH- (i.e., -L 5 - is a single bond, -X 5 - is -NH-), -Cy 5 -Cy 5A and -Cy 5A is piperidin-3-yl, One or more groups -R on the carbon Cy5AC and optionally substituted by -R group on secondary nitrogen Cy5AN and optionally substituted by -R 3 Ga-R 3B and -R 3B The compound according to (1), wherein is cyclopropyl.

[0369] Specific Compounds (284) A compound according to (1) selected from compounds of the following formulae, and pharmaceutically acceptable salts and solvates thereof:

[0370] [Table 1] TIFF0007806100000042.tif252149TIFF0007806100000043.tif252149TIFF0007806 100000044.tif248148TIFF0007806100000045.tif240148TIFF0007806100000046.t if253147TIFF0007806100000047.tif236147TIFF0007806100000048.tif236147TIF F0007806100000049.tif245147TIFF0007806100000050.tif251146TIFF00078061000 00051.tif242147TIFF0007806100000052.tif252147TIFF0007806100000053.tif25 3147TIFF0007806100000054.tif253147TIFF0007806100000055.tif253147TIFF000 7806100000056.tif255146TIFF0007806100000057.tif249149TIFF00078061000000 58.tif249149TIFF0007806100000059.tif250149TIFF0007806100000060.tif250149

[0371] combination It is understood that certain features of the invention, which are, for clarity, described in the context of individual embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. 7 -, -Ar 1 -, -Ar 2 , -X 5 -, -L 5 -, -Cy 5 , -R 3All combinations of embodiments for chemical groups represented by the formula (e.g., ", ", ", ", ", ", ", ", ", ", ", ", ", ", ", ", ", ", ", ",,,,," etc.) are specifically encompassed by the present invention, and each and every combination is disclosed herein just as if individually and explicitly disclosed to the extent that such combinations encompass compounds that are stable compounds (i.e., compounds that can be isolated, identified, and tested for biological activity). In this context, one of skill in the art will readily recognize that certain combinations of groups (e.g., substituents) may result in compounds that cannot be readily synthesized and / or that are chemically unstable. Furthermore, all subcombinations of chemical groups listed in embodiments describing such variables are also specifically encompassed by the present invention, and are disclosed herein just as if each and every such subcombination of chemical groups were individually and explicitly disclosed herein.

[0372] Substantially Purified Form One aspect of the present invention pertains to the PPA compounds described herein in a substantially purified form and / or substantially free of impurities.

[0373] In one embodiment the substantially purified form is at least 50% by weight, such as at least 60% by weight, for example at least 70% by weight, such as at least 80% by weight, for example at least 90% by weight, such as at least 95% by weight, for example at least 97% by weight, such as at least 98% by weight, for example at least 99% by weight.

[0374] Unless otherwise specified, a substantially purified form refers to a compound in any stereoisomer or enantiomer. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, a substantially purified form refers to a single stereoisomer, e.g., an optically pure stereoisomer. In one embodiment, a substantially purified form refers to a mixture of enantiomers. In one embodiment, a substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, a substantially purified form refers to a single enantiomer, e.g., an optically pure enantiomer.

[0375] In one embodiment, the impurities are 50% by weight or less, such as 40% by weight or less, for example 30% by weight or less, such as 20% by weight or less, for example 10% by weight or less, such as 5% by weight or less, for example 3% by weight or less, such as 2% by weight or less, for example 1% by weight or less.

[0376] Unless specified, impurities refer to other compounds, i.e., other than stereoisomers or enantiomers. In one embodiment, impurities refer to other compounds and other stereoisomers. In one embodiment, impurities refer to other compounds and other enantiomers.

[0377] In one embodiment the substantially purified form is at least 60% optically pure (i.e. 60% of the compound is the desired stereoisomer or enantiomer on a molar basis and 40% is the undesired stereoisomer or enantiomer), such as at least 70% optically pure, such as at least 80% optically pure, such as at least 90% optically pure, for example at least 95% optically pure, such as at least 97% optically pure, for example at least 98% optically pure, such as at least 99% optically pure.

[0378] Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, stereoconfigurative, or anomeric forms, including, but not limited to, cis and trans forms; E and Z forms; c, t, and r forms; endo and exo forms; R, S, and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol, and enolate forms; syn and anti forms; synclinal and anticlinal forms; α and β forms; axial and equatorial forms; boat, chair, twisted, envelope, and half-chair forms; and combinations thereof, collectively referred to hereinafter as "isomers" (or "isomeric forms").

[0379] When referring to a class of structures, structural isomeric forms that fall within that class can of course be included (e.g., C 1~7 Alkyl includes n-propyl and iso-propyl, butyl includes n-, iso-, sec- and tert-butyl; methoxyphenyl includes ortho-, meta- and para-methoxyphenyl).

[0380] However, when referring to a particular group or substitution pattern, it is not intended to include other structures (or constitutional isomers) that differ with respect to the bonds between atoms, rather than by their position in space. For example, when referring to a methoxy group, -OCH3 should not be construed as referring to its constitutional isomer, a hydroxymethyl group, i.e., -CH2OH. Similarly, when referring to ortho-chlorophenyl, it should not be construed as referring to its constitutional isomer, meta-chlorophenyl.

[0381] The above exclusion does not relate to tautomeric forms, such as keto, enol and enolate, imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo and nitro / aci-nitro, as in the following tautomeric pairs: keto / enol (exemplified below). When one tautomer is mentioned herein, it is intended to encompass both tautomers.

[0382] [ka]

[0383] For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of each other, and when one is mentioned herein, both are intended to be included.

[0384] [ka]

[0385] It should be noted that the term "isomer" specifically includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H may be any isotope, including T; C may be 12 C. 13 C and 14 Any isotope, including C; O 16 O and 18 It may be any isotope containing O, etc.

[0386] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures thereof (e.g., racemic mixtures). Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallization and chromatographic means) of such isomeric forms are either known in the art or readily obtainable by the methods taught herein or by the adaptation of known methods in a known manner.

[0387] salt It may be convenient or desirable to prepare, purify, and / or handle the corresponding salt of a compound, e.g., a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., 66, 1-19.

[0388] For example, if the compound is anionic, or if a functional group that can be anionic (e.g., -COOH can be replaced with -COO - (which may be ##STR00002##), salts can be formed with suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions, such as Na. + and K. + , alkaline earth cations, e.g., Ca 2+ and Mg 2+ , as well as other cations, such as Al 3+ , and ammonium ions (i.e., NH4 + Suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ), for example, where each R is independently a linear or branched saturated C 1~18 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl-C 1~6 Alkyl and phenyl-C 1~6The substituted ammonium ions are alkyl, and the phenyl group is optionally substituted. Some suitable examples of substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and those derived from amino acids such as lysine and arginine. One example of a common quaternary ammonium ion is N(CH3)4 + is.

[0389] If a compound is cationic, or if it is protonated, it can become cationic (e.g., -NH2 becomes -NH3 + If the compound has a functional group which may be a salt, salts may be formed with suitable anions.

[0390] For example, if the parent structure contains a cationic group (e.g., -NMe2 + ), or when protonated, can be cationic (e.g., -NH2 becomes -NH3 + If the compound has a functional group (e.g., -NMe2), salts can be formed with a suitable anion. In the case of quaternary ammonium compounds, a counter anion is generally always present to counteract the positive charge. The compound may also have a cationic group (e.g., -NMe2). + , -NH3 + ), if the compound contains a group capable of forming an anion (e.g., —COOH), an internal salt (also called a zwitterion) may be formed.

[0391] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0392] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic acid, acetic acid, trifluoroacetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalenecarboxylic acid, isethionic acid, lactic acid, lactobioic acid, lauric acid, maleic acid, malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, toluenesulfonic acid, and valeric acid. Examples of suitable organic anionic polymers include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0393] Quaternary ammonium compounds (e.g., -NMe2 + Examples of particularly suitable counterions for the hydroxyl groups (those bearing the -COOH group) include 1-adamantanesulfonate, benzenesulfonate, hydrogensulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, and sulfate. Again, if the compound also contains a group capable of forming an anion (e.g., —COOH), internal salts may also be formed.

[0394] Unless otherwise specified, a reference to a particular compound also includes its salt forms.

[0395] Solvates and Hydrates It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of a compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. When the solvent is water, the solvate may be conveniently referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc.

[0396] Unless otherwise specified, when a particular compound is mentioned, solvates and hydrate forms thereof are also included.

[0397] chemical protection form It may be convenient or desirable to prepare, purify, and / or handle compounds in chemically protected form. The term "chemically protected form" is used herein in its conventional chemical sense to refer to a compound in which one or more reactive functional groups are protected from undesired chemical reactions under certain conditions (e.g., pH, temperature, radiation, solvent, etc.). Indeed, well-known chemical methods are used to reversibly render unreactive functional groups that would otherwise be reactive under certain conditions. In chemically protected form, one or more reactive functional groups are in the form of protected or protecting groups (alternatively, as masked or blocked groups). By protecting reactive functional groups, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected groups. Typically, in a subsequent step, the protecting group may be removed or the masking group may be transformed without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 4th ed.; John Wiley and Sons, 2006).

[0398] A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound having two unequal reactive functional groups (both of which are reactive under certain conditions) can be derivatized to render one of the functional groups "protected" and therefore unreactive under certain conditions; the compound, so protected, can be used as a reactant effectively possessing only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group can be "deprotected" to return it to its original functionality.

[0399] For example, a hydroxy group can be protected as an ether (-OR) or ester (-OC(=O)R), such as a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl) or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH, -OAc).

[0400] For example, aldehyde or ketone groups can be protected as acetals (R-CH(OR)2) or ketals (RC(OR)2), respectively, where the carbonyl group (>C=O) is converted to a 1,1-diether (>C(OR)2) by reaction with, for example, a primary alcohol in the presence of acid. The aldehyde or ketone group is readily regenerated by hydrolysis, for example, using water in the presence of acid.

[0401] For example, amine groups can be represented, for example, as amides (-NRCO-R) or urethanes (-NRCO-OR), such as acetamides (-NHCO-CH3); benzyloxyamides (-NHCO-OCH2C6H5, -NH-Cbz); t-butoxyamides (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamides (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc), 9-fluorenylmethoxyamides (-NH- Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), as 2(phenylsulfonyl)ethyloxyamide (-NH-Psec); or in suitable cases (e.g., cyclic amines), as a nitroxide radical (>NO●).

[0402] For example, a carboxylic acid group can be reacted as an ester, e.g., C 1~7 Alkyl esters (e.g., methyl esters; t-butyl esters); C 1~7 Haloalkyl esters (e.g., 2,2,2-trihaloethyl esters); 2-tri(C 1~7 alkyl)silyl-ethyl ester; or C 5~20 Aryl-C 1~7 It can be protected as an alkyl ester (eg, benzyl ester; nitrobenzyl ester); or as an amide or hydrazide, for example, as acetamide or N,N,N'-trimethylhydrazide.

[0403] For example, thiol groups can be protected as thioethers (-SR), such as benzyl thioethers; acetamidomethyl ethers (-S-CH2NHC(=O)CH3).

[0404] Prodrug It may be convenient or desirable to prepare, purify, and / or handle compounds in the form of a prodrug. The term "prodrug," as used herein, refers to a compound that yields the desired active compound in vivo. Typically, prodrugs are inactive or less active than the desired active compound, but may offer advantageous handling, administration, or metabolic properties.

[0405] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable, metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters can be formed, for example, by esterifying any carboxylic acid groups (-C(=O)OH) in the parent compound, optionally before protecting any other reactive groups present in the parent compound, followed by deprotection, if necessary.

[0406] Similarly, some prodrugs are activated by enzymes to yield the active compound or a compound that, upon further chemical reaction, yields the active compound (e.g., antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lipid-directed enzyme prodrug therapy (LIDEPT), etc. For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

[0407] composition One aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising a PPA compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0408] Another aspect of the invention relates to a method of preparing a composition (e.g., a pharmaceutical composition), comprising mixing a PPA compound described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0409] use The PPA compounds described herein are useful in treating, for example, proliferative disorders (as "antiproliferative agents"), cancer (as "anticancer agents"), viral infections (as "antiviral agents"), neurodegenerative diseases (as "anti-neurodegenerative agents"), and the like.

[0410] Use in methods of inhibiting CDK One aspect of the present invention relates to a method of inhibiting CDK (e.g., CDK12 and / or CDK13) function in vitro or in vivo (e.g., in a cell), comprising contacting the cell with an effective amount of a PPA compound described herein.

[0411] One of ordinary skill in the art can readily determine whether a candidate compound inhibits a CDK (e.g., CDK12 and / or CDK13). For example, suitable assays are described herein or known in the art.

[0412] In one embodiment, the method is performed in vitro.

[0413] In one embodiment, the method is performed in vivo.

[0414] In one embodiment, the PPA compound is provided in the form of a pharmaceutically acceptable composition.

[0415] Any type of cell can be treated, including fat, lung, gastrointestinal tract (including, e.g., intestine, colon), breast (breast), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0416] For example, a sample of cells can be grown in vitro, a compound can be contacted with the cells, and the effect of the compound on the cells can be observed. As an example of "effect," the morphological state of the cells (e.g., alive or dead) can be determined. If the compound is found to have an effect on the cells, this can be used as a prognostic or diagnostic marker of the compound's efficacy in treating patients with cells of the same cell type.

[0417] Use in methods for inhibiting cell proliferation, etc. The PPA compounds described herein may, for example, (a) modulate (e.g., inhibit) cell proliferation, (b) inhibit cell cycle progression, (c) promote apoptosis, or (d) a combination of one or more of these.

[0418] One aspect of the present invention relates to a method for modulating (e.g., inhibiting) cell proliferation (e.g., cell growth), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more thereof, in vitro or in vivo, comprising contacting a cell with an effective amount of a PPA compound described herein.

[0419] In one embodiment, the method is a method for modulating (e.g., inhibiting) cell proliferation (e.g., cell growth) in vitro or in vivo, comprising contacting a cell with an effective amount of a PPA compound described herein.

[0420] In one embodiment, the method is performed in vitro.

[0421] In one embodiment, the method is performed in vivo.

[0422] In one embodiment, the PPA compound is provided in the form of a pharmaceutically acceptable composition.

[0423] Any type of cell can be treated, including lung, gastrointestinal tract (including, for example, intestine, colon), breast (breast), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0424] One of ordinary skill in the art can readily determine whether a candidate compound modulates (e.g., inhibits) cell proliferation, etc. For example, assays that can be conveniently used to evaluate the activity offered by a particular compound are described herein.

[0425] For example, a sample of cells (e.g., from a tumor) can be grown in vitro, a compound can be contacted with the cells, and the effect of the compound on the cells can be observed. As an example of "effect," the morphological state of the cells (e.g., alive or dead) can be determined. If the compound is found to have an effect on the cells, this can be used as a prognostic or diagnostic marker of the compound's efficacy in treating patients with cells of the same cell type.

[0426] Use in methods of treatment Another aspect of the present invention relates to the PPA compounds described herein for use in methods of treatment of the human or animal body by therapy, e.g., for use in methods of treatment of disorders (e.g., diseases) described herein.

[0427] Use in the manufacture of medicines Another aspect of the invention relates to the use of a PPA compound as described herein in the manufacture of a medicament, e.g., for use in a method of treatment, e.g., for use in a method of treatment of a disorder (e.g., a disease) as described herein.

[0428] In one embodiment, the medicament comprises a PPA compound.

[0429] Treatment method Another aspect of the invention relates to methods of treatment, e.g., methods of treating a disorder (e.g., a disease) described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of a PPA compound described herein, preferably in the form of a pharmaceutical composition.

[0430] Disorders to be treated - CDK-related disorders In one embodiment (e.g., for use in methods of treatment, use in the manufacture of a medicament, method of treatment), the treatment is treatment of a disorder (e.g., disease) associated with a CDK, particularly CDK12 and / or CDK13; a disorder (e.g., disease) caused by inappropriate activity of a CDK, particularly CDK12 and / or CDK13; a disorder (e.g., disease) associated with a CDK mutation, particularly a CDK12 and / or CDK13 mutation; a disorder (e.g., disease) associated with CDK overexpression, particularly CDK12 and / or CDK13 overexpression; a disorder (e.g., disease) associated with pathway activation upstream of a CDK, particularly CDK12 and / or CDK13; or a disorder (e.g., disease) that is ameliorated by inhibition (e.g., selective inhibition) of a CDK, particularly CDK12 and / or CDK13.

[0431] In one embodiment (eg, for use in methods of therapy, use in the manufacture of a medicament, methods of treatment), the treatment is treatment of a disorder (eg, a disease) associated with a CDK, particularly CDK12 and / or CDK13.

[0432] In one embodiment, the treatment is treatment of a disorder (eg, a disease) resulting from inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0433] In one embodiment, the treatment is treatment of a disorder (e.g., a disease) associated with a CDK mutation, particularly a CDK12 mutation; CDK overexpression, particularly CDK12 and / or CDK13 overexpression (e.g., compared to a corresponding normal cell; for example, overexpression is 1.5, 2, 3, 5, 10, 20, or 50-fold); or pathway activation upstream of a CDK, particularly CDK12 and / or CDK13.

[0434] In one embodiment, the treatment is treatment of a disorder (eg, a disease) that is ameliorated by inhibition (eg, selective inhibition) of a CDK, particularly CDK12 and / or CDK13.

[0435] Disorders to be treated In one embodiment (e.g., for use in a method of therapy, use in the manufacture of a medicament, method of treatment), the treatment is treatment of a proliferative disorder; cancer; viral infection (e.g., HIV); neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease); ischemia; renal disease; cardiovascular disorder (e.g., atherosclerosis); or autoimmune disorder (e.g., rheumatoid arthritis).

[0436] In one embodiment (e.g., for use in methods of therapy, use in the manufacture of a medicament, method of treatment), the treatment is treatment of a disorder (e.g., disease) caused by a dysfunction of translation in a cell, such as muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, and fragile X syndrome.

[0437] In one embodiment (e.g., for use in methods of treatment, use in the manufacture of a medicament, methods of treatment), the treatment is treatment of a disorder (e.g., disease) in a patient who has received prior therapeutic treatment but who receives little or no further clinical benefit from those treatments. This includes, for example, patients who have received prior therapeutic treatment with a PARP inhibitor, a CDK inhibitor, and / or a HER2-directed therapy (see, e.g., Johnson et al., 2016; Choi et al., 2019).

[0438] Disorders Treated - Proliferative Disorders In one embodiment (eg, for use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of a proliferative disorder.

[0439] The term "proliferative disorder," as used herein, relates to unwanted or uncontrolled cell proliferation of unwanted excess or abnormal cells, eg, neoplastic or hypertrophic growth.

[0440] In one embodiment, the treatment is treatment of a proliferative disorder characterized by benign, pre-cancerous or malignant cell proliferation.

[0441] In one embodiment, the treatment is treatment of hyperplasia; neoplasia; tumor (e.g., histiocytoma, glioma, astrocytoma, osteoma); cancer; psoriasis; bone disease; fibroproliferative disorder (e.g., of connective tissue); pulmonary fibrosis; atherosclerosis; or smooth muscle cell proliferation in blood vessels (e.g., stenosis or restenosis after angioplasty).

[0442] Disorders Treated - Cancer In one embodiment (eg, use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of cancer.

[0443] In one embodiment, the treatment is treatment of cancer metastasis.

[0444] Cancers include: (1) Carcinoma, including tumors derived from stratified squamous epithelium (squamous cell carcinoma) and tumors arising within organs or glands (adenocarcinoma). Examples include breast, colon, lung, prostate, and ovary.

[0445] (2) Sarcomas, including osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (musculoskeletal); mesosarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (fatty tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive connective tissue); mesenchymal and mixed mesodermal tumors (mixed connective tissue type).

[0446] (3) Myeloma.

[0447] (4) Myeloid and granulocytic leukemias (malignancies of the bone marrow and granulocytic leukemia series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphoid, lymphocytic, and lymphoblastic leukemias (malignancies of lymphocytes and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); hematopoietic tumors, including polycythemia vera (malignancies of various blood cell products, but with a predominance of erythrocytes).

[0448] (5) Lymphoma, including Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0449] (6) Mixed types, including, for example, adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; and teratocarcinoma.

[0450] For example, in one embodiment, the treatment is treatment of breast cancer.

[0451] In one embodiment, the cancer is associated with a CDK, particularly CDK12 and / or CDK13.

[0452] In one embodiment, the cancer is characterized or further characterized by inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0453] In one embodiment, the cancer is characterized or further characterized by overexpression of a CDK, particularly CDK12 and / or CDK13.

[0454] In one embodiment, the cancer is characterized or further characterized by amplification of the CDK12 and / or CDK13 genes, including, for example, cancers that overexpress the protein HER2, in which the 17q12-q21 locus is amplified (see, e.g., Choi et al., 2019).

[0455] In one embodiment, the cancer is characterized or further characterized by a gene fusion that causes the appearance of the cancer, including, for example, a cancer with an EWS-FLI (see, e.g., Inigues et al., 2018), BCR-ABL, EML4-ALK, FGFR3-TACC3, KIF5B-RET, ETV6-RUNX1, or TMPRSS2-ERG gene fusion.

[0456] Anti-cancer effects may occur through one or more mechanisms, including, but not limited to, regulating cell proliferation, inhibiting cell cycle progression, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of tumors from their origin), inhibiting cell migration (the spread of cancer cells to other parts of the body), inhibiting invasion (the spread of tumor cells to adjacent normal structures), promoting apoptosis (programmed cell death), inducing necrotic death or autophagy death. The compounds described herein may be used to treat the cancers described herein, regardless of the mechanism discussed herein.

[0457] Damages Treated - DNA Repair In one embodiment (e.g., use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of a disorder (e.g., disease) in a patient having underexpression, defects, and / or mutations in genes for proteins involved in DNA repair, including, for example, BRCA1, BRCA2, ATM, ATR, BAP1, CDK12, CDK13, CHK1, CHK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCI, PALB2, NBS1, WRN, RAD51B, RAD51C, RAD51D, MRE11A, BLM, BRIP1. This includes, for example, cancer patients whose tumors exhibit "BRCA-ness" (see, e.g., Lord et al., 2016).

[0458] In one embodiment (e.g., use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of a disorder (e.g., disease) in a patient having underexpression, defects and / or mutations in genes for proteins involved in non-homologous DNA repair, including, for example, XLF, RAD50, NBS1, MRE11, LIG4, XRCC4, POLL, POLM.

[0459] Disorders Treated - Viral Infections In one embodiment (eg, for use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of a viral infection.

[0460] In one embodiment, the treatment is treatment of a viral infection by: (Group I:) dsDNA viruses, e.g., adenoviruses, herpesviruses, poxviruses (Group II:) ssDNA viruses, e.g., parvoviruses (Group III:) dsRNA viruses, e.g., reoviruses (Group IV:) (+)ssRNA viruses, e.g., picornaviruses, togaviruses (Group V:) (-) ssRNA viruses, e.g., orthomyxoviruses, rhabdoviruses (Group VI:) ssRNA-RT viruses, e.g., retroviruses; or (Group VII:) dsDNA-RT viruses, such as hepadnaviruses.

[0461] Used above: ds: double-stranded; ss: positive-stranded; (+)ssRNA: positive-stranded RNA; (-)ssRNA: negative-stranded RNA; ssRNA-RT: (positive-stranded) RNA that contains a DNA intermediate in the life cycle.

[0462] In one embodiment, the treatment is treatment of human immunodeficiency virus (HIV); hepatitis B virus (HBV); hepatitis C virus (HCV); human papillomavirus (HPV); cytomegalovirus (CMV); or Epstein-Barr virus (EBV); Kaposi's sarcoma-associated human herpesvirus 8 (HHV); Coxsackievirus B3; Borna virus; influenza virus.

[0463] Disorders Treated - Autoimmune Disorders In one embodiment (eg, for use in methods of therapy, use in the manufacture of medicaments, methods of treatment), the treatment is treatment of an autoimmune disorder.

[0464] In one embodiment, the treatment is treatment of an autoimmune disorder involving connective tissue, joints, skin, or eyes.

[0465] In one embodiment, the treatment is treatment of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or Sjogren's syndrome.

[0466] Disorders to be treated - Disorders caused by translational dysfunction in cells In one embodiment (eg, for use in methods of therapy, use in the manufacture of a medicament, methods of treatment), the treatment is treatment of a disorder caused by a dysfunction of translation in a cell.

[0467] In one embodiment, the treatment is treatment of muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, or fragile X syndrome.

[0468] treatment The term "treatment," as used herein generally, in the context of treating a disorder, relates to the treatment of a human or animal (e.g., in veterinary applications), where some desired therapeutic effect is achieved, such as inhibiting the progression of the disorder, including slowing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use by patients who have not yet developed the disorder, but are at risk of developing the disorder, is encompassed by the term "treatment."

[0469] For example, treatment includes preventing cancer, reducing the incidence of cancer, ameliorating the symptoms of cancer, and the like.

[0470] The term "therapeutically effective amount," as used herein, relates to that amount of a compound or agent, composition or dosage form containing the compound, that, when administered in accordance with a desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0471] Combination therapy The term "treatment" includes combination treatments and therapies, where two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapy, e.g., in conjunction with other agents. Examples of treatments and therapies include chemotherapy (e.g., administration of active agents including drugs, antibodies (e.g., immunotherapy), prodrugs (e.g., including photodynamic therapy, GDEPT, ADEPT, etc.)), surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

[0472] One aspect of the present invention pertains to a compound as described herein in combination with one or more (e.g., one, two, three, four, etc.) additional therapeutic agents, as described below.

[0473] The particular combination is at the discretion of the physician, who will select the dosage using his or her common general knowledge and dosage regimens known to the skilled physician.

[0474] The agents (i.e., a compound described herein and one or more other agents) may be administered simultaneously or sequentially, at different individual dose schedules, and by different routes. For example, if the agents are administered sequentially, they may be administered closely spaced apart (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 hour, 2 hours, 3 hours, 4 hours, or more, spaced apart, or even longer periods if necessary), with the exact dosing regimen being consistent with the properties of the therapeutic agents.

[0475] The agents (i.e., a compound described herein and one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and supplied together in the form of a kit, optionally with instructions for their use.

[0476] Examples of additional agents / therapies that may be co-administered / combined with treatment with the PPA compounds described herein include: DNA repair inhibitors; e.g., PARP inhibitors, e.g., olaparib, niraparib, etc. Immune checkpoint inhibitors, such as PD1, PD1L, and CTLA4 inhibitors, including pembrolizumab, atezolizumab, and ipilimumab Immune system stimulants, such as Toll-like receptor (TLR1-13) agonists and stimulator of interferon genes (STING) agonists Cell cycle checkpoint inhibitors; for example, inhibitors of ATM, ATR, Wee1, etc., such as AZD0156, AZD1390, AZD6738, adavoselitib, etc. Her2 blockers; e.g., Herceptin, Pertuzumab, Lapatinib, etc. Transcription inhibitors; for example, inhibitors of BRD4, BRD2, CDK9, etc., such as JQ-1, OTX015, AZD4573, etc.; Cytotoxic chemotherapeutic agents; such as taxanes (e.g., paclitaxel, also known as taxol; docetaxel, also known as taxotere), cyclophosphamide, antimetabolites (e.g., carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, 5-fluorouracil, etc.).

[0477] Thus, in one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, e.g., a DNA repair inhibitor, an immune checkpoint inhibitor, an immune system stimulator, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcription inhibitor, a cytotoxic chemotherapeutic agent, etc.

[0478] Further examples of additional agents / therapies that may be co-administered / combined with treatment with the PPA compounds described herein include: Aromatase inhibitors, such as exemestane (also known as Aromasin), letrozole (also known as Femara), and anastrozole (also known as alumidex) Antiestrogens; such as Faslodex (also known as Fulvestrant and ICI182780), Tamoxifen (also known as Nolvadex), Hydroxytamoxifen, and the like; Antiandrogens; for example, antiandrogens used in the treatment of prostate cancer, such as flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, and the like.

[0479] Other uses The PPA compounds described herein may also be used as cell culture additives to inhibit CDKs (eg, CDK12 and / or CDK13).

[0480] The PPA compounds described herein may also be used as part of an in vitro assay, for example, to determine whether a candidate host is likely to benefit from treatment with the compound of interest.

[0481] The PPA compounds described herein may also be used, for example, as standards in assays to identify other active compounds, such as other CDK12 and / or CDK13 inhibitors.

[0482] kit One aspect of the present invention relates to a kit that includes (a) a PPA compound described herein or a composition comprising a PPA compound described herein, preferably supplied, e.g., in a suitable container and / or in suitable packaging, and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

[0483] The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

[0484] Administration route The PPA compounds, or pharmaceutical compositions containing the PPA compounds, may be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0485] pulmonary (e.g., by using, e.g., via an aerosol, e.g., by inhalation or breath therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal;

[0486] Subjects / patients The subject / patient can be a chordate, vertebrate, mammal, placental mammal, marsupial (e.g., kangaroo, wombat), rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), lagomorph (e.g., rabbit), avian (e.g., bird), canine (e.g., dog), feline (e.g., cat), equine (e.g., horse), porcine (e.g., pig), ovine (e.g., sheep), bovine (e.g., cow), primate, simian (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon), or human.

[0487] Furthermore, the subject / patient may be in any of its forms of development, for example, a fetus.

[0488] In a preferred embodiment, the subject / patient is a human.

[0489] formulation While it is possible for a PPA compound to be administered alone, it is preferable to provide such a compound as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one PPA compound described herein together with one or more other pharmaceutically acceptable ingredients known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweetening agents. The formulation may further comprise other active agents, such as other therapeutic or prophylactic agents.

[0490] Thus, the present invention further provides a method of making a pharmaceutical composition, comprising the step of mixing the pharmaceutical composition as defined above and at least one PPA compound described herein together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, such as carriers, diluents, excipients, etc. When formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0491] The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, substances, compositions, dosage forms, and the like, that are suitable for use in contact with the tissues of the subject in question (e.g., humans) without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0492] Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical textbooks, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th ed., 2005.

[0493] The formulations may be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing the compound into association with a carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the compound into association with a carrier (e.g., a liquid carrier, a finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0494] The formulations may be prepared to provide fast or slow release; immediate release, delayed release, time-modulated release or sustained release; or a combination thereof.

[0495] Formulations may suitably be in the form of a liquid, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, syrup, electuary, mouthwash, drops, tablets (including, e.g., coated tablets), granules, powders, lozenges, pastilles, capsules (e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mist or aerosols.

[0496] The formulations may be suitably supplied as patches, adhesive plasters, bandages, dressings, etc., which are impregnated with one or more compounds and, optionally, one or more other pharmaceutically acceptable ingredients, including, for example, penetration enhancers, permeation enhancers and absorption enhancers. The formulations may also be suitably supplied in the form of a depot or reservoir.

[0497] The compound may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients. The compound may also be delivered in liposomes or other microparticles designed to target the compound, for example, to blood components or one or more organs.

[0498] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, lozenges, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0499] Formulations suitable for oral administration include mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically contain the compound in a flavored base, typically sucrose and acacia or tragacanth. Pastilles typically contain the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically contain the compound in a suitable liquid carrier.

[0500] Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.

[0501] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

[0502] Formulations suitable for parenteral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

[0503] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0504] Tablets may be prepared by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the compound in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with one or more of the following: binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose); surfactants, dispersants, or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavors, flavor enhancers, and sweeteners. Tablets can also be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets may optionally be coated or engraved and may be formulated using, for example, various percentages of hydroxypropyl methylcellulose to provide a slow or controlled release of the compound therein to provide a desired release profile. Tablets may optionally be provided with a coating to affect release, for example, an enteric coating, to provide release in parts of the digestive tract other than the stomach.

[0505] Ointments are typically prepared from the compound and a paraffinic base or a water-miscible ointment base.

[0506] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base can contain, for example, at least about 30% w / w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably contain a compound that enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0507] Emulsions are usually prepared from the present compounds and an oily phase that may optionally contain an emulsifier (otherwise known as an emulsion), or the emulsion may contain a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer.It is also preferred that the hydrophilic emulsifier contains both an oil and a fat.At the same time, the emulsifier with or without a stabilizer constitutes the so-called emulsifying wax, and the wax together with the oil and / or fat constitutes the so-called emulsifying ointment, which forms the oily dispersed phase of a cream formulation.

[0508] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. Because the solubility of the present compounds in most oils likely to be used in pharmaceutical emulsion formulations can be very low, the selection of an oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. Therefore, creams should preferably be non-sticky, non-staining, and washable products with a suitable consistency to avoid leakage from tubes or other containers. Linear or branched mono- or dibasic alkyl esters, such as diisoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters (known as Crodamol CAP), may also be used, the last three being preferred esters. These may be used alone or in combination, depending on the desired properties. Alternatively, high melting point lipids such as white petrolatum and / or liquid paraffin or other mineral oils can be used.

[0509] Suitable formulations for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebulizer, include aqueous or oily solutions of the compound.

[0510] Where the carrier is a solid, formulations suitable for nasal administration include those supplied as a coarse powder having a particle size, for example, in the range from about 20 to about 500 microns, administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

[0511] Formulations suitable for pulmonary administration (e.g., by inhalation or inhalation therapy) include those delivered as an aerosol spray from pressurized packs by use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide or other suitable gas.

[0512] Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0513] Formulations suitable for rectal administration may be presented as suppositories with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, such as cocoa butter or salicylates; or as solutions or suspensions for administration by enema.

[0514] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the compound, such carriers as are known in the art to be appropriate.

[0515] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., liposomes or other microparticles). Such liquids may further contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostats, suspending agents, thickeners, and solutes that render the formulation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, e.g., from about 10 ng / mL to about 1 μg / mL. The formulations may be supplied in unit-dose or multi-dose hermetically sealed containers, for example ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

[0516] Dosage Those skilled in the art will appreciate that appropriate dosages of PPA compounds and compositions containing PPA compounds may vary from patient to patient. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dosage level will depend on a variety of factors, including the activity of the specific PPA compound, the route of administration, the time of administration, the rate of excretion of the PPA compound, the duration of treatment, other drugs, concomitant compounds and / or substances, the severity of the disorder, and the patient's species, sex, age, weight, condition, general health, and medical history. The amount and route of administration of the PPA compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dosage will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing significant harm or adverse side effects.

[0517] Administration can be in a single dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those skilled in the art and will vary depending on the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or repeated administration can be carried out with the dose level and pattern selected by the treating physician, veterinarian, or clinician.

[0518] In general, suitable doses of PPA compounds range from about 10 μg to about 250 mg (more typically, from about 100 μg to about 25 mg) per kilogram of subject body weight per day. Where the compound is a salt, ester, amide, prodrug, or the like, the amount administered is calculated on the basis of the parent compound and therefore the actual weight used is increased proportionately.

[0519] chemical synthesis Abbreviation aq: water-based, BOC: tert-butoxycarbonyl, Boc2O: di-tert-butyl dicarbonate, br: wide, ca.: approx. d: doublet, t BuBrettPhos Pd G3: [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, DCM: dichloromethane, DCE: 1,2-dichloroethane; Dioxane: 1,4-dioxane, DIPEA: diisopropylethylamine; DMAP: 4-(dimethylamino)pyridine; EtOAc: ethyl acetate, EtOH: ethanol, h: time, HPLC: high performance liquid chromatography; IPA: 2-isopropanol, LCMS: liquid chromatography-mass spectrometry; LiHMDS: lithium hexamethyldisilazide; m: multiplet, M: Molar concentration, molecular ion, mCPBA: 3-chloroperbenzoic acid; MeCN: acetonitrile, MeOH: methanol, min:minutes, MS: mass spectrometry; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide, NMR: nuclear magnetic resonance; Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; Pd-162: chloro(crotyl)(tri-tert-butylphosphine)palladium(II), Pd-171: Chloro(crotyl)(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)palladium(II) q: quartet, RT: Room temperature (about 20℃), R T :holding time, Ruphos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, s: singlet, solid, SCX: strong cation exchange; t: triplet, TBME: tert-butyl methyl ether, TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC / MS: Ultra-high performance liquid chromatography-mass spectrometry.

[0520] Other abbreviations are intended to convey their generally accepted meaning.

[0521] Structural names were generated using the "Structure to Name" conversion in ChemDraw® Professional 20 (PerkinElmer).

[0522] General synthesis method Methods for the chemical synthesis of PPA compounds are described herein. These and / or other known methods can be modified and / or adapted in known ways to provide alternative or improved methods for the synthesis of PPA compounds.

[0523] In the first method, the synthesis begins with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with an amine affords the corresponding 5-amino-pyrazolopyrimidine I-2. Boc protection of the amino group affords intermediate I-3. The latter is used in a Buchwald-Hartwig cross-coupling with a primary or secondary amine to afford intermediate I-4. Final global Boc deprotection affords the target compound I-5.

[0524] This method is illustrated in the following chemical scheme.

[0525] [ka]

[0526] Representative reaction conditions for the above scheme are as follows: (a) RNH, DIPEA, EtOH or IPA, 50° C. to 90° C.; (b) Boc, DMAP, THF, room temperature to 60° C.; (c) t BuBurettPhos Pd G3, LiHMDS, THF, 60°C; or Pd-171, Cs2CO3, dioxane, 90°C, (d) TFA, DCM, room temperature; or HCl, dioxane, room temperature to 40°C.

[0527] In the second method, intermediate I-3 is used in a Buchwald-Hartwig cross-coupling with an alcohol to give intermediate I-6. Final global Boc-deprotection affords the target compound I-7.

[0528] This method is illustrated in the following chemical scheme.

[0529] [ka]

[0530] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 to 90°C; (b) Boc2O, DMAP, THF, room temperature to 60°C; (c) Pd-171, Cs2CO3, dioxane, 90°C; (d) TFA, DCM, room temperature or HCl, dioxane, room temperature to 40°C.

[0531] In the third method, intermediate I-2 is used in a Buchwald-Hartwig cross-coupling with a primary or secondary amine to give intermediate I-8. Final global Boc-deprotection affords the target compound I-5.

[0532] This method is illustrated in the following chemical scheme.

[0533] [ka]

[0534] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50°C to 90°C; (b) t BuBrettPhos Pd G3, LiHMDS, dioxane, 90°C, (c) TFA, DCM, room temperature or HCl, dioxane, room temperature to 40°C.

[0535] In the fourth method, intermediate I-2 is used in a nucleophilic aromatic substitution with an amine to give I-8. Final global Boc-deprotection affords the target compound I-5.

[0536] This method is illustrated in the following chemical scheme.

[0537] [ka]

[0538] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 to 90 °C; (b) DIPEA, NMP, 120 °C, microwave; (c) TFA, DCM, room temperature or HCl, dioxane, room temperature to 40 °C.

[0539] In the fifth method, intermediate I-3 is used in a Negishi cross-coupling to give I-12. Final global Boc-deprotection affords the target compound I-13.

[0540] This method is illustrated in the following chemical scheme.

[0541] [ka]

[0542] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 to 90°C; (b) Boc2O, DMAP, THF, room temperature to 60°C; (c) Pd(dppf)Cl2, THF, 50°C; (d) TFA, DCM, room temperature or HCl, dioxane, room temperature to 40°C.

[0543] In the sixth method, intermediate I-3 is used in a Suzuki cross-coupling to give I-12. Final global Boc-deprotection affords the target compound I-13.

[0544] This method is illustrated in the following chemical scheme.

[0545] [ka]

[0546] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH, 50 to 90°C; (b) Boc2O, DMAP, THF, room temperature to 60°C; (c) Pd(dppf)Cl2, potassium phosphate tribasic, dioxane, water, 90°C; (d) TFA, DCM, room temperature or HCl, dioxane, room temperature to 40°C.

[0547] Chemical synthesis examples The following examples are provided merely to illustrate the invention and are not intended to limit the scope of the invention described herein.

[0548] General experimental conditions All starting materials and solvents were obtained from commercial sources or prepared according to literature references. Reaction mixtures were magnetically stirred unless otherwise indicated.

[0549] Column chromatography was carried out on an automated flash chromatography system, such as a CombiFlash Rf system, using Grace™ GraceResolv™ pre-packed silica (40 μm) cartridges unless otherwise indicated.

[0550] Using a Bruker Avance III spectrometer (400 MHz) or a Bruker (500 MHz), 1 H NMR spectra were recorded. Chemical shifts are expressed in parts per million using either the central peak of the residual protic solvent or an internal standard of tetramethylsilane as reference. Spectra were recorded at ambient temperature unless otherwise noted.

[0551] Analytical LCMS experiments to determine retention times and associated mass ions were performed using an Agilent or Waters HPLC / UPLC system coupled to a mass spectrometer, implementing methods 1-8 described below.

[0552] Preparative HPLC purification was performed using a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm column using a gradient of MeCN and 10 mM ammonium bicarbonate (aqueous). Fractions were collected after UV detection at a single wavelength measured with a variable wavelength detector.

[0553] SCX resin was purchased from Sigma Aldrich or Silicycle and washed with MeOH before use.

[0554] Analysis method Method 1: LCMS_acidic, Instrument: Agilent 1260, Quaternary Pump, HiP Sampler, Column Compartment, DAD: 260 + / - 90 nm, G6150 MSD: ESI, Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 μm, Temperature: 40 °C, Flow Rate: 1.35 mL / min, Gradient: t0 = 5% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0555] Method 2: UPLC_acidic, instrument: Waters HClass, quaternary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, column: Waters CSH C18, 30 × 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 mL / min, gradient: t0 = 5% B, t3.0 min = 95% B, eluent A: 0.1% formic acid in water, eluent B: acetonitrile.

[0556] Method 3: UPLC_basic, instrument: Waters HClass, binary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, column: Waters BEH C18, 30 × 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 mL / min, gradient: t0 = 5% B, t3.0 min = 95% B, eluent A: 0.1% NH3 or 10 nM ammonium bicarbonate in water, eluent B: acetonitrile.

[0557] Method 4: UPLC_acid, instrument: Waters HClass, quaternary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, column: Waters CSH C18, 30 × 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 mL / min, gradient: t0 = 2% B, t2.5 min = 100% B, t3.0 min = 100% B, eluent A: 0.1% formic acid in water, eluent B: acetonitrile.

[0558] Method 5: UPLC_basic, instrument: Waters HClass, binary solvent pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, column: Waters BEH C18, 30 × 2.1 mm, 1.7 μm, temperature: 40 °C, flow rate: 0.77 mL / min, gradient: t0 = 2% B, t2.5 min = 100% B, t3.0 min = 100% B, eluent A: 0.1% NH3 or 10 nM ammonium bicarbonate in water, eluent B: acetonitrile.

[0559] Method 6: UPLC_basic, Instrument: Waters HClass, Binary Solvent Pump, SM-FTN, CMA, PDA: 210-400 nm, QDa: ACQ-QDa ESI, Column: Waters BEH C18, 30 × 2.1 mm, 1.7 μm, Temperature: 40 °C, Flow rate: 0.77 mL / min, Gradient: t0 = 2% B, t9.5 min = 100% B, t10.0 min = 100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

[0560] Method 7: LCMS_acidic, Instrument: Agilent 1260, Binary Pump, HiP Sampler, Column Compartment, DAD: 260 + / - 90 nm, G6150 MSD: ESI, Column: Waters Cortecs C18, 30 x 2.1 mm, 2.7 μm, Temperature: 40 °C, Flow Rate: 1.35 mL / min, Gradient: t0 = 5% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% formic acid in water, Eluent B: acetonitrile.

[0561] Method 8: LCMS_basic, Instrument: Agilent 1260, Binary Pump, HiP Sampler, Column Compartment, DAD: 260 + / - 90 nm, G6150 MSD: ESI, Column: Waters XBridge C18, 30 x 2.1 mm, 2.5 μm, Temperature: 40 °C, Flow Rate: 1.35 mL / min, Gradient: t0 = 5% B, t2.5 min = 100% B, t3.0 min = 100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

[0562] Synthesis 001 (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-001)

[0563] [ka]

[0564] Step 1 of 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate DIPEA (0.34 mL, 1.95 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (150 mg, 0.65 mmol) and (4-(pyridin-2-yl)phenyl)methanamine, 2HCl (184 mg, 0.72 mmol) in dioxane (5.0 mL). The reaction mixture was heated to 90° C. for 2 h. At room temperature, DCM (25 mL) and water (10 mL) were added. The organic layer was separated, dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in THF (4.0 mL). DMAP (3.9 mg, 33 μmol) and BOC-anhydride (171 mg, 0.78 mmol) were added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-50% EtOAc / isohexane) gave the title compound (219 mg, 0.45 mmol, 69% yield, 99% purity) as a colourless oil. LCMS (Method 1): m / z 478 (M+H) + , R T 2.80 minutes.

[0565] Step 3 of 4 (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (100 mg, 210 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (58 mg, 251 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by tBuBrettPhos Pd G3 (8.9 mg, 10.5 μmol) and LiHMDS (1 M in THF) (209 μL, 209 μmol) were added. The reaction was concentrated in vacuo, and the residue was dissolved in dioxane (3.0 mL). Hydrogen chloride (4 M in dioxane) (5.0 mL, 20 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour, then concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL), and the product was eluted with 0.7 M NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (28 mg, 59 μmol, 28% yield, 99% purity) as a white solid. LCMS (Method 1): m / z 472 (M+H) + , R T 0.98 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.00 (t, J = 6.5 Hz, 1H), 7.93 (dt, J = 8.1, 1.2 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.66 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.34 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 6.85 - 6.73 (m, 1H), 5.62 - 5.48 (m, 1H), 5.16 (s, 1H), 4.50 (d, J = 6.5 Hz, 2H), 3.62 - 3.46 (m, 1H), 3.23 - 3.14 (m, 1H), 3.13 - 3.04 (m, 1H), 3.00 - 2.89 (m, 2H), 2.89 - 2.82 (m, 1H), 2.44 - 2.35 (m, 1H), 2.30 - 2.21 (m, 1H), 1.63 - 1.55 (m, 1H), 1.45 - 1.31 (m, 1H), 1.23 (dd, J = 6.9, 5.8 Hz, 6H), 1.19 - 1.13 (m, 1H).1H under water.

[0566] Synthesis 002 (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-4-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-002)

[0567] [ka]

[0568] Step 1: 5-chloro-3-isopropyl-N-(4-(pyridin-4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.35 mL, 2.0 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (80 mg, 0.35 mmol) and (4-(pyridin-4-yl)phenyl)methanamine (77 mg, 0.42 mmol) in EtOH (1.5 mL). The reaction mixture was heated to 65°C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (120 mg, 0.25 mmol, 73% yield, 80% purity) as a brown oil. UPLC / MS (Method 3): m / z 378 (M+H) + , R T 0.78 minutes.

[0569] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-4-yl)benzyl)carbamate DMAP (9 mg, 74.6 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyridin-4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 255 μmol) and BOC-anhydride (98 mg, 0.45 mmol) in anhydrous THF (5.0 mL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 mL) and washed with brine (3×10 mL). The combined organics were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (76 mg, 0.15 mmol, 59% yield, 95% purity) as a yellow solid. UPLC / MS (Method 2): m / z 478 (M+H) + , R T 1.57 minutes.

[0570] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-4-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-4-yl)benzyl)carbamate (76 mg, 135 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (38 mg, 166 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by tBuBrettPhos Pd G3 (12 mg, 13.5 μmol) and LiHMDS (1 M in THF) (195 μL, 195 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60–65 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc (15 mL). The filtrate was diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) followed by further purification on RP flash C18 (12 g cartridge, 30–100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (39 mg, 55 μmol, 17% yield, 95% purity) as a colorless glassy solid. UPLC / MS (Method 2): m / z 672 (M+H) + , R T 1.48 minutes.

[0571] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-4-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.31 mL, 1.22 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-4-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (43 mg, 61 μmol) in dioxane (0.5 mL). The reaction mixture was stirred at 40° C. for 1 h and concentrated in vacuo. The solid was triturated with MeCN (3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (21 mg, 42 μmol, 69% yield, 95% purity) as a yellow solid. UPLC / MS (Method 2): m / z 472 (M+H)+, R T 0.51 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 - 8.58 (m, 2H), 7.96 (t, J = 6.5 Hz, 1H), 7.81 - 7.75 (m, 2H), 7.71 - 7.67 (m, 2H), 7.65 (s, 1H), 7.53 - 7.46 (m, 2H), 6.78 - 6.72 (m, 1H), 5.55 - 5.45 (m, 1H), 5.18 (s, 1H), 4.51 (d, J = 6.5 Hz, 2H), 3.63 - 3.43 (m, 1H), 3.27 - 3.18 (m, 1H), 3.18 - 3.07 (m, 1H), 3.03 - 2.82 (m, 3H), 2.47 - 2.37 (m, 1H), 2.34 - 2.24 (m, 1H), 1.66 - 1.57 (m, 1H), 1.45 - 1.33 (m, 1H), 1.26 - 1.17 (m, 7H). 1H under water.

[0572] Synthesis 003 (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-3-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-003)

[0573] [ka]

[0574] Step 1: 5-chloro-3-isopropyl-N-(4-(pyridin-3-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.35 mL, 2.0 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (80 mg, 0.35 mmol) and (4-(pyridin-3-yl)phenyl)methanamine (77 mg, 0.42 mmol) in EtOH (1.5 mL). The reaction mixture was heated to 65° C. for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (124 mg, 0.26 mmol, 75% yield, 80% purity) as a brown oil. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 - 8.95 (m, 1H), 8.90 - 8.84 (m, 1H), 8.55 (dd, J = 4.7, 1.6 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.75 - 7.67 (m, 2H), 7.58 - 7.49 (m, 2H), 7.49 - 7.45 (m, 1H), 6.14 (s, 1H), 4.68 (d, J = 6.1 Hz, 2H), 3.09 (p, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H).

[0575] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-3-yl)benzyl)carbamate DMAP (9 mg, 74.6 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyridin-3-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (124 mg, 255 μmol) and BOC-anhydride (98 mg, 0.45 mmol) in anhydrous THF (5 mL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 mL) and washed with brine (3×10 mL). The combined organics were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (103 mg, 183 μmol, 66% yield, 85% purity) as a yellow oil. UPLC / MS (Method 2): m / z 478 (M+H) + , R T 1.79 minutes.

[0576] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-3-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-3-yl)benzyl)carbamate (103 mg, 183 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (52 mg, 225 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by tBuBrettPhos Pd G3 (15.6 mg, 18.3 μmol) and LiHMDS (1 M in THF) (225 μL, 225 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60–65 °C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc (15 mL). The filtrate was diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) followed by further purification on RP flash C18 (12 g cartridge, 30–100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (79 mg, 110 μmol, 33% yield, 90% purity) as a colorless glassy solid. UPLC / MS (Method 2): m / z 672 (M+H) + , R T 1.66 minutes.

[0577] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(pyridin-3-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.47 mL, 1.89 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-3-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (79 mg, 94 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 40° C. for 2 hours and concentrated in vacuo. The solid was triturated with MeCN (3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (38 mg, 76 μmol, 80% yield, 95% purity) as a yellow solid. LCMS (Method 2): m / z 472 (M+H) + , R T 0.58 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.89 - 8.86 (m, 1H), 8.56 (dd, J = 4.7, 1.6 Hz, 1H), 8.07 - 8.01 (m, 1H), 7.97 (t, J = 6.5 Hz, 1H), 7.73 - 7.68 (m, 2H), 7.65 (s, 1H), 7.53 - 7.43 (m, 3H), 6.79 (t, J = 6.2 Hz, 1H), 5.64 (s, 1H), 5.19 (s, 1H), 4.51 (d, J = 6.5 Hz, 2H), 3.56 - 3.46 (m, 1H), 3.28 - 3.15 (m, 3H), 3.08 - 2.99 (m, 1H), 2.99 - 2.88 (m, 2H), 2.43 - 2.31 (m, 1H), 1.71 - 1.61 (m, 1H), 1.53 - 1.38 (m, 1H), 1.34 - 1.26 (m, 1H), 1.23 (dd, J = 6.9, 5.2 Hz, 6H). 1H under water.

[0578] Synthesis 004 (3R,4R)-4-(((7-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-004)

[0579] [ka]

[0580] Step 1: N-([1,1'-biphenyl]-4-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.37 mL, 2.1 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (81 mg, 0.35 mmol) and [1,1'-biphenyl]-4-ylmethanamine (77 mg, 0.42 mmol) in EtOH (1.4 mL). The reaction mixture was heated to 80 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (95 mg, 0.24 mmol, 68% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 377 (M+H) + , R T 1.97 minutes.

[0581] Step 2: tert-Butyl ([1,1'-biphenyl]-4-ylmethyl) (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate DMAP (5.8 mg, 48 μmol) was added to a solution of N-([1,1'-biphenyl]-4-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (95 mg, 239 μmol) and BOC-anhydride (63 mg, 287 μmol) in anhydrous THF (4.8 mL). The reaction mixture was heated at 65° C. for 2 h, then additional BOC-anhydride (45 mg, 210 μmol) was added and the reaction mixture was heated at 65° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 mL) and washed with brine (3×10 mL). The combined organics were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (91 mg, 180 μmol, 75% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 421 (M- t Bu+H) + , R T 2.20 minutes.

[0582] Step 3: tert-Butyl (3R,4R)-4-(((7-(([1,1'-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl ([1,1'-biphenyl]-4-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (91 mg, 180 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (62 mg, 271 μmol) in THF (2.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (15.4 mg, 18.0 μmol) and LiHMDS (1 M in THF) (217 μL, 217 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60–65°C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc (15 mL). The filtrate was diluted with water (10 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organics were washed with brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (95 mg, 130 μmol, 74% yield, 95% purity) as a yellow solid. UPLC / MS (Method 3): m / z 671 (M+H) + , R T 2.10 minutes.

[0583] Step 4: (3R,4R)-4-(((7-(([1,1'-biphenyl]-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-(([1,1'-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (94 mg, 130 μmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was triturated in EtO (2 × 3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH in MeOH (60 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (43 mg, 90 μmol, 67% yield, 98% purity) as a beige solid. UPLC / MS (Method 3): m / z 471 (M+H) + , RT 1.57 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (t, J = 6.5 Hz, 1H), 7.68 - 7.59 (m, 5H), 7.49 - 7.41 (m, 4H), 7.39 - 7.32 (m, 1H), 6.74 - 6.68 (m, 1H), 5.34 - 5.27 (m, 1H), 5.20 (s, 1H), 4.49 (d, J = 6.0 Hz, 2H), 3.59 - 3.45 (m, 1H), 3.25 - 3.15 (m, 1H), 3.08 - 2.98 (m, 1H), 2.98 - 2.87 (m, 2H), 2.83 - 2.73 (m, 1H), 2.37 - 2.26 (m, 1H), 2.20 - 2.11 (m, 1H), 1.62 - 1.51 (m, 1H), 1.37 - 1.28 (m, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.18 - 1.11 (m, 1H). 1H under water.

[0584] Synthesis 005 (3R,4R)-4-(((3-ethyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-005)

[0585] [ka]

[0586] Step 1: 5-chloro-3-ethyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.99 mL, 5.70 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (176 mg, 0.81 mmol) and (4-(pyridin-2-yl)phenyl)methanamine (150 mg, 814 μmol) in EtOH (4.0 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (179 mg, 0.48 mmol, 59% yield, 98% purity) as a yellow oil. UPLC / MS (Method 3): m / z 365 (M+H) + , R T 1.58 minutes.

[0587] Step 2: tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate DMAP (11.8 mg, 96 μmol) was added to a solution of 5-chloro-3-ethyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (179 mg, 482 μmol) and BOC-anhydride (126 mg, 579 μmol) in anhydrous THF (5.0 mL). The reaction mixture was stirred overnight at room temperature and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-5% MeOH / DCM) afforded the title compound (95 mg, 180 μmol, 38% yield, 90% purity) as a yellow oil. UPLC / MS (Method 3): m / z 465 (M+H) + , R T 1.94 minutes.

[0588] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (95 mg, 200 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (57 mg, 250 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (17 mg, 20.0 μmol) and LiHMDS (1 M in THF) (270 μL, 270 μmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 60-65 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP flash C18 (12 g cartridge, 0-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (76 mg, 110 μmol, 55% yield, 97% purity) as a white solid. UPLC / MS (Method 3): m / z 658 (M+H) + , R T 1.80 minutes.

[0589] Step 4: (3R,4R)-4-(((3-ethyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.2 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (76 mg, 120 μmol) in DCM (0.8 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was triturated in EtO (2 × 3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanolic solution was concentrated in vacuo and the solid was triturated in Et2O (2 mL) to give the title compound (38 mg, 83 μmol, 72% yield, 99% purity) as an off-white solid. UPLC / MS (Method 3): m / z 458 (M+H) + , RT 1.20 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (dt, J = 4.6, 1.6 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 - 7.90 (m, 2H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.65 (s, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1H), 6.74 (t, J = 6.1 Hz, 1H), 5.47 - 5.38 (m, 1H), 5.18 (s, 1H), 4.51 (d, J = 6.3 Hz, 2H), 3.60 - 3.46 (m, 1H), 3.19 - 3.11 (m, 1H), 3.05 - 2.95 (m, 1H), 2.89 (dd, J = 11.6, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.48 - 2.44 (m, 2H), 2.34 - 2.25 (m, 1H), 2.15 (dd, 1H), 1.57 - 1.49 (m, 1H), 1.35 - 1.26 (m, 1H), 1.17 (t, J = 7.5 Hz, 3H), 1.15 - 1.07 (m, 1H).1H under water.

[0590] Synthesis 006 (3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-006)

[0591] [ka]

[0592] Step 1: 5-chloro-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.99 mL, 5.70 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (186 mg, 814 μmol) and (4-(pyridin-2-yl)phenyl)methanamine (150 mg, 814 μmol) in EtOH (4.0 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (239 mg, 0.52 mmol, 64% yield, 82% purity) as a yellow oil. UPLC / MS (Method 3): m / z 376 (M+H) + , R T 1.59 minutes.

[0593] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate DMAP (15 mg, 0.12 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (239 mg, 521 μmol) and BOC-anhydride (167 mg, 765 μmol) in anhydrous THF (6.0 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-5% MeOH / DCM) afforded the title compound (164 mg, 0.32 mmol, 62% yield, 94% purity) as a yellow oil. UPLC / MS (Method 3): m / z 476 (M+H) + , R T 1.94 minutes.

[0594] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (164 mg, 345 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (95 mg, 413 μmol) in THF (4.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (29 mg, 34.5 μmol) and LiHMDS (1 M in THF) (448 μL, 448 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60 °C for 3 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP flash C18 (12 g cartridge, 0-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (124 mg, 0.17 mmol, 50% yield, 93% purity) as a white solid. UPLC / MS (Method 3): m / z 670 (M+H) + , R T 1.80 minutes.

[0595] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.3 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (124 mg, 185 μmol) in DCM (1.2 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in EtO (2 mL) to give the title compound (44 mg, 93 μmol, 50% yield, 99% purity) as an off-white solid. UPLC / MS (Method 3): m / z 470 (M+H) + , RT 1.22 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.96 - 7.91 (m, 1H), 7.90 - 7.83 (m, 2H), 7.52 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 6.71 (t, J = 5.8 Hz, 1H), 5.33 - 5.26 (m, 1H), 5.18 (s, 1H), 4.50 (d, J = 6.2 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.24 - 3.13 (m, 1H), 3.06 - 2.97 (m, 1H), 2.90 (dd, J = 11.5, 4.5 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.33 - 2.24 (m, 1H), 2.21 - 2.08 (m, 1H), 1.76 - 1.66 (m, 1H), 1.58 - 1.51 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.09 (m, 1H), 0.79 - 0.72 (m, 2H), 0.70 - 0.60 (m, 2H). 1H under water.

[0596] Synthesis 007 (3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-007)

[0597] [ka]

[0598] Step 1: 5-chloro-3-isopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.34 mL, 2.0 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (75 mg, 0.33 mmol) and (4-(pyrimidin-2-yl)phenyl)methanamine (63 mg, 0.34 mmol) in EtOH (3.0 mL). The reaction mixture was heated to 75 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (120 mg, 0.30 mmol, 92% yield, 95% purity) as an off-white solid. UPLC / MS (Method 3): m / z 401 (M+Na) + , R T 1.65 minutes.

[0599] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-2-yl)benzyl)carbamate DMAP (2.1 mg, 17 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 0.32 mmol) and BOC-anhydride (104 mg, 0.48 mmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at room temperature for 3 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (130 mg, 0.26 mmol, 81% yield, 95% purity) as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 6.5 Hz, 1H), 8.89 (d, J = 4.9 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 8.06 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1H), 6.10 (s, 1H), 4.72 (d, J = 5.7 Hz, 2H), 3.09 (p, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz, 6H).

[0600] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-2-yl)benzyl)carbamate (130 mg, 0.26 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (69 mg, 0.30 mmol) in THF (2.5 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (23 mg, 27.1 μmol) and LiHMDS (1 M in THF) (285 μL, 285 μmol) were added. The reaction was degassed for an additional 5 min before being heated to 60-65 °C for 1.5 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3) in DCM) followed by further purification on RP Flash C18 (12 g cartridge, 15-75% MeCN in 10 mM ammonium bicarbonate) afforded the title compound (108 mg, 150 μmol, 56% yield, 95% purity) as a colorless oil. UPLC / MS (Method 3): m / z 673 (M+H) + , RT 1.83 minutes.

[0601] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.61 mL, 2.4 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (108 mg, 0.16 mmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35° C. for 2 hours and concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (60 mg, 120 μmol, 76% yield, 96% purity) as a pink solid. LCMS (Method 3): m / z 473 (M+H)+, RT 1.24 min. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 4.8 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 7.94 (t, J = 6.4 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1H), 6.70 (t, J = 5.7 Hz, 1H), 5.31 - 5.24 (m, 1H), 5.16 (s, 1H), 4.53 (d, J = 6.4 Hz, 2H), 3.59 - 3.43 (m, 1H), 3.22 - 3.13 (m, 1H), 3.05 - 2.96 (m, 1H), 2.96 - 2.92 (m, 1H), 2.92 - 2.85 (m, 1H), 2.79 - 2.73 (m, 1H), 2.32 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 1.56 - 1.49 (m, 1H), 1.36 - 1.27 (m, 1H), 1.25 - 1.20 (m, 6H), 1.18 - 1.12 (m, 1H). 1H under water.

[0602] Synthesis 008 (3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-4-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-008)

[0603] [ka]

[0604] Step 1: 5-chloro-3-isopropyl-N-(4-(pyrimidin-4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (90 μL, 520 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (34 mg, 150 μmol) and (4-(pyrimidin-4-yl)phenyl)methanamine (29 mg, 74 μmol) in EtOH (1.0 mL). The reaction mixture was heated to 50° C. for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (32 mg, 73 μmol, 100% yield, 87% purity) as a white solid. UPLC / MS (Method 3): m / z 379 (M+H) + , R T 1.54 minutes.

[0605] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-4-yl)benzyl)carbamate DMAP (2.1 mg, 17 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyrimidin-4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (32 mg, 84 μmol) and BOC-anhydride (22 mg, 100 μmol) in anhydrous THF (1.0 mL). The reaction mixture was heated at room temperature overnight and then concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (23 mg, 47 μmol, 55% yield, 97% purity) as a colorless glassy solid. UPLC / MS (Method 3): m / z 379 (M-Boc+H) + , R T 1.87 minutes.

[0606] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-4-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-4-yl)benzyl)carbamate (23 mg, 48 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (13 mg, 58 μmol) in THF (1.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (4.1 mg, 4.8 μmol) and LiHMDS (1 M in THF) (62 μL, 62 μmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 75°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (26 mg, 37 μmol, 78% yield, 97% purity) as a yellow solid. UPLC / MS (Method 3): m / z 673 (M+H) + , R T 1.76 minutes.

[0607] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-4-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.10 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-4-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (26 mg, 37 μmol) in DCM (0.4 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in EtO (3 × 1 mL) to give the title compound (16 mg, 32 μmol, 86% yield, 95% purity) as an off-white solid. UPLC / MS (Method 3): m / z 473 (M+H) + , RT 1.15 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 1.4 Hz, 1H), 8.84 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.06 (dd, J = 5.4, 1.4 Hz, 1H), 7.95 (t, J = 6.5 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 6.69 (s, 1H), 5.30 - 5.23 (m, 1H), 5.16 (s, 1H), 4.54 (d, J = 6.4 Hz, 2H), 3.57 - 3.43 (m, 1H), 3.22 - 3.14 (m, 1H), 3.06 - 2.97 (m, 1H), 2.97 - 2.92 (m, 1H), 2.92 - 2.85 (m, 1H), 2.79 - 2.72 (m, 1H), 2.32 - 2.22 (m, 1H), 2.19 - 2.10 (m, 1H), 1.58 - 1.49 (m, 1H), 1.30 (s, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.14 - 1.07 (m, 1H). 1H under water.

[0608] Synthesis 009 (4-(pyrimidin-4-yl)phenyl)methanamine

[0609] [ka]

[0610] Step A: 4-(pyrimidin-4-yl)benzonitrile 4-Chloropyrimidine, HCl (100 mg, 662 μmol), Pd(PhP) (23 mg, 19.9 μmol), (4-cyanophenyl)boronic acid (107 mg, 729 μmol), and sodium carbonate (211 mg, 1.99 mmol) were dissolved in toluene (5.0 mL), methanol (2.5 mL), and water (2.5 mL). The mixture was sparged with N for 15 minutes, then heated to 100° C. for 24 hours and then cooled to room temperature. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The layers were separated, and the organic layer was washed with brine (10 mL), then dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (42 mg, 220 μmol, 33% yield, 95% purity) as a white solid. UPLC / MS (Method 3): m / z 182 (M+H)+, R T 0.953 minutes.

[0611] Step B: (4-(pyrimidin-4-yl)phenyl)methanamine 4-(Pyrimidin-4-yl)benzonitrile (42 mg, 0.23 mmol) in MeOH (20 mL) was hydrogenated in an H-cube at room temperature using a Raney nickel cartridge for 4 h, and the mixture was recycled through the cartridge (flow rate: 1 mL / min). The solvent was concentrated in vacuo to give the title compound (27 mg, 69 μmol, 30% yield, 47% purity) as a white solid. UPLC / MS (Method 3): m / z 186 (M+H)+, R T 0.67 minutes.

[0612] Synthesis 010 (3R,4R)-4-(((7-((4-(1H-pyrazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-009)

[0613] [ka]

[0614] Step 1: N-(4-(1H-pyrazol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.64 mL, 3.67 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (120 mg, 0.53 mmol) and (4-(1H-pyrazol-1-yl)phenyl)methanamine (100 mg, 0.58 mmol) in EtOH (3.0 mL). The reaction mixture was heated to 50°C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (170 mg, 0.44 mmol, 84% yield, 95% purity) as a white solid. UPLC / MS (Method 3): m / z 365 (M+H) + , R T 1.54 minutes.

[0615] Step 2: tert-Butyl (4-(1H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate DMAP (11 mg, 93 μmol) was added to a solution of N-(4-(1H-pyrazol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (122 mg, 466 μmol) and BOC-anhydride (122 mg, 559 μmol) in anhydrous THF (4.0 mL). The reaction mixture was heated at room temperature overnight and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (158 mg, 290 μmol, 63% yield, 86% purity) as a yellow oil. UPLC / MS (Method 3): m / z 365 (M-Boc+H) + , R T 1.87 minutes.

[0616] Step 3: tert-Butyl (3R,4R)-4-(((7-((4-(1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (4-(1H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (158 mg, 340 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (86 mg, 374 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (29 mg, 34 μmol) and LiHMDS (1 M in THF) (0.44 mL, 0.44 mmol) were added. The reaction was degassed for an additional 5 min before being heated to 60 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (182 mg, 0.26 mmol, 77% yield, 95% purity) as a brown glassy solid. UPLC / MS (Method 3): m / z 659 (M+H) + , R T 1.76 minutes.

[0617] Step 4: (3R,4R)-4-(((7-((4-(1H-pyrazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.80 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((4-(1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (182 mg, 276 μmol) in DCM (2.2 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in EtO (3 × 1 mL) to give the title compound (81 mg, 170 μmol, 62% yield, 97% purity) as a cream-colored solid. UPLC / MS (method 3): m / z 459 (M+H)+, RT 1.20 min. 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.5 Hz, 1H), 7.88 (t, J = 6.5 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 6.70 (t, J = 6.1 Hz, 1H), 6.56 - 6.49 (m, 1H), 5.35 - 5.26 (m, 1H), 5.18 (s, 1H), 4.47 (d, J = 6.4 Hz, 2H), 3.59 - 3.44 (m, 1H), 3.23 - 3.15 (m, 1H), 3.07 - 2.98 (m, 1H), 2.90 (dd, J = 11.7, 4.5 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.35 - 2.24 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1H), 1.77 - 1.67 (m, 1H), 1.59 - 1.51 (m, 1H), 1.40 - 1.26 (m, 1H), 1.20 - 1.11 (m, 1H), 0.76 (dq, J = 8.2, 1.3 Hz, 2H), 0.69 - 0.60 (m, 2H). 1H under water.

[0618] Synthesis 011 5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (PPA-010)

[0619] [ka]

[0620] Step 1: 5-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile DIPEA (0.99 mL, 5.70 mmol) was added to a solution of 5,7-dichloropyrazolo[1,5-a]pyrimidine-3-carbonitrile (173 mg, 0.81 mmol) and (4-(pyridin-2-yl)phenyl)methanamine (150 mg, 0.81 mmol) in EtOH (4.0 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (166 mg, 0.45 mmol, 55% yield, 98% purity) as an orange solid. UPLC / MS (Method 3): m / z 361 (M+H) + , R T 1.35 minutes.

[0621] Step 2: tert-Butyl (5-chloro-3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate DMAP (10.8 mg, 89 μmol) was added to a solution of 5-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (160 mg, 443 μmol) and BOC-anhydride (116 mg, 532 μmol) in anhydrous THF (4.0 mL). The reaction mixture was heated at room temperature overnight and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-5% MeOH / DCM) afforded the title compound (120 mg, 250 μmol, 56% yield, 95% purity) as a yellow glassy solid. UPLC / MS (Method 3): m / z 461 (M+H) + , R T 1.71 minutes.

[0622] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (120 mg, 247 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (72 mg, 310 μmol) in THF (3.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (22 mg, 26 μmol) and LiHMDS (1 M in THF) (0.34 mL, 0.34 mmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 60 °C for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP flash C18 (24 g cartridge, 20-80% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (113 mg, 0.16 mmol, 65% yield, 93% purity) as a yellow glassy solid. UPLC / MS (Method 3): m / z 655 (M+H) + , R T 1.67 minutes.

[0623] Step 4: 5-((((3R,4R)-3-hydroxypiperidin-4-yl)methyl)amino)-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile TFA (0.30 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-cyanopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (113 mg, 173 μmol) in DCM (0.90 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated with EtO (3 × 1 mL). Purification by RP preparative HPLC (45-100% MeCN / 0.3% NH3 in water) afforded the title compound (22 mg, 46 μmol, 27% yield, 95% purity) as a white solid. UPLC / MS (Method 3): m / z 455 (M+H) + , RT 1.12 minutes. 1 H was carried out at 50°C. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 - 7.91 (m, 1H), 7.91 - 7.81 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.38 - 7.26 (m, 1H), 7.03 - 6.94 (m, 1H), 5.47 (s, 1H), 4.62 - 4.53 (m, 3H), 3.50 (dt, J = 13.6, 4.8 Hz, 1H), 3.38 - 3.27 (m, 1H), 3.26 - 3.17 (m, 1H), 2.91 - 2.83 (m, 1H), 2.41 (td, J = 12.1, 2.9 Hz, 1H), 2.33 - 2.25 (m, 1H), 1.78 - 1.66 (m, 1H), 1.54 - 1.43 (m, 1H), 1.24 - 1.11 (m, 1H).2H under water.

[0624] Synthesis 012 (3R,4R)-4-(((3-isopropyl-7-((3-methyl-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-011)

[0625] [ka]

[0626] Step 1: 5-chloro-3-isopropyl-N-(3-methyl-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.68 mL, 3.89 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (128 mg, 217 μmol) and (3-methyl-4-(pyridin-2-yl)phenyl)methanamine (110 mg, 555 μmol) in EtOH (4.0 mL). The reaction mixture was heated to 50° C. overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (49 mg, 88 μmol, 40% yield, 70% purity) as a colorless oil. UPLC / MS (Method 3): m / z 392 (M+H) + , R T 1.79 minutes.

[0627] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methyl-4-(pyridin-2-yl)benzyl)carbamate DMAP (2.1 mg, 18 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(3-methyl-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (49 mg, 88 μmol) and BOC-anhydride (23 mg, 110 μmol) in anhydrous THF (1.0 mL). The reaction mixture was heated at room temperature for 3 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (55 mg, 75 μmol, 86% yield, 67% purity) as a colorless oil. UPLC / MS (Method 3): m / z 392 (M-Boc+H) + , R T 2.03 minutes.

[0628] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methyl-4-(pyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methyl-4-(pyridin-2-yl)benzyl)carbamate (55 mg, 75 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (31 mg, 130 μmol) in THF (1.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (9.5 mg, 11 μmol) and LiHMDS (1 M in THF) (0.14 mL, 0.14 mmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP flash C18 (4 g cartridge, 0-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (33 mg, 48 μmol, 64% yield, 99% purity) as a white solid. UPLC / MS (Method 3): m / z 686 (M+H) + , R T 1.89 minutes.

[0629] Step 4: (3R,4R)-4-(((3-isopropyl-7-((3-methyl-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.25 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methyl-4-(pyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (33 mg, 48 μmol) in DCM (0.75 mL). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in EtO (3 × 1 mL) to give the title compound (13 mg, 25 μmol, 53% yield, 95% purity) as a yellow solid. UPLC / MS (Method 3): m / z 486 (M+H)+, RT 1.35 min. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.94 - 7.81 (m, 2H), 7.64 (s, 1H), 7.54 - 7.46 (m, 1H), 7.39 - 7.31 (m, 2H), 7.31 - 7.21 (m, 2H), 6.78 - 6.68 (m, 1H), 5.47 - 5.23 (m, 1H), 5.19 (s, 1H), 4.47 (d, J = 6.4 Hz, 2H), 3.62 - 3.45 (m, 1H), 3.24 - 3.16 (m, 1H), 3.09 - 2.99 (m, 1H), 2.99 - 2.87 (m, 2H), 2.83 - 2.75 (m, 1H), 2.36 - 2.25 (m, 4H), 2.17 (t, J = 10.6 Hz, 1H), 1.61 - 1.51 (m, 1H), 1.40 - 1.29 (m, 1H), 1.27 - 1.19 (m, 6H), 1.18 - 1.12 (m, 1H).1H under water.

[0630] Synthesis 013 (3-methyl-4-(pyridin-2-yl)phenyl)methanamine

[0631] [ka]

[0632] Step A: 3-Methyl-4-(pyridin-2-yl)benzonitrile 2-Bromopyridine (250 mg, 1.58 mmol), (4-cyano-2-methylphenyl)boronic acid (331 mg, 2.06 mmol), Pd(dppf)Cl.DCM (129 mg, 158 μmol), and potassium carbonate (656 mg, 4.75 mmol) were dissolved in dioxane (9.0 mL) and water (1.0 mL). The reaction mixture was sparged with N for 15 minutes, then heated to 90° C. for 2 hours and then cooled to room temperature. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The layers were separated, and the organic layer was washed with brine (10 mL), then dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (290 mg, 1.3 mmol, 85% yield, 90% purity) as an orange oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.87 - 7.80 (m, 1H), 7.76 (dd, J = 8.0, 1.7 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.44 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 2.35 (s, 3H).

[0633] Step B: (3-methyl-4-(pyridin-2-yl)phenyl)methanamine 3-Methyl-4-(pyridin-2-yl)benzonitrile (143 mg, 736 μmol) in MeOH / 0.7M NH3 (20 mL) was subjected to hydrogenation in an H-cube at 40 °C for 3 h using a Raney nickel cartridge, and the mixture was recycled through the cartridge (flow rate: 1 mL / min). The solvent was concentrated in vacuo. The solid was loaded onto an SCX column. The column was washed with MeOH (20 mL), and the product was eluted with 0.7M NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (128 mg, 250 μmol, 34% yield, 39% purity) as a brown oil. UPLC / MS (Method 3): m / z 199 (M+H) + , R T 0.99 minutes.

[0634] Synthesis 014 (3R,4R)-4-(((3-isopropyl-7-((4-(3-methylpyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-012)

[0635] [ka]

[0636] Step 1: 5-chloro-3-isopropyl-N-(4-(3-methylpyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.18 mL, 1.0 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (40 mg, 0.17 mmol) and (4-(3-methylpyridin-2-yl)phenyl)methanamine (34 mg, 0.17 mmol) in EtOH (3.0 mL). The reaction mixture was heated to 75 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (59 mg, 150 μmol, 86% yield, 99% purity) as a colorless oil. UPLC / MS (Method 3): m / z 392 (M+H)+, R T 1.73 minutes.

[0637] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methylpyridin-2-yl)benzyl)carbamate DMAP (4.0 mg, 33 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(3-methylpyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (59 mg, 150 μmol) and BOC-anhydride (60 mg, 270 μmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at 65° C. for 3 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (68 mg, 0.13 mmol, 88% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 492 (M+H)+, R T 2.03 minutes.

[0638] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methylpyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methylpyridin-2-yl)benzyl)carbamate (67 mg, 129 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (36 mg, 155 μmol) in THF (2.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (11.1 mg, 12.9 μmol) and LiHMDS (1 M in THF) (155 μL, 0.155 mmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60-65°C for 4 hours. At room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite, rinsing with EtOAc (15 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (67 mg, 84 μmol, 65% yield, 85% purity) as an orange oil. UPLC / MS (Method 3): m / z 686 (M+H) + , R T 1.98 minutes.

[0639] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(3-methylpyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.40 mL, 1.6 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methylpyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (65 mg, 81 μmol) in dioxane (1.2 mL). The reaction mixture was stirred at 40° C. for 1 hour and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added, then the reaction mixture was stirred at 40° C. for 1 hour and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH3 in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated with Et0 (2 x 1 mL). Further purification by RP preparative HPLC (55-100% MeCN / 0.3% NH in water) afforded the title compound (29 mg, 59 μmol, 73% yield, 99% purity) as a white solid. LCMS (Method 3): m / z 486 (M+H) + , RT 1.36 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.50 - 8.42 (m, 1H), 7.99 - 7.85 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.64 (s, 1H), 7.56 - 7.49 (m, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.31 - 7.22 (m, 1H), 6.77 - 6.64 (m, 1H), 5.34 - 5.26 (m, 1H), 5.23 (s, 1H), 4.55 - 4.48 (m, 2H), 3.61 - 3.46 (m, 1H), 3.22 - 3.14 (m, 1H), 3.08 - 2.85 (m, 3H), 2.82 - 2.72 (m, 1H), 2.36 - 2.22 (m, 4H), 2.19 - 2.06 (m, 1H), 1.62 - 1.49 (m, 1H), 1.40 - 1.28 (m, 1H), 1.27 - 1.17 (m, 6H), 1.18 - 1.08 (m, 1H). 1H under water.

[0640] Synthesis 015 (4-(3-methylpyridin-2-yl)phenyl)methanamine

[0641] [ka]

[0642] Step A: (4-(3-methylpyridin-2-yl)phenyl)methanamine A mixture of 2-chloro-3-methylpyridine (60 mg, 470 μmol), (4-(aminomethyl)phenyl)boronic acid, HCl (97 mg, 517 μmol), and Pd(dppf)Cl (34.4 mg, 47.0 μmol) in dioxane (2.5 mL) was sparged with N for 5 minutes. A solution of potassium phosphate tribasic (399 mg, 1.88 mmol) in water (1.1 mL) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated to 60 °C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water (3 mL) and DCM / MeOH 90:10 (10 mL). The layers were separated, and the aqueous layer was extracted with DCM / MeOH 90:10 (5 mL). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH 3 ) / DCM) afforded the title compound (36 mg, 0.18 mmol, 38% yield, 99% purity) as a brown solid. UPLC / MS (Method 3): m / z 199 (M+H) + , R T 0.93 minutes.

[0643] Synthesis 016 (3R,4R)-4-(((3-isopropyl-7-((4-(3-methoxypyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-013)

[0644] [ka]

[0645] Step 1: 5-chloro-3-isopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.27 mL, 1.57 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (60 mg, 0.26 mmol) and (4-(3-methoxypyridin-2-yl)phenyl)methanamine (62 mg, 0.29 mmol) in EtOH (2.0 mL). The reaction mixture was heated to 75° C. for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (91 mg, 0.19 mmol, 73% yield, 86% purity) as a colorless oil. UPLC / MS (Method 3): m / z 408 (M+H)+, R T 1.68 minutes.

[0646] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methoxypyridin-2-yl)benzyl)carbamate DMAP (4.6 mg, 38 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (90 mg, 190 μmol) and BOC-anhydride (53 mg, 240 μmol) in anhydrous THF (3.8 mL). The reaction mixture was heated at 65° C. for 2 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (80 mg, 160 μmol, 83% yield, 99% purity) as a colorless oil. UPLC / MS (Method 2): m / z 508 (M+H) + , R T 2.01 minutes.

[0647] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methoxypyridin-2-yl)benzyl)carbamate (80 mg, 157 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (44 mg, 189 μmol) in THF (2.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (13.5 mg, 15.7 μmol) and LiHMDS (1 M in THF) (189 μL, 189 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60 °C for 2 hours. At room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite, rinsing with EtOAc (15 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75 / isohexane) followed by further purification on RP flash C18 (12 g cartridge, 30-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (83 mg, 110 μmol, 72% yield, 96% purity) as an off-white solid. UPLC / MS (Method 3): m / z 702 (M+H) + , R T 1.86 minutes.

[0648] Step 4: (3R,4R)-4-(((3-isopropyl-7-((4-(3-methoxypyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.59 mL, 2.37 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 118 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 40° C. for 1 h and concentrated in vacuo. The solid was triturated in MeCN (2×2 mL) and then loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in EtO (2×1 mL). Further purification by RP preparative HPLC (55-100% MeCN / 0.3% NH3 in water) afforded the title compound (53 mg, 100 μmol, 88% yield, 98% purity) as an off-white solid. LCMS (Method 3): m / z 502 (M+H) + , RT 1.32 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(dd, J = 4.6, 1.3 Hz, 1H), 7.90 (t, J = 6.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.64 (s, 1H), 7.54 (dd, J = 8.4, 1.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 8.4, 4.6 Hz, 1H), 6.76 - 6.68 (m, 1H), 5.33 - 5.26 (m, 1H), 5.19 (s, 1H), 4.50 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.58 - 3.46 (m, 1H), 3.23 - 3.15 (m, 1H), 3.06 - 2.98 (m, 1H), 2.98 - 2.91 (m, 1H), 2.91 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.32 - 2.25 (m, 1H), 2.20 - 2.11 (m, 1H), 1.61 - 1.50 (m, 1H), 1.37 - 1.27 (m, 1H), 1.23 (dd, J = 6.9, 5.1 Hz, 6H), 1.19 - 1.11 (m, 1H). 1H under water.

[0649] Synthesis 017 (4-(3-methoxypyridin-2-yl)phenyl)methanamine

[0650] [ka]

[0651] Step A: (4-(3-methoxypyridin-2-yl)phenyl)methanamine A mixture of 2-chloro-3-methoxypyridine (200 mg, 1.39 mmol), (4-(aminomethyl)phenyl)boronic acid, HCl (287 mg, 1.53 mmol), and Pd(dppf)Cl (102 mg, 139 μmol) in dioxane (8.0 mL) was sparged with N for 5 minutes. A solution of potassium phosphate tribasic (1.18 g, 5.57 mmol) in water (3.4 mL) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with brine (15 mL) and DCM / IPA 70:30 (30 mL). The layers were separated, and the aqueous layer was extracted with DCM / IPA 70:30 (2 × 30 mL). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (110 mg, 0.52 mmol, 38% yield, 99% purity) as a red oil. UPLC / MS (Method 3): m / z 215 (M+H) + , R T 0.96 minutes.

[0652] Synthesis 018 (3R,4R)-4-(((7-((4-(3-fluoropyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-014)

[0653] [ka]

[0654] Step 1: 5-chloro-N-(4-(3-fluoropyridin-2-yl)benzyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.34 mL, 1.96 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (75 mg, 0.33 mmol) and (4-(3-fluoropyridin-2-yl)phenyl)methanamine (80 mg, 0.38 mmol) in EtOH (2.8 mL). The reaction mixture was heated to 80° C. for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (111 mg, 0.27 mmol, 82% yield, 96% purity) as a yellow oil. UPLC / MS (Method 3): m / z 396 (M+H) + , R T 1.78 minutes.

[0655] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-fluoropyridin-2-yl)benzyl)carbamate DMAP (6.8 mg, 56 μmol) was added to a solution of 5-chloro-N-(4-(3-fluoropyridin-2-yl)benzyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (110 mg, 278 μmol) and BOC-anhydride (79 mg, 361 μmol) in anhydrous THF (5.4 mL). The reaction mixture was heated at 65° C. for 2 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (136 mg, 0.25 mmol, 89% yield, 90% purity) as a yellow oil. UPLC / MS (Method 3): m / z 396 (M-Boc+H) + , R T 2.08 minutes.

[0656] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-fluoropyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-fluoropyridin-2-yl)benzyl)carbamate (136 mg, 247 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (68 mg, 296 μmol) in THF (3.2 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (21.1 mg, 24.7 μmol) and LiHMDS (1 M in THF) (296 μL, 296 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60–65°C for 2 hours. At room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite, rinsing with EtOAc (15 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOH in EtOAc 25:75 / isohexane) followed by further purification on RP flash C18 (12 g cartridge, 30–100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (152 mg, 0.20 mmol, 82% yield, 92% purity) as an off-white solid. UPLC / MS (Method 3): m / z 690 (M+H) + , R T 1.92 minutes.

[0657] Step 4: (3R,4R)-4-(((7-((4-(3-fluoropyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.10 mL, 4.41 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-fluoropyridin-2-yl)benzyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (152 mg, 220 μmol) in dioxane (2.2 mL). The reaction mixture was stirred at 40° C. for 1 hour, then hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added and the reaction mixture was stirred at 40° C. for 30 minutes, then concentrated in vacuo. The solid was triturated with MeCN (2×2 mL) and then loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The ammoniacal methanolic solution was concentrated in vacuo and the solid was triturated with EtO (2 × 1 mL) to give the title compound (83 mg, 0.17 mmol, 75% yield, 98% purity) as a white solid. UPLC / MS (Method 3): m / z 490 (M+H) + , RT 1.74 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (dt, J = 4.6, 1.7 Hz, 1H), 7.94 (t, J = 6.5 Hz, 1H), 7.89 (dd, J = 8.3, 1.7 Hz, 2H), 7.82 (ddd, J = 11.7, 8.3, 1.3 Hz, 1H), 7.64 (s, 1H), 7.53 - 7.43 (m, 3H), 6.75 - 6.68 (m, 1H), 5.31 - 5.25 (m, 1H), 5.18 (s, 1H), 4.52 (d, J = 6.4 Hz, 2H), 3.57 - 3.45 (m, 1H), 3.21 - 3.14 (m, 1H), 3.06 - 2.98 (m, 1H), 2.97 - 2.91 (m, 1H), 2.91 - 2.85 (m, 1H), 2.81 - 2.73 (m, 1H), 2.31 - 2.23 (m, 1H), 2.14 (t, J = 10.7 Hz, 1H), 1.59 - 1.50 (m, 1H), 1.39 - 1.26 (m, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.19 - 1.11 (m, 1H).1H under water.

[0658] Synthesis 019 (4-(3-fluoropyridin-2-yl)phenyl)methanamine

[0659] [ka]

[0660] Step A: (4-(3-fluoropyridin-2-yl)phenyl)methanamine A mixture of 2-bromo-3-fluoropyridine (200 mg, 1.14 mmol), (4-(aminomethyl)phenyl)boronic acid, HCl (234 mg, 1.25 mmol), and Pd(dppf)Cl (83 mg, 114 μmol) in dioxane (6.7 mL) was sparged with N for 5 minutes. A solution of potassium phosphate tribasic (965 mg, 4.55 mmol) in water (2.9 mL) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 mL) and DCM / MeOH 90:10 (15 mL). The layers were separated, and the aqueous layer was extracted with DCM / MeOH 90:10 (2 × 10 mL). The combined organic layers were filtered through a phase separator and concentrated in vacuo. The oil was loaded onto an SCX column. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH3 in MeOH (100 mL) to give the title compound (165 mg, 0.79 mmol, 61% yield, 97% purity) as a red oil. UPLC / MS (Method 3): m / z 203 (M+H) + , R T 0.93 minutes.

[0661] Synthesis 020 (3R,4R)-4-(((3-cyclopropyl-7-((3-methoxy-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-015)

[0662] [ka]

[0663] Step 1: 5-chloro-3-cyclopropyl-N-(3-methoxy-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.73 mL, 4.16 mmol) was added to a solution of (3-methoxy-4-(pyridin-2-yl)phenyl)methanamine (140 mg, 653 μmol) and 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (135 mg, 594 μmol) in EtOH (6.0 mL). The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (105 mg, 0.25 mmol, 41% yield, 95% purity) as a white crystalline solid. UPLC / MS (Method 3): m / z 406 (M+H) + , R T 1.59 minutes.

[0664] Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methoxy-4-(pyridin-2-yl)benzyl)carbamate BOC-anhydride (68 mg, 310 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(3-methoxy-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (105 mg, 259 μmol) and DMAP (6.3 mg, 52 μmol) in THF (3.0 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (112 mg, 0.21 mmol, 81% yield, 95% purity) as a green oil. UPLC / MS (Method 3): m / z 506 (M+H) + , R T 1.91 minutes.

[0665] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methoxy-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methoxy-4-(pyridin-2-yl)benzyl)carbamate (112 mg, 221 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (61 mg, 266 μmol) in THF (3.0 mL) was degassed with N for 10 minutes, followed by t BuBrettPhos Pd G3 (19 mg, 22 μmol) and LiHMDS (1 M in THF) (288 μL, 288 μmol) were added. The reaction was degassed for an additional 5 min and then heated to 60 °C for 2.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (147 mg, 0.18 mmol, 81% yield, 85% purity) as a brown glass. UPLC / MS (Method 3): m / z 663 (M+H) + , R T 1.61 minutes.

[0666] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((3-methoxy-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (1.0 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methoxy-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (147 mg, 210 μmol) in DCM (3.0 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (73 mg, 0.14 mmol, 66% yield, 95% purity) as a pink solid. UPLC / MS (Method 3): m / z 500 (M+H)+, R T 1.59 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.60 (m, 1H), 7.88 (t, J = 6.4 Hz, 1H), 7.85 - 7.74 (m, 2H), 7.69 (d, J = 7.9, 2.1 Hz, 1H), 7.53 (s, 1H), 7.32 - 7.26 (m, 1H), 7.19 (s, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.76 - 6.69 (m, 1H), 5.36 - 5.27 (m, 1H), 5.21 (s, 1H), 4.49 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.58 - 3.45 (m, 1H), 3.25 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.95 - 2.87 (m, 1H), 2.83 - 2.75 (m, 1H), 2.35 - 2.26 (m, 1H), 2.20 - 2.12 (m, 1H), 1.77 - 1.67 (m, 1H), 1.60 - 1.52 (m, 1H), 1.39 - 1.28 (m, 1H), 1.20 - 1.11 (m, 1H), 0.79 - 0.74 (m, 2H), 0.70 - 0.59 (m, 2H).1H under water.

[0667] Synthesis 021 (3-Methoxy-4-(pyridin-2-yl)phenyl)methanamine

[0668] [ka]

[0669] Step A: 4-cyano-2-methoxyphenyl trifluoromethanesulfonate Trifluoromethanesulfonic anhydride (0.73 mL, 4.36 mmol) was added to a solution of 3,4-hydroxy-3-methoxybenzonitrile (500 mg, 3.35 mmol) and triethylamine (509 mg, 701 μL, 1.5 equiv, 5.03 mmol) in DCM (15 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated aqueous NaHCO (20 mL) and extracted with DCM (3 × 10 mL). The combined organic fractions were washed with brine (50 mL), dried over MgSO, filtered, and then concentrated in vacuo to give the title compound (938 mg, 3.20 mmol, 95% yield, 95% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 1.9 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 3.97 (s, 3H).

[0670] Step B: 3-Methoxy-4-(pyridin-2-yl)benzonitrile A solution of 2-(tributylstannyl)pyridine (1.47 g, 4.00 mmol), 4-cyano-2-methoxyphenyl trifluoromethanesulfonate (938 mg, 3.34 mmol), Pd(PhP) (385 mg, 334 μmol), and lithium chloride (141 mg, 3.34 mmol) in DMF (15.0 mL) was degassed with N for 15 minutes. The bubbling was stopped, and the reaction mixture was heated to 90 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was cooled to room temperature, then diluted with water (50 mL) and brine (50 mL), and extracted into MTBE (3 × 50 mL). The combined organic layers were washed with brine (50 mL), then dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (233 mg, 0.94 mmol, 28% yield, 85% purity) as a white solid. UPLC / MS (Method 3): m / z 211 (M+H) + , RT 1.16 minutes.

[0671] Step C: (3-Methoxy-4-(pyridin-2-yl)phenyl)methanamine LiAlH (4 M in EtO) (180 μL, 720 μmol) was added to a solution of 3-methoxy-4-(pyridin-2-yl)benzonitrile (155 mg, 627 μmol) in THF (8.0 mL) at 0° C. The mixture was stirred at 0° C. for 15 min, then warmed to room temperature and stirred for an additional 15 min. The mixture was quenched with methanol until effervescence ceased, then the mixture was diluted with water (100 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO, filtered, and concentrated in vacuo to give the title compound (140 mg, 0.52 mmol, 83% yield, 80% purity) as a brown solid. UPLC / MS (Method 3): m / z 215 (M+H) + , R T 0.93 minutes.

[0672] Synthesis 022 (3R,4R)-4-(((3-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-016)

[0673] [ka]

[0674] Step 1: 3,5-Dichloro-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (1.1 mL, 6.47 mmol) was added to a solution of 3,5,7-trichloropyrazolo[1,5-a]pyrimidine (240 mg, 1.08 mmol) and (4-(pyridin-2-yl)phenyl)methanamine, HCl (238 mg, 1.08 mmol) in EtOH (10.0 mL). The reaction mixture was heated at 70 °C overnight. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (206 mg, 0.55 mmol, 51% yield, 99% purity) as a colorless oil. UPLC / MS (Method 3): m / z 370 (M+H) + , R T 1.52 minutes.

[0675] Step 2: tert-Butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate DMAP (13.7 mg, 0.112 mmol) was added to a solution of 3,5-dichloro-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (207 mg, 560 μmol) and BOC-anhydride (175 mg, 802 μmol) in THF (10 mL). The reaction mixture was heated at 65° C. for 1.5 hours and 20 minutes. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (274 mg, 0.55 mmol, 98% yield, 94% purity) as a yellow gum. UPLC / MS (Method 3): m / z 470 (M+H) + , R T 1.87 minutes.

[0676] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (270 mg, 574 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (145 mg, 631 μmol) in THF (2.5 mL) was degassed with N for 5 minutes, and then t BuBrettPhos Pd G3 (49 mg, 57 μmol) and LiHMDS (1 M in THF) (603 μL, 603 μmol) were added. The reaction was degassed for an additional 5 min and then heated to 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3) in DCM) afforded the title compound (324 mg, 0.46 mmol, 81% yield, 95% purity) as a colorless oil. UPLC / MS (Method 3): m / z 664 (M+H) + , R T 2.15 minutes.

[0677] Step 4: (3R,4R)-4-(((3-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (1.81 mL, 7.23 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (320 mg, 482 μmol) in dioxane (3.0 mL). The reaction mixture was stirred at 35° C. for 3 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (87 mg, 0.17 mmol, 36% yield, 93% purity) as a pink solid. UPLC / MS (Method 3): m / z 464 (M+H) + , R T 1.55 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.67 - 8.62 (m, 1H), 8.13 (t, J = 6.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.96 - 7.91 (m, 1H), 7.89 (s, 1H), 7.89 - 7.83 (m, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.37 - 7.30 (m, 1H), 6.96 (t, J = 5.9 Hz, 1H), 5.29 (s, 1H), 5.08 - 5.00 (m, 1H), 4.52 (d, J = 6.3 Hz, 2H), 3.46 - 3.35 (m, 1H), 3.29 - 3.22 (m, 1H), 3.07 - 2.99 (m, 1H), 2.94 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.35 - 2.23 (m, 1H), 2.20 - 2.11 (m, 1H), 1.62 - 1.54 (m, 1H), 1.38 - 1.27 (m, 1H), 1.17 - 1.03 (m, 1H). 1H under water.

[0678] Synthesis 023 (3R,4R)-4-(((7-((4-(1H-pyrrol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-017)

[0679] [ka]

[0680] Step 1: N-(4-(1H-pyrrol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine DIPEA (412 μL, 2.37 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (90.0 mg, 395 μmol) and (4-(1H-pyrrol-1-yl)phenyl)methanamine (81.6 mg, 474 μmol) in EtOH (2.5 mL). The reaction mixture was heated at 65° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (135 mg, 0.35 mmol, 88% yield, 93% purity) as a yellow gum. UPLC / MS (Method 3): m / z 364 (M+H) + , R T 2.12 minutes.

[0681] Step 2: tert-Butyl (4-(1H-pyrrol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate DMAP (8.98 mg, 73.5 μmol) was added to a solution of N-(4-(1H-pyrrol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (135 mg, 367 μmol) and BOC-anhydride (104 mg, 478 μmol) in THF (6.80 mL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 25% EtOH / isohexane in 0-100% EtOAc) afforded the title compound (183 mg, 0.35 mmol, 96% yield, 89% purity) as a yellow oil. UPLC / MS (Method 3): m / z 408 (M+H-tBu) + , R T 2.04 minutes.

[0682] Step 3: tert-Butyl (3R,4R)-4-(((7-((4-(1H-pyrrol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (4-(1H-pyrrol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (183 mg, 0.351 mmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (97 mg, 0.421 mmol) in THF (4.0 mL) was degassed with N for 5 minutes, followed by t BuBrettPhos Pd G3 (30 mg, 35 μmol) and LiHMDS (1 M in THF) (421 μL, 0.421 mmol) were added. The reaction was degassed for an additional 5 min before being heated to 60–65°C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (75:25 EtOH in EtOAc / isohexane) afforded the title compound (139 mg, 0.20 mmol, 57% yield, 94% purity) as a brown solid. UPLC / MS (Method 3): m / z 658 (M+H) + , R T 1.91 minutes.

[0683] Step 4: (3R,4R)-4-(((7-((4-(1H-pyrrol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (1.08 mL, 4.33 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((4-(1H-pyrrol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (150 mg, 217 μmol) in dioxane (2.80 mL). The suspension was stirred at 40° C. for 3 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with DCM / MeOH (1:2, 120 mL) and the product was eluted with 0.7 M NH in DCM / MeOH (1:2, 150 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (71 mg, 0.15 mmol, 69% yield, 97% purity) as a beige solid. UPLC / MS (Method 3): m / z 458 (M+H) + , R T 1.41 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.87 (t, J = 6.5 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 2.2 Hz, 2H), 6.74 - 6.67 (m, 1H), 6.24 (t, J = 2.2 Hz, 2H), 5.34 - 5.29 (m, 1H), 5.19 (s, 1H), 4.45 (d, J = 6.4 Hz, 2H), 3.55 - 3.45 (m, 1H), 3.24 - 3.15 (m, 1H), 3.07 - 2.98 (m, 1H), 2.95 - 2.87 (m, 1H), 2.83 - 2.75 (m, 1H), 2.32 - 2.26 (m, 1H), 2.16 (t, J = 10.8 Hz, 1H), 1.76 - 1.66 (m, 1H), 1.59 - 1.52 (m, 1H), 1.40 - 1.27 (m, 1H), 1.20 - 1.11 (m, 1H), 0.79 - 0.72 (m, 2H), 0.68 - 0.59 (m, 2H).1H under water.

[0684] Synthesis 024 (3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-018)

[0685] [ka]

[0686] Step 1: 5-chloro-3-cyclopropyl-N-(4-(thiazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (550 μL, 3.16 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (80.0 mg, 351 μmol) and (4-thiazol-2-ylphenyl)methanamine HCl (95.4 mg, 421 μmol) in EtOH (1.2 mL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (125 mg, 0.31 mmol, 90% yield, 96% purity) as a yellow oil. UPLC / MS (Method 3): m / z 382 (M+H) + , R T 1.63 minutes.

[0687] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thiazol-2-yl)benzyl)carbamate DMAP (7.9 mg, 65.0 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(thiazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (124 mg, 0.325 mmol) and BOC-anhydride (92 mg, 423 μmol) in THF (6.4 mL). The reaction mixture was heated at 65° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (151 mg, 0.29 mmol, 90% yield, 93% purity) as a yellow oil. UPLC / MS (Method 3): m / z 482 (M+H) + , R T 2.04 minutes.

[0688] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thiazol-2-yl)benzyl)carbamate (148 mg, 286 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (79 mg, 343 μmol) in THF (3.8 mL) was degassed with N for 5 minutes, followed by t BuBrettPhos Pd G3 (24.4 mg, 28.6 μmol) and LiHMDS (1 M in THF) (343 μL, 343 μmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 60-65°C for 2 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH / isohexane in EtOAc) afforded the title compound (150 mg, 0.21 mmol, 73% yield, 94% purity) as a brown oil. UPLC / MS (Method 3): m / z 676 (M+H) + , R T 1.84 minutes.

[0689] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (1.05 mL, 4.22 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (150 mg, 211 μmol) in dioxane (2.80 mL). The suspension was stirred at 40° C. for 1 h, after which HCl (1.25 M in methanol) (1.00 mL, 1.25 mmol) was added and further stirred at 40° C. for 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (150 mL) and the product was eluted with 0.7 M NH3 in MeOH (150 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (90 mg, 0.18 mmol, 88% yield, 98% purity) as a beige solid. UPLC / MS (Method 3): m / z 476 (M+H) + , R T 1.42 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.88 (m, 4H), 7.77 (d, J = 3.2 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 6.70 (t, J = 6.0 Hz, 1H), 5.32 - 5.26 (m, 1H), 5.15 (s, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.56 - 3.43 (m, 1H), 3.23 - 3.14 (m, 1H), 3.07 - 2.97 (m, 1H), 2.93 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.34 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 - 1.66 (m, 1H), 1.59 - 1.50 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.05 (m, 1H), 0.81 - 0.71 (m, 2H), 0.70 - 0.60 (m, 2H).1H under water.

[0690] Synthesis 025 (3R,4R)-4-(((3-cyclopropyl-7-((4-(5-fluoropyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-019)

[0691] [ka]

[0692] Step 1 of 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(5-fluoropyridin-2-yl)benzyl)carbamate DIPEA (0.46 mL, 2.63 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (100 mg, 438 μmol) and (4-(5-fluoropyridin-2-yl)phenyl)methanamine (102 mg, 504 μmol) in EtOH (3.0 mL). The reaction mixture was heated at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (12 g cartridge, 0-10% MeOH / DCM) gave the intermediate 5-chloro-3-cyclopropyl-N-(4-(5-fluoropyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine.

[0693] 5-Chloro-3-cyclopropyl-N-(4-(5-fluoropyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine was dissolved in THF (2.5 mL), followed by the addition of BOC-anhydride (87.3 mg, 400 μmol) and DMAP (3.26 mg, 26.7 μmol). The reaction mixture was concentrated under reduced pressure. Purification by column chromatography on silica gel (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (115 mg, 0.22 mmol, 50% yield, 95% purity) as a yellow foam. 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.9 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J = 8.9, 4.4 Hz, 1H), 7.99 - 7.92 (m, 2H), 7.79 (td, J = 8.8, 3.0 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.18 (s, 1H), 5.05 (s, 2H), 1.96 (tt, J = 8.3, 5.1 Hz, 1H), 1.28 (s, 9H), 0.97 - 0.86 (m, 2H), 0.82 - 0.72 (m, 2H).

[0694] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(5-fluoropyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(5-fluoropyridin-2-yl)benzyl)carbamate (116 mg, 222 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (61 mg, 266 μmol) in THF (3.8 mL) was degassed with N for 5 minutes, followed by tBuBrettPhos Pd G3 (19 mg, 22 μmol) and LiHMDS (1 M in THF) (267 μL, 267 μmol) were added with a N sparge. The reaction was degassed for an additional 5 min and then heated to 60-65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH / isohexane in EtOAc) afforded the title compound (97 mg, 0.14 mmol, 61% yield, 96% purity) as a brown oil. UPLC / MS (Method 3): m / z 688 (M+H) + , R T 1.88 minutes.

[0695] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(5-fluoropyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (0.67 mL, 2.7 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(5-fluoropyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (96 mg, 0.13 mmol) in dioxane (1.8 mL). The suspension was stirred at 40° C. for 1.5 hours, after which HCl (1.25 M in MeOH) (1.00 mL, 1.25 mmol) was added and further stirred at 40° C. for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with DCM / MeOH (1:2, 120 mL) and the product was eluted with 0.7 M NH in DCM / MeOH (1:2, 150 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (61.5 mg, 0.12 mmol, 91% yield, 97% purity) as a beige solid. UPLC / MS (Method 3: m / z 488 (M+H) + , R T 1.49 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 3.0 Hz, 1H), 8.05 - 7.97 (m, 3H), 7.90 (t, J = 6.5 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 6.74 - 6.68 (m, 1H), 5.36 - 5.26 (m, 1H), 5.17 (s, 1H), 4.50 (d, J = 6.2 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.23 - 3.16 (m, 1H), 3.07 - 2.98 (m, 1H), 2.94 - 2.87 (m, 1H), 2.81 - 2.74 (m, 1H), 2.32 - 2.24 (m, 1H), 2.19 - 2.12 (m, 1H), 1.77 - 1.67 (m, 1H), 1.59 - 1.50 (m, 1H), 1.39 - 1.27 (m, 1H), 1.19 - 1.11 (m, 1H), 0.79 - 0.73 (m, 2H), 0.69 - 0.60 (m, 2H).1H under water.

[0696] Synthesis 026 (3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-020)

[0697] [ka]

[0698] Step 1: 5-chloro-3-cyclopropyl-N-(2-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.15 mL, 0.88 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (38 mg, 0.15 mmol) and (2-fluoro-4-(pyridin-2-yl)phenyl)methanamine (30 mg, 0.15 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (40 mg, 96 μmol, 66% yield, 95% purity) as a colorless oil. UPLC / MS (Method 3): m / z 394 (M+H) + , R T 1.68 minutes.

[0699] Step 2: tert-Butyl (5-amino-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-(pyridin-2-yl)benzyl)carbamate BOC-anhydride (27 mg, 0.12 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(2-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (40 mg, 0.10 mmol) and DMAP (2.5 mg, 20 μmol) in THF (3.0 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (43 mg, 86 μmol, 85% yield, 99% purity) as a dark green oil. UPLC / MS (Method 3): m / z 494 (M+H) + , R T 1.99 minutes.

[0700] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-(pyridin-2-yl)benzyl)carbamate (40.0 mg, 81.0 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (28.0 mg, 121 μmol), and cesium carbonate (79.2 mg, 243 μmol) in dioxane (1.5 mL) was degassed with N for 5 minutes. Pd-171 (1.6 mg, 2.4 μmol) and Ruphos phosphane (1.3 mg, 2.8 μmol) were added, and N was bubbled through the reaction mixture for an additional 5 minutes. The reaction mixture was stirred at 90 °C for 5 hours. At room temperature, the reaction mixture was diluted with EtOAc (10 mL) and filtered through Celite, rinsing with EtOAc (20 mL). The filtrate was concentrated in vacuo and purified by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) / DCM) to give the title compound (39 mg, 50 μmol, 62% yield, 89% purity) as a yellow glassy solid. UPLC / MS (Method 3): m / z 688 (M+H) + , R T 1.92 minutes.

[0701] Step 4: ((3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (126 μL, 505 μmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (39 mg, 50 μmol) in dioxane (2.0 mL). The suspension was stirred at 35° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (140 mL) and the product was eluted with 0.7 M NH in MeOH (10 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (16 mg, 32 μmol, 64% yield, 98% purity) as a yellow solid. UPLC / MS (Method 3): m / z 488 (M+H) + , R T 1.53 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.88 (m, 4H), 7.77 (d, J = 3.2 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 6.70 (t, J = 6.0 Hz, 1H), 5.32 - 5.26 (m, 1H), 5.15 (s, 1H), 4.50 (d, J = 6.1 Hz, 2H), 3.56 - 3.43 (m, 1H), 3.23 - 3.14 (m, 1H), 3.07 - 2.97 (m, 1H), 2.93 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.34 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 - 1.66 (m, 1H), 1.59 - 1.50 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.05 (m, 1H), 0.81 - 0.71 (m, 2H), 0.70 - 0.60 (m, 2H).1H under water.

[0702] Synthesis 027 (2-fluoro-4-(pyridin-2-yl)phenyl)methanamine

[0703] [ka]

[0704] Step A: (2-fluoro-4-(pyridin-2-yl)phenyl)methanamine A suspension of 2-bromopyridine (60 μL, 633 μmol), (4-(aminomethyl)-3-fluorophenyl)boronic acid (118 mg, 696 μmol), Pd(dppf)Cl.DCM (52 mg, 63 μmol), and cesium carbonate (206 mg, 633 μmol) in dioxane (9.0 mL) and water (1.0 mL) was degassed with N for 5 minutes. The reaction mixture was stirred at 90° C. for 2 hours. At room temperature, the reaction mixture was diluted with water (50 mL), extracted with EtOAc (2×25 mL), filtered through Celite, and rinsed with EtOAc (20 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (38 mg, 0.17 mmol, 26% yield, 88% purity) as an orange oil. UPLC / MS (Method 6): m / z 203 (M+H) + , R T 1.98 minutes.

[0705] Synthesis 028 (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-021)

[0706] [ka]

[0707] Step 1: N-([2,3'-bipyridin]-6'-ylmethyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine DIPEA (698 μL, 4.01 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (130 mg, 572 μmol) and [2,3'-bipyridin]-6'-ylmethanamine, 2HCl (211 mg, 572 μmol) in EtOH (8.0 mL). The reaction mixture was heated at 50°C for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (96 mg, 0.24 mmol, 42% yield, 95% purity) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.25 - 9.20 (m, 1H), 8.82 (t, J = 6.2 Hz, 1H), 8.73 - 8.66 (m, 1H), 8.44 (dd, J = 8.2, 2.3 Hz, 1H), 8.08 - 8.00 (m, 1H), 7.96 (s, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 7.53 - 7.45 (m, 1H), 7.41 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.13 (s, 1H), 4.79 (d, J = 6.2 Hz, 2H), 1.96 - 1.84 (m, 1H), 0.93 - 0.80 (m, 2H), 0.84 - 0.71 (m, 2H).

[0708] Step 2: tert-Butyl ([2,3'-bipyridin]-6'-ylmethyl) (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate BOC-anhydride (67 mg, 0.31 mmol) was added to a solution of N-([2,3'-bipyridin]-6'-ylmethyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (96 mg, 0.25 mmol) and DMAP (6.2 mg, 51 μmol) in THF (3.0 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (84 mg, 0.16 mmol, 62% yield, 90% purity) as a green solid. UPLC / MS (Method 3): m / z 477 (M+H) + , R T 2.15 minutes.

[0709] Step 3: tert-Butyl (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl ([2,3'-bipyridin]-6'-ylmethyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (84 mg, 0.18 mmol) (150 mg, 311 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (49 mg, 0.21 mmol) in THF (2.0 mL) was degassed with N for 5 minutes, followed by t BuBrettPhos Pd G3 (15 mg, 18 μmol) and LiHMDS (1 M in THF) (0.23 mL, 0.23 mmol) were added. The reaction was degassed for an additional 10 min and then heated to 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (93 mg, 0.13 mmol, 75% yield, 95% purity) as a brown glass. UPLC / MS (Method 3): m / z 671 (M+H)+ , R T 2.03 minutes.

[0710] Step 4: (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (93 mg, 0.14 mmol) in DCM (1.5 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (150 mL) and the product was eluted with 0.7 M NH3 in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (39.9 mg, 81 μmol, 58% yield, 96% purity) as a beige solid. UPLC / MS (Method 2): m / z 471 (M+H) + , R T 0.62 minutes. 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J = 2.3 Hz, 1H), 8.74 - 8.66 (m, 1H), 8.42 (dd, J = 8.2, 2.4 Hz, 1H), 8.06 - 8.01 (m, 1H), 7.94 - 7.90 (m, 1H), 7.90 - 7.82 (m, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.43 - 7.38 (m, 1H), 6.79 - 6.72 (m, 1H), 5.38 - 5.26 (m, 1H), 5.18 (s, 1H), 4.66 - 4.56 (m, 2H), 3.60 - 3.43 (m, 1H), 3.24 - 3.16 (m, 1H), 3.09 - 3.00 (m, 1H), 2.91 (dd, J = 11.5, 4.6 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.36 - 2.27 (m, 1H), 2.22 - 2.13 (m, 1H), 1.77 - 1.68 (m, 1H), 1.60 - 1.51 (m, 1H), 1.41 - 1.28 (m, 1H), 1.26 - 1.10 (m, 1H), 0.81 - 0.73 (m, 2H), 0.71 - 0.59 (m, 2H). 1H under water.

[0711] Synthesis 029 [2,3'-bipyridin]-6'-ylmethanamine 2HCl

[0712] [ka]

[0713] Step A: [2,3'-bipyridine]-6'-carbonitrile 2-(Tributylstannyl)pyridine (529 μL, 1.64 mmol), 5-bromopicolinonitrile (250 mg, 1.37 mmol), Pd(PhP) (158 mg, 137 μmol), and lithium chloride (58 mg, 1.37 mmol) were dissolved in DMF (5.0 mL). The mixture was sparged with N for 10 min, then heated to 90 °C for 18 h and then cooled to room temperature. The mixture was diluted with saturated aqueous LiCl (40 mL) and water (40 mL) and then extracted with MTBE (2 × 40 mL). The organic layer was washed with brine (40 mL), then dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0–10% MeOH / DCM) afforded the title compound (146 mg, 0.76 mmol, 56% yield, 95% purity) as a white solid. UPLC / MS (Method 2): m / z 182 (M+H)+, R T 1.23 minutes.

[0714] Step B: [2,3'-bipyridin]-6'-ylmethanamine 2HCl [2,3'-Bipyridine]-6'-carbonitrile (139 mg, 767 μmol) in HCl (1.25 M in MeOH) (20 mL) was hydrogenated in an H-cube using a 10% palladium on carbon cartridge at room temperature for 1.5 h, and the mixture was recycled through the cartridge (flow rate: 1 mL / min). The solvent was concentrated in vacuo to give the title compound (211 mg, 0.57 mmol, 75% yield, 70% purity) as a yellow solid. UPLC / MS (Method 3): m / z 186 (M+H) + , R T 0.75 minutes.

[0715] Synthesis 030 (3R,4R)-4-(((3-cyclopropyl-7-((3-fluoro-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-022)

[0716] [ka]

[0717] Step 1: 5-chloro-3-cyclopropyl-N-(3-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (367 μL, 2.10 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (80 mg, 351 μmol) and (3-fluoro-4-(pyridin-2-yl)phenyl)methanamine (82 mg, 389 μmol) in EtOH (1.4 mL). The reaction mixture was heated at 65° C. for 2.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (93 mg, 0.21 mmol, 59% yield, 88% purity) as a yellow oil. UPLC / MS (Method 2): m / z 394 (M+H) + , R T 1.60 minutes.

[0718] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-fluoro-4-(pyridin-2-yl)benzyl)carbamate DMAP (5.1 mg, 42 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(3-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (93 mg, 208 μmol) and BOC-anhydride (59 mg, 270 μmol) in THF (4.6 mL). The resulting reaction mixture was heated at 65° C. for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (94 mg, 0.16 mmol, 79% yield, 87% purity) as a yellow oil. UPLC / MS (Method 2): m / z 494 (M+H) + , R T 1.98 minutes.

[0719] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-fluoro-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-fluoro-4-(pyridin-2-yl)benzyl)carbamate (93 mg, 185 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (51 mg, 221 μmol) in THF (2.0 mL) was degassed with N for 5 minutes, followed by t BuBrettPhos Pd G3 (15.8 mg, 18.5 μmol) and LiHMDS (1 M in THF) (221 μL, 221 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60-65°C for 4 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (36 mg, 50 μmol, 27% yield, 95% purity) as a yellow oil. UPLC / MS (Method 2): m / z 688 (M+H) + , R T 1.84 minutes.

[0720] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((3-fluoro-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (244 μL, 974 μmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-fluoro-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (33.5 mg, 48.7 μmol) in dioxane (1.0 mL). The suspension was stirred at 40° C. for 2 h, then HCl in methanol (1.25 M in MeOH) (1.00 mL, 1.25 mmol) was added and stirred for an additional 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (100 mL) and the product was eluted with 0.7 M NH3 in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (20 mg, 40 μmol, 82% yield, 97% purity) as a grey solid. UPLC / MS (Method 3): m / z 488 (M+H)+, R T 1.31 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.65 (m, 1H), 7.99 - 7.85 (m, 3H), 7.79 - 7.73 (m, 1H), 7.53 (s, 1H), 7.43 - 7.36 (m, 1H), 7.34 - 7.25 (m, 2H), 6.72 (t, J = 6.0 Hz, 1H), 5.31 - 5.24 (m, 1H), 5.18 (s, 1H), 4.51 (d, J = 6.3 Hz, 2H), 3.57 - 3.41 (m, 1H), 3.25 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.94 - 2.86 (m, 1H), 2.82 - 2.74 (m, 1H), 2.35 - 2.24 (m, 1H), 2.18 - 2.11 (m, 1H), 1.76 - 1.67 (m, 1H), 1.59 - 1.51 (m, 1H), 1.38 - 1.26 (m, 1H), 1.18 - 1.06 (m, 1H), 0.79 - 0.73 (m, 2H), 0.70 - 0.60 (m, 2H).1H under water.

[0721] Synthesis 031 (3-fluoro-4-(pyridin-2-yl)phenyl)methanamine

[0722] [ka]

[0723] Step A: 3-Fluoro-4-(pyridin-2-yl)benzonitrile 2-Bromopyridine (250 mg, 151 μL, 1.58 mmol), (4-cyano-2-fluorophenyl)boronic acid (346 mg, 2.06 mmol), and Pd(dppf)Cl (116 mg, 158 μmol) were dissolved in dioxane (7.0 mL). The mixture was sparged with N for 10 minutes, then a solution of potassium carbonate (656 mg, 4.75 mmol) in water (778 μL) was added, and N was bubbled through the reaction mixture for an additional 5 minutes. The mixture was heated to 90 °C overnight and then cooled to room temperature. The reaction mixture was diluted with EtOAc (20 mL) and filtered through Celite. The filtrate was further diluted with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organics were washed with brine (2 × 15 mL), dried over MgSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 25% EtOH / isohexane in 0-100% EtOAc) gave the title compound (297 mg, 1.4 mmol, 89% yield, 94% purity) as a white solid. UPLC / MS (Method 2): m / z 199 (M+H)+, R T 1.16 minutes.

[0724] Step B: (3-fluoro-4-(pyridin-2-yl)phenyl)methanamine 3-Fluoro-4-(pyridin-2-yl)benzonitrile (142 mg, 573 μmol) and acetic acid (1.00 mL, 17.4 mmol) in MeOH (19 mL) were subjected to hydrogenation (hydrogen pressure set at 30 bar) in an H-cube using a 10% palladium on carbon cartridge at 45° C. for 2.5 hours, and the mixture was recycled through the cartridge (flow rate: 1 mL / min). The reaction mixture was concentrated under reduced pressure (azeotroped with MeCN). The crude product precipitated and was triturated in MeCN in an ice bath. The suspension was filtered, and the solid was evaporated to dryness under reduced pressure to give the title compound (82 mg, 0.33 mmol, 48% yield, 80% purity) as a yellow solid. UPLC / MS (Method 3): m / z 203 (M+H) + , R T 1.12 minutes.

[0725] Synthesis 032 (3R,4R)-4-(((3-cyclopropyl-7-((4-(2-methyl-1H-imidazol-1-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-023)

[0726] [ka]

[0727] Step 1: 5-chloro-3-cyclopropyl-N-(4-(2-methyl-1H-imidazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (367 μL, 2.10 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (80.0 mg, 351 μmol) and (4-(2-methyl-1H-imidazol-1-yl)phenyl)methanamine (78.8 mg, 421 μmol) in EtOH (1.4 mL). The reaction mixture was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (121 mg, 0.31 mmol, 89% yield, 97% purity) as a colorless oil. UPLC / MS (Method 3): m / z 379 (M+H) + , R T 1.69 minutes.

[0728] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(2-methyl-1H-imidazol-1-yl)benzyl)carbamate DMAP (7.6 mg, 62 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(2-methyl-1H-imidazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (121 mg, 310 μmol) and BOC-anhydride (88 mg, 403 μmol) in THF (6.2 mL). The resulting reaction mixture was heated at 65° C. for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (105 mg, 0.21 mmol, 67% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 479 (M+H) + , R T 2.04 minutes.

[0729] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(2-methyl-1H-imidazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(2-methyl-1H-imidazol-1-yl)benzyl)carbamate (105 mg, 219 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (60.6 mg, 263 μmol) in THF (2.4 mL) was degassed with N for 5 minutes, followed by tBuBrettPhos Pd G3 (18.7 mg, 21.9 μmol) and LiHMDS (1 M in THF) (263 μL, 263 μmol) were added. The reaction was degassed for an additional 5 minutes before being heated to 60-65°C for 2 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc) / isohexane) afforded the title compound (90 mg, 0.13 mmol, 59% yield, 96% purity) as an orange oil. UPLC / MS (Method 2): m / z 673 (M+H) + , R T 1.20 minutes.

[0730] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(2-methyl-1H-imidazol-1-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (631 μL, 2.52 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(2-methyl-1H-imidazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (87 mg, 126 μmol) in dioxane (2.0 mL). The suspension was stirred at 40° C. for 2 hours. Hydrogen chloride (1.25 M in MeOH) (0.80 mL, 1.00 mol) was added and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (150 mL) and the product was eluted with 0.7 M NH in MeOH (150 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (53 mg, 0.11 mmol, 84% yield, 95% purity) as an orange solid. UPLC / MS (Method 3): m / z 473 (M+H) + , R T 1.12 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J = 6.6 Hz, 1H), 7.52 (s, 1H), 7.51 - 7.47 (m, 2H), 7.43 - 7.39 (m, 2H), 7.24 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.71 (t, J = 6.0 Hz, 1H), 5.32 - 5.25 (m, 1H), 5.23 (s, 1H), 4.50 (d, J = 6.3 Hz, 2H), 3.54 - 3.44 (m, 1H), 3.27 - 3.19 (m, 1H), 3.09 - 2.99 (m, 1H), 2.95 - 2.88 (m, 1H), 2.83 - 2.75 (m, 1H), 2.35 - 2.23 (m, 4H), 2.21 - 2.12 (m, 1H), 1.76 - 1.66 (m, 1H), 1.62 - 1.54 (m, 1H), 1.39 - 1.27 (m, 1H), 1.19 - 1.08 (m, 1H), 0.79 - 0.71 (m, 2H), 0.69 - 0.61 (m, 2H).1H under water.

[0731] Synthesis 033 (3R,4R)-4-(((3-cyclopropyl-7-(((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-024)

[0732] [ka]

[0733] Step 1: 5-chloro-3-cyclopropyl-N-((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.32 mL, 1.8 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (70 mg, 0.31 mmol) and (1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methanamine (58 mg, 0.31 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (87 mg, 0.23 mmol, 74% yield, 99% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (t, J = 5.5 Hz, 1H), 8.47 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.94 (s, 1H), 7.84 - 7.72 (m, 2H), 7.70 (s, 1H), 7.17 (ddd, J = 6.8, 4.8, 1.7 Hz, 1H), 6.47 (s, 1H), 4.71 (d, J = 5.3 Hz, 2H), 3.73 (s, 3H), 1.89 (tt, J = 8.4, 5.2 Hz, 1H), 0.92 - 0.83 (m, 2H), 0.78 - 0.70 (m, 2H).

[0734] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate BOC-anhydride (73 mg, 0.34 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (85 mg, 0.22 mmol) and DMAP (1.5 mg, 45 μmol) in THF (1.5 mL). The resulting reaction mixture was heated at 50° C. for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (105 mg, 0.21 mmol, 95% yield, 97% purity) as a yellow foam. UPLC / MS (Method 3): m / z 480 (M+H) + , R T 1.83 minutes.

[0735] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (104 mg, 217 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (55 mg, 238 μmol), and tA solution of BuBrettPhos Pd G3 (18.5 mg, 21.7 μmol) in THF (2.5 mL) was degassed with N2 for 5 min. LiHMDS (1 M in THF) (228 μL, 228 μmol) was added in one portion while bubbling with N2. After 5 min, the bubbling was stopped, and the reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (with 0.7 M NH3) in DCM) followed by RP flash C18 chromatography (12 g cartridge, 15-80% MeCN in 10 mM ammonium bicarbonate) afforded the title compound (57 mg, 84 μmol, 39% yield, 99% purity) as a white solid. UPLC / MS (Method 3): m / z 674 (M+H) + , R T 1.88 minutes.

[0736] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-(((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (0.32 mL, 1.3 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (57 mg, 85 μmol) in dioxane (1.0 mL). The suspension was stirred at 35° C. for 2 hours. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (14 mg, 29 μmol, 34% yield, 98% purity) as a white solid. UPLC / MS (Method 3): m / z 474 (M+H)+ , R T 1.04 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.50 - 8.42 (m, 1H), 7.90 - 7.84 (m, 1H), 7.76 (td, J = 7.7, 1.9 Hz, 1H), 7.69 (s, 1H), 7.66 - 7.59 (m, 1H), 7.52 (s, 1H), 7.21 - 7.12 (m, 1H), 6.89 - 6.74 (m, 1H), 5.50 (s, 1H), 5.36 - 5.20 (m, 1H), 4.55 (d, J = 5.5 Hz, 2H), 3.73 (s, 3H), 3.60 - 3.45 (m, 1H), 3.28 - 3.18 (m, 1H), 3.10 - 3.00 (m, 1H), 2.94 - 2.86 (m, 1H), 2.82 - 2.74 (m, 1H), 2.34 - 2.25 (m, 1H), 2.20 - 2.11 (m, 1H), 1.77 - 1.67 (m, 1H), 1.63 - 1.55 (m, 1H), 1.42 - 1.31 (m, 1H), 1.22 - 1.08 (m, 1H), 0.80 - 0.71 (m, 2H), 0.71 - 0.58 (m, 2H).1H under water.

[0737] Synthesis 034 (1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methanamine

[0738] [ka]

[0739] Step A: tert-Butyl ((4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate A solution of K2CO3 (330 mg, 2.38 mmol) in water (400 μL) was added to a mixture of tert-butyl (2-amino-2-iminoethyl)carbamate, HCl (100 mg, 477 μmol) and 2-bromo-1-(pyridin-2-yl)ethan-1-one, HBr (134 mg, 477 μmol) in THF (4.0 mL). The reaction mixture was stirred at 60 °C overnight. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (10 mL, 2 × 5 mL). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered, and then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) / DCM) / DCM to give the title compound (80 mg, 0.28 mmol, 58% yield, 95% purity) as a brown oil. UPLC / MS (Method 3): m / z 275 (M+H) + , R T 0.96 minutes.

[0740] Step B: tert-Butyl ((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate At 0° C., sodium hydride (66 mg, 1.65 mmol) was added to a solution of tert-butyl ((4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (432 mg, 1.57 mmol) in DMF (4.0 mL). The reaction mixture was stirred at 0° C. for 1 h, and then iodomethane (224 mg, 1.57 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM / MeOH (90:10) (40 ml). The organic fraction was washed with brine (3×15 mL), dried over Na2SO4, filtered, and then concentrated in vacuo. The crude product was purified by chromatography on RP flash C18 (40 g cartridge, 15-50% MeCN / 10 mM ammonium bicarbonate) to give the title compound (204 mg, 0.67 mmol, 43% yield, 95% purity) as a brown solid. UPLC / MS (Method 3): m / z 289 (M+H) + , R T 1.16 minutes.

[0741] Step C: (1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methanamine HCl (4 M in dioxane) (2.60 mL, 10.4 mmol) was added to a solution of tert-butyl ((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (200 mg, 694 μmol) in dioxane (2.0 mL). The suspension was stirred at 35° C. overnight. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL), and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (133 mg, 0.64 mmol, 92% yield, 90% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 2H), 8.67 - 8.61 (m, 1H), 8.37 (s, 1H), 8.26 (t, J = 7.8 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 6.4 Hz, 1H), 4.29 (d, J = 5.2 Hz, 2H), 3.85 (s, 3H).

[0742] Synthesis 035 (3R,4R)-4-(((3-cyclopropyl-7-(((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-025)

[0743] [ka]

[0744] Step 1: 5-chloro-3-cyclopropyl-N-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.23 mL, 1.32 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (50 mg, 219 μmol) and (1-(pyridin-2-yl)-1H-imidazol-4-yl)methanamine (47 mg, 241 μmol) in EtOH (3.0 mL). The reaction mixture was heated at 60°C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (43 mg, 0.12 mmol, 53% yield, 99% purity) as a colorless oil. UPLC / MS (Method 3): m / z 366 (M+H) + , R T 1.32 minutes.

[0745] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)carbamate BOC-anhydride (31 mg, 0.14 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (43 mg, 0.12 mmol) and DMAP (2.9 mg, 24 μmol) in THF (3.0 mL). The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (38 mg, 80 μmol, 68% yield, 98% purity) as a yellow oil. UPLC / MS (Method 3): m / z 466 (M+H) + , R T 1.67 minutes.

[0746] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)carbamate (38 mg, 81.6 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (23 mg, 98 μmol) in THF (2.0 mL) was degassed with N for 5 minutes, followed by t BuBrettPhos Pd G3 (7.0 mg, 8.2 μmol) and LiHMDS (1 M in THF) (106 μL, 106 μmol) were added. The reaction was degassed for an additional 10 min and then heated to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) in DCM) afforded the title compound (46 mg, 56 μmol, 69% yield, 81% purity) as a colorless solid. UPLC / MS (Method 3): m / z 660 (M+H) + , R T 1.59 minutes.

[0747] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-(((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol HCl (4 M in dioxane) (0.17 mL, 0.70 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (46 mg, 70 μmol) in dioxane (2.0 mL). The suspension was stirred at 35° C. for 4 hours. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product was eluted with 0.7 M NH3 in MeOH (10 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (21 mg, 44 μmol, 63% yield, 96% purity) as a yellow solid. UPLC / MS (Method 6): m / z 460 (M+H) + , R T 2.67 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 1.4 Hz, 1H), 8.48 - 8.45 (m, 1H), 8.00 - 7.95 (m, 1H), 7.83 - 7.78 (m, 2H), 7.50 (s, 1H), 7.47 (t, J = 6.2 Hz, 1H), 7.40 - 7.32 (m, 1H), 6.81 - 6.73 (m, 1H), 5.36 (s, 1H), 4.44 - 4.35 (m, 2H), 3.60 - 3.46 (m, 1H), 3.26 - 3.17 (m, 1H), 3.10 - 2.98 (m, 2H), 2.98 - 2.88 (m, 1H), 2.85 - 2.76 (m, 1H), 2.33 - 2.28 (m, 1H), 2.22 - 2.12 (m, 1H), 1.76 - 1.68 (m, 1H), 1.62 - 1.56 (m, 1H), 1.39 - 1.30 (m, 1H), 1.22 - 1.13 (m, 1H), 0.80 - 0.70 (m, 2H), 0.68 - 0.60 (m, 2H).1H under water.

[0748] Synthesis 036 (3R,4R)-4-(((3-cyclopropyl-7-(((6-phenylpyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-026)

[0749] [ka]

[0750] Step 1: 5-chloro-3-cyclopropyl-N-((6-phenylpyridin-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (902 μL, 5.18 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (169 mg, 740 μmol) and (6-phenylpyridin-3-yl)methanamine (150 mg, 814 μmol) in EtOH (4.0 mL). The reaction mixture was heated at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (219 mg, 0.52 mmol, 71% yield, 90% purity) as a yellow oil. UPLC / MS (Method 3): m / z 376 (M+H) + , R T 2.04 minutes.

[0751] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-phenylpyridin-3-yl)methyl)carbamate BOC-anhydride (153 mg, 699 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((6-phenylpyridin-3-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (219 mg, 583 μmol) and DMAP (14.2 mg, 117 μmol) in THF (5.0 mL). The resulting reaction mixture was stirred at room temperature for 3 h, and then additional BOC-anhydride (153 mg, 699 μmol) was added, and the mixture was stirred for an additional 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (200 mg, 0.34 mmol, 58% yield, 80% purity) as a yellow oil. UPLC / MS (Method 3): m / z 476 (M+H) + , R T 1.98 minutes.

[0752] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-phenylpyridin-3-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (116 mg, 504 μmol) and tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-phenylpyridin-3-yl)methyl)carbamate (200 mg, 420 μmol) in THF (5.0 mL) was degassed with N for 10 minutes, followed by tBuBrettPhos Pd G3 (36 mg, 42 μmol) and LiHMDS (1 M in THF) (546 μL, 546 μmol) were added. The reaction was degassed for an additional 10 min before being heated to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) followed by RP flash C18 chromatography (12 g cartridge, 25-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (131 mg, 0.19 mmol, 44% yield, 95% purity) as a white solid. UPLC / MS (Method 3): m / z 670 (M+H) + , R T 2.22 minutes.

[0753] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-(((6-phenylpyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-phenylpyridin-3-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (131 mg, 196 μmol) in DCM (1.5 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo, and then the solid was triturated with EtO (3 × 2 mL) to give the title compound (75 mg, 0.16 mmol, 80% yield, 98% purity) as an off-white solid. UPLC / MS (Method 3): m / z 470 (M+H) + , R T 1.71 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.2 Hz, 1H), 8.09 - 8.02 (m, 2H), 7.97 - 7.90 (m, 2H), 7.84 (dd, J = 8.2, 2.3 Hz, 1H), 7.52 (s, 1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.39 (m, 1H), 6.72 (t, J = 6.0 Hz, 1H), 5.32 - 5.19 (m, 2H), 4.50 (d, J = 6.4 Hz, 2H), 3.54 - 3.43 (m, 1H), 3.26 - 3.18 (m, 1H), 3.07 - 2.98 (m, 1H), 2.94 - 2.88 (m, 1H), 2.82 - 2.75 (m, 1H), 2.34 - 2.25 (m, 1H), 2.20 - 2.11 (m, 1H), 1.75 - 1.66 (m, 1H), 1.60 - 1.52 (m, 1H), 1.37 - 1.27 (m, 1H), 1.19 - 1.11 (m, 1H), 0.80 - 0.70 (m, 2H), 0.70 - 0.59 (m, 2H).1H under water.

[0754] Synthesis 037 (3R,4R)-4-(((3-cyclopropyl-7-((4-(3-methoxypyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-027)

[0755] [ka]

[0756] Step 1: 5-chloro-3-cyclopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.26 mL, 1.50 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (57 mg, 250 μmol) and (4-(3-methoxy)pyridin-2-yl)phenyl)methanamine (57 mg, 250 μmol) in EtOH (1.0 mL). The reaction mixture was heated to 65° C. for 4 hours. The reaction mixture was concentrated in vacuo, and the residue was then redissolved in EtOH (1.0 mL), followed by the addition of DIPEA (0.17 mL, 1.00 mmol) and 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (20 mg, 88 μmol). The reaction mixture was heated to 65° C. for 2 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75 / isohexane) gave the title compound (126 mg, 0.30 mmol, 90% yield, 98% purity) as a yellow solid. UPLC / MS (Method 2): m / z 406 (M+H) + , R T 1.60 minutes.

[0757] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methoxypyridin-2-yl)benzyl)carbamate DMAP (7.4 mg, 61 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (124 mg, 304 μmol) and BOC-anhydride (100 mg, 456 μmol) in anhydrous THF (6.0 mL). The reaction mixture was heated at 65° C. for 4 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75 / isohexane) afforded the title compound (151 mg, 0.29 mmol, 96% yield, 98% purity) as a yellow oil. UPLC / MS (Method 3): m / z 506 (M+H) + , R T 1.92 minutes.

[0758] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-methoxypyridin-2-yl)benzyl)carbamate (149 mg, 295 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (81 mg, 353 μmol) in THF (3.3 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (25.2 mg, 29.5 μmol) and LiHMDS (1 M in THF) (353 μL, 353 μmol) were added. The reaction was degassed for an additional 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75 / isohexane) afforded the title compound (114 mg, 0.15 mmol, 52% yield, 95% purity) as a brown oil. UPLC / MS (Method 3): m / z 700 (M+H) + , R T 1.89 minutes.

[0759] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(3-methoxypyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.77 mL, 3.07 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (113 mg, 153 μmol) in dioxane (2.4 mL). The reaction mixture was stirred at 40° C. for 2 hours, then hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added and the reaction mixture was stirred at 40° C. for 30 minutes, then concentrated in vacuo. The solid was triturated with MeCN (2×2 mL) and then loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The ammoniacal methanolic solution was concentrated in vacuo and the solid was triturated with EtO (2 × 1 mL) to give the title compound (68 mg, 0.13 mmol, 87% yield, 97% purity) as an orange solid. LCMS (Method 2): m / z 500 (M+H) + , RT 0.65 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(dd, J = 4.6, 1.3 Hz, 1H), 7.89 (t, J = 6.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.4, 1.4 Hz, 1H), 7.53 (s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 8.3, 4.6 Hz, 1H), 6.73 (t, J = 6.0 Hz, 1H), 5.42 - 5.29 (m, 1H), 5.19 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.57 - 3.44 (m, 1H), 3.24 - 3.16 (m, 1H), 3.09 - 2.99 (m, 1H), 2.91 (dd, J = 11.6, 4.6 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.36 - 2.27 (m, 1H), 2.17 (dd, J = 11.6, 9.9 Hz, 1H), 1.78 - 1.65 (m, 1H), 1.61 - 1.53 (m, 1H), 1.39 - 1.29 (m, 1H), 1.21 - 1.08 (m, 1H), 0.83 - 0.71 (m, 2H), 0.70 - 0.59 (m, 2H). 1H under water.

[0760] Synthesis 038 (4-(3-methoxypyridin-2-yl)phenyl)methanamine

[0761] [ka]

[0762] Step A: (4-(3-methoxypyridin-2-yl)phenyl)methanamine A mixture of 2-chloro-3-methoxypyridine (60 mg, 418 μmol), (4-(aminomethyl)phenyl)boronic acid, HCl (86 mg, 460 μmol), and Pd(dppf)Cl (31 mg, 42 μmol) in dioxane (2.5 mL) was sparged with N for 5 minutes. A solution of potassium phosphate tribasic (355 mg, 1.67 mmol) in water (1.1 mL) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated to 90 °C for 2 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM / MeOH 90:10 (10 mL) and water (3 mL). The layers were separated, and the aqueous layer was further extracted with DCM / MeOH 90:10 (5 mL). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH 3 ) / DCM) afforded the title compound (59 mg, 0.27 mmol, 64% yield, 97% purity) as a brown solid. UPLC / MS (Method 3): m / z 215 (M+H) + , R T 0.87 minutes.

[0763] Synthesis 039 (3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-028)

[0764] [ka]

[0765] Step 1: 5-chloro-3-cyclopropyl-N-(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.28 mL, 1.58 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (60 mg, 263 μmol) and (4-(3-trifluoromethoxy)pyridin-2-yl)phenyl)methanamine (71 mg, 263 μmol) in EtOH (3.0 mL). The reaction mixture was heated to 60°C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (92 mg, 0.19 mmol, 73% yield, 96% purity) as a colorless oil. UPLC / MS (Method 3): m / z 460 (M+H) + , R T 1.78 minutes.

[0766] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)carbamate DMAP (4.9 mg, 40 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (92 mg, 200 μmol) and BOC-anhydride (52 mg, 240 μmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at room temperature for 1.5 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (110 mg, 0.19 mmol, 95% yield, 97% purity) as a yellow oil. UPLC / MS (Method 3): m / z 560 (M+H) + , R T 2.05 minutes.

[0767] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)carbamate (106 mg, 189 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (52 mg, 227 μmol) in THF (3.2 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (16.2 mg, 18.9 μmol) and LiHMDS (1 M in THF) (246 μL, 246 μmol) were added. The reaction was degassed for an additional 5 minutes and then heated to 60°C for 3 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (135 mg, 0.16 mmol, 85% yield, 90% purity) as a yellow solid. UPLC / MS (Method 3): m / z 754 (M+H) + , R T 2.01 minutes.

[0768] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.84 mL, 3.34 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-(trifluoromethoxy)pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (134 mg, 167 μmol) in dioxane (2.4 mL). The reaction mixture was stirred at 40° C. for 2 hours, then hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added and the reaction mixture was stirred at 40° C. for 30 minutes, then concentrated in vacuo. The solid was triturated with MeCN (2×2 mL) and then loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The ammoniacal methanolic solution was concentrated in vacuo and the solid was triturated with EtO (2 × 1 mL) to give the title compound (67 mg, 0.11 mmol, 69% yield, 95% purity) as a beige solid. LCMS (Method 2): m / z 554 (M+H) + , RT 0.88 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (dd, J = 4.6, 1.4 Hz, 1H), 7.98 (dt, J = 8.4, 1.5 Hz, 1H), 7.90 (t, J = 6.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 8.4, 4.6 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 6.76 - 6.68 (m, 1H), 5.37 - 5.28 (m, 1H), 5.21 (s, 1H), 4.52 (d, J = 6.4 Hz, 2H), 3.60 - 3.42 (m, 1H), 3.25 - 3.16 (m, 1H), 3.09 - 2.98 (m, 1H), 2.91 (dd, J = 11.5, 4.6 Hz, 1H), 2.83 - 2.75 (m, 1H), 2.33 - 2.25 (m, 1H), 2.17 (t, J = 10.8 Hz, 1H), 1.75 - 1.67 (m, 1H), 1.61 - 1.51 (m, 1H), 1.38 - 1.28 (m, 1H), 1.18 - 1.11 (m, 1H), 0.80 - 0.71 (m, 2H), 0.69 - 0.59 (m, 2H). 1H under water.

[0769] Synthesis 040 (4-(3-(trifluoromethoxy)pyridin-2-yl)phenyl)methanamine

[0770] [ka]

[0771] Step A: (4-(3-(trifluoromethoxy)pyridin-2-yl)phenyl)methanamine A mixture of 2-chloro-3-(trifluoromethoxy)pyridine (150 mg, 759 μmol), (4-(aminomethyl)phenyl)boronic acid (206 mg, 1.37 mmol), and Pd(dppf)Cl.DCM (62 mg, 76 μmol) in dioxane (9.0 mL) was sparged with N for 5 minutes. A solution of cesium carbonate (990 mg, 3.04 mmol) in water (1.0 mL) was added, and the reaction mixture was sparged with N for 5 minutes. The mixture was heated to 90° C. for 2 hours. At room temperature, water (50 mL) was added, and the mixture was extracted with EtOAc (2×25 mL). The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (160 mg, 0.55 mmol, 72% yield, 92% purity) as an orange oil. UPLC / MS (Method 1): m / z 269 (M+H) + , R T 1.15 minutes.

[0772] Synthesis 041 (3R,4R)-4-(((3-cyclopropyl-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-029)

[0773] [ka]

[0774] Step 1: 5-chloro-3-cyclopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.28 mL, 1.63 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (62 mg, 272 μmol) and (4-(pyrimidin-2-yl)phenyl)methanamine (60 mg, 324 μmol) in EtOH (3.0 mL). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (67 mg, 0.18 mmol, 65% yield, 99% purity) as a colorless oil. UPLC / MS (Method 3): m / z 377 (M+H) + , R T 1.56 minutes.

[0775] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-2-yl)benzyl)carbamate DMAP (3.9 mg, 32 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 159 μmol) and BOC-anhydride (42 mg, 191 μmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at room temperature for 1.5 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (69 mg, 0.14 mmol, 86% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 477 (M+H) + , R T 1.98 minutes

[0776] Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrimidin-2-yl)benzyl)carbamate (65 mg, 136 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (38 mg, 164 μmol) in THF (2.0 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (11.6 mg, 13.6 μmol) and LiHMDS (1 M in THF) (177 μL, 177 μmol) were added. The reaction was degassed for an additional 5 min and then heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3) in DCM) afforded the title compound (95 mg, 0.12 mmol, 90% yield, 87% purity) as a yellow solid. UPLC / MS (Method 3): m / z 671 (M+H) + , R T 1.87 minutes.

[0777] Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.62 mL, 2.5 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (95 mg, 0.12 mmol) in dioxane (2.0 mL). The reaction mixture was stirred at 40° C. for 2 hours, then hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added and the reaction mixture was stirred at 40° C. for 30 minutes, then concentrated in vacuo. The solid was triturated with MeCN (2×2 mL) and then loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The ammoniacal methanolic solution was concentrated in vacuo and the solid was triturated with EtO (2 × 1 mL) to give the title compound (42 mg, 86 μmol, 69% yield, 96% purity) as a beige solid. LCMS (Method 2): m / z 471 (M+H) + , RT 0.68 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J = 4.8 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H), 7.92 (t, J = 6.5 Hz, 1H), 7.53 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1H), 6.76 - 6.67 (m, 1H), 5.38 - 5.28 (m, 1H), 5.16 (s, 1H), 4.53 (d, J = 6.3 Hz, 2H), 3.58 - 3.43 (m, 1H), 3.24 - 3.14 (m, 1H), 3.08 - 2.98 (m, 1H), 2.91 (dd, J = 11.5, 4.4 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.34 - 2.24 (m, 1H), 2.16 (t, J = 10.8 Hz, 1H), 1.77 - 1.66 (m, 1H), 1.59 - 1.50 (m, 1H), 1.39 - 1.26 (m, 1H), 1.21 - 1.06 (m, 1H), 0.80 - 0.72 (m, 2H), 0.69 - 0.59 (m, 2H).1H under water.

[0778] Synthesis 042 (3R,4R)-4-(((3-cyclopropyl-7-((2-methoxy-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (PPA-030)

[0779] [ka]

[0780] Step 1: 5-chloro-3-cyclopropyl-N-(2-methoxy-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine DIPEA (0.41 mL, 2.4 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (90 mg, 0.39 mmol) and (2-methoxy-4-(pyridin-2-yl)phenyl)methanamine (110 mg, 0.51 mmol) in EtOH (3.0 mL). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH) in DCM) afforded the title compound (150 mg, 0.33 mmol, 84% yield, 90% purity) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 - 8.62 (m, 2H), 7.97 (dt, J = 8.1, 1.1 Hz, 1H), 7.94 (s, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 7.9, 1.6 Hz, 1H), 7.35 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.05 (s, 1H), 4.61 (d, J = 6.4 Hz, 2H), 3.98 (s, 3H), 1.95 - 1.84 (m, 1H), 0.92 - 0.83 (m, 2H), 0.80 - 0.70 (m, 2H).

[0781] Step 2: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-methoxy-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of 5-chloro-3-cyclopropyl-N-(2-methoxy-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (130 mg, 320 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (81 mg, 352 μmol) in dioxane (2.5 mL) was degassed under N for 5 minutes, followed by t BuBrettPhos Pd G3 (27 mg, 32 μmol) and LiHMDS (1 M in THF) (416 μL, 416 μmol) were added. The reaction was degassed for an additional 5 min and then heated to 90 °C overnight. At room temperature, the reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3) in DCM) followed by further purification on RP flash C18 (12 g cartridge, 15-75% MeCN in 10 mM ammonium bicarbonate) afforded the title compound (94 mg, 150 μmol, 46% yield, 95% purity) as a white solid. UPLC / MS (Method 3): m / z 600 (M+H) + , R T 1.19 minutes.

[0782] Step 3: (3R,4R)-4-(((3-cyclopropyl-7-((2-methoxy-4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.59 mL, 2.4 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-methoxy-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (94 mg, 160 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35° C. for 2 hours and then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (61 mg, 0.11 mmol, 73% yield, 94% purity) as a white solid. LCMS (Method 2): m / z 500 (M+H) + , RT 0.71 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (ddd, J = 4.7, 1.9, 0.9 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (s, 1H), 7.35 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.82 (t, J = 6.1 Hz, 1H), 5.89 - 5.79 (m, 1H), 5.10 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.59 - 3.48 (m, 1H), 3.29 - 3.22 (m, 2H), 3.12 (dd,...

Claims

1. A compound of the formula: 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof (In the formula, -L 7 - is independently -CH 2 -, -CH(R L7 )- or -C(R L7 ) 2 - and -R L7 each independently represents a linear or branched saturated C 1～4 is alkyl, -Ar 1 - is 1,4-phenylene and one or more groups -R AR1C and optionally substituted by -Ar 2 is pyridin-2-yl and has one or more groups -R AR2C and optionally substituted by -X 5 - is independently -NH-, -NR X5 -, -O- or a single bond, -R X5 is a linear or branched saturated C 1～4 is alkyl, -L 5 - is independently -CH 2 -, -CH(R L5 )-, -C(R L5 ) 2 - or a single bond, -R L5 each independently represents a linear or branched saturated C 1～4 is alkyl, -Cy 5 are independently -Cy 5A or -Cy 5B and -Cy 5A is a non-aromatic C having at least one nitrogen ring atom 4～10 is heterocyclyl, One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN and optionally substituted by -Cy 5B is a C having at least one nitrogen ring atom 5～6 is heteroaryl, One or more groups -R on the carbon Cy5BC and optionally substituted by If present, a group -R on the secondary nitrogen Cy5BN and optionally substituted by -R 3 Ga-R 3B and -R 3B is cyclopropyl, -R AR1C are respectively and -R AR2C are respectively, -R TT 、 -F, -Cl, -Br, -I, -OH、-OR TT 、 -L T -OH、-L T -OR TT 、 -CF 3 、-CHF 2 、-OCF 3 、-OCHF 2 、 -NH 2 -NHR TT 、-NR TT 2 -R TM 、 -L T -NH 2 -L T -NHR TT -L T -NR TT 2 -L T -R TM 、 -C(=O)OH、-C(=O)OR TT 、 -OC(=O)R TT 、 -C(=O)NH 2 -C(=O)NHR TT -C(=O)NR TT 2 -C(=O)R TM 、 -NHC(=O)R TT 、-NR TN C(=O)R TT 、 -NHC(=O)NH 2 -NHC(=O)NHR TT -NHC(=O)NR TT 2 -NHC(=O)R TM 、 -NR TN C(=O)NH 2 、-NR TN C(=O)NHR TT 、-NR TN C(=O)NR TT 2 、-NR TN C(=O)R TM 、 -NHC(=O)OR TT 、-NR TN C(=O)OR TT 、 -OC(=O)NH 2 -OC(=O)NHR TT -OC(=O)NR TT 2 -OC(=O)R TM 、 -C(=O)R TT 、 -SR TT -S(=O)R TT -S(=O) 2 R TT 、 -S(=O)NH 2 -S(=O)NHR TT -S(=O)NR TT 2 -S(=O)R TM 、 -S(=O) 2 NH 2 -S(=O) 2 NHR TT -S(=O) 2 ARN TT 2 -S(=O) 2 R TM 、 -NHS(=O) 2 R TT 、-NR TN S(=O) 2 R TT 、 -CN and -NO 2 are independently selected from During the ceremony, -L T - each independently represents a linear or branched saturated C 1～4 is alkylene, -R TT are each independently -R TT1 , -R TT2 , -L TT -R TT2 , -R TT3 or -L TT -R TT3 and -R TT1 each independently represents a linear or branched saturated C 1～6 Alkyl, -F, -OH and -OR TTT and optionally substituted with one or more groups selected from -R TT2 are saturated C 3～6 cycloalkyl, -F, -R TTT , -OH and -OR TTT and optionally substituted with one or more groups selected from -R TT3 are each independently phenyl or naphthyl, -F, -Cl, -Br, -I, -R TTT , OH, -OR TTT , -OCF 3 , -NH 2 , -NHR TTT and -NR TTT 2 and optionally substituted with one or more groups selected from -L TT - each independently represents a linear or branched saturated C 1～4 is alkylene, -R TN are linear or branched saturated C 1～4 alkyl, phenyl or benzyl; -R TM are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; -R on carbon TMM , -C(=O)R TMM , -S(=O) 2 R TMM , -F, -NH 2 , -NHR TMM , -NR TMM 2 , -OH and -OR TMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R TMM , -C(=O)R TMM , -C(=O)OR TMM and -S(=O) 2 R TMM and optionally substituted with a group selected from -R TTT each independently represents a linear or branched saturated C 1～4 alkyl, phenyl or benzyl; -R TMM each independently represents a linear or branched saturated C 1～4 alkyl, phenyl or benzyl; -R Cy5AC are respectively and -R Cy5BC are respectively, -R JJ 、 -F, -Cl, -Br, -I, -OH、-OR JJ 、 -L J -OH、-L J -OR JJ 、 -CF 3 、-CHF 2 、-OCF 3 、-OCHF 2 、 -NH 2 -NHR JJ 、-NR JJ 2 -R JM 、 -L J -NH 2 -L J -NHR JJ -L J -NR JJ 2 -L J -R JM 、 -C(=O)OH、-C(=O)OR JJ 、 -OC(=O)R JJ 、 -C(=O)NH 2 -C(=O)NHR JJ -C(=O)NR JJ 2 -C(=O)R JM 、 -NHC(=O)R JJ 、-NR JN C(=O)R JJ 、 -NHC(=O)NH 2 -NHC(=O)NHR JJ -NHC(=O)NR JJ 2 -NHC(=O)R JM 、 -NR JN C(=O)NH 2 、-NR JN C(=O)NHR JJ 、-NR JN C(=O)NR JJ 2 、-NR JN C(=O)R JM 、 -NHC(=O)OR JJ 、-NR JN C(=O)OR JJ 、 -OC(=O)NH 2 -OC(=O)NHR JJ -OC(=O)NR JJ 2 -OC(=O)R JM 、 -C(=O)R JJ 、 -SR JJ -S(=O)R JJ -S(=O) 2 R JJ 、 -S(=O)NH 2 -S(=O)NHR JJ -S(=O)NR JJ 2 -S(=O)R JM 、 -S(=O) 2 NH 2 -S(=O) 2 NHR JJ -S(=O) 2 ARN JJ 2 -S(=O) 2 R JM 、 -NHS(=O) 2 R JJ 、-NR JN S(=O) 2 R JJ 、 -CN and -NO 2 are independently selected from -R Cy5AN are respectively and -R Cy5BN are respectively, -R JJ 、 -L J -OH、-L J -OR JJ 、 -L J -NH 2 -L J -NHR JJ -L J -NR JJ 2 -L J -R JM 、 -C(=O)R JJ 、 -C(=O)OR JJ 、 -C(=O)NH 2 、-C(=O)NHR JJ 、-C(=O)NR JJ 2 、-C(=O)R JM 、&& -S(=O) 2 R JJ are independently selected from During the ceremony, -L J - each independently represents a linear or branched saturated C 1～4 is alkylene, -R JJ are each independently -R JJ1 , -R JJ2 , -L JJ -R JJ2 , -R JJ3 or -L JJ -R JJ3 and -R JJ1 each independently represents a linear or branched saturated C 1～6 Alkyl, -F, -OH and -OR JJJ and optionally substituted with one or more groups selected from -R JJ2 are saturated C 3～6 cycloalkyl, -F, -R JJJ , -OH and -OR JJJ and optionally substituted with one or more groups selected from -R JJ3 are each independently phenyl or naphthyl, -F, -Cl, -Br, -I, -R JJJ , OH, -OR JJJ , -OCF 3 , -NH 2 , -NHR JJJ and -NR JJJ 2 and optionally substituted with one or more groups selected from -L JJ - each independently represents a linear or branched saturated C 1～4 is alkylene, -R JN are linear or branched saturated C 1～4 alkyl, phenyl or benzyl; -R JM are each independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; -R on carbon JMM , -C(=O)R JMM , -S(=O) 2 R JMM , -F, -NH 2 , -NHR JMM , -NR JMM 2 , -OH and -OR JMM and optionally substituted with one or more groups selected from If present, on the secondary nitrogen, -R JMM , -C(=O)R JMM , -C(=O)OR JMM and -S(=O) 2 R JMM and optionally substituted with a group selected from -R JJJ each independently represents a linear or branched saturated C 1～4 alkyl, phenyl or benzyl; -R JMM each independently represents a linear or branched saturated C 1～4 alkyl, phenyl or benzyl.

2. -L 7 -G, -CH 2 -is, 2. The compound of claim 1.

3. -X 5 -, independently, -NH-, -NR X5 - or a single bond, The compound of claim 1.

4. -X 5 - is -NH-, The compound of claim 1.

5. -L 5 - but independently, -CH 2 - or a single bond, The compound of claim 1.

6. -L 5 -G, -CH 2 -is, The compound of claim 1.

7. -Ar 1 - is 1,4-phenylene; The compound of claim 1.

8. -Ar 2 is pyridin-2-yl; The compound of claim 1.

9. -Ar 1 - is 1,4-phenylene, -Ar 2 is pyridin-2-yl; The compound of claim 1.

10. -R AR1C and -R, respectively, if present AR2C respectively, when present, -F, -Me, -OMe, -CF 3 and -OCF 3 are independently selected from The compound of claim 1.

11. -Cy 5 -Cy 5A and -Cy 5A is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN optionally substituted by The compound of claim 1.

12. (a)-Cy 5A is piperidinyl, if present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; If present, a group -R on the secondary nitrogen Cy5AN optionally replaced by, or (b)-Cy 5A is piperidin-3-yl, when present; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN optionally replaced by, or (c)-Cy 5A when present, is (3S)-piperidin-3-yl; One or more groups -R on the carbon Cy5AC and optionally substituted by optionally substituted on carbon with =O; -R group on secondary nitrogen Cy5AN optionally substituted by The compound of claim 1.

13. -R Cy5AC When present, -F, -Me, -OH, -OMe, and -NH are respectively present, and when -RCy5BC is respectively present, 2 are independently selected from -R Cy5AN and -R, respectively, if present Cy5BN If each exists, -R JJ , -C(=O)R JJ and -C(=O)OR JJ are independently selected from -R JJ are respectively, -R JJ1 and -R JJ1 each independently a linear or branched saturated C 1～4 is alkyl, The compound of claim 1.

14. -Cy 5A is piperidin-3-yl, when present; The compound of claim 1.

15. -Cy 5A when present, is (3S)-piperidin-3-yl; The compound of claim 1.

16. -Cy 5A When present, it is (3R,4R)-3-hydroxy-piperidin-4-yl; The compound of claim 1.

17. A compound of the formula: 【Chemistry 2】 【change】 【change】 【change】 【change】 and pharmaceutically acceptable salts and solvates thereof.

18. The compound of claim 17: 【Transformation 3】 or a pharmaceutically acceptable salt or solvate thereof.

19. The compound of claim 19: 【Chemistry 4】 or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of claim 1: 【Transformation 5】 or a pharmaceutically acceptable salt or solvate thereof.

21. A compound of the following nature: 【Transformation 6】 or a pharmaceutically acceptable salt or solvate thereof.

22. 10. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

23. 10. A method of making a composition, comprising the step of mixing a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

24. 10. A method for inhibiting cyclin-dependent protein kinase (CDK) function in a cell in vitro, comprising contacting the cell with an effective amount of a compound of claim 1.

25. A method for regulating cell proliferation, inhibiting cell cycle progression, or promoting apoptosis in vitro, comprising contacting a cell with an effective amount of a compound of claim 1.

26. 10. A composition comprising a compound according to claim 1 for use in a method of treatment of the human or animal body by therapy.

27. 10. A composition comprising a compound of claim 1 for use in a method for the treatment of a disorder.

28. 10. Use of a compound according to claim 1 in the manufacture of a medicament for use in a method of treating a disorder.

29. 28. The composition of claim 27, wherein the disorder is a disorder associated with a cyclin-dependent protein kinase (CDK); a disorder caused by inappropriate activity of a CDK; a disorder associated with a CDK mutation; a disorder associated with CDK overexpression; a disorder associated with pathway activation upstream of a CDK; or a disorder that is ameliorated by inhibition of a CDK.

30. 30. The composition of claim 29, wherein the disorder is a disorder associated with CDK12 and / or CDK13; a disorder caused by inappropriate activity of CDK12 and / or CDK13; a disorder associated with CDK12 and / or CDK13 mutations; a disorder associated with CDK12 and / or CDK13 overexpression; a disorder associated with pathway activation upstream of CDK12 and / or CDK13; or a disorder that is ameliorated by inhibition of CDK12 and / or CDK13.

31. 28. The composition of claim 27, wherein the disorder is a proliferative disorder; cancer; viral infection; neurodegenerative disorder; ischemia; kidney disease; cardiovascular disorder; autoimmune disorder; or a disorder caused by translation dysfunction in a cell.

32. 32. The composition of claim 31, wherein the viral infection is HIV; the neurodegenerative disorder is Alzheimer's disease or Parkinson's disease; the cardiovascular disorder is atherosclerosis; the autoimmune disorder is rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or Sjogren's syndrome; or the disorder caused by translation dysfunction in cells is muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, or fragile X syndrome.

33. 28. The composition of claim 27, wherein the disorder is a proliferative disorder.

34. 28. The composition of claim 27, wherein the disorder is cancer.

35. The treatment may include a DNA repair inhibitor, immune checkpoint inhibitors, immune system stimulants, cell cycle checkpoint inhibitors, Her2 blockers, transcription inhibitors, or Further cytotoxic chemotherapeutic agents 28. The composition of claim 27, further comprising treatment with

36. 36. The composition of claim 35, wherein the treatment is simultaneous or sequential treatment.

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