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

Abstract

The present invention generally relates to the field of therapeutic compounds. More specifically, the present invention relates to certain H-APPAMP compounds (referred to herein as "H-APPAMP compounds") that inhibit, in particular, cyclin-dependent protein kinases (CDKs), in particular CDK12 and / or CDK13, and, for example, CDK12 and / or CDK13 over CDK7, selectively. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby removing key signaling mechanisms required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. The present invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions in vitro and in vivo for inhibiting CDK, especially CDK12 and / or CDK13; and for treating diseases, including: diseases associated with CDK, especially CDK12 and / or CDK13; diseases caused by inappropriate activity of CDK, especially CDK12 and / or CDK13; diseases associated with CDK mutations, especially CDK12 and / or CDK13 mutations; diseases associated with CDK overexpression, especially CDK12 and / or CDK 13 overexpression-related disorders; disorders associated with activation of upstream pathways of CDK, especially CDK12 and / or CDK13; disorders improved by inhibiting CDK, especially CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischemia; renal disease; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis); and disorders caused by abnormal translation function in cells (including muscular dystrophy). Optionally, treatment also includes treatment (e.g., simultaneous or sequential treatment) with other active agents such as aromatase inhibitors, antiestrogens, antiandrogens, Her2 blockers, cytotoxic chemotherapeutics, agents that stimulate the immune system, checkpoint inhibitors, DNA repair inhibitors, etc.

Description

[0001] Related applications

[0002] This application is related to United Kingdom (GB) patent application No. 1918541.2 filed on December 16, 2019, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention generally relates to the field of therapeutic compounds. More specifically, the present invention relates to certain H-APPAMP compounds (referred to herein as "H-APPAMP compounds") that inhibit, inter alia, cyclin-dependent protein kinases (CDKs), in particular CDK12 and / or CDK13, and, for example, are selective for CDK12 and / or CDK13 over CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective cyclin K degraders, thereby removing the key signaling mechanisms required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. The present invention also relates to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions for inhibiting CDKs, particularly CDK12 and / or CDK13, in vitro 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 activation of upstream pathways of CDKs, particularly CDK12 and / or CDK13; disorders ameliorated by inhibiting CDKs, particularly CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); disease); ischemia; nephropathy; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis); and disorders caused by abnormal translation function in cells (including muscular dystrophy). Optionally, treatment also includes treatment (e.g., simultaneous or sequential treatment) with other active agents such as aromatase inhibitors, anti-estrogen agents, anti-androgen agents, Her2 blockers, cytotoxic chemotherapeutics, agents that stimulate the immune system, checkpoint inhibitors, DNA repair inhibitors, etc. Background Art

[0004] A number of publications are cited herein in order to more fully describe and disclose the present invention and the state of the art to which the invention 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 had been specifically and individually indicated to be incorporated by reference.

[0005] Throughout this specification, including the following claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" 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.

[0006] It must be noted that, as used in the 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, etc.

[0007] 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 is understood that the particular value forms another embodiment.

[0008] This disclosure includes information that may be useful in understanding the present invention. No admission is made that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

[0009] Cyclin-dependent kinases (CDKs)

[0010] 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 the progression of cells through the stages of growth, DNA replication, and mitosis (see, e.g., Pines, 1995; Morgan, 1995). Activation of specific CDKs is required for proper progression through the different phases of the cell cycle and for entry into the next phase of the cell cycle.

[0011] Cyclin-dependent kinase 12 (CDK12) and its ortholog 13 (CDK13) belong to the serine / threonine protein kinase of the cyclin-dependent kinase (CDK) family, which regulates transcription and post-transcriptional processes, thereby regulating various cellular functions. Studies have characterized CDK12 and CDK13 as transcription CDKs that complex with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II (see, for example, Li et al., 2016; Greifenberg et al., 2016). The CDK12 / cyclin K and CDK13 / cyclin K complexes phosphorylate RNA Pol II at Ser2 (Ser2p-RNA Pol II), which is considered to be a key step in the transition from transcription initiation to elongation. In addition, CDK12 can form a complex with cyclins L1 and L2 to regulate the selective splicing of mRNA transcripts (see, for example, 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). Compared to CDK12, CDK13 regulates a different set of genes, with CDK3 activity primarily implicated in growth signaling pathways including tyrosine kinase signaling (Greifenberg et al., 2016). Studies have also implicated CDK12 in regulating 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 indicate that CDK12 inhibition is an effective strategy for inhibiting tumor growth, and synthetic lethal interactions with numerous pathways relevant to cancer survival and progression have been described (see, e.g., Johnson et al., 2016; Choi et al., 2019).

[0012] Cyclin K degradation is a property of some but not all inhibitors of CDK 12 (see e.g. et al., 2020). Upon binding of an inhibitor with degrader activity, CDK12 acts as an alternative substrate acceptor for the CUL4-DDB1 ubiquitin ligase complex, presenting cyclin K for ubiquitination by CRL4 and 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 via this mechanism, whereas the CDK12-selective covalent inhibitor THZ-531 did not.

[0013] Cyclin K degradation can complement direct inhibition of CDK12 and / or CDK13 in cells. This is advantageous for many reasons. First, degradation can lead to enhanced efficacy compared to kinase inhibition alone, as shown by the increased efficacy of the molecule in cell killing assays. Enhanced cellular efficacy can lead to reduced off-target interactions and effects between the inhibitor and kinases other than CDK12 and / or CDK13. Second, cyclin K is an obligate partner of both CDK12 and CDK13 and is required to achieve their activity. Therefore, cyclin K degraders will result in impaired activity of both kinases, even if the compound shows differential selectivity between CDK12 and CDK13. Finally, cyclin K has been shown to have a half-life of more than 12 hours in cells (see, for example, Lei et al., 2018). Therefore, degraders can have an effect in cells and tumors that can extend beyond the duration of exposure to the compound.

[0014] Known compounds

[0015] Bondke et al. (2015) describe certain pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors, including, for example, the following compound (referred to therein as PPDA-001):

[0016]

[0017] Hazel et al. (2017) describe studies of the selectivity of CDK7 inhibitors, including ICEC0942 (shown below). Patel et al. (2018) describe studies of the CDK7 inhibitor ICEC0942 in the treatment of cancer.

[0018]

[0019] Johannes et al. (2018) describe studies to identify a class of selective CDK12 inhibitors including the lead compound shown below and denoted therein as "Compound 7."

[0020]

[0021] Bahl et al. (2019) describe four specific pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK inhibitors, including, for example, the following compound (referred to therein as APPAMP-001):

[0022]

[0023] Kugel (2019) describes the use of CDK7 in general in the treatment of certain subtypes of pancreatic cancer. A list of known CDK7 inhibitors is shown on pages 26-30.

[0024] Kwiatkowski et al. (2019) describe the use of CDK7 in the treatment of tuberous sclerosis complex in general. A list of known CDK7 inhibitors is shown on pages 25-55.

[0025] Roush et al. (2019) describe certain small molecule inhibitors of CDK12 / CDK13 that are said to be useful in treating cancers such as breast cancer, brain cancer, and ovarian cancer. The compounds have the formula, where R 1 is an aryl group or a heteroaryl group. Examples thereof include compounds 6 and 7 shown below.

[0026]

[0027] Efficacy / Selectivity

[0028] The H-APPAMP compounds described herein are potent CDK12 and / or CDK13 inhibitors, for example, the inhibitors are also highly selective for CDK12 and / or CDK13 over CDK7.

[0029] In addition to selectively inhibiting CDK12 and / or CDK13, the H-APPAMP compounds described herein can also act as selective cyclin K degraders, thereby removing key signaling machinery required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. Summary of the Invention

[0030] 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") as described herein.

[0031] Another aspect of the present invention relates to a composition (eg, a pharmaceutical composition) comprising an H-APPAMP compound as described herein and a pharmaceutically acceptable carrier or diluent.

[0032] Another aspect of the present invention relates to a method of preparing a composition (eg, a pharmaceutical composition) comprising the step of mixing an H-APPAMP compound as described herein and a pharmaceutically acceptable carrier or diluent.

[0033] Another aspect of the present invention relates to a method of inhibiting CDK12 and / or CDK13 function in vitro or in vivo (eg, in a cell), comprising contacting the cell with an effective amount of an H-APPAMP compound as described herein.

[0034] Another aspect of the present invention relates to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of cells), 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 as described herein.

[0035] Another aspect of the invention relates to an H-APPAMP compound as described herein for use in a method of treating the human or animal body by therapy, such as for use in a method of treating a condition (eg, a disease) as described herein.

[0036] Another aspect of the invention relates to the use of an H-APPAMP compound as described herein in the manufacture of a medicament, eg, for use in a method of treatment, eg, for use in a method of treating a condition (eg, a disease) as described herein.

[0037] Another aspect of the invention relates to a method of treatment, e.g., a method of treating a condition (e.g., a disease) as described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of an H-APPAMP compound as described herein, preferably in the form of a pharmaceutical composition.

[0038] In one embodiment, the treatment further comprises treatment (e.g., concurrently or sequentially) with other active agents as described herein, e.g., aromatase inhibitors, antiestrogens, antiandrogens, Her2 blockers, cytotoxic chemotherapeutic agents, agents that stimulate the immune system, checkpoint inhibitors, DNA repair inhibitors, etc.

[0039] Another aspect of the invention relates to a kit comprising (a) an H-APPAMP compound as described herein, preferably in the form of a pharmaceutical composition and in a suitable container and / or provided in suitable packaging; and (b) instructions for use, such as written instructions on how to administer the compound.

[0040] Another aspect of the present invention relates to an H-APPAMP compound obtainable by a synthesis method as described herein or a method comprising a synthesis method as described herein.

[0041] Another aspect of the present invention relates to an H-APPAMP compound obtained by a synthesis method as described herein or a method comprising a synthesis method as described herein.

[0042] Another aspect of the present invention relates to novel intermediates as described herein that are suitable for use in the synthetic methods described herein.

[0043] Another aspect of the present invention relates to the use of such novel intermediates as described herein in the synthetic methods described herein.

[0044] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. DETAILED DESCRIPTION

[0045] Compound

[0046] One aspect of the present invention relates to certain compounds related to pyrazolo[1,5-a]pyrimidine-5,7-diamine ("PPDA"):

[0047]

[0048] More specifically, the compounds are related to (3R,4R)-4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol ("APPAMP"):

[0049]

[0050] In addition, all compounds of the present invention have:

[0051] (a) a substituted amino group at position 7 (denoted herein as -NH-L 7 -R 7 );and

[0052] (b) an alkyl or cycloalkyl group (represented herein as -R 3 ).

[0053] More specifically, the group -R7 is a fused bicyclic C having exactly 1, 2 or 3 ring heteroatoms 8-10 Heteroaryl, wherein each ring heteroatom is N, S or O.

[0054] For the avoidance of doubt, the fused bicyclic C 8-10 The heteroaryl group has a 6 / 6, 6 / 5, 5 / 6, or 5 / 5 fused ring structure; that is, 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.

[0055] Therefore, one aspect of the present invention is a compound of the formula: or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein -R 7 、-L 7 -and-R 3 As defined herein (collectively referred to herein as "H-APPAMP compounds" for convenience):

[0056]

[0057] Some embodiments include the following:

[0058] (1) A compound of the following formula:

[0059]

[0060] or a pharmaceutically acceptable salt or solvate thereof;

[0061] in:

[0062] -R 7 is a fused bicyclic C having exactly 1, 2 or 3 ring heteroatoms 8-10 heteroaryl, wherein each ring heteroatom is N, S or O;

[0063] And among them -R 7 :

[0064] Optionally, the carbon is supported by one or more groups -R SC replace; and

[0065] Optionally, on the secondary nitrogen, if present, a group -R SN replace;

[0066] in:

[0067] Each -R SC Independently it is:

[0068] -R TT ,

[0069] -F, -Cl, -Br, -I,

[0070] -OH、-OR TT ,

[0071] -L T -OH、-L T -OR TT ,

[0072] -CF3、-CHF2、-OCF3、-OCHF2、

[0073] -NH2、-NHR TT 、-NR TT 2、-R TM ,

[0074] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2、-L T -R TM ,

[0075] -C(=O)OH、-C(=O)OR TT ,

[0076] -OC(=O)R TT ,

[0077] -C(=O)NH2、-C(=O)NHR TT 、-C(=O)NR TT 2、-C(=O)R TM ,

[0078] -NHC(=O)R TT 、-NR TN C(=O)R TT ,

[0079] -NHC(=O)NH2、-NHC(=O)NHR TT 、-NHC(=O)NR TT 2、-NHC(=O)R TM ,

[0080] -NR TN C(=O)NH2、-NR TN C(=O)NHR TT 、-NR TN C(=O)NR TT 2、-NR TN C(=O)R TM ,

[0081] -NHC(=O)ORTT 、-NR TN C(=O)OR TT ,

[0082] -OC(=O)NH2, -OC(=O)NHR TT 、-OC(=O)NR TT 2. -OC(=O)R TM ,

[0083] -C(=O)R TT ,

[0084] -SR TT 、-S(=O)R TT 、-S(=O)2R TT ,

[0085] -S(=O)NH2, -S(=O)NHR TT 、-S(=O)NR TT 2. -S(=O)R TM ,

[0086] -S(=O)2NH2, -S(=O)2NHR TT 、-S(=O)2NR TT 2. -S(=O)2R TM ,

[0087] -NHS(=O)2R TT 、-NR TN S(=O)2R TT ,

[0088] -CN or -NO2;

[0089] Each -R SN Independently it is:

[0090] -R TT ,

[0091] -L T -OH, -L T -OR TT ,

[0092] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2. -L T -R TM ,

[0093] -C(=O)R TT ,

[0094] -C(=O)OR TT ,

[0095] -C(=O)NH2, -C(=O)NHR TT 、-C(=O)NR TT 2. -C(=O)R TM ,or

[0096] -S(=O)2R TT ;

[0097] in:

[0098] Each -L T - are independently straight or branched chain saturated C 1-4 alkylene;

[0099] Each -R TT Independently -R TT1 、-R TT2 、-L TT -R TT2 、-R TT3 or -L TT -R TT3 ;

[0100] Each -R TT1 are independently straight-chain or branched saturated C 1-6 Alkyl, and optionally substituted by one or more selected from -F, -OH and -OR TTT The group substitution;

[0101] Each -R TT2 Is saturated C 3-6 Cycloalkyl, and optionally substituted by one or more selected from -F, -R TTT , -OH and -OR TTT The group substitution;

[0102] Each -R TT3 is independently phenyl or naphthyl, and is optionally substituted by one or more selected from -F, -Cl, -Br, -I, -R TTT 、OH、-OR TTT 、-OCF3、-NH2、-NHR TTT and -NR TTT 2 group substitution;

[0103] Each -L TT - are independently straight or branched chain saturated C 1-4 alkylene;

[0104] Each -R TN Is a straight chain or branched saturated C 1-4 alkyl, phenyl or benzyl;

[0105] Each -R TM are independently azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, azepanino or diazepanino, and:

[0106] is optionally substituted on carbon with one or more groups selected from: -R TMM 、-C(=O)R TMM 、-S(=O)2R TMM 、-F、-NH2、-NHR TMM 、-NR TMM 2. -OH and -OR TMM ;and

[0107] Optionally substituted on the secondary nitrogen, if present, by a group selected from: -R TMM 、-C(=O)R TMM 、-C(=O)OR TMM and -S(=O)2R TMM ;

[0108] Each -R TTT are independently straight-chain or branched saturated C 1-4 alkyl, phenyl, or benzyl; and

[0109] Each -R TMM are independently straight-chain or branched saturated C 1-4 alkyl, phenyl or benzyl;

[0110] And among them:

[0111] -L 7 - are independently straight or branched chain saturated C 1-3 alkylene, and optionally substituted with one or more groups selected from -F, -OH and -OMe;

[0112] -R 3 Independently -R 3A or -R 3B ;

[0113] -R 3A are independently straight-chain or branched saturated C 1-6 alkyl, and is optionally substituted with one or more groups selected from -F, -OH and -OMe; and

[0114] -R 3B Independently saturated C 3-7 cycloalkyl, and is optionally substituted with one or more groups selected from -F, -OH and -OMe.

[0115] For the avoidance of doubt:

[0116] Such as "C 9-10 Heteroaryl", "C 3-7 The symbol "C" in the term "heterocyclic group" x-y " refers to the number of ring atoms, which may be carbon atoms or heteroatoms (eg, N, O, S, as appropriate). For example, pyridyl is an example of a C6 heteroaryl group, and piperidino is an example of a C6 heterocyclyl group.

[0117] The term "heteroaryl" refers to a group that is attached to the rest of the molecule through an atom that is part of an aromatic ring, wherein the aromatic ring is part of an aromatic ring system, and the aromatic ring system has one or more heteroatoms (e.g., N, O, S, as appropriate). For example, pyridyl is an example of a C6 heteroaryl group, and quinolinyl is a C 10 An example of a heteroaryl group.

[0118] The phrase "substituent on carbon" means a substituent attached to a carbon ring atom. Similarly, the phrase "substituent on a secondary nitrogen" means a substituent attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Thus, a pyridyl group can only have "substituents on carbon," whereas a 1H-pyrrole group can have both "substituents on carbon" and "substituents on secondary nitrogen," as described below.

[0119]

[0120] Similarly, a piperidino group may only have "substituents on carbon," whereas a piperazino group may have both "substituents on carbon" and "substituents on secondary nitrogen," as described below.

[0121]

[0122] Unless otherwise indicated, when a compound is shown or described with one or more chiral centers, and two or more stereoisomers are possible, all such stereoisomers are disclosed and encompassed individually (e.g., as separated from one or more other stereoisomers) and in mixtures (e.g., as an equimolar or non-equimolar mixture of two or more stereoisomers). For example, when a compound has one chiral center, each of the (R) enantiomer and the (S) enantiomer is disclosed and encompassed individually (e.g., as separated from the other enantiomer) and in mixtures (e.g., as an equimolar or non-equimolar mixture of two enantiomers) unless otherwise indicated. For example, the initial carbon atom from which the pendant sec-butyl group -CH(CH3)CH2CH3 is typically chiral, thus producing stereoisomers, such as the (R) enantiomer and the (S) enantiomer (if it is the only chiral center), each of which is disclosed and encompassed.

[0123] Group -R 7

[0124] (2) The compound according to (1), wherein -R 7 is a fused bicyclic C having exactly 1, 2 or 3 ring heteroatoms 9-10 Heteroaryl, wherein each ring heteroatom is N.

[0125] C9 heteroaryl:

[0126] (3) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 1, 2 or 3 ring heteroatoms, wherein each ring heteroatom is N.

[0127] (4) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N.

[0128] (5) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 1 ring heteroatom, wherein the ring heteroatom is N.

[0129] (6) The compound according to (1), wherein -R 7 Independently it is:

[0130] indolyl; indolizinyl; 2H-isoindolyl; 2H-cyclopenta[c]pyridinyl; or 1H-cyclopenta[b]pyridinyl.

[0131]

[0132] (7) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 2 ring heteroatoms, wherein each ring heteroatom is N.

[0133] (8) The compound according to (1), wherein -R 7 Independently it is:

[0134] 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.

[0135]

[0136] (9) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 3 ring heteroatoms, wherein each ring heteroatom is N.

[0137] (10) The compound according to (1), wherein -R 7 Independently it is:

[0138] 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.

[0139]

[0140]

[0141]

[0142] (11) The compound according to (1), wherein -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.

[0143] (12) The compound according to (1), wherein -R 7 are independently: imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; or benzimidazolyl.

[0144] (13) The compound according to (1), wherein -R 7 It is imidazo[1,2-a]pyridinyl.

[0145] (14) The compound according to (1), wherein -R 7 Independently: 2-imidazo[1,2-a]pyridinyl; or 3-imidazo[1,2-a]pyridinyl.

[0146] (15) The compound according to (1), wherein -R 7 is 2-imidazo[1,2-a]pyridinyl (shown below).

[0147]

[0148] (16) The compound according to (1), wherein -R 7 is 3-imidazo[1,2-a]pyridinyl (shown below).

[0149]

[0150] (17) The compound according to (1), wherein -R 7 It is imidazo[1,2-a]pyrimidinyl.

[0151] (18) The compound according to (1), wherein -R 7 is 2-imidazo[1,2-a]pyrimidinyl (shown below).

[0152]

[0153] (19) The compound according to (1), wherein -R 7 It is imidazo[1,2-b]pyridazinyl.

[0154] (20) The compound according to (1), wherein -R 7 is 2-imidazo[1,2-b]pyridazinyl (shown below).

[0155]

[0156] (21) The compound according to (1), wherein -R 7 It is [1,2,4]triazolo[1,5-a]pyridinyl.

[0157] (22) The compound according to (1), wherein -R 7 is 2-[1,2,4]triazolo[1,5-a]pyridinyl (shown below).

[0158]

[0159] (23) The compound according to (1), wherein -R 7 It is a benzimidazolyl group.

[0160] (24) The compound according to (1), wherein -R 7 Independently: 2-benzimidazolyl or 5-benzimidazolyl.

[0161] (25) The compound according to (1), wherein -R 7 is 2-benzimidazolyl (shown below).

[0162]

[0163] (26) The compound according to (1), wherein -R 7 is 5-benzimidazolyl (shown below).

[0164]

[0165] (27) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently N or O.

[0166] (28) The compound according to (1), wherein -R 7 is a fused bicyclic C9 heteroaryl having exactly 1 ring heteroatom, wherein said ring heteroatom is O.

[0167] (29) The compound according to (1), wherein -R 7 It is benzofuranyl.

[0168] (30) The compound according to (1), wherein -R 7 Independently: 2-benzofuranyl or 3-benzofuranyl.

[0169] (31) The compound according to (1), wherein -R 7 is 2-benzofuranyl (shown below).

[0170]

[0171] (32) The compound according to (1), wherein -R 7 is 3-benzofuranyl (shown below).

[0172]

[0173] C8 heteroaryl:

[0174] (33) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 1, 2 or 3 ring heteroatoms, wherein each ring heteroatom is N, S or O.

[0175] (34) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 1, 2 or 3 ring heteroatoms, wherein each ring heteroatom is N or S.

[0176] (35) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N, S or O.

[0177] (36) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N or S.

[0178] (37) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 ring heteroatoms, wherein each ring heteroatom is N, S or O.

[0179] (38) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 ring heteroatoms, wherein each ring heteroatom is N or S.

[0180] (39) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 ring heteroatoms, wherein 1 of the ring heteroatoms is N and 1 of the ring heteroatoms is S or O.

[0181] (40) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 2 ring heteroatoms, wherein 1 of the ring heteroatoms is N and 1 of the ring heteroatoms is S.

[0182] (41) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 3 ring heteroatoms, wherein each ring heteroatom is N, S or O.

[0183] (42) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 3 ring heteroatoms, wherein each ring heteroatom is N or S.

[0184] (43) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 3 ring heteroatoms, wherein 2 of the ring heteroatoms are N and 1 of the ring heteroatom is S or O.

[0185] (44) The compound according to (1), wherein -R 7 is a fused bicyclic C8 heteroaryl having exactly 3 ring heteroatoms, wherein 2 of the ring heteroatoms are N and 1 of the ring heteroatom is S.

[0186] (45) The compound according to (1), wherein -R 7 are independently: imidazo[2,1-b]thiazolyl or imidazo[2,1-b]thiazolyl or imidazo[2,1-b]oxazolyl.

[0187]

[0188] (46) The compound according to (1), wherein -R 7 It is imidazo[2,1-b]thiazolyl.

[0189] (47) The compound according to (1), wherein -R 7 is 6-imidazo[2,1-b]thiazolyl (shown below).

[0190]

[0191] C 10 Heteroaryl:

[0192] (48) The compound according to (1), wherein -R 7 is a fused bicyclic C having exactly 1, 2 or 3 ring heteroatoms 10 Heteroaryl, wherein each ring heteroatom is N.

[0193] (49) The compound according to (1), wherein -R 7 is a fused bicyclic C having exactly 1 or 2 ring heteroatoms 10 Heteroaryl, wherein each ring heteroatom is N.

[0194] (50) The compound according to (1), wherein -R 7 is a fused bicyclic C having exactly 1 ring heteroatom 10 Heteroaryl, wherein the ring heteroatom is N.

[0195] (51) The compound according to (1), wherein -R 7 Independently: quinolinyl or isoquinolinyl.

[0196]

[0197] (52) The compound according to (1), wherein -R 7 It is quinolinyl.

[0198] (53) The compound according to (1), wherein -R 7 is 2-quinolinyl (shown below).

[0199]

[0200] (54) The compound according to (1), wherein -R 7 is 3-quinolinyl (shown below).

[0201]

[0202] (55) The compound according to (1), wherein -R 7 It is isoquinolinyl.

[0203] (56) The compound according to (1), wherein -R 7 is a fused bicyclic C having exactly 2 ring heteroatoms 10 Heteroaryl, wherein each ring heteroatom is N.

[0204] (57) The compound according to (1), wherein -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.

[0205]

[0206] Group -R 7 : Connection point

[0207] (58) The compound according to any one of (1) to (57), wherein -R 7 By -R 7 The ring carbon atoms (e.g. -R 7 non-bridging ring carbon atom of -L 7 -.

[0208] (59) The compound according to any one of (1) to (57), wherein -R 7 By -R 7 The ring nitrogen atom (e.g. -R 7 The non-bridging ring nitrogen atom of 7 -.

[0209] An example of a benzimidazolyl group attached through a non-bridged ring carbon atom is shown below.

[0210]

[0211] Similarly, an example of a benzimidazolyl group attached through a non-bridged ring nitrogen atom is shown below.

[0212]

[0213] Substituent -R SC

[0214] (60) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0215] -R TT ,

[0216] -F, -Cl, -Br, -I,

[0217] -OH, -OR TT ,

[0218] -L T -OH, -L T -OR TT ,

[0219] -CF3, -CHF2, -OCF3, -OCHF2,

[0220] -NH2, -NHR TT 、-NR TT 2. -R TM ,

[0221] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2. -L T -R TM ,

[0222] -C(=O)OH, -C(=O)OR TT ,

[0223] -OC(=O)R TT ,

[0224] -C(=O)NH2, -C(=O)NHR TT 、-C(=O)NR TT 2. -C(=O)R TM ,

[0225] -NHC(=O)R TT ,

[0226] -NHC(=O)NH2, -NHC(=O)NHR TT 、-NHC(=O)NR TT 2. -NHC(=O)R TM ,

[0227] -NHC(=O)OR TT ,

[0228] -OC(=O)NH2, -OC(=O)NHR TT 、-OC(=O)NR TT 2. -OC(=O)R TM ,

[0229] -C(=O)R TT ,

[0230] -S(=O)2R TT ,

[0231] -S(=O)2NH2, -S(=O)2NHR TT 、-S(=O)2NR TT 2. -S(=O)2R TM ,

[0232] -NHS(=O)2R TT ,

[0233] -CN or -NO2.

[0234] (61) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0235] -R TT ,

[0236] -F, -Cl, -Br, -I,

[0237] -OH, -OR TT ,

[0238] -L T -OH, -L T -OR TT ,

[0239] -CF3, -CHF2, -OCF3, -OCHF2,

[0240] -NH2, -NHR TT 、-NR TT 2. -R TM ,

[0241] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2. -L T -R TM ,

[0242] -C(=O)OH, -C(=O)OR TT ,

[0243] -OC(=O)R TT ,

[0244] -C(=O)NH2, -C(=O)NHR TT 、-C(=O)NR TT 2. -C(=O)R TM ,

[0245] -NHC(=O)R TT ,

[0246] -C(=O)R TT ,

[0247] -S(=O)2NH2, -S(=O)2NHR TT 、-S(=O)2NR TT 2. -S(=O)2R TM ,

[0248] -NHS(=O)2R TT ,

[0249] -CN or -NO2.

[0250] (62) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0251] -R TT ,

[0252] -F, -Cl, -Br, -I,

[0253] -OH, -OR TT ,

[0254] -L T -OH, -L T -OR TT ,

[0255] -CF3, -CHF2, -OCF3, -OCHF2,

[0256] -NH2, -NHR TT 、-NR TT 2. -R TM ,

[0257] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2. -L T -R TM ,

[0258] -C(=O)OH, -C(=O)OR TT ,

[0259] -OC(=O)R TT ,

[0260] -C(=O)NH2, -C(=O)NHR TT 、-C(=O)NR TT 2. -C(=O)R TM ,

[0261] -NHC(=O)R TT ,

[0262] -C(=O)R TT ,

[0263] -S(=O)2NH2, -S(=O)2NHR TT 、-S(=O)2NR TT 2. -S(=O)2R TM ,

[0264] -NHS(=O)2R TT ,

[0265] -CN or -NO2.

[0266] (63) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0267] -R TT ,

[0268] -F, -Cl, -Br, -I,

[0269] -OH, -OR TT ,

[0270] -L T -OH, -L T -OR TT ,

[0271] -CF3, -CHF2, -OCF3, -OCHF2,

[0272] -NH2, -NHR TT 、-NR TT 2. -R TM ,

[0273] -L T -NH2、-L T -NHR TT 、-L T -NR TT 2 or -L T -R TM .

[0274] (64) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0275] -R TT ,

[0276] -F, -Cl, -Br, -I,

[0277] -OH, -OR TT ,

[0278] -L T -OH, -L T -OR TT ,

[0279] -CF3, -CHF2, -OCF3 or -OCHF2.

[0280] (65) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0281] -R TT ,

[0282] -F, -Cl, -Br, -I,

[0283] -OH, -OR TT ,

[0284] -CF3, -CHF2, -OCF3 or -OCHF2.

[0285] (66) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0286] -R TT ,

[0287] -F, -Cl, -Br or -I.

[0288] (67) A compound according to any one of (1) to (59), wherein each -R SC Independently it is:

[0289] -R TT .

[0290] Substituent -R SN

[0291] (68) A compound according to any one of (1) to (67), wherein each -R SN Independently it is:

[0292] -R TT ,

[0293] -C(=O)R TT ,

[0294] -C(=O)OR TT ,

[0295] -C(=O)NH2, -C(=O)NHR TT 、-C(=O)NR TT 2. -C(=O)R TM ,or

[0296] -S(=O)2R TT .

[0297] (69) A compound according to any one of (1) to (67), wherein each -R SN Independently it is:

[0298] -R TT ,

[0299] -C(=O)R TT ,or

[0300] -C(=O)OR TT .

[0301] (70) A compound according to any one of (1) to (67), wherein each -R SN yes:

[0302] -R TT .

[0303] Group-L T -

[0304] (71) A compound according to any one of (1) to (70), wherein each -L, if present T - are independently straight or branched chain saturated C 1-3 Alkylene.

[0305] (72) A compound according to any one of (1) to (70), wherein each -L, if present T - is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2- or -CH2CH(CH3)-.

[0306] (73) A compound according to any one of (1) to (70), wherein each -L, if present T - is independently -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0307] (74) A compound according to any one of (1) to (70), wherein each -L, if present T -is-CH2-.

[0308] Group -R TT

[0309] (75) A compound according to any one of (1) to (74), wherein each -R TT Independently -R TT1 、-R TT2 、-R TT3 or -L TT -R TT3 .

[0310] (76) A compound according to any one of (1) to (74), wherein each -R TT Independently -R TT1 、-R TT3 or -L TT -R TT3 .

[0311] (77) A compound according to any one of (1) to (74), wherein each -R TT Yes-R TT1 .

[0312] Group -R TT1

[0313] (78) A compound according to any one of (1) to (77), wherein each -RTT1 are independently straight-chain or branched saturated C 1-6 alkyl.

[0314] (79) A compound according to any one of (1) to (77), wherein each -R TT1 are independently straight-chain or branched saturated C 1-4 Alkyl, and optionally substituted by one or more selected from -F, -OH and -OR TTT The group is substituted.

[0315] (80) A compound according to any one of (1) to (77), wherein each -R TT1 are independently straight-chain or branched saturated C 1-4 alkyl.

[0316] (81) A compound according to any one of (1) to (77), wherein each -R TT1 is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu or -tBu.

[0317] (82) A compound according to any one of (1) to (77), wherein each -R TT1 is independently -Me, -Et, -nPr or -iPr.

[0318] (83) A compound according to any one of (1) to (77), wherein each -R TT1 Yes-Me.

[0319] Group -R TT2

[0320] (84) A compound according to any one of (1) to (83), wherein each -R TT2 Is saturated C 3-6 Cycloalkyl, and optionally substituted by one or more selected from -F, -OH and -OR TTT substituted by a group.

[0321] (85) A compound according to any one of (1) to (83), wherein each -R TT2 Is saturated C 3-6 Cycloalkyl.

[0322] (86) A compound according to any one of (1) to (83), wherein each -R TT2 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0323] (87) A compound according to any one of (1) to (83), wherein each -R TT2 It is cyclopropyl.

[0324] Group -R TT3

[0325] (88) A compound according to any one of (1) to (87), wherein each -R TT3 is phenyl, and is optionally substituted by one or more selected from -F, -Cl, -Br, -I, -R TTT 、OH、-OR TTT 、-OCF3、-NH2、-NHR TTT and -NR TTT 2 group substitution;

[0326] (89) A compound according to any one of (1) to (87), wherein each -R TT3 is phenyl, and is optionally substituted by one or more selected from -F, -Cl, -Br, -I, -R TTT 、OH、-OR TTT and -OCF3 groups.

[0327] (90) A compound according to any one of (1) to (87), wherein each -R TT3 is phenyl, and is optionally substituted by one or more selected from -F, -Cl, -Br, -I and -R TTT substituted by a group.

[0328] (91) A compound according to any one of (1) to (87), wherein each -R TT3 It is phenyl.

[0329] Group-L TT -

[0330] (92) A compound according to any one of (1) to (91), wherein each -L, if present TT - are independently straight or branched chain saturated C 1-3 Alkylene.

[0331] (93) A compound according to any one of (1) to (91), wherein each -L, if present TT - is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2- or -CH2CH(CH3)-.

[0332] (94) A compound according to any one of (1) to (91), wherein each -L, if present TT - is independently -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0333] (95) A compound according to any one of (1) to (91), wherein each -L, if present TT -is-CH2-.

[0334] Group -R TN

[0335] (96) A compound according to any one of (1) to (95), wherein each -R TN are independently straight-chain or branched saturated C 1-4 alkyl.

[0336] (97) A compound according to any one of (1) to (95), wherein each -R TN Yes-Me.

[0337] Group -R TM

[0338] (98) A compound according to any one of (1) to (97), wherein each -R TM are independently azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, azepanino or diazepanino, and:

[0339] is optionally substituted on carbon with one or more groups selected from: -R TMM , -F, -OH and -OR TMM ;and

[0340] Optionally substituted on the secondary nitrogen, if present, by a group selected from: -R TMM 、-C(=O)R TMM and -C(=O)OR TMM .

[0341] (99) A compound according to any one of (1) to (97), wherein each -R TM are independently pyrrolidino, piperidino, piperazino or morpholino, and:

[0342] is optionally substituted on carbon with one or more groups selected from: -R TMM , -F, -OH and -OR TMM ;and

[0343] Optionally substituted on the secondary nitrogen, if present, by a group selected from: -R TMM 、-C(=O)R TMM and -C(=O)OR TMM .

[0344] (100) A compound according to any one of (1) to (97), wherein each -R TM are independently pyrrolidino, piperidino, piperazino or morpholino, and:

[0345] is optionally substituted on carbon with one or more groups selected from: -R TMM ;and

[0346] Optionally substituted on the secondary nitrogen, if present, by a group selected from: -R TMM 、-C(=O)R TMM and -C(=O)OR TMM .

[0347] (101) A compound according to any one of (1) to (97), wherein each -R TM are independently pyrrolidino, piperidino, piperazino or morpholino, and:

[0348] is optionally substituted on carbon with one or more groups selected from: -R TMM ;and

[0349] Optionally substituted on the secondary nitrogen, if present, by a group selected from: -R TMM .

[0350] Group -R TTT

[0351] (102) A compound according to any one of (1) to (101), wherein each -R TTT are independently straight-chain or branched saturated C 1-4 alkyl.

[0352] (103) A compound according to any one of (1) to (101), wherein each -R TTT Yes-Me.

[0353] Group -R TMM

[0354] (104) A compound according to any one of (1) to (103), wherein each -R TMM are independently straight-chain or branched saturated C 1-4 alkyl.

[0355] (105) A compound according to any one of (1) to (103), wherein each -R TMM Yes-Me.

[0356] Group-L 7 -

[0357] (106) The compound according to any one of (1) to (105), wherein -L 7 - are independently straight or branched chain saturated C 1-3 Alkylene.

[0358] (107) The compound according to any one of (1) to (105), wherein -L 7 - is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)CH2- or -CH2CH(CH3)-.

[0359] (108) The compound according to any one of (1) to (105), wherein -L 7 - is independently -CH2-, -CH2CH2- or -CH2CH2CH2-.

[0360] (109) The compound according to any one of (1) to (105), wherein -L 7 - is independently -CH2-, -CH(CH3)-, -C(CH3)2- or -CH(CH2CH3)-.

[0361] (110) The compound according to any one of (1) to (105), wherein -L 7 - is independently -CH2- or -CH(CH3)-.

[0362] (111) The compound according to any one of (1) to (105), wherein -L 7 -is-CH2-.

[0363] (112) The compound according to any one of (1) to (105), wherein -L 7 - is -CH2-, and further, wherein -L 7 -Yes-CD2-.

[0364] Group -R 3

[0365] (113) The compound according to any one of (1) to (112), wherein -R 3 Yes-R 3A .

[0366] (114) The compound according to any one of (1) to (112), wherein -R 3 Yes-R 3B .

[0367] Group -R 3A

[0368] (115) A compound according to any one of (1) to (114), wherein -R 3A are independently straight-chain or branched saturated C 1-6 alkyl.

[0369] (116) A compound according to any one of (1) to (114), wherein -R 3A and -2-butyl, 3-methyl-1-pentyl, 3-methyl-2-pentyl, 3-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.

[0370] (117) A compound according to any one of (1) to (114), wherein -R 3A are independently straight-chain or branched saturated C 1-4 alkyl.

[0371] (118) A compound according to any one of (1) to (114), wherein -R 3A is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu or -tBu.

[0372] (119) A compound according to any one of (1) to (114), wherein -R 3A is independently -Me, -Et, -nPr or -iPr.

[0373] (120) A compound according to any one of (1) to (114), wherein -R 3A is independently -Et, -nPr or -iPr.

[0374] (121) A compound according to any one of (1) to (114), wherein -R 3A Yes -iPr.

[0375] Group -R 3B

[0376] (122) A compound according to any one of (1) to (121), wherein -R 3B Is saturated C 3-7 Cycloalkyl.

[0377] (123) A compound according to any one of (1) to (121), wherein -R 3B is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0378] (124) A compound according to any one of (1) to (121), wherein -R 3B is independently cyclopropyl or cyclobutyl.

[0379] (125) A compound according to any one of (1) to (121), wherein -R 3B It is cyclopropyl.

[0380] (126) A compound according to any one of (1) to (121), wherein -R 3B It is cyclobutyl.

[0381] Some preferred combinations

[0382] (127) The compound according to (1), wherein:

[0383] -R 7 Independently it is:

[0384] imidazo[1,2-a]pyridinyl;

[0385] imidazo[1,2-a]pyrimidinyl;

[0386] benzimidazolyl;

[0387] imidazo[2,1-b]thiazolyl;

[0388] imidazo[1,2-b]pyridazinyl;

[0389] [1,2,4]triazolo[1,5-a]pyridinyl;

[0390] quinolinyl; or

[0391] Benzofuranyl;

[0392] and are optionally substituted as described herein;

[0393] -L 7 - is -CH2- or -CH(CH3)-;

[0394] -R 3 Yes-R 3A or -R 3B ;

[0395] -R 3A is -iPr; and

[0396] -R 3B It is cyclopropyl.

[0397] (128) The compound according to (1), wherein:

[0398] -R 7 Independently it is:

[0399] 2-imidazo[1,2-a]pyridinyl;

[0400] 3-imidazo[1,2-a]pyridinyl;

[0401] 2-imidazo[1,2-a]pyrimidinyl;

[0402] 2-Benzimidazolyl;

[0403] 5-Benzimidazolyl;

[0404] 6-imidazo[2,1-b]thiazolyl;

[0405] 2-imidazo[1,2-b]pyridazinyl;

[0406] 2-[1,2,4]triazolo[1,5-a]pyridinyl;

[0407] 2-quinolinyl;

[0408] 3-quinolinyl; or

[0409] 2-Benzofuryl;

[0410] and are optionally substituted as described herein;

[0411] -L 7 - is -CH2- or -CH(CH3)-;

[0412] -R 3 Yes-R 3A or -R 3B ;

[0413] -R 3Ais -iPr; and

[0414] -R 3B It is cyclopropyl.

[0415] (129) The compound according to (1), wherein:

[0416] -R 7 Independently it is:

[0417] imidazo[1,2-a]pyridinyl; or

[0418] imidazo[1,2-a]pyrimidinyl;

[0419] and are optionally substituted as described herein;

[0420] -L 7 - is -CH2- or -CH(CH3)-;

[0421] -R 3 Yes-R 3A or -R 3B ;

[0422] -R 3A is -iPr; and

[0423] -R 3B It is cyclopropyl.

[0424] (130) The compound according to (1), wherein:

[0425] -R 7 Independently it is:

[0426] 2-imidazo[1,2-a]pyridinyl;

[0427] 2-imidazo[1,2-a]pyrimidinyl;

[0428] and are optionally substituted as described herein;

[0429] -L 7 - is -CH2- or -CH(CH3)-;

[0430] -R 3 Yes-R 3A or -R 3B ;

[0431] -R 3A is -iPr; and

[0432] -R 3B It is cyclopropyl.

[0433] (131) The compound according to (1), wherein:

[0434] -R 7 Independently it is:

[0435] imidazo[1,2-a]pyridinyl;

[0436] imidazo[1,2-a]pyrimidinyl;

[0437] benzimidazolyl; or

[0438] imidazo[2,1-b]thiazolyl;

[0439] and are optionally substituted as described herein;

[0440] -L 7 - is -CH2-;

[0441] -R 3 Yes-R 3A ;and

[0442] -R 3A Yes -iPr.

[0443] (132) The compound according to (1), wherein:

[0444] -R 7 Independently it is:

[0445] imidazo[1,2-a]pyridinyl;

[0446] imidazo[1,2-a]pyrimidinyl; or

[0447] benzimidazolyl;

[0448] and are optionally substituted as described herein;

[0449] -L 7 - is -CH2-;

[0450] -R 3 Yes-R 3A ;and

[0451] -R 3A Yes -iPr.

[0452] (133) The compound according to (1), wherein:

[0453] -R 7 Independently it is:

[0454] 3-imidazo[1,2-a]pyridinyl;

[0455] 2-imidazo[1,2-a]pyridinyl;

[0456] 2-imidazo[1,2-a]pyrimidinyl;

[0457] 2-Benzimidazolyl;

[0458] 5-benzimidazolyl; or

[0459] imidazo[2,1-b]thiazol-6-yl;

[0460] and are optionally substituted as described herein;

[0461] -L 7 - is -CH2-;

[0462] -R 3 Yes-R 3A ;and

[0463] -R 3A Yes -iPr.

[0464] (134) The compound according to (1), wherein:

[0465] -R 7 Independently it is:

[0466] 3-imidazo[1,2-a]pyridinyl;

[0467] 2-imidazo[1,2-a]pyridinyl;

[0468] 2-imidazo[1,2-a]pyrimidinyl;

[0469] 2-benzimidazolyl; or

[0470] 5-Benzimidazolyl;

[0471] and are optionally substituted as described herein;

[0472] -L 7 - is -CH2-;

[0473] -R 3 Yes-R 3A ;and

[0474] -R 3A Yes -iPr.

[0475] Specific compounds

[0476] (135) The compound according to (1), which is selected from the following compounds and pharmaceutically acceptable salts, hydrates and solvates thereof:

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489] combination

[0490] It will be appreciated that certain features of the invention described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination. 7 、-L 3- 、-R 3 All combinations of embodiments of chemical groups represented by , such as , ...

[0491] substantially purified form

[0492] One aspect of the present invention pertains to H-APPAMP compounds as described herein in a substantially purified form and / or in a form that is substantially free of contaminants.

[0493] In one embodiment, the substantially purified form is at least 50% by weight, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, such as at least 95% by weight, such as at least 97% by weight, such as at least 98% by weight, such as at least 99% by weight.

[0494] Unless otherwise specified, a substantially purified form refers to a compound in any stereoisomer or enantiomeric form. For example, in one embodiment, a substantially purified form refers to a mixture of stereoisomers, i.e., purified relative to other compounds. In one embodiment, a substantially purified form refers to one 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 (i.e., a racemic mixture, a racemate) of enantiomers. In one embodiment, a substantially purified form refers to one enantiomer, e.g., an optically pure enantiomer.

[0495] In one embodiment, the contaminants comprise at most 50 wt%, such as at most 40 wt%, such as at most 30 wt%, such as at most 20 wt%, such as at most 10 wt%, such as at most 5 wt%, such as at most 3 wt%, such as at most 2 wt%, such as at most 1 wt%.

[0496] Unless otherwise 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 other enantiomers.

[0497] In one embodiment, the substantially purified form is at least 60% optically pure (i.e., on a molar basis, 60% of the compound 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.

[0498] Isomers

[0499] Certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, atropisometric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis and trans forms; E and Z forms; c, t and r forms; endo and exo forms; R, S and meso forms; D and L forms; d and l forms; (+) and (-) forms; keto, enol and enolate forms; cis and trans forms; cis- and anti-anorthore forms; α and β forms; axial and equatorial forms; boat, chair, twist, envelope and hemi-chair forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0500] Reference to a class of structures necessarily includes structural isomeric forms falling within that class (e.g., C 1-7 Alkyl includes n-propyl and isopropyl; butyl includes n-butyl, isobutyl, sec-butyl and tert-butyl; methoxyphenyl includes o-methoxyphenyl, m-methoxyphenyl and p-methoxyphenyl). However, reference to a specific group or substitution pattern is not intended to include other structures (or constitutional isomers) that differ with respect to the connections between atoms other than by their position in space. For example, reference to methoxy -OCH3 should not be construed as a reference to its structural isomer hydroxymethyl -CH2OH. Similarly, a specific reference to o-chlorophenyl should not be construed as a reference to its structural isomer m-chlorophenyl.

[0501] The above exclusions do not relate to tautomeric forms, such as keto, enol and enolate forms, as in, for example, the following tautomeric pairs: keto / enol (described below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / acid nitro. Reference to one tautomer in this article is intended to encompass both tautomers.

[0502]

[0503] For example, 1H-pyridin-2-one-5-yl and 2-hydroxy-pyridin-5-yl (shown below) are tautomers of one another. Reference to one herein is intended to encompass both.

[0504]

[0505] Note that the term "isomer" specifically includes compounds having one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including 12 C. 13 C and 14 C; O can be in any isotopic form, including 16O and 18 O; etc.

[0506] Unless otherwise specified, 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 known in the art or are readily obtained by modifying the methods taught herein or known methods in a known manner.

[0507] Salt

[0508] It may be appropriate or desirable to prepare, purify and / or handle the corresponding salts of the compounds, such as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are described in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J.Pharm.Sci. , volume 66, pages 1–19.

[0509] For example, if the compound is anionic, or has a functional group that can be anionic (e.g., -COOH can be -COO - ), then the salt can be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth metal cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ and ammonium ions (NH4 + Examples of suitable organic cations include, but are not limited to, substituted ammonium ions (e.g., NH3R + NH2R2 + 、NHR3 + NR4 + ), for example, wherein each R is independently a linear or branched saturated C 1-18 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl-C 1-6 Alkyl and phenyl-C 1-6 An alkyl group, wherein the phenyl group is optionally substituted. Examples of some suitable substituted ammonium ions are those derived from ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 + .

[0510] If the compound is cationic, or has a functional group that can become cationic upon protonation (e.g., -NH2 can become -NH3 + ), then salts can be formed with suitable anions.

[0511] For example, if the parent structure contains a cationic group (e.g., -NMe2 + ) or have a functional group that can become a cation after protonation (e.g. -NH2 can become -NH3 + ), then the salt can be formed with a suitable anion. In the case of quaternary ammonium compounds, a counter anion is usually always present to balance the positive charge. If the cationic group (e.g. -NMe2 + 、-NH3 + ), if the compound contains a group capable of forming an anion (e.g., -COOH), an inner salt (also known as a zwitterion) can be formed.

[0512] Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid, and phosphorous acid.

[0513] Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic 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, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthoic 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, benzenesulfonic 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, those derived from the following polymeric acids: tannic acid, carboxymethylcellulose.

[0514] Particularly suitable for quaternary ammonium compounds (e.g., with -NMe2 + Examples of suitable counterions for the compounds (those containing a group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-naphthalene-bissulfonate, 4-nitrobenzenesulfonate, formate, tartrate, toluenesulfonate, trifluoroacetate, trifluoromethylsulfonate, sulfate. Similarly, if the compound also contains a group capable of forming an anion (e.g., -COOH), an inner salt may be formed.

[0515] Unless otherwise specified, a reference to a particular compound also includes its salt forms.

[0516] Solvates and hydrates

[0517] It may be appropriate or desirable to prepare, purify and / or process the corresponding solvates of the compounds. The term "solvate" is used herein in a conventional sense to refer to a complex of a solute (e.g., a compound, a salt of a compound) and a solvent. If the solvent is water, the solvate may be appropriately referred to as a hydrate, such as a monohydrate, dihydrate, trihydrate, etc.

[0518] Unless otherwise specified, a reference to a particular compound also includes its solvate and hydrate forms.

[0519] Chemical protection forms

[0520] It may be appropriate or desirable to prepare, purify and / or process compounds in chemically protected forms. The term "chemically protected form" is used herein in the conventional chemical sense and relates to compounds in which one or more reactive functional groups are protected to prevent undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvents, etc.). In practice, it is well known that chemical methods are used to reversibly render otherwise reactive functional groups unreactive under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (or in the form of a masked or masking group or blocked or blocked group). By protecting the reactive functional groups, reactions involving other unprotected reactive functional groups can be carried out without affecting the protected group; typically in subsequent steps, the protecting group can be removed or the masking group can be transformed without substantially affecting the rest of the molecule. See, for example Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th ed.; John Wiley and Sons, 2006).

[0521] In organic synthesis, a wide variety of such "protection," "blocking," or "masking" methods are widely used and well known. For example, a compound having two non-equivalent reactive functional groups (both of which would be reactive under specified conditions) can be derivatized so that one functional group is "protected," and therefore unreactive under the specified conditions; so protected, the compound can be used as a reactant having only one reactive functional group. After the desired reaction (involving the other functional group) is completed, the protected group can be "deprotected" to restore it to its original functionality.

[0522] For example, a hydroxy group can be protected as an ether (—OR) or an ester (—OC(═O)R), such as: tert-butyl ether; benzyl ether, diphenylmethyl (diphenylmethyl) ether, or trityl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH , —OAc).

[0523] For example, an aldehyde or ketone group can be protected as an acetal (R—CH(OR) 2 ) or ketal (R 2 C(OR) 2 ), respectively, in which the carbonyl group (>C═O) is converted to a 1,1-diether (>C(OR) 2 ) by reaction with, for example, a primary alcohol in the presence of an acid. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis with water in the presence of an acid.

[0524] For example, an amine group can be protected as an amide (-NRCO-R) or a carbamate (-NRCO-OR), such as: acetamide (-NHCO-CH3); benzyloxyamide (-NHCO-OCH2C6H5, -NH-Cbz); tert-butoxyamide (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propoxyamide (-NHCO-OC(CH3)2C6H4C6H5, -NH-B oxyamide (-NH-Psec); or, where appropriate (e.g., cyclic amines), nitroxide radicals (>NO·).

[0525] For example, a carboxylic acid group can be protected as an ester, for example: C 1-7 Alkyl esters (e.g. methyl ester; tert-butyl ester); C 1-7 Halogenated alkyl esters (e.g., 2,2,2-trihalogenated ethyl esters); 2-tri(C 1-7 Alkyl) silyl-ethyl ester; or C 5-20 Aryl-C 1-7 Alkyl esters (eg benzyl ester; nitrobenzyl ester); or amides or hydrazides, such as acetamide or N,N,N'-trimethylhydrazide.

[0526] For example, a thiol group can be protected as a thioether (—SR), such as benzyl thioether; acetamidomethyl ether (—S—CH 2 NHC(═O)CH 3 ).

[0527] Prodrug

[0528] It may be appropriate or desirable to prepare, purify and / or process the compound in a prodrug form. As used herein, the term "prodrug" refers to a compound that produces a desired active compound in vivo. Typically, a prodrug is inactive or less active than the desired active compound, but may provide advantageous handling, administration or metabolic properties.

[0529] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable metabolically labile esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters can be formed, for example, by esterification of any carboxylic acid group (-C(=O)OH) in the parent compound, where appropriate, any other reactive groups present in the parent compound are previously protected, followed by deprotection if necessary.

[0530] In addition, some prodrugs are enzymatically activated to produce the active compound, or a compound that, after further chemical reaction, produces the active compound (e.g., as 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.

[0531] Composition

[0532] One aspect of the present invention relates to a composition (eg, a pharmaceutical composition) comprising an H-APPAMP compound as described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0533] Another aspect of the present invention relates to a method of preparing a composition (eg, a pharmaceutical composition) comprising mixing an H-APPAMP compound as described herein and a pharmaceutically acceptable carrier, diluent, or excipient.

[0534] use

[0535] The H-APPAMP compounds described herein are useful for treating, for example, proliferative disorders (as "anti-proliferative agents"), cancer (as "anti-cancer agents"), viral infections (as "anti-viral agents"), neurodegenerative diseases (as "anti-neurodegenerative agents"), and the like.

[0536] Use in methods of inhibiting CDK

[0537] One aspect of the present invention relates to a method of inhibiting CDK (eg, CDK12 and / or CDK13) function in vitro or in vivo (eg, in a cell), comprising contacting the cell with an effective amount of an H-APPAMP compound as described herein.

[0538] 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 are known in the art.

[0539] In one embodiment, the method is performed in vitro.

[0540] In one embodiment, the method is performed in vivo.

[0541] In one embodiment, the H-APPAMP compound is provided as a pharmaceutically acceptable composition.

[0542] Any cell type can be treated, including adipose, lung, gastrointestinal (including, e.g., intestine, colon), breast (mammary gland), ovary, prostate, liver (liver), kidney (kidney), bladder, pancreas, brain, and skin.

[0543] For example, a sample of cells can be grown in vitro, and a compound can be contacted with the cells, and the effect of the compound on the cells can be observed. As an example of an "effect," the morphological state of the cells (e.g., alive or dead, etc.) can be determined. When a compound is found to exert an effect on a cell, this can be used as a prognostic or diagnostic marker for the compound's efficacy in a method of treating a patient carrying cells of the same cell type.

[0544] Use in methods for inhibiting cell proliferation, etc.

[0545] The H-APPAMP compounds described herein, for example, (a) modulate (eg, inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) achieve a combination of one or more of these.

[0546] One aspect of the present invention relates to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of cells), 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 as described herein.

[0547] In one embodiment, the method is a method of modulating (eg, inhibiting) cell proliferation (eg, proliferation of a cell) in vitro or in vivo, comprising contacting the cell with an effective amount of an H-APPAMP compound as described herein.

[0548] In one embodiment, the method is performed in vitro.

[0549] In one embodiment, the method is performed in vivo.

[0550] In one embodiment, the H-APPAMP compound is provided as a pharmaceutically acceptable composition.

[0551] Any cell type can be treated, including lung, gastrointestinal (including, e.g., intestine, colon), breast (mammary gland), ovary, prostate, liver (hepatic), kidney (kidney), bladder, pancreas, brain, and skin.

[0552] One of ordinary skill in the art can readily determine whether a candidate compound modulates (e.g., inhibits) cell proliferation, etc. For example, assays are described herein that may be suitably used to assess the activity provided by a particular compound.

[0553] For example, a sample of cells (e.g., from a tumor) can be grown in vitro, and a compound can be contacted with the cells, and the effect of the compound on the cells can be observed. As an example of an "effect," the morphological state of the cells (e.g., alive or dead, etc.) can be determined. When a compound is found to exert an effect on a cell, this can be used as a prognostic or diagnostic marker for the compound's efficacy in a method of treating a patient carrying cells of the same cell type.

[0554] Use in therapeutic methods

[0555] Another aspect of the invention relates to an H-APPAMP compound as described herein for use in a method of treating the human or animal body by therapy, such as for use in a method of treating a condition (eg, a disease) as described herein.

[0556] Use in the manufacture of medicines

[0557] Another aspect of the invention relates to the use of an H-APPAMP compound as described herein in the manufacture of a medicament, eg, for use in a method of treatment, eg, for use in a method of treating a condition (eg, a disease) as described herein.

[0558] In one embodiment, the medicament comprises an H-APPAMP compound.

[0559] Treatment

[0560] Another aspect of the invention relates to a method of treatment, e.g., a method of treating a condition (e.g., a disease) as described herein, comprising administering to a subject in need of treatment a therapeutically effective amount of an H-APPAMP compound as described herein, preferably in the form of a pharmaceutical composition.

[0561] Conditions Treated - CDK-Related Conditions

[0562] In one embodiment (e.g., an embodiment of the use in a method of treatment, an embodiment of the use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is for: a condition (e.g., a disease) associated with CDK, especially CDK12 and / or CDK13; a condition (e.g., a disease) caused by inappropriate activity of CDK, especially CDK12 and / or CDK13; a condition (e.g., a disease) associated with CDK mutations, especially CDK12 and / or CDK13 mutations; a condition (e.g., a disease) associated with overexpression of CDK, especially overexpression of CDK12 and / or CDK13; a condition (e.g., a disease) associated with activation of upstream pathways of CDK, especially CDK12 and / or CDK13; a condition (e.g., a disease) improved by inhibiting (e.g., selectively inhibiting) CDK, especially CDK12 and / or CDK13.

[0563] In one embodiment (eg, an embodiment of use in a method of treatment, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a condition (eg, a disease) associated with a CDK, particularly CDK12 and / or CDK13.

[0564] In one embodiment, the treatment is of a condition (eg, a disease) caused by inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0565] In one embodiment, the treatment is for a condition (e.g., a disease) associated with a CDK mutation, particularly a CDK12 mutation; CDK overexpression, particularly CDK12 and / or CDK13 overexpression (e.g., compared to corresponding normal cells; e.g., wherein the overexpression is 1.5, 2, 3, 5, 10, 20, or 50-fold); or activation of an upstream pathway of a CDK, particularly CDK12 and / or CDK13.

[0566] In one embodiment, the treatment is treatment of a condition (eg, a disease) that is ameliorated by inhibition (eg, selective inhibition) of a CDK, particularly CDK12 and / or CDK13.

[0567] Conditions treated

[0568] In one embodiment (e.g., embodiments of use in methods of treatment, embodiments of use in the manufacture of a medicament, embodiments of methods of treatment), the treatment is of a proliferative disorder; cancer; a viral infection (e.g., HIV); a neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease); ischemia; renal disease; a cardiovascular disorder (e.g., atherosclerosis); or an autoimmune disorder (e.g., rheumatoid arthritis).

[0569] In one embodiment (e.g., an embodiment of use in a method of treatment, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a condition (e.g., a disease) caused by abnormal translation function in a cell, such as muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, and fragile X syndrome.

[0570] In one embodiment (e.g., embodiments of use in methods of treatment, embodiments of use in the manufacture of a medicament, embodiments of methods of treatment), the treatment is of a condition (e.g., a disease) in patients who have received prior therapeutic treatments but received little or no further clinical benefit from those treatments. This includes, for example, patients who have received prior therapeutic treatment with PARP inhibitors, CDK inhibitors, and / or HER2-directed therapies (see, e.g., Johnson et al., 2016; Choi et al., 2019).

[0571] Conditions Treated - Proliferative Disorders

[0572] In one embodiment (eg, an embodiment of the use in a method of treatment, an embodiment of the use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a proliferative disorder.

[0573] As used herein, the term "proliferative disorder" involves unwanted or uncontrolled cell proliferation of excessive or abnormal cells, which is undesirable, such as neoplastic or hyperplastic growth.

[0574] In one embodiment, the treatment is of a proliferative disorder characterized by benign, pre-malignant, or malignant cell proliferation.

[0575] In one embodiment, the treatment is of a hyperplasia; a neoplasm; a tumor (e.g., histiocytoma, glioma, astrocytoma, osteoma); cancer; psoriasis; a bone disease; a fibroproliferative disorder (e.g., a connective tissue fibroproliferative disorder); pulmonary fibrosis; atherosclerosis; or smooth muscle cell proliferation in a blood vessel (e.g., stenosis or restenosis following angioplasty).

[0576] Conditions treated - cancer

[0577] In one embodiment (eg, an embodiment of the use in a method of treatment, an embodiment of the use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of cancer.

[0578] In one embodiment, the treatment is treatment of cancer metastasis.

[0579] Included among the cancers are:

[0580] (1) Epithelial cancers, including tumors arising from stratified squamous epithelium (squamous cell carcinoma) and tumors arising within organs or glands (adenocarcinoma). Examples include breast cancer, colon cancer, lung cancer, prostate cancer, and ovarian cancer.

[0581] (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesotheliomas and mesotheliomas (membranous linings of body cavities); fibrosarcomas (fibrous tissue); angiosarcomas and hemangioendotheliomas (blood vessels); liposarcoma (fatty tissue); gliomas and astrocytomas (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); and mesenchymal and mixed mesodermal tumors (mixed connective tissue types).

[0582] (3) Myeloma.

[0583] (4) Hematopoietic system tumors, including: myeloid and granulocytic leukemias (malignant tumors of myeloid and granulocytic white blood cell series), such as chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); lymphoid, lymphocytic and lymphoblastic leukemias (malignant tumors of lymphoid and lymphocytic blood cell series), such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL); polycythemia vera (malignant tumor of various blood cell products, but red blood cells are dominant).

[0584] (5) Lymphoma, including Hodgkin's and non-Hodgkin's lymphoma.

[0585] (6) Mixed types, including, for example, adenosquamous carcinoma; mixed mesodermal tumor; carcinosarcoma; teratoma.

[0586] For example, in one embodiment, the therapy is treatment of breast cancer.

[0587] In one embodiment, the cancer is associated with CDK, particularly CDK12 and / or CDK13.

[0588] In one embodiment, the cancer is characterized or further characterized by inappropriate activity of a CDK, particularly CDK12 and / or CDK13.

[0589] In one embodiment, the cancer is characterized or further characterized by overexpression of a CDK, particularly CDK12 and / or CDK13.

[0590] In one embodiment, the cancer is characterized or further characterized by amplification of the CDK12 and / or CDK13 genes, including, for example, cancers that overexpress the protein HER2, in which the 17q12-q21 locus is amplified (see, e.g., Choi et al., 2019).

[0591] In one embodiment, the cancer is characterized by or is further characterized by a fusion of a gene that contributes to the emergence of the cancer, including, for example, cancers having a gene fusion of EWS-FLI (see, e.g., Inigues et al., 2018), BCR-ABL, EML4-ALK, FGFR3-TACC3, KIF5B-RET, ETV6-RUNX1, or TMPRSS2-ERG.

[0592] The anti-cancer effect may occur through one or more mechanisms including, but not limited to, regulating cell proliferation, inhibiting cell cycle progression, inhibiting angiogenesis (formation of new blood vessels), inhibiting metastasis (spread of a tumor from its origin), inhibiting cell migration (spread of cancer cells to other parts of the body), inhibiting invasion (spread of tumor cells into adjacent normal structures), promoting apoptosis (programmed cell death), achieving death by necrosis, or inducing death by autophagy. The compounds described herein may be used to treat the cancers described herein independently of the mechanisms discussed herein.

[0593] Conditions Treated - DNA Repair

[0594] In one embodiment (e.g., an embodiment of the use in a method of treatment, an embodiment of the use in the manufacture of a medicament, an embodiment of the method of treatment), the treatment is treatment of a condition (e.g., a disease) in a patient with underexpression, defects, and / or mutations in genes involved in proteins in DNA repair, including, for example, BRCA1, BRCA2, ATM, ATR, BAP1, CDK12, CDK13, CHK1, CHK2, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCI, PALB2, NBS1, WRN, RAD51B, RAD51C, RAD51D, MRE11A, BLM, BRIP1. This includes, for example, cancer patients whose tumors exhibit "BRCAness" (see, e.g., Lord et al., 2019).

[0595] In one embodiment (e.g., an embodiment of use in a method of treatment, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a condition (e.g., a disease) in a patient having underexpression, defects, and / or mutations in genes for proteins involved in non-homologous DNA repair, including, for example, XLF, RAD50, NBS1, MRE11, LIG4, XRCC4, POLL, POLM.

[0596] Conditions treated - viral infections

[0597] In one embodiment (eg, an embodiment of use in a method of treatment, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a viral infection.

[0598] In one embodiment, the treatment is treatment of a viral infection caused by:

[0599] (Group I:) dsDNA viruses, such as adenovirus, herpes virus, pox virus;

[0600] (Group II:) ssDNA viruses, such as parvovirus;

[0601] (Group III:) dsRNA viruses, such as reovirus;

[0602] (Group IV:) (+) ssRNA viruses, such as picornaviruses and togaviruses;

[0603] (Group V:) (-)ssRNA viruses, such as orthomyxoviruses and rhabdoviruses;

[0604] (Group VI:) ssRNA-RT viruses, such as retroviruses; or

[0605] (Group VII:) dsDNA-RT viruses, such as hepadnaviruses.

[0606] As used above: ds: double strand; ss: + strand; (+)ssRNA: + strand RNA; (-)ssRNA: - strand RNA; ssRNA-RT: (+ strand) RNA with a DNA intermediate in the life cycle.

[0607] In one embodiment, the treatment is for human immunodeficiency virus (HIV); hepatitis B virus (HBV); hepatitis C virus (HCV); human papillomavirus (HPV); cytomegalovirus (CMV); or Epstein-Barr virus (EBV); human herpesvirus 8 (HHV) associated with Kaposi sarcoma; Coxsackievirus B3; Borna virus; or influenza virus.

[0608] Conditions Treated - Autoimmune Disorders

[0609] In one embodiment (eg, an embodiment of the use in a method of treatment, an embodiment of the use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of an autoimmune disorder.

[0610] In one embodiment, the treatment is of an autoimmune disorder associated with connective tissue, joints, skin, or eyes.

[0611] In one embodiment, the treatment is treatment of rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or Sjogren's syndrome.

[0612] Conditions treated - Conditions caused by abnormal translation function in cells

[0613] In one embodiment (eg, an embodiment of use in a method of treatment, an embodiment of use in the manufacture of a medicament, an embodiment of a method of treatment), the treatment is treatment of a disorder caused by abnormal translation function in a cell.

[0614] In one embodiment, the treatment is treatment of muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, or fragile X syndrome.

[0615] treat

[0616] The term "treating," as used herein in the context of treating a disorder, generally relates to treating a human or animal (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of the disorder, and includes reducing the rate of progression, halting the rate of progression, alleviating the symptoms of the disorder, ameliorating the disorder, and curing the disorder. Treatment as a preventative measure (i.e., prevention) is also included. For example, the term "treating" encompasses use in situations where a patient has not yet developed a disorder, but is at risk of developing the disorder.

[0617] For example, treatment includes preventing cancer, reducing the occurrence of cancer, alleviating the symptoms of cancer, etc.

[0618] As used herein, the term "therapeutically effective amount" relates to that amount of a compound, or a material, composition, or dosage form containing a compound, effective to produce some desired therapeutic effect when administered according to the desired treatment regimen, commensurate with a reasonable benefit / risk ratio.

[0619] Combination therapy

[0620] The term "treatment" includes combination therapy and therapy, wherein, for example, two or more treatments or therapies are combined sequentially or simultaneously. For example, the compounds described herein can also be used in combination therapy, for example, with other agents. Examples of treatment and therapy include chemotherapy (administration of active agents, including, for example, drugs, antibodies (e.g., as in immunotherapy), prodrugs (including, for example, as in photodynamic therapy, GDEPT, ADEPT, etc.)); surgery; radiotherapy; photodynamic therapy; gene therapy; and controlled diet.

[0621] One aspect of the invention pertains to a compound as described herein, in combination with one or more (eg, 1, 2, 3, 4, etc.) additional therapeutic agents as described below.

[0622] The particular combination will be at the discretion of the physician who will select the dosage using his common general knowledge and dosing regimens known to skilled practitioners.

[0623] The various agents (i.e., the compounds described herein plus one or more other agents) can be administered simultaneously or sequentially, and can each be administered on a different dosage schedule and by different routes. For example, when administered sequentially, the various agents can be administered closely spaced (e.g., within a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 hours or more, or even longer periods when necessary), with the exact dosage regimen being commensurate with the nature of the therapeutic agent(s).

[0624] The various agents (ie, a compound described herein plus one or more other agents) can be formulated together in a single dosage form, or the individual agents can be formulated separately and presented together in a kit, optionally with instructions for their use.

[0625] Examples of additional agents / therapies that may be co-administered / combined with treatment with the H-APPAMP compounds described herein include the following:

[0626] Aromatase inhibitors, such as exemestane (also known as Aromasin), letrozole (also known as Femara), anastrozole (also known as Arimidex), etc.

[0627] Antiestrogens, such as faslodex (also known as Fulvestrant and ICI182780), tamoxifen (also known as Nolvadex), hydroxytamoxifen, etc.;

[0628] Antiandrogens, such as those used to treat prostate cancer, such as flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, and the like;

[0629] Her2 blockers, such as herceptin, pertuzumab, and lapatinib;

[0630] 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.),

[0631] Agents that stimulate the immune system, such as Toll-like receptor (TLR1-13) agonists, stimulator of interferon genes (STING) agonists, etc.;

[0632] Checkpoint inhibitors, such as inhibitors of PD1, PD1L, CTLA4, etc., such as pembrolizumab, atezolizumab, ipilimumab, etc.;

[0633] DNA repair inhibitors, such as PARP inhibitors, such as Olaparib, Niraparib, etc.

[0634] Thus, in one embodiment, treatment further includes treatment (e.g., concurrently or sequentially) with other active agents such as aromatase inhibitors, antiestrogens, antiandrogens, Her2 blockers, cytotoxic chemotherapeutic agents, agents that stimulate the immune system, checkpoint inhibitors, DNA repair inhibitors, and the like.

[0635] Other Uses

[0636] The H-APPAMP compounds described herein can also be used as cell culture additives to inhibit CDKs (eg, CDK12 and / or CDK13).

[0637] 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 in question.

[0638] 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, and the like.

[0639] medicine box

[0640] One aspect of the invention relates to a kit comprising (a) an H-APPAMP compound as described herein or a composition comprising an H-APPAMP compound as described herein, e.g., preferably in a suitable container and / or provided in suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

[0641] The written instructions may also include a list of indications for which the active ingredient is a suitable therapeutic agent.

[0642] Route of administration

[0643] An H-APPAMP compound or a pharmaceutical composition comprising an H-APPAMP compound can be administered to a subject by any suitable route of administration, whether systemically / peripherally or topically (ie, at the desired site of action).

[0644] Examples of routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal sprays); ocular (e.g., by eye drops); pulmonary (e.g., by use of, for example, an aerosol, such as inhalation or insufflation therapy, through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by vaginal suppository); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal injection; and by implantation of a reservoir or depot, for example, subcutaneously or intramuscularly.

[0645] Individual / patient

[0646] The subject / patient can be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., a kangaroo, a wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), a murine (e.g., a mouse), a lagomorph (e.g., a rabbit), an avian (e.g., a bird), a canine (e.g., a dog), a feline (e.g., a cat), an equine (e.g., a horse), a porcine (e.g., a pig), an ovine (e.g., a sheep), a bovine (e.g., a cow), a primate, a simian (e.g., a monkey or ape), a monkey (e.g., a marmoset, a baboon), an ape (e.g., a gorilla, a chimpanzee, an orangutan, a gibbon), or a human.

[0647] Furthermore, the individual / patient may be in any developmental form thereof, such as a fetus.

[0648] In a preferred embodiment, the individual / patient is a human.

[0649] preparation

[0650] While it is possible to administer an H-APPAMP compound alone, it is preferred to provide it as a pharmaceutical formulation (e.g., composition, formulation, medicament) comprising at least one H-APPAMP compound as described herein and one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents), masking agents, colorants, flavorings, and sweeteners. The formulation may also contain other active agents, such as other therapeutic or prophylactic agents.

[0651] Therefore, the present invention also provides pharmaceutical compositions as defined above and methods for preparing pharmaceutical compositions, said methods comprising mixing at least one H-APPAMP compound as described herein and one or more other pharmaceutically acceptable ingredients known to those skilled in the art, such as carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dose) of the compound.

[0652] 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 the individual (e.g., human) in question 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.

[0653] 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.

[0654] The formulations can be prepared by any method well known in the pharmaceutical art. Such methods include the step of associating the compound with a carrier that constitutes one or more auxiliary ingredients. In general, the formulation is prepared by uniformly and intimately associating the compound with a carrier (e.g., a liquid carrier, a finely dispersed solid carrier, etc.), and then, if necessary, shaping the product.

[0655] The formulations may be prepared to provide fast or slow release; immediate, delayed, timed or sustained release; or a combination thereof.

[0656] 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 (including, e.g., coated tablets), granules, powder, lozenge, pastille, capsule (including, e.g., hard and soft gelatin capsules), cachet, pill, ampoule, bolus, suppository, pessary, tincture, gel, paste, ointment, cream, lotion, oil, foam, spray, mist or aerosol.

[0657] The preparation can be suitably provided as a patch, adhesive plaster, bandage, dressing etc., which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation and absorption enhancers. The preparation can also be suitably provided in a reservoir or depot form.

[0658] The compound may be dissolved, suspended, or mixed with one or more other pharmaceutically acceptable ingredients.The compound may be provided in liposomes or other microparticles designed to target the compound, for example, to blood components or one or more organs.

[0659] Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, and boluses.

[0660] Preparations suitable for buccal administration include mouthwashes, lozenges, pastilles, and patches, adhesive plasters, reservoirs, and depots. Lozenges typically contain the compound in a flavoring matrix that is typically sucrose and gum arabic or tragacanth. Pastilles typically contain the compound in an inert matrix such as gelatin and glycerol, or sucrose and gum arabic. Mouthwashes typically contain the compound in a suitable liquid carrier.

[0661] Formulations suitable for sublingual administration include tablets, lozenges, pastilles, capsules, and pills.

[0662] Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, lozenges, pastilles, as well as patches, adhesive plasters, reservoirs, and depots.

[0663] Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive patches, reservoirs, and depots.

[0664] Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, reservoirs, and depots.

[0665] Tablets can be prepared by conventional means, such as compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing in a suitable machine a compound in a free-flowing form (such as a powder or granules), optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropyl methylcellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silicon dioxide); disintegrants (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose); surfactants or dispersants or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methylparaben, propylparaben, sorbic acid); flavorings, flavor enhancers, and sweeteners. Tablets can be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethylcellulose in varying proportions to provide the desired release profile. The tablets may optionally have a coating, for example, to affect the release, such as an enteric coating to provide release in parts of the digestive tract other than the stomach.

[0666] Ointments are typically prepared from the compound and a paraffinic or water-miscible ointment base.

[0667] Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w / w of a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol, and mixtures thereof. Topical formulations may desirably include a compound that enhances absorption or penetration of the compound through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogs.

[0668] Emulsions are typically prepared from a compound and an oil phase, which may optionally contain only an emulsifier (also referred to as an emulgent), or it may contain a mixture of at least one emulsifier with a fat or oil or 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 oil and fat. In summary, one or more emulsifiers, with or without one or more stabilizers, constitute a so-called emulsifying wax, and the wax, together with the oil and / or fat, constitutes a so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.

[0669] Suitable emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The selection of oils or fats suitable for the formulation is based on achieving the desired cosmetic properties, because the solubility of the compound in most oils that may be used in pharmaceutical emulsion formulations can be very low. Therefore, the cream should preferably be a non-greasy, non-colored and washable product with a suitable consistency to avoid leakage from tubes or other containers. Straight or branched monoalkyl esters or dialkyl esters can be used, 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), of which the latter three are preferred esters. Depending on the desired properties, these can be used alone or in combination. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used.

[0670] Formulations suitable for intranasal administration wherein the carrier is a liquid include, for example, nasal spray, nasal drops, or aerosol administration by nebulizer, including aqueous or oily solutions of the compound.

[0671] Formulations suitable for intranasal administration wherein the carrier is a solid include, for example, those provided as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns, for administration by sniffing (i.e., rapid inhalation through the nasal passages from a container containing the powder held close to the nose).

[0672] Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those provided as an aerosol spray from pressurized packs, with the use of a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gas.

[0673] Suitable formulations for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

[0674] Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols such as cocoa butter or salicylates, or as a solution or suspension for treatment by enema.

[0675] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the compound, such carriers as are known in the art to be appropriate.

[0676] Formulations suitable for parenteral administration (e.g., by injection) include aqueous or non-aqueous isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions) in which the compound is dissolved, suspended, or otherwise provided (e.g., in liposomes or other microparticles). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as antioxidants, buffers, preservatives, stabilizers, bacteriostatics, suspending agents, thickeners, and solutes that render the formulation isotonic with the blood (or other relevant body fluids) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of isotonic carriers suitable for use in such formulations include sodium chloride injection, Ringer's solution, or lactated Ringer's injection. Typically, the concentration of the compound in the liquid is from about 1 ng / mL to about 10 μg / mL, for example, from about 10 ng / mL to about 1 μg / mL. The formulations can be provided in single-dose or multi-dose sealed containers such as ampoules and vials and can be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

[0677] dose

[0678] Those skilled in the art will appreciate that appropriate dosages of H-APPAMP compounds and compositions comprising H-APPAMP compounds can vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit with any risks or adverse side effects. The selected dosage level will depend on a variety of factors, including 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 materials used in combination; the severity of the condition; and the patient's species, sex, age, weight, condition, general health, and prior medical history. The amount and route of administration of the H-APPAMP compound will ultimately be at the discretion of the physician, veterinarian, or clinician, but the dosage will generally be selected to achieve a local concentration at the site of action that achieves the desired effect without causing substantial adverse or adverse side effects.

[0679] During the entire course of treatment, administration can be achieved in one dose continuously or intermittently (e.g., in divided doses at appropriate intervals). Methods for determining the most effective means of administration and dosage are well known to those skilled in the art and will vary with the formulation used for therapy, the purpose of therapy, the one or more target cells being treated, and the individual being treated. Single or multiple administrations can be performed at the dosage level and pattern selected by the treating physician, veterinarian, or clinician.

[0680] In general, suitable dosages of H-APPAMP compounds are in the range of about 10 μg to about 250 mg (more usually about 100 μg to about 25 mg) per kilogram of body weight of the subject per day. When the compound is a salt, ester, amide, prodrug, etc., the dosage is calculated based on the parent compound, so the actual weight to be used is increased proportionally.

[0681] Chemical synthesis

[0682] abbreviation

[0683] aq: water-based;

[0684] Boc: tert-butoxycarbonyl;

[0685] Boc2O: di-tert-butyl dicarbonate;

[0686] br: broad peak;

[0687] ca.: about;

[0688] d: doublet;

[0689] t BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium(II);

[0690] DCM: dichloromethane;

[0691] DCE: 1,2-dichloroethane;

[0692] Dioxane: 1,4-dioxane;

[0693] DIPEA: diisopropylethylamine;

[0694] DMAP: 4-(dimethylamino)pyridine;

[0695] EtOAc: ethyl acetate;

[0696] EtOH: ethanol;

[0697] h: hour;

[0698] HPLC: high performance liquid chromatography;

[0699] IPA: isopropyl alcohol;

[0700] LCMS: liquid chromatography–mass spectrometry;

[0701] LiHMDS: lithium hexamethyldisilazide

[0702] m: multiple peak;

[0703] M: volume molar concentration, molecular ion;

[0704] mCPBA: 3-chloroperbenzoic acid;

[0705] MeCN: acetonitrile;

[0706] MeOH: methanol;

[0707] min: minute;

[0708] MS: mass spectrometry;

[0709] NCS: N-chlorosuccinimide;

[0710] NIS: N-iodosuccinimide;

[0711] NMR: nuclear magnetic resonance;

[0712] PdCl2(dppf)·DCM: [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane;

[0713] q: quartet;

[0714] RT: room temperature (about 20°C);

[0715] R T : retention time;

[0716] s: single peak, solid;

[0717] SCX: strong cation exchange;

[0718] t: triplet;

[0719] TBME: tert-butyl methyl ether;

[0720] TFA: trifluoroacetic acid;

[0721] THF: tetrahydrofuran;

[0722] UPLC / MS: Ultra-performance liquid chromatography–mass spectrometry.

[0723] Other abbreviations are intended to convey their generally accepted meanings.

[0724] The structure is named using Produced using the 'Structure to Name' conversion of Professional 17 (PerkinElmer).

[0725] General synthetic methods

[0726] Methods for chemically synthesizing H-APPAMP compounds are described herein. These and / or other well-known methods can be modified and / or adapted in a known manner to provide alternative or improved synthetic methods for H-APPAMP compounds.

[0727] In the first approach, the synthesis begins with a 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with an amine provides the corresponding 5-amino-pyrazolopyrimidine I-2. Boc protection of the amino group provides intermediate I-3. This intermediate is then used in a Buchwald-Hartwig cross-coupling to generate intermediate I-4. Final overall Boc deprotection yields the target compound.

[0728] This approach is illustrated in the following chemical schemes. In one embodiment, R' is isopropyl.

[0729] Solution 1

[0730]

[0731] Representative reaction conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH, 50°C to 90°C; (b) Boc2O, DMAP, THF, RT to 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.

[0732] In the second approach, the synthesis begins with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with sodium thiomethoxide provides 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 produces the 5-amino-pyrazolopyrimidine intermediate I-9. Final Boc deprotection yields the target compound.

[0733] This approach is illustrated in the following chemical schemes. In one embodiment, R' is isopropyl.

[0734] Option 2

[0735]

[0736] Representative reaction conditions for the above scheme are as follows: (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 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.

[0737] In the third approach, the synthesis begins with a 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with ammonium hydroxide provides the corresponding 5-amino-pyrazolopyrimidine I-10. Boc protection of the amino group provides intermediate I-11. Substitution with an alkyl halide Rx provides intermediate I-3. This latter is used in a Buchwald-Hartwig cross-coupling to produce intermediate I-4. Final overall Boc deprotection yields the target compound.

[0738] This approach is illustrated in the following chemical schemes. In one embodiment, R' is isopropyl.

[0739] Option 3

[0740]

[0741] Representative reaction conditions for the above scheme are as follows: (a) NH4OH, 85℃; (b) Boc2O, DMAP, THF, RT to 60℃; (c) RCl, K2CO3 DMF, 70℃; (d) t BuXPhos-Pd-G3, LiHMDS, THF, 60°C; (e) TFA, DCM, RT; or HCl, dioxane, RT to 40°C.

[0742] In the fourth approach, the synthesis begins with a 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative, I-1. Nucleophilic aromatic substitution with an amine provides the corresponding 5-amino-pyrazolopyrimidine, I-2. This is followed by a second nucleophilic aromatic substitution with an amine to provide intermediate I-4. Final Boc deprotection yields the target compound.

[0743] This approach is illustrated in the following chemical schemes. In one embodiment, R' is isopropyl.

[0744] Option 4

[0745]

[0746] 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.

[0747] Chemical Synthesis Examples

[0748] The following examples are provided merely to illustrate the invention and are not intended to limit the scope of the invention as described herein.

[0749] General experimental conditions

[0750] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations.Reaction mixtures were stirred magnetically unless otherwise indicated.

[0751] Unless otherwise indicated, use Grace TM GraceResolv TM Column chromatography is performed on pre-packed silica (40 μm) cartridges on an automated flash chromatography system such as the CombiFlash Rf system.

[0752] Recorded using a Bruker Avance III spectrometer (400 MHz) or a Bruker (500 MHz) 1 H NMR spectra. Chemical shifts are expressed in parts per million and are referenced to the central peak of the residual protic solvent or to an internal tetramethylsilane standard. Spectra were recorded at ambient temperature unless otherwise stated.

[0753] 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 either Method 1 or Method 2 described below.

[0754] 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 (aq.) Fractions were collected after detection by UV at a single wavelength measured by a variable wavelength detector.

[0755] SCX resin was purchased from Sigma Aldrich or Silicycle and washed with MeOH before use.

[0756] Analytical methods

[0757] Method 1 – LCMS acidic 4 minute method:

[0758] Column: Waters X-Select CSH C18, 2.5μm, 4.6×30mm

[0759] Detection: UV at 254 nm unless otherwise indicated

[0760] MS ionization: electrospray

[0761] Solvent A: Water / 0.1% formic acid

[0762] Solvent B: MeCN / 0.1% formic acid

[0763]

[0764] Method 2 - LCMS Basic 4 Minute Method:

[0765] Column: Waters X-Bridge BEH C18, 2.5μm, 4.6×30mm

[0766] Solvent A: water / 10 mM ammonium bicarbonate

[0767] Solvent B: MeCN

[0768] (Other parameters are the same as method 1)

[0769] Method 3 - UPLC / MS Acidic 3-Minute Method:

[0770] Column: Waters Acquity CSH C18 (2.1×30mm)

[0771] Detection: Waters Acquity PDA detector, between 210 and 400 nm

[0772] MS ionization: electrospray

[0773] Solvent A: Water / 0.1% formic acid

[0774] Solvent B: MeCN / 0.1% formic acid

[0775] 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 in 3 minutes at a constant flow rate of 0.77 mL / min.

[0776] Method 4 - UPLC / MS Basic 3-Minute Method:

[0777] Column: Waters Acquity BEH C18 column (2.1×30mm)

[0778] Detection: Waters Acquity PDA detector, between 210 and 400 nm

[0779] MS ionization: electrospray

[0780] Solvent A: water / 10 mM ammonium bicarbonate

[0781] Solvent B: MeCN

[0782] (Other parameters are the same as method 3)

[0783] Method 5 - UPLC / MS Basic 3-Minute Method:

[0784] Column: Waters Acquity BEH C18 column (2.1×30mm)

[0785] Detection: Waters Acquity PDA detector, between 210 and 400 nm

[0786] MS ionization: electrospray

[0787] Solvent A: Water / 10 mM ammonium hydroxide

[0788] Solvent B: MeCN

[0789] (Other parameters are the same as method 3)

[0790] Method 6 - UPLC / MS Basic 1-Minute Method:

[0791] Column: Waters Acquity BEH C18 column (2.1×30mm)

[0792] Detection: Waters Acquity PDA detector, between 210 and 400 nm

[0793] MS ionization: electrospray

[0794] Solvent A: water / 10 mM ammonium bicarbonate

[0795] Solvent B: MeCN

[0796] 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 in 1 minute at a constant flow rate of 0.77 mL / min.

[0797] Synthesis 1

[0798] (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

[0799] (H-APPAMP-003)

[0800]

[0801] Step 1:

[0802] 5-Chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[0803] Imidazo[1,2-a]pyridin-2-ylmethylamine dihydrochloride (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 hours. 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 Na2SO4 and concentrated under reduced pressure to produce the title compound (0.160 g, 0.42 mmol, 80% yield, 90% purity) as a white solid.

[0804] UPLC / MS (Method 4): m / z 341 (M+H)+, R T 1.38 minutes.

[0805] Step 2:

[0806] tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl)carbamate

[0807] 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 hours. 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 Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) gave the title compound (0.170 g, 0.37 mmol, 78% yield, 95% purity) as a cream solid.

[0808] UPLC / MS (Method 4): m / z 441 (M+H)+, R T 1.73 minutes.

[0809] Step 3:

[0810] 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

[0811] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (0.094 g, 0.41 mmol) and t A solution of BuBrettPhos Pd G3 (0.029 g, 0.03 mmol) in THF (3 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.51 ml, 0.51 mmol) was added once under bubbling N2. 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 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridges, 0-10% MeOH / DCM) produced the title compound (0.075 g, 0.12 mmol, 34% yield, 98% purity) as a white solid.

[0812] UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.65 minutes.

[0813] Step 4:

[0814] (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

[0815] 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) was added hydrogen chloride (4 M in dioxane) (0.44 mL, 1.77 mmol). The reaction mixture was stirred at room temperature for 16 hours and concentrated in vacuo. The residue was diluted in MeOH (5 mL) and loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL) and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The methanolic ammonia solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH 3 ) / DCM) gave the title compound (0.030 g, 0.07 mmol, 57% yield, 95% purity) as a clear glassy solid.

[0816] UPLC / MS (Method 4): m / z 435 (M+H)+, R T 0.96 minutes.

[0817] 1H NMR (500MHz, DMSO-d6) δ8.50–8.46(m,1H),7.78(s,1H),7.65(t,J=6.3Hz,1H),7.63(s,1H),7.50(d,J=9.1Hz,1H),7.24–7.16(m,1 H),6.85(td,J=6.8,1.2Hz,1H),6.76–6.70(m,1H),5.35–5.30(m,1H),5.28(s,1H),4.56(d,J=5.9Hz,2H),4.12–4.05(m,1H),3.60– 3.48(m,1H),3.17(d,J=4.2Hz,1H),3.06–2.99(m,1H),2.98–2.92(m,1H),2.92(dd,J=11.6,4.8Hz,1H),2.81–2.74(m,1H),2.30(td ,J=12.2,2.7Hz,1H),2.16(dd,J=11.6,9.9Hz,1H),1.58–1.51(m,1H),1.38–1.28(m,1H),1.23(t,J=6.5Hz,6H),1.19–1.10(m,1H).

[0818] Synthesis 2

[0819] (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

[0820] (H-APPAMP-002)

[0821]

[0822] Step 1:

[0823] 5-Chloro-N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[0824] Imidazo[1,2-a]pyrimidin-2-ylmethylamine dihydrochloride (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 hours. 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 Na 2 SO 4 and concentrated under reduced pressure to give the title compound (5.10 g, 14.62 mmol, 96% yield, 98% purity) as a white solid.

[0825] UPLC / MS (Method 3): m / z 342 (M+H)+, R T 1.06 minutes

[0826] Step 2:

[0827] tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)carbamate

[0828] 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 hours. 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 Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) produced the title compound (4 g, 8.60 mmol, 82% yield, 95% purity) as a cream-colored solid.

[0829] UPLC / MS (Method 3): m / z 442 (M+H)+, R T 1.44 minutes.

[0830] Step 3:

[0831] 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

[0832] Tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)carbamate (3.19 g, 7.22 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (1.75 g, 7.58 mmol) and t A solution of BuBrettPhos Pd G3 (0.62 g, 0.72 mmol) in THF (30 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (10.8 ml, 10.8 mmol) was added once under bubbling N2. 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 × 30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (80 g cartridges, 0-10% MeOH / DCM) produced the title compound (2.10 g, 3.24 mmol, 44% yield, 98% purity) as an orange solid.

[0833] UPLC / MS (Method 4): m / z 636 (M+H)+, R T 1.50 minutes.

[0834] Step 4:

[0835] (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

[0836] Hydrogen chloride (4M 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 an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M ammonia in MeOH (30 mL). The methanolic ammonia solution was concentrated in vacuo to produce a yellow solid. Further purification by column chromatography (24 g cartridge, 0-20% MeOH (containing 0.7 M NH3) / DCM) produced a yellow solid. The solid was dissolved in DCM (20 mL) and MeOH (about 1 mL). Diethyl ether (100 mL) was added. A brown solid was formed and collected by filtration to produce the title compound (0.700 g, 1.56 mmol, 47% yield, 98% purity).

[0837] UPLC / MS (Method 4): m / z 436 (M+H)+, R T 0.85 minutes.

[0838] 1 H NMR(500MHz,DMSO-d6)δ8.89(dd,J=6.8,2.1Hz,1H),8.49(dd,J=4.1,2.0Hz,1H),7.78–7.72(m,2H),7.64(s,1H),7.0 2(dd,J=6.7,4.1Hz,1H),6.76(d,J=5.0Hz,1H),5.47(s,1H),5.27(s,1H),4.60(d,J=6.0Hz,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=12.2Hz,1H),2.39(td,J=12.3,2. 9Hz, 1H), 2.25 (d, J = 11.0Hz, 1H), 1.63–1.57 (m, 1H), 1.37 (d, J = 11.7Hz, 1H), 1.24 (t, J = 6.5Hz, 6H), 1.21–1.17 (m, 1H).

[0839] Synthesis 3

[0840] (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

[0841] (H-APPAMP-006)

[0842]

[0843] Step 1:

[0844] 5-Chloro-3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidine

[0845] A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (8.00g, 34.8mmol) in THF (100mL) was cooled to -5 °C and sodium thiomethoxide (2.44g, 34.8mmol) was added. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (400ml) and washed with saturated NaHCO3 aqueous solution (500mL). The aqueous layer was extracted with EtOAc (260mL), and the combined organic layer was washed with brine (160mL), dried over MgSO4 and concentrated in vacuo. The purification by column chromatography (40g cartridges, 0-20% EtOAc / isohexane) produced the title compound (6.00g, 24.6mmol, 71% yield, 99% purity) as a light yellow oil, which solidified upon standing.

[0846] LCMS (method 1): m / z 242 (M+H)+, R T 2.40 minutes.

[0847] Step 2:

[0848] tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate

[0849] 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) and tA solution of BuBrettPhos Pd G3 (300 mg, 0.35 mmol) in THF (10 mL) was degassed for 5 minutes. LiHMDS (1 M in THF) (7.8 mL, 7.74 mmol) was added, and the mixture was degassed for another 5 minutes. The reaction mixture was heated to 60 ° C and stirred for 0.5 hours. The solvent was evaporated, and the residue was 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 cartridges, 0-100% EtOAc / isohexane) produced the title compound (2.30 g, 5.12 mmol, 66% yield, 97% purity) as a yellow solid.

[0850] LCMS (method 1): m / z 436 (M+H)+, R T 2.25 minutes.

[0851] Step 3:

[0852] tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate

[0853] Tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfanyl)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 hour. The reaction mixture was worked up by adding DCM (30 mL) and washed with saturated aqueous NaHCO3 solution (2×30 mL). The aqueous layer was extracted with DCM (3×20 mL). The organic layer was washed with brine, dried over Na2SO4, and the solvent was evaporated to afford the title compound (1.50 g, 3.16 mmol, 81% yield, 95% purity).

[0854] UPLC / MS (Method 4): m / z 452 (M+H)+, R T 1.43 minutes.

[0855] Step 4:

[0856] 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

[0857] 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) was added 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). 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 followed by 0 to 5% MeOH / DCM) gave the title compound (28 mg, 0.046 mmol, 31% yield, 90% purity) as a pale yellow glass.

[0858] UPLC / MS (Method 4): m / z 549 (M+H)+, R T 1.44 minutes.

[0859] Step 5:

[0860] (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

[0861] 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 hours. The mixture was concentrated, 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.

[0862] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 0.97 minutes.

[0863] 1 H NMR(500MHz,DMSO-d6)δ8.14(s,1H),7.88(t,J=6.5Hz,1H),7.65–7.62(m,2H),7.51(d,J=8.3Hz,1H),7.31(dd,J=8.3,1 .6Hz,1H),6.73–6.66(m,1H),5.35–5.29(m,1H),5.22(s,1H),4.53(d,J=6.4Hz,2H),3.81(s,3H),3.57–3.47(m,1H),3.1 9–3.12(m,1H),3.05–2.96(m,1H),2.96–2.91(m,1H),2.89(dd,J=12.0,4.3Hz,1H),2.79–2.73(m,1H),2.34–2.25(m,1H),2.15(dd,J=11.6,10.0Hz,1H),1.55–1.49(m,1H),1.34–1.27(m,1H),1.22(t,J=7.0Hz,6H),1.15–1.07(m,1H),1H under water.

[0864] Synthesis 4

[0865] (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

[0866] (H-APPAMP-005)

[0867]

[0868] 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

[0869] A solution 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% purity) (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 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7 M NH3) / DCM) gave the title compound (26 mg, 0.041 mmol, 5% yield, 85% purity) as a brown solid.

[0870] UPLC / MS (Method 4): m / z 535 (M+H)+, R T 1.45 minutes.

[0871] Step 5:

[0872] (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

[0873] 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 hours and concentrated in vacuo. The residue was diluted in MeOH (5 mL) and loaded onto an SCX cartridge, washed with MeOH (3× column volumes) and eluted with 0.7 M ammonia in MeOH (3× column volumes). The methanolic ammonia solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7 M NH 3 ) / DCM) gave the title compound (5 mg, 10.9 μmol, 27% yield, 95% purity) as a yellow solid.

[0874] UPLC / MS (same method as method 4, but with a 10-minute run): m / z 435 (M+H)+, R T 3.87 minutes.

[0875] 1H NMR (500MHz, DMSO-d6) δ12.30(s,1H),7.71(t,J=6.2Hz,1H),7.66(s,1H),7.55(s,1H),7.44(s,1H),7.14(dd,J=6. 1,3.0Hz,2H),6.81–6.71(m,1H),5.29(s,1H),5.22(s,1H),4.69(d,J=5.8Hz,2H),3.59–3.44(m,1H),3.23–3.14(m ,2H),3.06–2.99(m,1H),2.96(p,J=6.9Hz,1H),2.89(dd,J=11.7,4.6Hz,1H),2.79–2.73(m,1H),2.32–2.24(m,1H) ,2.15(dd,J=11.6,9.9Hz,1H),1.53(dd,J=13.0,3.4Hz,1H),1.32(s,1H),1.24(t,J=6.5Hz,6H),1.18–1.07(m,1H).

[0876] Synthesis 5

[0877] (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

[0878] (H-APPAMP-004)

[0879]

[0880] Step 4:

[0881] 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

[0882] By dioxane (0.5 mL) containing 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) methylamine (0.107 g, 0.666 mmol) 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) gave the title compound (48 mg, 0.041 mmol, 38% yield, 95% purity) as an orange glassy solid.

[0883] UPLC / MS (method 1): m / z 549 (M+H)+, R T 1.32 minutes.

[0884] Step 5:

[0885] (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

[0886] 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) was added hydrogen chloride (4 M in dioxane) (0.40 mL, 1.51 mmol). 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) and loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL) and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The methanolic ammonia solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH 3 ) / DCM) gave the title compound (24 mg, 0.052 mmol, 63% yield, 98% purity) as a brown glassy solid.

[0887] LCMS (method 2): m / z 449 (M+H)+, R T 1.67 minutes.

[0888] 1H NMR (400MHz, DMSO-d6) δ8.32(dt,J=6.8,1.1Hz,1H),7.74(s,1H),7.66(t,J=6.2Hz,1H),7.63(s,1H),7.01(dt,J=6.8,1.2Hz,1H ),6.75(t,J=6.8Hz,1H),6.72–6.68(m,1H),5.35–5.29(m,1H),5.27(s,1H),4.57(d,J=6.1Hz,2H),3.59–3.46(m,1H),3.24–3.1 4(m,1H),3.08–2.99(m,1H),2.96(p,J=6.8Hz,1H),2.90(dd,J=11.9,4.3Hz,1H),2.82–2.73(m,1H),2.47(s,3H),2.35–2.26(m,1H),2.16(dd,J=11.6,9.9Hz,1H),1.59–1.51(m,1H),1.39–1.28(m,1H),1.23(dd,J=6.9,4.8Hz,6H),1.20–1.08(m,1H),1H under water.

[0889] Synthesis 6

[0890] (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

[0891] (H-APPAMP-001)

[0892]

[0893] Steps 4 and 5:

[0894] (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

[0895] 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) 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 (containing 0.7 M NH 3 ) / DCM) gave the corresponding Boc intermediate (40 mg).

[0896] 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 (4M in dioxane) (505 μL, 16.6 mmol) was stirred at room temperature for 16 hours. The solvent was evaporated. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) gave the title compound (15 mg, 45% yield, 95% purity) as a brown solid.

[0897] LCMS (method 2): m / z 449 (M+H)+, R T 1.64 minutes.

[0898] 1 H NMR (500MHz, DMSO-d6) δ7.61(s,1H),7.58(t,J=5.3Hz,1H),7.51(s,1H),7.40(d,J=9.0Hz,1H),7.13(dd,J=9.0,6 .8Hz,1H),6.81–6.74(m,1H),6.68(d,J=6.9Hz,1H),5.42(s,1H),5.31(s,1H),4.96(d,J=5.0Hz,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=6.9,5.2Hz,6H),1.20–1.13(m,1H),1H under water.

[0899] Synthesis 7

[0900] (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

[0901] (H-APPAMP-007)

[0902]

[0903] 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

[0904] A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (80.0 mg, 0.145 mmol), (3-methylimidazo[2,1-b]thiazol-6-yl)methanamine dihydrochloride hydrate (74.9 mg, 0.290 mmol), and DIPEA (0.228 mL, 1.305 mmol) in ethanol (2 mL) was heated under microwave irradiation at 140° C. 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) gave the title compound (40 mg, 0.071 mmol, 49% yield, 97% purity) as a tan solid.

[0905] UPLC / MS (Method 4): m / z 555 (M+H)+, R T 0.52 minutes.

[0906] 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

[0907] 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 hour. The solvent was evaporated. The residue was diluted in MeOH (1 mL) and loaded onto an SCX cartridge, washed with MeOH (approximately 5 mL) and eluted with 0.7 M ammonia in MeOH (approximately 5 mL). The methanolic ammonia solution was concentrated under reduced pressure to afford the title compound (18 mg, 0.038 mmol, 84% yield, 96% purity) as a brown solid after trituration in Et 2 O followed by drying under vacuum at 50° C. overnight.

[0908] UPLC / MS (Method 4): m / z 455 (M+H)+, R T 1.03 minutes.

[0909] 1 H NMR (500MHz, DMSO-d6) δ7.62(s,1H),7.59(s,1H),7.49(t,J=6.1Hz,1H),6.85(q,J=1.3Hz,1H),6.7 9-6.73(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=1.3Hz,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=6.9,6.0Hz,6H),1.21-1.13(m,1H),1H under water.

[0910] Synthesis 8

[0911] 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

[0912] (H-APPAMP-008)

[0913]

[0914] 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

[0915] 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 dihydrochloride (102 mg, 0.435 mmol) and DIPEA (0.23 mL, 1.305 mmol / L) 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) gave the title compound (67 mg, 0.112 mmol, 77% yield, 92% purity) as a yellow oil.

[0916] UPLC / MS (Method 3): m / z 549 (M+H)+, R T 0.84 minutes.

[0917] Step 5: 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

[0918] 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 (4M 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 (containing 0.7 M NH3) / DCM) gave the title compound (32 mg, 0.068 mmol, 55% yield, 95% purity) as an off-white solid after drying under vacuum overnight at 50 °C.

[0919] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 1.08 minutes.

[0920] 1 H NMR(500MHz,DMSO-d6)δ8.93–8.82(m,1H),8.65–8.52(m,1H),8.32(s,1H),7.73(s,1H),7.67(s,1H),7.44(d,J =9.2Hz,1H),7.13(d,J=9.3Hz,1H),6.99–6.86(m,1H),6.12–6.03(m,1H),5.27(s,1H),4.56(d,J=6.0Hz,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=6.6Hz,6H).

[0921] Synthesis 9

[0922] (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

[0923] (H-APPAMP-009)

[0924]

[0925] 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

[0926] 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 dihydrochloride (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 NH 3 ) / DCM) gave the title compound (60 mg, 0.093 mmol, 64% yield, 85% purity) as a brown oil.

[0927] UPLC / MS (Method 3): m / z 549 (M+H)+, R T 0.83 minutes.

[0928] 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

[0929] 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 overnight at room temperature and concentrated to dryness. Purification by column chromatography (4 g cartridge, 0-15% MeOH (containing 0.7 M NH3) / DCM) gave the title compound (33 mg, 0.070 mmol, 67% yield, 95% purity) as an off-white solid after drying under vacuum overnight at 50 °C.

[0930] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 1.07 minutes.

[0931] 1H NMR(500MHz,DMSO-d6)δ8.36(d,J=6.9Hz,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=7.0,1.7Hz,1H),5.61–5.55(m,1H),5.27(s,1H),4.53(d,J=5.9Hz,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 was under water.

[0932] Synthesis 10

[0933] (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

[0934] (H-APPAMP-010)

[0935]

[0936] Step 4: 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

[0937] (3R, 4R) -3-hydroxy -4- (((3-isopropyl -7- (methylsulfinyl) pyrazolo [1,5-a] pyrimidin-5-yl) amino) methyl) piperidine -1- carboxylic acid tert-butyl ester (80 mg, 0.145 mmol) was added to a solution of (5-methylimidazo [1,2-a] pyridin-2-yl) methylamine dihydrochloride (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 allowed to cool to room temperature and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3) / DCM) gave the title compound (85 mg, 0.116 mmol, 80% yield, 75% purity) as a brown oil.

[0938] UPLC / MS (Method 4): m / z 549 (M+H)+, R T 1.50 minutes.

[0939] 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

[0940] 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 overnight at room temperature and concentrated to dryness. Purification was performed by RP flash C18 column chromatography (4 g cartridge, 15-50% MeCN / 10 mM ammonium bicarbonate) to yield 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.

[0941] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 1.07 minutes.

[0942] 1H NMR (500MHz, DMSO-d6) δ7.67(s,1H),7.63(s,1H),7.58(t,J=6.1Hz,1H),7.43(dd,J=8.9,1.2Hz,1H),7.21(d d,J=9.0,6.8Hz,1H),6.79–6.75(m,2H),5.44–5.37(m,1H),5.33(s,1H),4.59(d,J=5.9Hz,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 was under water.

[0943] Synthesis 11

[0944] (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

[0945] (H-APPAMP-011)

[0946]

[0947] 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

[0948] 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 MeOH (15 mL), eluted with 0.7 M NH in MeOH (15 mL) to give a brown oil. Purification by column (4 g cartridge (dry load), 0-10% MeOH (containing 0.7 M NH) / DCM, then 100% MeOH (containing 0.7 M NH)) was followed by purification by RP flash C18 column chromatography (4 g cartridge, 15-75% MeCN / 10 mM ammonium bicarbonate) to give the title compound (5 mg, 9.94 μmol, 9% yield, 90% purity) as a brown solid after precipitation from EtO.

[0949] UPLC / MS (Method 4): m / z 453 (M+H)+, R T 1.01 minutes.

[0950] 1H NMR (500MHz, DMSO-d6) δ8.69(dd,J=4.7,2.5Hz,1H),7.79(s,1H),7.68(t,J=6.2Hz,1H),7.63(s,1H),7.57(dd,J=10.0,5.3 Hz,1H),7.30(ddd,J=10.2,8.4,2.5Hz,1H),6.75-6.68(m,1H),5.30-5.27(m,1H),5.26(s,1H),4.56(d,J=6.1Hz,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 is under water.

[0951] Synthesis 12

[0952] (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

[0953] (H-APPAMP-012)

[0954]

[0955] Step 4: 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

[0956] 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), eluted with 0.7 M NH in MeOH (15 mL)) to give a brown oil. Purification by RP flash C18 column chromatography (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.

[0957] UPLC / MS (Method 4): m / z 569 (M+H)+, R T 1.55 minutes.

[0958] 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

[0959] 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 overnight at room temperature and concentrated to dryness. The crude oil was filtered through SCX (2 g - washed with MeOH (15 mL), 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 (containing 0.7 M NH3) / DCM) followed by purification by RP flash C18 column chromatography (4 g cartridge, 35-100% MeCN / 10 mM ammonium bicarbonate) gave the title compound (10 mg, 0.020 mmol, 44% yield, 92% purity) as a tan solid after precipitation from Et2O followed by drying under vacuum at 50°C overnight.

[0960] UPLC / MS (Method 4): m / z 469 (M+H)+, R T 1.08 minutes.

[0961] 1 H NMR (500MHz, DMSO-d6) δ8.76(d,J=2.1Hz,1H),7.77(s,1H),7.69(t,J=6.3Hz,1H),7.63(s,1H),7.55(d,J=9.6Hz ,1H),7.26(dd,J=9.6,2.1Hz,1H),6.76-6.68(m,1H),5.32-5.27(m,1H),5.25(s,1H),4.56(d,J=6.1Hz,2H),3.6 0-3.47 (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 is under water.

[0962] Synthesis 13

[0963] (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

[0964] (H-APPAMP-013)

[0965]

[0966] 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

[0967] To a solution of (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine acetate (0.11 g, 0.43 mmol) and DIPEA (0.19 mL, 1.1 mmol) in NMP (2 mL) was added 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% by weight, 0.22 mmol). The resulting mixture was heated at 140 °C for 4 h, followed by 160 °C for 4 h under microwave irradiation. The crude oil was filtered over SCX (4 g - washed with MeOH (30 mL), 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 NH 3 ) / DCM) gave the title compound (42 mg, 67 μmol, 31% yield, 92% purity) as a brown oil.

[0968] UPLC / MS (Method 4): m / z 575 (M+H)+, R T 1.58 minutes.

[0969] 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

[0970]

[0266] A solution of 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 hour and concentrated to dryness. The crude oil was purified by SCX (4 g - washed with MeOH (30 mL), eluted with 0.7 M NH 3 in MeOH (30 mL)) to afford the title compound (17 mg, 34 μmol, 92% yield, 95% purity) as a brown solid after precipitation from Et 2 O followed by drying under vacuum at 50° C. overnight.

[0971] UPLC / MS (Method 4): m / z 475 (M+H)+, R T 1.14 minutes.

[0972] 1 H NMR(500MHz,DMSO-d6)δ8.30–8.23(m,1H),7.74(s,1H),7.67(t,J=6.2Hz,1H),7.64(s,1H),6.74–6.69(m,3H),5.36–5.3 0(m,1H),5.28(s,1H),4.58(d,J=5.9Hz,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=11.8,4.9Hz,1H),2.81–2.75(m,1H),2.48–2.43(m,1H),2.35–2.26(m,1H),2.16(dd,J=11.7,9.9Hz,1H),1. 59–1.52(m,1H),1.39–1.29(m,1H),1.24(dd,J=6.9,5.9Hz,6H),1.20–1.11(m,1H),1.04–0.98(m,2H),0.98–0.92(m,2H). 1H under water.

[0973] Intermediate Synthesis A1

[0974] (8-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine acetate

[0975]

[0976] Step A :8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde

[0977] A solution of potassium phosphate (755 mg, 3.55 mmol) in water (2.5 mL) was added to a solution of 8-bromoimidazo[1,2-a]pyridine-2-carboxaldehyde (200 mg, 0.889 mmol) and cyclopropylboronic acid (229 mg, 2.67 mmol) in 1,4-dioxane (10 mL). N2 was bubbled through the reaction mixture for 10 minutes, followed by the addition of PdCl2(dppf) (65.0 mg, 0.089 mmol). N2 was bubbled through the reaction mixture for another 5 minutes, followed by heating at 100 ° C for 3 hours. 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 layer was 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.

[0978] Step B / C :8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methylamine acetate

[0979] A solution of 8-cyclopropylimidazo[1,2-a]pyridine-2-carboxaldehyde (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 hours. At room temperature, the precipitate was collected by filtration and rinsed with EtOH (2 × 2 mL). The solid was further dried under vacuum to provide 8-cyclopropylimidazo[1,2-a]pyridine-2-carboxaldehyde oxime (135 mg) as a brown solid, which was dissolved in AcOH (3 mL). The solution was cooled at 0 ° C, followed by the addition of sodium acetate (11.0 mg, 134 μmol) and zinc powder (658 mg, 10.1 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through celite, rinsed with DCM (20 mL) and MeOH (20 mL). The filtrate was concentrated to dryness to afford an oil. Filtration over SCX (10 g - washed with MeOH (50 mL), eluted with 0.7 M NH3 in MeOH (50 mL)) gave the title compound (164 mg, 663 μmol, 99% yield, 95% purity) as a yellowish oil.

[0980] 1H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[0981] Synthesis 14

[0982] (3R,4R)-4-(((3-Isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[0983] (H-APPAMP-014)

[0984]

[0985] Step 1: 5-Chloro-3-isopropyl-N-(quinolin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

[0986] Quinolin-2-ylmethylamine (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 yield an orange solid.

[0987] Purification by column (12 g cartridge, DCM) gave the title compound (240 mg, 0.67 mmol, 78% yield, 99% purity) as an orange solid.

[0988] 1 H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[0989] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2-ylmethyl)carbamate

[0990] BOC anhydride (193 mg, 886.1 μmol) is 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 for 1.5 hours at 60 ° C. The reaction mixture was concentrated under reduced pressure, then diluted in DCM (15 mL) and washed with brine (3 × 10 mL). The combined organic layer was filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-2.5% MeOH / DCM) produced the title compound (317 mg, 0.67 mmol, 98% yield, 95% purity) as an orange oil.

[0991] UPLC / MS (Method 6): m / z 453 (M+H)+, R T 0.92 minutes.

[0992] Step 3: 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

[0993] Tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2-ylmethyl)carbamate (115 mg, 0.25 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (63 mg, 0.27 mmol) and t A solution of BuBrettPhos Pd G3 (21 mg, 25 μmol) in THF (2.1 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.37 mL, 0.37 mmol) was added once under bubbling N2. 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 cartridges, 0-100% EtOAc / isohexane) produced the title compound (130 mg, 0.19 mmol, 77% yield, 95% purity) as a yellow oil.

[0994] UPLC / MS (Method 4): m / z 646 (M+H)+, R T 1.85 minutes.

[0995] Step 4:(3R,4R)-4-(((3-Isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[0996] 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) was added hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.5 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (66 mg, 0.14 mmol, 81% yield, 97% purity) as an off-white solid after precipitation from Et 2 O and drying under vacuum at 40° C. overnight.

[0997] UPLC / MS (Method 4): m / z 446 (M+H)+, R T 1.18 minutes.

[0998] 1 H NMR(500MHz,DMSO-d6)δ8.35(d,J=8.5Hz,1H),8.04–7.99(m,2H),7.97(dd,J=8.2,1.4Hz,1H),7.81–7.74(m,1H),7.68(s ,1H),7.62–7.57(m,1H),7.53(d,J=8.5Hz,1H),6.75–6.68(m,1H),5.29–5.23(m,1H),5.19(s,1H),4.73(d,J=6.0Hz,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=11.5,4.5Hz,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 is under water.

[0999] Synthesis 15

[1000] (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

[1001] (H-APPAMP-015)

[1002]

[1003] Step 1: 5-Chloro-N-((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1004] (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 / isohexane) gave the title compound (233 mg, 0.57 mmol, 70% yield, 90% purity) as an off-white solid.

[1005] UPLC / MS (Method 6): m / z 369 (M+H)+, R T 0.73 minutes

[1006] 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

[1007] BOC anhydride (179 mg, 819 μmol) is 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 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was distributed 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) produced the title compound (249 mg, 0.50 mmol, 79% yield, 94% purity) as a light yellow solid.

[1008] UPLC / MS (Method 6): m / z 469 (M+H)+, R T 0.84 minutes.

[1009] Step 3: 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

[1010] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (64.9 mg, 0.282 mmol) and t A solution of BuBrettPhos Pd G3 (21.9 mg, 0.0256 mmol) in THF (2.5 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.33 mL, 333 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 4.5 hours. At room temperature, the reaction mixture was filtered through diatomaceous earth and rinsed with EtOAc (15 mL). The filtrate was diluted with water, and the aqueous layer 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) produced the title compound (89 mg, 0.10 mmol, 39% yield, 75% purity) as a brown oil.

[1011] UPLC / MS (Method 4): m / z 663 (M+H)+, R T 1.75 minutes.

[1012] 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

[1013] 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 (1.0 mL) was added hydrogen chloride (4 M in 1,4-dioxane) (0.66 mL, 2.62 mmol). The reaction mixture was stirred at 35 °C for 2.5 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 in MeOH (60 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (40 mg, 83 mmol, 63% yield, 95% purity) as a light yellow solid after precipitation from Et 2 O and drying under vacuum at 40° C. overnight.

[1014] UPLC / MS (Method 4): m / z 463 (M+H)+, R T 1.05 minutes.

[1015] 1H NMR(500MHz,DMSO-d6)δ8.51(d,J=7.0Hz,1H),7.80(t,J=5.4Hz,1H),7.59(s,1H),7.21(s,1H),6.85–6.7 9(m,1H),6.75(dd,J=7.0,1.7Hz,1H),5.33–5.28(m,1H),5.17(s,1H),4.73(d,J=5.1Hz,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 is under water.

[1016] Intermediate Synthesis A2

[1017] (2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)methanamine

[1018]

[1019] Step A / B :2,7-dimethylimidazo[1,2-a]pyridine-3-carbaldehyde oxime / (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methylamine

[1020] A solution of 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxaldehyde (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 hours. The reaction mixture was concentrated under reduced pressure and then redissolved in AcOH (10.5 mL). The solution was cooled at 0 ° C, followed by the addition of sodium acetate (50 mg, 604 μmol) and zinc powder (2.96 g, 45.3 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through celite and rinsed with DCM (100 mL). The filtrate was concentrated to dryness to provide an oil. Filtration over SCX (14 g - washed with MeOH (100 mL), eluted with 0.7 M NH 3 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.

[1021] UPLC / MS (Method 6): m / z 176 (M+H)+, R T 0.42 minutes.

[1022] Synthesis 16

[1023] (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

[1024] (H-APPAMP-016)

[1025]

[1026] Step 1: 5-Chloro-N-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1027] Imidazo[1,2-a]pyridin-3-ylmethylamine dihydrochloride (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 under reflux overnight. The reaction mixture was concentrated in vacuo.

[1028] Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) gave 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.

[1029] 1 H NMR (500 MHz, DMSO-d6) was consistent with the structure of the product.

[1030] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-3-ylmethyl)carbamate

[1031] 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.

[1032] Purification by column chromatography (24 g cartridge, 0-100% EtOAc / isohexane) gave 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.

[1033] UPLC / MS (Method 4): m / z 441 (M+H)+, R T 1.71 minutes.

[1034] 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

[1035] Tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-3-ylmethyl)carbamate (167 mg, 379 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (96.0 mg, 417 μmol) and t A solution of BuBrettPhos Pd G3 (32.4 mg, 37.9 μmol) in THF (3.3 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (492 μl, 492 μmol) was added once under bubbling N2. Bubbling was stopped and the reaction mixture was heated to 60 ° C for 2 hours. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layer was filtered through a phase separator and concentrated under reduced pressure.

[1036] Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane followed by 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.

[1037] UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.64 minutes.

[1038] 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

[1039] 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) was added hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.53 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (40 mL) and the product was eluted with MeOH (40 mL) containing 0.7 M NH. The methanolic ammonia solution was concentrated in vacuo to give the title compound as a white solid after precipitation from Et 2 0 (57 mg, 0.13 mmol, 73% yield, 98% purity).

[1040] UPLC / MS (Method 4): m / z 435 (M+H)+, R T 0.97 minutes.

[1041] 1H NMR(500MHz,DMSO-d6)δ8.48(dd,J=6.8,1.2Hz,1H),7.78(s,1H),7.65(t,J=6.1Hz,1H),7.63(s,1H),7.50(d,J=9.1Hz,1H), 7.24–7.18(m,1H),6.85(td,J=6.7,1.2Hz,1H),6.75–6.69(m,1H),5.33–5.29(m,1H),5.28(s,1H),4.56(d,J=6.0Hz,2H),3.6 0–3.47 (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 is under water.

[1042] Synthesis 17

[1043] (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

[1044] (H-APPAMP-017)

[1045]

[1046] Step 1: 5-Chloro-3-isopropyl-N-((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1047] (3-Methylimidazo[1,2-a]pyridin-2-yl)methylamine (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, 4.8 g) in EtOH (3.2 mL). The reaction mixture was heated overnight at 80 ° C. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) produced the title compound (130 mg, 0.31 mmol, 48% yield, 85% purity) as a yellow solid.

[1048] UPLC / MS (Method 4): m / z 355 (M+H)+, R T 1.48 minutes

[1049] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1050] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (51 mg, 0.11 mmol, 89% yield, 99% purity) as a white solid.

[1051] UPLC / MS (Method 4): m / z 455 (M+H)+, R T 1.80 minutes.

[1052] Step 3: 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

[1053] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (49 mg, 0.21 mmol) and tA solution of BuBrettPhos Pd G3 (17 mg, 19 μmol) in THF (1.9 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.25 mL, 0.25 mmol) was added once under bubbling N2. 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) produced the title compound (140 mg, 0.18 mmol, 95% yield, 85% purity) as a brown oil.

[1054] UPLC / MS (Method 4): m / z 649 (M+H)+, R T 1.69 minutes.

[1055] 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

[1056] 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) was added hydrogen chloride (4 M in dioxane) (1.02 mL, 4.10 mmol). The reaction mixture was stirred at 35 °C for 1.5 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 NH3MeOH solution (50 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (30 mg, 60 μmol, 32%, 95% purity) as a cream solid after precipitation from Et 2 O and drying under vacuum at 40° C. overnight.

[1057] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 1.02 minutes.

[1058] 1H NMR (400MHz, DMSO-d6) δ8.23(d,J=6.9Hz,1H),7.61(s,1H),7.53–7.49(m,1H),7.44(t,J=5.8Hz,1H),7.26–7.17( m,1H),6.93(td,J=6.8,1.2Hz,1H),6.80–6.74(m,1H),5.39(s,1H),5.35–5.31(m,1H),4.55(d,J=5.7Hz,2H),3.6 1–3.47(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=11.6,9.9Hz,1H),1.61–1.52(m,1H),1.40–1.29(m,1H),1.22(dd,J=6.9,5.0Hz,6H),1.19–1.13(m,1H). 4H is not visible.

[1059] Intermediate Synthesis A3

[1060] 3-Methylimidazo[1,2-a]pyridin-2-yl)methanamine

[1061]

[1062] Step A / B :3-Methylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (3-methylimidazo[1,2-a]pyridin-2-yl)methylamine

[1063] A suspension of 3-methylimidazo[1,2-a]pyridine-2-carboxaldehyde (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 hours. The reaction mixture was concentrated under reduced pressure and then redissolved in AcOH (5.0 mL). The solution was cooled at 0 ° C, followed by the addition of sodium acetate (51 mg, 616 μmol) and zinc powder (2.02 g, 30.8 mmol). The reaction mixture was stirred at room temperature overnight, then filtered through celite and rinsed with DCM (50 mL) and MeOH (50 mL). The filtrate was concentrated to dryness to provide an oil. Filtration over SCX (14 g - washed with MeOH (50 mL), eluted with 0.7 M NH 3 in MeOH (50 mL)) gave the title compound (371 mg, 2.2 mmol, 71% yield, 95% purity) as a white solid.

[1064] 1 H NMR (in DMSO-d6) was consistent with the product structure.

[1065] Synthesis 18

[1066] (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

[1067] (H-APPAMP-018)

[1068]

[1069] Step 1: 5-Chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl-d2)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1070] Imidazo [1,2-a] pyridin-2-ylmethyl -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 overnight at 80 ° C. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridges, 0-100% EtOAc / isohexane) produced the title compound (180 mg, 0.50 mmol, 73% yield, 95% purity) as a white solid.

[1071] UPLC / MS (Method 4): m / z 345 (M+H)+, R T 1.36 minutes.

[1072] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2-ylmethyl-d2)carbamate

[1073] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (184 mg, 0.36 mmol, 72% yield, 87% purity) as a white solid.

[1074] UPLC / MS (Method 4): m / z 445 (M+H)+, R T 1.72 minutes.

[1075] 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

[1076] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (105 mg, 457 μmol) and t A solution of BuBrettPhos Pd G3 (35.5 mg, 41.5 μmol) in THF (1.9 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (540 μL, 540 μmol) was added in one portion under bubbling N2. Bubbling was stopped and the reaction mixture was heated to 60 ° C for 1.5 hours. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (236 mg, 0.33 mmol, 80% yield, 90% purity) as a white solid.

[1077] UPLC / MS (Method 4): m / z 637 (M+H)+, R T 1.64 minutes.

[1078] 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

[1079] 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) was added hydrogen chloride (4 M in dioxane) (0.79 mL, 3.14 mmol). The reaction mixture was stirred at 35 °C for 4 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 methanolic ammonia solution was concentrated in vacuo to give the title compound (61 mg, 0.13 mmol, 85% yield, 95% purity) as a white solid after precipitation from Et 2 O and drying under vacuum at 40° C. overnight.

[1080] UPLC / MS (Method 4): m / z 437 (M+H)+, R T 1.03 minutes.

[1081] 1 H NMR(400MHz, DMSO-d6)δ8.48(dt,J=6.8,1.3Hz,1H),7.78(s,1H),7.63(s,2H),7.50(d,J=9.1Hz, 1H),7.20(m,1H),6.85(td,J=6.8,1.2Hz,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 is under water.

[1082] Intermediate synthesis A4

[1083] imidazo[1,2-a]pyridin-2-ylmethyl-d2-amine

[1084]

[1085] Step A :Imidazolo[1,2-a]pyridin-2-ylmethyl-d2-ol

[1086] 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, followed by the addition of water (0.1 mL), followed by the addition of 2M aqueous NaOH solution (0.1 mL), and then water (0.3 mL). The solution was allowed to warm to room temperature and stirred for 15 minutes, followed by the addition of anhydrous MgSO4, and the mixture was stirred for an additional 15 minutes. The mixture was concentrated under reduced pressure.

[1087] Purification by chromatography (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / isohexane) gave the title compound (211 mg, 1.4 mmol, 65% yield, 98% purity) as a white solid.

[1088] UPLC / MS (Method 4): m / z 151 (M+H)+, R T 0.47 minutes.

[1089] Step B :2-(Chloromethyl-d2)imidazo[1,2-a]pyridine hydrochloride

[1090] 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 hours, then concentrated to dryness under reduced pressure to give the title compound (278 mg, 1.3 mmol, 92% yield, 95% purity) as a cream solid.

[1091] UPLC / MS (Method 3): m / z 169 (M+H)+, R T 0.16 minutes.

[1092] Step C :2-(Azidomethyl-d2)imidazo[1,2-a]pyridine

[1093] A solution of 2-(chloromethyl-d2)imidazo[1,2-a]pyridine hydrochloride (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 hours. The mixture was cooled to room temperature and diluted with water (100 mL). It was extracted 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) produced the title compound (150 mg, 0.66 mmol, 49% yield, 77% purity) as a yellow oil.

[1094] UPLC / MS (Method 4): m / z 176 (M+H)+, R T 0.77 minutes.

[1095] Step D :Imidazolo[1,2-a]pyridin-2-ylmethyl-d2-amine

[1096] 2- (azidomethyl -d2) imidazo [1,2-a] pyridine (150mg, 659μmol) and triphenylphosphine (208mg, 791μmol) are dissolved in THF (8.0mL) and water (0.8mL). The mixture is heated to 50 ° C and stirred for 1 hour, and then the solvent is removed in a vacuum. The residue is loaded onto an SCX column. The column is washed with MeOH (30mL) and the product is eluted with 0.7M NH3MeOH solution (30mL). The ammonia methanol solution is concentrated in a vacuum to produce the title compound (102mg, 0.65mmol, 99% yield, 95% purity) as a white solid.

[1097] 1 H NMR (in DMSO-d6) was consistent with the product structure.

[1098] Synthesis 19

[1099] (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

[1100] (H-APPAMP-019)

[1101]

[1102] Step 1:5-Chloro-N-(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1103] 1-(Imidazolo[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.

[1104] 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.

[1105] UPLC / MS (Method 4): m / z 355 (M+H)+, R T 1.47 minutes.

[1106] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)carbamate

[1107] 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 overnight at 50 ° C. BOC anhydride (136 mg, 623 μmol) was further added, and the reaction mixture was stirred at 50 ° C for 3 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (171 mg, 0.36 mmol, 80% yield, 95% purity) as a yellow oil.

[1108] UPLC / MS (Method 3): m / z 455 (M+H)+, R T 1.79 minutes.

[1109] 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

[1110] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (95 mg, 413 μmol) and t A solution of BuBrettPhos Pd G3 (32 mg, 37.6 μmol) in THF (3.2 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.49 mL, 489 μmol) was added once under bubbling N2. 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 layer was filtered through a phase separator and concentrated. Purification by column chromatography (12 g cartridges, 0-10% MeOH / DCM) produced the title compound (168 mg, 0.24 mmol, 64% yield, 93% purity) as a yellow oil.

[1111] UPLC / MS (Method 4): m / z 649 (M+H)+, R T 1.68 minutes.

[1112] 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

[1113] 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) was added hydrogen chloride (4 M in dioxane) (1.17 mL, 4.69 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. 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 (40 mL). The methanolic ammonia 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 Et 2 O and drying under vacuum at 40° C. overnight.

[1114] UPLC / MS (Method 4): m / z 449 (M+H)+, R T 1.02 minutes.

[1115] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=6.8Hz,1H),7.80(d,J=4.9Hz,1H),7.62(s,1H),7.52(d,J=9.1Hz,1H),7.26–7.18(m,1H) ,7.13(d,J=7.8Hz,1H),6.85(t,J=6.7Hz,1H),6.76–6.68(m,1H),5.32(d,J=2.0Hz,1H),5.31–5.23(m,1H),4.87–4.81(m,1 H), 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, 4.3 Hz, 1H), 1.66 (d, J=6.6 Hz, 3H), 1.60–1.51 (m, 1H), 1.40–1.28 (m, 1H), 1.26–1.20 (m, 6H), 1.18–1.12 (m, 1H). 1H was under water.

[1116] Intermediate Synthesis A5

[1117] 1-(Imidazolo[1,2-a]pyridin-2-yl)ethan-1-amine

[1118]

[1119] Step A :1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[1120] Methylmagnesium bromide (3M in Et2O) (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 give the title compound (350 mg, 2.1 mmol, 61% yield, 96% purity) as a white solid.

[1121] UPLC / MS (Method 3): m / z 163 (M+H)+, R T 0.15 minutes.

[1122] Step B :2-(1-chloroethyl)imidazo[1,2-a]pyridine hydrochloride

[1123] 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.

[1124] UPLC / MS (Method 3): m / z 181 (M+H)+, R T 0.15 minutes.

[1125] Step C :2-(1-azidoethyl)imidazo[1,2-a]pyridine

[1126] A solution of 2-(1-chloroethyl)imidazo[1,2-a]pyridine hydrochloride (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 hours. The mixture was cooled to room temperature, diluted with water (40 mL) and brine (60 mL). It was extracted with TBME (3×50 mL) and EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (12 g cartridge, 0-100% EtOAc / isohexane) produced the title compound (190 mg, 0.81 mmol, 88% yield, 80% purity) as a brown oil.

[1127] UPLC / MS (Method 4): m / z 188 (M+H)+, R T 0.90 minutes.

[1128] Step D :1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-amine

[1129] 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 and stirred for 1 hour, and then the solvent was removed in a vacuum. 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 MeOH solution (30 mL). The ammonia methanol solution was concentrated in a vacuum to produce the title compound (144 mg, 0.85 mmol, 93% yield, 95% purity) as a yellow oil.

[1130] UPLC / MS (Method 4): m / z 162 (M+H)+, R T 0.48 minutes.

[1131] Synthesis 20

[1132] (3R,4R)-4-(((7-((Benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[1133] (H-APPAMP-020)

[1134]

[1135] Step 1: N-(Benzofuran-2-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1136] Benzofuran-2-ylmethylamine hydrochloride (100mg, 0.547mmol) is added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (105mg, 0.456mmol) and DIPEA (0.48mL, 2.74mmol) in EtOH (1.9mL). The reaction mixture is heated overnight at 90°C. The reaction mixture is concentrated in vacuo. Purification by column chromatography (12g cartridges, 0-30% EtOAc / heptane) produces the title compound (157mg, 0.42mmol, 91% yield, 90% purity) as a yellow oil.

[1137] UPLC / MS (Method 4): m / z 341 (M+H)+, R T 1.82 minutes

[1138] Step 2: tert-Butyl (benzofuran-2-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate

[1139] BOC anhydride (109 mg, 0.498 mmol) is 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 for 2 hours at 65 ° C. The reaction mixture was concentrated under reduced pressure, and the residue was distributed between DCM (15 mL) and water (30 mL). The aqueous layer was extracted with DCM (2 × 30 mL), and the combined organic layer was 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) produced the title compound (164 mg, 0.37 mmol, 89% yield, 99% purity) as a cream-colored solid.

[1140] UPLC / MS (Method 4): m / z 385 (M+H-tBu)+, R T 2.10 minutes.

[1141] 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

[1142] Tert-butyl (benzofuran-2-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)carbamate (164 mg, 0.372 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (94 mg, 0.409 mmol) and t A solution of BuBrettPhos Pd G3 (31.8 mg, 37.2 μmol) in THF (3.6 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.48 mL, 0.48 mmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 2 hours. 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) produced the title compound (235 mg, 0.33 mmol, 89% yield, 90% purity) as an orange solid.

[1143] UPLC / MS (Method 4): m / z 635 (M+H)+, R T 1.96 minutes.

[1144] Step 4: (3R,4R)-4-(((7-((Benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[1145] 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) was added hydrogen chloride (4 M in dioxane) (2.0 mL, 8.0 mmol). The reaction mixture was stirred at 35 °C for 2 hours before 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 before being concentrated in vacuo.

[1146] 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 NH3MeOH solution (20 mL). The ammonia methanol solution was concentrated in vacuo to produce the title compound (88 mg, 0.20 mmol, 54% yield, 97% purity) as a beige solid after being wet-triturated from Et2O and dried under vacuum at 40 °C overnight.

[1147] UPLC / MS (Method 4): m / z 435 (M+H)+, R T 1.37 minutes.

[1148] 1 H NMR (400MHz, DMSO-d6) δ7.81(t,J=6.3Hz,1H),7.63(s,1H),7.58(dd,J=7.5,1.6Hz,1H),7.53(d,J=8.0Hz,1H),7 .30–7.17(m,2H),6.78(s,1H),6.74(t,J=6.1Hz,1H),5.37(s,1H),5.28–5.20(m,1H),4.62(d,J=6.1Hz,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 is under water.

[1149] Synthesis 21

[1150] (3R,4R)-4-(((3-Isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[1151] (H-APPAMP-021)

[1152]

[1153] Step 1: 5-Chloro-3-isopropyl-N-(quinolin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1154] Quinolin-3-ylmethylamine dihydrochloride (121 mg, 0.522 mmol) is 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 is heated overnight at 90 ° C. The reaction mixture is concentrated in vacuo, and the residue is distributed between DCM (20 mL) and saturated NaHCO3 aqueous solution (10 mL). The organic layer is washed with saturated NaHCO3 aqueous solution (3 × 10 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (80 g cartridges, 0-30% EtOAc / isohexane) produces the title compound (109 mg, 0.29 mmol, 66% yield, 93% purity) as a yellow solid.

[1155] UPLC / MS (Method 3): m / z 352 (M+H)+, R T 1.56 minutes

[1156] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3-ylmethyl)carbamate

[1157] 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 hours. BOC anhydride (34 mg, 0.154 mmol) was added and the reaction mixture was stirred at 65 ° C for 1.5 hours. 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 layer was 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.

[1158] UPLC / MS (Method 4): m / z 452 (M+H)+, R T 1.91 minutes.

[1159] 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

[1160] Tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3-ylmethyl)carbamate (139 mg, 0.308 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (78 mg, 0.339 mmol) and t A solution of BuBrettPhos Pd G3 (26.3 mg, 30.8 μmol) in THF (3.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (399 μl, 0.399 mmol) was added in one portion under bubbling N2. Bubbling was stopped and the reaction mixture was heated to 60°C for 1.5 hours.

[1161] 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) produced the title compound (146 mg, 0.18 mmol, 67% yield, 80% purity) as a brown oil.

[1162] UPLC / MS (Method 4): m / z 646 (M+H)+, R T 1.80 minutes.

[1163] Step 4: (3R,4R)-4-(((3-Isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

[1164] 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) was added hydrogen chloride (4 M in dioxane) (0.23 mL, 0.90 mmol). The reaction mixture was stirred at 35° C. for 3 hours. Additional 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 before being concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH 3 in MeOH (60 mL). The methanolic ammonia 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 Et 2 O and drying under vacuum at 40° C. overnight.

[1165] UPLC / MS (Method 3): m / z 446 (M+H)+, R T 0.67 minutes.

[1166] 1 H NMR(400MHz, DMSO-d6)δ8.96(d,J=2.2Hz,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=1.2,6.8,8.1Hz,1H),6.66(t,J=6.1Hz,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 was under water.

[1167] Synthesis 22

[1168] (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

[1169] (H-APPAMP-022)

[1170]

[1171] Step 1: 5-Chloro-3-cyclopropyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1172] (8-Methylimidazo[1,2-a]pyridin-2-yl)methylamine dihydrochloride (101 mg, 0.432 mmol) is 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 hour. The reaction mixture was concentrated in a vacuum, and the residue was diluted with DCM (20 mL), and the solution was then washed with saturated NaHCO3 aqueous solution (20 mL) and brine (20 mL) in sequence. The organic layer was filtered through a phase separator and concentrated under reduced pressure to produce the title compound (129 mg, 0.36 mmol, 99% yield, 99% purity) as an off-white solid.

[1173] UPLC / MS (Method 5): m / z 353 (M+H)+, R T 1.37 minutes

[1174] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1175] 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 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 brine (15 mL) in sequence. 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) gave the title compound (150 mg, 0.33 mmol, 91% yield, 99% purity) as a yellow solid.

[1176] UPLC / MS (Method 5): m / z 452 (M+H)+, R T 1.73 minutes.

[1177] 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

[1178] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (84.02 mg, 0.3645 mmol) and tA solution of BuBrettPhos Pd G3 (28.33 mg, 0.033 mmol) in THF (3.2 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.37 g, 0.431 mL, 431.1 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 1.5 hours. 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) produced the title compound (221 mg, 0.30 mmol, 92% yield, 89% purity) as a beige solid.

[1179] UPLC / MS (Method 5): m / z 647 (M+H)+, R T 1.62 minutes.

[1180] 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

[1181] 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 an SCX column. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3MeOH solution (50 mL). The methanolic ammonia solution was concentrated in vacuo to produce the title compound (42 mg, 90 μmol, 78% yield, 95% purity) as a white solid after trituration from Et2O and drying under vacuum overnight at 40 °C.

[1182] UPLC / MS (Method 5): m / z 447 (M+H)+, R T 1.09 minutes.

[1183] 1H NMR (400MHz, DMSO-d6) δ8.32(d,J=6.7Hz,1H),7.73(s,1H),7.64(t,J=6.1Hz,1H),7.52(s,1H),7.01(dt,J=6.9,1.3H z,1H),6.78–6.69(m,2H),5.36–5.30(m,1H),5.27(s,1H),4.56(d,J=5.8Hz,2H),3.57–3.46(m,1H),3.25–3.15(m,1H) ,3.10–2.97(m,1H),2.91(dd,J=11.6,4.5Hz,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.

[1184] Synthesis 23

[1185] (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

[1186] (H-APPAMP-023)

[1187]

[1188] Step 1: 5-Chloro-3-isopropyl-N-((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1189] (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 hours. The reaction mixture was concentrated in vacuo. At room temperature, water (50 mL) was added, 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.

[1190] UPLC / MS (Method 4): m / z 409 (M+H)+, R T 0.83 minutes

[1191] 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

[1192] 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.

[1193] The mixture was diluted with water (100 mL) and then extracted with DCM (3 x 30 mL).The combined organic layers were dried over MgSO4 and concentrated in vacuo.

[1194] Purification by column chromatography (12 g cartridge, 0-70% EtOAc / cyclohexane) gave the title compound (226 mg, 400 μιηοΐ, 66% yield, 90% purity) as a yellow solid.

[1195] UPLC / MS (Method 4): m / z 509 (M+H)+, R T 1.99 minutes.

[1196] 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

[1197] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (45.3 mg, 196 μmol) and t A solution of BuBrettPhos Pd G3 (16.8 mg, 19.6 μmol) in THF (2.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (255 μL, 255 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. Purified by column chromatography (12 g cartridges, 0-100% EtOAc / isohexane), then purified by column chromatography (12 g cartridges, 0-10% MeOH / DCM), and then further purified on RP fast C18 (12 g cartridges, 5-100% MeCN / 10 mM ammonium bicarbonate) to produce the title compound (68 mg, 92 μmol, 47% yield, 95% purity) as a white solid.

[1198] UPLC / MS (Method 5): m / z 704 (M+H)+, R T 0.85 minutes.

[1199] 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

[1200] 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 an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH3MeOH solution (20 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (20 mg, 39 μmol, 40% yield, 98% purity) as a white solid after trituration from Et 2 O and drying under vacuum at 40° C. overnight.

[1201] UPLC / MS (Method 3): m / z 504 (M+H)+, R T 0.78 minutes.

[1202] 1 H NMR(400MHz, DMSO-d6)δ8.52(d,J=6.9Hz,1H),7.83–7.78(m,1H),7.64(s,1H),7.55(m,1H),7.49(t,J= 5.7Hz,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=5.3Hz,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 is under water.

[1203] Intermediate synthesis A6

[1204] (3-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1205]

[1206] Step A :3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[1207] Under N2, trifluoromethyltrimethylsilane (1.50g, 1.6mL, 10.5mmol) is added to a mixture of imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (500mg, 2.63mmol), iodobenzene diacetate (1.69g, 5.26mmol) and cesium fluoride (1.60g, 10.5mmol) in MeCN (15mL). The reaction mixture is heated to 30°C for 3 hours and then concentrated to dryness under reduced pressure. Purification by column (12g cartridge, 0-100% EtOAc / isohexane) produces the title compound (203mg, 680μmol, 26% yield, 87% purity) as a white solid.

[1208] UPLC / MS (Method 5): m / z 259 (M+H)+, R T 1.17 minutes.

[1209] Step B :(3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol

[1210] LiAlH4 (2M 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 allowed to warm to room temperature and stirred for 1 hour. At 0 ° C, saturated NH4Cl aqueous solution (10 mL) and water (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. Purification by column (12 g cartridge, 0-100% (3: 1 EtOAc / EtOH) / isohexane) produced the title compound (102 mg, 0.45 mmol, 58% yield, 96% purity) as a white solid.

[1211] UPLC / MS (Method 5): m / z 217 (M+H)+, R T 0.81 minutes.

[1212] Step C :2-(Chloromethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine hydrochloride

[1213] Thionyl chloride (203 μί, 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.

[1214] 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.

[1215] UPLC / MS (Method 5): m / z 235 (M-OH)+, R T 1.19 minutes.

[1216] Step D :2-(azidomethyl)-3-(trifluoromethyl)imidazo[1,2-a]pyridine

[1217] 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 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL). It was extracted with DCM (3 × 20 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by column (12 g cartridge, 0-100% EtOAc / cyclohexane) produced the title compound (209 mg, 0.75 mmol, 81% yield, 86% purity) as a colorless oil.

[1218] UPLC / MS (Method 3): m / z 242 (M+H)+, R T 1.20 minutes.

[1219] Step E :(3-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1220] 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, and then the solvent was removed in vacuo.

[1221] 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 NH3MeOH solution (40 mL). The methanolic ammonia solution was concentrated in vacuo to yield the title compound (139 mg, 588 μmol, 77% yield, 91% purity) as a white solid.

[1222] UPLC / MS (Method 5): m / z 216 (M+H)+, RT 0.82 minutes.

[1223] Synthesis 24

[1224] (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

[1225] (H-APPAMP-024)

[1226]

[1227] Step 1: 5-Chloro-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine

[1228] (3-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methylamine (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 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-50% (3: 1 EtOAc / EtOH) / isohexane) produced the title compound (74 mg, 155 μmol, 70% yield, 80% purity) as a pink solid.

[1229] UPLC / MS (Method 5): m / z 381 (M+H)+, R T 1.63 minutes.

[1230] Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1231] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (74 mg, 154 μmol, 99% yield, 99% purity) as a white solid.

[1232] UPLC / MS (Method 5): m / z 783 (M+H)+, R T 1.89 minutes.

[1233] Step 3: 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

[1234] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (40.0 mg, 0.170 mmol) and t A solution of BuBrettPhos Pd G3 (13.9mh, 0.015mmol) in THF (3.0mL) was degassed with N2 for 10 minutes. LiHMDS (1M in THF) (0.200mL, 0.200mmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. Purified by column chromatography (4g cartridges, 0-100% EtOAc / isohexane), followed by further purification on RP fast C18 (4g cartridges, 15-100% MeCN / 10mM ammonium bicarbonate), resulting in the title compound (60mg, 89μmol, 58% yield, 99% purity) as a white solid.

[1235] UPLC / MS (Method 5): m / z 675 (M+H)+, R T 1.77 minutes.

[1236] 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

[1237] 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) was added TFA (0.3 mL). The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuo.

[1238] 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 NH3MeOH solution (20 mL). The methanolic ammonia solution was concentrated in vacuo to produce the title compound (13 mg, 27 μmol, 30% yield, 99% purity).

[1239] UPLC / MS (Method 5): m / z 475 (M+H)+, R T 1.25 minutes.

[1240] 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=6.8Hz,1H),7.61(s,1H),7.54(d,J=9.1,1H),7.26(m,2H),6.98(td,J=6. 8,1.2Hz,1H),6.85–6.76(m,1H),5.43-5.36(m,2H),4.58(d,J=5.1Hz,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 is under water.

[1241] Intermediate synthesis A7

[1242] Synthesis of (3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine

[1243]

[1244] Step A :3-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde

[1245] 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-carboxaldehyde (500 mg, 1.84 mmol), cyclopropaneboronic acid (474 ​​mg, 5.51 mmol) and PdCl2(dppf)-CH2Cl2 adduct (300 mg, 368 μmol) in dioxane (20 mL). N2 was bubbled through the reaction mixture for 10 minutes, and then the reaction mixture was heated at 80 ° C for 20 hours. 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 MgSO4 and concentrated in vacuo. Purification by column (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (111 mg, 513 μιηοΐ, 28% yield, 90% purity) as a white solid.

[1246] UPLC / MS (Method 5): m / z 187 (M+H)+, R T 0.80 minutes.

[1247] Step B :(S,E)-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methylene)-2-methylpropane-2-sulfenamide

[1248] (S) -2- methylpropane -2- sulfenamide (86.7 mg, 715 μmol) and propan-2-ol titanium (IV) (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 for 18 hours at 40 ° C. Brine (50 mL) and diatomaceous earth were added to the reaction mixture under stirring. The mixture was filtered through a diatomaceous earth pad 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 layer was dried over MgSO4 and then concentrated under reduced pressure. Purification by column (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / cyclohexane) gave the title compound (139 mg, 0.39 mmol, 65% yield, 81% purity) as a yellow oil.

[1249] UPLC / MS (Method 5): m / z 290 (M+H)+, R T 1.08 minutes.

[1250] Step C :(S)-N-((3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)-2-methylpropane-2-sulfenamide

[1251] 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 hour. 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.

[1252] UPLC / MS (Method 4): m / z 292 (M-OH)+, R T 1.05 minutes.

[1253] Step D :(3-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine

[1254] 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-sulfenamide (139 mg, 382 μmol) in MeOH (1.0 mL). The reaction was stirred at room temperature for 2 hours, followed by the addition of hydrogen chloride (1.25 M in MeOH) (0.9 mL, 1.14 mmol), and the mixture was stirred for 1 hour 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 NH3MeOH solution (20 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (53 mg, 226 μmol, 59% yield, 80% purity) as a yellow oil.

[1255] 1 H NMR (in DMSO-d6) was consistent with the product structure.

[1256] Synthesis 25

[1257] (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

[1258] (H-APPAMP-025)

[1259]

[1260] Step 1: 5-Chloro-3-cyclopropyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1261] (5-Methylimidazo [1,2-a] pyridin-2-yl) methylamine dihydrochloride (111 mg, 0.474 mmol) is 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 hours. The reaction mixture was concentrated in a vacuum. The residue was diluted in DCM (15 mL) and washed with saturated NaHCO3 aqueous solution (15 mL) and brine (15 mL). The organic layer was filtered through a phase separator and concentrated under reduced pressure to produce the title compound (118 mg, 0.33 mmol, 83% yield, 98% purity) as a gray solid.

[1262] UPLC / MS (Method 3): m / z 353 (M+H)+, R T 1.36 minutes

[1263] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1264] 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 hour, then charged with BOC anhydride (87 mg, 0.398 mmol) and DMAP (8.1 mg, 66 μmol) and stirred at 65 ° C for 1 hour. 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.

[1265] UPLC / MS (Method 3): m / z 453 (M+H)+, R T 1.71 minutes.

[1266] 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

[1267] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 360 μmol) and tA solution of BuBrettPhos Pd G3 (26 mg, 30 μmol) in THF (2.9 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.39 mL, 390 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 2 hours. At room temperature, the mixture was filtered through diatomaceous earth and washed with EtOAc (15 mL). The filtrate was distributed 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) produced the title compound (163 mg, 0.22 mmol, 74% yield, 88% purity) as a brown oil.

[1268] UPLC / MS (Method 3): m / z 647 (M+H)+, RT 1.22 min.

[1269] 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

[1270] 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 an SCX column. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3MeOH solution (60 mL). The methanolic ammonia solution was concentrated in vacuo to produce the title compound (81 mg, 0.18 mmol, 71% yield, 98% purity) as a beige solid after trituration from Et2O and drying under vacuum at 40 °C overnight.

[1271] UPLC / MS (Method 5): m / z 447 (M+H)+, R T 1.42 minutes.

[1272] 1H NMR (400MHz, DMSO-d6) δ7.66(s,1H),7.56(t,J=6.0Hz,1H),7.51(s,1H),7.42(d,J=9.0Hz,1H),7.21(dd,J=9.1,6.8H z,1H),6.79–6.73(m,2H),5.44–5.37(m,1H),5.32(s,1H),4.57(d,J=5.9Hz,2H),3.58–3.46(m,1H),3.26–3.17(m,1H) ,3.12–3.03(m,1H),2.94(dd,J=11.5,4.5Hz,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.

[1273] Synthesis 26

[1274] (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

[1275] (H-APPAMP-026)

[1276]

[1277] Step 1: 5-Chloro-3-ethyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1278] (8-Methylimidazo[1,2-a]pyridin-2-yl)methanamine hydrochloride (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.

[1279] 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.

[1280] UPLC / MS (Method 5): m / z 341 (M+H)+, R T 1.22 minutes.

[1281] Step 2: tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1282] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / isohexane) gave the title compound (138 mg, 0.30 mmol, 80% yield, 96% purity) as a brown solid.

[1283] UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.61 minutes.

[1284] Step 3: 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

[1285] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 361 μmol) and tA solution of BuBrettPhos Pd G3 (0.62 g, 0.72 mmol) in THF (2.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (391 μL, 391 μmol) was added once under bubbling N2. 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 MNH3 / MeOH) / DCM) produced the title compound (141 mg, 222 μmol, 74% yield, 98% purity) as a white solid.

[1286] UPLC / MS (Method 3): m / z 635 (M+H)+, R T 1.62 minutes.

[1287] 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

[1288] 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 NH3MeOH solution (50 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (71 mg, 160 μmol, 73% yield, 98% purity).

[1289] UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.02 minutes.

[1290] 1H NMR(400MHz, DMSO-d6)δ8.32(d,J=6.5Hz,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=6.0Hz,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 in DMSO. 1H in water.

[1291] Synthesis 27

[1292] (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

[1293] (H-APPAMP-027)

[1294]

[1295] Step 1 :5-chloro-3-cyclopropyl-N-((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1296] (5-Methoxyimidazo[1,2-a]pyridin-2-yl)methylamine (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 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (105 mg, 0.27 mmol, 78% yield, 94% purity) as a brown solid.

[1297] UPLC / MS (Method 5): m / z 369 (M+H)+, RT 1.35 min.

[1298] Step 2 : tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methoxyimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1299] 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 hour. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (120 mg, 256 μmol, 95% yield, 99% purity) as a white solid.

[1300] UPLC / MS (Method 5): m / z 469 (M+H)+, R T 0.81 minutes.

[1301] Step 3 : (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-carboxylic acid tert-butyl ester

[1302] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83 mg, 358 μmol) and t A solution of BuBrettPhos Pd G3 (25 mg, 29.9 μmol) in THF (2.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (388 μL, 388 μmol) was added once under bubbling N2. 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) produced the title compound (167 mg, 0.21 mmol, 69% yield, 82% purity) as a white solid.

[1303] UPLC / MS (Method 5): m / z 663 (M+H)+, RT 1.61 minutes.

[1304] 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

[1305] 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) was added hydrogen chloride (4 M in dioxane) (1.04 mL, 4.16 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (62 mg, 0.13 mmol, 61% yield, 95% purity).

[1306] UPLC / MS (Method 5): m / z 463 (M+H)+, R T 1.04 minutes.

[1307] 1H NMR (400MHz, DMSO-d6) δ7.61(t,J=6.1Hz,1H),7.56(s,1H),7.52(s,1H),7.29(dd,J=9.0,7.5Hz,1H),7.15(d,J=9.0Hz,1H),6 .77–6.71(m,1H),6.34(d,J=7.4Hz,1H),5.36–5.32(m,1H),5.30(s,1H),4.55(d,J=5.9Hz,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=11.5,4.6Hz,1H),2.83–2.76(m,1H),2.36–2.26(m,1H),2.17(dd,J=11.6,9.9Hz,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 is under water.

[1308] Intermediate synthesis A8

[1309] (5-Methoxyimidazo[1,2-a]pyridin-2-yl)methanamine

[1310]

[1311] Step A :5-methoxyimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[1312] Under microwave irradiation, IPA (2.0 ml) and water (2.0 ml) containing 6-methoxypyridine-2-amine (400 mg, 3.22 mmol) and ethyl 3-bromo-2-oxopropanoate (0.81 mL, 6.44 mmol) were heated at 80 ° C for 1 hour. The reaction mixture was diluted with water (50 mL) and extracted with DCM (3 × 25 mL). The combined organic fractions were dried over MgSO4, filtered, and then concentrated under vacuum. Purification by column chromatography (40 g cartridges, 0-10% MeOH / DCM) produced the title compound (280 mg, 1.3 mmol, 39% yield, 99% purity) as a yellow solid.

[1313] UPLC / MS (Method 5): m / z 221 (M+H)+, R T 0.93 minutes.

[1314] Step B:(5-methoxyimidazo[1,2-a]pyridin-2-yl)methanol

[1315] Lithium borohydride (2M in THF) (0.63mL, 1.26mmol) was added to a solution of ethyl 5-methoxyimidazo[1,2-a]pyridine-2-carboxylate (280mg, 1.26mmol) in THF (6.0mL) at 0°C. The reaction mixture was allowed to warm to room temperature overnight. At 0°C, water (5mL) and saturated NH4Cl aqueous solution (10mL) were added. The aqueous layer was extracted with DCM (3×20mL), and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column (24g cartridge, 0-10% MeOH / DCM) produced the title compound (120mg, 0.61mmol, 49% yield, 91% purity) as a white solid.

[1316] UPLC / MS (Method 5): m / z 179 (M+H)+, R T 0.62 minutes.

[1317] Step C :2-(Chloromethyl)-5-methoxyimidazo[1,2-a]pyridine hydrochloride

[1318] Thionyl chloride (112 μί, 1.53 mmol) was added dropwise to a solution of (5-methoxyimidazo[1,2-a]pyridin-2-yl)methanol (120 mg, 613 μιηοΐ) in DCM (7.0 mL) at 0 °C.

[1319] The mixture was stirred for 2 hours at 0° C. Concentration to dryness under reduced pressure gave the title compound (142 mg, 0.60 mmol, 98% yield, 99% purity) as an off-white solid.

[1320] 1 H NMR (in DMSO-d6) was consistent with the product structure.

[1321] Step D :2-(Azidomethyl)-5-methoxyimidazo[1,2-a]pyridine

[1322] A solution of 2-(chloromethyl)-5-methoxyimidazo[1,2-a]pyridine hydrochloride (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 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL), and then extracted with TBME (3 × 20 mL) and EtOAc (3 × 20 mL) in sequence. The combined organic layer was washed with brine (4 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure. The purification by column (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (91 mg, 0.37 mmol, 62% yield, 83% purity) as a white solid.

[1323] UPLC / MS (Method 5): m / z 205 (M+H)+, R T 0.94 minutes.

[1324] Step E :(5-methoxyimidazo[1,2-a]pyridin-2-yl)methanamine

[1325] 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 before the solvent was removed in vacuo.

[1326] 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 NH3MeOH solution (50 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (64 mg, 0.34 mmol, 77% yield, 95% purity) as a white solid.

[1327] UPLC / MS (Method 5): m / z 178 (M+H)+, R T 0.64 minutes.

[1328] Synthesis 28

[1329] (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

[1330] (H-APPAMP-028)

[1331]

[1332] Step 1: 5-Chloro-3-cyclopropyl-N-((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1333] (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.

[1334] UPLC / MS (Method 5): m / z 380 (M+H)+, R T 1.45 minutes

[1335] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methyl)carbamate

[1336] BOC anhydride (129 mg, 592 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((6-cyclopropylimidazo[1,2-b]pyridazine-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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) produced the title compound (231 mg, 0.46 mmol, 93% yield, 95% purity) as a brown solid.

[1337] UPLC / MS (Method 5): m / z 480 (M+H)+, R T 1.83 minutes.

[1338] 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

[1339] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (146 mg, 635 μmol) and t A solution of BuBrettPhos Pd G3 (45 mg, 52.9 μmol) in THF (5.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (688 μL, 688 μmol) was added once under bubbling N2. 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) produced the title compound (230 mg, 0.32 mmol, 61% yield, 94% purity) as a brown solid.

[1340] UPLC / MS (Method 4): m / z 674 (M+H)+, R T 1.72 minutes.

[1341] 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

[1342] 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) was added hydrogen chloride (4 M in dioxane) (1.71 mL, 6.83 mmol). The reaction mixture was stirred at 35 °C for 4 hours and concentrated in vacuo. 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 methanolic ammonia solution was concentrated in vacuo to give the title compound (145 mg, 0.30 mmol, 87% yield, 97% purity) after trituration from Et20 and drying under vacuum at 40°C overnight.

[1343] UPLC / MS (Method 5): m / z 475 (M+H)+, R T 1.14 minutes.

[1344] 1 H NMR (400MHz, DMSO-d6) δ7.98(s,1H),7.92(d,J=9.4Hz,1H),7.61(t,J=6.1Hz,1H),7.51(s,1H),7.08(d,J=9.4Hz,1H),6.77(t,J=6 .0Hz,1H),5.47–5.42(m,1H),5.30(s,1H),4.55(d,J=5.9Hz,2H),3.59–3.47(m,1H),3.28–3.20(m,1H),3.20–3.05(m,1H),2.97(dd , J=11.6,4.5Hz,1H),2.90–2.82(m,1H),2.44–2.34(m,1H),2.25(dd,J=11.6,10.0Hz,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 is under water.

[1345] Intermediate synthesis A9

[1346] (6-Cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanamine

[1347]

[1348] Step A :6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester

[1349] A mixture of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (400 mg, 1.77 mmol), cesium fluoride (1.21 g, 7.98 mmol), PdCl2(dtbpf) (116 mg, 177 μmol), cyclopropylboronic acid (685 mg, 7.98 mmol) in dioxane (10 mL) was degassed with N2 for 10 minutes. The mixture was then heated to 60 ° C for 5.5 hours and then concentrated to dryness under reduced pressure. Purification by column chromatography (24 g cartridges, 0-10% MeOH / DCM) produced the title compound (400 mg, 1.6 mmol, 93% yield, 95% purity) as a yellow solid.

[1350] UPLC / MS (Method 3): m / z 232 (M+H)+, R T1.13 minutes.

[1351] Step B :(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanol

[1352] Diisobutylaluminum hydride (1M in DCM) (4.32mL, 4.32mmol) is added to a solution of 6-cyclopropylimidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (400mg, 1.73mmol) in THF (20mL) at -10°C. The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. At 0°C, MeOH (10mL) is added, followed by water (10mL) and 1M HCl aqueous solution (10mL). The mixture is vigorously stirred for 30 minutes and extracted with ethyl acetate (3×35mL). The combined organic layer is washed with brine (20mL), filtered through a phase separator, and concentrated in vacuo. Purification by column chromatography (12g cartridges, 0-10% MeOH / DCM) produces the title compound (220mg, 1.10mmol, 66% yield, 98% purity) as a brown oil.

[1353] UPLC / MS (Method 3): m / z 190 (M+H)+, RT 0.44 min.

[1354] Step C :2-(Chloromethyl)-6-cyclopropylimidazo[1,2-b]pyridazine hydrochloride

[1355] 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 hour. Concentration to dryness under reduced pressure gave the title compound as a green solid (290 mg, 1.1 mmol, 95% yield, 95% purity).

[1356] UPLC / MS (Method 5): m / z 209 (M+H)+, R T 1.00 minute.

[1357] Step D :2-(Azidomethyl)-6-cyclopropylimidazo[1,2-b]pyridazine

[1358] A solution of 2- (chloromethyl) -6- cyclopropylimidazo [1,2-b] pyridazine hydrochloride (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 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The purification by column chromatography (24 g cartridges, 0-10% MeOH / DCM) produced the title compound (155 mg, 0.67 mmol, 57% yield, 93% purity) as a colorless oil.

[1359] UPLC / MS (Method 5): m / z 216 (M+H)+, R T 1.10 minutes.

[1360] Step E :(6-cyclopropylimidazo[1,2-b]pyridazin-2-yl)methanamine

[1361] 2- (azidomethyl) -6- cyclopropyl imidazo [1,2-b] pyridazine (155mg, 673μmol) and triphenylphosphine (212mg, 807μmol) are dissolved in THF (3.6mL) and water (0.4mL). The mixture is stirred at room temperature overnight, and the solvent is subsequently removed in vacuo. The residue is loaded onto an SCX post. The post is washed with MeOH (50mL), and the product is eluted with 0.7M NH3MeOH solution (50mL). The ammonia methanol solution is concentrated in vacuo to produce the title compound (130mg, 0.66mmol, 98% yield, 95% purity) as a white solid.

[1362] UPLC / MS (Method 5): m / z 189 (M+H)+, R T 0.76 minutes.

[1363] Synthesis 29

[1364] (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

[1365] (H-APPAMP-029)

[1366]

[1367] Step 1: 5-Chloro-3-iodo-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1368] (8-Methylimidazo[1,2-a]pyridin-2-yl)methylamine dihydrochloride (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 overnight at 85 ° C. The precipitated solid was collected by filtration at room temperature and rinsed with EtOH (100 mL) to produce the title compound (3.57 g, 8.03 mmol, 94% yield, 98% purity) as a beige solid.

[1369] UPLC / MS (Method 5): m / z 439 (M+H)+, R T 1.77 minutes

[1370] Step 2: tert-Butyl (5-chloro-3-iodopyrazolo[1,5-a]pyrimidin-7-yl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1371] BOC anhydride (1.74 g, 7.99 mmol) is 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 for 1.5 hours at 50 ° C. Water (20 mL) was added and the resulting solid was collected by filtration and then rinsed with water (25 mL) and TBME (25 mL) to provide the title compound (3.1 g, 5.68 mmol, 85% yield, 99% purity) as an off-white solid after drying under vacuum overnight at 40 ° C.

[1372] UPLC / MS (Method 5): m / z 539 (M+H)+, R T 2.24 minutes.

[1373] 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

[1374] 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), tert-butyl (3R,4R)-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 N2 and then heated at 110°C for 2 hours. The reaction mixture was cooled at 0°C and water (30 mL) was added. The solid was collected by filtration, rinsed with more water (10 mL), and then dried under reduced pressure at 40°C to give the title compound (1.28 g, 1.6 mmol, 87% yield, 92% purity) as a pale white solid.

[1375] UPLC / MS (Method 5): m / z 733 (M+H)+, R T 2.06 minutes.

[1376] 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

[1377] 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) and XPhos Pd G3 (8 mg, 9.28 μmol) in THF (2.0 mL) was added dropwise cyclobutylzinc(II) bromide (0.38 M in THF) (prepared according to literature procedure) (3.59 mL, 1.37 mmol) under N2. The reaction mixture was stirred at room temperature for 18 hours, then quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and 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% aq. NH 3 ) gave the title compound (19 mg, 29 μmol, 11% yield, 99% purity) as a white solid.

[1378] UPLC / MS (Method 3): m / z 662 (M+H)+, R T1.34 minutes.

[1379] 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

[1380] 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 an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3MeOH solution (30 mL). The methanolic ammonia solution was concentrated in vacuo to produce the title compound (10 mg, 21 μmol, 72% yield, 95% purity).

[1381] UPLC / MS (Method 5): m / z 461 (M+H)+, R T 1.82 minutes.

[1382] 1 H NMR (400MHz, DMSO-d6) δ8.32(d,J=6.7Hz,1H),7.75(d,J=4.9Hz,2H),7.66(t,J=6.2Hz,1H),7.02(d t,J=6.8,1.2Hz,1H),6.78-6.69(m,2H),5.32-5.25(m,2H),4.58(d,J=6.0Hz,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 is under water.

[1383] Synthesis 30

[1384] (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

[1385] (H-APPAMP-030)

[1386]

[1387] Step 1: 5-Chloro-3-cyclopropyl-N-((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1388] (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.

[1389] UPLC / MS (Method 5): m / z 379 (M+H)+, RT 1.48 minutes

[1390] Step 2: tert-Butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1391] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% MeOH / DCM) gave the title compound (145 mg, 0.29 mmol, 60% yield, 96% purity) as a brown solid.

[1392] UPLC / MS (Method 5): m / z 479 (M+H)+, R T 1.80 minutes.

[1393] 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

[1394] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83.7 mg, 363 μmol) and t A solution of BuBrettPhos Pd G3 (25.9 mg, 30.3 μmol) in THF (2.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.39 ml, 394 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 18 hours. The reaction mixture was concentrated under reduced pressure. Purified by column chromatography (12 g cartridges, 0-10% MeOH / DCM), followed by further purification on RP fast C18 (24 g cartridges, 10-100% (0.1% formic acid MeCN solution) / (0.1% formic acid aqueous solution)), resulting in the title compound (83 mg, 0.12 mmol, 39% yield, 97% purity) as a white solid.

[1395] UPLC / MS (Method 5): m / z 673 (M+H)+, R T 1.70 minutes.

[1396] 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

[1397] 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 an SCX column. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH3MeOH solution (50 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (49 mg, 0.10 mmol, 81% yield, 96% purity).

[1398] UPLC / MS (Method 5): m / z 473 (M+H)+, R T 1.16 minutes.

[1399] 1 H NMR (400MHz, DMSO-d6) δ7.91(s,1H),7.57(t,J=6.0Hz,1H),7.52(s,1H),7.43(d,J=9.0Hz,1H),7.20(dd,J=9.0,7.0Hz,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=5.8Hz,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). 1H is under water.

[1400] Intermediate synthesis A10

[1401] (5-Cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine

[1402]

[1403] Step A:5-cyclopropylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[1404] A mixture of 5-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (500mg, 1.86mmol), cesium fluoride (564mg, 3.72mmol), PdCl2(dtbpf) (121mg, 186μmol), cyclopropylboronic acid (319mg, 3.72mmol) in dioxane (10.0mL) was degassed with N2 for 10 minutes. The mixture was then heated to 90°C overnight. At room temperature, the reaction mixture was filtered through a short diatomaceous earth pad, rinsed with 20% MeOH / DCM (20mL), and the filtrate was concentrated under reduced pressure. Purification by column chromatography (24g cartridges, 0-10% (0.7MNH3 / MeOH) / DCM) produced the title compound (440mg, 1.7mmol, 93% yield, 90% purity) as a brown oil.

[1405] UPLC / MS (Method 3): m / z 231 (M+H)+, R T 0.86 minutes.

[1406] Step B / C :(5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol / 2-(chloromethyl)-5-cyclopropylimidazo[1,2-a]pyridine hydrochloride

[1407] Lithium borohydride (2M 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 allowed to warm to room temperature and then stirred for 20 hours. At 0 ° C, MeOH (5 mL) was added, followed by water (5 mL) and 1M HCl aqueous solution (5 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 produce the crude alcohol intermediate (5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanol (235 mg, 1.25 mmol), which was redissolved in anhydrous 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 gave the title compound (260 mg, 1.00 mmol, 55% yield, 96% purity) as a yellow liquid.

[1408] UPLC / MS (Method 3): m / z 207 (M+H)+, R T 0.52 minutes.

[1409] Step D :2-(Azidomethyl)-5-cyclopropylimidazo[1,2-a]pyridine

[1410] A solution of 2- (chloromethyl) -5- cyclopropylimidazo [1,2-a] pyridine hydrochloride (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 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. Purification by column chromatography (24 g cartridges, 0-10% MeOH / DCM) produced the title compound (218 mg, 0.97 mmol, 80% yield, 95% purity) as a colorless oil.

[1411] UPLC / MS (Method 6): m / z 214 (M+H)+, R T 0.63 minutes.

[1412] Step E :(5-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine

[1413] 2- (azidomethyl) -5- cyclopropyl imidazoles [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 subsequently removed in a vacuum. The residue was loaded onto an SCX post. The post was washed with MeOH (30 mL), and the product was eluted with 0.7 M NH3MeOH solution (30 mL). The ammonia methanol solution was concentrated in a vacuum to produce the title compound (90 mg, 0.46 mmol, 48% yield, 96% purity) as a white solid.

[1414] UPLC / MS (Method 5): m / z 188 (M+H)+, R T 0.83 minutes.

[1415] Synthesis 31

[1416] (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

[1417] (H-APPAMP-031)

[1418]

[1419] Step 1: 5-Chloro-3-ethyl-N-((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1420] (5-Methylimidazo[1,2-a]pyridin-2-yl)methylamine (100 mg, 620 μmol) is 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 is heated at 50 ° C for 2.5 hours. The reaction mixture is concentrated in vacuo. Purification by column chromatography (12 g cartridges, 0-10% MeOH / DCM) produces the title compound (70 mg, 0.20 mmol, 35% yield, 97% purity) as a white solid.

[1421] UPLC / MS (Method 5): m / z 341 (M+H)+, R T 1.33 minutes.

[1422] Step 2: tert-Butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((5-methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate

[1423] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (83 mg, 0.16 mmol, 82% yield, 87% purity) as a brown solid.

[1424] UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.69 minutes.

[1425] 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

[1426] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (83.0 mg, 314 μmol) and t A solution of BuBrettPhos Pd G3 (26.8 mg, 31.4 μmol) in THF (3.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (408 μl, 408 μmol) was added once under bubbling N2. 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) produced the title compound (61 mg, 91 μmol, 29% yield, 95% purity) as a yellow solid.

[1427] UPLC / MS (Method 5): m / z 635 (M+H)+, R T 1.63 minutes.

[1428] 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

[1429] 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 an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3MeOH solution (30 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (26 mg, 57 μmol, 62% yield, 95% purity) as an off-white solid.

[1430] UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.03 minutes.

[1431] 1H NMR (400MHz, DMSO-d6) δ7.67(s,1H),7.64(s,1H),7.58(t,J=6.0Hz,1H),7.43(d,J=9.1Hz,1H),7.21(dd,J=9. 1,6.8Hz,1H),6.80-6.73(m,2H),5.49–5.42(m,1H),5.34(s,1H),4.59(d,J=5.7Hz,2H),3.62-3.50(m,1H),3.2 2–3.13 (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 was under water.

[1432] Synthesis 32

[1433] (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

[1434] (H-APPAMP-032)

[1435]

[1436] Step 1: 5-Chloro-3-cyclopropyl-N-((5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1437] (5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methylamine (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 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (108 mg, 0.28 mmol, 74% yield, 95% purity) as a yellow oil.

[1438] UPLC / MS (Method 5): m / z 367 (M+H)+, R T 1.44 minutes.

[1439] 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

[1440] BOC anhydride (82.0 mg, 376 μmol) is 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 is stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produces the title compound (148 mg, 0.29 mmol, 99% yield, 90% purity) as a white solid.

[1441] UPLC / MS (Method 5): m / z 467 (M+H)+, R T 1.78 minutes.

[1442] 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

[1443] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (76.9 mg, 334 μmol) and tA solution of BuBrettPhos Pd G3 (35.7 mg, 41.8 μmol) in THF (2.3 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (418 μL, 418 μmol) was added once under bubbling N2. Bubbling was stopped and the reaction mixture was heated to 60 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure. Purification was carried out 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) to produce the title compound (140 mg, 0.19 mmol, 68% yield, 90% purity) as a brown solid.

[1444] UPLC / MS (Method 4): m / z 661 (M+H)+, R T 1.68 minutes.

[1445] 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

[1446] 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) was added hydrogen chloride (4 M in dioxane) (953 μL, 3.81 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. 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 (40 mL). The methanolic ammonia 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.

[1447] UPLC / MS (Method 4): m / z 461 (M+H)+, R T 1.17 minutes.

[1448] 1H NMR (400MHz, DMSO-d6) δ7.56 (s, 1H), 7.53–7.47 (m, 2H), 7.19 (s, 1H), 6.74 (t, J = 6.1Hz, 1H), 6.61 (s, 1H), 5. 35–5.29(m,2H),4.54(d,J=5.8Hz,2H),3.61–3.46(m,1H),3.25–3.17(m,1H),3.08–2.99(m,1H),2.90(dd,J =11.7,4.5Hz,1H),2.81–2.74(m,1H),2.36–2.31(m,3H),2.30–2.25(m,1H),2.15(dd,J=11.6,9.9Hz,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 in DMSO. 1H in water.

[1449] Intermediate synthesis A11

[1450] (5,7-Dimethylimidazo[1,2-a]pyridin-2-yl)methanamine

[1451]

[1452] Step A :(5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanol

[1453] Diisobutylaluminum hydride (1M in hexane) (3.44mL, 3.44mmol) was added to a solution of 5,7-dimethylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (300mg, 1.37mmol) in THF (8.0mL) at 0°C. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, followed by the addition of MeOH (10mL), followed by the addition of water (10mL) and 1MHCl aqueous solution (10mL). The mixture was vigorously stirred for 30 minutes and extracted with ethyl acetate (3×25mL). The combined organic layers were washed with brine (15mL), dried over MgSO4, and concentrated in vacuo. Purification by column chromatography (12g cartridges, 0-10% MeOH / DCM) produced the title compound (93mg, 0.51mmol, 37% yield, 98% purity) as a brown solid.

[1454] UPLC / MS (Method 5): m / z 177 (M+H)+, R T 0.77 minutes.

[1455] Step B :2-(Chloromethyl)-5,7-dimethylimidazo[1,2-a]pyridine hydrochloride

[1456] 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 hour. Concentration to dryness under reduced pressure gave the title compound (132 mg, 0.52 mmol, 98% yield, 91% purity) as a yellow solid.

[1457] 1 H NMR (in DMSO-d6) was consistent with the product structure.

[1458] Step C :2-(Azidomethyl)-5,7-dimethylimidazo[1,2-a]pyridine

[1459] 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 hours. The mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridges, 0-10% MeOH / DCM) produced the title compound (117 mg, 0.38 mmol, 61% yield, 65% purity) as a colorless oil.

[1460] UPLC / MS (Method 5): m / z 202 (M+H)+, R T 0.46 minutes.

[1461] Step D :(5,7-dimethylimidazo[1,2-a]pyridin-2-yl)methanamine

[1462] 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, and the solvent was subsequently removed in a vacuum. 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 NH3MeOH solution (30 mL). The ammonia methanol solution was concentrated in a vacuum to produce the title compound (66 mg, 377 μmol, 99% yield, 99% purity) as a brown solid.

[1463] UPLC / MS (Method 5): m / z 176 (M+H)+, R T 0.79 minutes.

[1464] Synthesis 33

[1465] (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

[1466] (H-APPAMP-033)

[1467]

[1468] 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

[1469] (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 hours. 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.

[1470] UPLC / MS (Method 5): m / z 441 (M+H)+, R T 1.61 minutes

[1471] 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

[1472] 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), (3R,4R)-tert-butyl 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 under microwave irradiation at 150 ° C for 5 hours. At room temperature, water was added. The resulting solid was collected by filtration to produce the title compound (175 mg, 0.19 mmol, 65%, 69% purity) as a yellow solid.

[1473] UPLC / MS (Method 3): m / z 535 (M-Boc)+, R T 1.09 minutes.

[1474] 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

[1475] 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) was added hydrogen chloride (4 M in dioxane) (1.29 mL, 5.16 mmol). The reaction mixture was stirred at 35 °C for 1 hour and concentrated in vacuo. 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 methanolic ammonia solution was concentrated in vacuo. Further purification by RP preparative HPLC (25-100% MeCN / 0.1% aqueous formic acid) gave the title compound (84 mg, 0.15 mmol, 60% yield, 98% purity) as an off-white solid.

[1476] UPLC / MS (Method 5): m / z 535 (M+H)+, R T 1.27 minutes.

[1477] 1H NMR(400MHz, DMSO-d6)δ9.18(t,J=1.5Hz,1H),8.00(s,1H),7.85–7.77(m,2H),7.54(s,1H),6.72(t,J=5.9Hz, 1H),5.34–5.28(m,1H),5.25(s,1H),4.63(d,J=6.1Hz,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 is under water.

[1478] Intermediate synthesis A12

[1479] (8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1480]

[1481] Step A :(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol

[1482] Diisobutylaluminum hydride (1M in hexane) (18.8 mL, 18.8 mmol) was added to a solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (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 hours, followed by the addition of MeOH (10 mL) followed by the addition of water (10 mL) and 1M HCl aqueous solution (10 mL). The mixture was vigorously stirred for 30 minutes 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.

[1483] UPLC / MS (Method 5): m / z 251 (M+H)+, RT 0.94 min.

[1484] Step B:8-chloro-2-(chloromethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine

[1485] 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).

[1486] The mixture was stirred for 3 hours at 45° C. Concentration to dryness under reduced pressure gave the title compound (2.0 g, 6.7 mmol, 93% yield, 90% purity) as a yellow solid.

[1487] UPLC / MS (Method 5): m / z 269 (M+H)+, R T 1.25 minutes.

[1488] Step C :2-(Azidomethyl)-8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine

[1489] 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 hours. The mixture was cooled to room temperature, diluted with water (40 mL) and brine (60 mL), and then extracted with TBME (4 × 50 mL) and EtOAc (50 mL) in sequence. The combined organic layers were washed with brine (4 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (12 g cartridges, 0-100% TBME / isohexane) produced the title compound (1.80 g, 6.2 mmol, 93% yield, 95% purity) as a brown oil.

[1490] UPLC / MS (Method 5): m / z 276 (M+H)+, R T 1.27 minutes.

[1491] Step D :(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1492] 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 subsequently 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 NH3MeOH solution (100 mL). The ammonia methanol solution was concentrated in vacuo to produce the title compound (1.32 g, 5.0 mmol, 77% yield, 95% purity) as a white solid.

[1493] UPLC / MS (Method 5): m / z 250 (M+H)+, R T 0.92 minutes.

[1494] Synthesis 34

[1495] (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

[1496] (H-APPAMP-034)

[1497]

[1498] Step 1: 5-Chloro-3-ethyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1499] (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 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) produced the title compound (136 mg, 0.34 mmol, 91% yield, 98% purity) as an orange solid.

[1500] UPLC / MS (Method 3): m / z 395 (M+H)+, R T 1.51 minutes.

[1501] 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

[1502] 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 hours. 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 Na SO and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (159 mg, 0.29 mmol, 86% yield, 90% purity) as a yellow oil.

[1503] UPLC / MS (Method 5): m / z 495 (M+H)+, R T 1.88 minutes.

[1504] 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

[1505] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (91.0 mg, 0.395 mmol) and tA solution of BuBrettPhos Pd G3 (28 mg, 32.9 μmol) in THF (3.2 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (395 μl, 395 μmol) was added once under bubbling N2. Bubbling was stopped, and the reaction mixture was heated to 60 ° C for 2 hours. 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. Purified by column chromatography (12 g cartridges, 0-5% MeOH / DCM), followed by further purification on RP fast C18 (24 g cartridges, 30-100% MeCN / 10 mM ammonium bicarbonate), resulting in the title compound (153 mg, 0.18 mmol, 55% yield, 80% purity) as a yellow solid.

[1506] UPLC / MS (Method 5): m / z 689 (M+H)+, R T 1.77 minutes.

[1507] 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

[1508] 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) was added hydrogen chloride (4 M in dioxane) (900 μL, 3.6 mmol). The reaction mixture was stirred at room temperature at 40° C. for 2 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH in MeOH (100 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (89 mg, 0.18 mmol, 99% yield, 98% purity).

[1509] UPLC / MS (Method 3): m / z 489 (M+H)+, R T 0.70 minutes.

[1510] 1H NMR (400MHz, DMSO-d6) δ7.95–7.87(m,2H),7.68–7.60(m,2H),7.57(d,J=7.1Hz,1H),7.41(dd,J=7.1,9.2Hz,1H ),6.77(t,J=5.9Hz,1H),5.41–5.36(m,1H),5.35(s,1H),4.62(d,J=6.3Hz,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 is under water.

[1511] Synthesis 35

[1512] (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

[1513] (H-APPAMP-035)

[1514]

[1515] Step 1: 5-Chloro-3-cyclopropyl-N-((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1516] (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 hours. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 10% MeOH / DCM) produced the title compound (79 mg, 0.16 mmol, 54% yield, 84% purity) as a beige solid.

[1517] UPLC / MS (Method 5): m / z 407 (M+H)+, R T 1.51 minutes.

[1518] 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

[1519] 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 hours. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (57 mg, 0.10 mmol, 74% yield, 89% purity) as a yellow gum.

[1520] UPLC / MS (Method 5): m / z 507 (M+H)+, R T 1.84 minutes.

[1521] Step 3: 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

[1522] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (27 mg, 0.12 mmol) and tA solution of BuBrettPhos Pd G3 (9.3 mg, 11.3 μmol) in THF (1.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (0.14 mL, 0.14 mmol) was added once under bubbling N2. 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) produced the title compound (53 mg, 73 μmol, 67% yield, 96% purity) as a white solid.

[1523] UPLC / MS (Method 5): m / z 701 (M+H)+, R T 1.72 minutes.

[1524] 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

[1525] 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 an SCX column. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH3MeOH solution (20 mL). The methanolic ammonia solution was concentrated in vacuo to afford the title compound (23 mg, 44 μmol, 61% yield, 95% purity) as an off-white solid after trituration from Et 2 O and drying under vacuum at 40° C. overnight.

[1526] UPLC / MS (Method 5): m / z 501 (M+H)+, R T 1.21 minutes.

[1527] 1H NMR(400MHz, DMSO-d6)δ8.70(d,J=7.1Hz,1H),7.99(s,2H),7.73(t,J=6.2Hz ,1H),7.52(s,1H),7.15(dd,J=7.2,1.9Hz,1H),6.73-6.68(m,1H),5.33–5.2 7(m,1H),5.25(s,1H),4.62(d,J=6.1Hz,2H),3.56-3.44(m,1H),3.25–3.15( m,1H),3.08–2.97(m,1H),2.90(dd,J=11.7,4.5Hz,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.

[1528] Intermediate synthesis A13

[1529] (7-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1530]

[1531] Step A :2-((7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione

[1532] By 4- (trifluoromethyl) pyridine -2- amine (200mg, 1.23mmol), 2- (3- bromo -2- oxopropyl) isoindoline -1,3- dione (366mg, 1.23mmol) and sodium bicarbonate (104mg, 1.23mmol) in ethanol (0.60mL) under microwave irradiation, heated to 80 ° C for 1 hour. The mixture was then concentrated under reduced pressure. Purification by column chromatography (24g cartridge, 0-10% MeOH / DCM) produced the title compound (348mg, 0.80mmol, 65% yield, 79% purity) as a yellow solid.

[1533] UPLC / MS (Method 5): m / z 364 (M+H)+, R T 1.02 minutes.

[1534] Step B :(7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1535] 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 hours. The mixture was concentrated in vacuo and then diluted with 1M aqueous HCl (20 mL). The white solid was filtered off and washed with 1M aqueous HCl (2×20 mL). The combined aqueous layers were then basified with solid NaHCO 3 and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO 4 , filtered, and then concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH 3 in MeOH (30 mL). The methanolic ammonia solution was concentrated in vacuo to afford the title compound as a brown oil (90 mg, 0.31 mmol, 38% yield, 73% purity).

[1536] UPLC / MS (Method 5): m / z 216 (M+H)+, R T 0.82 minutes Synthesis 36

[1537] (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

[1538] (H-APPAMP-036)

[1539]

[1540] 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

[1541] (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 produce the title compound (170 mg, 0.43 mmol, 61% yield, 99% purity) as a white solid.

[1542] UPLC / MS (Method 3): m / z 389 (M+H)+, R T 1.52 minutes

[1543] 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

[1544] 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 Na 2 SO 4 and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-10% (0.7 M NH 3 / MeOH) / DCM) gave the title compound (190 mg, 0.25 mmol, 60% yield, 64% purity) as a yellow solid.

[1545] UPLC / MS (Method 5): m / z 488 (M+H)+, R T 1.83 minutes.

[1546] Step 3: 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

[1547] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (68.7 mg, 298 μmol) and t A solution of BuBrettPhos Pd G3 (21.3 mg, 24.9 μmol) in THF (2.0 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (323 μL, 323 μmol) was added once under bubbling N2. 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) produced the title compound (103 mg, 0.13 mmol, 50% yield, 83% purity) as a yellow solid.

[1548] UPLC / MS (Method 5): m / z 684 (M+H)+, R T 1.73 minutes.

[1549] 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

[1550] 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) was added hydrogen chloride (4 M in dioxane) (626 μL, 2.50 mmol). The reaction mixture was stirred at 35 °C for 4 hours and concentrated in vacuo. 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 NH3MeOH solution (10 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (28 mg, 54 μmol, 43% yield, 93% purity).

[1551] UPLC / MS (Method 3): m / z 484 (M+H)+, R T 0.72 minutes.

[1552] 1H NMR(400MHz, DMSO-d6)δ7.79–7.70(m,2H),7.66(dd,J=11.1,7.4Hz,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=5.5Hz,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.

[1553] Intermediate synthesis A14

[1554] (5,6-Difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methanamine

[1555]

[1556] Step A :N-(2-amino-4,5-difluorophenyl)-2-(1,3-dioxoisoindolin-2-yl)acetamide

[1557] 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 hours. 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 produce the title compound (1.81 g, 5.4 mmol, 78% yield, 99% purity) as an off-white solid.

[1558] UPLC / MS (Method 5): m / z 332 (M+H)+, R T 1.46 minutes.

[1559] Step B :2-((5,6-difluoro-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione

[1560] 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 co-evaporated 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.

[1561] UPLC / MS (Method 5): m / z 314 (M+H)+, R T 1.47 minutes.

[1562] Step C :2-((5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methyl)isoindoline-1,3-dione

[1563] 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 minutes, then at room temperature overnight, after which the resulting solid was collected by filtration and washed sequentially with water (2.0 mL) and MeCN (2.0 mL) to give the title compound (610 mg, 1.7 mmol, 88% yield, 90% purity) as a grey solid.

[1564] UPLC / MS (Method 5): m / z 328 (M+H)+, R T 1.21 minutes.

[1565] Step D :(5,6-difluoro-1-methyl-1H-benzo[d]imidazol-2-yl)methanamine

[1566] 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 overnight at 65 ° C. 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 NH3MeOH solution (10 mL). The methanolic ammonia solution was concentrated in vacuo to give the title compound (300 mg, 1.40 mmol, 89% yield, 89% purity) as a white solid.

[1567] UPLC / MS (Method 5): m / z 199 (M+H)+, R T 0.78 minutes.

[1568] Synthesis 37

[1569] (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

[1570] (H-APPAMP-037)

[1571]

[1572] Step 1: 5-Chloro-3-cyclopropyl-N-((5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

[1573] (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 hours and then concentrated in vacuo.

[1574] Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (185 mg, 0.37 mmol, 99% yield, 82% purity) as a beige solid.

[1575] UPLC / MS (Method 3): m / z 407 (M+H)+, R T 1.54 minutes.

[1576] 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

[1577] 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 hours. 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 Na 2 SO 4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (167 mg, 0.32 mmol, 87% yield, 98% purity) as an orange oil.

[1578] UPLC / MS (Method 3): m / z 507 (M+H)+, R T 1.87 minutes.

[1579] 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

[1580] 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), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (91 mg, 0.395 mmol) and tA solution of BuBrettPhos Pd G3 (28 mg, 0.0329 mmol) in THF (3.2 mL) was degassed with N2 for 10 minutes. LiHMDS (1 M in THF) (395 μL, 0.395 mmol) was added once under bubbling N2. 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 cartridges, 0-10% MeOH / DCM) produced the title compound (177 mg, 0.16 mmol, 49% yield, 64% purity) as an orange solid.

[1581] UPLC / MS (Method 3): m / z 701 (M+H)+, R T 1.76 minutes.

[1582] 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

[1583] 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) was added hydrogen chloride (4 M in dioxane) (0.80 mL, 3.20 mmol). The reaction mixture was stirred at 40 °C for 3 hours and concentrated in vacuo. The residue was loaded onto an SCX column. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3MeOH solution (30 mL). The methanolic ammonia solution was concentrated in vacuo to give a yellow solid. Further purification by preparative HPLC (20-100% MeCN / 0.1% aq. NH 3 ) gave the title compound as a white solid (41 mg, 79 μmol, 50% yield, 98% purity).

[1584] UPLC / MS (Method 5): m / z 501 (M+H)+, R T 1.20 minutes.

[1585] 1H NMR (400MHz, DMSO-d6) δ7.91(d,J=9.3Hz,2H),7.61(t,J=6.2Hz,1H),7.57(d,J=7.1Hz,1H),7.51(s,1H),7.44–7 .35(m,1H),6.74(t,J=6.1Hz,1H),5.35(s,1H),5.26(s,1H),4.61(d,J=6.0Hz,2H),3.50(s,1H),3.27–3.18(m,1 H),3.10–2.95(m,1H),2.90(dd,J=11.6,4.5Hz,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).

[1586] Intermediate synthesis A15

[1587] (5-(Trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1588]

[1589] Step A :5-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[1590] Under microwave irradiation, IPA (5.8 mL) and water (5.8 mL) containing 6- (trifluoromethyl) pyridine -2- amine (1.00 g, 6.17 mmol) and ethyl 3- bromo-2-oxopropanoate (1.6 mL, 12.3 mmol) were heated at 80 ° C for 1 hour. The reaction mixture was concentrated under vacuum. The purification by column (80 g cartridge, 0-5% (0.7 M NH / MeOH) / DCM) produced the title compound (1.24 g, 4.32 mmol, 67% yield, 90% purity) as a brown oil.

[1591] UPLC / MS (Method 5): m / z 259 (M+H)+, R T 1.13 minutes.

[1592] Step B :(5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanol

[1593] Diisobutylaluminum hydride (1M in hexane) (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 1M HCl aqueous solution (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 produce the title compound (453 mg, 2.0 mmol, 57% yield, 95% purity) as a brown oil.

[1594] UPLC / MS (Method 5): m / z 217 (M+H)+, R T 0.82 minutes.

[1595] Step C :2-(Chloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine hydrochloride

[1596] 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.

[1597] The mixture was stirred at 0° C. for 2 hours and then at room temperature for 1 hour. Concentration to dryness under reduced pressure gave the title compound as a brown oil (494 mg, 1.7 mmol, 87% yield, 95% purity).

[1598] UPLC / MS (Method 3): m / z 271 (M+H)+, R T 1.14 minutes.

[1599] Step D :2-(azidomethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine

[1600] A solution of 2-(chloromethyl)-5-(trifluoromethyl)imidazo[1,2-a]pyridine hydrochloride (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 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and brine (10 mL). It was extracted with TBME (3 × 20 mL) and EtOAc (3 × 20 mL) in sequence. The combined organic layers were washed with brine (4 × 20 mL), dried over Na2SO4, and concentrated under reduced pressure to produce the title compound (383 mg, 1.5 mmol, 89% yield, 97% purity) as a brown oil.

[1601] UPLC / MS (Method 5): m / z 242 (M+H)+, R T 1.12 minutes.

[1602] Step E :(5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)methanamine

[1603] 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 subsequently 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 NH3MeOH solution (100 mL). The ammonia methanol solution was concentrated in vacuo to produce the title compound (336 mg, 1.4 mmol, 91% yield, 90% purity) as a brown oil.

[1604] UPLC / MS (Method 5): m / z 216 (M+H)+, R T 0.82 minutes.

[1605] Synthesis 38

[1606] (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

[1607] (H-APPAMP-038)

[1608]

[1609] 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

[1610] (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 hours and then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (103.6 mg, 0.23 mmol, 82% yield, 96% purity) as a light beige solid.

[1611] UPLC / MS (Method 5): m / z 435 (M+H)+, R T 1.67 minutes

[1612] 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

[1613] 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 (10...

Claims

1. The compound of the formula: or a pharmaceutically acceptable salt thereof; in: -R 7 is 2-imidazo[1,2-a]pyridinyl and is substituted on carbon with one or more -R groups SC optionally substituted; Each-R SC Independently are: -R TT ， -F, -Cl, -Br, -I, -OH、-OR TT , -CF3, -CHF2, -OCF3 or -OCHF2; Each-R TT Independently -R TT1 or -R TT2 ; Each-R TT1 are independently straight-chain or branched saturated C 1-6 alkyl; Each-R TT2 It is saturated C 3-6 Cycloalkyl; -L 7 - is -CH2-; and -R 3 It is saturated C 3-7 Cycloalkyl.

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

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

4. The compound of claim 1, wherein if present, each -R TT2 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

5. The compound of claim 1, wherein if present, each -R TT2 It is cyclopropyl.

6. The compound according to claim 1, wherein: If present, then each -R TT1 is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu or -tBu; and If present, then each -R TT2 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

7. The compound according to claim 1, wherein: If present, then each -R TT1 is-Me; and If present, then each -R TT2 It is cyclopropyl.

8. The compound of claim 1, wherein if present, each -R TT Yes-R TT1 .

9. The compound of claim 8, wherein if present, each -R TT1 is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu or -tBu.

10. The compound of claim 8, wherein if present, each -R TT1 Yes-Me.

11. The compound according to claim 1, wherein -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

12. The compound according to claim 6, wherein -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

13. The compound according to claim 7, wherein -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

14. The compound according to claim 8, wherein -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

15. The compound according to claim 10, wherein -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

16. The compound according to claim 1, wherein -R 3 is independently cyclopropyl or cyclobutyl.

17. The compound according to claim 6, wherein -R 3 is independently cyclopropyl or cyclobutyl.

18. The compound according to claim 7, wherein -R 3 is independently cyclopropyl or cyclobutyl.

19. The compound according to claim 8, wherein -R 3 is independently cyclopropyl or cyclobutyl.

20. The compound according to claim 10, wherein -R 3 is independently cyclopropyl or cyclobutyl.

21. The compound according to claim 1, wherein -R 3 It is cyclopropyl.

22. The compound according to claim 6, wherein -R 3 It is cyclopropyl.

23. The compound according to claim 7, wherein -R 3 It is cyclopropyl.

24. The compound according to claim 8, wherein -R 3 It is cyclopropyl.

25. The compound according to claim 9, wherein -R 3 It is cyclopropyl.

26. The compound according to claim 10, wherein -R 3 It is cyclopropyl.

27. The compound according to claim 1, wherein the compound is selected from the following compounds and pharmaceutically acceptable salts thereof:

28. A composition comprising a compound as claimed in any one of claims 1 to 27 and a pharmaceutically acceptable carrier or diluent.

29. A method for preparing a composition, the method comprising the step of mixing a compound as claimed in any one of claims 1 to 27 and a pharmaceutically acceptable carrier or diluent.

30. A method for inhibiting cyclin-dependent protein kinase function in a cell in vitro, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 27.

31. A method for inhibiting cyclin-dependent protein kinase 12 function in a cell in vitro, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 27.

32. Use of a compound as claimed in any one of claims 1 to 27 for the preparation of a medicament for the treatment of a proliferative disorder.

33. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of cancer.

34. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of a viral infection.

35. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of HIV.

36. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of a neurodegenerative disorder.

37. Use of a compound as claimed in any one of claims 1 to 27 for the preparation of a medicament for the treatment of Alzheimer's disease or Parkinson's disease.

38. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for treating kidney disease.

39. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of a cardiovascular disorder.

40. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for treating atherosclerosis.

41. Use of a compound as claimed in any one of claims 1 to 27 in the preparation of a medicament for the treatment of an autoimmune disorder.

42. Use of a compound as claimed in any one of claims 1 to 27 for the preparation of a medicament for the treatment of rheumatoid arthritis, systemic lupus erythematosus, psoriasis or Sjögren's syndrome.

43. Use of a compound as claimed in any one of claims 1 to 27 for the preparation of a medicament for treating a disorder caused by abnormal translation function in a cell.

44. Use of a compound as claimed in any one of claims 1 to 27 for the preparation of a medicament for the treatment of muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy or fragile X syndrome.

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