4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol compounds and their therapeutic uses

Abstract

The present invention relates generally to the field of therapeutic compounds. More specifically, the present invention relates to certain H-APPAMP compounds (herein referred to as "H-APPAMP compounds") that inhibit, inter alia, cyclin-dependent protein kinases (CDKs), particularly CDK12 and / or CDK13, and are selective for CDK12 and / or CDK13, e.g., compared to CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby eliminating a key signaling mechanism required for CDK12 and / or CDK13 activation, which confers additional cellular potency and selectivity. The present invention also relates to pharmaceutical compositions comprising such compounds, as well as in vitro and in vivo assays of such compounds and compositions. and for the inhibition of CDKs, particularly CDK12 and / or CDK13, both in vivo and in vivo; and for treating disorders including disorders associated with CDKs, particularly CDK12 and / or CDK13; disorders caused by inappropriate activity of CDKs, particularly CDK12 and / or CDK13; disorders associated with CDK mutations, particularly CDK12 and / or CDK13 mutations; disorders associated with CDK overexpression, particularly CDK12 and / or CDK13 overexpression; disorders associated with upstream pathway activation of CDKs, particularly CDK12 and / or CDK13; disorders that are ameliorated by inhibition of CDKs, particularly CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (e.g., HIV); neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease); ischemia; kidney disease; cardiovascular disorders (e.g., atherosclerosis); autoimmune disorders (e.g., rheumatoid arthritis) and disorders caused by translation dysfunction in cells (e.g., muscular dystrophies). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, such as, for example, an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent that stimulates the immune system, a checkpoint inhibitor, a DMA repair inhibitor, etc.

Description

[Technical Field]

[0001] (Related Applications) This application is related to United Kingdom (GB) Patent Application No. 1918541.2, filed December 16, 2019, 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 specifically, the present invention relates to certain H-APPAMP compounds (herein referred to as "H-APPAMP compounds") that inhibit, inter alia, cyclin-dependent protein kinases (CDKs), particularly CDK12 and / or CDK13, and are selective for CDK12 and / or CDK13, e.g., compared to CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby eliminating a key signaling mechanism required for CDK12 and / or CDK13 activation, which confers additional cellular potency and selectivity. The present invention also relates to pharmaceutical compositions comprising such compounds, as well as in vitro and in vivo assays of such compounds and compositions. and for the treatment of disorders including disorders associated with CDKs, especially CDK12 and / or CDK13; disorders caused by inappropriate activity of CDKs, especially CDK12 and / or CDK13; disorders associated with CDK mutations, especially CDK12 and / or CDK13 mutations; disorders associated with CDK overexpression, especially CDK12 and / or CDK13 overexpression; disorders associated with upstream pathway activation of CDKs, especially CDK12 and / or CDK13; disorders that are ameliorated by inhibition of CDKs, especially CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (e.g., HIV); neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease); ischemia; kidney disease; cardiovascular disorders (e.g., atherosclerosis); autoimmune disorders (e.g., rheumatoid arthritis) and disorders caused by translation dysfunction in cells (e.g., muscular dystrophies). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, such as an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent that stimulates the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc. [Background technology]

[0003] Numerous publications are cited herein 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 and the claims that follow, unless the context requires otherwise, the word "comprise" and variations thereof, such as "comprises" and "compring," will be understood to imply the inclusion of a stated 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 antecedent "about," it will be understood that the particular value forms another embodiment.

[0007] This disclosure contains information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the invention(s) 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 cell progression through developmental stages, DNA replication, and mitosis (see, e.g., Pines, 1995; Morgan, 1995). Activation of specific CDKs is required for proper progression through different stages of the cell cycle and for 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 regulating multiple cellular functions. Studies have characterized CDK12 and CDK13 as transcriptional CDKs that mediate gene transcription by complexing with cyclin K and phosphorylating RNA polymerase II (see, e.g., Li et al., 2016; Greifenberg et al., 2016). The CDK12 / cyclin K complex and the CDK13 / cyclin K complex 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. Furthermore, CDK12 can form a complex with cyclins L1 and L2 to regulate alternative splicing of mRNA transcripts (see, e.g., Chen et al., 2016). CDK12 has been shown to specifically upregulate the expression of genes involved in responses to DNA damage, stress, and heat shock (see, e.g., Blazek et al., 2011; Lord et al., 2016). CDK13 regulates a distinct set of genes, and CDK3 activity is primarily involved in growth signaling pathways, such as tyrosine kinase kinase signaling (Greifenberg et al., 2016). Studies have also implicated CDK12 in the regulation of mRNA splicing, 3'-end processing, pre-replication complex assembly, and genome stability. 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). Numerous studies have cited CDK12 inhibition as an effective strategy for inhibiting tumor growth, and synthetic lethal interactions have been described with many pathways related to cancer survival and progression (see, e.g., Johnson et al., 2016 ; Choi et al., 2019 ).

[0010] Cyclin K degradation is a characteristic of some, but not all, CDK12 inhibitors (see, e.g., Slabicki et al., 2020). When an inhibitor couples degrader activity, 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 was found to cause cyclin K degradation by this mechanism, whereas the CDK12-selective covalent inhibitor THZ-531 did not.

[0011] Cyclin K degradation can complement direct inhibition of CDK12 and / or 13 in cells. This is advantageous for a number of reasons. First, degradation can result in enhanced efficacy over kinase inhibition alone, as indicated by increased molecular potency in cytotoxicity assays. Enhanced cellular potency can lead to reduced off-target interactions and reduced interactions between the inhibitor and kinases other than CDK12 and / or CDK13. Second, cyclin K is an essential partner of both CDK12 and CDK13 and is required for their activity. Therefore, cyclin K degraders will impair the activity of both kinases, even if the compound exhibits differential selectivity between CDK12 and CDK13. Finally, cyclin K has been shown to have an intracellular half-life of more than 12 hours (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 Bondke et al., 2015, describes certain pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors, such as the following compound (referred to therein as PPDA-001):

[0013] [ka] Examples include:

[0014] Hazel et al., 2017, reported that inhibitors of CDK7, such as ICEC0942 (shown below),

[0015] [ka] Patel et al., 2018, described a study of the CDK7 inhibitor ICEC0942 in the treatment of cancer.

[0016] Johannes et al., 2018, used it to identify a class of selective CDK12 inhibitors, such as the lead compound designated "Compound 7" therein, shown below:

[0017] [ka] This article describes research to identify the following:

[0018] Bahl et al., 2019, described four specific pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors, including the following compound (referred to in the literature as APPAMP-001):

[0019] [ka] Examples include:

[0020] Kugel, 2019, generally describes the use of CDK7 in the treatment of certain subtypes of pancreatic cancer, and various known CDK7 inhibitors are listed on pages 26-30 of the publication.

[0021] Kwiatkowski et al., 2019, generally discusses the use of CDK7 in the treatment of tuberous sclerosis complex. Various known CDK7 inhibitors are listed on pages 25-55 of the document.

[0022] Roush et al., 2019, describe certain small molecule inhibitors of CDK12 / CDK13 that are said to be useful in the treatment of cancers such as breast, brain, and ovarian cancer. The compounds have the following formula: 1 is aryl or heteroaryl. Examples in the document include compounds 6 and 7 shown below.

[0023] [ka] Summary of the Invention

[0024] Potency / selectivity The H-APPAMP compounds described herein are potent CDK12 and / or CDK13 inhibitors, and they are also highly selective for CDK12 and / or CDK13 over, for example, CDK7.

[0025] In addition to selectively inhibiting CDK12 and / or CDK13, the H-APPAMP compounds described herein can also act as selective cyclin K degraders, thereby eliminating key signaling mechanisms required for CDK12 and / or CDK13 activation; this provides additional cellular potency and selectivity.

[0026] Summary of the Invention One aspect of the present invention pertains to certain 4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol compounds (referred to herein as "H-APPAMP compounds") described herein.

[0027] Another aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising the H-APPAMP compounds described herein and a pharmaceutically acceptable carrier or diluent.

[0028] Another aspect of the present invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing an H-APPAMP compound described herein with a pharmaceutically acceptable carrier or diluent.

[0029] Another aspect of the present invention relates to a method of inhibiting CDK12 and / or CDK13 (the function (e.g., in a cell)) in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound described herein.

[0030] Another aspect of the present invention relates to a method of regulating (e.g., inhibiting) cell proliferation (e.g., cell growth), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more of these, in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound described herein.

[0031] Another aspect of the present invention relates to the H-APPAMP compounds described herein for use in methods of treatment of the human or animal body by therapy, such as for use in methods of treating a disorder (e.g., a disease) described herein.

[0032] Another aspect of the present invention relates to the use of an H-APPAMP compound as described herein, e.g., in the manufacture of a medicament for use in a method of treatment, e.g., for use in a method of treating a disorder (e.g., a disease) as described herein.

[0033] Another aspect of the present 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 an H-APPAMP compound described herein, preferably in the form of a pharmaceutical composition.

[0034] In one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, e.g., an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent that stimulates the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc., as described herein.

[0035] Another aspect of the present invention relates to a kit comprising: (a) an H-APPAMP compound described herein, preferably provided as a pharmaceutical composition, in a suitable container and / or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound.

[0036] Another aspect of the present invention relates to H-APPAMP compounds obtainable by the synthetic methods described herein or by methods including the synthetic methods described herein.

[0037] Another aspect of the present invention pertains to H-APPAMP compounds obtained by the synthetic methods described herein or by a method including the synthetic methods described herein.

[0038] Another aspect of the present invention pertains to novel intermediates, as described herein, that are suitable for use in the synthetic methods described herein.

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

[0040] 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. DETAILED DESCRIPTION OF THE INVENTION

[0041] Detailed Description of the Invention compound One aspect of the present invention is a specific compound related to pyrazolo[1,5-a]pyrimidine-5,7-diamine ("PPDA"):

[0042] [ka] Regarding.

[0043] More specifically, the compound is (3R,4R)-4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol ("APPAMP"):

[0044] [ka] Regarding.

[0045] Additionally, all compounds of the present invention have the following: (a) a substituted amino group at the 7-position (referred to herein as -NH-L 7 -R 7 denoted as ); and (b) an alkyl group or a cycloalkyl group (in this specification -R 3 (denoted as ).

[0046] More specifically, the group -R 7 is a fused bicyclic C ring with exactly 1, 2 or 3 ring heteroatoms 8-10It is a heteroaryl group, where each ring heteroatom is N, S, or O.

[0047] For the avoidance of doubt, fused bicyclic C 8-10 Heteroaryl groups have 6 / 6, 6 / 5, 5 / 6, or 5 / 5 fused ring structures; i.e., a 6-membered aromatic ring fused to a 6-membered aromatic ring; a 6-membered aromatic ring fused to a 5-membered aromatic ring; a 5-membered aromatic ring fused to a 6-membered aromatic ring; or a 5-membered aromatic ring fused to a 5-membered aromatic ring, respectively.

[0048] Accordingly, one aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:

[0049] [ka] where -R 7 , -L 7 - and -R 3 as defined herein (for convenience, collectively referred to herein as "H-APPAMP compounds").

[0050] Some embodiments include:

[0051] (1) A compound of the following formula:

[0052] [ka] or a pharmaceutically acceptable salt or solvate thereof (In the formula, -R 7 is a fused bicyclic C ring with exactly 1, 2 or 3 ring heteroatoms 8-10 a heteroaryl group, wherein each ring heteroatom is N, S, or O; And-R 7 teeth, Optionally, on the carbon, one or more groups -R SC is replaced by; Optionally, on the secondary nitrogen, if present, there is a group -RSN is replaced by; where: Each-R SC are independently: -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 , -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 , -NRTN 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 or -NO2 and Each-R SN are independently: -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 , or -S(=O)2R TT and Each-L T - independently, a linear or branched saturated C 1-4 is alkylene; Each-R TT independently, -R TT1 , -R TT2 , -L TT -R TT2 , -R TT3 , or -L TT -R TT3 and; Each-R TT1 are independently linear or branched saturated C 1-6 alkyl, optionally -F, -OH, and -OR TTT and is substituted with one or more groups selected from: Each-R TT2 is the saturated C 3-6 cycloalkyl, optionally -F, -R TTT , -OH, and -OR TTT and is substituted with one or more groups selected from: Each-R TT3 are independently phenyl or naphthyl, and optionally -F, -Cl, -Br, -I, -R TTT , OH, -OR TTT , -OCF3, -NH2, -NHR TTT , and -NR TTT substituted with one or more groups selected from Each-L TT - independently, a linear or branched saturated C 1-4 is alkylene; Each-R TN is a linear or branched saturated C 1-4 alkyl, phenyl or benzyl; Each-R TM is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano; Optionally, on carbon, -R TMM , -C(=O)R TMM , -S(=O)2R TMM , -F, -NH2, -NHR TMM , -NR TMM2, -OH, and -OR TMM and is substituted with one or more groups selected from: Optionally, on the secondary nitrogen, if present, -R TMM , -C(=O)R TMM , -C(=O)OR TMM , and -S(=O)R TMM substituted with a group selected from Each-R TTT are independently linear or branched saturated C 1-4 alkyl, phenyl or benzyl; Each-R TMM are independently linear or branched saturated C 1-4 alkyl, phenyl or benzyl; See you again here -L 7 - independently, a linear or branched saturated C 1-3 alkylene, optionally substituted with one or more groups selected from -F, -OH, and -OMe; -R 3 independently, -R 3A or -R 3B and; -R 3A are independently linear or branched saturated C 1-6 alkyl, optionally substituted with one or more groups selected from -F, -OH, and -OMe; -R 3B are independently saturated C 3-7 cycloalkyl, optionally substituted with one or more groups selected from -F, -OH, and -OMe.

[0053] For the avoidance of doubt: "C 9-10 Heteroaryl, C 3-7 The subscript "C" in terms such as "heterocyclyl" x-y " refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., optionally N, O, S). For example, pyridyl is an example of a C6 heteroaryl group, and piperidino is an example of a C6 heterocyclyl group.

[0054] 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 C6 heteroaryl group. 10 It is an example of a heteroaryl group.

[0055] The phrase "carbon substituent" is intended to refer to a substituent attached to a carbon ring atom. Similarly, the phrase "secondary nitrogen substitution" is intended to refer to a substituent attached to a nitrogen ring atom that would be a secondary nitrogen ring atom in the absence of the substituent (i.e., -NH-). Consequently, as shown 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, while a piperidino group may have only a "carbon substituent," a piperidino may have both a "carbon substituent" and a "secondary nitrogen substituent," as shown below.

[0058] [ka]

[0059] Unless otherwise indicated, when a compound is shown or described as having one or more chiral centers and as having two or more stereoisomers possible, all such stereoisomers are disclosed and included, both individually (e.g., isolated from the other stereoisomer(s)) and in admixture (e.g., equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, when a compound has one chiral center, each of the (R) and (S) enantiomers is disclosed and included, both individually (e.g., isolated from the other enantiomer) and in admixture (e.g., equimolar or non-equimolar mixtures of the two enantiomers). For example, the first carbon atom of the pendant sec-butyl group, —CH(CH3)CH2CH3, is typically chiral, and thus, when this carbon atom is the only chiral center, it gives rise to stereoisomers, e.g., the (R) enantiomer and the (S) enantiomer, each of which is disclosed and included.

[0060] Group-R 7 (2) -R 7 is a fused bicyclic C ring having exactly 1, 2 or 3 ring heteroatoms 9-10 The compound according to (1), wherein the heteroaryl group is a heteroaryl group and each ring heteroatom is N.

[0061] C9 heteroaryl groups: (3) -R 7 is a fused bicyclic C9 heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, each ring heteroatom being N.

[0062] (4) -R 7 is a fused bicyclic C9 heteroaryl group having exactly 2 or 3 ring heteroatoms, each ring heteroatom being N.

[0063] (5) -R 7is a fused bicyclic C9 heteroaryl group having exactly one ring heteroatom, and the ring heteroatom is N.

[0064] (6) -R 7 are independently indolyl; indolizinyl; 2H-isoindolyl; 2H-cyclopenta[c]pyridinyl; or 1H-cyclopenta[b]pyridinyl

[0065] [ka] The compound according to (1),

[0066] (7) -R 7 is a fused bicyclic C9 heteroaryl group having exactly two ring heteroatoms, each ring heteroatom being N.

[0067] (8) -R 7 are independently 1H-indazolyl; benzimidazolyl; 1H-pyrrolo[3,2-b]pyridinyl; 1H-pyrrolo[3,2-c]pyridinyl; 1H-pyrrolo[2,3-c]pyridinyl; 1H-pyrrolo[2,3-b]pyridinyl; pyrazolo[1,5-a]pyridinyl; imidazo[1,5-a]pyridinyl; imidazo[1,2-a]pyridinyl; pyrrolo[1,2-a]pyrimidinyl; pyrrolo[1,2-a]pyrazinyl; pyrrolo[1,2-c]pyrimidinyl; pyrrolo[1,2-b]pyridazinyl; 2H-pyrrolo[3,4-c]pyridinyl; or 6H-pyrrolo[3,4-b]pyridinyl.

[0068] [ka] TIFF0007635237000014.tif101136

[0069] (9) -R 7 is a fused bicyclic C9 heteroaryl group having exactly three ring heteroatoms, each ring heteroatom being N.

[0070] (10) -R 7 are independently 1H-pyrazolo[4,3-b]pyridinyl; 1H-pyrazolo[4,3-c]pyridinyl; 1H-pyrazolo[3,4-c]pyridinyl; 1H-pyrazolo[3,4-b]pyridinyl; 1H-imidazo[4,5-b]pyridinyl; 1H-imidazo[4,5-c]pyridinyl; 3H-imidazo[4,5-c]pyridinyl; 3H-imidazo[4,5-b]pyridinyl; 5H-pyrrolo[3,2-c]pyridazinyl; 5H-pyrrolo[3,2-d ]pyrimidinyl;5H-Pyrrolo[2,3-b]pyrazinyl;1H-Pyrrolo[2,3-d]pyridazinyl;7H-Pyrrolo[2,3-d]pyrimidinyl;7H-Pyrrolo[2,3-c]pyridazinyl;6H-Pyrrolo[3,4-d]pyridazinyl;6H-Pyrrolo[3,4-d]pyrimidinyl;6H-Pyrrolo[3,4-c]pyridazinyl;6H-Pyrrolo[3,4-b]pyrazinyl;Triazolo[1,5-a]pyridinyl;[1,2,4]triazolo[1,5 -a]pyridinyl;Pyrazolo[1,5-a]pyrimidinyl;Pyrazolo[1,5-a]pyrazinyl;Pyrazolo[1,5-c]pyrimidinyl;Pyrazolo[1,5-b]pyridazinyl;[1,2,4]triazolo[4,3-a]pyridinyl;Imidazo[1,5-a]pyrimidinyl;Imidazo[1,5-a]pyrazinyl;Imidazo[1,5-c]pyrimidinyl;Imidazo[1,5-b]pyridazinyl;Imidazo[1,2-a]pyrimidinyl;Imidazo[1 ,2-a]pyrazinyl; imidazo[1,2-c]pyrimidinyl; imidazo[1,2-b]pyridazinyl; pyrrolo[2,1-c][1,2,4]triazinyl; pyrrolo[1,2-a][1,3,5]triazinyl; pyrrolo[1,2-b][1,2,4]triazinyl; pyrrolo[1,2-d][1,2,4]triazinyl; pyrrolo[2,1-f][1,2,4]triazinyl; or pyrrolo[1,2-c]triazinyl.

[0071] [ka] TIFF0007635237000016.tif224148TIFF0007635237000017.tif71150

[0072] (11) -R 7 are independently imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; benzimidazolyl; imidazo[1,2-b]pyridazinyl; or [1,2,4]triazolo[1,5-a]pyridinyl.

[0073] (12) -R 7 is independently imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; or benzimidazolyl.

[0074] (13) -R 7 is imidazo[1,2-a]pyridinyl.

[0075] (14) -R 7 is independently 2-imidazo[1,2-a]pyridinyl; or 3-imidazo[1,2-a]pyridinyl.

[0076] (15) -R 7 is 2-imidazo[1,2-a]pyridinyl (shown below):

[0077] [ka] The compound according to (1),

[0078] (16) -R 7 but 3-imidazo[1,2-a]pyridinyl (shown below):

[0079] [ka] The compound according to (1),

[0080] (17) -R 7 is imidazo[1,2-a]pyrimidinyl.

[0081] (18) -R 7 but 2-imidazo[1,2-a]pyrimidinyl (shown below):

[0082] [ka] The compound according to (1),

[0083] (19) -R 7 is imidazo[1,2-b]pyridazinyl.

[0084] (20) -R 7 but 2-imidazo[1,2-b]pyridazinyl (shown below):

[0085] [ka] The compound according to (1),

[0086] (21) -R 7 is [1,2,4]triazolo[1,5-a]pyridinyl.

[0087] (22) -R 7 but 2-[1,2,4]triazolo[1,5-a]pyridinyl (shown below):

[0088] [ka] The compound according to (1),

[0089] (23) -R 7 is benzimidazolyl.

[0090] (24) -R 7is independently 2-benzimidazolyl or 5-benzimidazolyl.

[0091] (25) -R 7 but 2-benzimidazolyl (shown below):

[0092] [ka] The compound according to (1),

[0093] (26) -R 7 but 5-benzimidazolyl (shown below):

[0094] [ka] The compound according to (1),

[0095] (27) -R 7 is a fused bicyclic C9 heteroaryl group having exactly 1 or 2 ring heteroatoms, each ring heteroatom being independently N or O.

[0096] (28) -R 7 is a fused bicyclic C9 heteroaryl group having exactly one ring heteroatom, and the ring heteroatom is O.

[0097] (29) -R 7 The compound according to (1), wherein is benzofuranyl.

[0098] (30) -R 7 is independently 2-benzofuranyl or 3-benzofuranyl.

[0099] (31) -R 7 but 2-benzofuranyl (shown below):

[0100] [ka] The compound according to (1),

[0101] (32) -R 7 but 3-benzofuranyl (shown below):

[0102] [ka] The compound according to (1),

[0103] C8 heteroaryl groups: (33) -R 7 is a fused bicyclic C heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, each ring heteroatom being N, S, or O.

[0104] (34) -R 7 is a fused bicyclic C heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, each ring heteroatom being N or S.

[0105] (35) -R 7 is a fused bicyclic C heteroaryl group having exactly 2 or 3 ring heteroatoms, each ring heteroatom being N, S, or O.

[0106] (36) -R 7 is a fused bicyclic C heteroaryl group having exactly 2 or 3 ring heteroatoms, each ring heteroatom being N or S.

[0107] (37) -R 7 is a fused bicyclic C8 heteroaryl group having exactly two ring heteroatoms, each ring heteroatom being N, S, or O.

[0108] (38) -R 7is a fused bicyclic C8 heteroaryl group having exactly two ring heteroatoms, each ring heteroatom being N or S.

[0109] (39) -R 7 is a fused bicyclic C heteroaryl group having exactly two ring heteroatoms, one of which is N, and one of which is S or O.

[0110] (40) -R 7 is a fused bicyclic C heteroaryl group having exactly two ring heteroatoms, one of which is N and one of which is S.

[0111] (41) -R 7 is a fused bicyclic C8 heteroaryl group having exactly three ring heteroatoms, each ring heteroatom being N, S, or O.

[0112] (42) -R 7 is a fused bicyclic C heteroaryl group having exactly three ring heteroatoms, each ring heteroatom being N or S.

[0113] (43) -R 7 is a fused bicyclic C heteroaryl group having exactly three ring heteroatoms, two of which are N, and one of which is S or O.

[0114] (44) -R 7 is a fused bicyclic C heteroaryl group having exactly three ring heteroatoms, two of which are N, and one of which is S.

[0115] (45) -R 7is independently imidazo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl, or imidazo[2,1-b]oxazolyl.

[0116] [ka]

[0117] (46) -R 7 is imidazo[2,1-b]thiazolyl.

[0118] (47) -R 7 but 6-imidazo[2,1-b]thiazolyl (shown below):

[0119] [ka] The compound according to (1),

[0120] C 10 Heteroaryl groups: (48) -R 7 is a fused bicyclic C ring having exactly 1, 2 or 3 ring heteroatoms 10 The compound according to (1), wherein the heteroaryl group is a heteroaryl group and each ring heteroatom is N.

[0121] (49) -R 7 is a fused bicyclic C ring having exactly 1 or 2 ring heteroatoms 10 The compound according to (1), wherein the heteroaryl group is a heteroaryl group and each ring heteroatom is N.

[0122] (50) -R 7 fused bicyclic C rings with exactly one ring heteroatom 10 The compound according to (1), wherein the heteroaryl group is a heteroaryl group and the ring heteroatom is N.

[0123] (51) -R 7 is independently quinolinyl or isoquinolinyl.

[0124] [ka]

[0125] (52) -R 7 is quinolinyl.

[0126] (53) -R 7 but 2-quinolinyl (shown below):

[0127] [ka] The compound according to (1),

[0128] (54) -R 7 but 3-quinolinyl (shown below):

[0129] [ka] The compound according to (1),

[0130] (55) -R 7 is isoquinolinyl.

[0131] (56) -R 7 is a fused bicyclic C ring with exactly two ring heteroatoms 10 The compound according to (1), wherein the heteroaryl group is a heteroaryl group and each ring heteroatom is N.

[0132] (57) -R 7 are independently cinnolinyl; quinazolinyl; quinoxalinyl; 1,5-naphthyridinyl; 1,6-naphthyridinyl; 1,7-naphthyridinyl; 1,8-naphthyridinyl; phthalazinyl; 2,6-naphthyridinyl; or 2,7-naphthyridinyl.

[0133] [ka] TIFF0007635237000033.tif49135

[0134] Group-R 7 :Connection point (58) -R 7 But -R 7 ring carbon atoms (e.g., -R 7 through a non-bridging ring carbon atom of -L 7 The compound according to any one of (1) to (57), wherein

[0135] (59) -R 7 But -R 7 ring nitrogen atoms (e.g., -R 7 through the non-bridging ring nitrogen atom of -L 7 The compound according to any one of (1) to (57), wherein the compound is bonded to -.

[0136] An example of a benzimidazolyl attached through a non-bridging ring carbon atom is shown below:

[0137] [ka]

[0138] Similarly, an example of a benzimidazolyl attached through a non-bridged ring nitrogen atom is shown below:

[0139] [ka]

[0140] Substituent -R SC (60) Each-R SC but, if present, independently: -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 , -NHC(=O)NH2, -NHC(=O)NHR TT , -NHC(=O)NR TT 2. -NHC(=O)R TM , -NHC(=O)OR TT , -OC(=O)NH2, -OC(=O)NHR TT , -OC(=O)NR TT 2. -OC(=O)R TM , -C(=O)R TT , -S(=O)2R TT , -S(=O)2NH2, -S(=O)2NHR TT , -S(=O)2NR TT 2. -S(=O)2R TM , -NHS(=O)2R TT , -CN or -NO2 The compound according to any one of (1) to (59),

[0141] (61) Each-R SC but, if present, independently: -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 , -C(=O)R TT , -S(=O)2NH2, -S(=O)2NHR TT , -S(=O)2NR TT 2. -S(=O)2R TM , -NHS(=O)2R TT , -CN or -NO2 The compound according to any one of (1) to (59),

[0142] (62) Each-R SC but, if present, independently: -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 , -C(=O)R TT , -S(=O)2NH2, -S(=O)2NHR TT , -S(=O)2NR TT 2. -S(=O)2R TM , -NHS(=O)2R TT , -CN or -NO2 The compound according to any one of (1) to (59),

[0143] (63) Each-R SC but, if present, independently: -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, or -L T -R TM The compound according to any one of (1) to (59),

[0144] (64) Each-R SC but, if present, independently: -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -L T -OH, -L T -OR TT , -CF3, -CHF2, -OCF3, or -OCHF2 The compound according to any one of (1) to (59),

[0145] (65) Each-R SC but, if present, independently: -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -CF3, -CHF2, -OCF3, or -OCHF2 The compound according to any one of (1) to (59),

[0146] (66) Each-R SC but, if present, independently: -R TT , -F, -Cl, -Br, or -I The compound according to any one of (1) to (59),

[0147] (67) Each-R SC but, if present, independently: -R TT The compound according to any one of (1) to (59),

[0148] Substituent -R SN (68) Each-R SN but, if present, independently: -R TT , -C(=O)R TT , -C(=O)OR TT , -C(=O)NH2, -C(=O)NHR TT , -C(=O)NR TT 2. -C(=O)R TM , or -S(=O)2R TT The compound according to any one of (1) to (67),

[0149] (69) Each-R SN but, if present, independently: -R TT , -C(=O)R TT , or -C(=O)OR TT The compound according to any one of (1) to (67),

[0150] (70) Each-R SN But if it exists: -R TT The compound according to any one of (1) to (67),

[0151] Group-L T -

[0152] (71) Each-L T -, if present, independently, a straight-chain or branched saturated C 1-3 The compound according to any one of (1) to (70), which is alkylene.

[0153] (72) Each-L T The compound according to any one of (1) to (70), wherein -, when present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0154] (73) Each-L T The compound according to any one of (1) to (70), wherein -, when present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0155] (74) Each-L T The compound according to any one of (1) to (70), wherein -, if present, is -CH2-.

[0156] Group-R TT (75) Each-R TT , if present, independently, -R TT1 , -R TT2 , -R TT3 , or -L TT -R TT3 The compound according to any one of (1) to (74),

[0157] (76) Each-R TT , if present, independently, -R TT1 , -R TT3 , or -L TT -R TT3 The compound according to any one of (1) to (74),

[0158] (77) Each-R TT If present, -R TT1The compound according to any one of (1) to (74),

[0159] Group-R TT1 (78) Each-R TT1 , if present, independently represent a linear or branched saturated C 1-6 The compound according to any one of (1) to (77), wherein the aryl group is alkyl.

[0160] (79) Each-R TT1 , if present, independently represent a linear or branched saturated C 1-4 alkyl, optionally -F, -OH, and -OR TTT The compound according to any one of (1) to (77), which is substituted with one or more groups selected from the following:

[0161] (80) Each-R TT1 , if present, independently represent a linear or branched saturated C 1-4 The compound according to any one of (1) to (77), wherein the aryl group is alkyl.

[0162] (81) Each-R TT1 The compound according to any one of (1) to (77), wherein, when present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

[0163] (82) Each-R TT1 The compound according to any one of (1) to (77), wherein, if present, is independently -Me, -Et, -nPr, or -iPr.

[0164] (83) Each-R TT1 The compound according to any one of (1) to (77), wherein, if present, is -Me.

[0165] Group-R TT2 (84) Each-R TT2 If exists, the saturated C 3-6cycloalkyl, optionally selected from -F, -OH, and -OR; TTT The compound according to any one of (1) to (83), which is substituted with one or more groups selected from the following:

[0166] (85) Each-R TT2 If exists, the saturated C 3-6 The compound according to any one of (1) to (83), which is cycloalkyl.

[0167] (86) Each-R TT2 The compound according to any one of (1) to (83), wherein, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0168] (87) Each-R TT2 The compound according to any one of (1) to (83), wherein, if present, is cyclopropyl.

[0169] Group-R TT3 (88) Each-R TT3 is, if present, phenyl and optionally —F, —Cl, —Br, —I, —R TTT , OH, -OR TTT , -OCF3, -NH2, -NHR TTT , and -NR TTT The compound according to any one of (1) to (87), which is substituted with one or more groups selected from the group consisting of:

[0170] (89) Each-R TT3 is, if present, phenyl and optionally —F, —Cl, —Br, —I, —R TTT , OH, -OR TTT The compound according to any one of (1) to (87), which is substituted with one or more groups selected from -OCF3.

[0171] (90) Each-R TT3 is, if present, phenyl and optionally —F, —Cl, —Br, —I, and —RTTT The compound according to any one of (1) to (87), which is substituted with one or more groups selected from the following:

[0172] (91) Each-R TT3 The compound according to any one of (1) to (87), wherein, when present, is phenyl.

[0173] Group-L TT - (92) Each-L TT -, if present, independently, a straight-chain or branched saturated C 1-3 The compound according to any one of (1) to (91), which is alkylene.

[0174] (93) Each-L TT The compound according to any one of (1) to (91), wherein -, if present, is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0175] (94) Each-L TT The compound according to any one of (1) to (91), wherein -, when present, is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0176] (95) Each-L TT The compound according to any one of (1) to (91), wherein -, if present, is -CH2-.

[0177] Group-R TN (96) Each-R TN , if present, independently represent a linear or branched saturated C 1-4 The compound according to any one of (1) to (95), wherein the aryl group is alkyl.

[0178] (97) Each-R TNThe compound according to any one of (1) to (95), wherein, if present, is -Me.

[0179] Group-R TM (98) Each-R TM is, if present, independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano: Optionally, on carbon, -R TMM , -F, -OH, and -OR TMM and is substituted with one or more groups selected from: Optionally, on the secondary nitrogen, if present, -R TMM , -C(=O)R TMM , and -C(=O)OR TMM substituted with a group selected from The compound according to any one of (1) to (97).

[0180] (99) Each-R TM is, if present, independently pyrrolidino, piperidino, piperazino, or morpholino; Optionally, on carbon, -R TMM , -F, -OH, and -OR TMM and is substituted with one or more groups selected from: Optionally, on the secondary nitrogen, if present, -R TMM , -C(=O)R TMM , and -C(=O)OR TMM The compound according to any one of (1) to (97), which is substituted with a group selected from the following:

[0181] (100) each-R TM is, when present, independently pyrrolidino, piperidino, piperazino, or morpholino: Optionally, on carbon, -R TMM and is substituted with one or more groups selected from: Optionally, on the secondary nitrogen, if present, -R TMM , -C(=O)R TMM, and -C(=O)OR TMM substituted with a group selected from The compound according to any one of (1) to (97).

[0182] (101) Each-R TM is, when present, independently pyrrolidino, piperidino, piperazino, or morpholino: Optionally, on carbon, -R TMM and is substituted with one or more groups selected from Optionally, on the secondary nitrogen, if present, -R TMM substituted with a group selected from The compound according to any one of (1) to (97).

[0183] Group-R TTT (102) Each-R TTT , if present, independently represent a linear or branched saturated C 1-4 The compound according to any one of (1) to (101), wherein the aryl group is alkyl.

[0184] (103) Each-R TTT The compound according to any one of (1) to (101), wherein, if present, is -Me.

[0185] Group-R TMM (104) Each-R TMM , if present, independently represent a linear or branched saturated C 1-4 The compound according to any one of (1) to (103), wherein the aryl group is alkyl.

[0186] (105) Each-R TMM The compound according to any one of (1) to (103), wherein, if present, is -Me.

[0187] Group-L 7 - (106) -L7 - independently, linear or branched saturated C 1-3 The compound according to any one of (1) to (105), which is alkylene.

[0188] (107) -L 7 The compound according to any one of (1) to (105), wherein - is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2-, or -CH2CH(CH3)-.

[0189] (108) -L 7 The compound according to any one of (1) to (105), wherein - is independently -CH2-, -CH2CH2-, or -CH2CH2CH2-.

[0190] (109) -L 7 The compound according to any one of (1) to (105), wherein - is independently -CH2-, -CH(CH3)-, -C(CH3)2-, or -CH(CH2CH3)-.

[0191] (110) -L 7 The compound according to any one of (1) to (105), wherein - is independently -CH2- or -CH(CH3)-.

[0192] (111) -L 7 The compound according to any one of (1) to (105), wherein - is -CH2-.

[0193] (112) -L 7 - is -CH2-, and -L 7 The compound according to any one of (1) to (105), wherein - is -CD2-.

[0194] Group-R 3 (113) -R 3 Ga-R 3A The compound according to any one of (1) to (112),

[0195] (114) -R 3 Ga-R 3B The compound according to any one of (1) to (112),

[0196] Group-R 3A (115) -R 3A , if present, independently represent a linear or branched saturated C 1-6 The compound according to any one of (1) to (114), wherein the aryl group is alkyl.

[0197] (116) -R 3A is, 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.

[0198] (117) -R 3A , if present, independently represent a linear or branched saturated C 1-4 The compound according to any one of (1) to (114), wherein the aryl group is alkyl.

[0199] (118) -R 3A The compound according to any one of (1) to (114), wherein, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu.

[0200] (119) -R 3A The compound according to any one of (1) to (114), wherein, if present, is independently -Me, -Et, -nPr, or -iPr.

[0201] (120) -R 3A The compound according to any one of (1) to (114), wherein, if present, is independently -Et, -nPr, or -iPr.

[0202] (121) -R 3A The compound according to any one of (1) to (114), wherein, if present, is -iPr.

[0203] Group-R 3B (122) -R 3B If exists, the saturated C 3-7 The compound according to any one of (1) to (121), which is cycloalkyl.

[0204] (123) -R 3B The compound according to any one of (1) to (121), wherein, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0205] (124) -R 3B The compound according to any one of (1) to (121), wherein, when present, is independently cyclopropyl or cyclobutyl.

[0206] (125) -R 3B The compound according to any one of (1) to (121), wherein, if present, is cyclopropyl.

[0207] (126) -R 3B The compound according to any one of (1) to (121), wherein, if present, is cyclobutyl.

[0208] Some preferred combinations (127) -R7 But independently: Imidazo[1,2-a]pyridinyl; Imidazo[1,2-a]pyrimidinyl; benzimidazolyl; Imidazo[2,1-b]thiazolyl; Imidazo[1,2-b]pyridazinyl; [1,2,4]triazolo[1,5-a]pyridinyl; quinolinyl; or benzofuranyl and optionally substituted as described herein; -L 7 - is -CH2- or -CH(CH3)-; -R 3 But -R 3A or -R 3B and; -R 3A is -iPr; -R 3B is cyclopropyl; The compound according to (1).

[0209] (128) -R 7 But independently: 2-Imidazo[1,2-a]pyridinyl; 3-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyrimidinyl; 2-Benzimidazolyl; 5-Benzimidazolyl; 6-Imidazo[2,1-b]thiazolyl; 2-Imidazo[1,2-b]pyridazinyl; 2-[1,2,4]triazolo[1,5-a]pyridinyl; 2-quinolinyl; 3-quinolinyl; or 2-Benzofuranyl and optionally substituted as described herein; -L 7- is -CH2- or -CH(CH3)-; -R 3 But -R 3A or -R 3B and; -R 3A is -iPr; -R 3B is cyclopropyl; The compound according to (1).

[0210] (129) -R 7 But independently: imidazo[1,2-a]pyridinyl; or Imidazo[1,2-a]pyrimidinyl; and optionally substituted as described herein; -L 7 - is -CH2- or -CH(CH3)-; -R 3 But -R 3A or -R 3B and; -R 3A is -iPr; -R 3B is cyclopropyl; The compound according to (1).

[0211] (130) -R 7 But independently: 2-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyrimidinyl and optionally substituted as described herein; -L 7 - is -CH2- or -CH(CH3)-; -R 3 But -R 3A or -R 3B and; -R 3A is -iPr; -R 3B is cyclopropyl; The compound according to (1).

[0212] (131) -R 7 But independently: Imidazo[1,2-a]pyridinyl; Imidazo[1,2-a]pyrimidinyl; benzimidazolyl; or Imidazo[2,1-b]thiazolyl and optionally substituted as described herein; -L 7 - is -CH2-; -R 3 Ga-R 3A and; -R 3A is -iPr, The compound according to (1).

[0213] (132) -R 7 But independently: Imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; or benzimidazolyl; and optionally substituted as described herein; -L 7 - is -CH2-; -R 3 Ga-R 3A and; -R 3A is -iPr, The compound according to (1).

[0214] (133) -R 7 But independently: 3-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyrimidinyl; 2-Benzimidazolyl; 5-benzimidazolyl; or Imidazo[2,1-b]thiazol-6-yl; and optionally substituted as described herein; -L 7 - is -CH2-; -R 3 Ga-R 3A and; -R 3A is -iPr, The compound according to (1).

[0215] (134) -R 7 But independently: 3-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyridinyl; 2-Imidazo[1,2-a]pyrimidinyl; 2-benzimidazolyl; or 5-Benzimidazolyl; and optionally substituted as described herein; -L 7 - is -CH2-; -R 3 Ga-R 3A and; -R 3A is -iPr, The compound according to (1).

[0216] Specific compounds (135) The compound according to (1), selected from compounds of the following formulae, and pharmaceutically acceptable salts, hydrates and solvates thereof:

[0217] [Table A] TIFF0007635237000037.tif229129TIFF0007635237000038.tif223129TIFF0007635237000039.t if224129TIFF0007635237000040.tif205129TIFF0007635237000041.tif214129TIFF00076352370 00042.tif213129TIFF0007635237000043.tif228129TIFF0007635237000044.tif218129TIFF000 7635237000045.tif230129TIFF0007635237000046.tif237129TIFF0007635237000047.tif191129

[0218] combination It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate 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 , -L 3 -, -R 3All combinations of embodiments relating to chemical groups represented by the formula (e.g., aryl, aryloxy ...

[0219] Substantially Purified Form One aspect of the present invention pertains to the H-APPAMP compounds described herein in a substantially purified form and / or substantially free of contaminants.

[0220] 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.

[0221] Unless otherwise specified, a substantially purified form refers to any stereoisomeric or enantiomeric form of a compound. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., a form that is 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.

[0222] In one embodiment, the contaminants 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.

[0223] Unless specified, contaminants refer to other compounds, i.e., compounds other than stereoisomers or enantiomers. In one embodiment, contaminants refer to other compounds and other stereoisomers. In one embodiment, contaminants refer to other compounds and the other enantiomer.

[0224] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound on a molar basis is the desired stereoisomer or enantiomer 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, such as at least 95% optically pure, such as at least 97% optically pure, such as at least 98% optically pure, such as at least 99% optically pure.

[0225] Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, such as, 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-, twist-, envelope-, and half-chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0226] Reference to a class of structures may fully encompass structural isomeric forms within that class (e.g., C 1-7 Alkyl includes n-propyl and isopropyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a particular group or substitution pattern is not intended to include other structural isomers (or constitutional isomers) that differ with respect to the bonds between the atoms rather than their positions in space. For example, a reference to a methoxy group -OCH3 should not be construed as a reference to its constitutional isomer, the hydroxymethyl group -CH2OH. Similarly, a specific reference to ortho-chlorophenyl should not be construed as a reference to its constitutional isomer, meta-chlorophenyl.

[0227] The above exclusion does not relate to tautomeric forms such as, for example, keto-, enol- and enolate-forms, as in the following tautomeric pairs: keto / enol (exemplified below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro. Reference herein to one tautomer is intended to encompass both tautomers.

[0228] [ka]

[0229] For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of each other, and reference herein to one is intended to encompass both.

[0230] [ka]

[0231] It should be noted that specifically included within the term "isomer" are compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3 H(T) can be in any isotopic form; C can be in any isotopic form, including 12 C. 13 C and 14 C can be any isotopic form, including 16 O and 18 It can be any isotopic form containing O, etc.

[0232] Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures thereof (e.g., racemic mixtures). Methods for preparing (e.g., asymmetric synthesis) and separating (e.g., fractional crystallization and chromatographic means) such isomeric forms are either known or readily obtainable by adapting the methods taught herein or known methods in a known manner.

[0233] salt It may be convenient or desirable to prepare, purify, and / or handle the corresponding salts of the compounds, e.g., pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci. , Vol. 66, pp. 1-19.

[0234] For example, the compound may be anionic or may have a functional group that can be anionic (e.g., -COOH may be -COO - In the case of cations having an amine group, salts can be formed with suitable cations. Examples of suitable inorganic cations include, but are not limited to, Na + and K. + Alkali metal ions such as Ca 2+ and Mg 2+ alkaline earth cations such as Al 3+ Other cations such as ammonium ions (i.e., NH4 + Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NHR + , NH2R2 + , NHR3 + , NR4 + ) for example, each R independently represents a linear or branched saturated C 1-18 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl and phenyl-C 1-6When alkyl, the phenyl group is optionally substituted. Some examples of suitable substituted ammonium ions are ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, and substituted ammonium ions derived from amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + is.

[0235] The compound is cationic or has a functional group that can become cationic upon protonation (e.g., -NH2 becomes -NH3 + When the aryl group has a substituent, a salt can be formed with a suitable anion.

[0236] For example, if the parent structure is a cationic group (e.g., -NMe2 + ) or functional groups that can become cationic upon protonation (e.g., -NH2 becomes -NH3 + If the compound has a cationic group (e.g., -NMe2), a salt can be formed with a suitable anion. In the case of quaternary ammonium compounds, a counter anion is generally always present to balance the positive charge. ... + , -NH3 + ), if the compound also contains a group capable of forming an anion (e.g., —COOH), an internal salt (also called a zwitterion) can be formed.

[0237] Examples of suitable inorganic anions include, but are not limited to, anions 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.

[0238] Examples of suitable organic anions include, but are not limited to, anions 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, lactobionic 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 polymeric organic anions include, but are not limited to, anions derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

[0239] Quaternary ammonium compounds (e.g., -NMe2 + Examples of particularly suitable counterions for the quaternary ammonium compounds having a group include 1-adamantanesulfonate, benzenesulfonate, hydrogen sulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-naphthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, and sulfate. Similarly, if the compound also contains a group capable of forming an anion (e.g., —COOH), an inner salt may be formed.

[0240] Unless otherwise specified, a reference to a particular compound also includes its salt forms.

[0241] Solvates and Hydrates It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the 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 conveniently be referred to as a hydrate, e.g., a monohydrate, a dihydrate, a trihydrate, etc.

[0242] Unless otherwise specified, a reference to a particular compound also includes solvated and hydrated forms thereof.

[0243] chemical protection form It may be convenient or desirable to prepare, purify, and / or handle compounds in a 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, solvents, etc.). Indeed, well-known chemical methods are used to reversibly render unreactive functional groups that would otherwise be reactive under certain conditions. In a chemically protected form, one or more reactive functional groups are in the form of protected or protecting groups (or masked or blocked or blocking groups). Protecting a reactive functional group allows reactions involving other unprotected reactive functional groups to be carried out without affecting the protected groups; usually, in a subsequent step, the protecting group can be removed or the masking group can be transformed without substantially affecting the remainder of the molecule. For example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th ed.; John Wiley & Sons, 2006).

[0244] 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 may be reactive under certain conditions, can be derivatized so that one of the functional groups is "protected" and therefore unreactive under certain conditions; a compound thus protected can be used as a reactant effectively possessing only one reactive functional group. After completion of the desired reaction (the reaction involving the other functional group), the protecting group can be "deprotected" to return to the original functional group.

[0245] 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 ether, a benzhydryl (diphenylmethyl) ether, or a trityl (triphenylmethyl) ether; a trimethylsilyl ether, or a t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3, -OAc).

[0246] For example, aldehyde or ketone groups can be protected as acetals (R-CH(OR)2) or ketals (RC(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a 1,1-diether (>C(OR)2), e.g., by reaction with a primary alcohol in the presence of acid. The aldehyde or ketone group is readily regenerated by hydrolysis, e.g., with water in the presence of acid.

[0247] For example, amine groups can be substituted, for example, as amides (-NRCO-R) or urethanes (-NRCO-OR), e.g., 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-fluorenylmethacrylates (-NHCO-OC(CH3)2C6H4C6H5, -NH-Bpoc); as oxyamide (-NH-Fmoc), as 6-nitroveratryloxyamide (-NH-Nvoc), as 2-trimethylsilylethyloxyamide (-NH-Teoc), as 2,2,2-trichloroethyloxyamide (-NH-Troc), as allyloxyamide (-NH-Alloc), 2(-phenylsulfonyl)ethyloxyamide (-NH-Psec), or, where appropriate (e.g., cyclic amines), as a nitroxide radical

[0248] [ka] can be protected as

[0249] For example, carboxylic acid groups can be used as esters, 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.

[0250] For example, thiol groups can be protected as thioethers (-SR), such as benzyl thioethers; acetamidomethyl ethers (-S-CH2NHC(=O)CH3).

[0251] Prodrug It may be convenient or desirable to prepare, purify, and / or handle compounds in the form of a prodrug. As used herein, the term "prodrug" refers to a compound that generates 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.

[0252] For example, some prodrugs are esters of active compounds (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 group (-C(=O)OH) in the parent compound, where appropriate, after first protecting and, if necessary, deprotecting any other reactive groups present in the parent compound.

[0253] Also, some prodrugs are enzymatically activated to yield the active compound, or to yield a compound that, upon further chemical reaction, yields the active compound (e.g., in 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.

[0254] composition One aspect of the present invention pertains to compositions (eg, pharmaceutical compositions) comprising the H-APPAMP compounds described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0255] Another aspect of the present invention relates to a method for preparing a composition (e.g., a pharmaceutical composition) comprising mixing an H-APPAMP compound described herein with a pharmaceutically acceptable carrier, diluent, or excipient.

[0256] Purpose The H-APPAMP compounds described herein are useful, for example, in the treatment of proliferative disorders (as "antiproliferative agents"), the treatment of cancer (as "anticancer agents"), the treatment of viral infections (as "antiviral agents"), the treatment of neurodegenerative diseases (as "anti-neurodegenerative agents"), and the like.

[0257] Use in methods for inhibiting CDK One aspect of the present invention relates to a method of inhibiting CDK (e.g., CDK12 and / or CDK13) function (e.g., in a cell) in vitro or in vivo, comprising contacting the cell with an effective amount of an H-APPAMP compound described herein.

[0258] 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.

[0259] In one embodiment, the above method is carried out in vitro.

[0260] In one embodiment, the above method is performed in vivo.

[0261] In one embodiment, the H-APPAMP compound is provided in the form of a pharmaceutically acceptable composition.

[0262] Any type of cell can be treated, including adipose, lung, gastrointestinal (including, e.g., intestine, colon), breast (mammary gland), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0263] For example, a cell sample can be grown in vitro, a compound can be contacted with the cells, and the effect of the compound on those cells can be observed. As an example of an "effect," the morphological state of the cells (e.g., alive or dead) can be determined. If a 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.

[0264] Use in a method for inhibiting cell proliferation, etc. The H-APPAMP compounds described herein may, for example, (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) perform a combination of one or more of these.

[0265] One aspect of the present invention relates to a method of regulating (e.g., inhibiting) cell proliferation (e.g., cell growth), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more of these, in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound described herein.

[0266] In one embodiment, the method is a method of controlling (e.g., inhibiting) cell proliferation (e.g., cell proliferation) in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound described herein.

[0267] In one embodiment, the method is carried out in vitro.

[0268] In one embodiment, the method is performed in vivo.

[0269] In one embodiment, the H-APPAMP compound is provided in the form of a pharmaceutically acceptable composition.

[0270] Any type of cell can be treated, including lung, gastrointestinal (e.g., including intestine, colon), breast (mammary gland), ovary, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

[0271] One of ordinary skill in the art can readily determine whether a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays that can be conveniently used to evaluate the activity conferred by a particular compound are described herein.

[0272] For example, a cell sample (e.g., a cell sample from a tumor) can be grown in vitro, a compound can be contacted with the cells, and the effect of the compound on those cells can be observed. As an example of an "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 for the compound's effectiveness in treating patients with cells of the same cell type.

[0273] Therapeutic Use Another aspect of the present invention relates to the H-APPAMP compounds described herein for use in methods of treatment of the human or animal body by therapy, e.g., for the treatment of disorders (e.g., diseases) described herein.

[0274] Use in the manufacture of medicines Another aspect of the present invention relates to the use of the H-APPAMP compounds described herein, e.g., in the manufacture of a medicament for use in a method of treatment of a disorder (e.g., a disease) described herein.

[0275] In one embodiment, the medicament comprises an H-APPAMP compound.

[0276] Treatment method Another aspect of the present 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 an H-APPAMP compound described herein, preferably in the form of a pharmaceutical composition.

[0277] Disorders Treated - CDK-Related Disorders In one embodiment (e.g., an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a disorder (e.g., a disease) associated with a CDK, particularly CDK12 and / or CDK13; a disorder (e.g., a disease) caused by inappropriate activity of a CDK, particularly CDK12 and / or CDK13; a disorder (e.g., a disease) associated with a CDK mutation, particularly a CDK12 and / or CDK13 mutation; a disorder (e.g., a disease) associated with CDK overexpression, particularly CDK12 and / or CDK13 overexpression; a disorder (e.g., a disease) associated with upstream pathway activation of a CDK, particularly CDK12 and / or CDK13; or a disorder (e.g., a disease) that is ameliorated by inhibition (e.g., selective inhibition) of a CDK, particularly CDK12 and / or CDK13.

[0278] In one embodiment (e.g., an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a disorder (e.g., a disease) associated with a CDK, particularly CDK12 and / or CDK13.

[0279] In one embodiment, the treatment is treatment of a disorder (eg, a disease) caused by inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0280] In one embodiment, the treatment is treatment of 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 a disorder (e.g., disease) associated with upstream pathway activation of a CDK, particularly CDK12 and / or CDK13.

[0281] 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.

[0282] Disorders treated In one embodiment (e.g., an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a proliferative disorder; cancer; a viral infection (e.g., HIV); a neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease); ischemia; kidney disease; a cardiovascular disorder (e.g., atherosclerosis); or an autoimmune disorder (e.g., rheumatoid arthritis).

[0283] In one embodiment (e.g., an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a disorder (e.g., a disease) caused by translation dysfunction in a cell, such as muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, and fragile X syndrome.

[0284] In one embodiment (e.g., an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a disorder (e.g., a disease) in a patient who has previously received therapeutic treatment but has received little or no additional clinical benefit from those treatments. This includes, for example, patients who have previously received 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).

[0285] Disorders Treated - Proliferative Disorders In one embodiment (eg, an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a proliferative disorder.

[0286] The term "proliferative disorder" as used herein relates to unwanted, unnecessary or uncontrolled, excessive or abnormal cell proliferation, such as neoplastic or hyperplastic growth, of cells.

[0287] In one embodiment, the treatment is treatment of a proliferative disorder characterized by benign, pre-cancerous or malignant cell proliferation.

[0288] 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., fibroproliferative disorder of connective tissue); pulmonary fibrosis; atherosclerosis; or smooth muscle cell proliferation in blood vessels (e.g., stenosis or restenosis after angioplasty).

[0289] Disorders Treated - Cancer In one embodiment (eg, a use in therapy embodiment, a use in the manufacture of a medicament embodiment, a method of treatment embodiment), the treatment is treatment of cancer.

[0290] In one embodiment, the treatment is treatment of cancer metastasis.

[0291] Cancers include: (1) Carcinomas, such as tumors arising from stratified squamous epithelium (squamous cell carcinoma) and tumors arising within organs or glands (adenocarcinoma). Examples include the breast, colon, lung, prostate, and ovaries.

[0292] (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); Chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelioma and mesothelioma (membrane 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 embryonic connective tissue); mesenchymoma and mixed mesodermal tumor (mixed connective tissue type).

[0293] (3) Myeloma.

[0294] (4) Hematopoietic tumors, such as myeloid leukemia and granulocytic leukemia (malignant tumors of the myeloid and granulocytic leukemia lines), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphocytic leukemia, lymphocytic leukemia, and lymphoblastic leukemia (malignant tumors of the lymphoid and lymphocytic blood lines), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythemia vera (malignant tumors of various blood cell products, but primarily erythrocyte products)).

[0295] (5) Lymphomas, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma.

[0296] (6) Mixed types, such as adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; teratocarcinoma.

[0297] For example, in one embodiment, the treatment is treatment of breast cancer.

[0298] In one embodiment, the cancer is associated with a CDK, particularly CDK12 and / or CDK13.

[0299] In one embodiment, the cancer is characterized or further characterized by inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0300] In one embodiment, the cancer is characterized or further characterized by overexpression of a CDK, in particular CDK12 and / or CDK13.

[0301] In one embodiment, the cancer is characterized or further characterized by amplification of the CDK12 and / or CDK13 genes, such as cancers that have amplification of the 17q12-q21 locus or that overexpress the protein HER2 (see, e.g., Choi et al., 2019).

[0302] In one embodiment, the cancer is characterized or further characterized by a fusion of a cancer-causing gene, such as, 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.

[0303] Anti-cancer effects can occur through one or more mechanisms, for example, but not limited to, controlling cell proliferation, inhibiting cell cycle progression, inhibiting angiogenesis (the formation of new blood vessels), inhibiting metastasis (the spread of tumors from the 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 tissues), promoting apoptosis (programmed cell death), inducing necrotic death, or autophagic death. The compounds described herein can be used in the treatment of cancers described herein, regardless of the mechanism discussed herein.

[0304] Disorders Treated - DNA Repair In one embodiment (e.g., a use in therapy embodiment, a use in the manufacture of a medicament embodiment, a method of treatment embodiment), the treatment is treatment of a disorder (e.g., disease) in a patient with underexpression, deletion, and / or mutation in a gene for a protein involved in DNA repair, such as BRCA1, BRCA2, ATM, ATR, BAP1, CDK12, CDK13, CHK1, CHK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCI, PALB2, NBS1, WRN, RAD51B, RAD51C, RAD51D, MRE11A, BLM, BRIP1, etc., including, for example, cancer patients whose tumors exhibit "BRCAness" (see, e.g., Lord et al., 2019).

[0305] In one embodiment (e.g., an embodiment of use in therapy, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a disorder (e.g., a disease) in a patient having underexpression, deficiency, and / or mutation in a gene for a protein involved in non-homologous DNA repair, such as, for example, XLF, RAD50, NBS1, MRE11, LIG4, XRCC4, POLL, POLM, etc.

[0306] Disorders Treated - Viral Infections In one embodiment (eg, an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a viral infection.

[0307] In one embodiment, the treatment comprises: (Group I:) dsDNA viruses, such as adenoviruses, herpesviruses, and 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, e.g., hepadnaviruses It is a treatment for viral infections.

[0308] As used above: ds: double-stranded; ss: positive-stranded; (+)ssRNA: positive-stranded RNA; (-)ssRNA: negative-stranded RNA; ssRNA-RT: (positive-stranded) RNA that has a DNA intermediate in its life cycle.

[0309] 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); human herpesvirus type 8 (HHV) associated with Kaposi's sarcoma; coxsackievirus type B3; borna virus; influenza virus.

[0310] Disorders Treated - Autoimmune Disorders In one embodiment (eg, an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of an autoimmune disorder.

[0311] In one embodiment, the treatment is treatment of an autoimmune disorder involving connective tissue, joints, skin, or eyes.

[0312] In one embodiment, the treatment is treatment of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or Sjogren's syndrome.

[0313] Disorders treated - Disorders caused by translation dysfunction in cells In one embodiment (eg, an embodiment for use in therapy, an embodiment for use in the manufacture of a medicament, an embodiment for a method of treatment), the treatment is treatment of a disorder caused by translation dysfunction in a cell.

[0314] In one embodiment, the treatment is treatment of muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, or fragile X syndrome.

[0315] treatment As used herein in the context of treating a disorder, the term "treatment" generally relates to the treatment of a human or animal (e.g., in veterinary applications) to achieve some desired therapeutic effect, such as inhibiting the progression of the disorder, including, for example, 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 in patients who have not yet developed the disorder but are at risk of developing the disorder is encompassed by the term "treatment."

[0316] For example, "treatment" includes prevention of cancer, reduction of the incidence of cancer, alleviation of symptoms of cancer, and the like.

[0317] As used herein, the term "therapeutically effective amount" relates to an amount of a compound, or a material, composition, or dosage form containing a 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.

[0318] Combination therapy The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, e.g., sequentially or simultaneously. For example, the compounds described herein can also be used in combination therapy, e.g., in combination with other agents. Examples of treatments and therapies include chemotherapy (e.g., administration of active agents such as drugs, antibodies (e.g., as immunotherapy), prodrugs (e.g., as photodynamic therapy, GDEPT, ADEPT, etc.)); surgery; radiation therapy; photodynamic therapy; gene therapy; and dietary restrictions.

[0319] One aspect of the present invention pertains to the compounds described herein in combination with one or more (eg, 1, 2, 3, 4, etc.) additional therapeutic agents, as described below.

[0320] The particular combination is left to the discretion of the physician, who will select dosages using his or her common knowledge and dosing regimens known to skilled physicians.

[0321] The agents (i.e., a compound described herein and one or more other agents) may be administered simultaneously or sequentially, and may be administered on different individual dosing schedules and via different routes. For example, when administered sequentially, the agents can be administered closely spaced (e.g., over 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 hours or more, or even longer if necessary), with the exact dosing regimen depending on the characteristics of the therapeutic agent(s).

[0322] The agents (i.e., a compound described herein and one or more other agents) may be formulated together in a single dosage form, or the individual agents may be formulated separately and provided together in the form of a kit, optionally with instructions for use.

[0323] Examples of additional agents / therapies that can be co-administered / combined with treatment with the H-APPAMP compounds described herein include: aromatase inhibitors, such as exemestane (also known as Aromasin), letrozole (also known as Femara), anastrozole (also known as Arimidex), etc.; Antiestrogens, such as Faslodex (also known as Fulvestrant and ICI182780), Tamoxifen (also known as Nolvadex), Hydroxytamoxifen, etc.; Antiandrogens, for example, antiandrogens used in the treatment of prostate cancer, such as flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.; Her2 blockers, such as Herceptin, Pertuzumab, Lapatinib, 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.). Agents that stimulate the immune system, such as Toll-like receptor (TLR1-13) agonists, stimulator of interferon genes (STING) agonists, etc.; Checkpoint inhibitors, such as inhibitors of PD1, PD1L, CTLA4, etc., such as pembrolizumab, atezolizumab, ipilimumab, etc.; DNA repair inhibitors, for example, PARP inhibitors, such as olaparib, niraparib, etc.

[0324] Thus, in one embodiment, the above treatment further comprises treatment (e.g., simultaneous or sequential treatment) with an additional active agent, such as an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent that stimulates the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc.

[0325] Other uses The H-APPAMP compounds described herein can also be used as cell culture additives to inhibit CDKs (eg, CDK12 and / or CDK13).

[0326] The H-APPAMP compounds described herein can 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.

[0327] The H-APPAMP compounds described herein can also be used, for example, as standards in assays to identify other active compounds, other CDK12 and / or CDK13 inhibitors, etc.

[0328] kit One aspect of the present invention relates to a kit comprising: (a) an H-APPAMP compound described herein, or a composition comprising an H-APPAMP compound described herein, e.g., preferably provided in a suitable container and / or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

[0329] The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

[0330] Route of administration The H-APPAMP compound or a pharmaceutical composition comprising the H-APPAMP compound can be administered to a subject by any convenient route of administration, whether systemically / peripherally or locally (i.e., at the desired site of action).

[0331] Examples of routes of administration include oral (e.g., administration by ingestion); buccal; sublingual; transdermal (including, e.g., administration by patches, plasters, etc.); transmucosal (including, e.g., administration by patches, plasters, etc.); intranasal (e.g., administration by nasal spray); intraocular (e.g., administration by eye drops); pulmonary (e.g., administration by inhalation or insufflation therapy using an aerosol, e.g., through the mouth or nose); rectal (e.g., administration by suppository or enema); intravaginal (e.g., administration by pessary); parenteral, e.g., administration by injection, such as subcutaneous, intradermal, intramuscular, intratracheal, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, subcuticular, intraarticular, subarachnoid, and intrasternal; and administration by implantation of a depot or reservoir, e.g., subcutaneous or intramuscular.

[0332] 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.

[0333] Furthermore, the subject / patient may be in any of its forms of development, for example, a fetus.

[0334] In one preferred embodiment, the subject / patient is a human.

[0335] formulation Although the H-APPAMP compound can be administered alone, it is preferable to provide it as a pharmaceutical formulation (e.g., a composition, a pharmaceutical preparation, a medicament) comprising at least one H-APPAMP compound described herein together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, such as pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavoring agents, and sweeteners. The formulation may further comprise other active agents, such as other therapeutic or prophylactic agents.

[0336] Thus, the present invention further provides pharmaceutical compositions as defined above, as well as methods for making pharmaceutical compositions, which comprise mixing at least one H-APPAMP compound described herein 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.

[0337] As used herein, the term "pharmaceutically acceptable" refers to compounds, ingredients, materials, compositions, dosage forms, etc., that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g., a human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0338] 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 Edition, 2005.

[0339] The formulations can 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., liquid carrier, finely divided solid carrier, etc.), and then, if necessary, shaping the product.

[0340] The formulations may be prepared to provide fast or slow release; immediate, delayed, timed, or sustained release; or combinations thereof.

[0341] The formulation 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, tablet (e.g., coated tablets), granules, powder, troches, pastilles, capsules (e.g., hard gelatin capsules and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

[0342] The formulations may be suitably presented as patches, adhesive plasters, bandages, dressings, etc. impregnated with one or more compounds and, optionally, one or more other pharmaceutically acceptable ingredients, such as penetration enhancers, permeation enhancers, absorption enhancers, etc. The formulations may also be suitably presented in the form of a depot or reservoir.

[0343] The compounds can be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients. The compounds can be provided in liposomes or other microparticles designed to target the compounds, for example, to blood components or one or more organs.

[0344] Formulations suitable for oral administration (e.g., administration 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.

[0345] Formulations suitable for oral administration include mouthwash, lozenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Lozenges typically contain the compound in a flavored base, which is usually sucrose and gum arabic or tragacanth gum. Pastilles typically contain the compound in an inert matrix, such as gelatin and glycerin, or sucrose and gum arabic. Mouthwashes typically contain the compound in a suitable liquid carrier.

[0346] Formulations suitable for sublingual administration include tablets, troches, pastilles, capsules, and pills.

[0347] Formulations suitable for oral transmucosal administration include solutions, 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.

[0348] Formulations suitable for parenteral transmucosal administration include solutions, 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.

[0349] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

[0350] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by mixing the above compounds in a free-flowing form, such as powder or granules, with one or more binders (e.g., povidone, gelatin, gum arabic, sorbitol, gum 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 or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavorants, flavor enhancers, and sweeteners, and compressing the mixture in a suitable machine. Tablets can be prepared by molding a mixture of the above powdered compounds moistened with an inert liquid diluent in a suitable machine. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the compound therein, for example, using various ratios of hydroxypropyl methylcellulose to provide a desired release profile. Tablets may optionally be provided with a coating that affects release, for example, an enteric coating that provides release in parts of the intestine other than the stomach.

[0351] Ointments are typically prepared from the above compounds and a paraffinic or a water-miscible ointment base.

[0352] Creams are typically prepared from the above-described compounds 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 can desirably contain a compound that enhances the absorption or penetration of the above-described compounds through the skin or other affected areas. Examples of such percutaneous penetration enhancers include dimethyl sulfoxide and related analogs.

[0353] Emulsions are typically prepared from the above compounds and an oil phase, and may optionally contain only an emulsifier (also known as an emulgent), or a mixture of at least one emulsifier with a fat or oil, or a mixture of at least one emulsifier with 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 to include both an oil and a fat. Taken together, the above emulsifier(s), together with or without stabilizer(s), constitute the so-called emulsifying wax, which, together with the oil and / or fat, constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of a cream formulation.

[0354] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate. The solubility of the above compounds in most oils likely to be used in pharmaceutical emulsion formulations can be very low, so the selection of an oil or fat suitable for the formulation is based on achieving the desired cosmetic properties. For this reason, the cream should preferably be a non-greasy, non-staining, and washable product 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 acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate, or a blend of branched esters known as Crodamol CAP can be used, the last three being preferred. These can be used alone or in combination depending on the properties required. Alternatively, high-melting lipids such as white soft paraffin and / or liquid paraffin, or other mineral oils, can be used.

[0355] 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.

[0356] Formulations suitable for intranasal administration, where the carrier is a solid, include those provided as a coarse powder having a particle size in the range, for example, from about 20 to about 500 microns, which are administered in the manner of nasal insufflation, i.e., by rapid inhalation through the nasal passages from a container of the powder held close to the nose.

[0357] Formulations suitable for pulmonary administration (e.g., administration by inhalation or insufflation therapy) include formulations delivered as an aerosol spray from pressurized packs with a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.

[0358] Formulations suitable for intraocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the above compounds.

[0359] Formulations suitable for rectal administration may be presented as a suppository with a suitable base including, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or salicylates; or as solutions or suspensions for therapeutic enema.

[0360] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the compounds, such carriers as are known in the art to be appropriate.

[0361] Suitable formulations for parenteral administration (e.g., administration 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., in 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 about 1 ng / mL to about 10 μg / mL, e.g., about 10 ng / mL to about 1 μg / mL. The formulations may be presented in unit-dose or multi-dose 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 (e.g., water for injections) immediately prior to use. Extemporaneous injection solutions and suspensions may also be prepared from sterile powders, granules, and tablets.

[0362] dose Those skilled in the art will understand that appropriate doses of H-APPAMP compounds and compositions containing H-APPAMP compounds may vary from patient to patient. Determining the optimal dose generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The selected dose level will depend on various factors, such as the activity of the particular H-APPAMP compound, the route of administration, the time of administration, the rate of excretion of the H-APPAMP compound, the duration of treatment, other drugs, compounds, and / or substances used in combination, 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 H-APPAMP compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally, the dose will be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial harmful or adverse side effects.

[0363] Administration can be in one 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 are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out, with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

[0364] In general, a suitable dose of H-APPAMP compound is in the range of about 10 μg to about 250 mg (more typically 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 based on the parent compound, and therefore the actual weight used will be increased proportionately. [Example]

[0365] chemical synthesis Abbreviation aq: aqueous; Boc: tert-butoxycarbonyl; Boc2O: di-tert-butyl dicarbonate; br: broad; ca.: approx. d: doublet; t BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-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: isopropanol; LCMS: liquid chromatography-mass spectrometry; LiHMDS: lithium hexamethyldisilazide; m:multiplet; M: mole, 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; PdCl2(dppf) DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; q:quartet; RT: Room temperature (approx. 20℃); R T :holding time; 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.

[0366] Other abbreviations are intended to convey their generally accepted meaning.

[0367] Structural names were generated using the "Structure to Name" conversion in ChemDraw® Professional 17 (PerkinElmer).

[0368] General synthesis method Methods for the chemical synthesis of H-APPAMP 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 H-APPAMP compounds.

[0369] 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, which is used in a Buchwald-Hartwig cross-coupling to generate intermediate I-4. Final global Boc deprotection affords the target compound.

[0370] This method is illustrated in the following chemical scheme: In one embodiment, R' is isopropyl. Scheme 1

[0371] [ka]

[0372] Representative reaction conditions for the above scheme are as follows: (a) RNH, DIPEA, EtOH, 50-90°C; (b) BocO, DMAP, THF, RT-60°C; (c) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (d) TFA, DCM, RT; or HCl, dioxane, RT to 40°C; for example: (a) RNH2, DIPEA, EtOH, 90°C; (b) Boc2O, DMAP, THF, RT; (c) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (d) HCl, dioxane, RT.

[0373] In the second method, the synthesis begins with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with sodium thiomethoxide affords the thioether intermediate I-6. Buchwald-Hartwig cross-coupling leads to the formation of intermediate I-7, which can be converted to the sulfoxide intermediate I-8 by oxidation of the thioether. Nucleophilic aromatic substitution affords the 5-amino-pyrazolopyrimidine intermediate I-9. Final Boc-deprotection affords the target compound.

[0374] This method is illustrated in the following chemical scheme: In one embodiment, R' is isopropyl. Scheme 2

[0375] [ka]

[0376] Representative reaction conditions for the above scheme are as follows: (a) MeSNa, THF, RT; (b) tBuXPhos-Pd-G3, LiHMDS, THF, 60°C; (c) mCPBA, DCM, RT; (d) RNH2, DIPEA, dioxane, 110°C; (e) TFA, DCM, RT; or HCl, dioxane, RT to 40°C; for example: (a) MeSNa, THF, RT; (b) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (c) mCPBA, DCM, RT; (d) RNH2, DIPEA, dioxane, 110°C; (e) TFA, DCM, RT; or HCl, dioxane, RT.

[0377] In the third method, the synthesis begins with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with ammonium hydroxide affords the corresponding 5-amino-pyrazolopyrimidine I-10. Boc protection of the amino group affords intermediate I-11. Substitution with an alkyl halide RX affords intermediate I-3. Intermediate I-3 is used in a Buchwald-Hartwig cross-coupling to afford intermediate I-4. Final global Boc-deprotection affords the target compound.

[0378] This method is illustrated in the following chemical scheme: In one embodiment, R' is isopropyl. Scheme 3

[0379] [ka]

[0380] Representative reaction conditions for the above scheme are as follows: (a) NH4OH, 85°C; (b) Boc2O, DMAP, THF, RT-60°C; (c) RCl, K2CO3, DMF, 70°C; (d) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (e) TFA, DCM, RT; or HCl, dioxane, RT to 40°C.

[0381] In the fourth 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. Subsequent nucleophilic aromatic substitution with a second amine affords intermediate I-4. Final Boc-deprotection affords the target compound.

[0382] This method is illustrated in the following chemical scheme: In one embodiment, R' is isopropyl. Scheme 4

[0383] [ka]

[0384] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH, 50°C; (b) DIPEA, NMP, 150°C, microwave; (c) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (d) HCl, dioxane, 35°C.

[0385] 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.

[0386] 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.

[0387] Column chromatography was performed on an automated flash chromatography system such as a CombiFlash Rf system using Grace™ GraceResolv™ pre-packed silica (40 μm) cartridges unless otherwise indicated.

[0388] 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 (ppm) 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.

[0389] Analytical LCMS experiments to determine retention times and associated mass ions were performed using an Agilent 1200 series HPLC system coupled to an Agilent 6110 or 6120 series single quadrupole mass spectrometer running Method 1 or Method 2 described below.

[0390] Preparative HPLC purification was performed using a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm column with a gradient of MeCN and 10 mM ammonium bicarbonate (aqueous). Fractions were collected after UV detection at a single wavelength measured by a variable wavelength detector.

[0391] SCX resin was purchased from Sigma Aldrich or Silicycle and washed with MeOH before use.

[0392] Analysis method Method 1 - LCMS Acid Quadrant Method: Column: Waters X-Select CSH C18, 2.5 μm, 4.6 x 30 mm Detection: UV at 254 nm unless otherwise indicated MS ionization: electrospray Solvent A: Water / 0.1% formic acid Solvent B: MeCN / 0.1% formic acid

[0393] [Table B]

[0394] Method 2 - LCMS Basic Quadrant Method: Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6 x 30 mm Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN (Other parameters are the same as Method 1)

[0395] Method 3 - UPLC / MS Acidic Trisection Method: Column: Waters Acquity CSH C18 (2.1 x 30 mm) Detection: Waters Acquity PDA detector 210-400nm MS ionization: electrospray Solvent A: Water / 0.1% formic acid Solvent B: MeCN / 0.1% formic acid

[0396] The column was maintained at a temperature of 40° C. and eluted with a linear acetonitrile gradient from 95.0% A to 5.0% B over 3 min at a constant flow rate of 0.77 mL / min.

[0397] Method 4 - UPLC / MS basic trisection method: Column: Waters Acquity BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity PDA detector 210-400nm MS ionization: electrospray Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN (Other parameters are the same as Method 3)

[0398] Method 5 - UPLC / MS Basic Trisection Method: Column: Waters Acquity BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity PDA detector 210-400nm MS ionization: electrospray Solvent A: Water / 10 mM ammonium hydroxide Solvent B: MeCN (Other parameters are the same as Method 3)

[0399] Method 6 - UPLC / MS Basic 1 Minute Method: Column: Waters Acquity BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity PDA detector 210-400nm MS ionization: electrospray Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN

[0400] The column was maintained at a temperature of 40° C. and eluted with a linear acetonitrile gradient from 95.0% A to 5.0% B over 1 min at a constant flow rate of 0.77 mL / min.

[0401] Synthesis 1 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-003)

[0402] [ka]

[0403] Step 1 : 5-chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Imidazo[1,2-a]pyridin-2-ylmethanamine, 2HCl (0.175 g, 0.80 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (0.122 g, 0.53 mmol) and DIPEA (0.74 mL, 4.24 mmol) in EtOH (10 mL). The reaction mixture was heated at 90 °C for 6 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (0.160 g, 0.42 mmol, 80% yield, 90% purity) as a white solid. UPLC / MS (Method 4): m / z 341 (M+H)+, R T 1.38 minutes.

[0404] Step 2 : tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl)carbamate BOC anhydride (0.14 mL, 0.61 mmol) was added to a solution of 5-chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (0.160 g, 0.47 mmol) and DMAP (0.011 g, 0.09 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 × 10 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) afforded the title compound (0.170 g, 0.37 mmol, 78% yield, 95% purity) as a cream-colored solid. UPLC / MS (method 4): m / z 441 (M+H)+, R T 1.73 minutes.

[0405] Step 3 : tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl)carbamate (0.150 g, 0.34 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (0.094 g, 0.41 mmol) in THF (3 mL). t A solution of BuBrettPhos Pd G3 (0.029 g, 0.03 mmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.51 mL, 0.51 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1 hour. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (0.075 g, 0.12 mmol, 34% yield, 98% purity) as a white solid. UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.65 minutes.

[0406] Step 4 : (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.44 mL, 1.77 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (0.075 g, 0.12 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was diluted in MeOH (5 mL), loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL), and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (0.030 g, 0.07 mmol, 57% yield, 95% purity) as a clear glassy solid. UPLC / MS (Method 4): m / z 435 (M+H)+, R T 0.96 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.50 - 8.46 (m, 1H), 7.78 (s, 1H), 7.65 (t, J = 6.3 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.24 - 7.16 (m, 1H), 6.85 (td, J = 6.8, 1.2 Hz, 1H), 6.76 - 6.70 (m, 1H), 5.35 - 5.30 (m, 1H), 5.28 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.12 - 4.05 (m, 1H), 3.60 - 3.48 (m, 1H), 3.17 (d, J = 4.2 Hz, 1H), 3.06 - 2.99 (m, 1H), 2.98 - 2.92 (m, 1H), 2.92 (dd, J = 11.6, 4.8 Hz, 1H), 2.81 - 2.74 (m, 1H), 2.30 (td, J = 12.2, 2.7 Hz, 1H), 2.16 (dd, J = 11.6, 9.9 Hz, 1H), 1.58 - 1.51 (m, 1H), 1.38 - 1.28 (m, 1H), 1.23 (t, J = 6.5 Hz, 6H), 1.19 - 1.10 (m, 1H).

[0407] Synthesis 2 (3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-002)

[0408] [ka]

[0409] Step 1 : 5-chloro-N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Imidazo[1,2-a]pyrimidin-2-ylmethanamine, 2HCl (5.04 g, 22.82 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (3.50 g, 15.21 mmol) and DIPEA (21.3 mL, 122.0 mmol) in EtOH (80 mL). The reaction mixture was heated at 90 °C for 5 h. The reaction mixture was concentrated in vacuo, and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 50 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the title compound (5.10 g, 14.62 mmol, 96% yield, 98% purity) as a white solid. UPLC / MS (Method 3): m / z 342 (M+H)+, R T 1.06 minutes.

[0410] Step 2 : tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)carbamate BOC anhydride (3.2 mL, 13.69 mmol) was added to a solution of 5-chloro-N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (3.60 g, 10.53 mmol) and DMAP (0.26 g, 2.11 mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 × 30 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0–10% MeOH / DCM) afforded the title compound (4 g, 8.60 mmol, 82% yield, 95% purity) as a cream-colored solid. UPLC / MS (Method 3): m / z 442 (M+H)+, R T 1.44 minutes.

[0411] Step 3 : tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)carbamate (3.19, 7.22 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (1.75 g, 7.58 mmol) in THF (30 mL). t A solution of BuBrettPhos Pd G3 (0.62 g, 0.72 mmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (10.8 mL, 10.8 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) afforded the title compound (2.10 g, 3.24 mmol, 44% yield, 98% purity) as an orange solid. UPLC / MS (Method 4): m / z 636 (M+H)+, R T 1.50 minutes.

[0412] Step 4 : (3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (12.4 mL, 49.5 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (2.10 g, 3.30 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour and 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 ammonia in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give a yellow solid. Further purification by column chromatography (24 g cartridge, 0-20% MeOH (containing 0.7 M NH) / DCM) gave a yellow solid. The solid was dissolved in DCM (20 mL) and MeOH (approximately 1 mL). Diethyl ether (100 mL) was added. A brown solid formed and was collected by filtration to give the title compound (0.700 g, 1.56 mmol, 47% yield, 98% purity). UPLC / MS (Method 4): m / z 436 (M+H)+, R T 0.85 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.89 (dd, J = 6.8, 2.1 Hz, 1H), 8.49 (dd, J = 4.1, 2.0 Hz, 1H), 7.78 - 7.72 (m, 2H), 7.64 (s, 1H), 7.02 (dd, J = 6.7, 4.1 Hz, 1H), 6.76 (d, J = 5.0 Hz, 1H), 5.47 (s, 1H), 5.27 (s, 1H), 4.60 (d, J = 6.0 Hz, 2H), 3.58 - 3.48 (m, 1H), 3.45 - 3.25 (m, 2H), 3.25 - 3.19 (m, 1H), 3.14 - 3.07 (m, 1H), 3.00 - 2.95 (m, 1H), 2.85 (d, J = 12.2 Hz, 1H), 2.39 (td, J = 12.3, 2.9 Hz, 1H), 2.25 (d, J = 11.0 Hz, 1H), 1.63 - 1.57 (m, 1H), 1.37 (d, J = 11.7 Hz, 1H), 1.24 (t, J = 6.5 Hz, 6H), 1.21 - 1.17 (m, 1H).

[0413] Synthesis 3 (3R,4R)-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-006)

[0414] [ka] Step 1 : 5-chloro-3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidine A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (8.00 g, 34.8 mmol) in THF (100 mL) was cooled to -5 °C and sodium thiomethoxide (2.44 g, 34.8 mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (400 mL) and washed with saturated aqueous NaHCO3 (500 mL). The aqueous layer was extracted with EtOAc (260 mL), and the combined organic layers were washed with brine (160 mL), dried over MgSO4, and concentrated in vacuo. Purification by column chromatography (40 g cartridge, 0–20% EtOAc / isohexane) afforded the title compound (6.00 g, 24.6 mmol, 71% yield, 99% purity) as a pale yellow oil that solidified on standing. LCMS (Method 1): m / z 242 (M+H)+, R T 2.40 minutes.

[0415] Step 2 : tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate 5-chloro-3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidine (1.70 g, 7.03 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (1.62 g, 7.03 mmol) in THF (10 mL) tA solution of BuBrettPhos Pd G3 (300 mg, 0.35 mmol) was degassed for 5 min. LiHMDS (1 M in THF) (7.8 mL, 7.74 mmol) was added, and the mixture was degassed for an additional 5 min. The reaction mixture was heated to 60 °C and stirred for 0.5 h. The solvent was evaporated, the residue redissolved in EtOAc, washed with 1:1 water / brine (50 mL), and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated. Purification by column chromatography (80 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (2.30 g, 5.12 mmol, 66% yield, 97% purity) as a yellow solid. LCMS (Method 1): m / z 436 (M+H)+, R T 2.25 minutes.

[0416] Step 3 : tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (1.70 g, 3.90 mmol) was dissolved in DCM (30 mL). The solution was cooled to 0 °C and mCPBA (1.35 g, 5.85 mmol) was added in one portion. The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was worked up by adding DCM (30 mL) and washed with saturated aqueous NaHCO (2 × 30 mL). The aqueous layer was extracted with DCM (3 × 20 mL). The organic layer was washed with brine, dried over NaSO, and the solvent was evaporated to give the title compound (1.50 g, 3.16 mmol, 81% yield, 95% purity). UPLC / MS (Method 4): m / z 452 (M+H)+, R T 1.43 minutes.

[0417] Step 4 : tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (90 mg, 0.149 mmol) in dioxane (0.5 mL) was added to a solution of (1-methyl-1H-benzo[d]imidazol-5-yl)methanamine (72 mg, 0.448 mmol) and DIPEA (0.25 mL, 1.431 mmol) in dioxane (0.5 mL). The resulting mixture was heated at 100° C. for 3 days. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane then 0-5% MeOH / DCM) gave the title compound (28 mg, 0.046 mmol, 31% yield, 90% purity) as a pale yellow glass. UPLC / MS (Method 4): m / z 549 (M+H)+, R T 1.44 minutes.

[0418] Step 5 : (3R,4R)-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (28 mg, 0.051 mmol) was treated with a mixture of TFA (50 μL, 0.649 mmol) in DCM (0.5 mL). The resulting mixture was stirred for 3 h. The mixture was concentrated and then partitioned between EtOAc (5 mL) and saturated aqueous NaHCO3 (3 mL), and the phases were separated. The organic phase was washed with water (2 mL) and brine (2 mL), dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (10 mg, 0.021 mmol, 41% yield, 95% purity) as a white powder. UPLC / MS (method 4): m / z 449 (M+H)+, R T 0.97 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.88 (t, J = 6.5 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.51 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 8.3, 1.6 Hz, 1H), 6.73 - 6.66 (m, 1H), 5.35 - 5.29 (m, 1H), 5.22 (s, 1H), 4.53 (d, J = 6.4 Hz, 2H), 3.81 (s, 3H), 3.57 - 3.47 (m, 1H), 3.19 - 3.12 (m, 1H), 3.05 - 2.96 (m, 1H), 2.96 - 2.91 (m, 1H), 2.89 (dd, J = 12.0, 4.3 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.34 - 2.25 (m, 1H), 2.15 (dd, J = 11.6, 10.0 Hz, 1H), 1.55 - 1.49 (m, 1H), 1.34 - 1.27 (m, 1H), 1.22 (t, J = 7.0 Hz, 6H), 1.15 - 1.07 (m, 1H), 1H under water.

[0419] Synthesis 4 (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-005)

[0420] [ka]

[0421] Step 4 tert-Butyl (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A mixture of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80% pure) (0.467 g, 0.827 mmol) and (1H-benzo[d]imidazol-2-yl)methanamine (0.146 g, 0.993 mmol) in dioxane (1 mL) was heated to 105 °C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0–20% MeOH (0.7 M NH3) in DCM) afforded the title compound (26 mg, 0.041 mmol, 5% yield, 85% purity) as a brown solid. UPLC / MS (Method 4): m / z 535 (M+H)+, R T 1.45 minutes.

[0422] Step 5 : (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.15 mL, 0.61 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (30 mg, 0.040 mmol) in DCM (10 mL). The reaction was stirred for 16 h and concentrated in vacuo. The residue was diluted in MeOH (5 mL), loaded onto an SCX cartridge, washed with MeOH (3 x column volumes) and eluted with 0.7 M ammonia in MeOH (3 x column volumes). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7 M NH 3 ) / DCM) afforded the title compound (5 mg, 10.9 μmol, 27% yield, 95% purity) as a yellow solid. UPLC / MS (same method as method 4, but run length was 10 min): m / z 435 (M+H)+, R T 3.87 minutes. 1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 7.71 (t, J = 6.2 Hz, 1H), 7.66 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 7.14 (dd, J = 6.1, 3.0 Hz, 2H), 6.81 - 6.71 (m, 1H), 5.29 (s, 1H), 5.22 (s, 1H), 4.69 (d, J = 5.8 Hz, 2H), 3.59 - 3.44 (m, 1H), 3.23 - 3.14 (m, 2H), 3.06 - 2.99 (m, 1H), 2.96 (p, J = 6.9 Hz, 1H), 2.89 (dd, J = 11.7, 4.6 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.32 - 2.24 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1H), 1.53 (dd, J = 13.0, 3.4 Hz, 1H), 1.32 (s, 1H), 1.24 (t, J = 6.5 Hz, 6H), 1.18 - 1.07 (m, 1H).

[0423] Synthesis 5 (3R,4R)-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-004)

[0424] [ka]

[0425] Step 4 : tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate A mixture of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (0.100 g, 0.221 mmol) and (8-methylimidazo[1,2-a]pyridin-2-yl)methanamine (0.107 g, 0.666 mmol) in dioxane (0.5 mL) was heated to 105 °C for 4 days. The reaction mixture was cooled to room temperature and concentrated. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (48 mg, 0.041 mmol, 38% yield, 95% purity) as an orange glassy solid. UPLC / MS (Method 1): m / z 549 (M+H)+, R T 1.32 minutes.

[0426] Step 5 : (3R,4R)-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.40 mL, 1.51 mmol) was added to a suspension of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (48 mg, 0.083 mmol) in dioxane (3 mL). The reaction mixture was stirred at 40° C. for 4 hours. The solvent was removed in vacuo. The residue was diluted in MeOH (1 mL), loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL), and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (24 mg, 0.052 mmol, 63% yield, 98% purity) as a brown glassy solid. LCMS (Method 2): m / z 449 (M+H)+, R T 1.67 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (dt, J = 6.8, 1.1 Hz, 1H), 7.74 (s, 1H), 7.66 (t, J = 6.2 Hz, 1H), 7.63 (s, 1H), 7.01 (dt, J = 6.8, 1.2 Hz, 1H), 6.75 (t, J = 6.8 Hz, 1H), 6.72 - 6.68 (m, 1H), 5.35 - 5.29 (m, 1H), 5.27 (s, 1H), 4.57 (d, J = 6.1 Hz, 2H), 3.59 - 3.46 (m, 1H), 3.24 - 3.14 (m, 1H), 3.08 - 2.99 (m, 1H), 2.96 (p, J = 6.8 Hz, 1H), 2.90 (dd, J = 11.9, 4.3 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.47 (s, 3H), 2.35 - 2.26 (m, 1H), 2.16 (dd, J = 11.6, 9.9 Hz, 1H), 1.59 - 1.51 (m, 1H), 1.39 - 1.28 (m, 1H), 1.23 (dd, J = 6.9, 4.8 Hz, 6H), 1.20 - 1.08 (m, 1H), 1H under water.

[0427] Synthesis 6 (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-001)

[0428] [ka]

[0429] Steps 4 and 5 : (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Step 4: tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (0.100 g, 0.221 mmol) and (8-methylimidazo[1,2-a]pyridin-2-yl)methanamine (0.107 g, 0.666 mmol) in dioxane (0.5 mL) were heated to 105 °C for 4 days. The reaction mixture was cooled to room temperature and concentrated. Purification by column chromatography (12 g cartridge, 0–10% MeOH (with 0.7 M NH) in DCM) afforded the corresponding Boc intermediate (40 mg).

[0430] Step 5: A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (40 mg, 0.073 mmol) and HCl (4 M in dioxane) (505 μL, 16.6 mmol) was stirred at room temperature for 16 h. The solvent was evaporated. Purification by column chromatography (12 g cartridge, 0–10% MeOH (with 0.7 M NH) in DCM) afforded the title compound (15 mg, 45% yield, 95% purity) as a brown solid. LCMS (Method 2): m / z 449 (M+H)+, R T 1.64 minutes. 1H NMR (500 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.58 (t, J = 5.3 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.13 (dd, J = 9.0, 6.8 Hz, 1H), 6.81 - 6.74 (m, 1H), 6.68 (d, J = 6.9 Hz, 1H), 5.42 (s, 1H), 5.31 (s, 1H), 4.96 (d, J = 5.0 Hz, 2H), 3.60 - 3.49 (m, 1H), 3.28 - 3.21 (m, 1H), 3.11 - 3.03 (m, 1H), 2.98 - 2.91 (m, 2H), 2.89 (s, 3H), 2.84 - 2.79 (m, 1H), 2.38 - 2.31 (m, 1H), 2.23 - 2.16 (m, 1H), 1.64 - 1.57 (m, 1H), 1.42 - 1.32 (m, 1H), 1.23 (dd, J = 6.9, 5.2 Hz, 6H), 1.20 - 1.13 (m, 1H), 1H under water.

[0431] Synthesis 7 (3R,4R)-4-[[[3-Isopropyl-7-[(3-methylimidazo[2,1-b]thiazol-6-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol (H-APPAMP-007)

[0432] [ka]

[0433] Step 4 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((3-methylimidazo[2,1-b]thiazol-6-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80.0 mg, 0.145 mmol), (3-methylimidazo[2,1-b]thiazol-6-yl)methanamine, diHCl, hydrate (74.9 mg, 0.290 mmol) and DIPEA (0.228 mL, 1.305 mmol) in ethanol (2 mL) were heated at 140° C. under microwave irradiation for 4 hours. The reaction mixture was cooled to room temperature and concentrated. Purification by column chromatography (4 g cartridge, 0–10% MeOH (containing 0.7 M NH3) / DCM) followed by reverse-phase C18 chromatography (4 g cartridge, 15–75% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (40 mg, 0.071 mmol, 49% yield, 97% purity) as a brown solid. UPLC / MS (Method 4): m / z 555 (M+H)+, R T 0.52 minutes.

[0434] Step 5 (3R,4R)-4-[[[3-Isopropyl-7-[(3-methylimidazo[2,1-b]thiazol-6-yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.169 mL, 0.676 mmol) was added to a solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((3-methylimidazo[2,1-b]thiazol-6-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (25 mg, 0.045 mmol) in dioxane (2 mL). The reaction mixture was stirred at 35° C. for 1 h. The solvent was evaporated. The residue was diluted in MeOH (1 mL), loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL), and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The ammoniacal methanolic solution was concentrated under reduced pressure to give the title compound (18 mg, 0.038 mmol, 84% yield, 96% purity) as a brown solid after trituration in Et2O and subsequent drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 455 (M+H)+, R T 1.03 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.59 (s, 1H), 7.49 (t, J = 6.1 Hz, 1H), 6.85 (q, J = 1.3 Hz, 1H), 6.79 - 6.73 (m, 1H), 5.38 - 5.35 (m, 1H), 5.35 (s, 1H), 4.47 - 4.43 (m, 2H), 3.25 - 3.19 (m, 1H), 3.10 - 3.02 (m, 1H), 2.98 - 2.90 (m, 2H), 2.85 - 2.79 (m, 2H), 2.36 (d, J = 1.3 Hz, 3H), 2.35 - 2.30 (m, 1H), 2.23 - 2.16 (m, 1H), 1.63 - 1.56 (m, 1H), 1.40 - 1.32 (m, 1H), 1.23 (dd, J = 6.9, 6.0 Hz, 6H), 1.21 - 1.13 (m, 1H), 1H under water.

[0435] Synthesis 8 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (H-APPAMP-008)

[0436] [ka]

[0437] Step 4 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate

[0438] tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (6-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.23 mL, 1.305 mmol RPl) in EtOH (2.0 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH 3 ) / DCM) afforded the title compound (67 mg, 0.112 mmol, 77% yield, 92% purity) as a yellow oil. UPLC / MS (Method 3): m / z 549 (M+H)+, R T 0.84 minutes.

[0439] Step 5tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (67 mg, 0.122 mmol) in 1,4-dioxane (2.0 mL) was treated with HCl (4 M in 1,4-dioxane) (458 μL, 1.832 mmol). The reaction mixture was stirred overnight at room temperature and concentrated to dryness. Purification by column chromatography (4 g cartridge, 0–15% MeOH (with 0.7 M NH) in DCM) afforded the title compound (32 mg, 0.068 mmol, 55% yield, 95% purity) as an off-white solid after drying under vacuum at 50° C. overnight. UPLC / MS (method 4): m / z 449 (M+H)+, R T 1.08 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.93 - 8.82 (m, 1H), 8.65 - 8.52 (m, 1H), 8.32 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.44 (d, J = 9.2 Hz, 1H), 7.13 (d, J = 9.3 Hz, 1H), 6.99 - 6.86 (m, 1H), 6.12 - 6.03 (m, 1H), 5.27 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.60 - 3.50 (m, 1H), 3.47 - 3.39 (m, 1H), 3.25 - 3.13 (m, 2H), 3.01 - 2.92 (m, 1H), 2.84 - 2.72 (m, 1H), 2.66 - 2.59 (m, 1H), 2.53 - 2.52 (m, 1H), 2.26 (s, 3H), 1.85 - 1.76 (m, 1H), 1.68 - 1.56 (m, 1H), 1.52 - 1.41 (m, 1H), 1.24 (t, J = 6.6 Hz, 6H).

[0440] Synthesis 9 (3R,4R)-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-009)

[0441] [ka]

[0442] Step 4 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (7-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.228 mL, 1.305 mmol) in EtOH (2.0 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 3.5 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (60 mg, 0.093 mmol, 64% yield, 85% purity) as a brown oil. UPLC / MS (Method 3): m / z 549 (M+H)+, R T 0.83 minutes.

[0443] Step 5 (3R,4R)-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((6-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (60 mg, 0.104 mmol) in 1,4-dioxane (2.0 mL) was treated with HCl (4 M in 1,4-dioxane) (0.390 mL, 1.558 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. Purification by column chromatography (4 g cartridge, 0–15% MeOH (with 0.7 M NH) in DCM) afforded the title compound (33 mg, 0.070 mmol, 67% yield, 95% purity) as an off-white solid after drying under vacuum at 50° C. overnight. UPLC / MS (method 4): m / z 449 (M+H)+, R T 1.07 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.36 (d, J = 6.9 Hz, 1H), 7.68 (s, 1H), 7.67 - 7.65 (m, 1H), 7.64 (s, 1H), 7.30 - 7.25 (m, 1H), 6.82 - 6.76 (m, 1H), 6.70 (dd, J = 7.0, 1.7 Hz, 1H), 5.61 - 5.55 (m, 1H), 5.27 (s, 1H), 4.53 (d, J = 5.9 Hz, 2H), 3.62 - 3.51 (m, 1H), 3.25 - 3.20 (m, 1H), 3.19 - 3.12 (m, 1H), 3.01 (dd, J = 11.6, 4.4 Hz, 1H), 2.99 - 2.93 (m, 1H), 2.92 - 2.87 (m, 1H), 2.47 - 2.42 (m, 1H), 2.33 (s, 3H), 2.32 - 2.26 (m, 1H), 1.67 - 1.61 (m, 1H), 1.46 - 1.38 (m, 1H), 1.30 - 1.26 (m, 1H), 1.24 (t, J = 6.6 Hz, 6H). 1H under water.

[0444] Synthesis 10 (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-010)

[0445] [ka]

[0446] Step 4tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (5-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.228 mL, 1.305 mmol) in EtOH (2.0 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) afforded the title compound (85 mg, 0.116 mmol, 80% yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 549 (M+H)+, R T 1.50 minutes.

[0447] Step 5 (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (85 mg, 0.116 mmol) in 1,4-dioxane (2.0 mL) was treated with HCl (4 M in 1,4-dioxane) (0.436 mL, 1.743 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. Purification by column chromatography on RP flash C18 (4 g cartridge, 15–50% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (12 mg, 0.025 mmol, 21% yield, 93% purity) as an off-white solid after drying under vacuum at 50° C. overnight. UPLC / MS (method 4): m / z 449 (M+H)+, R T 1.07 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.63 (s, 1H), 7.58 (t, J = 6.1 Hz, 1H), 7.43 (dd, J = 8.9, 1.2 Hz, 1H), 7.21 (dd, J = 9.0, 6.8 Hz, 1H), 6.79 - 6.75 (m, 2H), 5.44 - 5.37 (m, 1H), 5.33 (s, 1H), 4.59 (d, J = 5.9 Hz, 2H), 3.61- 3.49 (m, 1H), 3.25 - 3.19 (m, 1H), 3.11 - 3.05 (m, 1H), 2.99 - 2.92 (m, 2H), 2.87 - 2.81 (m, 1H), 2.56 (s, 3H), 2.40 - 2.33 (m, 1H), 2.26 - 2.20 (m, 1H), 1.64 - 1.57 (m, 1H), 1.42 - 1.34 (m, 1H), 1.24 (dd, J = 6.9, 6.0 Hz, 6H), 1.21 - 1.15 (m, 1H). 1H under water.

[0448] Synthesis 11 (3R,4R)-4-(((7-(((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-011)

[0449] [ka]

[0450] Step 4 (3R,4R)-4-(((7-(((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (60 mg, 0.109 mmol) was added to a solution of (6-fluoroimidazo[1,2-a]pyridin-2-yl)methanamine (53.9 mg, 0.326 mmol) and DIPEA (0.171 mL, 0.979 mmol) in EtOH (4.0 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 4 hours, concentrated to dryness, and redissolved in NMP (3.0 mL). The resulting mixture was heated at 160° C. under microwave irradiation for 4 hours. The crude oil was filtered through SCX (2 g - washed with 15 mL of MeOH and eluted with 15 mL of 0.7 M NH3 in MeOH) to give a brown oil. Purification by column (4 g cartridge (dry load), 0-10% MeOH (0.7 M NH3) in DCM, then 100% MeOH (0.7 M NH3)) followed by column chromatography on a RP flash C18 (4 g cartridge, 15-75% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (5 mg, 9.94 μmol, 9% yield, 90% purity) as a brown solid after precipitation from Et2O. UPLC / MS (Method 4): m / z 453 (M+H)+, R T 1.01 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.69 (dd, J = 4.7, 2.5 Hz, 1H), 7.79 (s, 1H), 7.68 (t, J = 6.2 Hz, 1H), 7.63 (s, 1H), 7.57 (dd, J = 10.0, 5.3 Hz, 1H), 7.30 (ddd, J = 10.2, 8.4, 2.5 Hz, 1H), 6.75 - 6.68 (m, 1H), 5.30 - 5.27 (m, 1H), 5.26 (s, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.60 - 3.47 (m, 1H), 3.23 - 3.15 (m, 1H), 3.07 - 2.99 (m, 1H), 2.98 - 2.92 (m, 1H), 2.89 (dd, J = 11.4, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.33 - 2.23 (m, 1H), 2.14 (dd, J = 11.7, 9.9 Hz, 1H), 1.58 - 1.51 (m, 1H), 1.37 - 1.27 (m, 1H), 1.23 (t, J = 6.5 Hz, 6H), 1.19 - 1.11 (m, 1H). 1H under water.

[0451] Synthesis 12 (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-012)

[0452] [ka]

[0453] Step 4tert-Butyl (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (60 mg, 0.109 mmol) was added to a solution of (6-chloroimidazo[1,2-a]pyridin-2-yl)methanamine (59.3 mg, 0.326 mmol) and DIPEA (0.171 mL, 0.979 mmol) in EtOH (4 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 4 hours, concentrated to dryness, and redissolved in NMP (3 mL). The resulting mixture was heated at 160° C. under microwave irradiation for 4 hours. The crude oil was filtered through SCX (2 g - washed with MeOH (15 mL) and eluted with 0.7 M NH in MeOH (15 mL)) to give a brown oil. Purification by column chromatography on a RP flash C18 (4 g cartridge, 35-100% MeCN / 10 mM ammonium bicarbonate) gave the title compound (32 mg, 42 μmol, 38% yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 569 (M+H)+, R T 1.55 minutes.

[0454] Step 5 (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (32 mg, 0.045 mmol) in 1,4-dioxane (2 mL) was treated with HCl (4 M in 1,4-dioxane) (0.169 mL, 0.675 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The crude oil was filtered through SCX (2 g - washed with MeOH (15 mL) and eluted with 0.7 M NH in MeOH (15 mL)) to give a brown oil. Purification by column (4 g cartridge (dry load), 0-20% MeOH (with 0.7 M NH) / DCM) followed by column chromatography on RP flash C18 (4 g cartridge, 35-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (10 mg, 0.020 mmol, 44% yield, 92% purity) as a brown solid after precipitation from Et2O and subsequent drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 469 (M+H)+, R T 1.08 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J = 2.1 Hz, 1H), 7.77 (s, 1H), 7.69 (t, J = 6.3 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J = 9.6 Hz, 1H), 7.26 (dd, J = 9.6, 2.1 Hz, 1H), 6.76 - 6.68 (m, 1H), 5.32 - 5.27 (m, 1H), 5.25 (s, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.60 - 3.47 (m, 1H), 3.24 - 3.16 (m, 1H), 3.05 - 2.98 (m, 1H), 2.98 - 2.91 (m, 1H), 2.91 - 2.87 (m, 1H), 2.80 - 2.73 (m, 1H), 2.33 - 2.24 (m, 1H), 2.18 - 2.11 (m, 1H), 1.58 - 1.50 (m, 1H), 1.39 - 1.27 (m, 1H), 1.26 - 1.21 (m, 6H), 1.18 - 1.09 (m, 1H). 1H under water.

[0455] Synthesis 13 (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-013)

[0456] [ka]

[0457] Step 4 tert-Butyl (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (120 mg, 99% wt, 0.22 mmol) was added to a solution of (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, acetic acid (0.11 g, 0.43 mmol), and DIPEA (0.19 mL, 1.1 mmol) in NMP (2 mL). The resulting mixture was heated at 140° C. for 4 h under microwave irradiation and then at 160° C. for 4 h. The crude oil was filtered through SCX (4 g - washed with MeOH (30 mL) and eluted with 0.7 M NH in MeOH (30 mL)) to give a brown oil. Purification by column (4 g cartridge (dry load), 0-15% MeOH (containing 0.7 M NH3) / DCM) gave the title compound (42 mg, 67 μmol, 31% yield, 92% purity) as a brown oil. UPLC / MS (Method 4): m / z 575 (M+H)+, R T 1.58 minutes.

[0458] Step 5 (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (23 mg, 37 μmol) in 1,4-dioxane (0.25 mL) was treated with HCl (4 M in 1,4-dioxane) (0.14 mL, 0.55 mmol). The reaction mixture was stirred at 35° C. for 1 h and concentrated to dryness. The crude oil was purified through SCX (4 g - washed with MeOH (30 mL) and eluted with 0.7 M NH in MeOH (30 mL)) to give the title compound (17 mg, 34 μmol, 92% yield, 95% purity) as a brown solid after precipitation from EtO and subsequent drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 475 (M+H)+, R T 1.14 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.30 - 8.23 ​​(m, 1H), 7.74 (s, 1H), 7.67 (t,J= 6.2 Hz, 1H), 7.64 (s, 1H), 6.74 - 6.69 (m, 3H), 5.36 - 5.30 (m, 1H), 5.28 (s, 1H), 4.58 (d,J = 5.9 Hz, 2H), 3.59 - 3.49 (m, 1H), 3.23 - 3.16 (m, 1H), 3.08 - 3.00 (m, 1H), 2.99 - 2.92 (m, 1H), 2.91 (dd,J = 11.8, 4.9 Hz, 1H), 2.81 - 2.75 (m, 1H), 2.48 - 2.43 (m, 1H), 2.35 - 2.26 (m, 1H), 2.16 (dd,J = 11.7, 9.9 Hz, 1H), 1.59 - 1.52 (m, 1H), 1.39 - 1.29 (m, 1H), 1.24 (dd,J = 6.9, 5.9 Hz, 6H), 1.20 - 1.11 (m, 1H), 1.04 - 0.98 (m, 2H), 0.98 - 0.92 (m, 2H). 1H under water.

[0459] Intermediate Synthesis A1 (8-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, AcOH

[0460] [ka]

[0461] Step A :8-Cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde A solution of potassium phosphate tribasic (755 mg, 3.55 mmol) in water (2.5 mL) was added to a solution of 8-bromoimidazo[1,2-a]pyridine-2-carbaldehyde (200 mg, 0.889 mmol) and cyclopropylboronic acid (229 mg, 2.67 mmol) in 1,4-dioxane (10 mL). N was bubbled through the reaction mixture for 10 min, and then PdCl(dppf) (65.0 mg, 0.089 mmol) was added. N was bubbled through the reaction mixture for an additional 5 min, then heated at 100 °C for 3 h. At room temperature, water (20 mL) and EtOAc (40 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were filtered through a phase separator and concentrated. Purification by column (12 g cartridge (dry load), 0-100% EtOAc / isohexane) gave the title compound (141 mg, 0.750 mmol, 71% yield, 99% purity) as a yellow solid.

[0462] Step B / C :8-Cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, AcOH A solution of 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (130 mg, 698 μmol), hydroxylamine hydrochloride (121 mg, 1.75 mmol), and pyridine (0.14 mL, 1.75 mmol) in EtOH (3.5 mL) was stirred at 80°C for 2 h. At room temperature, the precipitate was collected by filtration and rinsed with EtOH (2 × 2 mL). The solid was further dried under vacuum to give 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde oxime (135 mg) as a brown solid, which was dissolved in AcOH (3 mL). The solution was cooled to 0°C, and then sodium acetate (11.0 mg, 134 μmol) and zinc powder (658 mg, 10.1 mmol) were added. The reaction mixture was stirred at room temperature overnight, then filtered through Celite and rinsed with DCM (20 mL) and MeOH (20 mL). The filtrate was concentrated to dryness to give an oil. Filtration through SCX (10 g - washed with MeOH (50 mL) and eluted with 0.7 M NH in MeOH (50 mL)) gave the title compound (164 mg, 663 μmol, 99% yield, 95% purity) as a slightly yellow oil. 1 H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[0463] Synthesis 14 (3R,4R)-4-(((3-isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-014)

[0464] [ka]

[0465] Step 1 :5-chloro-3-isopropyl-N-(quinolin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine Quinolin-2-ylmethanamine (165 mg, 1.04 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (200 mg, 0.869 mmol) and DIPEA (908 μL, 5.21 mmol) in EtOH (3.3 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo to give an orange solid. Purification by column chromatography (12 g cartridge, DCM) afforded the title compound (240 mg, 0.67 mmol, 78% yield, 99% purity) as an orange solid. 1 H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[0466] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2-ylmethyl)carbamate BOC anhydride (193 mg, 886.1 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(quinolin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (240 mg, 681.6 μmol) and DMAP (17 mg, 136.3 μmol) in THF (13.6 mL). The reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure, then diluted in DCM (15 mL) and washed with brine (3 × 10 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–2.5% MeOH / DCM) afforded the title compound (317 mg, 0.67 mmol, 98% yield, 95% purity) as an orange oil. UPLC / MS (Method 6): m / z 453 (M+H)+, R T 0.92 minutes.

[0467] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2-ylmethyl)carbamate (115 mg, 0.25 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (63 mg, 0.27 mmol) and THF (2.1 mL) t A solution of BuBrettPhos Pd G3 (21 mg, 25 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.37 mL, 0.37 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1 hour. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (130 mg, 0.19 mmol, 77% yield, 95% purity) as a yellow oil. UPLC / MS (Method 4): m / z 646 (M+H)+, R T 1.85 minutes.

[0468] Step 4 (3R,4R)-4-(((3-isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.5 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (120 mg, 0.18 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at 35° C. for 1 h and 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 methanolic solution was concentrated in vacuo and the title compound (66 mg, 0.14 mmol, 81% yield, 97% purity) was obtained as an off-white solid after precipitation from Et2O and drying overnight under vacuum at 40 °C. UPLC / MS (Method 4): m / z 446 (M+H)+, R T 1.18 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.35 (d,J = 8.5 Hz, 1H), 8.04 - 7.99 (m, 2H), 7.97 (dd,J = 8.2, 1.4 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.68 (s, 1H), 7.62 - 7.57 (m, 1H), 7.53 (d,J= 8.5 Hz, 1H), 6.75 - 6.68 (m, 1H), 5.29 - 5.23 (m, 1H), 5.19 (s, 1H), 4.73 (d,J = 6.0 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.21 - 3.14 (m, 1H), 3.05 - 2.98 (m, 1H), 2.99 - 2.92 (m, 1H), 2.88 (dd,J = 11.5, 4.5 Hz, 1H), 2.78 - 2.72 (m, 1H), 2.31 - 2.23 (m, 1H), 2.17 - 2.11 (m, 1H), 1.55 - 1.49 (m, 1H), 1.36 - 1.27 (m, 1H), 1.27 - 1.22 (m, 6H), 1.16 - 1.11 (m, 1H). 1H under water.

[0469] Synthesis 15 (3R,4R)-4-(((7-(((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-015)

[0470] [ka]

[0471] Step 1 :5-chloro-N-((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)methanamine (171 mg, 0.976 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (187 mg, 0.813 mmol) and DIPEA (0.85 mL, 4.874 mmol) in EtOH (3.2 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc in isohexane) afforded the title compound (233 mg, 0.57 mmol, 70% yield, 90% purity) as an off-white solid. UPLC / MS (Method 6): m / z 369 (M+H)+, R T 0.73 minutes.

[0472] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)carbamate BOC anhydride (179 mg, 819 μmol) was added to a solution of 5-chloro-N-((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (233 mg, 0.63 mmol) and DMAP (15.4 mg, 126 μmol) in THF (12.6 mL). The reaction mixture was stirred at 60 °C for 16 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (15 mL) and water (10 mL). The organic layer was washed with brine (2 × 10 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–4% MeOH / DCM) afforded the title compound (249 mg, 0.50 mmol, 79% yield, 94% purity) as a pale yellow solid. UPLC / MS (Method 6): m / z 469 (M+H)+, R T 0.84 minutes.

[0473] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)carbamate (120 mg, 0.256 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (64.9 mg, 0.282 mmol) in THF (2.5 mL). t A solution of BuBrettPhos Pd G3 (21.9 mg, 0.0256 mmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.33 mL, 333 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 4.5 h. At room temperature, the reaction mixture was filtered through Celite and rinsed with EtOAc (15 mL). The filtrate was diluted with water, and the aqueous was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–80% (1:3 EtOH / EtOAc) / isohexane) afforded the title compound (89 mg, 0.10 mmol, 39% yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 663 (M+H)+, R T 1.75 minutes.

[0474] Step 4 (3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.66 mL, 2.62 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (87 mg, 0.131 mmol) in 1,4-dioxane (10 mL). The reaction mixture was stirred at 35° C. for 2.5 hours and 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 (60 mL). The ammoniacal methanolic solution was concentrated in vacuo and the title compound (40 mg, 83 mmol, 63% yield, 95% purity) was obtained as a pale yellow solid after precipitation from Et2O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 463 (M+H)+, R T 1.05 minutes. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 7.0 Hz, 1H), 7.80 (t, J = 5.4 Hz, 1H), 7.59 (s, 1H), 7.21 (s, 1H), 6.85 - 6.79 (m, 1H), 6.75 (dd, J = 7.0, 1.7 Hz, 1H), 5.33 - 5.28 (m, 1H), 5.17 (s, 1H), 4.73 (d, J = 5.1 Hz, 2H), 3.61 - 3.48 (m, 1H), 3.23 - 3.16 (m, 1H), 3.06 - 2.98 (m, 1H), 2.95 - 2.86 (m, 2H), 2.84 - 2.76 (m, 1H), 2.48 (s, 3H), 2.33 - 2.30 (m, 4H), 2.19 - 2.12 (m, 1H), 1.61 - 1.53 (m, 1H), 1.39 - 1.32 (m, 1H), 1.22 - 1.18 (m, 6H), 1.19 - 1.12 (m, 1H). 1H under water.

[0475] Intermediate synthesis A2 (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methanamine

[0476] [ka]

[0477] Step A / B :2,7-Dimethylimidazo[1,2-a]pyridine-3-carbaldehyde oxime / (2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)methanamine A solution of 2,7-dimethylimidazo[1,2-a]pyridine-3-carbaldehyde (0.525 g, 3.01 mmol), hydroxylamine hydrochloride (0.524 g, 7.54 mmol), and pyridine (0.61 mL, 7.54 mmol) in EtOH (14.8 mL) was stirred at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and then redissolved in AcOH (10.5 mL). The solution was cooled to 0° C., and then sodium acetate (50 mg, 604 μmol) and zinc powder (2.96 g, 45.3 mmol) were added. The reaction mixture was stirred overnight at room temperature, then filtered through Celite and rinsed with DCM (100 mL). The filtrate was concentrated to dryness to give an oil. Filtration through SCX (14 g - washed with MeOH (100 mL) and eluted with 0.7 M NH3 in MeOH (100 mL)) gave the title compound (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methanamine (0.259 g, 1.33 mmol, 44% yield, 90% purity) as a white solid. UPLC / MS (Method 6): m / z 176 (M+H)+, R T 0.42 minutes.

[0478] Synthesis 16 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-016)

[0479] [ka]

[0480] Step 1 :5-chloro-N-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Imidazo[1,2-a]pyridin-3-ylmethanamine, 2HCl (115 mg, 522 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 435 μmol) and DIPEA (0.38 mL, 2.17 mmol) in EtOH (1.5 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo.

[0481] Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound 5-chloro-N-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (137 mg, 0.38 mmol, 88% yield, 95% purity) as a white solid. 1 H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[0482] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-3-ylmethyl)carbamate BOC anhydride (97 mg, 442 μmol) was added to a solution of 5-chloro-N-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (137 mg, 402 μmol) and DMAP (5 mg, 40.2 μmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure.

[0483] Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-3-ylmethyl)carbamate (169 mg, 0.36 mmol, 91% yield, 95% purity) as a white solid. UPLC / MS (method 4): m / z 441 (M+H)+, R T 1.71 minutes.

[0484] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-3-ylmethyl)carbamate (167 mg, 379 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (96.0 mg, 417 μmol) in THF (3.3 mL). t A solution of BuBrettPhos Pd G3 (32.4 mg, 37.9 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (492 μL, 492 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure.

[0485] Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane, then 0-5% (0.7 M NH in MeOH) / DCM) gave an oil. Further purification by column chromatography (12 g cartridge, 0-10% (0.7 M NH in MeOH) / DCM) gave the title compound (112 mg, 0.17 mmol, 46% yield, 98% purity) as a yellow oil. UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.64 minutes.

[0486] Step 4 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.53 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (112 mg, 176 μmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 35°C for 1 hour and 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 (40 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (57 mg, 0.13 mmol, 73% yield, 98% purity) as a white solid after precipitation from Et2O. UPLC / MS (Method 4): m / z 435 (M+H)+, R T 0.97 minutes. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (dd,J = 6.8, 1.2 Hz, 1H), 7.78 (s, 1H), 7.65 (t,J = 6.1 Hz, 1H), 7.63 (s, 1H), 7.50 (d,J = 9.1 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.85 (td,J = 6.7, 1.2 Hz, 1H), 6.75 - 6.69 (m, 1H), 5.33 - 5.29 (m, 1H), 5.28 (s, 1H), 4.56 (d,J = 6.0 Hz, 2H), 3.60 - 3.47 (m, 1H), 3.22 - 3.15 (m, 1H), 3.06 - 2.99 (m, 1H), 2.99 - 2.92 (m, 1H), 2.90 (dd,J = 11.6, 4.5 Hz, 1H), 2.81 - 2.74 (m, 1H), 2.33 - 2.25 (m, 1H), 2.15 (dd,J = 11.6, 9.9 Hz, 1H), 1.57 - 1.51 (m, 1H), 1.38 - 1.28 (m, 1H), 1.23 (t,J = 6.5 Hz, 6H), 1.19 - 1.10 (m, 1H).1H under water.

[0487] Synthesis 17 (3R,4R)-4-(((3-isopropyl-7-(((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-017)

[0488] [ka]

[0489] Step 1 :5-chloro-3-isopropyl-N-((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3-Methylimidazo[1,2-a]pyridin-2-yl)methanamine (105 mg, 652 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (150 mg, 652 μmol) and DIPEA (0.85 mL, 4.89 mL) in EtOH (3.2 mL). The reaction mixture was heated at 80° C. overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (130 mg, 0.31 mmol, 48% yield, 85% purity) as a yellow solid. UPLC / MS (Method 4): m / z 355 (M+H)+, R T 1.48 minutes.

[0490] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (32 mg, 0.15 mmol) was added to a solution of 5-chloro-3-isopropyl-N-((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (44 mg, 0.12 mmol) and DMAP (3 mg, 25 μmol) in THF (1.2 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0–100% EtOAc / isohexane) on N2 afforded the title compound (51 mg, 0.11 mmol, 89% yield, 99% purity) as a white solid. UPLC / MS (Method 4): m / z 455 (M+H)+, R T 1.80 minutes.

[0491] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (88 mg, 0.19 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (49 mg, 0.21 mmol) and t A solution of BuBrettPhos Pd G3 (17 mg, 19 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.25 mL, 0.25 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane, then 0-100% (1:3 EtOH / EtOAc) / isohexane) afforded the title compound (140 mg, 0.18 mmol, 95% yield, 85% purity) as a brown oil. UPLC / MS (Method 4): m / z 649 (M+H)+, R T 1.69 minutes.

[0492] Step 4 ((3R,4R)-4-(((3-isopropyl-7-(((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.02 mL, 4.10 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (140 mg, 205 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35° C. for 1.5 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanolic solution was concentrated in vacuo and the title compound (30 mg, 60 μmol, 32%, 95% pure) was obtained as a cream solid after precipitation from Et 2 O and drying overnight at 40° C. under vacuum. UPLC / MS (method 4): m / z 449 (M+H)+, R T 1.02 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(d,J = 6.9 Hz, 1H), 7.61 (s, 1H), 7.53 - 7.49 (m, 1H), 7.44 (t,J = 5.8 Hz, 1H), 7.26 - 7.17 (m, 1H), 6.93 (td,J = 6.8, 1.2 Hz, 1H), 6.80 - 6.74 (m, 1H), 5.39 (s, 1H), 5.35 - 5.31 (m, 1H), 4.55 (d,J = 5.7 Hz, 2H), 3.61 - 3.47 (m, 1H), 3.24 - 3.15 (m, 1H), 3.08 - 2.99 (m, 1H), 2.99 - 2.86 (m, 2H), 2.82 - 2.74 (m, 1H), 2.35 - 2.24 (m, 1H), 2.16 (dd,J = 11.6, 9.9 Hz, 1H), 1.61 - 1.52 (m, 1H), 1.40 - 1.29 (m, 1H), 1.22 (dd,J = 6.9, 5.0 Hz, 6H), 1.19 - 1.13 (m, 1H). 4H is not visible.

[0493] Intermediate Synthesis A3 3-Methylimidazo[1,2-a]pyridin-2-yl)methanamine

[0494] [ka]

[0495] Step A / B :3-Methylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (3-Methylimidazo[1,2-a]pyridin-2-yl)methanamine A suspension of 3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (500 mg, 3.12 mmol), hydroxylamine hydrochloride (542 mg, 7.80 mmol), and pyridine (0.63 mL, 7.80 mmol) in EtOH (5.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure and then redissolved in AcOH (5.0 mL). The solution was cooled to 0 °C, and then sodium acetate (51 mg, 616 μmol) and zinc powder (2.02 g, 30.8 mmol) were added. The reaction mixture was stirred overnight at room temperature, then filtered through Celite and rinsed with DCM (50 mL) and MeOH (50 mL). The filtrate was concentrated to dryness to give an oil. Filtration through SCX (14 g - washed with MeOH (50 mL) and eluted with 0.7 M NH3 in MeOH (50 mL)) afforded the title compound (371 mg, 2.2 mmol, 71% yield, 95% purity) as a white solid. in DMSO-d6 1 1 H NMR was consistent with the product structure.

[0496] Synthesis 18 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-018)

[0497] [ka]

[0498] Step 1 :5-chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl-d2)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Imidazo[1,2-a]pyridin-2-ylmethan-d2-amine (102 mg, 684 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (157 mg, 684 μmol) and DIPEA (0.89 mL, 893 μmol) in EtOH (7.0 mL). The reaction mixture was heated at 80 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (180 mg, 0.50 mmol, 73% yield, 95% purity) as a white solid. UPLC / MS (Method 4): m / z 345 (M+H)+, R T 1.36 minutes.

[0499] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl-d2)carbamate BOC anhydride (131 mg, 599 μmol) was added to a solution of 5-chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl-d2)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (180 mg, 499 μmol) and DMAP (12 mg, 99.8 μmol) in THF (5.0 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (184 mg, 0.36 mmol, 72% yield, 87% purity) as a white solid. UPLC / MS (Method 4): m / z 445 (M+H)+, R T 1.72 minutes.

[0500] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl-d2)carbamate (184 mg, 415 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (105 mg, 457 μmol) in THF (1.9 mL). t A solution of BuBrettPhos Pd G3 (35.5 mg, 41.5 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (540 μL, 540 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1.5 h. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (236 mg, 0.33 mmol, 80% yield, 90% purity) as a white solid. UPLC / MS (Method 4): m / z 637 (M+H)+, R T 1.64 minutes.

[0501] Step 4 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.79 mL, 3.14 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 157 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35° C. for 4 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanolic solution was concentrated in vacuo and the title compound (61 mg, 0.13 mmol, 85% yield, 95% purity) was obtained as a white solid after precipitation from Et2O and drying overnight under vacuum at 40°C. UPLC / MS (Method 4): m / z 437 (M+H)+, R T 1.03 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.48 (dt,J = 6.8, 1.3 Hz, 1H), 7.78 (s, 1H), 7.63 (s, 2H), 7.50 (d,J = 9.1 Hz, 1H), 7.20 (m, 1H), 6.85 (td,J = 6.8, 1.2 Hz, 1H), 6.76 - 6.68 (m, 1H), 5.29 (m, 2H), 3.60 - 3.48 (m, 1H), 3.23 - 3.13 (m, 1H), 3.07 - 2.85 (m, 3H), 2.80 - 2.72 (m, 1H), 2.34 - 2.23 (m, 1H), 2.14 (dd,J = 11.5, 10.0 Hz, 1H), 1.58 - 1.49 (m, 1H), 1.37 - 1.27 (m, 1H), 1.23 (dd,J = 6.9, 4.9 Hz, 6H), 1.19 - 1.11 (m, 1H). 1H under water.

[0502] Intermediate Synthesis A4 Imidazo[1,2-a]pyridin-2-ylmethane-d2-amine

[0503] [ka]

[0504] Step A : Imidazo[1,2-a]pyridin-2-ylmethane-d2-ol Lithium aluminum deuteride (88 mg, 2.10 mmol) was added to a solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (400 mg, 2.10 mmol) in THF (21 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes, then water (0.1 mL) was added, followed by 2 M aqueous NaOH (0.1 mL), then water (0.3 mL). The solution was warmed to room temperature and stirred for 15 minutes, then anhydrous MgSO4 was added, and the mixture was stirred for an additional 15 minutes. The mixture was concentrated under reduced pressure.

[0505] Purification by chromatography (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (211 mg, 1.4 mmol, 65% yield, 98% purity) as a white solid. UPLC / MS (Method 4): m / z 151 (M+H)+, R T 0.47 minutes.

[0506] Step B : 2-(chloromethyl-d2)imidazo[1,2-a]pyridine, HCl Thionyl chloride (205 μL, 2.81 mmol) was added dropwise to a solution of imidazo[1,2-a]pyridin-2-ylmethan-d2-ol (211 mg, 1.40 mmol) in DCM (14 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and then concentrated to dryness under reduced pressure to give the title compound (278 mg, 1.3 mmol, 92% yield, 95% purity) as a cream-colored solid. UPLC / MS (Method 3): m / z 169 (M+H)+, R T 0.16 minutes.

[0507] Step C :2-(azidomethyl-d2)imidazo[1,2-a]pyridine A solution of 2-(chloromethyl-d2)imidazo[1,2-a]pyridine, HCl (278 mg, 1.36 mmol), and DIPEA (708 μL, 4.07 mmol) in DMF (14 mL) was treated with sodium azide (132 mg, 2.03 mmol). The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to room temperature and diluted with water (100 mL). Extraction was performed with TBME (3 × 25 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by chromatography (12 g cartridge, 0–100% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (150 mg, 0.66 mmol, 49% yield, 77% purity) as a yellow oil. UPLC / MS (Method 4): m / z 176 (M+H)+, R T 0.77 minutes.

[0508] Step D :Imidazo[1,2-a]pyridin-2-ylmethane-d2-amine 2-(Azidomethyl-d2)imidazo[1,2-a]pyridine (150 mg, 659 μmol) and triphenylphosphine (208 mg, 791 μmol) were dissolved in THF (8.0 mL) and water (0.8 mL). The mixture was heated to 50 °C and stirred for 1 h, after which the solvent was removed 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 (102 mg, 0.65 mmol, 99% yield, 95% purity) as a white solid. in DMSO-d6 1 1 H NMR was consistent with the product structure.

[0509] Synthesis 19 (3R,4R)-4-(((7-((1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-019)

[0510] [ka]

[0511] Step 1 :5-chloro-N-(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine 1-(Imidazo[1,2-a]pyridin-2-yl)ethan-1-amine (133 mg, 782 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 435 μmol) and DIPEA (0.38 mL, 2.17 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was concentrated in vacuo.

[0512] Purification by chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (158 mg, 0.42 mmol, 97% yield, 95% purity) as a white solid. UPLC / MS (Method 4): m / z 355 (M+H)+, R T 1.47 minutes.

[0513] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)carbamate BOC anhydride (136 mg, 623 μmol) was added to a solution of 5-chloro-N-(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (158 mg, 445 μmol) and DMAP (5.4 mg, 44.5 μmol) in THF (2.5 mL). The reaction mixture was stirred at 50° C. overnight. Additional BOC anhydride (136 mg, 623 μmol) was added and the reaction mixture was stirred 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 (171 mg, 0.36 mmol, 80% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 455 (M+H)+, R T 1.79 minutes.

[0514] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)carbamate (171 mg, 376 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (95 mg, 413 μmol) and tA solution of BuBrettPhos Pd G3 (32 mg, 37.6 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.49 mL, 489 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 hours. At room temperature, water (15 mL) and EtOAc (25 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (2 × 15 mL). The combined organic layers were filtered through a phase separator and concentrated. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (168 mg, 0.24 mmol, 64% yield, 93% purity) as a yellow oil. UPLC / MS (Method 4): m / z 649 (M+H)+, R T 1.68 minutes.

[0515] Step 4 (3R,4R)-4-(((7-((1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.17 mL, 4.69 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (160 mg, 234 μmol) in dioxane (1.2 mL). The reaction mixture was stirred at 35° C. for 1 h and 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 (40 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (70 mg, 0.15 mmol, 63% yield, 95% purity) as an off-white solid after trituration from Et2O and drying overnight at 40 °C under vacuum. UPLC / MS (method 4): m / z 449 (M+H)+, R T 1.02 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (d,J = 6.8 Hz, 1H), 7.80 (d,J = 4.9 Hz, 1H), 7.62 (s, 1H), 7.52 (d,J = 9.1 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.13 (d,J = 7.8 Hz, 1H), 6.85 (t,J = 6.7 Hz, 1H), 6.76 - 6.68 (m, 1H), 5.32 (d,J = 2.0 Hz, 1H), 5.31 - 5.23 (m, 1H), 4.87 - 4.81 (m, 1H), 3.60 - 3.43 (m, 1H), 3.27 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.99 - 2.86 (m, 2H), 2.82 - 2.73 (m, 1H), 2.35 - 2.25 (m, 1H), 2.16 (td,J = 10.8, 1H under water. 1H under water.

[0516] Intermediate synthesis A5 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-amine

[0517] [ka]

[0518] Step A : 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-ol Methylmagnesium bromide (3 M in EtO) (1.71 mL, 5.13 mmol) was added to a solution of imidazo[1,2-a]pyridine-2-carbaldehyde (0.500 g, 3.42 mmol) in THF (10 mL) at −10° C. The mixture was slowly warmed to room temperature and stirred overnight. Water (50 mL) was added, and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were collected, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (350 mg, 2.1 mmol, 61% yield, 96% purity) as a white solid. UPLC / MS (method 3): m / z 163 (M+H)+, R T 0.15 minutes.

[0519] Step B : 2-(1-chloroethyl)imidazo[1,2-a]pyridine, HCl Thionyl chloride (675 μL, 9.25 mmol) was added dropwise to a solution of 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-ol (300 mg, 1.85 mmol) in DCE (5.0 mL) at room temperature. The mixture was stirred at 45° C. for 3 hours and then concentrated to dryness under reduced pressure to give the title compound (300 mg, 1.4 mmol, 74% yield, 82% purity) as a colorless oil. UPLC / MS (Method 3): m / z 181 (M+H)+, R T 0.15 minutes.

[0520] Step C :2-(1-azidoethyl)imidazo[1,2-a]pyridine A solution of 2-(1-chloroethyl)imidazo[1,2-a]pyridine, HCl (200 mg, 921 μmol), and DIPEA (390 μL, 2.76 mmol) in DMF (14 mL) was treated with sodium azide (90 mg, 1.38 mmol). The mixture was heated to 60 °C and stirred for 6 h. The mixture was cooled to room temperature and diluted with water (40 mL) and brine (60 mL). Extraction was performed with TBME (3 × 50 mL) and EtOAc (50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. Purification by chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (190 mg, 0.81 mmol, 88% yield, 80% purity) as a brown oil. UPLC / MS (Method 4): m / z 188 (M+H)+, R T 0.90 minutes.

[0521] Step D :1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-amine 2-(1-Azidoethyl)imidazo[1,2-a]pyridine (190 mg, 913 μmol) and triphenylphosphine (287 mg, 1.10 mmol) were dissolved in THF (4.5 mL) and water (0.5 mL). The mixture was stirred at room temperature for 1 hour, then at 50°C for 1 hour, after which the solvent was removed 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 (144 mg, 0.85 mmol, 93% yield, 95% purity) as a yellow oil. UPLC / MS (Method 4): m / z 162 (M+H)+, R T 0.48 minutes.

[0522] Synthesis 20 (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-020)

[0523] [ka]

[0524] Step 1 N-(benzofuran-2-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Benzofuran-2-ylmethanamine hydrochloride (100 mg, 0.547 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (105 mg, 0.456 mmol) and DIPEA (0.48 mL, 2.74 mmol) in EtOH (1.9 mL). The reaction mixture was heated at 90 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-30% EtOAc / heptane) afforded the title compound (157 mg, 0.42 mmol, 91% yield, 90% purity) as a yellow oil. UPLC / MS (Method 4): m / z 341 (M+H)+, R T 1.82 minutes.

[0525] Step 2 tert-Butyl (benzofuran-2-ylmethyl) (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate BOC anhydride (109 mg, 0.498 mmol) was added to a solution of N-(benzofuran-2-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (157 g, 0.415 mmol) and DMAP (10 mg, 83 μmol) in THF (8.0 mL). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (15 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 × 30 mL), and the combined organic layers were washed with brine (30 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–20% EtOAc / isohexane) afforded the title compound (164 mg, 0.37 mmol, 89% yield, 99% purity) as a cream-colored solid. UPLC / MS (method 4): m / z 385 (M+H-tBu)+, R T 2.10 minutes.

[0526] Step 3 tert-Butyl (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (benzofuran-2-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (164 mg, 0.372 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (94 mg, 0.409 mmol) in THF (3.6 mL). tA solution of BuBrettPhos Pd G3 (31.8 mg, 37.2 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.48 mL, 0.48 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 h. At room temperature, the mixture was filtered through Celite and rinsed with EtOAc (15 mL). The filtrate was washed with water (15 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (235 mg, 0.33 mmol, 89% yield, 90% purity) as an orange solid. UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.96 minutes.

[0527] Step 4 (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (2.0 mL, 8.0 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (233 mg, 0.367 mmol) in dioxane (2.5 mL). The reaction mixture was stirred at 35° C. for 2 hours, then additional hydrogen chloride (4 M in dioxane) (0.92 mL, 3.67 mmol) was added. The reaction mixture was stirred at 35° C. for 2.5 hours and then concentrated in vacuo.

[0528] 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, and the title compound (88 mg, 0.20 mmol, 54% yield, 97% purity) was obtained as a beige solid after trituration from EtO and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 435 (M+H)+, R T 1.37 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (t, J = 6.3 Hz, 1H), 7.63 (s, 1H), 7.58 (dd, J = 7.5, 1.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.30 - 7.17 (m, 2H), 6.78 (s, 1H), 6.74 (t, J = 6.1 Hz, 1H), 5.37 (s, 1H), 5.28 - 5.20 (m, 1H), 4.62 (d, J = 6.1 Hz, 2H), 3.56 - 3.45 (m, 1H), 3.27 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.98 - 2.87 (m, 2H), 2.82 - 2.72 (m, 1H), 2.36 - 2.23 (m, 1H), 2.15 (dd, J = 11.5, 10.0 Hz, 1H), 1.62 - 1.52 (m, 1H), 1.39 - 1.29 (m, 1H), 1.23 (dd, J = 6.9, 4.7 Hz, 6H), 1.18 - 1.09 (m, 1H). 1H under water.

[0529] Synthesis 21 (3R,4R)-4-(((3-Isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-021)

[0530] [ka]

[0531] Step 1 :5-chloro-3-isopropyl-N-(quinolin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine Quinolin-3-ylmethanamine dihydrochloride (121 mg, 0.522 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 0.435 mmol) and DIPEA (0.68 mL, 3.92 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 90 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was partitioned between DCM (20 mL) and saturated aqueous NaHCO (10 mL). The organic layer was washed with saturated aqueous NaHCO (3 × 10 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0–30% EtOAc / isohexane) afforded the title compound (109 mg, 0.29 mmol, 66% yield, 93% purity) as a yellow solid. UPLC / MS (method 3): m / z 352 (M+H)+, R T 1.56 minutes.

[0532] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3-ylmethyl)carbamate BOC anhydride (80 mg, 0.368 mmol) was added to a solution of 5-chloro-3-isopropyl-N-(quinolin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (108 mg, 0.307 mmol) and DMAP (7.5 mg, 61.4 μmol) in THF (6.0 mL). The reaction mixture was stirred at 65° C. for 2.5 h. Additional BOC anhydride (34 mg, 0.154 mmol) was added, and the reaction mixture was stirred at 65° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (15 mL) and water (30 mL). The aqueous layer was extracted with DCM (2×30 mL), and the combined organic layers were washed with brine (30 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (143 mg, 0.29 mmol, 94% yield, 91% purity) as a yellow oil. UPLC / MS (Method 4): m / z 452 (M+H)+, R T 1.91 minutes.

[0533] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3-ylmethyl)carbamate (139 mg, 0.308 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (78 mg, 0.339 mmol) in THF (3.0 mL) t A solution of BuBrettPhos Pd G3 (26.3 mg, 30.8 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (399 μL, 0.399 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1.5 h.

[0534] At room temperature, the mixture was filtered through Celite and rinsed with EtOAc (15 mL). The filtrate was washed with water (15 mL), and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) afforded the title compound (146 mg, 0.18 mmol, 67% yield, 80% purity) as a brown oil. UPLC / MS (Method 4): m / z 646 (M+H)+, R T 1.80 minutes.

[0535] Step 4 (3R,4R)-4-(((3-isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.90 mL, 3.60 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (116 mg, 0.18 mmol) in dioxane (2.6 mL). The reaction mixture was stirred at 35° C. for 3 hours. Further hydrogen chloride (4 M in dioxane) (0.23 mL, 0.90 mmol) was added and the reaction mixture was stirred at 35° C. for 1 hour, then 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 (60 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (51 mg, 0.11 mmol, 71% yield, 99% purity) as an off-white solid after trituration from Et2O and drying overnight under vacuum at 40 °C. UPLC / MS (Method 3): m / z 446 (M+H)+, R T 0.67 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (d,J = 2.2 Hz, 1H), 8.24 (s, 1H), 8.07 - 7.99 (m, 2H), 7.99 - 7.95 (m, 1H), 7.80 - 7.71 (m, 1H), 7.66 (s, 1H), 7.60 (ddd,J = 1.2, 6.8, 8.1 Hz, 1H), 6.66 (t,J = 6.1 Hz, 1H), 5.23 (s, 2H), 4.68 (d,J = 6.2 Hz, 2H), 3.59 - 3.41 (m, 1H), 3.22 - 3.13 (m, 1H), 3.05 - 2.84 (m, 3H), 2.79 - 2.70 (m, 1H), 2.30 - 2.21 (m, 1H), 2.18 - 2.05 (m, 1H), 1.59 - 1.46 (m, 1H), 1.37 - 1.26 (m, 1H), 1.23 (dd,J = 5.3, 6.9 Hz, 6H), 1.17 - 1.04 (m, 1H). 1H under water.

[0536] Synthesis 22 (3R,4R)-4-(((3-cyclopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-022)

[0537] [ka]

[0538] Step 1 :5-chloro-3-cyclopropyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (8-Methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (101 mg, 0.432 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (83.0 mg, 0.364 mmol) and DIPEA (0.57 mL, 3.28 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 65 °C for 1 h. The reaction mixture was concentrated in vacuo, the residue was diluted with DCM (20 mL), and the solution was washed with saturated aqueous NaHCO (20 mL) followed by brine (20 mL). The organic layer was filtered through a phase separator and concentrated under reduced pressure to give the title compound (129 mg, 0.36 mmol, 99% yield, 99% purity) as an off-white solid. UPLC / MS (Method 5): m / z 353 (M+H)+, R T 1.37 minutes.

[0539] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (94.50 mg, 0.433 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (128.6 mg, 0.361 mmol) and DMAP (8.8 mg, 0.072 mmol) in THF (10 mL). The reaction mixture was stirred at 65° C. for 3 hours, followed by the addition of additional BOC anhydride (94.50 mg, 0.433 mmol). The reaction mixture was stirred at 65° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (20 mL). The solution was washed with water (15 mL) and then with brine (15 mL). The organic layer was filtered through a phase separator and then concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / heptane) afforded the title compound (150 mg, 0.33 mmol, 91% yield, 99% purity) as a yellow solid. UPLC / MS (Method 5): m / z 452 (M+H)+, RT 1.73 minutes.

[0540] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-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)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (150.2 mg, 0.332 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (84.02 mg, 0.3645 mmol) in THF (3.2 mL). t A solution of BuBrettPhos Pd G3 (28.33 mg, 0.033 mmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.37 g, 0.431 mL, 431.1 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 1.5 h. At room temperature, the reaction mixture was filtered through Celite and washed with EtOAc (15 mL). The filtrate was diluted with water, and the aqueous layer was extracted with EtOAc (3 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (221 mg, 0.30 mmol, 92% yield, 89% purity) as a beige solid. UPLC / MS (Method 5): m / z 647 (M+H)+, R T 1.62 minutes.

[0541] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.6 mL) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (77 mg, 0.115 mmol) in DCM (2.4 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (42 mg, 90 μmol, 78% yield, 95% purity) as a white solid after trituration from Et 2 O and drying overnight at 40° C. under vacuum. UPLC / MS (Method 5): m / z 447 (M+H)+, R T 1.09 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d,J = 6.7 Hz, 1H), 7.73 (s, 1H), 7.64 (t,J = 6.1 Hz, 1H), 7.52 (s, 1H), 7.01 (dt,J = 6.9, 1.3 Hz, 1H), 6.78 - 6.69 (m, 2H), 5.36 - 5.30 (m, 1H), 5.27 (s, 1H), 4.56 (d,J = 5.8 Hz, 2H), 3.57 - 3.46 (m, 1H), 3.25 - 3.15 (m, 1H), 3.10 - 2.97 (m, 1H), 2.91 (dd,J = 11.6, 4.5 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.47 (s, 3H), 2.35 - 2.24 (m, 1H), 2.20 - 2.12 (m, 1H), 1.78 - 1.67 (m, 1H), 1.61 - 1.51 (m, 1H), 1.40 - 1.26 (m, 1H), 1.22 - 1.11 (m, 1H), 0.79 - 0.73 (m, 2H), 0.70 - 0.59 (m, 2H). 1H under water.

[0542] Synthesis 23 (3R,4R)-4-(((3-isopropyl-7-(((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-023)

[0543] [ka]

[0544] Step 1 :5-chloro-3-isopropyl-N-((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (3-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (139 mg, 646 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (149 mg, 646 μmol) and DIPEA (0.84 mL, 4.84 mmol) in EtOH (6.0 mL). The reaction mixture was heated at 60° C. for 3 h. The reaction mixture was concentrated in vacuo. Water (50 mL) was added at room temperature, and the mixture was extracted with DCM (3×25 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound (246 mg, 487 μmol, 76% yield, 81% purity) as a white solid. UPLC / MS (Method 4): m / z 409 (M+H)+, R T 0.83 minutes.

[0545] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (158 mg, 166 μL, 722 μmol) was added to a solution of 5-chloro-3-isopropyl-N-((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (246 mg, 602 μmol) and DMAP (14.7 mg, 120 μmol) in THF (6.0 mL). The reaction mixture was stirred at room temperature for 3 hours.

[0546] The mixture was diluted with water (100 mL) and then extracted with DCM (3x30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo.

[0547] Purification by column chromatography (12 g cartridge, 0-70% EtOAc / cyclohexane) afforded the title compound (226 mg, 400 μmol, 66% yield, 90% purity) as a yellow solid. UPLC / MS (method 4): m / z 509 (M+H)+, R T 1.99 minutes.

[0548] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (100 mg, 196 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (45.3 mg, 196 μmol) and THF (2.0 mL) tA solution of BuBrettPhos Pd G3 (16.8 mg, 19.6 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (255 μL, 255 μmol) was added in one portion under bubbling N2. 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, 0-100% EtOAc / isohexane) followed by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP Flash C18 (12 g cartridge, 5-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (68 mg, 92 μmol, 47% yield, 95% purity) as a white solid. UPLC / MS (Method 5): m / z 704 (M+H)+, R T 0.85 minutes.

[0549] Step 4 (3R,4R)-4-(((3-isopropyl-7-(((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.6 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (68 mg, 96.8 μmol) in DCM (2.4 mL). The reaction mixture was stirred at room temperature for 6 hours and 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 methanolic solution was concentrated in vacuo and the title compound (20 mg, 39 μmol, 40% yield, 98% purity) was obtained as a white solid after trituration from Et 2 O and drying overnight at 40° C. under vacuum. UPLC / MS (Method 3): m / z 504 (M+H)+, R T 0.78 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (d,J = 6.9 Hz, 1H), 7.83 - 7.78 (m, 1H), 7.64 (s, 1H), 7.55 (m, 1H), 7.49 (t,J = 5.7 Hz, 1H), 7.20 (m, 1H), 6.78 - 6.70 (m, 1H), 5.31 (s, 1H), 5.29 - 5.20 (m, 1H), 4.72 (d,J = 5.3 Hz, 2H), 3.59 - 3.47 (m, 1H), 3.25 - 3.19 (m, 1H), 3.08 - 2.87 (m, 3H), 2.81 - 2.74 (m, 1H), 2.34 - 2.25 (m, 1H), 2.15 (dd,J = 11.6, 9.9 Hz, 1H), 1.60 - 1.53 (m, 1H), 1.40 - 1.29 (m, 1H), 1.24 (dd,J = 6.9, 4.3 Hz, 6H), 1.21 - 1.12 (m, 1H). 1H under water.

[0550] Intermediate synthesis A6 (3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[0551] [ka]

[0552] Step A :Ethyl 3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate Under N2, trifluoromethyltrimethylsilane (1.50 g, 1.6 mL, 10.5 mmol) was added to a mixture of ethyl imidazo[1,2-a]pyridine-2-carboxylate (500 mg, 2.63 mmol), iodobenzene diacetate (1.69 g, 5.26 mmol), and cesium fluoride (1.60 g, 10.5 mmol) in MeCN (15 mL). The reaction mixture was heated to 30 °C for 3 h and then concentrated to dryness under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (203 mg, 680 μmol, 26% yield, 87% purity) as a white solid. UPLC / MS (Method 5): m / z 259 (M+H)+, R T 1.17 minutes.

[0553] Step B (3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol LiAlH (2 M in THF) (0.393 mL, 786 μmol) was added to a solution of ethyl 3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (203 mg, 786 μmol) in THF (8.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. Saturated aqueous NH Cl (10 mL) and water (10 mL) were added at 0 °C. The aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (102 mg, 0.45 mmol, 58% yield, 96% purity) as a white solid. UPLC / MS (Method 5): m / z 217 (M+H)+, R T 0.81 minutes.

[0554] Step C : 2-(chloromethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine, HCl Thionyl chloride (203 μL, 2.78 mmol) was added dropwise to a solution of (3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol (250 mg, 1.11 mmol) in DCM (5.0 mL) at 0° C.

[0555] The mixture was stirred for 2 hours at 0° C. Concentration to dryness under reduced pressure gave the title compound (250 mg, 0.89 mmol, 80% yield, 96% purity) as a yellow solid. UPLC / MS (Method 5): m / z 235 (M-OH)+, R T 1.19 minutes.

[0556] Step D :2-(azidomethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 2-(chloromethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridin-1-ium chloride (250 mg, 922 μmol) and DIPEA (0.48 mL, 2.77 mmol) in DMF (4.0 mL) was treated with sodium azide (90 mg, 1.38 mmol). The mixture was heated to 50 °C and stirred for 2 h. The mixture was cooled to room temperature and diluted with water (10 mL) and brine (10 mL). Extraction was performed with DCM (3 × 20 mL). The combined organic layers were dried over MgSO and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / cyclohexane) afforded the title compound (209 mg, 0.75 mmol, 81% yield, 86% purity) as a colorless oil. UPLC / MS (Method 3): m / z 242 (M+H)+, R T 1.20 minutes.

[0557] Step E :(3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine (209 mg, 780 μmol) and triphenylphosphine (245 mg, 936 μmol) were dissolved in dioxane (4.0 mL) and water (0.4 mL). The mixture was stirred at 50° C. overnight, after which the solvent was removed in vacuo.

[0558] The residue was loaded onto an SCX column. The column was washed with MeOH (60 mL), and the product was eluted with 0.7 M NH3 in MeOH (40 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (139 mg, 588 μmol, 77% yield, 91% purity) as a white solid. UPLC / MS (Method 5): m / z 216 (M+H)+, R T 0.82 minutes.

[0559] Synthesis 24 (3R,4R)-4-(((7-(((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-024)

[0560] [ka]

[0561] Step 1 :5-chloro-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (3-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (52 mg, 0.22 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (61 mg, 0.27 mmol) and DIPEA (0.29 mL, 1.70 mmol) in EtOH (2.2 mL). The reaction mixture was heated at 60 °C for 18 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0–50% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (74 mg, 155 μmol, 70% yield, 80% purity) as a pink solid. UPLC / MS (Method 5): m / z 381 (M+H)+, R T 1.63 minutes.

[0562] Step 2 tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (51 mg, 0.23 mmol) was added to a solution of 5-chloro-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (74 mg, 155 μmol) and DMAP (5 mg, 40 μmol) in THF (1.9 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (74 mg, 154 μmol, 99% yield, 99% purity) as a white solid. UPLC / MS (Method 5): m / z 783 (M+H)+, R T 1.89 minutes.

[0563] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (74.0 mg, 0.154 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (40.0 mg, 0.170 mmol) in THF (3.0 mL). t A solution of BuBrettPhos Pd G3 (13.9 mh, 0.015 mmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.200 mL, 0.200 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane) followed by further purification on RP flash C18 (4 g cartridge, 15-100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (60 mg, 89 μmol, 58% yield, 99% purity) as a white solid. UPLC / MS (Method 5): m / z 675 (M+H)+, R T 1.77 minutes.

[0564] Step 4 (3R,4R)-4-(((7-(((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[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)((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (60 mg, 89 μmol) in DCM (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo.

[0565] 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 NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (13 mg, 27 μmol, 30% yield, 99% purity). UPLC / MS (Method 5): m / z 475 (M+H)+, R T 1.25 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d,J = 6.8 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 9.1, 1H), 7.26 (m, 2H), 6.98 (td,J = 6.8, 1.2 Hz, 1H), 6.85 - 6.76 (m, 1H), 5.43 - 5.36 (m, 2H), 4.58 (d,J = 5.1 Hz, 2H), 3.61 - 3.51 (m, 1H), 3.27 - 3.20 (m, 1H), 3.14 - 3.06 (m, 1H), 3.00 - 2.90 (m, 2H), 2.88 - 2.79 (m, 1H), 2.41 - 2,31 (m, 1H), 2.26 - 2.17 (m, 1H), 1.96 - 1.87 (m, 1H), 1.65 - 1.57 (m, 1H), 1.44 - 1.34 (m, 1H), 1.28 - 1.17 (m, 7H), 1.15 - 1.08 (m, 2H), 0.74 - 0.67 (m, 2H). 1H under water.

[0566] Intermediate synthesis A7 (3-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine Synthesis

[0567] [ka]

[0568] Step A :3-Cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde A solution of tripotassium phosphate (1.56 g, 7.35 mmol) in water (4.0 mL) was added to a solution of 3-iodoimidazo[1,2-a]pyridine-2-carbaldehyde (500 mg, 1.84 mmol), cyclopropaneboronic acid (474 ​​mg, 5.51 mmol), and PdCl(dppf)-CHCl adduct (300 mg, 368 μmol) in dioxane (20 mL). N was bubbled through the reaction mixture for 10 min, and then the reaction mixture was heated at 80 °C for 20 h. At room temperature, the mixture was filtered through Celite and rinsed with DCM (25 mL). Water (50 mL) was added to the filtrate, the layers were separated, and the aqueous layer was extracted with DCM (2 × 25 mL). The combined organic fractions were dried over MgSO and concentrated in vacuo. Purification by column (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (111 mg, 513 μmol, 28% yield, 90% purity) as a white solid. UPLC / MS (Method 5): m / z 187 (M+H)+, R T 0.80 minutes.

[0569] Step B (S,E)-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (S)-2-Methylpropane-2-sulfinamide (86.7 mg, 715 μmol) followed by titanium(IV) propan-2-olate (0.53 mL, 1.79 mmol) were added to a solution of 3-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (111 mg, 596 μmol) in DCM (6.0 mL) at 0° C. The reaction mixture was stirred at 40° C. for 18 h. Brine (50 mL) and Celite were added to the reaction mixture with stirring. The mixture was filled through a pad of Celite and washed with DCM (100 mL). The organic layer was collected from the filtrate, and the aqueous layer was further extracted with DCM (2×25 mL). The combined organic layers were dried over MgSO4 and then concentrated under reduced pressure. Purification by column (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / cyclohexane) afforded the title compound (139 mg, 0.39 mmol, 65% yield, 81% purity) as a yellow oil. UPLC / MS (Method 5): m / z 290 (M+H)+, R T 1.08 minutes.

[0570] Step C (S)-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide Sodium borohydride (18 mg, 476 μmol) was added to a solution of (S,E)-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (139 mg, 389 μmol) in MeOH (2.4 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 h. Water (30 mL) and DCM (25 mL) were added. The layers were separated and the aqueous layer was further extracted with DCM (2×25 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (139 mg, 382 μmol, 98% yield, 80% purity) as a pink solid. UPLC / MS (Method 4): m / z 292 (M-OH)+, R T 1.05 minutes.

[0571] Step D (3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine Hydrogen chloride (1.25 M in MeOH) (0.9 mL, 1.14 mmol) was added to a solution of (S)—N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-methylpropane-2-sulfinamide (139 mg, 382 μmol) in MeOH (1.0 mL). The reaction was stirred at room temperature for 2 h, then additional hydrogen chloride (1.25 M in MeOH) (0.9 mL, 1.14 mmol) was added and the mixture was stirred for 1 h before being concentrated under reduced pressure. The residue was loaded onto an SCX column. The column was washed with MeOH (50 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 (53 mg, 226 μmol, 59% yield, 80% purity) as a yellow oil. in DMSO-d6 1 1 H NMR was consistent with the product structure.

[0572] Synthesis 25 (3R,4R)-4-(((3-cyclopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-025)

[0573] [ka]

[0574] Step 1 :5-Chloro-3-cyclopropyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-Methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (111 mg, 0.474 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (90 mg, 0.395 mmol) and DIPEA (0.62 mL, 3.55 mmol) in EtOH (1.5 mL). The reaction mixture was heated at 65° C. for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was diluted in DCM (15 mL) and washed with saturated aqueous NaHCO (15 mL) and brine (15 mL). The organic layer was filtered through a phase separator and concentrated under reduced pressure to give the title compound (118 mg, 0.33 mmol, 83% yield, 98% purity) as a gray solid. UPLC / MS (method 3): m / z 353 (M+H)+, R T 1.36 minutes.

[0575] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (87 mg, 0.398 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (117.0 mg, 331.6 mmol) and DMAP (8.1 mg, 66 μmol) in THF (6.5 mL). The reaction mixture was stirred at 65° C. for 1 h, then recharged with BOC anhydride (87 mg, 0.398 mmol) and DMAP (8.1 mg, 66 μmol) and stirred at 65° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted in DCM (15 mL). The organic layer was washed with brine (3×10 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (135 mg, 0.29 mmol, 87% yield, 97% purity) as a green solid. UPLC / MS (Method 3): m / z 453 (M+H)+, R T 1.71 minutes.

[0576] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-methylimidazo[1,2-a]pyridin-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)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (136 mg, 0.30 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 360 μmol) in THF (2.9 mL). t A solution of BuBrettPhos Pd G3 (26 mg, 30 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.39 mL, 390 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 h. At room temperature, the mixture was filtered through Celite and washed with EtOAc (15 mL). The filtrate was partitioned with water (10 mL), and the aqueous layer was re-extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% EtOAc / isohexane) afforded the title compound (163 mg, 0.22 mmol, 74% yield, 88% purity) as a brown oil. UPLC / MS (Method 3): m / z 647 (M+H)+, R T 1.22 minutes.

[0577] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2-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)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (163 mg, 252 μmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (60 mL). The ammoniacal methanolic solution was concentrated in vacuo and the title compound (81 mg, 0.18 mmol, 71% yield, 98% purity) was obtained as a beige solid after trituration from Et2O and drying under vacuum at 40°C overnight. UPLC / MS (Method 5): m / z 447 (M+H)+, R T 1.42 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.56 (t,J = 6.0 Hz, 1H), 7.51 (s, 1H), 7.42 (d,J = 9.0 Hz, 1H), 7.21 (dd,J = 9.1, 6.8 Hz, 1H), 6.79 - 6.73 (m, 2H), 5.44 - 5.37 (m, 1H), 5.32 (s, 1H), 4.57 (d,J = 5.9 Hz, 2H), 3.58 - 3.46 (m, 1H), 3.26 - 3.17 (m, 1H), 3.12 - 3.03 (m, 1H), 2.94 (dd,J = 11.5, 4.5 Hz, 1H), 2.87 - 2.78 (m, 1H), 2.55 (s, 3H), 2.40 - 2.31 (m, 1H), 2.27 - 2.16 (m, 1H), 1.76 - 1.67 (m, 1H), 1.63 - 1.55 (m, 1H), 1.42 - 1.32 (m, 1H), 1.25 - 1.11 (m, 1H), 0.80 - 0.71 (m, 2H), 0.69 - 0.58 (m, 2H). 1H under water.

[0578] Synthesis 26 (3R,4R)-4-(((3-ethyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-026)

[0579] [ka]

[0580] Step 1 :5-chloro-3-ethyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (8-Methylimidazo[1,2-a]pyridin-2-yl)methanamine, HCl (96.1 mg, 486 μmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (100 mg, 463 μmol) and DIPEA (0.56 mL, 3.24 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo.

[0581] Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (128 mg, 0.36 mmol, 77% yield, 95% purity) as a white solid. UPLC / MS (Method 5): m / z 341 (M+H)+, R T 1.22 minutes.

[0582] Step 2 tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (98 mg, 451 μmol) was added to a solution of 5-chloro-3-ethyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (128 mg, 376 μmol) and DMAP (9 mg, 75 μmol) in THF (4.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% (3:1 EtOAc / EtOH) / isohexane) afforded the title compound (138 mg, 0.30 mmol, 80% yield, 96% purity) as a brown solid. UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.61 minutes.

[0583] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (138 mg, 300 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 361 μmol) and t A solution of BuBrettPhos Pd G3 (0.62 g, 0.72 mmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (391 μL, 391 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0–10% (0.7 M NH3 / MeOH) / DCM) afforded the title compound (141 mg, 222 μmol, 74% yield, 98% purity) as a white solid. UPLC / MS (Method 3): m / z 635 (M+H)+, R T 1.62 minutes.

[0584] Step 4 (3R,4R)-4-(((3-ethyl-7-(((8-methylimidazo[1,2-a]pyridin-2-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)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (140 mg, 221 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (71 mg, 160 μmol, 73% yield, 98% purity). UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.02 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 6.5 Hz, 1H), 7.74 (s, 1H), 7.69 - 7.63 (m, 2H), 7.01 (dt,J = 6.9, 1.3 Hz, 1H), 6.71 - 6.79 (m, 2H), 5.46 - 5.37 (m, 1H), 5.27 (s, 1H), 4.57 (d,J = 6.0 Hz, 2H), 3.49 - 3.60 (m, 1H), 3.11 - 3.20 (m, 1H), 3.06 - 2.95 (m, 1H), 2.89 (dd,J = 11.5, 4.6 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.47 (s, 3H), 2.24 - 2.34 (m, 1H), 2.19 - 2.10 (m, 1H), 1.57 - 1.48 (m, 1H), 1.36 - 1.25 (m, 1H), 1.11 - 1.20 (m, 4H). 1CH2 under DMSO. 1H under water.

[0585] Synthesis 27 (3R,4R)-4-(((3-cyclopropyl-7-(((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-027)

[0586] [ka]

[0587] Step 1 :5-chloro-3-cyclopropyl-N-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-Methoxyimidazo[1,2-a]pyridin-2-yl)methanamine (64 mg, 0.34 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (86 mg, 0.38 mmol) and DIPEA (0.42 mL, 2.4 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 50 °C for 20 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (105 mg, 0.27 mmol, 78% yield, 94% purity) as a brown solid. UPLC / MS (Method 5): m / z 369 (M+H)+, RT 1.35 min.

[0588] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (70 mg, 321 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (105 mg, 268 μmol) and DMAP (6.5 mg, 54 μmol) in THF (3.0 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (120 mg, 256 μmol, 95% yield, 99% purity) as a white solid. UPLC / MS (Method 5): m / z 469 (M+H)+, R T 0.81 minutes.

[0589] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-methoxyimidazo[1,2-a]pyridin-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)((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (140 mg, 299 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 358 μmol) in THF (2.0 mL). t A solution of BuBrettPhos Pd G3 (25 mg, 29.9 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (388 μL, 388 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (167 mg, 0.21 mmol, 69% yield, 82% purity) as a white solid. UPLC / MS (Method 5): m / z 663 (M+H)+, R T 1.61 minutes.

[0590] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.04 mL, 4.16 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (168 mg, 208 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 35° C. for 1 hour and 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 (62 mg, 0.13 mmol, 61% yield, 95% purity). UPLC / MS (Method 5): m / z 463 (M+H)+, R T 1.04 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.61 (t,J = 6.1 Hz, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.29 (dd,J = 9.0, 7.5 Hz, 1H), 7.15 (d,J = 9.0 Hz, 1H), 6.77 - 6.71 (m, 1H), 6.34 (d,J = 7.4 Hz, 1H), 5.36 - 5.32 (m, 1H), 5.30 (s, 1H), 4.55 (d,J = 5.9 Hz, 2H), 4.06 (s, 3H), 3.57 - 3.49 (m, 1H), 3.26 - 3.15 (m, 1H), 3.09 - 2.99 (m, 1H), 2.92 (dd,J = 11.5, 4.6 Hz, 1H), 2.83 - 2.76 (m, 1H), 2.36 - 2.26 (m, 1H), 2.17 (dd,J = 11.6, 9.9 Hz, 1H), 1.78 - 1.66 (m, 1H), 1.61 - 1.53 (m, 1H), 1.36 - 1.29 (m, 1H), 1.22 - 1.11 (m, 1H), 0.82 - 0.72 (m, 2H), 0.76 - 0.59 (m, 2H). 1H under water.

[0591] Intermediate Synthesis A8 (5-Methoxyimidazo[1,2-a]pyridin-2-yl)methanamine

[0592] [ka]

[0593] Step A :Ethyl 5-methoxyimidazo[1,2-a]pyridine-2-carboxylate 6-Methoxypyridin-2-amine (400 mg, 3.22 mmol) and ethyl 3-bromo-2-oxopropanoate (0.81 mL, 6.44 mmol) in IPA (2.0 mL) and water (2.0 mL) were heated at 80 °C under microwave irradiation for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 x 25 mL). The combined organic fractions were dried over MgSO, filtered, and then concentrated in vacuo. Purification by column chromatography (40 g cartridge, 0-10% MeOH / DCM) afforded the title compound (280 mg, 1.3 mmol, 39% yield, 99% purity) as a yellow solid. UPLC / MS (Method 5): m / z 221 (M+H)+, R T 0.93 minutes.

[0594] Step B :(5-Methoxyimidazo[1,2-a]pyridin-2-yl)methanol Lithium borohydride (2 M in THF) (0.63 mL, 1.26 mmol) was added to a solution of ethyl 5-methoxyimidazo[1,2-a]pyridine-2-carboxylate (280 mg, 1.26 mmol) in THF (6.0 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature overnight. At 0 °C, water (5 mL) and saturated aqueous NH4Cl (10 mL) were added. The aqueous layer was extracted with DCM (3 × 20 mL), and the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Column purification (24 g cartridge, 0–10% MeOH / DCM) afforded the title compound (120 mg, 0.61 mmol, 49% yield, 91% purity) as a white solid. UPLC / MS (Method 5): m / z 179 (M+H)+, R T 0.62 minutes.

[0595] Step C : 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine, HCl Thionyl chloride (112 μL, 1.53 mmol) was added dropwise to a solution of (5-methoxyimidazo[1,2-a]pyridin-2-yl)methanol (120 mg, 613 μmol) in DCM (7.0 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. Concentration to dryness under reduced pressure afforded the title compound (142 mg, 0.60 mmol, 98% yield, 99% purity) as an off-white solid. in DMSO-d6 1 1 H NMR was consistent with the product structure.

[0596] Step D :2-(azidomethyl)-5-methoxyimidazo[1,2-a]pyridine A solution of 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine, HCl (142 mg, 597 μmol), and DIPEA (0.31 mL, 1.79 mmol) in DMF (3.0 mL) was treated with sodium azide (58 mg, 0.90 mmol). The mixture was heated to 50 °C and stirred for 2 h. The mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL), and then extracted with TBME (3 × 20 mL) followed by EtOAc (3 × 20 mL). The combined organic layers were washed with brine (4 × 20 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (91 mg, 0.37 mmol, 62% yield, 83% purity) as a white solid. UPLC / MS (Method 5): m / z 205 (M+H)+, R T 0.94 minutes.

[0597] Step E :(5-Methoxyimidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-5-methoxyimidazo[1,2-a]pyridine (91 mg, 0.45 mmol) and triphenylphosphine (0.14 g, 0.54 mmol) were dissolved in THF (1.8 mL) and water (0.2 mL). The mixture was stirred at room temperature overnight, and the solvent was removed in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (50 mL), and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (64 mg, 0.34 mmol, 77% yield, 95% purity) as a white solid. UPLC / MS (Method 5): m / z 178 (M+H)+, R T 0.64 minutes.

[0598] Synthesis 28 (3R,4R)-4-(((3-cyclopropyl-7-(((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-028)

[0599] [ka]

[0600] Step 1 :5-chloro-3-cyclopropyl-N-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanamine (130 mg, 691 μmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (158 mg, 691 μmol) and DIPEA (0.84 mL, 4.83 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 50° C. for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (449 mg, 0.69 mmol, 99% yield, 58% purity) as a brown solid. UPLC / MS (Method 5): m / z 380 (M+H)+, R T 1.45 minutes.

[0601] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate BOC anhydride (129 mg, 592 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (206 mg, 494 μmol) and DMAP (12.1 mg, 99 μmol) in THF (5.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (231 mg, 0.46 mmol, 93% yield, 95% purity) as a brown solid. UPLC / MS (Method 5): m / z 480 (M+H)+, R T 1.83 minutes.

[0602] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-cyclopropylimidazo[1,2-b]pyridazin-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)((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate (254 mg, 529 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (146 mg, 635 μmol) in THF (5.0 mL). tA solution of BuBrettPhos Pd G3 (45 mg, 52.9 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (688 μL, 688 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 72 hours. The reaction was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (230 mg, 0.32 mmol, 61% yield, 94% purity) as a brown solid. UPLC / MS (Method 4): m / z 674 (M+H)+, R T 1.72 minutes.

[0603] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.71 mL, 6.83 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (230 mg, 341 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 35° C. for 4 hours and 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 methanolic solution was concentrated in vacuo and the title compound (145 mg, 0.30 mmol, 87% yield, 97% purity) was obtained after trituration from Et2O and drying under vacuum at 40°C overnight. UPLC / MS (Method 5): m / z 475 (M+H)+, R T 1.14 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 1H), 7.92 (d,J = 9.4 Hz, 1H), 7.61 (t,J = 6.1 Hz, 1H), 7.51 (s, 1H), 7.08 (d,J = 9.4 Hz, 1H), 6.77 (t,J = 6.0 Hz, 1H), 5.47 - 5.42 (m, 1H), 5.30 (s, 1H), 4.55 (d,J = 5.9 Hz, 2H), 3.59 - 3.47 (m, 1H), 3.28 - 3.20 (m, 1H), 3.20 - 3.05 (m, 1H), 2.97 (dd,J = 11.6, 4.5 Hz, 1H), 2.90 - 2.82 (m, 1H), 2.44 - 2.34 (m, 1H), 2.25 (dd,J = 11.6, 10.0 Hz, 1H), 2.21 - 2.11 (m, 1H), 1.77 - 1.66 (m, 1H), 1.65 - 1.57 (m, 1H), 1.48 - 1.30 (m, 1H), 1.49 - 1.11 (m, 1H), 1.11 - 1.01 (m, 2H), 1.01 - 0.92 (m, 2H), 0.81 - 0.72 (m, 2H), 0.72 - 0.59 (m, 2H). 1H underwater.

[0604] Intermediate synthesis A9 (6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanamine

[0605] [ka]

[0606] Step A :Ethyl 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylate A mixture of ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (400 mg, 1.77 mmol), cesium fluoride (1.21 g, 7.98 mmol), PdCl(dtbpf) (116 mg, 177 μmol), and cyclopropylboronic acid (685 mg, 7.98 mmol) in dioxane (10 mL) was degassed with N for 10 min. The mixture was then heated to 60 °C for 5.5 h and then concentrated to dryness under reduced pressure. Purification by column chromatography (24 g cartridge, 0–10% MeOH / DCM) afforded the title compound (400 mg, 1.6 mmol, 93% yield, 95% purity) as a yellow solid. UPLC / MS (Method 3): m / z 232 (M+H)+, R T 1.13 minutes.

[0607] Step B :(6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanol Diisobutylaluminum hydride (1 M in DCM) (4.32 mL, 4.32 mmol) was added to a solution of ethyl 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylate (400 mg, 1.73 mmol) in THF (20 mL) at -10 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. At 0 °C, MeOH (10 mL) was added, followed by water (10 mL) and 1 M aqueous HCl (10 mL). The mixture was vigorously stirred for 30 min and extracted with ethyl acetate (3 × 35 mL). The combined organic layers were washed with brine (20 mL), filtered through a phase separator, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (220 mg, 1.10 mmol, 66% yield, 98% purity) as a brown oil. UPLC / MS (method 3): m / z 190 (M+H)+, RT 0.44 min.

[0608] Step C : 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine, HCl Thionyl chloride (434 μL, 5.95 mmol) was added to a solution of (6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanol (225 mg, 1.19 mmol) in DCE (5.0 mL). The reaction mixture was stirred at 45° C. for 1 h. Concentration to dryness under reduced pressure afforded the title compound (290 mg, 1.1 mmol, 95% yield, 95% purity) as a green solid. UPLC / MS (Method 5): m / z 209 (M+H)+, R T 1.00 minutes.

[0609] Step D :2-(azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine A solution of 2-(chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine, HCl (290 mg, 1.19 mmol), and DIPEA (0.62 mL, 3.56 mmol) in DMF (5.0 mL) was treated with sodium azide (116 mg, 1.78 mmol). The mixture was heated to 50 °C and stirred for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (155 mg, 0.67 mmol, 57% yield, 93% purity) as a colorless oil. UPLC / MS (Method 5): m / z 216 (M+H)+, R T 1.10 minutes.

[0610] Step E :(6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanamine 2-(Azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine (155 mg, 673 μmol) and triphenylphosphine (212 mg, 807 μmol) were dissolved in THF (3.6 mL) and water (0.4 mL). The mixture was stirred at room temperature overnight, and then the solvent was removed in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (50 mL), and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (130 mg, 0.66 mmol, 98% yield, 95% purity) as a white solid. UPLC / MS (Method 5): m / z 189 (M+H)+, R T 0.76 minutes.

[0611] Synthesis 29 (3R,4R)-4-(((3-cyclobutyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-029)

[0612] [ka]

[0613] Step 1 :5-chloro-3-iodo-N-((8-methyl-midazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (8-Methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (1.98 g, 8.47 mmol) was added to a solution of 5,7-dichloro-3-iodopyrazolo[1,5-a]pyrimidine (2.80 g, 8.47 mmol) and DIPEA (4.4 mL, 25.4 mmol) in EtOH (38 mL). The reaction mixture was heated at 85° C. overnight. At room temperature, the precipitated solid was collected by filtration and rinsed with EtOH (100 mL) to give the title compound (3.57 g, 8.03 mmol, 94% yield, 98% purity) as a beige solid. UPLC / MS (Method 5): m / z 439 (M+H)+, R T 1.77 minutes.

[0614] Step 2 tert-Butyl (5-chloro-3-iodopyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (1.74 g, 7.99 mmol) was added to a solution of 5-chloro-3-iodo-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (2.92 g, 6.66 mmol) and DMAP (81 mg, 0.66 mmol) in THF (23 mL) and DMF (23 mL). The reaction mixture was stirred at 50° C. for 1.5 hours. Water (20 mL) was added at room temperature, and the resulting solid was collected by filtration, then rinsed with water (25 mL) and TBME (25 mL) to give the title compound (3.1 g, 5.68 mmol, 85% yield, 99% purity) as an off-white solid after drying under vacuum at 40° C. overnight. UPLC / MS (Method 5): m / z 539 (M+H)+, R T 2.24 minutes.

[0615] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-iodopyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (1.00 g, 1.86 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (1.71 g, 7.42 mmol), and DIPEA (1.29 mL, 7.42 mmol) in anhydrous NMP (11 mL) was degassed with N and then heated at 110° C. for 2 h. The reaction mixture was cooled to 0° C., and water (30 mL) was added. The solid was collected by filtration, rinsed with more water (10 mL), and then dried under vacuum at 40° C. to give the title compound (1.28 g, 1.6 mmol, 87% yield, 92% purity) as a pale solid. UPLC / MS (Method 5): m / z 733 (M+H)+, R T 2.06 minutes.

[0616] Step 4 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclobutylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate Under N2, cyclobutylzinc(II) bromide (0.38 M in THF) (prepared according to literature procedures) (3.59 mL, 1.37 mmol) was added dropwise to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (200 mg, 273 μmol), XPhos Pd G3 (8 mg, 9.28 μmol) in THF (2.0 mL). The reaction mixture was stirred at room temperature for 18 h, then quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and then concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification by RP preparative HPLC (25-100% MeCN / 0.1% NH in water) afforded the title compound (19 mg, 29 μmol, 11% yield, 99% purity) as a white solid. UPLC / MS (Method 3): m / z 662 (M+H)+, R T 1.34 minutes.

[0617] Step 5 (3R,4R)-4-(((3-cyclobutyl-7-(((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)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)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclobutylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (19 mg, 29 μmol) in DCM (0.4 mL). The reaction mixture was stirred at room temperature for 16 hours and 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 (10 mg, 21 μmol, 72% yield, 95% purity). UPLC / MS (Method 5): m / z 461 (M+H)+, R T 1.82 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d,J = 6.7 Hz, 1H), 7.75 (d,J = 4.9 Hz, 2H), 7.66 (t,J = 6.2 Hz, 1H), 7.02 (dt,J = 6.8, 1.2 Hz, 1H), 6.78 - 6.69 (m, 2H), 5.32 - 5.25 (m, 2H), 4.58 (d,J = 6.0 Hz, 2H), 3.59 - 3.42 (m, 2H), 3.24 - 3.14 (m, 1H), 3.07 - 2.96 (m, 1H), 2.90 (dd,J = 11.5, 4.5 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.48 (s, 3H), 2.34 - 2.11 (m, 6H), 1.97 - 1.78 (m, 2H), 1.59 - 1.50 (m, 1H), 1.38 - 1.28 (m, 1H), 1.21 - 1.07 (m, 1H). 1H under water.

[0618] Synthesis 30 (3R,4R)-4-(((3-cyclopropyl-7-(((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-030)

[0619] [ka]

[0620] Step 1 :5-chloro-3-cyclopropyl-N-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine (90 mg, 481 μmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (110 mg, 481 μmol) and DIPEA (0.59 mL, 3.36 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated in vacuo to give the title compound (325 mg, 0.48 mmol, 99% yield, 56% purity) as a yellow liquid. UPLC / MS (Method 5): m / z 379 (M+H)+, RT 1.48 min.

[0621] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (126 mg, 0.58 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (325 mg, 0.48 mmol) and DMAP (12 mg, 96 μmol) in THF (5.0 mL). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (145 mg, 0.29 mmol, 60% yield, 96% purity) as a brown solid. UPLC / MS (Method 5): m / z 479 (M+H)+, R T 1.80 minutes.

[0622] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate, 0.3 formate tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (145 mg, 303 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83.7 mg, 363 μmol) in THF (2.0 mL). tA solution of BuBrettPhos Pd G3 (25.9 mg, 30.3 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.39 mL, 394 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) followed by further purification on RP flash C18 (24 g cartridge, 10-100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) afforded the title compound (83 mg, 0.12 mmol, 39% yield, 97% purity) as a white solid. UPLC / MS (Method 5): m / z 673 (M+H)+, R T 1.70 minutes.

[0623] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5-cyclopropylimidazo[1,2-a]pyridin-2-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)((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 0.12 mmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3 in MeOH (50 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (49 mg, 0.10 mmol, 81% yield, 96% purity). UPLC / MS (Method 5): m / z 473 (M+H)+, R T 1.16 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H), 7.57 (t,J = 6.0 Hz, 1H), 7.52 (s, 1H), 7.43 (d,J = 9.0 Hz, 1H), 7.20 (dd,J = 9.0, 7.0 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.69 - 6.64 (m, 1H), 5.36 (s, 1H), 5.34 - 5.29 (m, 1H), 4.60 (d,J = 5.8 Hz, 2H), 3.59 - 3.47 (m, 1H), 3.26 - 3.19 (m, 1H), 3.10 - 3.00 (m, 1H), 2.91 (dd,J = 11.5, 4.5 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.36 - 2.26 (m, 1H), 2.22 - 2.12 (m, 2H), 1.77 - 1.68 (m, 1H), 1.63 - 1.53 (m, 1H), 1.40 - 1.29 (m, 1H), 1.22 - 1.10 (m, 1H), 1.10 - 1.03 (m, 2H), 0.82 - 0.73 (m, 4H), 0.71 - 0.61 (m, 2H).

[0624] Intermediate Synthesis A10 (5-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine

[0625] [ka]

[0626] Step A :Ethyl 5-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate A mixture of ethyl 5-bromoimidazo[1,2-a]pyridine-2-carboxylate (500 mg, 1.86 mmol), cesium fluoride (564 mg, 3.72 mmol), PdCl(dtbpf) (121 mg, 186 μmol), and cyclopropylboronic acid (319 mg, 3.72 mmol) in dioxane (10.0 mL) was degassed with N for 10 min. The mixture was then heated to 90 °C overnight. At room temperature, the reaction mixture was filtered through a short pad of Celite, rinsed with 20% MeOH / DCM (20 mL), and the filtrate was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0–10% (0.7 M NH / MeOH) / DCM) afforded the title compound (440 mg, 1.7 mmol, 93% yield, 90% purity) as a brown oil. UPLC / MS (Method 3): m / z 231 (M+H)+, R T 0.86 minutes.

[0627] Step B / C :(5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol / 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine, HCl Lithium borohydride (2 M in THF) (860 μL, 1.72 mmol) was added to a solution of ethyl 5-cyclopropylimidazo[1,2-a]pyridine-2-carboxylate (440 mg, 1.72 mmol) in THF (8.0 mL) at 0° C. The reaction mixture was warmed to room temperature and then stirred for 20 h. At 0° C., MeOH (5 mL) was added, followed by water (5 mL) and 1 M aqueous HCl (5 mL). The mixture was vigorously stirred for 30 min and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo to give the crude alcohol intermediate (5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (235 mg, 1.25 mmol), which was redissolved in dry DCE (5.0 mL). Thionyl chloride (455 μL, 6.24 mmol) was added, and the reaction mixture was stirred for 1 hour at 45° C. Concentration to dryness under reduced pressure afforded the title compound (260 mg, 1.00 mmol, 55% yield, 96% purity) as a yellow liquid. UPLC / MS (method 3): m / z 207 (M+H)+, R T 0.52 minutes.

[0628] Step D :2-(azidomethyl)-5-cyclopropylimidazo[1,2-a]pyridine A solution of 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine, HCl (260 mg, 1.21 mmol), and DIPEA (0.63 mL, 3.62 mmol) in DMF (6.0 mL) was treated with sodium azide (118 mg, 1.81 mmol). The mixture was heated to 50 °C and stirred for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (218 mg, 0.97 mmol, 80% yield, 95% purity) as a colorless oil. UPLC / MS (Method 6): m / z 214 (M+H)+, R T 0.63 minutes.

[0629] Step E:(5-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-5-cyclopropylimidazo[1,2-a]pyridine (218 mg, 971 μmol) and triphenylphosphine (255 mg, 971 μmol) were dissolved in THF (3.6 mL) and water (0.4 mL). The mixture was stirred at room temperature overnight, and the solvent was removed 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 (90 mg, 0.46 mmol, 48% yield, 96% purity) as a white solid. UPLC / MS (Method 5): m / z 188 (M+H)+, R T 0.83 minutes.

[0630] Synthesis 31 (3R,4R)-4-(((3-ethyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-031)

[0631] [ka]

[0632] Step 1 :5-chloro-3-ethyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-Methylimidazo[1,2-a]pyridin-2-yl)methanamine (100 mg, 620 μmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (122 mg, 564 μmol) and DIPEA (0.69 mL, 3.95 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 50 °C for 2.5 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (70 mg, 0.20 mmol, 35% yield, 97% purity) as a white solid. UPLC / MS (Method 5): m / z 341 (M+H)+, R T 1.33 minutes.

[0633] Step 2 tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (52 mg, 0.24 mmol) was added to a solution of 5-chloro-3-ethyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (70 mg, 0.20 mmol) and DMAP (4.9 mg, 40 μmol) in THF (2.0 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (83 mg, 0.16 mmol, 82% yield, 87% purity) as a brown solid. UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.69 minutes.

[0634] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (166 mg, 376 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83.0 mg, 314 μmol) in THF (3.0 mL). t A solution of BuBrettPhos Pd G3 (26.8 mg, 31.4 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (408 μL, 408 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2.5 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (61 mg, 91 μmol, 29% yield, 95% purity) as a yellow solid. UPLC / MS (Method 5): m / z 635 (M+H)+, R T 1.63 minutes.

[0635] Step 4 (3R,4R)-4-(((3-ethyl-7-(((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.4 mL) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (61 mg, 91 μmol) in DCM (1.6 mL). The reaction mixture was stirred at room temperature for 18 hours and 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 (26 mg, 57 μmol, 62% yield, 95% purity) as an off-white solid. UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.03 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.64 (s, 1H), 7.58 (t,J = 6.0 Hz, 1H), 7.43 (d,J = 9.1 Hz, 1H), 7.21 (dd,J = 9.1, 6.8 Hz, 1H), 6.80 - 6.73 (m, 2H), 5.49 - 5.42 (m, 1H), 5.34 (s, 1H), 4.59 (d,J = 5.7 Hz, 2H), 3.62 - 3.50 (m, 1H), 3.22 - 3.13 (m, 1H), 3.08 - 2.98 (m, 1H), 2.91 (dd,J = 11.7, 4.5 Hz, 1H), 2.84 - 2.75 (m, 1H), 2.56 (s, 3H), 2.51 - 2.44 (m, 2H), 2.36 - 2.26 (m, 1H), 2.17 (dd,J = 11.6, 9.9 Hz, 1H), 1.61 - 1.52 (m, 1H), 1.38 - 1.28 (m, 1H), 1.21 - 1.13 (m, 4H). 1H under water.

[0636] Synthesis 32 (3R,4R)-4-(((3-cyclopropyl-7-(((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-032)

[0637] [ka]

[0638] Step 1 :5-Chloro-3-cyclopropyl-N-((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5,7-Dimethylimidazo[1,2-a]pyridin-2-yl)methanamine (66 mg, 0.38 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (86 mg, 0.38 mmol) and DIPEA (0.46 mL, 2.6 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 50 °C for 16 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (108 mg, 0.28 mmol, 74% yield, 95% purity) as a yellow oil. UPLC / MS (Method 5): m / z 367 (M+H)+, R T 1.44 minutes.

[0639] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (82.0 mg, 376 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (106 mg, 289 μmol) and DMAP (1.9 mg, 57.8 μmol) in THF (2.0 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (148 mg, 0.29 mmol, 99% yield, 90% purity) as a white solid. UPLC / MS (Method 5): m / z 467 (M+H)+, R T 1.78 minutes.

[0640] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5,7-dimethylimidazo[1,2-a]pyridin-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)((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (130 mg, 278 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (76.9 mg, 334 μmol) in THF (2.3 mL). tA solution of BuBrettPhos Pd G3 (35.7 mg, 41.8 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (418 μL, 418 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0–10% (0.7 M NH3 / MeOH) / DCM) followed by further purification by column chromatography (4 g cartridge, 0–100% EtOAc / isohexane, then 0–5% (0.7 M NH3 / MeOH) / DCM) afforded the title compound (140 mg, 0.19 mmol, 68% yield, 90% purity) as a brown solid. UPLC / MS (Method 4): m / z 661 (M+H)+, R T 1.68 minutes.

[0641] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (953 μL, 3.81 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (140 mg, 191 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35° C. for 1 h and 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 (40 mL). The ammoniacal methanolic solution was concentrated in vacuo to give the title compound (67 mg, 0.14 mmol, 72% yield, 95% purity) as a beige solid after drying under vacuum at 50° C. overnight. UPLC / MS (Method 4): m / z 461 (M+H)+, RT 1.17 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 7.53 - 7.47 (m, 2H), 7.19 (s, 1H), 6.74 (t,J = 6.1 Hz, 1H), 6.61 (s, 1H), 5.35 - 5.29 (m, 2H), 4.54 (d,J = 5.8 Hz, 2H), 3.61 - 3.46 (m, 1H), 3.25 - 3.17 (m, 1H), 3.08 - 2.99 (m, 1H), 2.90 (dd,J = 11.7, 4.5 Hz, 1H), 2.81 - 2.74 (m, 1H), 2.36 - 2.31 (m, 3H), 2.30 - 2.25 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1H), 1.79 - 1.66 (m, 1H), 1.60 - 1.53 (m, 1H), 1.32 (s, 1H), 1.11 - 1.15 (m, 1H), 0.80 - 0.71 (m, 2H), 0.69 - 0.58 (m, 2H). 3H under DMSO. 1H under water.

[0642] Intermediate Synthesis A11 (5,7-Dimethylimidazo[1,2-a]pyridin-2-yl)methanamine

[0643] [ka]

[0644] Step A :(5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol Diisobutylaluminum hydride (1 M in hexanes) (3.44 mL, 3.44 mmol) was added to a solution of ethyl 5,7-dimethylimidazo[1,2-a]pyridine-2-carboxylate (300 mg, 1.37 mmol) in THF (8.0 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 18 h, then MeOH (10 mL) was added, followed by water (10 mL) and 1 M aqueous HCl (10 mL). The mixture was stirred vigorously for 30 min and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (93 mg, 0.51 mmol, 37% yield, 98% purity) as a brown solid. UPLC / MS (Method 5): m / z 177 (M+H)+, R T 0.77 minutes.

[0645] Step B : 2-(chloromethyl)-5,7-dimethylimidazo[1,2-a]pyridine, HCl Thionyl chloride (96 μL, 1.32 mmol) was added dropwise to a solution of (5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol (93.0 mg, 528 μmol) in DCM (2.5 mL) at 0° C. The mixture was stirred at room temperature for 1 h. Concentration to dryness under reduced pressure afforded the title compound (132 mg, 0.52 mmol, 98% yield, 91% purity) as a yellow solid. in DMSO-d6 1 1 H NMR was consistent with the product structure.

[0646] Step C :2-(azidomethyl)-5,7-dimethylimidazo[1,2-a]pyridine A solution of 2-(chloromethyl)-5,7-dimethylimidazo[1,2-a]pyridine (132 mg, 617 μmol) and DIPEA (322 μL, 1.85 mmol) in DMF (3.0 mL) was treated with sodium azide (40 mg, 617 μmol). The mixture was heated to 50 °C and stirred for 3 h. The mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (117 mg, 0.38 mmol, 61% yield, 65% purity) as a colorless oil. UPLC / MS (Method 5): m / z 202 (M+H)+, R T 0.46 minutes.

[0647] Step D :(5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-5,7-dimethylimidazo[1,2-a]pyridine (117 mg, 378 μmol) and triphenylphosphine (119 mg, 454 μmol) were dissolved in THF (1.8 mL) and water (0.2 mL). The mixture was stirred at 50° C. for 16 hours, after which the solvent was removed 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 (66 mg, 377 μmol, 99% yield, 99% purity) as a brown solid. UPLC / MS (Method 5): m / z 176 (M+H)+, R T 0.79 minutes.

[0648] Synthesis 33 (3R,4R)-4-(((7-(((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-033)

[0649] [ka]

[0650] Step 1 :5-chloro-N-((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (175 mg, 701 μmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (145 mg, 637 μmol) and DIPEA (666 μL, 3.82 mmol) in EtOH (10 mL). The reaction mixture was heated at 50° C. for 5 h. The reaction mixture was concentrated in vacuo to give the title compound (290 mg, 0.58 mmol, 91% yield, 88% purity) as a yellow solid. UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.61 minutes.

[0651] Step 2 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of 5-chloro-N-((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (130 mg, 295 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (271 mg, 1.18 mmol), and DIPEA (232 μL, 1.33 mmol) in NMP (1.5 mL) was heated at 150° C. for 5 hours under microwave irradiation. Water was added at room temperature. The resulting solid was collected by filtration to give the title compound (175 mg, 0.19 mmol, 65%, purity 69%) as a yellow solid. UPLC / MS (Method 3): m / z 535 (M-Boc)+, R T 1.09 minutes.

[0652] Step 3 (3R,4R)-4-(((7-(((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.29 mL, 5.16 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (164 mg, 258 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 35° C. for 1 hour and 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. Further purification by RP preparative HPLC (25-100% MeCN / 0.1% formic acid in water) afforded the title compound (84 mg, 0.15 mmol, 60% yield, 98% purity) as an off-white solid. UPLC / MS (Method 5): m / z 535 (M+H)+, R T 1.27 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (t,J = 1.5 Hz, 1H), 8.00 (s, 1H), 7.85 - 7.77 (m, 2H), 7.54 (s, 1H), 6.72 (t,J = 5.9 Hz, 1H), 5.34 - 5.28 (m, 1H), 5.25 (s, 1H), 4.63 (d,J = 6.1 Hz, 2H), 3.59 - 3.47 (m, 1H), 3.27 - 3.18 (m, 1H), 3.11 - 3.01 (m, 1H), 2.93 (dd,J = 11.6, 4.5 Hz, 1H), 2.84 - 2.77 (m, 1H), 2.36 - 2.26 (m, 1H), 2.18 (dd,J = 11.6, 9.9 Hz, 1H), 1.79 - 1.67 (m, 1H), 1.62 - 1.53 (m, 1H), 1.38 - 1.29 (m, 1H), 1.26 - 1.07 (m, 1H), 0.83 - 0.73 (m, 2H), 0.77 - 0.60 (m, 2H). 1H under water.

[0653] Intermediate Synthesis A12 (8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[0654] [ka]

[0655] Step A (8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol Diisobutylaluminum hydride (1M in hexanes) (18.8 mL, 18.8 mmol) was added to a solution of ethyl 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.20 g, 7.52 mmol) in THF (40 mL) at −40° C. The reaction mixture was warmed to 0° C. and stirred at 0° C. for 2 h, then MeOH (10 mL) was added, followed by water (10 mL) and 1 M aqueous HCl (10 mL). The mixture was vigorously stirred for 30 min and extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (1.80 g, 6.9 mmol, 92% yield, 96% purity) as a white solid. UPLC / MS (Method 5): m / z 251 (M+H)+, RT 0.94 min.

[0656] Step B :8-chloro-2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine Thionyl chloride (2.6 mL, 36 mmol) was added dropwise to a solution of (8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol (1.8 g, 7.2 mmol) in DCE (20 mL). The mixture was stirred at 45° C. for 3 h. Concentration to dryness under reduced pressure afforded the title compound (2.0 g, 6.7 mmol, 93% yield, 90% purity) as a yellow solid. UPLC / MS (Method 5): m / z 269 (M+H)+, R T 1.25 minutes.

[0657] Step C :2-(azidomethyl)-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 8-chloro-2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine (2.00 g, 6.69 mmol) and DIPEA (3.5 mL, 20.1 mmol) in DMF (30 mL) was treated with sodium azide (652 mg, 10.0 mmol). The mixture was heated to 60 °C and stirred for 6 h. The mixture was cooled to room temperature, diluted with water (40 mL) and brine (60 mL), and then extracted with TBME (4 × 50 mL) followed by EtOAc (50 mL). The combined organic layers were washed with brine (4 × 20 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–100% TBME / isohexane) afforded the title compound (1.80 g, 6.2 mmol, 93% yield, 95% purity) as a brown oil. UPLC / MS (Method 5): m / z 276 (M+H)+, R T 1.27 minutes.

[0658] Step D :(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine (1.8 g, 6.5 mmol), triphenylphosphine (2.1 g, 7.8 mmol) were dissolved in THF (36 mL) and water (4.0 mL). The mixture was stirred at room temperature overnight, and the solvent was removed 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 (1.32 g, 5.0 mmol, 77% yield, 95% purity) as a white solid. UPLC / MS (Method 5): m / z 250 (M+H)+, R T 0.92 minutes.

[0659] Synthesis 34 (3R,4R)-4-(((3-ethyl-7-(((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-034)

[0660] [ka]

[0661] Step 1 :5-chloro-3-ethyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (106 mg, 444 μmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (80 mg, 370 μmol) and DIPEA (387 μL, 2.22 mmol) in EtOH (1.6 mL). The reaction mixture was heated at 65 °C for 5 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (136 mg, 0.34 mmol, 91% yield, 98% purity) as an orange solid. UPLC / MS (method 3): m / z 395 (M+H)+, R T 1.51 minutes.

[0662] Step 2 tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (36.8 mg, 169 μmol) was added to a solution of 5-chloro-3-ethyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (136 mg, 338 μmol) and DMAP (8.3 mg, 67.5 μmol) in THF (6.8 mL). The reaction mixture was stirred at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (10 mL). The aqueous layer was extracted with DCM (2×10 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (159 mg, 0.29 mmol, 86% yield, 90% purity) as a yellow oil. UPLC / MS (Method 5): m / z 495 (M+H)+, R T 1.88 minutes.

[0663] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (159 mg, 0.321 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (91.0 mg, 0.395 mmol) in THF (3.2 mL). tA solution of BuBrettPhos Pd G3 (28 mg, 32.9 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (395 μL, 395 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–5% MeOH / DCM) followed by further purification on RP flash C18 (24 g cartridge, 30–100% MeCN / 10 mM ammonium bicarbonate) afforded the title compound (153 mg, 0.18 mmol, 55% yield, 80% purity) as a yellow solid. UPLC / MS (Method 5): m / z 689 (M+H)+, R T 1.77 minutes.

[0664] Step 4 (3R,4R)-4-(((3-ethyl-7-(((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (900 μL, 3.6 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (155 mg, 0.180 mmol) in dioxane (2.3 mL). The reaction mixture was stirred at 40° C. RT for 2 h and concentrated in vacuo. The residue 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 to give the title compound (89 mg, 0.18 mmol, 99% yield, 98% purity). UPLC / MS (method 3): m / z 489 (M+H)+, R T0.70 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.95 - 7.87 (m, 2H), 7.68 - 7.60 (m, 2H), 7.57 (d,J = 7.1 Hz, 1H), 7.41 (dd,J = 7.1, 9.2 Hz, 1H), 6.77 (t,J = 5.9 Hz, 1H), 5.41 - 5.36 (m, 1H), 5.35 (s, 1H), 4.62 (d,J = 6.3 Hz, 2H), 3.60 - 3.47 (m, 1H), 3.23 - 3.14 (m, 1H), 3.06 - 2.96 (m, 1H), 2.90 (dd,J = 4.5, 11.4 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.48 - 2.44 (m, 2H), 2.36 - 2.26 (m, 1H), 2.15 (dd,J = 9.9, 11.6 Hz, 1H), 1.60 - 1.50 (m, 1H), 1.42 - 1.27 (m, 1H), 1.17 (t,J = 7.5 Hz, 3H), 1.16 - 1.09 (m, 1H). 1H under water.

[0665] Synthesis 35 (3R,4R)-4-(((3-cyclopropyl-7-(((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-035)

[0666] [ka]

[0667] Step 1 :5-Chloro-3-cyclopropyl-N-((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (7-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (90 mg, 0.30 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (95 mg, 0.42 mmol) and DIPEA (0.69 mL, 3.9 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 50° C. for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 10% MeOH / DCM) afforded the title compound (79 mg, 0.16 mmol, 54% yield, 84% purity) as a beige solid. UPLC / MS (Method 5): m / z 407 (M+H)+, R T 1.51 minutes.

[0668] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (35 mg, 0.16 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (55 mg, 0.14 mmol) and DMAP (3.3 mg, 27 μmol) in THF (2.0 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, 0–100% EtOAc / isohexane) afforded the title compound (57 mg, 0.10 mmol, 74% yield, 89% purity) as a yellow gum. UPLC / MS (Method 5): m / z 507 (M+H)+, R T 1.84 minutes.

[0669] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((7-(trifluoromethyl)imidazo[1,2-a]pyridin-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)((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (55 mg, 0.11 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (27 mg, 0.12 mmol) and tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (55 mg, 0.11 mmol) in THF (1.0 mL). t A solution of BuBrettPhos Pd G3 (9.3 mg, 11.3 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.14 mL, 0.14 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH / DCM) afforded the title compound (53 mg, 73 μmol, 67% yield, 96% purity) as a white solid. UPLC / MS (Method 5): m / z 701 (M+H)+, R T 1.72 minutes.

[0670] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.20 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (50 mg, 71 μmol) in DCM (0.80 mL). The reaction mixture was stirred at room temperature for 18 hours and 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 methanolic solution was concentrated in vacuo and the title compound (23 mg, 44 μmol, 61% yield, 95% purity) was obtained as an off-white solid after trituration from Et2O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 5): m / z 501 (M+H)+, R T 1.21 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d,J = 7.1 Hz, 1H), 7.99 (s, 2H), 7.73 (t,J = 6.2 Hz, 1H), 7.52 (s, 1H), 7.15 (dd,J = 7.2, 1.9 Hz, 1H), 6.73 - 6.68 (m, 1H), 5.33 - 5.27 (m, 1H), 5.25 (s, 1H), 4.62 (d,J = 6.1 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.25 - 3.15 (m, 1H), 3.08 - 2.97 (m, 1H), 2.90 (dd,J = 11.7, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2 2.34 - 2.25 (m, 1H), 2.21 - 2.09 (m, 1H), 1.78 - 1.66 (m, 1H), 1.59 - 1.51 (m, 1H), 1.37 - 1.27 (m, 1H), 1.19 - 1.05 (m, 1H), 0.79 - 0.74 (m, 2H), 0.70 - 0.60 (m, 2H). 1H under water.

[0671] Intermediate Synthesis A13 (7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[0672] [ka]

[0673] Step A :2-((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione 4-(Trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol), 2-(3-bromo-2-oxopropyl)isoindoline-1,3-dione (366 mg, 1.23 mmol), and sodium bicarbonate (104 mg, 1.23 mmol) in ethanol (0.60 mL) were heated to 80 °C under microwave irradiation for 1 h. The mixture was then concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) afforded the title compound (348 mg, 0.80 mmol, 65% yield, 79% purity) as a yellow solid. UPLC / MS (Method 5): m / z 364 (M+H)+, R T 1.02 minutes.

[0674] Step B (7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine Hydrazine (35% wt. in water) (250 μL, 2.79 mmol) was added to a suspension of 2-(((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamoyl)benzoic acid (348 mg, 105 μmol) in EtOH (4.0 mL). The suspension was stirred at 65° C. for 3 h. The mixture was concentrated in vacuo and then diluted with 1 M aqueous HCl (20 mL). The white solid was filtered off and washed with 1 M aqueous HCl (2×20 mL). The combined aqueous layers were then basified with solid NaHCO and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO, filtered, and then 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 NH in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound as a brown oil (90 mg, 0.31 mmol, 38% yield, 73% purity). UPLC / MS (Method 5): m / z 216 (M+H)+, R T 0.82 minutes.

[0675] Synthesis 36 (3R,4R)-4-(((3-cyclopropyl-7-(((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-036)

[0676] [ka]

[0677] Step 1 :5-chloro-3-cyclopropyl-N-((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methanamine (155 mg, 786 μmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (163 mg, 715 μmol) and DIPEA (0.12 mL, 715 μmol) in EtOH (10 mL). The reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was concentrated in vacuo, and the residue was triturated in MeCN to give the title compound (170 mg, 0.43 mmol, 61% yield, 99% purity) as a white solid. UPLC / MS (Method 3): m / z 389 (M+H)+, R T 1.52 minutes.

[0678] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)carbamate BOC anhydride (180 mg, 823 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (160 mg, 412 μmol) and DMAP (10.1 mg, 82.3 μmol) in DMF (5.0 mL). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2×20 mL), and the combined organic layers were washed with brine (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% (0.7 M NH3 / MeOH) / DCM) afforded the title compound (190 mg, 0.25 mmol, 60% yield, 64% purity) as a yellow solid. UPLC / MS (Method 5): m / z 488 (M+H)+, R T 1.83 minutes.

[0679] Step 3tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5,6-difluoro-1-methyl-1H-benzo[d]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)((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)carbamate (190 mg, 249 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (68.7 mg, 298 μmol) in THF (2.0 mL). t A solution of BuBrettPhos Pd G3 (21.3 mg, 24.9 μmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (323 μL, 323 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 18 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (103 mg, 0.13 mmol, 50% yield, 83% purity) as a yellow solid. UPLC / MS (Method 5): m / z 684 (M+H)+, R T 1.73 minutes.

[0680] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (626 μL, 2.50 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (103 mg, 125 μmol) in dioxane (2.0 mL). The reaction mixture was stirred at 35° C. for 4 hours and 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 (28 mg, 54 μmol, 43% yield, 93% purity). UPLC / MS (Method 3): m / z 484 (M+H)+, R T 0.72 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 - 7.70 (m, 2H), 7.66 (dd,J = 11.1, 7.4 Hz, 1H), 7.53 (s, 1H), 6.84 - 6.73 (m, 1H), 5.38 (s, 1H), 5.28 - 5.20 (m, 1H), 4.73 (d,J = 5.5 Hz, 2H), 3.83 (s, 3H), 3.55 - 3.44 (m, 1H), 3.27 - 3.16 (m, 1H), 3.08 - 3.00 (m, 1H), 2.95 - 2.86 (m, 1H), 2.81 - 2.74 (m, 1H), 2.33 - 2.23 (m, 1H), 2.19 - 2.09 (m, 1H), 2.03 - 1.83 (m, 1H), 1.77 - 1.66 (m, 1H), 1.61 - 1.53 (m, 1H), 1.20 - 1.10 (m, 1H), 0.79 - 0.73 (m, 2H), 0.67 - 0.63 (m, 2H). 1H under water.

[0681] Intermediate Synthesis A14 (5,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methanamine

[0682] [ka]

[0683] Step A N-(2-amino-4,5-difluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) (3.96 g, 10.4 mmol) was added to a solution of 4,5-difluorobenzene-1,2-diamine (2.00 g, 13.9 mmol), 2-(1,3-dioxoisoindolin-2-yl)acetic acid (1.42 g, 6.94 mmol), and DIPEA (3.6 mL, 20.8 mmol) in THF (25 mL). The reaction mixture was stirred at 50 °C for 72 h. At room temperature, EtOAc (25 mL) and water (10 mL) were added. The resulting solid was collected by filtration and then triturated in MeCN to give the title compound (1.81 g, 5.4 mmol, 78% yield, 99% purity) as an off-white solid. UPLC / MS (Method 5): m / z 332 (M+H)+, R T 1.46 minutes.

[0684] Step B :2-((5,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione A solution of N-(2-amino-4,5-difluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide (1.81 g, 5.46 mmol) in AcOH (15 mL) was stirred for 3 h at 60° C. The reaction mixture was concentrated to dryness and coevaporated twice with toluene (2×10 mL), then triturated with MeCN to give the title compound (1.56 g, 4.9 mmol, 90% yield, 99% purity) as an off-white solid. UPLC / MS (Method 5): m / z 314 (M+H)+, R T 1.47 minutes.

[0685] Step C :2-((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione 2-((5,6-Difluoro-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione (600 mg, 1.92 mmol) was added to a solution of iodomethane (179 μL, 2.87 mmol) and KCO (529 mg, 3.83 mmol) in DMF (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 min and then at room temperature overnight, after which the resulting solid was collected by filtration and washed with water (2.0 mL) and then MeCN (2.0 mL) to give the title compound (610 mg, 1.7 mmol, 88% yield, 90% purity) as a gray solid. UPLC / MS (Method 5): m / z 328 (M+H)+, R T 1.21 minutes.

[0686] Step D :(5,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methanamine Hydrazine hydrate (259 μL, 5.33 mmol) was added to a solution of 2-((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione (600 mg, 1.52 mmol) in EtOH (10 mL). The suspension was stirred at 65° C. overnight. At room temperature, the suspension was filtered, and the solid was washed with IPA (5.0 mL). The filtrate was concentrated under reduced pressure. The residue was loaded onto an SCX column. 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 (300 mg, 1.40 mmol, 89% yield, 89% purity) as a white solid. UPLC / MS (Method 5): m / z 199 (M+H)+, R T0.78 minutes.

[0687] Synthesis 37 (3R,4R)-4-(((3-cyclopropyl-7-(((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-037)

[0688] [ka]

[0689] Step 1 :5-Chloro-3-cyclopropyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (5-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (106 mg, 0.443 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (86 mg, 0.377 mmol) and DIPEA (390 μL, 2.24 mmol) in EtOH (1.6 mL). The reaction mixture was heated at 65° C. for 2 h and then concentrated in vacuo.

[0690] Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (185 mg, 0.37 mmol, 99% yield, 82% purity) as a beige solid. UPLC / MS (Method 3): m / z 407 (M+H)+, R T 1.54 minutes.

[0691] Step 2 tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (97.8 mg, 0.448 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (185 mg, 0.373 mmol) and DMAP (9.1 mg, 74.6 μmol) in THF (7.5 mL). The reaction mixture was stirred at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (30 mL). The aqueous layer was extracted with DCM (2×30 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (167 mg, 0.32 mmol, 87% yield, 98% purity) as an orange oil. UPLC / MS (Method 3): m / z 507 (M+H)+, R T 1.87 minutes.

[0692] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-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)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (167 mg, 0.329 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (91 mg, 0.395 mmol) and tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (167 mg, 0.329 mmol) in THF (3.2 mL). tA solution of BuBrettPhos Pd G3 (28 mg, 0.0329 mmol) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (395 μL, 0.395 mmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 hours. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0–10% MeOH / DCM) afforded the title compound (177 mg, 0.16 mmol, 49% yield, 64% purity) as an orange solid. UPLC / MS (method 3): m / z 701 (M+H)+, R T 1.76 minutes.

[0693] Step 4 (3R,4R)-4-(((3-cyclopropyl-7-(((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.80 mL, 3.20 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (175 mg, 160 μmol) in dioxane (2.2 mL). The reaction mixture 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 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 a yellow solid. Further purification by preparative HPLC (20-100% MeCN / 0.1% NH3 in water) afforded the title compound (41 mg, 79 μmol, 50% yield, 98% purity) as a white solid. UPLC / MS (Method 5): m / z 501 (M+H)+, RT 1.20 minutes. 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 9.3 Hz, 2H), 7.61 (t, J = 6.2 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.51 (s, 1H), 7.44 - 7.35 (m, 1H), 6.74 (t, J = 6.1 Hz, 1H), 5.35 (s, 1H), 5.26 (s, 1H), 4.61 (d, J = 6.0 Hz, 2H), 3.50 (s, 1H), 3.27 - 3.18 (m, 1H), 3.10 - 2.95 (m, 1H), 2.90 (dd, J = 11.6, 4.5 Hz, 1H), 2.82 - 2.74 (m, 2H), 2.36 - 2.23 (m, 1H), 2.20 - 2.10 (m, 1H), 1.77 - 1.65 (m, 1H), 1.60 - 1.51 (m, 1H), 1.40 - 1.24 (m, 1H), 1.19 - 1.07 (m, 1H), 0.80 - 0.71 (m, 2H), 0.71 - 0.53 (m, 2H).

[0694] Intermediate synthesis A15 (5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[0695] [ka]

[0696] Step A :Ethyl 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate 6-(Trifluoromethyl)pyridin-2-amine (1.00 g, 6.17 mmol) and ethyl 3-bromo-2-oxopropanoate (1.6 mL, 12.3 mmol) in IPA (5.8 mL) and water (5.8 mL) were heated at 80 °C under microwave irradiation for 1 h. The reaction mixture was concentrated in vacuo. Purification by column (80 g cartridge, 0-5% (0.7 M NH3 / MeOH) / DCM) afforded the title compound (1.24 g, 4.32 mmol, 67% yield, 90% purity) as a brown oil. UPLC / MS (Method 5): m / z 259 (M+H)+, R T 1.13 minutes.

[0697] Step B (5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol Diisobutylaluminum hydride (1 M in hexanes) (11 mL, 11.0 mmol) was added to a solution of ethyl 5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (860 mg, 2.99 mmol) in THF (9.0 mL) at −40° C. The reaction mixture was allowed to warm to room temperature overnight. At 0° C., MeOH (5.0 mL) was added, followed by water (5.0 mL) and 1 M aqueous HCl (5.0 mL). The mixture was vigorously stirred for 30 minutes and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (453 mg, 2.0 mmol, 57% yield, 95% purity) as a brown oil. UPLC / MS (Method 5): m / z 217 (M+H)+, R T 0.82 minutes.

[0698] Step C : 2-(chloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine, HCl Thionyl chloride (363 μL, 4.98 mmol) was added dropwise to a solution of (5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol (453 mg, 1.99 mmol) in DCM (8.5 mL) at 0° C.

[0699] The mixture was stirred at 0° C. for 2 hours, then at room temperature for 1 hour, and concentrated to dryness under reduced pressure to give the title compound (494 mg, 1.7 mmol, 87% yield, 95% purity) as a brown oil. UPLC / MS (method 3): m / z 271 (M+H)+, R T 1.14 minutes.

[0700] Step D :2-(azidomethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine A solution of 2-(chloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine, HCl (494 mg, 1.73 mmol), and DIPEA (1.9 mL, 11 mmol) in DMF (8.0 mL) was treated with sodium azide (176 mg, 2.71 mmol). The mixture was heated to 60 °C and stirred for 2.5 h. The mixture was cooled to room temperature and diluted with water (10 mL) and brine (10 mL). Extraction with TBME (3 × 20 mL) followed by EtOAc (3 × 20 mL) was performed. The combined organic layers were washed with brine (4 × 20 mL), dried over Na SO , and concentrated under reduced pressure to give the title compound (383 mg, 1.5 mmol, 89% yield, 97% purity) as a brown oil. UPLC / MS (Method 5): m / z 242 (M+H)+, R T 1.12 minutes.

[0701] Step E (5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine 2-(Azidomethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine (383.5 mg, 1.54 mmol), triphenylphosphine (486 mg, 1.85 mmol) were dissolved in THF (8.0 mL) and water (0.90 mL). The mixture was stirred at room temperature overnight, and the solvent was removed 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 (336 mg, 1.4 mmol, 91% yield, 90% purity) as a brown oil. UPLC / MS (Method 5): m / z 216 (M+H)+, R T 0.82 minutes.

[0702] Synthesis 38 (3R,4R)-4-(((7-(((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-038)

[0703] [ka]

[0704] Step 1 :5-chloro-N-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-ethylpyrazolo[1,5-a]pyrimidin-7-amine (6-Cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine (125 mg, 0.333 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5-a]pyrimidine (60.1 mg, 0.278 mmol) and DIPEA (291 μL, 1.67 mmol) in EtOH (1.1 mL). The reaction mixture was heated at 80 °C for 3 h and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (103.6 mg, 0.23 mmol, 82% yield, 96% purity) as a pale beige solid. UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.67 minutes.

[0705] Step 2 tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC anhydride (60.8 mg, 279 μmol) was added to a solution of 5-chloro-N-((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-ethylpyrazolo[1,5-a]pyrimidin-7-amine (103 mg, 232 μmol) and DMAP (5.6 mg, 46.4 μmol) in THF (4.6 mL). The reaction mixture was stirred at 65° C. for 2.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between DCM (20 mL) and water (30 mL). The aqueous layer was extracted with DCM (2×30 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) afforded the title compound (116 mg, 0.20 mmol, 88% yield, 94% purity) as an orange oil. UPLC / MS (Method 3): m / z 535 (M+H)+, R T 2.01 minutes.

[0706] Step 3 tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)carbamate (115 mg, 202 μmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (60.5 mg, 263 μmol) and t A solution of BuBrettPhos Pd G3 (25.9 mg, 30.3 μmol) was degassed with N2 for 10 min. LiHMDS (1 M in THF) (0.26 mL, 263 μmol) was added in one portion under bubbling N2. The bubbling was stopped, and the reaction mixture was heated to 60 °C for 2 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0–10% MeOH / DCM) afforded the title compound (53 mg, 71 μmol, 35% yield, 98% purity) as a beige solid. UPLC / MS (Method 5): m / z 729 (M+H)+, R T 1.84 minutes.

[0707] Step 4 (3R,4R)-4-(((7-(((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.40 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-cyclopropyl-8-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (53 mg, 73 μmol) in DCM (1...

Claims

1. A compound of the formula: 【Chemistry 1】 or a pharma- ceutically acceptable salt or solvate thereof (In the formula, -R 7 is 2-imidazo[1,2-a]pyridinyl, optionally having one or more groups -R SC is replaced by; Each-R SC Independently: -R TT 、 -F, -Cl, -Br, -I, -OH, -OR TT, -CF3, -CHF 2 , -OCF 3 , or -OCHF2 and Each-R TT is independently -R TT1 or -R TT2 ; Each-R TT1 are independently linear or branched saturated C 1-6 is alkyl; Each-R TT2 is the saturated C 3-6 is cycloalkyl; -L 7 - is -CH 2 -; -R 3 is a saturated C 3-7 cycloalkyl.

2. The compound of claim 1, wherein each -R TT1 , if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu.

3. The compound of claim 1, wherein each -R TT1, if present, is -Me.

4. The compound of any one of claims 1 to 3, wherein each -R TT2, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

5. The compound of any one of claims 1 to 3, wherein each -R TT2, if present, is cyclopropyl.

6. The compound of claim 1, wherein R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

7. The compound of claim 1, wherein R 3 is independently cyclopropyl or cyclobutyl.

8. The compound according to claim 1, wherein R 3 is cyclopropyl.

9. A compound of the formula: 【Chemistry 2】 【change】 2. The compound of claim 1, selected from: and pharma- ceutically acceptable salts, hydrates and solvates thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or diluent.

11. A process for preparing a pharmaceutical composition, comprising the step of mixing a compound according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier or diluent.

12. 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 according to any one of claims 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof.

13. 10. A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more of these, in vitro, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 9, or a pharma-ceutically acceptable salt or solvate thereof.

14. 10. A composition for use in a method of treatment of the human or animal body by therapy comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt or solvate thereof.

15. A composition for use in a method for the treatment of a disorder comprising a compound according to any one of claims 1 to 9 or a pharma- ceutically acceptable salt or solvate thereof, The composition, wherein the disorder is a proliferative disorder; cancer; a viral infection; a neurodegenerative disorder; ischemia; a renal disease; a cardiovascular disorder; an autoimmune disorder; or a disorder caused by translation dysfunction in a cell.

16. The composition of claim 15 , wherein the disorder is cancer.

17. The treatment, Aromatase inhibitors, Antiestrogens, Antiandrogens, Her2 blockers, Further cytotoxic chemotherapeutic agents, Drugs that stimulate the immune system, Checkpoint inhibitors, or DNA repair inhibitors 17. The composition of claim 16, further comprising treatment with an additional active agent which is

18. the aromatase inhibitor is exemestane, letrozole, or anastrozole; the antiestrogen is faslodex, tamoxifen, or hydroxytamoxifen; the antiandrogen is flutamide, enzalutamide, apalutamide, bicalutamide, or nilutamide; the Her2 blocking agent is Herceptin, Pertuzumab or Lapatinib; 18. The composition of claim 17, wherein the cytotoxic chemotherapeutic agent is paclitaxel, docetaxel, cyclophosphamide, carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, or 5-fluorouracil.

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