4-[[(7-aminopyrazolo[1,5-a]pyrimidin-5-YL)amino]methyl]piperidin-3-OL compounds and their therapeutic use

Abstract

The present disclosure pertains generally to the field of therapeutic compounds. More specifically the present disclosure pertains to certain compounds of the following formula that, inter alia, inhibit cyclin-dependent protein kinases (CDKs), especially CDK12 and / or CDK13, and are selective, for example, for CDK12 and / or CDK13 as compared to CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective Cyclin K degraders thereby removing the key signaling mechanism required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. The present disclosure also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CDK, especially CDK12 and / or CDK13; and to treat disorders associated with CDK, especially CDK12 and / or CDK13, including cancer [Image disponible dans le document PDF, Image available in the PDF document]

Description

4-[[(7-AMINOPYRAZOLO[1,5-A]PYRIMIDIN-5-YL)AMINO]METHYL]PIPERIDIN-3-OL COMPOUNDS AND THEIR THERAPEUTIC USE TECHNICAL FIELD The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain H-APPAMP compounds (referred to herein as "H-APPAMP compounds") that, inter alia, inhibit cyclin-dependent protein kinases (CDKs), especially CDK12 and / or CDK13, and are selective, for example, for CDK12 and / or CDK13 as compared to CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the compounds also act as selective Cyclin K degraders thereby removing the key signaling mechanism required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CDK, especially CDK12 and / or CDK13; and to treat disorders including: disorders that are associated with CDK, especially CDK12 and / or CDK13; disorders that result from an inappropriate activity of a CDK, especially CDK12 and / or CDK13; disorders that are associated with CDK mutation, especially CDK12 and / or CDK13mutation; disorders that are associated with CDK overexpression, especially CDK12 and / or CDK13 overexpression; disorders that are associated with upstream pathway activation of CDK, especially CDK12 and / or CDK13; disorders that are ameliorated by the inhibition of CDK, especially CDK12 and / or CDK13; proliferative disorders; cancer; viral infections (including HIV); neurodegenerative disorders (including Alzheimer's disease and Parkinson's disease); ischaemia; renal diseases; cardiovascular disorders (including atherosclerosis); autoimmune disorders (including rheumatoid arthritis); and disorders caused by dysfunction of translation in cells (including muscular dystrophy). Optionally, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., an aromatase inhibitor, an anti estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent stimulating the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc. BACKGROUND A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Throughout this specification, including the claims which follow, 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. 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, and the like. 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 the use of the antecedent "about," it will be understood that the particular value forms another embodiment. This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. Cyclin-Dependent Protein Kinase (CDK) Cyclin-dependent protein kinases (CDK) are the catalytic subunits of a family of 21 serine / threonine protein kinases (see, e.g., Malumbres et al., 2009), some of which control progression of the cell through the stages of growth, DNA replication and mitosis (see, e.g., Pines, 1995; Morgan, 1995). Activation of specific CDKs is required for appropriate progression through the different stages of the cell cycle and entry into the next stage of the cell cycle. Cyclin-dependent kinase 12 (CDK12) and its orthologue 13 (CDK13) belong to the cyclin- dependent kinase (CDK) family of serine / threonine protein kinases that regulate transcriptional and posttranscriptional processes, thereby modulating multiple cellular functions. Studies have characterised CDK12 and CDK13 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II (see, e.g., Li et al., 2016; Greifenberg et al., 2016). The CDK12 / cyclin K and CDK13 / cyclin K complexes phosphorylate RNA Pol II at Ser2 (Ser2p-RNA Pol II), which is thought to be a critical step in transition from transcriptional initiation to elongation. Additionally, CDK12 can form a complex with cyclins L1 and L2 to regulate alternative splicing of mRNA transcripts (see, e.g., Chen et al., 2016). CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock (see, e.g., Blazek et al., 2011; Lord et al., 2016). CDK13 regulates a different set of genes to CDK12, with CDK3 activity mostly involved in growth signaling pathways, including tyrosine kinase signalling (Greifenberg et al., 2016). Studies have also implicated CDK12 in regulating mRNA splicing, 3'-end processing, pre- replication complex assembly, and genomic stability. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers (see, e.g., Gyl et al., 2018). A number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with a number of pathways relevant for cancer survival and progression (see, e.g., Johnson et al., 2016; Choi et al., 2019). Cyclin K degradation is a property of some, but not all inhibitors of CDK 12 (see, e.g., Słabicki et al., 2020). Upon binding of an inhibitor with a degrader activity, CDK12 acts as a surrogate substrate receptor for the CUL4-DDB1 ubiquitin ligase complex, presenting Cyclin K for ubiquitination by CRL4 and resulting in proteosomal degradation. Interaction between CDK12 and DDB1 is driven, in part, due to interactions of the inhibitor with DDB1. Therefore, only CDK12 inhibitors that simultaneously occupy the kinase active site and fill the hydrophobic pocket of DDB1 can promote Cyclin K degradation. For example, the pan-CDK inhibitor CR8 was found to cause Cyclin K degradation by this mechanism, whereas the CDK12 selective covalent inhibitor THZ-531 did not cause cyclin K degradation. Cyclin K degradation can complement the direct inhibition of CDK12 and / or 13 in cells. This is advantageous for a number of reasons. Firstly, degradation can lead to enhanced potency over kinase inhibition alone, as shown by the increased potency of molecules in cell killing assays. Enhanced cellular potency can lead to reduced off-target interactions and effects between the inhibitor and other kinases than CDK12 and / or CDK13. Secondly, Cyclin K is the obligate partner for both CDK12 and CDK13 and is needed for their activity. Cyclin K degraders will therefore cause 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 in cells in excess of 12 hours (see, e.g., Lei et al., 2018). Hence degraders may have effects in cells and tumours that may extend beyond the duration of exposure to the compound. Known Compounds Bondke et al., 2015, describes certain pyrazolo[1,5-a]pyrimidine-5,7-diamine compounds as CDK nhibitors, including, for example, the following compound (referred to therein as PPDA-001): [Image disponible dans le document PDF, Image available in the PDF document] Hazel et al., 2017, describes studies of the selectivity of inhibitors of CDK7, including ICEC0942 (shown below). Patel et al., 2018, describes studies of the CDK7 inhibitor ICEC0942 in the treatment of cancer. [Image disponible dans le document PDF, Image available in the PDF document] Johannes et al., 2018, describes studies used it identify a class of selective CDK12 inhibitors, including the lead compound, denoted "Compound 7" therein, shown below. [Image disponible dans le document PDF, Image available in the PDF document] Bahl et al., 2019, describes 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): [Image disponible dans le document PDF, Image available in the PDF document] Kugel, 2019, describes the use of CDK7, generally, in the treatment of certain sub-types of pancreatic cancer. A range of known CDK7 inhibitors are shown on pages 26-30 therein. Kwiatkowski et al., 2019, use of CDK7, generally, in the treatment of tuberous sclerosis complex. A range of known CDK7 inhibitors are shown on pages 25-55 therein. Roush et al., 2019, describes certain small molecule inhibitors of CDK12 / CDK13 which allegedly are useful in the treatment of cancers, such as breast cancer, brain cancer, and ovarian cancer. The compounds have the following formula, wherein R<com:Sup>1< / com:Sup> is aryl or heteroaryl. Examples therein include Compounds 6 and 7, shown below. [Image disponible dans le document PDF, Image available in the PDF document] Potency / Selectivity The H-APPAMP compounds described herein are potent CDK12 and / or CDK13 inhibitors that are also highly selective for CDK12 and / or CDK13, for example, as compared to CDK7. In addition to selectively inhibiting CDK12 and / or CDK13, the H-APPAMP compounds described herein may also act as selective Cyclin K degraders thereby removing the key signaling mechanism required for CDK12 and / or CDK13 activation; this confers additional cellular potency and selectivity. 5 SUMMARY Certain exemplary embodiments provide a compound of the following formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt or solvate thereof; wherein: -R' is 2-imidazo[1,2-a]pyridinyl, and is optionally substituted on carbon with one or more groups -R<com:Sup>SC< / com:Sup>; each -R<com:Sup>SC< / com:Sup> is independently -R<com:Sup>TT< / com:Sup>, -F, -Cl, -Br, -I, -OH, -OR<com:Sup>TT< / com:Sup>, -CF<com:Sub>3< / com:Sub>, -CHF<com:Sub>2< / com:Sub>, -OCF<com:Sub>3< / com:Sub>, or -OCHF<com:Sub>2< / com:Sub>; each -R<com:Sup>TT< / com:Sup> is independently -R<com:Sup>TT1< / com:Sup> or -R<com:Sup>TT2< / com:Sup>; each -R<com:Sup>TT1< / com:Sup> is independently linear or branched saturated C<com:Sub>1-6< / com:Sub>alkyl; each -R<com:Sup>TT2< / com:Sup> is saturated C<com:Sub>3-6< / com:Sub>cycloalkyl; <com:Math><semantics>−L′<annotation encoding="application / x-tex">-L'< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>-; and -R<com:Sup>3< / com:Sup> is saturated C<com:Sub>3-7< / com:Sub>cycloalkyl. Other exemplary embodiments provide a compound as defined herein for use to treat cancer. Yet other exemplary embodiments provide a compound for use as defined herein, wherein the disorder is breast cancer which is resistant to said aromatase inhibitor. Still yet other exemplary embodiments provide a compound for use as defined herein, wherein the disorder is breast cancer which is resistant to said anti-estrogen. One aspect of the 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. Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising an H-APPAMP compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of mixing an H-APPAMP compound, as described herein, and a pharmaceutically acceptable carrier or diluent. Another aspect of the present invention pertains to a method of inhibiting CDK12 and / or CDK13 (function (e.g., in a cell), in vitro or in vivo, comprising contacting the cell with an effective amount of an H-APPAMP compound, as described herein. Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound, as described herein. Another aspect of the present invention pertains to an H-APPAMP compound as described herein for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. Another aspect of the present invention pertains to use of an H-APPAMP compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. Another aspect of the present invention pertains to a method of treatment, for example, a method of treatment of a disorder (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. In one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent stimulating the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc., as described herein. Another aspect of the present invention pertains to a kit comprising (a) an H-APPAMP compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and / or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound. Another aspect of the present invention pertains to an H-APPAMP compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to an H-APPAMP compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein. Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein. As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. DETAILED DESCRIPTION OF THE INVENTION Compounds One aspect of the present invention relates to certain compounds which are related to pyrazolo[1,5-a]pyrimidine-5,7-diamine ("PPDA"): [Image disponible dans le document PDF, Image available in the PDF document] More specifically, the compounds are related to <com:Math><semantics>(3R,4R)−4−[[(7−aminopyrazolo<annotation encoding="application / x-tex">(3R,4R)-4-[[(7-aminopyrazolo< / annotation>< / semantics>< / com:Math> [1,5-a]pyrimidin-5-yl)amino]methyl]piperidin-3-ol ("APPAMP"): [Image disponible dans le document PDF, Image available in the PDF document] Furthermore, all of the compounds of the present invention have: (a) a substituted amino group at the 7-position (denoted herein as -NH-<com:Math><semantics>L7<annotation encoding="application / x-tex">L^7< / annotation>< / semantics>< / com:Math>-<com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math>); and (b) an alkyl or cycloalkyl group at the 3-position (denoted herein as -R<com:Sup>3< / com:Sup>). More specifically, the group <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> is a fused bicyclic <com:Math><semantics>C8−10<annotation encoding="application / x-tex">C_{8-10}< / annotation>< / semantics>< / com:Math>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N, S, or O. For the avoidance of doubt, the fused bicyclic <com:Math><semantics>C8−10<annotation encoding="application / x-tex">C_{8-10}< / annotation>< / semantics>< / com:Math>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. Thus, one aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein -R<com:Sup>7< / com:Sup>, -L<com:Sup>7< / com:Sup>-,and -R<com:Sup>3< / com:Sup> are as defined herein (for convenience, collectively referred to herein as "H-APPAMP" compounds"): [Image disponible dans le document PDF, Image available in the PDF document] . Some embodiments include the following: (1) A compound of the following formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt or solvate thereof; wherein: <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> is a fused bicyclic <com:Math><semantics>C8−10<annotation encoding="application / x-tex">C_{8-10}< / annotation>< / semantics>< / com:Math>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N, S, or O; and wherein -R<com:Sup>7< / com:Sup> is: optionally substituted on carbon with one or more groups -RSC; and optionally substituted on secondary nitrogen, if present, with a group -R<com:Sup>SN< / com:Sup>; wherein: each -R<com:Sup>SC< / com:Sup> is independently: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] <com:Math><semantics>−LT<annotation encoding="application / x-tex">-L^{T}< / annotation>< / semantics>< / com:Math>-OH, <com:Math><semantics>−LT<annotation encoding="application / x-tex">-L^{T}< / annotation>< / semantics>< / com:Math>-OR<com:Sup>TT< / com:Sup>, -CF<com:Sub>3< / com:Sub>, -CHF<com:Sub>2< / com:Sub>, -OCF<com:Sub>3< / com:Sub>, -OCHF<com:Sub>2< / com:Sub>, <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHRTT<annotation encoding="application / x-tex">-NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR2TT<annotation encoding="application / x-tex">-NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−RTM<annotation encoding="application / x-tex">-R^{TM}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>−LT−NH2<annotation encoding="application / x-tex">-L^{T}-NH_{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−NHRTT<annotation encoding="application / x-tex">-L^{T}-NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−NR2TT<annotation encoding="application / x-tex">-L^{T}-NR^{TT}_{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−RTM<annotation encoding="application / x-tex">-L^{T}-R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)OH,−C(=O)ORTT,<annotation encoding="application / x-tex">-C(=O)OH, -C(=O)OR^{TT},< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−OC(=O)RTT<annotation encoding="application / x-tex">-OC(=O)R^{TT}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−C(=O)NH2<annotation encoding="application / x-tex">-C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NHRTT<annotation encoding="application / x-tex">-C(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR2TT<annotation encoding="application / x-tex">-C(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTM<annotation encoding="application / x-tex">-C(=O)R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)RTT<annotation encoding="application / x-tex">-NHC(=O)R^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)RTT<annotation encoding="application / x-tex">-NR^{TN}C(=O)R^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)NH2<annotation encoding="application / x-tex">-NHC(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)NHRTT<annotation encoding="application / x-tex">-NHC(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)NR2TT<annotation encoding="application / x-tex">-NHC(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHC(=O)RTM<annotation encoding="application / x-tex">-NHC(=O)R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)NH2<annotation encoding="application / x-tex">-NR^{TN}C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)NHRTT<annotation encoding="application / x-tex">-NR^{TN}C(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)NR2TT<annotation encoding="application / x-tex">-NR^{TN}C(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)RTM<annotation encoding="application / x-tex">-NR^{TN}C(=O)R^{TM}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>−NHC(=O)ORTT<annotation encoding="application / x-tex">-NHC(=O)OR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNC(=O)ORTT<annotation encoding="application / x-tex">-NR^{TN}C(=O)OR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NH2<annotation encoding="application / x-tex">-OC(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NHRTT<annotation encoding="application / x-tex">-OC(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)NR2TT<annotation encoding="application / x-tex">-OC(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OC(=O)RTM<annotation encoding="application / x-tex">-OC(=O)R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTT<annotation encoding="application / x-tex">-C(=O)R^{TT}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−SRTT<annotation encoding="application / x-tex">-SR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)RTT<annotation encoding="application / x-tex">-S(=O)R^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2RTT<annotation encoding="application / x-tex">-S(=O)_2R^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)NH2<annotation encoding="application / x-tex">-S(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)NHRTT<annotation encoding="application / x-tex">-S(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)NR2TT<annotation encoding="application / x-tex">-S(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)RTM<annotation encoding="application / x-tex">-S(=O)R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NH2<annotation encoding="application / x-tex">-S(=O)_2NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NHRTT<annotation encoding="application / x-tex">-S(=O)_2NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2NR2TT<annotation encoding="application / x-tex">-S(=O)_2NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2RTM<annotation encoding="application / x-tex">-S(=O)_2R^{TM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHS(=O)2RTT<annotation encoding="application / x-tex">-NHS(=O)_2R^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NRTNS(=O)2RTT<annotation encoding="application / x-tex">-NR^{TN}S(=O)_2R^{TT}< / annotation>< / semantics>< / com:Math>, -CN, or -NO<com:Sub>2< / com:Sub>; each -R<com:Sup>SN< / com:Sup> is independently: <com:Math><semantics>−RTT<annotation encoding="application / x-tex">-R^{TT}< / annotation>< / semantics>< / com:Math>. <com:Math><semantics>−LT<annotation encoding="application / x-tex">-L^{T}< / annotation>< / semantics>< / com:Math>-OH, <com:Math><semantics>−LT<annotation encoding="application / x-tex">-L^{T}< / annotation>< / semantics>< / com:Math>-OR<com:Sup>TT< / com:Sup>, <com:Math><semantics>−LT−NH2<annotation encoding="application / x-tex">-L^{T}-NH_{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−NHRTT<annotation encoding="application / x-tex">-L^{T}-NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−NR2TT<annotation encoding="application / x-tex">-L^{T}-NR^{TT}_{2}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−LT−RTM<annotation encoding="application / x-tex">-L^{T}-R^{TM}< / annotation>< / semantics>< / com:Math>, -C(=O)R<com:Sup>11< / com:Sup>, -C(=O)OR<com:Sup>TT< / com:Sup>. <com:Math><semantics>−C(=O)NH2<annotation encoding="application / x-tex">-C(=O)NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NHRTT<annotation encoding="application / x-tex">-C(=O)NHR^{TT}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)NR2TT<annotation encoding="application / x-tex">-C(=O)NR^{TT}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTM<annotation encoding="application / x-tex">-C(=O)R^{TM}< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>−S(=O)2RTT<annotation encoding="application / x-tex">-S(=O)_2R^{TT}< / annotation>< / semantics>< / com:Math>; wherein: each -L<com:Sup>T< / com:Sup>- is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkylene; each -R<com:Sup>TT< / com:Sup> is independently -R<com:Sup>TT1< / com:Sup>, -R<com:Sup>TT2< / com:Sup>, -L<com:Sup>TT< / com:Sup>-R<com:Sup>TT2< / com:Sup>, -R<com:Sup>TT3< / com:Sup>, or -L<com:Sup>TT< / com:Sup>-R<com:Sup>TT3< / com:Sup>; each -R<com:Sup>TT1< / com:Sup> is independently linear or branched saturated C<com:Sub>1-6< / com:Sub>alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR<com:Sup>TTT< / com:Sup>; each -R<com:Sup>TT2< / com:Sup> is saturated C<com:Sub>3-6< / com:Sub>cycloalkyl, and is optionally substituted with one or more groups selected from -F, -R<com:Sup>TTT< / com:Sup>, -OH, and -OR<com:Sup>TTT< / com:Sup>; each -R<com:Sup>TT3< / com:Sup> is independently phenyl or naphthyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R<com:Sup>TTT< / com:Sup>, OH, -OR<com:Sup>TTT< / com:Sup>, -OCF<com:Sub>3< / com:Sub>, -NH<com:Sub>2< / com:Sub>, -NHR<com:Sup>TTT< / com:Sup>, and -NR<com:Sup>TTT< / com:Sup><com:Sub>2< / com:Sub>; each -L<com:Sup>TT< / com:Sup>- is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkylene; each -R<com:Sup>TN< / com:Sup> is linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl, phenyl, or benzyl; each -R<com:Sup>TM< / com:Sup> is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups selected from: -R<com:Sup>IMM< / com:Sup>, <com:Math><semantics>−C(=O)RTMM<annotation encoding="application / x-tex">-C(=O)R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−S(=O)2RTMM<annotation encoding="application / x-tex">-S(=O)_2R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−F<annotation encoding="application / x-tex">-F< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NH2<annotation encoding="application / x-tex">-NH_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NHRTMM<annotation encoding="application / x-tex">-NHR^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−NR2TMM<annotation encoding="application / x-tex">-NR^{TMM}_2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OH<annotation encoding="application / x-tex">-OH< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−ORTMM<annotation encoding="application / x-tex">-OR^{TMM}< / annotation>< / semantics>< / com:Math>; and optionally substituted on secondary nitrogen, if present, with a group selected from: <com:Math><semantics>−RTMM<annotation encoding="application / x-tex">-R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTMM<annotation encoding="application / x-tex">-C(=O)R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)ORTMM<annotation encoding="application / x-tex">-C(=O)OR^{TMM}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−S(=O)2RTMM<annotation encoding="application / x-tex">-S(=O)_2R^{TMM}< / annotation>< / semantics>< / com:Math>; each -R<com:Sup>TTT< / com:Sup> is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl, phenyl, or benzyl; and each -R<com:Sup>TMM< / com:Sup> is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl, phenyl, or benzyl; and wherein: -L<com:Sup>7< / com:Sup>- is independently linear or branched saturated C<com:Sub>1-3< / com:Sub>alkylene, and is optionally substituted with one or more groups selected from -F, -OH, and -OMe; -R<com:Sup>3< / com:Sup> is independently -R<com:Sup>3A< / com:Sup> or -R<com:Sup>3B< / com:Sup>; -R<com:Sup>3A< / com:Sup> is independently linear or branched saturated C<com:Sub>1-6< / com:Sub>alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OMe; and -R<com:Sup>3B< / com:Sup> is independently saturated C<com:Sub>3-7< / com:Sub>cycloalkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OMe. For the avoidance of doubt: The index "<com:Math><semantics>Cx−y<annotation encoding="application / x-tex">C_{x-y}< / annotation>< / semantics>< / com:Math>" in terms such as "<com:Math><semantics>C9−10<annotation encoding="application / x-tex">C_{9-10}< / annotation>< / semantics>< / com:Math>heteroaryl", "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math>heterocyclyl", and the like, refers to the number of ring atoms, which may be carbon atoms or heteroatoms (e.g., N, O, S, as the case may be). For example, pyridyl is an example of a C<com:Sub>6< / com:Sub>heteroaryl group, and piperidino is an example of a C<com:Sub>6< / com:Sub>heterocyclyl group. The term "heteroaryl" refers to a group that is attached to the rest of the molecule by an atom that is part of an aromatic ring, 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 the case may be). For example, pyridyl is an example of a C<com:Sub>6< / com:Sub>heteroaryl group, and quinolyl is an example of a C<com:Sub>10< / com:Sub>heteroaryl group. The phrase "substituent on carbon" is intended to refer to a substituent which is attached to a carbon ring atom. Similarly, the phrase "substituent on secondary nitrogen" is intended to refer to a substituent which is attached to a nitrogen ring atom which, in the absence of the substituent, would be a secondary nitrogen ring atom (i.e., -NH-). Consequently, a pyridyl group may only have "substituents on carbon", whereas 1H-pyrrole may have both "substituents on carbon" and a "substituent on secondary nitrogen", as illustrated below. [Image disponible dans le document PDF, Image available in the PDF document] Similarly, a piperidino group may only have "substituents on carbon", whereas piperizino may have both "substituents on carbon" and a "substituent on secondary nitrogen", as illustrated below. [Image disponible dans le document PDF, Image available in the PDF document] Unless otherwise indicated, where a compound is shown or described which has one or more chiral centres, and two or more stereoisomers are possible, all such stereoisomers are disclosed and encompassed, both individually (e.g., as isolated from the other stereoisomer(s)) and as mixtures (e.g., as equimolar or non-equimolar mixtures of two or more stereoisomers). For example, unless otherwise indicated, where a compound has one chiral centre, each of the <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math> enantiomers are disclosed and encompassed, both individually (e.g., as isolated from the other enantiomer) and as a mixture (e.g., as equimolar or non-equimolar mixtures of the two enantiomers). For example, the initial carbon atom of a pendant sec-butyl group, -CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub> is usually chiral, and so gives rise to stereoisomers, e.g., <com:Math><semantics>(R)<annotation encoding="application / x-tex">(R)< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>(S)<annotation encoding="application / x-tex">(S)< / annotation>< / semantics>< / com:Math> enantiomers if it is the only chiral centre, each of which is disclosed and encompassed. The Group -R<com:Sup>7< / com:Sup> (2) A compound according to (1), wherein <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> is a fused bicyclic <com:Math><semantics>C9−10<annotation encoding="application / x-tex">C_{9-10}< / annotation>< / semantics>< / com:Math>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N. C<com:Sub>9< / com:Sub>heteroaryl groups: (3) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N. (4) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N. (5) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 1 ring heteroatom, wherein the ring heteroatom is N. (6) A compound according to (1), wherein <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> is independently: indolyl; indolizinyl; 2H-isoindolyl; 2H-cyclopenta[c]pyridinyl; or 1H-cyclopenta[b]pyridinyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] indole indolizine 2H-isoindole [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 2H-cyclopenta[c]pyridine 1H-cyclopenta[b]pyridine (7) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein each ring heteroatom is N. (8) A compound according to (1), wherein <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> is independently: 1H-indazolyl, benzimidazolyl; 1H-pyrrolo[3,2-b]pyridinyl; 1H-pyrrolo[3,2-c]pyridinyl; 1H-pyrrolo[2,3-c]pyridinyl; 1H-pyrrolo[2,3-b]pyridinly; 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. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1H-indazole benzimidazole 1H-pyrrolo[3,2-b]pyridine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1H-pyrrolo[3,2-c]pyridine 1H-pyrrolo[2,3-c]pyridine 1H-pyrrolo[2,3-b]pyridine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pyrazolo[1,5-a]pyridine imidazo[1,5-a]pyridine imidazo[1,2-a]pyridine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pyrrolo[1,2-a]pyrimidine pyrrolo[1,2-a]pyrazine pyrrolo[1,2-c]pyrimidine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pyrrolo[1,2-b]pyridazine 2H-pyrrolo[3,4-c]pyridine 6H-pyrrolo[3,4-b]pyridine (9) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 3 ring heteroatoms, wherein each ring heteroatom is N. (10) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: 1H-pyrazolo[4,3-b]pyridinyl; 1H-pyrazolo[4,3-c]pyridinyl; 1H-pyrazolo[3,4-c]pyridinyl; 1H-pyrazolo[3,4-b]pyridinyl; 1H-imidazo[4,5-b]pyridinyl; 1H-imidazo[4,5-c]pyridinyl; 3H-imidazo[4,5-c]pyridinyl; 3H-imidazo[4,5-b]pyridinyl; 5H-pyrrolo[3,2-c]pyridazinyl; 5H-pyrrolo[3,2-d]pyrimidinyl; 5H-pyrrolo[2,3-b]pyrazinyl; 1H-pyrrolo[2,3-d]pyridazinyl; 7H-pyrrolo[2,3-d]pyrimidinyl; 7H-pyrrolo[2,3-c]pyridazinyl; 6H-pyrrolo[3,4-d]pyridazinyl; 6H-pyrrolo[3,4-d]pyrimidinyl; 6H-pyrrolo[3,4-c]pyridazinyl; 6H-pyrrolo[3,4-b]pyrazinyl; triazolo[1,5-a]pyridinyl; [1,2,4]triazolo[1,5-a]pyridinyl; pyrazolo[1,5-a]pyrimidinyl; pyrazolo[1,5-a]pyrazinyl; pyrazolo[1,5-c]pyrimidinyl; pyrazolo[1,5-b]pyridazinyl; [1,2,4]triazolo[4,3-a]pyridinyl; imidazo[1,5-a]pyrimidinyl; imidazo[1,5-a]pyrazinyl; imidazo[1,5-c]pyrimidinyl; imidazo[1,5-b]pyridazinyl; imidazo[1,2-a]pyrimidinyl; imidazo[1,2-a]pyrazinyl; imidazo[1,2-c]pyrimidinyl; imidazo[1,2-b]pyridazinyl; pyrrolo[2,1-c][1,2,4]triazinyl; pyrrolo[1,2-a][1,3,5]triazinyl; pyrrolo[1,2-b][1,2,4]triazinyl; pyrrolo[1,2-d][1,2,4]triazinyl; pyrrolo[2,1-f][1,2,4]triazinyl; or pyrrolo[1,2-c]triazinyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzotriazole 1H-pyrazolo[4,3-b]pyridine 1H-pyrazolo[4,3-c]pyridine - 17 - Н 1H-pyrazolo[3,4-b]pyridine 1H-imidazo[4,5-b]pyridine 1H-imidazo[4,5-c]pyridine <com:Math><semantics>N><annotation encoding="application / x-tex">N^{>}< / annotation>< / semantics>< / com:Math> 3H-imidazo[4,5-c]pyridine 3H-imidazo[4,5-b]pyridine 5H-pyrrolo[3,2-c]pyridazine N: N: IV 1 / 5H-pyrrolo[3,2-d]pyrimidine 5H-pyrrolo[2,3-b]pyrazine 1H-pyrrolo[2,3-d]pyridazine ÌΝΗ 7H-pyrrolo[2,3-d]pyrimidine 7H-pyrrolo[2,3-c]pyridazine 6H-pyrrolo[3,4-d]pyridazine N_N NΗ ΉN МH 5 6H-pyrrolo[3,4-d]pyrimidine 6H-pyrrolo[3,4-c]pyridazine 6H-pyrrolo[3,4-b]pyrazine triazolo[1,5-a]pyridine [1,2,4]triazolo[1,5-a]pyridine pyrazolo[1,5-a]pyrimidine N pyrazolo[1,5-a]pyrazine pyrazolo[1,5-c]pyrimidine pyrazolo[1,5-b]pyridazine [1,2,4]triazolo[4,3-a]pyridine imidazo[1,5-a]pyrimidine imidazo[1,5-a]pyrazine N: imidazo[1,5-c]pyrimidine imidazo[1,5-b]pyridazine imidazo[1,2-a]pyrimidine - 18 - [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] imidazo[1,2-a]pyrazine imidazo[1,2-c]pyrimidine imidazo[1,2-b]pyridazine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pyrrolo[2,1-c][1,2,4]triazine pyrrolo[1,2-a][1,3,5]triazine pyrrolo[1,2-b][1,2,4]triazine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] pyrrolo[1,2-d][1,2,4]triazine pyrrolo[2,1-f][1,2,4]triazine pyrrolo[1,2-c]triazine (11) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 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. (12) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; or benzimidazolyl. (13) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is imidazo[1,2-a]pyridinyl. (14) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: 2-imidazo[1,2-a]pyridinyl; or 3-imidazo[1,2-a]pyridinyl. (15) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-imidazo[1,2-a]pyridinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (16) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 3-imidazo[1,2-a]pyridinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (17) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is imidazo[1,2-a]pyrimidinyl. (18) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-imidazo[1,2-a]pyrimidinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (19) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is imidazo[1,2-b]pyridazinyl. (20) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-imidazo[1,2-b]pyridazinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (21) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is [1,2,4]triazolo[1,5-a]pyridinyl. (22) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-[1,2,4]triazolo[1,5-a]pyridinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (23) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is benzimidazolyl. (24) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: 2-benzimidazolyl or 5-benzimidazolyl. (25) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-benzimidazolyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (26) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 5-benzimidazolyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (27) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently N or O. (28) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>9< / com:Sub>heteroaryl group having exactly 1 ring heteroatom, wherein the ring heteroatom is O. (29) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is benzofuranyl. (30) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: 2-benzofuranyl or 3-benzofuranyl. (31) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-benzofuranyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (32) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 3-benzofuranyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] C<com:Sub>8< / com:Sub>heteroaryl groups: (33) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N, S, or O. (34) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N or S. (35) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N, S, or O. (36) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 or 3 ring heteroatoms, wherein each ring heteroatom is N or S. (37) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein each ring heteroatom is N, S, or O. (38) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein each ring heteroatom is N or S. (39) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein 1 of said ring heteroatoms is N and 1 of said ring heteroatoms is S or O. (40) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein 1 of said ring heteroatoms is N and 1 of said ring heteroatoms is S. (41) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 3 ring heteroatoms, wherein each ring heteroatom is N, S, or O. (42) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 3 ring heteroatoms, wherein each ring heteroatom is N or S. (43) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 3 ring heteroatoms, wherein 2 of said ring heteroatoms are N and 1 of said ring heteroatoms is S or O. (44) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>8< / com:Sub>heteroaryl group having exactly 3 ring heteroatoms, wherein 2 of said ring heteroatoms are N and 1 of said ring heteroatoms is S. (45) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: imidazo[2,1-b]thiazolyl or imidazo[2,1-b]thiazolyl or imidazo[2,1-b]oxazolyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] imidazo[2,1-b]thiazole imidazo[2,1-b]oxazole (46) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is imidazo[2,1-b]thiazolyl. (47) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 6-imidazo[2,1-b]thiazolyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] C<com:Sub>10< / com:Sub>heteroaryl groups: (48) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>10< / com:Sub>heteroaryl group having exactly 1, 2, or 3 ring heteroatoms, wherein each ring heteroatom is N. (49) A compound according to (1), wherein -R' is a fused bicyclic C<com:Sub>10< / com:Sub>heteroaryl group having exactly 1 or 2 ring heteroatoms, wherein each ring heteroatom is N. (50) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>10< / com:Sub>heteroaryl group having exactly 1 ring heteroatom, wherein the ring heteroatom is N. (51) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: quinolinyl or isoquinolinyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] quinoline isoquinoline (52) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is quinolinyl. (53) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 2-quinolinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (54) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is 3-quinolinyl (shown below). [Image disponible dans le document PDF, Image available in the PDF document] (55) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is isoquinolinyl. (56) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is a fused bicyclic C<com:Sub>10< / com:Sub>heteroaryl group having exactly 2 ring heteroatoms, wherein each ring heteroatom is N. (57) A compound according to (1), wherein -R<com:Sup>7< / com:Sup> is independently: cinnolinyl; quinazolinyl; quinoxalinyl; 1,5-naphthyridinyl; 1,6-naphthyridinyl; 1,7-naphthyridinyl; 1,8-naphthyridinyl; phthalazinyl; 2,6-naphthyridinyl; or 2,7-naphthyridinyl. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] cinnoline quinazoline quinoxaline [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1,5-naphthyridine 1,6-naphthyridine 1,7-naphthyridine [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] 1,8-naphthyridine phthalazine 2,6-naphthyridine 2,7-naphthyridine The Group -R<com:Sup>7< / com:Sup>: Point of Attachment (58) A compound according to any one of (1) to (57), wherein -R<com:Sup>7< / com:Sup> is attached to -L<com:Sup>7< / com:Sup>- via a ring carbon atom of -R<com:Sup>7< / com:Sup> (e.g., a non-bridging ring carbon atom of -R<com:Sup>7< / com:Sup>). (59) A compound according to any one of (1) to (57), wherein -R<com:Sup>7< / com:Sup> is attached to -L<com:Sup>7< / com:Sup>- via a ring nitrogen atom of <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math> (e.g., a non-bridging ring nitrogen atom of <com:Math><semantics>−R7<annotation encoding="application / x-tex">-R^7< / annotation>< / semantics>< / com:Math>). An example of benzimidazolyl attached via a non-bridging ring carbon atom is shown below. [Image disponible dans le document PDF, Image available in the PDF document] Similarly, an example of benzimidazolyl attached via a non-bridging ring nitrogen atom is shown below. [Image disponible dans le document PDF, Image available in the PDF document] The Substituents -R<com:Sup>SC< / com:Sup> (60) A compound according to any one of (1) to (59), wherein each -R<com:Sup>SC< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] - 25 - [Image disponible dans le document PDF, Image available in the PDF document] (61) A compound according to any one of (1) to (59), wherein each -RSC, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (62) A compound according to any one of (1) to (59), wherein each -RSC, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (63) A compound according to any one of (1) to (59), wherein each -RSC, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (64) A compound according to any one of (1) to (59), wherein each -RSC, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (65) A compound according to any one of (1) to (59), wherein each -R<com:Sup>SC< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (66) A compound according to any one of (1) to (59), wherein each -R<com:Sup>SC< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (67) A compound according to any one of (1) to (59), wherein each -R<com:Sup>SC< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] The Substituents -R<com:Sup>SN< / com:Sup> (68) A compound according to any one of (1) to (67), wherein each -R<com:Sup>SN< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (69) A compound according to any one of (1) to (67), wherein each -R<com:Sup>SN< / com:Sup>, if present, is independently: [Image disponible dans le document PDF, Image available in the PDF document] (70) A compound according to any one of (1) to (67), wherein each -R<com:Sup>SN< / com:Sup>, if present, is: [Image disponible dans le document PDF, Image available in the PDF document] The Group -L'- (71) A compound according to any one of (1) to (70), wherein each <com:Math><semantics>−LT<annotation encoding="application / x-tex">-L^{T}< / annotation>< / semantics>< / com:Math>-, if present, is independently linear or branched saturated C<com:Sub>1-3< / com:Sub>alkylene. (72) A compound according to any one of (1) to (70), wherein each -L<com:Sup>T< / com:Sup>-, if present, is independently -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>-, or -CH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>)-. (73) A compound according to any one of (1) to (70), wherein each -L<com:Sup>T< / com:Sup>-, if present, is independently -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, or -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-. (74) A compound according to any one of (1) to (70), wherein each -L<com:Sup>T< / com:Sup>-, if present, is -CH<com:Sub>2< / com:Sub>-. The Group -R<com:Sup>TT< / com:Sup> (75) A compound according to any one of (1) to (74), wherein each <com:Math><semantics>−RTT<annotation encoding="application / x-tex">-R^{TT}< / annotation>< / semantics>< / com:Math>, if present, is independently -R<com:Sup>TT1< / com:Sup>, -R<com:Sup>TT2< / com:Sup>, -R<com:Sup>TT3< / com:Sup>, or -L<com:Sup>TT< / com:Sup>-R<com:Sup>TT3< / com:Sup>. (76) A compound according to any one of (1) to (74), wherein each -R<com:Sup>TT< / com:Sup>, if present, is independently -R<com:Sup>TT1< / com:Sup>, -R<com:Sup>TT3< / com:Sup>, or -L<com:Sup>TT< / com:Sup>-R<com:Sup>TT3< / com:Sup>. (77) A compound according to any one of (1) to (74), wherein each -R<com:Sup>TT< / com:Sup>, if present, is <com:Math><semantics>−RTT1<annotation encoding="application / x-tex">-R^{TT1}< / annotation>< / semantics>< / com:Math>. The Group -R<com:Sup>TT1< / com:Sup> (78) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-6< / com:Sub>alkyl. (79) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR<com:Sup>TTT< / com:Sup>. (80) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl. (81) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, or -tBu. (82) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is independently -Me, -Et, -nPr, or -iPr. (83) A compound according to any one of (1) to (77), wherein each -R<com:Sup>TT1< / com:Sup>, if present, is -Me. The Group -R<com:Sup>112< / com:Sup> (84) A compound according to any one of (1) to (83), wherein each -R<com:Sup>TT2< / com:Sup>, if present, is saturated C<com:Sub>3-6< / com:Sub>cycloalkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR<com:Math><semantics>TTT<annotation encoding="application / x-tex">^{TTT}< / annotation>< / semantics>< / com:Math>. (85) A compound according to any one of (1) to (83), wherein each -R<com:Sup>TT2< / com:Sup>, if present, is saturated C<com:Sub>3-6< / com:Sub>cycloalkyl. (86) A compound according to any one of (1) to (83), wherein each -R<com:Sup>TT2< / com:Sup>, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (87) A compound according to any one of (1) to (83), wherein each -R<com:Sup>TT2< / com:Sup>, if present, is cyclopropyl. The Group -R<com:Sup>TT3< / com:Sup> (88) A compound according to any one of (1) to (87), wherein each -R<com:Sup>TT3< / com:Sup>, if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -l, -R<com:Sup>TTT< / com:Sup>, OH, -OR<com:Sup>TTT< / com:Sup>, -OCF<com:Sub>3< / com:Sub>, -NH<com:Sub>2< / com:Sub>, -NHR<com:Sup>TTT< / com:Sup>, and -NR<com:Sup>TTT< / com:Sup><com:Sub>2< / com:Sub>; (89) A compound according to any one of (1) to (87), wherein each -R<com:Sup>TT3< / com:Sup>, if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -l, -R<com:Sup>TTT< / com:Sup>, OH, -OR<com:Sup>TTT< / com:Sup>, and -OCF<com:Sub>3< / com:Sub>. (90) A compound according to any one of (1) to (87), wherein each -R<com:Sup>TT3< / com:Sup>, if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, and -R<com:Sup>TTT< / com:Sup>. (91) A compound according to any one of (1) to (87), wherein each -R<com:Sup>TT3< / com:Sup>, if present, is phenyl. The Group -L''- (92) A compound according to any one of (1) to (91), wherein each -LTT-, if present, is independently linear or branched saturated C<com:Sub>1-3< / com:Sub>alkylene. (93) A compound according to any one of (1) to (91), wherein each -LTT-, if present, is independently -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>-, or -CH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>)-. (94) A compound according to any one of (1) to (91), wherein each -L<com:Sup>TT< / com:Sup>-, if present, is independently -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, or -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-. (95) A compound according to any one of (1) to (91), wherein each -LTT-, if present, is -CH<com:Sub>2< / com:Sub>-. The Group -R<com:Sup>TN< / com:Sup> (96) A compound according to any one of (1) to (95), wherein each -R<com:Sup>TN< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl. (97) A compound according to any one of (1) to (95), wherein each -R<com:Sup>TN< / com:Sup>, if present, is -Me. The Group -R<com:Sup>TM< / com:Sup> (98) A compound according to any one of (1) to (97), wherein each -R<com:Sup>TM< / com:Sup>, if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups selected from: -R<com:Sup>TMM< / com:Sup>, -F, -OH, and -OR<com:Sup>™< / com:Sup>; and optionally substituted on secondary nitrogen, if present, with a group selected from: <com:Math><semantics>−RTMM<annotation encoding="application / x-tex">-R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTMM<annotation encoding="application / x-tex">-C(=O)R^{TMM}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)ORTMM<annotation encoding="application / x-tex">-C(=O)OR^{TMM}< / annotation>< / semantics>< / com:Math>. (99) A compound according to any one of (1) to (97), wherein each -R<com:Sup>TM< / com:Sup>, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups selected from: -R<com:Sup>TMM< / com:Sup>, -F, -OH, and -OR<com:Sup>™< / com:Sup>; and optionally substituted on secondary nitrogen, if present, with a group selected from: <com:Math><semantics>−RTMM<annotation encoding="application / x-tex">-R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTMM<annotation encoding="application / x-tex">-C(=O)R^{TMM}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)ORTMM<annotation encoding="application / x-tex">-C(=O)OR^{TMM}< / annotation>< / semantics>< / com:Math>. (100) A compound according to any one of (1) to (97), wherein each -R<com:Sup>TM< / com:Sup>, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups selected from: -R<com:Sup>TMM< / com:Sup>; and optionally substituted on secondary nitrogen, if present, with a group selected from: <com:Math><semantics>−RTMM<annotation encoding="application / x-tex">-R^{TMM}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−C(=O)RTMM<annotation encoding="application / x-tex">-C(=O)R^{TMM}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>−C(=O)ORTMM<annotation encoding="application / x-tex">-C(=O)OR^{TMM}< / annotation>< / semantics>< / com:Math>. (101) A compound according to any one of (1) to (97), wherein each -R<com:Sup>TM< / com:Sup>, if present, is independently pyrrolidino, piperidino, piperazino, or morpholino, and is: optionally substituted on carbon with one or more groups selected from: -R<com:Sup>IMM< / com:Sup>; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R<com:Sup>TMM< / com:Sup>. The Group -R<com:Sup>TTT< / com:Sup> (102) A compound according to any one of (1) to (101), wherein each -R<com:Sup>TTT< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl. (103) A compound according to any one of (1) to (101), wherein each -R<com:Sup>TTT< / com:Sup>, if present, is -Me. The Group -R<com:Sup>TMM< / com:Sup> (104) A compound according to any one of (1) to (103), wherein each -R<com:Sup>TMM< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl. (105) A compound according to any one of (1) to (103), wherein each -R<com:Sup>TMM< / com:Sup>, if present, is -Me. The Group -L'- (106) A compound according to any one of (1) to (105), wherein <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is independently linear or branched saturated C<com:Sub>1-3< / com:Sub>alkylene. (107) A compound according to any one of (1) to (105), wherein <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is independently -CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-, -CH(CH<com:Sub>3< / com:Sub>)CH<com:Sub>2< / com:Sub>-, or -CH<com:Sub>2< / com:Sub>CH(CH<com:Sub>3< / com:Sub>)-. (108) A compound according to any one of (1) to (105), wherein <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is independently -CH<com:Sub>2< / com:Sub>-. -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-. or -CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>CH<com:Sub>2< / com:Sub>-. (109) A compound according to any one of (1) to (105), wherein <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is independently -CH<com:Sub>2< / com:Sub>-, -CH(CH<com:Sub>3< / com:Sub>)-, -C(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>-, or -CH(CH<com:Sub>2< / com:Sub>CH<com:Sub>3< / com:Sub>)-. (110) A compound according to any one of (1) to (105), wherein <com:Math><semantics>−L′<annotation encoding="application / x-tex">-L^{\prime}< / annotation>< / semantics>< / com:Math>- is independently -CH<com:Sub>2< / com:Sub>- or -CH(CH<com:Sub>3< / com:Sub>)-. (111) A compound according to any one of (1) to (105), wherein -L'- is -CH<com:Sub>2< / com:Sub>-. (112) A compound according to any one of (1) to (105), wherein -L<com:Sup>7< / com:Sup>- is -CH<com:Sub>2< / com:Sub>-, and further wherein -L<com:Sup>7< / com:Sup>- is -CD<com:Sub>2< / com:Sub>-. The Group -R<com:Sup>3< / com:Sup> (113) A compound according to any one of (1) to (112), wherein <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math>. (114) A compound according to any one of (1) to (112), wherein -R<com:Sup>3< / com:Sup> is -R<com:Sup>3B< / com:Sup>. The Group -R<com:Sup>3A< / com:Sup> (115) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-6< / com:Sub>alkyl. (116) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu, n-pentyl, t-pentyl, neo-pentyl, iso-pentyl, sec-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 4-methyl-2-pentyl, 4-methyl-3-pentyl, 2-methyl-2-pentyl, 2-methyl-1-pentyl, 2-methyl-2-pentyl, 3,3-dimethyl-1-butyl, 3,3-dimethyl-2-butyl, 3-methyl-1-pentyl, 3-methyl-2-pentyl, 3-methyl-3-pentyl, 2,2-dimethyl-1-butyl, 2,3-dimethyl-1-butyl, or 2,3-dimethyl-2-butyl. (117) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently linear or branched saturated C<com:Sub>1-4< / com:Sub>alkyl. (118) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, or -tBu. (119) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently -Me, -Et, -nPr, or -iPr. (120) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is independently -Et, -nPr, or -iPr. (121) A compound according to any one of (1) to (114), wherein -R<com:Sup>3A< / com:Sup>, if present, is -iPr. The Group -R<com:Sup>3B< / com:Sup> (122) A compound according to any one of (1) to (121), wherein -R<com:Sup>3B< / com:Sup>, if present, is saturated C<com:Sub>3-7< / com:Sub>cycloalkyl. (123) A compound according to any one of (1) to (121), wherein -R<com:Sup>3B< / com:Sup>, if present, is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. (124) A compound according to any one of (1) to (121), wherein -R<com:Sup>3B< / com:Sup>, if present, is independently cyclopropyl or cyclobutyl. (125) A compound according to any one of (1) to (121), wherein -R<com:Sup>3B< / com:Sup>, if present, is cyclopropyl. (126) A compound according to any one of (1) to (121), wherein -R<com:Sup>3B< / com:Sup>, if present, is cyclobutyl. Some Preferred Combinations (127) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; benzimidazolyl; imidazo[2,1-b]thiazolyl; imidazo[1,2-b]pyridazinyl; [1,2,4]triazolo[1,5-a]pyridinyl; quinolinyl; or benzofuranyl; and is optionally substituted as described herein; <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CH(CH3)<annotation encoding="application / x-tex">-CH(CH_3)< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^{3}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−R3B<annotation encoding="application / x-tex">-R^{3B}< / annotation>< / semantics>< / com:Math>; -R<com:Sup>3A< / com:Sup> is -iPr; and -R<com:Sup>3B< / com:Sup> is cyclopropyl. (128) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: 2-imidazo[1,2-a]pyridinyl; 3-imidazo[1,2-a]pyridinyl; 5 2-imidazo[1,2-a]pyrimidinyl; 2-benzimidazolyl; 5-benzimidazolyl; 6-imidazo[2,1-b]thiazolyl; 2-imidazo[1,2-b]pyridazinyl; 10 2-[1,2,4]triazolo[1,5-a]pyridinyl; 2-quinolinyl; 3-quinolinyl; or 2-benzofuranyl; and is optionally substituted as described herein; 15 <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CH(CH3)<annotation encoding="application / x-tex">-CH(CH_3)< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^{3}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−R3B<annotation encoding="application / x-tex">-R^{3B}< / annotation>< / semantics>< / com:Math>; -R<com:Sup>3A< / com:Sup> is -iPr; and -R<com:Sup>3B< / com:Sup> is cyclopropyl. 20 (129) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: imidazo[1,2-a]pyridinyl; or imidazo[1,2-a]pyrimidinyl; and is optionally substituted as described herein; 25 <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CH(CH3)<annotation encoding="application / x-tex">-CH(CH_3)< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^{3}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−R3B<annotation encoding="application / x-tex">-R^{3B}< / annotation>< / semantics>< / com:Math>; -R<com:Sup>3A< / com:Sup> is -iPr; and -R<com:Sup>3B< / com:Sup> is cyclopropyl. 30 (130) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: 2-imidazo[1,2-a]pyridinyl; 2-imidazo[1,2-a]pyrimidinyl; and is optionally substituted as described herein; 35 <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>- or <com:Math><semantics>−CH(CH3)<annotation encoding="application / x-tex">-CH(CH_3)< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>−R3B<annotation encoding="application / x-tex">-R^{3B}< / annotation>< / semantics>< / com:Math>; -R<com:Sup>3A< / com:Sup> is -iPr; and -R<com:Sup>3B< / com:Sup> is cyclopropyl. (131) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; benzimidazolyl; or imidazo[2,1-b]thiazolyl; and is optionally substituted as described herein; <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^{7}< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_{2}< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math>; and -R<com:Sup>3A< / com:Sup> is -iPr. (132) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: imidazo[1,2-a]pyridinyl; imidazo[1,2-a]pyrimidinyl; or benzimidazolyl; and is optionally substituted as described herein; <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^{7}< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_{2}< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math>; and -R<com:Sup>3A< / com:Sup> is -iPr. (133) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: 3-imidazo[1,2-a]pyridinyl; 2-imidazo[1,2-a]pyridinyl; 2-imidazo[1,2-a]pyrimidinyl; 2-benzimidazolyl; 5-benzimidazolyl; or imidazo[2,1-b]thiazol-6-yl; and is optionally substituted as described herein; <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^7< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_2< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math>; and -R<com:Sup>3A< / com:Sup> is -iPr. (134) A compound according to (1), wherein: -R<com:Sup>7< / com:Sup> is independently: 3-imidazo[1,2-a]pyridinyl; 2-imidazo[1,2-a]pyridinyl; 2-imidazo[1,2-a]pyrimidinyl; 2-benzimidazolyl; or 5-benzimidazolyl; and is optionally substituted as described herein; <com:Math><semantics>−L7<annotation encoding="application / x-tex">-L^{7}< / annotation>< / semantics>< / com:Math>- is <com:Math><semantics>−CH2<annotation encoding="application / x-tex">-CH_{2}< / annotation>< / semantics>< / com:Math>-; <com:Math><semantics>−R3<annotation encoding="application / x-tex">-R^3< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>−R3A<annotation encoding="application / x-tex">-R^{3A}< / annotation>< / semantics>< / com:Math>; and -R<com:Sup>3A< / com:Sup> is -iPr. Specific Compounds (135) A compound according to (1), selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Combinations It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the chemical groups represented by the variables (e.g., -R<com:Sup>7< / com:Sup>, -L<com:Sup>3< / com:Sup>-, -R<com:Sup>3< / com:Sup>, etc.) are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace compounds that are stable compounds (i.e., compounds that can be isolated, characterised, and tested for biological activity). In this context, the skilled person will readily appreciate that certain combinations of groups (e.g., substituents) may give rise to compounds which may not be readily synthesized and / or are chemically unstable. In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination of chemical groups was individually and explicitly disclosed herein. Substantially Purified Forms One aspect of the present invention pertains to H-APPAMP compounds, as described herein, in substantially purified form and / or in a form substantially free from contaminants. In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight. Unless otherwise specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer. In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight. Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer. In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60%) of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure. Isomers Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, atropic, 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 I-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math>- and <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). A reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C<com:Sub>1-7< / com:Sub>alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). However, reference to a specific group or substitution pattern is not intended to include other structural (or constitutional isomers) which differ with respect to the connections between atoms rather than by positions in space. For example, a reference to a methoxy group, -OCH<com:Sub>3< / com:Sub>, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH<com:Sub>2< / com:Sub>OH. Similarly, a reference specifically to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, N-nitroso / hydroxyazo, and nitro / aci-nitro. A reference herein to one tautomer is intended to encompass both tautomers. [Image disponible dans le document PDF, Image available in the PDF document] For example, 1H-pyridin-2-one-5-yl and 2-hydroxyl-pyridin-5-yl (shown below) are tautomers of one another. A reference herein to one is intended to encompass both. [Image disponible dans le document PDF, Image available in the PDF document] Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including <com:Sup>1< / com:Sup>H, <com:Sup>2< / com:Sup>H (D), and <com:Sup>3< / com:Sup>H (T); C may be in any isotopic form, including <com:Sup>12< / com:Sup>C, <com:Sup>13< / com:Sup>C, and <com:Sup>14< / com:Sup>C; O may be in any isotopic form, including <com:Sup>16< / com:Sup>O and <com:Sup>18< / com:Sup>O; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Salts It may be convenient or desirable to prepare, purify, and / or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. For example, if the compound is anionic, or has a functional group, which may be anionic (e.g., -COOH may be -COO<com:Sup>-< / com:Sup>), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na<com:Sup>+< / com:Sup> and K<com:Sup>+< / com:Sup>, alkaline earth cations such as Ca<com:Sup>2+< / com:Sup> and Mg<com:Sup>2+< / com:Sup>, and other cations such as Al<com:Sup>3+< / com:Sup> as well as the ammonium ion (i.e., NH<com:Sub>4< / com:Sub><com:Sup>+< / com:Sup>). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NH<com:Sub>3< / com:Sub>R<com:Sup>+< / com:Sup>, NH<com:Sub>2< / com:Sub>R<com:Sub>2< / com:Sub><com:Sup>+< / com:Sup>, NHR<com:Sub>3< / com:Sub><com:Sup>+< / com:Sup>, NR<com:Sub>4< / com:Sub><com:Sup>+< / com:Sup>), for example, where each R is independently linear or branched saturated C<com:Sub>1-18< / com:Sub>alkyl, C<com:Sub>3-8< / com:Sub>cycloalkyl, C<com:Sub>3-8< / com:Sub>cycloalkyl-C<com:Sub>1-6< / com:Sub>alkyl, and phenyl-C<com:Sub>1-6< / com:Sub>alkyl, 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(CH<com:Sub>3< / com:Sub>)<com:Sub>4< / com:Sub><com:Sup>+< / com:Sup>. If the compound is cationic, or has a functional group, which upon protonation may become cationic (e.g., -NH<com:Sub>2< / com:Sub> may become -NH<com:Sub>3< / com:Sub><com:Sup>+< / com:Sup>), then a salt may be formed with a suitable anion. For example, if a parent structure contains a cationic group (e.g., -NMe<com:Sub>2< / com:Sub><com:Sup>+< / com:Sup>), or has a functional group, which upon protonation may become cationic (e.g., -NH<com:Sub>2< / com:Sub> may become -NH<com:Sub>3< / com:Sub><com:Sup>+< / com:Sup>), then a salt may be formed with a suitable anion. In the case of a quaternary ammonium compound a counter-anion is generally always present in order to balance the positive charge. If, in addition to a cationic group (e.g., -NMe<com:Sub>2< / com:Sub><com:Sup>+< / com:Sup>, -NH<com:Sub>3< / com:Sub><com:Sup>+< / com:Sup>), the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt (also referred to as a zwitterion) may be formed. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyloxybenzoic, acetic, trifluoroacetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, 1,2-ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Examples of suitable counter-ions which are especially suitable for quaternary ammonium compounds (e.g., those with a -NMe<com:Sub>2< / com:Sub><com:Sup>+< / com:Sup> group) include 1-adamantanesulfonate, benzenesulfonate, bisulfate, bromide, chloride, iodide, methanesulfonate, methylsulfate, 1,5-napthalene-bis-sulfonate, 4-nitrobenzenesulfonate, formate, tartrate, tosylate, trifluoroacetate, trifluoromethylsulfonate, sulphate. Again, if the compound also contains a group capable of forming an anion (e.g., -COOH), then an inner salt may be formed. Unless otherwise specified, a reference to a particular compound also includes salt forms thereof. Solvates and Hydrates It may be convenient or desirable to prepare, purify, and / or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof. Chemically Protected Forms It may be convenient or desirable to prepare, purify, and / or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well-known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (alternatively as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed or the masking group transformed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 4th Edition; John Wiley and Sons, 2006). A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality. For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester <com:Math><semantics>(−OC(=O)CH3,−OAc).<annotation encoding="application / x-tex">(-OC(=O)CH_3, -OAc).< / annotation>< / semantics>< / com:Math> For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)<com:Sub>2< / com:Sub>) or ketal (<com:Math><semantics>R2C(OR)2<annotation encoding="application / x-tex">R_2C(OR)_2< / annotation>< / semantics>< / com:Math>), respectively, in which the carbonyl group (>C=O) is converted to a 1,1- diether (>C(OR)<com:Sub>2< / com:Sub>), 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 using water in the presence of acid. For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: an acetamide (-NHCO-CH<com:Sub>3< / com:Sub>); a benzyloxy amide (-NHCO-OCH<com:Sub>2< / com:Sub>C<com:Sub>6< / com:Sub>H<com:Sub>5< / com:Sub>, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH<com:Sub>3< / com:Sub>)<com:Sub>3< / com:Sub>, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH<com:Sub>3< / com:Sub>)<com:Sub>2< / com:Sub>C<com:Sub>6< / com:Sub>H<com:Sub>4< / com:Sub>C<com:Sub>6< / com:Sub>H<com:Sub>5< / com:Sub>, -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O●). For example, a carboxylic acid group may be protected as an ester for example, as: an <com:Math><semantics>C1−7<annotation encoding="application / x-tex">C_{1-7}< / annotation>< / semantics>< / com:Math>alkyl ester (e.g., a methyl ester; a t-butyl ester); a <com:Math><semantics>C1−7<annotation encoding="application / x-tex">C_{1-7}< / annotation>< / semantics>< / com:Math>haloalkyl ester (e.g., a 2,2,2- trihaloethyl ester); a 2-tri(C<com:Sub>1-7< / com:Sub>alkyl)silyl-ethyl ester; or a C<com:Sub>5-20< / com:Sub>aryl-C<com:Sub>1-7< / com:Sub>alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide or hydrazide, for example, as acetamide or a N, N, N'-trimethylhydrazide. For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH<com:Sub>2< / com:Sub>NHC(=O)CH<com:Sub>3< / com:Sub>). Prodrugs It may be convenient or desirable to prepare, purify, and / or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound, which yields the desired active compound in vivo. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. Also, some prodrugs are activated enzymatically to yield the active compound, or a compound, which, upon further chemical reaction, yields the active compound (for example, 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. Compositions One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising an H-APPAMP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising mixing an H-APPAMP compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses The H-APPAMP compounds described herein are useful in the treatment of, 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"), etc. Use in Methods of Inhibiting CDK One aspect of the present invention pertains to a method of inhibiting CDK (e.g., CDK12) and / or CDK13) function (e.g., in a cell), in vitro or in vivo, comprising contacting the cell with an effective amount of an H-APPAMP compound, as described herein. One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits CDK (e.g., CDK12 and / or CDK13). For example, suitable assays are described herein or are known in the art. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. In one embodiment, the H-APPAMP compound is provided in the form of a pharmaceutically acceptable composition. Any type of cell may be treated, including adipose, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. For example, a sample of cells may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type. Use in Methods of Inhibiting Cell Proliferation, etc. The H-APPAMP compounds described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these. One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound, as described herein. In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of an H-APPAMP compound, as described herein. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. In one embodiment, the H-APPAMP compound is provided in the form of a pharmaceutically acceptable composition. Any type of cell may be treated, including lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays, which may conveniently be used to assess the activity offered by a particular compound are described herein. For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type. Use in Methods of Therapy Another aspect of the present invention pertains to an H-APPAMP compound, as described herein, for use in a method of treatment of the human or animal body by therapy, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. Use in the Manufacture of Medicaments Another aspect of the present invention pertains to use of an H-APPAMP compound, as described herein, in the manufacture of a medicament, for example, for use in a method of treatment, for example, for use a method of treatment of a disorder (e.g., a disease) as described herein. In one embodiment, the medicament comprises the H-APPAMP compound. Methods of Treatment Another aspect of the present invention pertains to a method of treatment, for example, a method of treatment of a disorder (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. Disorders Treated - Disorders Associated with CDK In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disorder (e.g., a disease) that is associated with CDK, especially CDK12 and / or CDK13; a disorder (e.g., a disease) resulting from an inappropriate activity of a CDK, especially CDK12 and / or CDK13; a disorder (e.g., a disease) that is associated with CDK mutation, especially CDK12 and / or CDK13 mutation; a disorder (e.g., a disease) that is associated with CDK overexpression, especially CDK12 and / or CDK13 overexpression; a disorder (e.g., a disease) that is associated with upstream pathway activation of CDK, especially CDK12 and / or CDK13; a disorder (e.g., a disease) that is ameliorated by the inhibition (e.g., selective inhibition) of CDK, especially CDK12 and / or CDK13. In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease) that is associated with CDK, especially CDK12 and / or CDK13. In one embodiment, the treatment is treatment of: a disorder (e.g., a disease) resulting from an inappropriate activity of CDK, especially CDK12 and / or CDK13. In one embodiment, the treatment is treatment of: a disorder (e.g., a disease) that is associated with CDK mutation, especially CDK12 mutation; CDK overexpression, especially CDK12 and / or CDK13 overexpression (e.g., as compared to corresponding normal cells; e.g., wherein the overexpression is by a factor of 1.5, 2, 3, 5, 10, 20 or 50); or upstream pathway activation of CDK, especially CDK12 and / or CDK13. In one embodiment, the treatment is treatment of a disorder (e.g., a disease) that is ameliorated by the inhibition (e.g., selective inhibition) of CDK, especially CDK12 and / or CDK13. Disorders Treated In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative disorder; cancer; a viral infection (e.g., HIV); a neurodegenerative disorder (e.g., Alzheimer's disease, Parkinson's disease); ischaemia; a renal disease; a cardiovascular disorder (e.g., atherosclerosis); or an autoimmune disorder (e.g., rheumatoid arthritis). In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disorder (e.g., a disease) caused by dysfunction of translation in cells, for example, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, and Fragile X syndrome. In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disorder (e.g., a disease) in a patient who has received prior therapeutic treatments, but who receives little or no further clinical benefit from those treatments. This includes, for example, patients who have received prior therapeutic treatments with PARP inhibitors, CDK inhibitors, and / or HER2 directed therapies (see, e.g., Johnson et al., 2016; Choi et al., 2019). Disorders Treated - Proliferative Disorders In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a proliferative disorder. The term "proliferative disorder," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as neoplastic or hyperplastic growth. In one embodiment, the treatment is treatment of: a proliferative disorder characterised by benign, pre-malignant, or malignant cellular proliferation. In one embodiment, the treatment is treatment of: hyperplasia; a neoplasm; a tumour (e.g., a histocytoma, a glioma, an astrocyoma, an osteoma); cancer; psoriasis; a bone disease; a fibroproliferative disorder (e.g., of connective tissues); pulmonary fibrosis; atherosclerosis; or smooth muscle cell proliferation in the blood vessels (e.g., stenosis or restenosis following angioplasty). Disorders Treated - Cancer In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of cancer. In one embodiment, the treatment is treatment of cancer metastasis. Included among cancers are: (1) Carcinomas, including tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary. (2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and haemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); mesenchymous and mixed mesodermal tumour (mixed connective tissue types). (3) Myeloma. (4) Haematopoietic tumours, including: myelogenous and granulocytic leukaemia (malignancy of the myeloid and granulocytic white blood cell series), e.g., chronic myeloid leukemia (CML), acute myeloid leukemia (AML); lymphatic, lymphocytic, and lymphoblastic leukaemia (malignancy of the lymphoid and lymphocytic blood cell series), e.g., acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL); polycythaemia vera (malignancy of various blood cell products, but with red cells predominating). (5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas. (6) Mixed Types, including, e.g., adenosquamous carcinoma; mixed mesodermal tumour; carcinosarcoma; teratocarcinoma. For example, in one embodiment, the treatment is treatment of breast cancer. In one embodiment, the cancer is associated with CDK, especially CDK12 and / or CDK13. In one embodiment, the cancer is characterised by, or further characterised by, inappropriate activity of CDK, especially CDK12 and / or CDK13. In one embodiment, the cancer is characterised by, or further characterised by, overexpression of CDK, especially CDK12 and / or CDK13. In one embodiment, the cancer is characterised by, or further characterised by, an amplification of the CDK12 and / or CDK13 gene, including, for example, cancers overexpressing the protein HER2 where the 17q12-q21 locus is amplified (see, e.g., Choi et al., 2019). In one embodiment, the cancer is characterised by, or further characterised by, a fusion of genes that cause cancers to appear, including, for example, cancers that have gene fusions of EWS-FLI (see, e.g., Inigues et al., 2018), BCR-ABL, EML4-ALK, FGFR3-TACC3, KIF5B-RET, ETV6-RUNX1, or TMPRSS2-ERG. The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of cell migration (the spread of cancer cells to other parts of the body), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), the promotion of apoptosis (programmed cell death), death by necrosis, or induction of death by autophagy. The compounds described herein may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein. Disorders Treated - DNA Repair In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease) in a patient having under-expression, defects, and / or mutations in the genes of proteins that are involved in DNA repair, including, e.g., 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 tumours display "BRCAness" (see, e.g., Lord et al., 2019). In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder (e.g., a disease) in a patient having under-expression, defects, and / or mutations in the genes of proteins that are involved in non-homologous DNA repair, including, e.g. XLF, RAD50, NBS1, MRE11, LIG4, XRCC4, POLL, POLM. Disorders Treated - Viral Infections In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a viral infection. In one embodiment, the treatment is treatment of a viral infection by: (Group I:) a dsDNA virus, e.g., an adenovirus, a herpesvirus, a poxvirus; (Group II:) a ssDNA virus, e.g., a parvovirus; (Group III:) a dsRNA virus, e.g., a reovirus; (Group IV:) a (+)ssRNA virus, e.g., a picornavirus, a togavirus; (Group V:) a (-)ssRNA virus, e.g., an orthomyxovirus, a rhabdovirus; (Group VI:) a ssRNA-RT virus, e.g., a retrovirus; or (Group VII:) a dsDNA-RT virus, e.g., a hepadnavirus. As used above: ds: double strand; ss: +strand; (+)ssRNA: +strand RNA; (-)ssRNA: -strand RNA; ssRNA-RT: (+ strand)RNA with DNA intermediate in life-cycle. In one embodiment, the treatment is treatment of: human immunodeficiency virus (HIV); hepatitis B virus (HBV); hepatitis C virus (HCV); human papilloma virus (HPV); cytomegalovirus (CMV); or Epstein-Barr virus (EBV); human herpesvirus 8 (HHV) associated with Kaposi sarcoma; Coxsackievirus B3; Borna virus; influenza virus. Disorders Treated - Autoimmune Disorders In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of an autoimmune disorder. In one embodiment, the treatment is treatment of: an autoimmune disorder associated with connective tissue, joints, skin, or the eye. In one embodiment, the treatment is treatment of: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, or Sjogren's syndrome. Disorders Treated - Disorders caused by Dysfunction of Translation in Cells In one embodiment (e.g., for use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disorder caused by dysfunction of translation in cells. In one embodiment, the treatment is treatment of: muscular dystrophy, myotonic dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy, or Fragile X syndrome. Treatment The term "treatment," as used herein in the context of treating a disorder, pertains generally to treatment of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the disorder, but who are at risk of developing the disorder, is encompassed by the term "treatment." For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc. The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio, when administered in accordance with a desired treatment regimen. Combination Therapies The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents. Examples of treatments and therapies include chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (including, e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.)); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets. One aspect of the present invention pertains to a compound as described herein, in combination with one or more (e.g., 1, 2, 3, 4, etc.) additional therapeutic agents, as described below. The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner. The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1, 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s). The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use. Examples of additional agents / therapies that may be co-administered / combined with treatment with the H-APPAMP compounds described herein include the following: an aromatase inhibitor, for example, exemestane (also known as Aromasin™), letrozole (also known as Femara™), anastrozole (also known as Arimidex™), etc.; an anti-estrogen, for example, faslodex (also known as Fulvestrant and ICI182780), tamoxifen (also known as Nolvadex™), hydroxytamoxifen, etc.; an anti-androgen, for example, an anti-androgen used in the treatment of prostate cancer, for example, flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.; a Her2 blocker, for example, herceptin, pertuzumab, lapatinib, etc.; a cytotoxic chemotherapeutic agent, for example, a taxane (e.g., paclitaxel also known as Taxol™; docetaxel also known as Taxotere™), cyclophosphamide, an antimetabolite (e.g., carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, 5-fluorouracil, etc.), an agent stimulating the immune system, for example, a Toll-like receptor (TLR1-13) agonist, a Stimulator of Interferon Genes (STING) agonist, etc.; a checkpoint inhibitor, for example, an inhibitor of PD1, PD1L, CTLA4, etc., for example, pembrolizumab, atezolizumab, ipilimumab, etc.; a DNA repair inhibitor, for example, a PARP inhibitor, for example, Olaparib, Niraparib, etc. Thus, in one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., an aromatase inhibitor, an anti-estrogen, an anti-androgen, a Her2 blocker, a cytotoxic chemotherapeutic agent, an agent stimulating the immune system, a checkpoint inhibitor, a DNA repair inhibitor, etc. Other Uses The H-APPAMP compounds described herein may also be used as cell culture additives to inhibit CDK (e.g., CDK12 and / or CDK13). The H-APPAMP compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question. The H-APPAMP compounds described herein may also be used as a standard, for example, in an assay, in order to identify other active compounds, other CDK12 and / or CDK13 inhibitors, etc. Kits One aspect of the invention pertains 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 provided in a suitable container and / or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition. The written instructions may also include a list of indications for which the active ingredient is a suitable treatment. Routes of Administration The H-APPAMP compound or pharmaceutical composition comprising the H-APPAMP compound may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action). Examples of routes of administration include oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. The Subject / Patient The subject / patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human. Furthermore, the subject / patient may be any of its forms of development, for example, a foetus. In one preferred embodiment, the subject / patient is a human. Formulations While it is possible for an H-APPAMP compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one H-APPAMP compound, as described herein, together with 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, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents. Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising mixing at least one H-APPAMP compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound. The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation. Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005. The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof. Formulations may suitably be in the form of 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, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols. Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like 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. Formulations may also suitably be provided in the form of a depot or reservoir. The compound may be dissolved in, suspended in, or mixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs. 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, boluses. Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier. Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills. 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, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. 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 plasters, depots, and reservoirs. Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs. Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the 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, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Tablets may be made by moulding 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 so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach. Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base. 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 polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and / or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Suitable emulgents and emulsion stabilisers include Tween™ 60, Span™ 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, 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 chain esters known as Crodamol™ CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used. Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound. Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases. Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound. 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, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema. 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. 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 a liposome or other microparticulate). Such liquids may additionally contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes, which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers 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 may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. Dosage It will be appreciated by one of skill in the art that appropriate dosages of the H-APPAMP compounds, and compositions comprising the H-APPAMP compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious 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 the treatment, other drugs, compounds, and / or materials used in combination, the severity of the disorder, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of H-APPAMP compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician. In general, a suitable dose of the H-APPAMP compound is in the range of about 10 µg to about 250 mg (more typically about 100 µg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. Chemical Synthesis Abbreviations 5 aq: aqueous; Boc: tert-butoxycarbonyl; Boc<com:Sub>2< / com:Sub>O: di-tert-butyl dicarbonate; br: broad; ca.: circa; 10 d: doublet; <com:Sup>1< / com:Sup>BuXPhos-Pd-G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino- 1,1'-biphenyl)] palladium(II) methanesulfonate; DCM: dichloromethane; DCE: 1,2-dichloroethane; 15 dioxane: 1,4-dioxane; DIPEA: diisopropylethylamine; DMAP: 4-(Dimethylamino)pyridine; EtOAc: ethyl acetate; EtOH: ethanol; 20 h: hours; HPLC: high performance liquid chromatography; IPA: isopropanol; LCMS: liquid chromatography – mass spectrometry; LiHMDS: lithium hexamethyldisilazide; 25 m: multiplet; M: molar, molecular ion; mCPBA: 3-chloroperbenzoic acid; MeCN: actetonitrile; MeOH: methanol; 30 min: minutes; MS: mass spectrometry; NCS: N-chlorosuccinimide; NIS: N-iodosuccinimide; NMR: nuclear magnetic resonance; 35 PdCl<com:Sub>2< / com:Sub>(dppf)·DCM: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane; q: quartet; RT: room temperature (ca. 20 °C); R<com:Sub>T< / com:Sub>: retention time; 40 s: singlet, solid; SCX: strong cation exchange; t: triplet; TBME: tert-butyl methyl ether; TFA: trifluoroacetic acid; THF: tetrahydrofuran; UPLC / MS: ultra performance liquid chromatography – mass spectrometry. Other abbreviations are intended to convey their generally accepted meaning. Nomenclature of structures was generated using 'Structure to Name' conversion from ChemDraw® Professional 17 (PerkinElmer™). General Synthetic Methods Methods for the chemical synthesis of the H-APPAMP compounds are described herein. These and / or other well-known methods may be modified and / or adapted in known ways in order to provide alternative or improved methods of synthesis of the H-APPAMP compounds. In a first method, the synthesis starts with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with amine affords the corresponding 5-amino-pyrazolopyrimidine I-2. Boc-protection of the amino group affords the intermediate I-3. The latter is used in a Buchwald-Hartwig cross-coupling to yield the intermediate I-4. Final global Boc-deprotection yields the target compounds. This method is illustrated in the following chemical scheme. In one embodiment, R' is isopropyl. Scheme 1 [Image disponible dans le document PDF, Image available in the PDF document] Representative reactions conditions for the above scheme are as follows: (a) RNH<com:Sub>2< / com:Sub>, DIPEA, EtOH, 50 °C to 90 °C; (b) Boc<com:Sub>2< / com:Sub>O, DMAP, THF, RT to 60 °C; (c) <com:Sup>t< / com:Sup>BuXPhos-Pd-G3, LiHMDS, THF, 60 °C; (d) TFA, DCM, RT; or HCl, dioxane, RT to 40 °C; for example: (a) RNH<com:Sub>2< / com:Sub>, DIPEA, EtOH, 90 °C; (b) Boc<com:Sub>2< / com:Sub>O, DMAP, THF, RT; (c) <com:Sup>t< / com:Sup>BuXPhos-Pd-G3, LiHMDS, THF, 60 °C; (d) HCl, dioxane, RT. In a second method, the synthesis starts with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with sodium thiomethoxide affords the thioether intermediate I-6. Buchwald-Hartwig cross-coupling leads to the formation of the intermediate I-7, which can be converted into sulfoxide intermediate I-8 by oxidation of the thioether. Nucleophilic aromatic substitution yields the 5-amino-pyrazolopyrimidine intermediate I-9. Final Boc-deprotection yields the target compounds. This method is illustrated in the following chemical scheme. In one embodiment, R' is isopropyl. Scheme 2 [Image disponible dans le document PDF, Image available in the PDF document] Representative reactions conditions for the above scheme are as follows: (a) MeSNa, THF, RT; (b) <com:Sup>t< / com:Sup>BuXPhos-Pd-G3, LiHMDS, THF, 60 °C; (c) mCPBA, DCM, RT; (d) RNH<com:Sub>2< / com:Sub>, DIPEA, dioxane, 110 °C; (e) TFA, DCM, RT; or HCl, dioxane, RT to 40 °C; for example: (a) MeSNa, THF, RT; (b) <com:Sup>t< / com:Sup>BuXPhos-Pd-G3, LiHMDS, THF, 60 °C; (c) mCPBA, DCM, RT; (d) RNH<com:Sub>2< / com:Sub>, DIPEA, dioxane, 110 °C; (e) TFA, DCM, RT; or HCl, dioxane, RT. In a third method, the synthesis starts with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with ammonium hydroxide affords the corresponding 5-amino-pyrazolopyrimidine I-10. Boc-protection of the amino group affords the intermediate I-11. Substitution with alkyl halide RX affords intermediate I-3. The latter is used in a Buchwald-Hartwig cross-coupling to yield the intermediate I-4. Final global Boc-deprotection yields the target compounds. This method is illustrated in the following chemical scheme. In one embodiment, R' is isopropyl. Scheme 3 [Image disponible dans le document PDF, Image available in the PDF document] Representative reactions conditions for the above scheme are as follows: (a) NH<com:Sub>4< / com:Sub>OH, 85 °C; (b) Boc<com:Sub>2< / com:Sub>O, DMAP, THF, RT to 60 °C; (c) RCI, K2CO3 DMF, 70 °C (d) <com:Sup>t< / com:Sup>BuXPhos- Pd-G3, LiHMDS, THF, 60 °C; (e) TFA, DCM, RT; or HCl, dioxane, RT to 40 °C. In a fourth method, the synthesis starts with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative I-1. Nucleophilic aromatic substitution with amine affords the corresponding 5-amino-pyrazolopyrimidine I-2. That is followed by a second nucleophilic aromatic substitution with amine to afford the intermediate I-4. Final Boc-deprotection yields the target compounds. This method is illustrated in the following chemical scheme. In one embodiment, R' is isopropyl. Scheme 4 [Image disponible dans le document PDF, Image available in the PDF document] Representative reactions conditions for the above scheme are as follows: (a) RNH<com:Sub>2< / com:Sub>, DIPEA, EtOH, 50 °C; (b) DIPEA, NMP, 150°C, micowave; (c) <com:Sup>t< / com:Sup>BuXPhos-Pd-G3, LiHMDS, THF, 60 °C; (d) HCl, dioxane, 35 °C. Chemical Synthesis Examples The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. General Experimental Conditions All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Reaction mixtures were magnetically stirred unless otherwise indicated. Column chromatography was performed on an automated flash chromatography system, such as a CombiFlash™ Rf system, using Grace™ GraceResolv™ pre-packed silica (40 μm) cartridges, unless otherwise indicated. <com:Sup>1< / com:Sup>H NMR spectra were recorded using a Bruker<com:Sup>™< / com:Sup> Avance III spectrometer (400 MHz) or Bruker™ (500 MHz). Chemical shifts are expressed in parts per million using either the central peaks of the residual protic solvent or an internal standard of tetramethylsilane as references. The spectra were recorded at ambient temperature unless otherwise stated. Analytical LCMS experiments to determine retention times and associated mass ions were performed using an Agilent™ 1200 series HPLC system coupled to an Agilent™ 6110 or 6120 series single quadrupole mass spectrometer running Method 1 or Method 2 described below. Preparative HPLC purifications were performed using a Waters X-Bridge™ BEH C18, 5 μm, 19x50 mm column using a gradient of MeCN and 10 mM ammonium bicarbonate (aq). Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector. SCX resin was purchased from Sigma Aldrich™ or Silicycle™ and washed with MeOH prior to use. Analytical Methods Method 1 – LCMS Acidic 4 min method: Column: Waters X-Select™ CSH C18, 2.5 µm, 4.6 x 30 mm Detection: UV at 254 nm unless otherwise indicated MS ionisation: Electrospray Solvent A: Water / 0.1% Formic acid Solvent B: MeCN / 0.1% Formic acid [Image disponible dans le document PDF, Image available in the PDF document] Method 2 - LCMS Basic 4 min method: Column: Waters X-Bridge™ BEH C18, 2.5 µm, 4.6 x 30 mm Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN (other parameters are the same as for Method 1) Method 3 - UPLC / MS Acidic 3 min method: Column: Waters Acquity™ CSH C18 (2.1 x 30 mm) Detection: Waters Acquity™ PDA detector between 210 and 400 nm MS ionisation: Electrospray Solvent A: Water / 0.1% Formic acid Solvent B: MeCN / 0.1% Formic acid Column maintained at a temperature of 40°C and eluted with a linear acetonitrile gradient from 95.0 % A to 5.0 % B over 3 min and at a constant flow rate of 0.77 mL / min. Method 4 - UPLC / MS Basic 3 min method: Column: Waters Acquity™ BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity™ PDA detector between 210 and 400 nm MS ionisation: Electrospray Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN (other parameters are the same as for Method 3) Method 5 - UPLC / MS Basic 3 min method: Column: Waters Acquity™ BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity™ PDA detector between 210 and 400 nm MS ionisation: Electrospray Solvent A: Water / 10 mM ammonium hydroxide Solvent B: MeCN (other parameters are the same as for Method 3) Method 6 - UPLC / MS Basic 1 min method: Column: Waters Acquity™ BEH C18 column (2.1 x 30 mm) Detection: Waters Acquity™ PDA detector between 210 and 400 nm MS ionisation: Electrospray Solvent A: Water / 10 mM ammonium bicarbonate Solvent B: MeCN Column maintained at a temperature of 40°C and eluted with a linear acetonitrile gradient from 95.0 % A to 5.0 % B over 1 min and at a constant flow rate of 0.77 mL / min. Synthesis 1 <com:Math><semantics>(3R,4R)−4−(((7−((imidazo[1,2−a]pyridin−2−ylmethyl)amino)−3−<annotation encoding="application / x-tex">(3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-< / annotation>< / semantics>< / com:Math> isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-003) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-Chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7- amine Imidazo[1,2-a]pyridin-2-ylmethanamine, 2HCl (0.175 g, 0.80 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (0.122 g, 0.53 mmol) and DIPEA (0.74 ml, 4.24 mmol) in EtOH (10 mL). The reaction mixture was heated at 90 °C for 6 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aq layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure to give the title compound (0.160 g, 0.42 mmol, 80% yield, 90% purity) as a white solid. UPLC / MS (Method 4): m / z 341 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.38 min. Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin-2- ylmethyl)carbamate BOC-anhydride (0.14 mL, 0.61 mmol) was added to a solution of 5-chloro-N-(imidazo[1,2- a]pyridin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (0.160 g, 0.47 mmol) and DMAP (0.011 g, 0.09 mmol) in THF (10 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (20 mL) and water (30 mL). The aq layer was extracted with DCM (2 x 10 mL) and the combined organic layers were washed with brine (30 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> 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. UPLC / MS (Method 4): m / z 441 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.73 min. Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2- a]pyridin-2-ylmethyl)carbamate (0.150 g, 0.34 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (0.094 g, 0.41 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (0.029 g, 0.03 mmol) in THF (3 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 minutes. LiHMDS (1 M in THF) (0.51 ml, 0.51 mmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture was heated to 60 °C for 1 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (0.075 g, 0.12 mmol, 34% yield, 98% purity) as a white solid. UPLC / MS (Method 4): m / z 635 (M+H)+, R<com:Sub>T< / com:Sub> 1.65 min. Step 4: (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.44 mL, 1.77 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (0.075 g, 0.12 mmol) in DCM (10 mL). The reaction mixture was stirred for 16 h at RT and concentrated in vacuo. The residue was diluted in MeOH (5 mL) and loaded onto a SCX cartridge, washed with MeOH (ca. 5 mL) and eluted with 0.7 M ammonia in MeOH (ca. 5 mL). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (0.030 g, 0.07 mmol, 57% yield, 95% purity) as a clear glass solid. UPLC / MS (Method 4): m / z 435 (M+H)+, R<com:Sub>T< / com:Sub> 0.96 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.50 – 8.46 (m, 1H), 7.78 (s, 1H), 7.65 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.3 Hz, 1H), 7.63 (s, 1H), 7.50 (d, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.24 – 7.16 (m, 1H), 6.85 (td, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), <com:Math><semantics>6.76−6.70<annotation encoding="application / x-tex">6.76 - 6.70< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.35−5.30<annotation encoding="application / x-tex">5.35 - 5.30< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.28<annotation encoding="application / x-tex">5.28< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.56<annotation encoding="application / x-tex">4.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>4.12<annotation encoding="application / x-tex">4.12< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−4.05<annotation encoding="application / x-tex">-4.05< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.60−3.48<annotation encoding="application / x-tex">3.60 - 3.48< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.17<annotation encoding="application / x-tex">3.17< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=4.2<annotation encoding="application / x-tex">J = 4.2< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>3.06−2.99<annotation encoding="application / x-tex">3.06 - 2.99< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.98−1.05<annotation encoding="application / x-tex">2.98 - 1.05< / annotation>< / semantics>< / com:Math> 2.92 (m, 1H), 2.92 (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 4.8 Hz, 1H), 2.81 – 2.74 (m, 1H), 2.30 (td, <com:Math><semantics>J=12.2<annotation encoding="application / x-tex">J = 12.2< / annotation>< / semantics>< / com:Math>, 2.7 Hz, 1H), 2.16 (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 9.9 Hz, 1H), <com:Math><semantics>1.58−1.51<annotation encoding="application / x-tex">1.58 - 1.51< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.38−1.28<annotation encoding="application / x-tex">1.38 - 1.28< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.23<annotation encoding="application / x-tex">1.23< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.5 Hz,6H),1.19−1.10(m,1H).<annotation encoding="application / x-tex">J = 6.5 \text{ Hz}, 6\text{H}), 1.19 - 1.10 (m, 1\text{H}).< / annotation>< / semantics>< / com:Math> Synthesis 2 <com:Math><semantics>(3R,4R)−4−(((7−((imidazo[1,2−a]pyrimidin−2−ylmethyl)amino)−3−<annotation encoding="application / x-tex">(3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-< / annotation>< / semantics>< / com:Math> isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-002) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-Chloro-N-(imidazo[1,2-a]pyrimidin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7- amine Imidazo[1,2-a]pyrimidin-2-ylmethanamine, 2HCl (5.04 g, 22.82 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (3.50 g, 15.21 mmol) and DIPEA (21.3 ml, 122.0 mmol) in EtOH (80 mL). The reaction mixture was heated at 90 °C for 5 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (50 mL) and water (50 mL). The aq layer was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure to give the title compound (5.10 g, 14.62 mmol, 96% yield, 98% purity) as a white solid. UPLC / MS (Method 3): m / z 342 (M+H)+, R<com:Sub>T< / com:Sub> 1.06 min Step 2: tert-Butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyrimidin-2- ylmethyl)carbamate BOC-Anhydride (3.2 ml, 13.69 mmol) was added to a solution of 5-chloro-N-(imidazo[1,2- a]pyrimidin-2-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (3.60 g, 10.53 mmol) and DMAP (0.26 g, 2.11 mmol) in THF (10 mL). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (20 mL) and water (30 mL). The aq layer was extracted with DCM (2 x 30 mL) and the combined organic layers were washed with brine (30 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) gave the title compound (4 g, 8.60) mmol, 82% yield, 95% purity) as a cream solid. UPLC / MS (Method 3): m / z 442 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.44 min. Step 3: tert-Butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)- 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2- a]pyrimidin-2-ylmethyl)carbamate (3.19, 7.22 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (1.75 g, 7.58 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (0.62 g, 0.72 mmol) in THF (30 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (10.8 ml, 10.8 mmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 1 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-10% MeOH / DCM) gave the title compound (2.10 g, 3.24 mmol, 44% yield, 98% purity) as an orange solid. UPLC / MS (Method 4): m / z 636 (M+H)+, R<com:Sub>T< / com:Sub> 1.50 min. Step 4: (3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (12.4 mL, 49.5 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)- 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (2.10 g, 3.30 mmol) in DCM (10 mL). The reaction mixture was stirred at RT for 1 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product eluted with 0.7 M ammonia in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give a yellow solid. Further purification by column chromatography (24 g cartridge, 0-20% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave a yellow solid. The solid was dissolved in DCM (20 mL) and MeOH (ca. 1 mL). Diethyl ether (100 mL) was added. A tan solid formed and was collected by filtration to give the title compound (0.700 g, 1.56 mmol, 47% yield, 98% purity). UPLC / MS (Method 4): m / z 436 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 0.85 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.89 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8, 2.1 Hz, 1H), 8.49 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 4.1, 2.0 Hz, 1H), <com:Math><semantics>7.78−7.72<annotation encoding="application / x-tex">7.78 - 7.72< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>7.64<annotation encoding="application / x-tex">7.64< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.02<annotation encoding="application / x-tex">7.02< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.1<annotation encoding="application / x-tex">4.1< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.76<annotation encoding="application / x-tex">6.76< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.47 (s, 1H), 5.27 (s, 1H), 4.60 (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.58−3.48<annotation encoding="application / x-tex">3.58 - 3.48< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.45−3.25<annotation encoding="application / x-tex">3.45 - 3.25< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,2H),3.25−3.19(m,1H),3.14−3.07(m,1H),3.00−2.95(m,1H),2.85(d,<math>J=12.2<annotation encoding="application / x-tex">(m, 2H), 3.25 - 3.19 (m, 1H), 3.14 - 3.07 (m, 1H), 3.00 - 2.95 (m, 1H), 2.85 (d, J = 12.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.39 (td, <com:Math><semantics>J=12.3<annotation encoding="application / x-tex">J = 12.3< / annotation>< / semantics>< / com:Math>, 2.9 Hz, 1H), 2.25 (d, <com:Math><semantics>J=11.0<annotation encoding="application / x-tex">J = 11.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.63 – 1.57 (m, 1H), 1.37 (d, <com:Math><semantics>J=11.7<annotation encoding="application / x-tex">J = 11.7< / annotation>< / semantics>< / com:Math> Hz, 1H), 1.24 (t, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 6H), 1.21 – 1.17 (m, 1H). Synthesis 3 <com:Math><semantics>(3R,4R)−4−(((3−isopropyl−7−(((1−methyl−1H−benzo[d]imidazol−5−<annotation encoding="application / x-tex">(3R,4R)-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5-< / annotation>< / semantics>< / com:Math> yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-006) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidine A solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (8.00 g, 34.8 mmol) in THF (100 mL) was cooled to -5 °C and sodium thiomethoxide (2.44 g, 34.8 mmol) was added. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with EtOAc (400 ml) and washed with aq. saturated NaHCO<com:Sub>3< / com:Sub> (500 mL). The aq layer was extracted with EtOAc (260 mL) and the combined organic layers were washed with brine (160 mL), dried over MgSO<com:Sub>4< / com:Sub> and concentrated in vacuo. Purification by column chromatography (40 g cartridge, 0-20% EtOAc / isohexane) gave the title compound (6.00 g, 24.6 mmol, 71% yield, 99% purity) as a pale yellow oil which solidified on standing. LCMS (Method 1): m / z 242 (M+H)+, R<com:Sub>T< / com:Sub> 2.40 min. Step 2: tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate A solution of 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 <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (300 mg, 0.35 mmol) in THF (10 mL) was degassed for 5 min. LiHMDS (1 M in THF) (7.8 mL, 7.74 mmol) was added and the mixture degassed for a further 5 min. The reaction mixture was heated to 60 °C and stirred for 0.5 h. The solvent was evaporated and the residue was redissolved in EtOAc, washed with 1:1 water / brine (50 mL) and the aq layer was extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub>, filtered and the solvent was evaporated. Purification by column chromatography (80 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (2.30 g, 5.12 mmol, 66% yield, 97% purity) as yellow solid. LCMS (Method 1): m / z 436 (M+H)+, R<com:Sub>T< / com:Sub> 2.25 min. Step 3: tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylthio)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (1.70 g, 3.90 mmol) was dissolved in DCM (30 mL). The solution was cooled to 0 °C and mCPBA (1.35 g, 5.85 mmol) was added in one portion. The reaction mixture stirred at 0 °C for 1 h. The reaction mixture was worked up by addition of DCM (30 mL) and washed with aq saturated NaHCO<com:Sub>3< / com:Sub> (2 x 30 mL). The aq layer was extracted with DCM (3 x 20 mL). The organic layer was washed with brine, dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and the solvent was evaporated to afford the title compound (1.50 g, 3.16 mmol, 81% yield, 95% purity). UPLC / MS (Method 4): m / z 452 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.43 min. Step 4: tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (90 mg, 0.149 mmol) in dioxane (0.5 mL) was added to a solution of (1-methyl-1H-benzo[d]imidazol-5-yl)methanamine (72 mg, 0.448 mmol) and DIPEA (0.25 mL, 1.431 mmol) in dioxane (0.5 mL). The resultant mixture was heated at 100 °C for 3 days. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane then 0 to 5% MeOH / DCM) gave the title compound (28 mg, 0.046 mmol, 31% yield, 90% purity) as a pale yellow glass. UPLC / MS (Method 4): m / z 549 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.44 min. Step 5: (3R,4R)-4-(((3-Isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((1-methyl-1H-benzo[d]imidazol-5- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (28 mg, 0.051 mmol) was treated with a mixture of TFA (50 μL, 0.649 mmol) in DCM (0.5 mL). The resultant mixture was stirred for 3 h. The mixture was concentrated then partitioned between EtOAc (5 mL) and aq saturated NaHCO<com:Sub>3< / com:Sub> (3 mL) and the phases separated. The organic phase was washed with water (2 mL) and brine (2 mL), dried over MgSO<com:Sub>4< / com:Sub>, filtered and concentrated in vacuo to give the title compound (10 mg, 0.021 mmol, 41% yield, 95% purity) as a white powder. UPLC / MS (Method 4): m / z 449 (M+H)+, R<com:Sub>T< / com:Sub> 0.97 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.14 (s, 1H), 7.88 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.5 Hz, 1H), 7.65 – 7.62 (m, 2H), 7.51 (d, <com:Math><semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.31 (dd, <com:Math><semantics>J=8.3<annotation encoding="application / x-tex">J = 8.3< / annotation>< / semantics>< / com:Math>, 1.6 Hz, 1H), 6.73 – 6.66 (m, 1H), 5.35 – 5.29 (m, 1H), 5.22 (s, 1H), 4.53 (d, <com:Math><semantics>J=6.4<annotation encoding="application / x-tex">J = 6.4< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.81 (s, 3H), 3.57 – 3.47 (m, 1H), 3.19 <com:Math><semantics>−3.12<annotation encoding="application / x-tex">-3.12< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.05−2.96<annotation encoding="application / x-tex">3.05 - 2.96< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.96−2.91<annotation encoding="application / x-tex">2.96 - 2.91< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.89<annotation encoding="application / x-tex">2.89< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=12.0<annotation encoding="application / x-tex">J = 12.0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.3<annotation encoding="application / x-tex">4.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.79−2.73<annotation encoding="application / x-tex">2.79 - 2.73< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.34−2.25<annotation encoding="application / x-tex">2.34 - 2.25< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.15<annotation encoding="application / x-tex">2.15< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 10.0 Hz, 1H), <com:Math><semantics>1.55−1.49<annotation encoding="application / x-tex">1.55 - 1.49< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.34−1.27<annotation encoding="application / x-tex">1.34 - 1.27< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.22<annotation encoding="application / x-tex">1.22< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math> Hz, 6H), <com:Math><semantics>1.15−1.07<annotation encoding="application / x-tex">1.15 - 1.07< / annotation>< / semantics>< / com:Math> (m, 1H), 1H under water. Synthesis 4 (3R,4R)-4-(((7-(((1 H-benzo[ d]imidazol-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-005) [Image disponible dans le document PDF, Image available in the PDF document] 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 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) were heated to 105 °C for 16 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (26 mg, 0.041 mmol, 5% yield, 85% purity) as a brown solid. UPLC / MS (Method 4): m / z 535 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.45 min. Step 5: (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.15 mL, 0.61 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (30 mg, 0.040 mmol) in DCM (10 mL). The reaction was stirred 16 h and concentrated in vacuo. The residue was diluted in MeOH (5 mL) and loaded onto a SCX cartridge, washing with MeOH (3 x column volumes) and eluting with 0.7 M ammonia in MeOH (3 x column volumes). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (5 mg, 10.9 µmol, 27% yield, 95% purity) as a yellow solid. UPLC / MS (same method as Method 4, but run length was 10 min): m / z 435 (M+H)+, R<com:Sub>T< / com:Sub> 3.87 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 12.30 (s, 1H), 7.71 (t, <com:Math><semantics>J=6.2<annotation encoding="application / x-tex">J = 6.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.66 (s, 1H), 7.55 <com:Math><semantics>(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<annotation encoding="application / x-tex">(s, 1H), 7.44 (s, 1H), 7.14 (dd, J = 6.1, 3.0 Hz, 2H), 6.81 - 6.71 (m, 1H), 5.29 (s, 1H), 5.22< / annotation>< / semantics>< / com:Math> (s, 1H), 4.69 (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.59−3.44<annotation encoding="application / x-tex">3.59 - 3.44< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.23−3.14<annotation encoding="application / x-tex">3.23 - 3.14< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.06−2.99<annotation encoding="application / x-tex">3.06 - 2.99< / annotation>< / semantics>< / com:Math> (m, 1H), 2.96 (p, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math> Hz, 1H), 2.89 (dd, <com:Math><semantics>J=11.7<annotation encoding="application / x-tex">J = 11.7< / annotation>< / semantics>< / com:Math>, 4.6 Hz, 1H), 2.79 – 2.73 (m, 1H), 2.32 – 2.24 (m, 1H), 2.15 (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 9.9 Hz, 1H), 1.53 (dd, <com:Math><semantics>J=13.0<annotation encoding="application / x-tex">J = 13.0< / annotation>< / semantics>< / com:Math>, 3.4 Hz, 1H), 1.32 (s, 1H), <com:Math><semantics>1.24(t,J=6.5Hz,6H),1.18−1.07(m,1H).<annotation encoding="application / x-tex">1.24 (t, J = 6.5 Hz, 6H), 1.18 - 1.07 (m, 1H).< / annotation>< / semantics>< / com:Math> Synthesis 5 (3R,4R)-4-(((3-isopropyl-7-(((8-methylimidazo[1,2- a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-004) [Image disponible dans le document PDF, Image available in the PDF document] Step 4: tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate 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 allowed to cool to RT 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 glass solid. UPLC / MS (Method 1): m / z 549 (M+H)+, R<com:Sub>T< / com:Sub> 1.32 min. Step 5: (3R,4R)-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.40 mL, 1.51 mmol) was added to a suspension of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (48 mg, 0.083 mmol) in dioxane (3 mL). The reaction mixture was stirred at 40 °C for 4 h. The solvent was removed in vacuo. The residue was diluted in MeOH (1 mL) and loaded onto a SCX cartridge, washing with MeOH (ca. 5 mL) and eluting with 0.7 M ammonia in MeOH (ca. 5 mL). The ammoniacal methanol solution was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (24 mg, 0.052 mmol, 63% yield, 98% purity) as a tan glass solid. LCMS (Method 2): <com:Math><semantics>m / z<annotation encoding="application / x-tex">m / z< / annotation>< / semantics>< / com:Math> 449 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.67 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.32 (dt, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8, 1.1 Hz, 1H), 7.74 (s, 1H), 7.66 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.2 Hz, 1H), 7.63 (s, 1H), 7.01 (dt, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), 6.75 (t, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.72 – 6.68 (m, 1H), <com:Math><semantics>5.35−5.29<annotation encoding="application / x-tex">5.35 - 5.29< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.27<annotation encoding="application / x-tex">5.27< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.57<annotation encoding="application / x-tex">4.57< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.59−3.46<annotation encoding="application / x-tex">3.59 - 3.46< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.24−3.14<annotation encoding="application / x-tex">3.24 - 3.14< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.08−2.99<annotation encoding="application / x-tex">3.08 - 2.99< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.96<annotation encoding="application / x-tex">2.96< / annotation>< / semantics>< / com:Math> (p, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>2.90<annotation encoding="application / x-tex">2.90< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.9<annotation encoding="application / x-tex">J = 11.9< / annotation>< / semantics>< / com:Math>, 4.3 Hz, 1H), <com:Math><semantics>2.82−2.73<annotation encoding="application / x-tex">2.82 - 2.73< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.47<annotation encoding="application / x-tex">2.47< / annotation>< / semantics>< / com:Math> (s, 3H), <com:Math><semantics>2.35−2.26<annotation encoding="application / x-tex">2.35 - 2.26< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 9.9 Hz, 1H), <com:Math><semantics>1.59−1.51<annotation encoding="application / x-tex">1.59 - 1.51< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.39−1.28<annotation encoding="application / x-tex">1.39 - 1.28< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.23<annotation encoding="application / x-tex">1.23< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.8<annotation encoding="application / x-tex">4.8< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>6H<annotation encoding="application / x-tex">6H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.20−1.28<annotation encoding="application / x-tex">1.20 - 1.28< / annotation>< / semantics>< / com:Math> 1.08 (m, 1H), 1H under water. Synthesis 6 (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-3- yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-001) [Image disponible dans le document PDF, Image available in the PDF document] Steps 4 and 5: (3R,4R)-4-(((3-Isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-3- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Step 4: tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (0.100 g, 0.221 mmol) and (8-methylimidazo[1,2-a]pyridin-2-yl)methanamine (0.107 g, 0.666 mmol) in dioxane (0.5 mL) was heated to 105 °C for 4 days. The reaction mixture was allowed to cool to RT and concentrated. Purification by column chromatography (12 g cartridge, 0-10%) MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the corresponding Boc intermediate (40 mg). Step 5: A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((5- methylimidazo[1,2-a]pyridin-3-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (40 mg, 0.073 mmol) and HCl (4 M in dioxane) (505 µL, 16.6 mmol) was stirred at RT for 16 h. The solvent was evaporated. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (15 mg, 45% yield, 95% purity) as a brown solid. LCMS (Method 2): m / z 449 (M+H)+, R<com:Sub>T< / com:Sub> 1.64 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.61 (s, 1H), 7.58 (t, <com:Math><semantics>J=5.3<annotation encoding="application / x-tex">J = 5.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.51 (s, 1H), 7.40 <com:Math><semantics>(d,J=9.0 Hz,1H),7.13(dd,J=9.0,6.8 Hz,1H),6.81−6.74(m,1H),6.68(d,J=6.9)<annotation encoding="application / x-tex">(d, J = 9.0 \text{ Hz}, 1\text{H}), 7.13 (dd, J = 9.0, 6.8 \text{ Hz}, 1\text{H}), 6.81 - 6.74 (m, 1\text{H}), 6.68 (d, J = 6.9)< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.42 (s, 1H), 5.31 (s, 1H), 4.96 (d, <com:Math><semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.60 <com:Math><semantics>−3.49<annotation encoding="application / x-tex">- 3.49< / annotation>< / semantics>< / com:Math> (m, 1H), 3.28 <com:Math><semantics>−3.49<annotation encoding="application / x-tex">- 3.49< / annotation>< / semantics>< / com:Math> <com:Math><semantics>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),<annotation encoding="application / x-tex">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),< / annotation>< / semantics>< / com:Math> 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 <com:Math><semantics>(dd,J=6.9,5.2Hz,6H),1.20−1.13(m,1H),1Hunderwater.<annotation encoding="application / x-tex">(dd, J = 6.9, 5.2 Hz, 6H), 1.20 - 1.13 (m, 1H), 1H under water.< / annotation>< / semantics>< / com:Math> Synthesis 7 <com:Math><semantics>(3R,4R)−4−[[[3−isopropyl−7−[(3−methylimidazo[2,1−b]thiazol−6−<annotation encoding="application / x-tex">(3R,4R)-4-[[[3-isopropyl-7-[(3-methylimidazo[2,1-b]thiazol-6-< / annotation>< / semantics>< / com:Math> yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol (H-APPAMP-007) [Image disponible dans le document PDF, Image available in the PDF document] Step 4: tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((3-methylimidazo[2,1-b]thiazol-6- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (80.0 mg, 0.145 mmol), (3-methylimidazo[2,1- b]thiazol-6-yl)methanamine, 2HCl, hydrate (74.9 mg, 0.290 mmol) and DIPEA (0.228 mL, 1.305 mmol) in Ethanol (2 mL) was heated at 140 °C under microwave irradiation for 4 hours. The reaction mixture was allowed to cool to RT and concentrated. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7M NH<com:Sub>3< / com:Sub>) / DCM) followed by purification 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. UPLC / MS (Method 4): m / z 555 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 0.52 min. Step 5: (3R,4R)-4-[[[3-isopropyl-7-[(3-methylimidazo[2,1-b]thiazol-6- yl)methylamino]pyrazolo[1,5-a]pyrimidin-5-yl]amino]methyl]piperidin-3-ol Hydrogen chloride (4M 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 1h. The solvent was evaporated. The residue was diluted in MeOH (1 mL) and loaded onto a SCX cartridge, washing with MeOH (ca. 5 mL) and eluting with 0.7M ammonia in MeOH (ca. 5 mL). The ammoniacal methanol solution was concentrated under reduced pressure to afford the title compound (18 mg, 0.038 mmol, 84 % yield, 96% purity) as a tan solid after trituration in Et<com:Sub>2< / com:Sub>O then drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 455 (M+H)+, R<com:Sub>T< / com:Sub> 1.03 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.62 (s, 1H), 7.59 (s, 1H), 7.49 (t, J = 6.1 Hz, 1H), 6.85 <com:Math><semantics>(q,J=1.3Hz,1H),6.79−6.73(m,1H),5.38−5.35(m,1H),5.35(s,1H),4.47−4.43(m,1H),5.35(s,1H),4.47−4.43(m,1H),5.35(s,1H),4.47−4.43(m,1H),5.35(s,1H),4.47−4.43(m,1H),5.35(s,1H),4.4<annotation encoding="application / x-tex">(q, J = 1.3 Hz, 1H), 6.79 - 6.73 (m, 1H), 5.38 - 5.35 (m, 1H), 5.35 (s, 1H), 4.47 - 4.43 (m, 1H), 5.35 (s, 1H), 4.47 - 4.43 (m, 1H), 5.35 (s, 1H), 4.47 - 4.43 (m, 1H), 5.35 (s, 1H), 4.47 - 4.43 (m, 1H), 5.35 (s, 1H), 4.4< / annotation>< / semantics>< / com:Math> 2H), 3.25 - 3.19 (m, 1H), 3.10 - 3.02 (m, 1H), 2.98 - 2.90 (m, 2H), 2.85 - 2.79 (m, 2H), 2.36 (d, J = 1.3 Hz, 3H), 2.35 - 2.30 (m, 1H), 2.23 - 2.16 (m, 1H), 1.63 - 1.56 (m, 1H), 1.40 - 1.32 (m, 1H), 1.23 (dd, J = 6.9, 6.0 Hz, 6H), 1.21 - 1.13 (m, 1H), 1H under water. Synthesis 8 tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (H-APPAMP-008) [Image disponible dans le document PDF, Image available in the PDF document] 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 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (6-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.23 mL, 1.305 mmoRPI) in EtOH (2.0 mL). The resultant mixture was heated at 140 °C under microwave irradiation for 4 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0- 10% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (67 mg, 0.112 mmol, 77% yield, 92% purity) as a yellow oil. UPLC / MS (Method 3): m / z 549 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 0.84 min. 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 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 at RT overnight and concentrated to dryness. Purification by column chromatography (4 g cartridge, 0-15%) MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (32 mg, 0.068 mmol, 55%) yield, 95% purity) as an off-white solid after drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 449 (M+H)+, R<com:Sub>T< / com:Sub> 1.08 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.93 – 8.82 (m, 1H), 8.65 – 8.52 (m, 1H), 8.32 (s, 1H), 7.73 (s, 1H), 7.67 (s, 1H), 7.44 (d, <com:Math><semantics>J=9.2<annotation encoding="application / x-tex">J = 9.2< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.13 (d, <com:Math><semantics>J=9.3<annotation encoding="application / x-tex">J = 9.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.99 – 6.86 <com:Math><semantics>(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),<annotation encoding="application / x-tex">(m, 1H), 6.12 - 6.03 (m, 1H), 5.27 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 3.60 - 3.50 (m, 1H),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>3.47−3.39<annotation encoding="application / x-tex">3.47 - 3.39< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.25−3.13<annotation encoding="application / x-tex">3.25 - 3.13< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>3.01−2.92<annotation encoding="application / x-tex">3.01 - 2.92< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.84−2.72<annotation encoding="application / x-tex">2.84 - 2.72< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.66−2.92<annotation encoding="application / x-tex">2.66 - 2.92< / annotation>< / semantics>< / com:Math> <com:Math><semantics>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),<annotation encoding="application / x-tex">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),< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1.52−1.41<annotation encoding="application / x-tex">1.52 - 1.41< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.24<annotation encoding="application / x-tex">1.24< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.6<annotation encoding="application / x-tex">J = 6.6< / annotation>< / semantics>< / com:Math> Hz, 6H). Synthesis 9 (3R,4R)-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-009) [Image disponible dans le document PDF, Image available in the PDF document] Step 4: tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((6-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (7-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.228 mL, 1.305 mmol) in EtOH (2.0 mL). The resultant mixture was heated at 140 °C under microwave irradiation for 3.5 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (60 mg, 0.093 mmol, 64 % yield, 85% purity) as a brown oil. UPLC / MS (Method 3): m / z 549 (M+H)+, R<com:Sub>T< / com:Sub> 0.83 min. Step 5: (3R,4R)-4-(((3-isopropyl-7-(((7-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((6-methylimidazo[1,2- a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1- carboxylate (60 mg, 0.104 mmol) in 1,4-dioxane (2.0 mL) was treated with HCl (4M in 1,4- dioxane) (0.390 mL, 1.558 mmol). The reaction mixture was stirred at RT overnight and concentrated to dryness. Purification by column chromatography (4 g cartridge, 0-15%) MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (33 mg, 0.070 mmol, 67 % yield, 95% purity) as an off-white solid after drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 449 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.07 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.36 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.9 Hz, 1H), 7.68 (s, 1H), 7.67 - 7.65 (m, 1H), 7.64 (s, 1H), 7.30 - 7.25 (m, 1H), 6.82 - 6.76 (m, 1H), 6.70 (dd, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math>, 1.7 Hz, 1H), <com:Math><semantics>5.61−5.55<annotation encoding="application / x-tex">5.61 - 5.55< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.27<annotation encoding="application / x-tex">5.27< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.53<annotation encoding="application / x-tex">4.53< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.62−3.51<annotation encoding="application / x-tex">3.62 - 3.51< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.25−3.51<annotation encoding="application / x-tex">3.25 - 3.51< / annotation>< / semantics>< / com:Math> <com:Math><semantics>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),<annotation encoding="application / x-tex">3.20 \text{ (m, 1H)}, 3.19 - 3.12 \text{ (m, 1H)}, 3.01 \text{ (dd, } J = 11.6, 4.4 \text{ Hz, 1H)}, 2.99 - 2.93 \text{ (m, 1H)},< / annotation>< / semantics>< / com:Math> 2.92 - 2.87 (m, 1H), 2.47 - 2.42 (m, 1H), 2.33 (s, 3H), 2.32 - 2.26 (m, 1H), 1.67 - 1.61 (m, 1H), 1.46 - 1.38 (m, 1H), 1.30 - 1.26 (m, 1H), 1.24 (t, J = 6.6 Hz, 6H). 1H under water. Synthesis 10 (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-010) [Image disponible dans le document PDF, Image available in the PDF document] 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 tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (80 mg, 0.145 mmol) was added to a solution of (5-methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (102 mg, 0.435 mmol) and DIPEA (0.228 ml, 1.305 mmol) in EtOH (2.0 mL). The resultant mixture was heated at 140 °C under microwave irradiation for 4 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0- 10% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (85 mg, 0.116 mmol, 80 % yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 549 (M+H)+, R<com:Sub>T< / com:Sub> 1.50 min. Step 5: (3R,4R)-4-(((3-isopropyl-7-(((5-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(((5-methylimidazo[1,2- a]pyridin-2-yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1- carboxylate (85 mg, 0.116 mmol) in 1,4-dioxane (2.0 mL) was treated with HCl (4M in 1,4- dioxane) (0.436 mL, 1.743 mmol). The reaction mixture was stirred at RT overnight and concentrated to dryness. Purification by column chromatography on RP Flash C18 (4) g cartridge, 15-50% MeCN / 10 mM ammonium bicarbonate) gave the title compound (12 mg, 0.025 mmol, 21% yield, 93% purity) as an off-white solid after drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 449 (M+H)+, R<com:Sub>T< / com:Sub> 1.07 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.67 (s, 1H), 7.63 (s, 1H), 7.58 (t, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.43 <com:Math><semantics>(dd,J=8.9,1.2Hz,1H),7.21(dd,J=9.0,6.8Hz,1H),6.79−6.75(m,2H),5.44−5.37<annotation encoding="application / x-tex">(dd, J = 8.9, 1.2 Hz, 1H), 7.21 (dd, J = 9.0, 6.8 Hz, 1H), 6.79 - 6.75 (m, 2H), 5.44 - 5.37< / annotation>< / semantics>< / com:Math> (m, 1H), 5.33 (s, 1H), 4.59 (d, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.61 - 3.49 (m, 1H), 3.25 - 3.19 (m, 1H), 3.11 - 3.05 (m, 1H), 2.99 - 2.92 (m, 2H), 2.87 - 2.81 (m, 1H), 2.56 (s, 3H), 2.40 - 2.33 (m, 1H), 2.26 - 2.20 (m, 1H), 1.64 - 1.57 (m, 1H), 1.42 - 1.34 (m, 1H), 1.24 (dd, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, 6.0 Hz, 6H), 1.21 - 1.15 (m, 1H). 1H under water. Synthesis 11 (3R,4R)-4-(((7-(((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-011) [Image disponible dans le document PDF, Image available in the PDF document] Step 4: (3R,4R)-4-(((7-(((6-fluoroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (60 mg, 0.109 mmol) was added to a solution of (6-fluoroimidazo[1,2-a]pyridin-2-yl)methanamine (53.9 mg, 0.326 mmol) and DIPEA (0.171 mL, 0.979 mmol) in EtOH (4.0 mL). The resultant mixture was heated at 140 °C under microwave irradiation for 4 h, concentrated to dryness and redissolved in NMP (3.0) mL). The resultant mixture was heated at 160 °C under microwave irradiation for 4 h. The crude oil was filtered through SCX (2g - wash with MeOH (15 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (15 mL)) gave a brown oil. Purification by column (4 g cartridge (dry load), 0-10% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM then 100% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>)) followed by purification by column chromatography on RP Flash C18 (4 g cartridge, 15-75% MeCN / 10 mM ammonium bicarbonate) gave the title compound (5 mg, 9.94 μmol, 9% yield, 90% purity) as a tan solid after precipitation from Et<com:Sub>2< / com:Sub>O. UPLC / MS (Method 4): m / z 453 (M+H)+, R<com:Sub>T< / com:Sub> 1.01 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.69 (dd, J = 4.7, 2.5 Hz, 1H), 7.79 (s, 1H), 7.68 (t, J = 6.2 Hz, 1H), 7.63 (s, 1H), 7.57 (dd, J = 10.0, 5.3 Hz, 1H), 7.30 (ddd, J = 10.2, 8.4, 2.5 Hz, 1H), 6.75 - 6.68 (m, 1H), 5.30 - 5.27 (m, 1H), 5.26 (s, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.60 - <com:Math><semantics>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=3.47(m,1H),3.23−3.15(m,1H),3.07−2.99(m,1H),3.98−2.92(m,1H),3.89(dd,J=3.47(m,1H),3.23−3.15(m,1H),3.0<annotation encoding="application / x-tex">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 = 3.47 (m, 1H), 3.23 - 3.15 (m, 1H), 3.07 - 2.99 (m, 1H), 3.98 - 2.92 (m, 1H), 3.89 (dd, J = 3.47 (m, 1H), 3.23 - 3.15 (m, 1H), 3.0< / annotation>< / semantics>< / com:Math> 11.4, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.33 - 2.23 (m, 1H), 2.14 (dd, J = 11.7, 9.9 Hz, 1H), 1.58 - 1.51 (m, 1H), 1.37 - 1.27 (m, 1H), 1.23 (t, J = 6.5 Hz, 6H), 1.19 - 1.11 (m, 1H). 1H under water. Synthesis 12 (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-012) [Image disponible dans le document PDF, Image available in the PDF document] Step4: 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 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 resultant mixture was heated at 140 °C under microwave irradiation for 4 h, concentrated to dryness and redissolved in NMP (3 mL). The resultant mixture was heated at 160 °C under microwave irradiation for 4 h. The crude oil was filtered through SCX (2g - wash with MeOH (15 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (15 mL)) gave a brown oil. Purification by column chromatography on RP Flash C18 (4 g cartridge, 35-100% MeCN / 10 mM ammonium bicarbonate) gave the title compound (32 mg, 42 µmol, 38% yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 569 (M+H)+, R<com:Sub>T< / com:Sub> 1.55 min. Step5: (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol A solution of tert-butyl (3R,4R)-4-(((7-(((6-chloroimidazo[1,2-a]pyridin-2-yl)methyl)amino)- 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (32 mg, 0.045 mmol) in 1,4-dioxane (2 mL) was treated with HCl (4M in 1,4-dioxane) (0.169 mL, 0.675 mmol). The reaction mixture was stirred at RT overnight and concentrated to dryness. The crude oil was filtered through SCX (2g - wash with MeOH (15 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (15 mL) to give a brown oil. Purification by column (4 g cartridge (dry load), 0-20% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) followed by purification by column chromatography on RP Flash C18 (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 Et<com:Sub>2< / com:Sub>O then drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 469 (M+H)+, R<com:Sub>T< / com:Sub> 1.08 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.76 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 2.1 Hz, 1H), 7.77 (s, 1H), 7.69 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.3 Hz, 1H), 7.63 (s, 1H), 7.55 (d, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.26 (dd, <com:Math><semantics>J=9.6<annotation encoding="application / x-tex">J = 9.6< / annotation>< / semantics>< / com:Math>, 2.1 Hz, 1H), 6.76 - 6.68 (m, 1H), <com:Math><semantics>5.32−5.27<annotation encoding="application / x-tex">5.32 - 5.27< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.25<annotation encoding="application / x-tex">5.25< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.56<annotation encoding="application / x-tex">4.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.60−3.47<annotation encoding="application / x-tex">3.60 - 3.47< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.24−1.00<annotation encoding="application / x-tex">3.24 - 1.00< / annotation>< / semantics>< / com:Math> 3.16 (m, 1H), 3.05 - 2.98 (m, 1H), 2.98 - 2.91 (m, 1H), 2.91 - 2.87 (m, 1H), 2.80 - 2.73 (m, 1H), 2.33 - 2.24 (m, 1H), 2.18 – 2.11 (m, 1H), 1.58 - 1.50 (m, 1H), 1.39 - 1.27 (m, 1H), 1.26 – 1.21 (m, 6H), 1.18 - 1.09 (m, 1H). 1H under water. Synthesis 13 (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-013) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Step4: tert-butyl (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)- 3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate tert-Butyl (3R,4R)-3-hydroxy-4-(((3-isopropyl-7-(methylsulfinyl)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidine-1-carboxylate (120 mg, 99% Wt, 0.22 mmol) was added to a solution of (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, Acetic acid (0.11 g, 0.43 mmol) and DIPEA (0.19 mL, 1.1 mmol) in NMP (2 mL). ). The resultant mixture was heated at 140 °C under microwave irradiation for 4 h then at 160 °C for 4 h. The crude oil was filtered through SCX (4g - wash with MeOH (30 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (30 mL)) gave a brown oil. Purification by column (4 g cartridge (dry load), 0- 15% MeOH (containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (42 mg, 67 µmol, 31% yield, 92% Purity) as a brown oil. UPLC / MS (Method 4): m / z 575 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.58 min. Step5: (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol tert-Butyl (3R,4R)-4-(((7-(((8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (23 mg, 37 μmol) in 1,4-dioxane (0.25 mL) was treated with HCl (4M 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 through SCX (4g - wash with MeOH (30 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (30 mL)) gave the title compound (17 mg, 34 µmol, 92% yield, 95% Purity) as a brown solid after precipitation from Et<com:Sub>2< / com:Sub>O then drying under vacuum at 50 °C overnight. UPLC / MS (Method 4): m / z 475 (M+H)+, R<com:Sub>T< / com:Sub> 1.14 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.30 – 8.23 (m, 1H), 7.74 (s, 1H), 7.67 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.2 Hz, 1H), 7.64 (s, 1H), <com:Math><semantics>6.74−6.69<annotation encoding="application / x-tex">6.74 - 6.69< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>5.36−5.30<annotation encoding="application / x-tex">5.36 - 5.30< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.28<annotation encoding="application / x-tex">5.28< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.58<annotation encoding="application / x-tex">4.58< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=5.9<annotation encoding="application / x-tex">J = 5.9< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.59−3.49<annotation encoding="application / x-tex">3.59 - 3.49< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.23−3.16<annotation encoding="application / x-tex">3.23 - 3.16< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.08−3.00<annotation encoding="application / x-tex">3.08 - 3.00< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.99−2.92<annotation encoding="application / x-tex">2.99 - 2.92< / annotation>< / semantics>< / com:Math> (m, 1H), 2.91 (dd, <com:Math><semantics>J=11.8<annotation encoding="application / x-tex">J = 11.8< / annotation>< / semantics>< / com:Math>, 4.9 Hz, 1H), 2.81 – 2.75 (m, 1H), 2.48 – 2.43 (m, 1H), 2.35 – 2.26 (m, 1H), 2.16 (dd, <com:Math><semantics>J=11.7<annotation encoding="application / x-tex">J = 11.7< / annotation>< / semantics>< / com:Math>, 9.9 Hz, 1H), <com:Math><semantics>1.59−1.52<annotation encoding="application / x-tex">1.59 - 1.52< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.39−1.29<annotation encoding="application / x-tex">1.39 - 1.29< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.24<annotation encoding="application / x-tex">1.24< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(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).<annotation encoding="application / x-tex">(dd, J = 6.9, 5.9 Hz, 6H), 1.20 - 1.11 (m, 1H), 1.04 - 0.98 (m, 2H), 0.98 - 0.92 (m, 2H).< / annotation>< / semantics>< / com:Math> 1H under water. Intermediate Synthesis A1 (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, AcOH [Image disponible dans le document PDF, Image available in the PDF document] Step A: 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde A solution of tripotassium phosphate (755 mg, 3.55 mmol) in water (2.5 mL) was added to a solution of 8-bromoimidazo[1,2-a]pyridine-2-carbaldehyde (200 mg, 0.889) mmol) and cyclopropylboronic acid (229 mg, 2.67 mmol) in 1,4-dioxane (10 mL). N<com:Sub>2< / com:Sub> was bubbled through the reaction mixture for 10 minutes then PdCl2(dppf) (65.0 mg, 0.089) mmol) was added. N<com:Sub>2< / com:Sub> was bubbled through the reaction mixture for another 5 minutes before being heated at 100 °C for 3 h. At RT, water (20 mL) and EtOAc (40 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a phase separator and concentrated. Purification by column (12 g cartridge (dry load), 0-100% EtOAc / isohexane) gave the title compound (141 mg, 0.750 mmol, 71% yield, 99% purity) as a yellow solid. Step B / C: 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (8-cyclopropylimidazo[1,2-a]pyridin-2-yl)methanamine, AcOH A solution of 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde (130 mg, 698 µmol), hydroxylamine hydrochloride (121 mg, 1.75 mmol) and pyridine (0.14 mL, 1.75 mmol) in EtOH (3.5 mL) was stirred at 80 °C for 2 h. At RT, the precipitate was collected by filtration, rinsing with EtOH (2 x 2 mL). The solid was further dried under vacuum to afford 8-cyclopropylimidazo[1,2-a]pyridine-2-carbaldehyde oxime (135 mg) as a tan solid which was dissolved in AcOH (3 mL). The solution was cooled at 0 °C then sodium acetate (11.0 mg, 134 µmol) and zinc dust (658 mg, 10.1 mmol) were added. The reaction mixture was stirred at RT overnight before being filtered through Celite™, rinsing with DCM (20 mL) and MeOH (20 mL). The filtrate was concentrated to dryness to afford an oil. Filtration through SCX (10g - wash with MeOH (50 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (50 mL)) gave the title compound (164 mg, 663 µmol, 99% yield, 95% purity) as a slightly yellow oil. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) was consistent with product structure. Synthesis 14 (3R,4R)-4-(((3-isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol (H-APPAMP-014) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-3-isopropyl-N-(quinolin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine Quinolin-2-ylmethanamine (165 mg, 1.04 mmol) was added to a solution of 5,7-dichloro- 3-isopropylpyrazolo[1,5-a]pyrimidine (200 mg, 0.869 mmol) and DIPEA (908 µL, 5.21 mmol) in EtOH (3.3 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo to give an orange solid Purification by column (12 g cartridge, DCM) gave the title compound (240 mg, 0.67 mmol, 78% yield, 99% purity) as an orange solid. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) was consistent with product structure. Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2- ylmethyl)carbamate BOC-Anhydride (193 mg, 886.1 µmol) was added to a solution of 5-chloro-3-isopropyl-N- (quinolin-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (240 mg, 681.6 µmol) and DMAP (17 mg, 136.3 µmol) in THF (13.6 mL). The reaction mixture was stirred at 60 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure then diluted in DCM (15 mL) and washed with brine (3 x 10 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-2.5% MeOH / DCM) gave the title compound (317 mg, 0.67 mmol, 98% yield, 95% purity) as an orange oil. UPLC / MS (Method 6): m / z 453 (M+H)+, R<com:Sub>T< / com:Sub> 0.92 min. 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-2- ylmethyl)carbamate (115 mg, 0.25 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (63 mg, 0.27 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (21 mg, 25 µmol) in THF (2.1 mL) was degassed with N2 for 10 min. LiHMDS (1M in THF) (0.37 mL, 0.37 mmol) was added in one portion under bubbling N2. Bubbling was ceased and the reaction mixture heated to 60 °C for 1 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (130 mg, 0.19 mmol, 77% yield, 95% purity) as a yellow oil. UPLC / MS (Method 4): m / z 646 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.85 min. Step 4: (3R,4R)-4-(((3-isopropyl-7-((quinolin-2-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.5 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-2-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (120 mg, 0.18 mmol) in 1,4-dioxane (1 mL). The reaction mixture was stirred at 35 °C for 1 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (30 mL). The ammoniacal methanol 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<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 446 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.18 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.35 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 8.5 Hz, 1H), 8.04 – 7.99 (m, 2H), 7.97 <com:Math><semantics>(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<annotation encoding="application / x-tex">(dd, J = 8.2, 1.4 Hz, 1H), 7.81 - 7.74 (m, 1H), 7.68 (s, 1H), 7.62 - 7.57 (m, 1H), 7.53< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(d,J=8.5 Hz,1H),6.75−6.68 (m, 1H),5.29−5.23 (m, 1H),5.19 (s, 1H),4.73 (d, J=6.0 (m, 1H),5.19 (m, 1H),5.19 (m, 1H),5.19 (m, 1H),5.19 (m, 1H),5.19 (m, 1H),<annotation encoding="application / x-tex">(d, J = 8.5 \text{ Hz}, 1\text{H}), 6.75 - 6.68 \text{ (m, 1H)}, 5.29 - 5.23 \text{ (m, 1H)}, 5.19 \text{ (s, 1H)}, 4.73 \text{ (d, } J = 6.0 \text{ (m, 1H)}, 5.19 \text{ (m, 1H)}, 5.19 \text{ (m, 1H)}, 5.19 \text{ (m, 1H)}, 5.19 \text{ (m, 1H)}, 5.19 \text{ (m, 1H)},< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.56−3.44<annotation encoding="application / x-tex">3.56 - 3.44< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.21−3.14<annotation encoding="application / x-tex">3.21 - 3.14< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.05−2.98<annotation encoding="application / x-tex">3.05 - 2.98< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.99−2.92<annotation encoding="application / x-tex">2.99 - 2.92< / annotation>< / semantics>< / com:Math> (m, 1H), 2.88 (dd, <com:Math><semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics>< / com:Math>, 4.5 Hz, 1H), 2.78 – 2.72 (m, 1H), 2.31 – 2.23 (m, 1H), 2.17 – 2.11 (m, 1H), 1.55 – 1.49 (m, 1H), 1.36 – 1.27 (m, 1H), 1.27 – 1.22 (m, 6H), 1.16 – 1.11 (m, 1H). 1H under water. Synthesis 15 (3R,4R)-4-(((7-(((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-015) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-N-((2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methyl)-3- isopropylpyrazolo[1,5-a]pyrimidin-7-amine (2,7-Dimethylimidazo[1,2-a]pyridin-3-yl)methanamine (171 mg, 0.976 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (187 mg, 0.813 mmol) and DIPEA (0.85 mL, 4.874 mmol) in EtOH (3.2 mL). The reaction mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc in isohexane) gave the title compound (233 mg, 0.57 mmol, 70% yield, 90% purity) as an off-white solid. UPLC / MS (Method 6): m / z 369 (M+H)+, R<com:Sub>T< / com:Sub> 0.73 min Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((2,7- dimethylimidazo[1,2-a]pyridin-3-yl)methyl)carbamate BOC-Anhydride (179 mg, 819 µmol) was added to a solution of 5-chloro-N-((2,7- dimethylimidazo[1,2-a]pyridin-3-yl)methyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (233 mg, 0.63 mmol) and DMAP (15.4 mg, 126 µmol) in THF (12.6 mL). The reaction mixture was stirred at 60 °C for 16 min. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (15 mL) and water (10 mL). The organic layer was washed with brine (2 x 10 mL), filtered through a phase separator, and concentrated under reduced pressure. Purification by column chromatography (12) g cartridge, 0-4% MeOH / DCM) gave the title compound (249 mg, 0.50 mmol, 79% yield, 94% purity) as a pale yellow solid. UPLC / MS (Method 6): m / z 469 (M+H)+, R<com:Sub>T< / com:Sub> 0.84 min. 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((2,7- dimethylimidazo[1,2-a]pyridin-3-yl)methyl)carbamate (120 mg, 0.256 mmol), (3R,4R)-tert- butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (64.9 mg, 0.282 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (21.9 mg, 0.0256 mmol) in THF (2.5 mL) was degassed with N2 for 10 min. LiHMDS (1M in THF) (0.33 mL, 333 µmol) was added in one portion under bubbling N2. Bubbling was ceased and the reaction mixture heated to 60 °C for 4.5 h. At RT, the reaction mixture was filtered through celite, rinsing with EtOAc (15 mL). The filtrate was diluted with water and the aqueous was extracted with EtOAc (3 x 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) gave the title compound (89 mg, 0.10 mmol, 39% yield, 75% purity) as a brown oil. UPLC / MS (Method 4): m / z 663 (M+H)+, R<com:Sub>T< / com:Sub> 1.75 min. Step 4: (3R,4R)-4-(((7-((imidazo[1,2-a]pyrimidin-2-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.66 mL, 2.62 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((2,7-dimethylimidazo[1,2-a]pyridin-3- yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (87 mg, 0.131 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was stirred at 35 °C for 2.5 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (60 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (40 mg, 83 mmol, 63% yield, 95%) purity) as a pale yellow solid after precipitation from Et<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 463 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.05 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.51 (d, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.80 (t, <com:Math><semantics>J=5.4<annotation encoding="application / x-tex">J = 5.4< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.59 (s, 1H), 7.21 (s, 1H), <com:Math><semantics>6.85−6.79<annotation encoding="application / x-tex">6.85 - 6.79< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>6.75<annotation encoding="application / x-tex">6.75< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=7.0<annotation encoding="application / x-tex">J = 7.0< / annotation>< / semantics>< / com:Math>, 1.7 Hz, 1H), <com:Math><semantics>5.33−5.28<annotation encoding="application / x-tex">5.33 - 5.28< / annotation>< / semantics>< / com:Math> (m, 1H), 5.17 (s, 1H), 4.73 (d, <com:Math><semantics>J=5.1<annotation encoding="application / x-tex">J = 5.1< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.61 – 3.48 (m, 1H), 3.23 – 3.16 (m, 1H), 3.06 – <com:Math><semantics>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),<annotation encoding="application / x-tex">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),< / annotation>< / semantics>< / com:Math> 2.19 – 2.12 (m, 1H), 1.61 – 1.53 (m, 1H), 1.39 – 1.32 (m, 1H), 1.22 – 1.18 (m, 6H), 1.19 – 1.12 (m, 1H). 1H under water. Intermediate Synthesis A2 (2,7-dimethylimidazo[1,2-a]pyridin-3-yl)methanamine [Image disponible dans le document PDF, Image available in the PDF document] Step A / B: 2,7-dimethylimidazo[1,2-a]pyridine-3-carbaldehyde oxime / (2,7- dimethylimidazo[1,2-a]pyridin-3-yl)methanamine A solution of 2,7-dimethylimidazo[1,2-a]pyridine-3-carbaldehyde (0.525 g, 3.01 mmol), hydroxylamine hydrochloride (0.524 g, 7.54 mmol) and pyridine (0.61 mL, 7.54 mmol) in EtOH (14.8 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then redissolved in AcOH (10.5 mL). The solution was cooled at 0 °C then sodium acetate (50 mg, 604 µmol) and zinc dust (2.96 g, 45.3 mmol) were added. The reaction mixture was stirred at RT overnight before being filtered through celite, rinsing with DCM (100 mL). The filtrate was concentrated to dryness to afford an oil. Filtration through SCX (14 g - wash with MeOH (100 mL), elution with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (100 mL)) gave the title compound (2,7-dimethylimidazo[1,2- a]pyridin-3-yl)methanamine (0.259 g, 1.33 mmol, 44% yield, 90% purity) as a white solid. UPLC / MS (Method 6): m / z 176 (M+H)+, R<com:Sub>T< / com:Sub> 0.42 min. Synthesis 16 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-016) [Image disponible dans le document PDF, Image available in the PDF document] Step1: 5-chloro-N-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin- 7-amine Imidazo[1,2-a]pyridin-3-ylmethanamine, 2HCl (115 mg, 522 µmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 435 µmol) and DIPEA (0.38 mL, 2.17 mmol) in EtOH (1.5 mL). The reaction mixture was heated at reflux overnight. The reaction mixture was concentrated in vacuo 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. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) was consistent with product structure. Step2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin- 3-ylmethyl)carbamate BOC-Anhydride (97 mg, 442 µmol) was added to a solution of 5-chloro-N-(imidazo[1,2- a]pyridin-3-ylmethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (137 mg, 402 µmol) and DMAP (5 mg, 40.2 µmol) in THF (2 mL). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure 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. UPLC / MS (Method 4): m / z 441 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.71 min. Step3: 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2- a]pyridin-3-ylmethyl)carbamate (167 mg, 379 µmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (96.0 mg, 417 µmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (32.4 mg, 37.9 µmol) in THF (3.3 mL) was degassed with N2 for 10 min. LiHMDS (1M in THF) (492 μl, 492 μmol) was added in one portion under bubbling N2. Bubbling was ceased and the reaction mixture heated to 60 °C for 2 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane then 0- 5% (MeOH containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave an oil. Further purification by column chromatography (12 g cartridge, 0-10% (MeOH containing 0.7 M NH<com:Sub>3< / com:Sub>) / DCM) gave the title compound (112 mg, 0.17 mmol, 46% yield, 98% purity) as a yellow oil. UPLC / MS (Method 4): m / z 635 (M+H)+, R<com:Sub>T< / com:Sub> 1.64 min. Step4: (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in 1,4-dioxane) (0.88 mL, 3.53 mmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-3-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (112 mg, 176 µmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 35 for 1 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product eluted with MeOH containing 0.7 M NH<com:Sub>3< / com:Sub> (40 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (57 mg, 0.13 mmol, 73% yield, 98% purity) as a white solid after precipitation from Et<com:Sub>2< / com:Sub>O. UPLC / MS (Method 4): m / z 435 (M+H)+, R<com:Sub>T< / com:Sub> 0.97 min. <com:Sup>1< / com:Sup>H NMR (500 MHz, DMSO-d<com:Sub>6< / com:Sub>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.48 (dd, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8, 1.2 Hz, 1H), 7.78 (s, 1H), 7.65 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.1 Hz, 1H), 7.63 (s, 1H), 7.50 (d, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.24 <com:Math><semantics>−7.18<annotation encoding="application / x-tex">- 7.18< / annotation>< / semantics>< / com:Math> (m, 1H), 6.85 (td, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), <com:Math><semantics>6.75−6.69<annotation encoding="application / x-tex">6.75 - 6.69< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.33−5.29<annotation encoding="application / x-tex">5.33 - 5.29< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.28<annotation encoding="application / x-tex">5.28< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>4.56<annotation encoding="application / x-tex">4.56< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=6.0<annotation encoding="application / x-tex">J = 6.0< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.60−3.47<annotation encoding="application / x-tex">3.60 - 3.47< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.22−3.15<annotation encoding="application / x-tex">3.22 - 3.15< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.06−2.99<annotation encoding="application / x-tex">3.06 - 2.99< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.99−2.92<annotation encoding="application / x-tex">2.99 - 2.92< / annotation>< / semantics>< / com:Math> (m, 1H), 2.90 (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 4.5 Hz, 1H), 2.81 – 2.74 (m, 1H), 2.33 – 2.25 (m, 1H), 2.15 (dd, <com:Math><semantics>J=<annotation encoding="application / x-tex">J =< / annotation>< / semantics>< / com:Math> 11.6, 9.9 Hz, 1H), <com:Math><semantics>1.57−1.51<annotation encoding="application / x-tex">1.57 - 1.51< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.38−1.28<annotation encoding="application / x-tex">1.38 - 1.28< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.23<annotation encoding="application / x-tex">1.23< / annotation>< / semantics>< / com:Math> (t, <com:Math><semantics>J=6.5<annotation encoding="application / x-tex">J = 6.5< / annotation>< / semantics>< / com:Math> Hz, 6H), <com:Math><semantics>1.19<annotation encoding="application / x-tex">1.19< / annotation>< / semantics>< / com:Math> - 1.10 (m, 1H). 1H under water. Synthesis 17 (3R,4R)-4-(((3-isopropyl-7-(((3-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-017) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] Step1: 5-chloro-3-isopropyl-N-((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5- a]pyrimidin-7-amine (3-Methylimidazo[1,2-a]pyridin-2-yl)methanamine (105 mg, 652 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (150 mg, 652 µmol) and DIPEA (0.85 mL, 4.89 ) in EtOH (3.2 mL). The reaction mixture was heated at 80 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (130 mg, 0.31 mmol, 48% yield, 85% purity) as a yellow solid. UPLC / MS (Method 4): m / z 355 (M+H)+, R<com:Sub>T< / com:Sub> 1.48 min Step2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-methylimidazo[1,2- a]pyridin-2-yl)methyl)carbamate BOC-Anhydride (32 mg, 0.15 mmol) was added to a solution of 5-chloro-3-isopropyl-N- ((3-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (44 mg, 0.12 mmol) and DMAP (3 mg, 25 µmol) in THF (1.2 mL). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure. Purification N<com:Sub>2< / com:Sub> 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. UPLC / MS (Method 4): m / z 455 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.80 min. Step3: 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3- methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (88 mg, 0.19 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (49 mg, 0.21 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (17 mg, 19 µmol) in THF (1.9 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (0.25 mL, 0.25 mmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 1.5 h. 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) gave the title compound (140 mg, 0.18 mmol, 95% yield, 85% purity) as a brown oil. UPLC / MS (Method 4): m / z 649 (M+H)+, R<com:Sub>T< / com:Sub> 1.69 min. Step4: ((3R,4R)-4-(((3-isopropyl-7-(((3-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.02 mL, 4.10 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (140 mg, 205 µmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35 °C for 1.5 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (50 mL). The ammoniacal methanol 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<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 449 (M+H)+, R<com:Sub>T< / com:Sub> 1.02 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.23 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.9 Hz, 1H), 7.61 (s, 1H), 7.53 – 7.49 (m, 1H), 7.44 (t, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.26 <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> 7.17 (m, 1H), 6.93 (td, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), 6.80 <com:Math><semantics>−<annotation encoding="application / x-tex">-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>6.74 (m, 1H)<annotation encoding="application / x-tex">6.74 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.39 (s, 1H)<annotation encoding="application / x-tex">5.39 \text{ (s, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>5.35−5.31 (m, 1H)<annotation encoding="application / x-tex">5.35 - 5.31 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.55 (d, J=5.7 Hz, 2H)<annotation encoding="application / x-tex">4.55 \text{ (d, } J = 5.7 \text{ Hz, 2H)}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>3.61−3.47 (m, 1H)<annotation encoding="application / x-tex">3.61 - 3.47 \text{ (m, 1H)}< / annotation>< / semantics>< / com:Math> 1H), <com:Math><semantics>3.24−3.15<annotation encoding="application / x-tex">3.24 - 3.15< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.08−2.99<annotation encoding="application / x-tex">3.08 - 2.99< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.99−2.86<annotation encoding="application / x-tex">2.99 - 2.86< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.82−2.74<annotation encoding="application / x-tex">2.82 - 2.74< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.35−2.24<annotation encoding="application / x-tex">2.35 - 2.24< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>9.9<annotation encoding="application / x-tex">9.9< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.61−1.52<annotation encoding="application / x-tex">1.61 - 1.52< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.40−1.29<annotation encoding="application / x-tex">1.40 - 1.29< / annotation>< / semantics>< / com:Math> (m, 1H), 1.22 (dd, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, 5.0 Hz, 6H), 1.19 – 1.13 (m, 1H). 4H not visible. Intermediate Synthesis A3 3-methylimidazo[1,2-a]pyridin-2-yl)methanamine [Image disponible dans le document PDF, Image available in the PDF document] Step A / B: 3-methylimidazo[1,2-a]pyridine-2-carbaldehyde oxime / (3-methylimidazo[1,2-a]pyridin-2-yl)methanamine A suspension of 3-methylimidazo[1,2-a]pyridine-2-carbaldehyde (500 mg, 3.12 mmol), hydroxylamine hydrochloride (542 mg, 7.80 mmol) and pyridine (0.63 mL, 7.80 mmol) in EtOH (5.0 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure then redissolved in AcOH (5.0 mL). The solution was cooled at 0 °C then sodium acetate (51 mg, 616 µmol) and zinc dust (2.02 g, 30.8 mmol) were added. The reaction mixture was stirred at RT overnight before being filtered through celite, rinsing with DCM (50 mL) and MeOH (50 mL). The filtrate was concentrated to dryness to afford an oil. Filtration through SCX (14 g - wash with MeOH (50 mL), elution with MeOH containing 0.7M NH<com:Sub>3< / com:Sub> (50 mL)) gave the title compound (371 mg, 2.2 mmol, 71% yield, 95% purity) as a white solid. <com:Sup>1< / com:Sup>H NMR in DMSO-d6 was consistent with product structure. Synthesis 18 (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-018) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-N-(imidazo[1,2-a]pyridin-2-ylmethyl-d2)-3-isopropylpyrazolo[1,5- a]pyrimidin-7-amine Imidazo[1,2-a]pyridin-2-ylmethan-d2-amine (102 mg, 684 µmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (157 mg, 684 µmol) and DIPEA (0.89) mL, 893 µmol) in EtOH (7.0 mL). The reaction mixture was heated at 80 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (180 mg, 0.50 mmol, 73% yield, 95% purity) as a white solid. UPLC / MS (Method 4): m / z 345 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.36 min. Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2-a]pyridin- 2-ylmethyl-d2)carbamate BOC-Anhydride (131 mg, 599 µmol) was added to a solution of 5-chloro-N-(imidazo[1,2- a]pyridin-2-ylmethyl-d2)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (180 mg, 499 µmol) and DMAP (12 mg, 99.8 µmol) in THF (5.0 mL). The reaction mixture was stirred at RT for 2 h. 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. UPLC / MS (Method 4): m / z 445 (M+H)+, R<com:Sub>T< / com:Sub> 1.72 min. 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(imidazo[1,2- a]pyridin-2-ylmethyl-d2)carbamate (184 mg, 415 µmol), (3R,4R)-tert-butyl 4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (105 mg, 457 µmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (35.5 mg, 41.5 µmol) in THF (1.9 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (540 μL, 540 μmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 1.5 h. 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. UPLC / MS (Method 4): m / z 637 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.64 min. Step 4: (3R,4R)-4-(((7-((imidazo[1,2-a]pyridin-2-ylmethyl-d2)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.79 mL, 3.14 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(imidazo[1,2-a]pyridin-2-ylmethyl- d2)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1- carboxylate (100 mg, 157 µmol) in dioxane (1.0 mL). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product eluted with 0.7 M NH₃ in MeOH (50 mL). The ammoniacal methanol 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<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 437 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.03 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.48 (dt, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8, 1.3 Hz, 1H), 7.78 (s, 1H), 7.63 (s, 2H), 7.50 (d, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.20 (m, 1H), 6.85 (td, <com:Math><semantics>J=6.8<annotation encoding="application / x-tex">J = 6.8< / annotation>< / semantics>< / com:Math>, 1.2 Hz, 1H), 6.76 – 6.68 (m, 1H), <com:Math><semantics>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<annotation encoding="application / x-tex">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< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.34−2.23<annotation encoding="application / x-tex">2.34 - 2.23< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.14<annotation encoding="application / x-tex">2.14< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=11.5<annotation encoding="application / x-tex">J = 11.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>10.0<annotation encoding="application / x-tex">10.0< / annotation>< / semantics>< / com:Math> Hz, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.58−1.49<annotation encoding="application / x-tex">1.58 - 1.49< / annotation>< / semantics>< / com:Math> (m, <com:Math><semantics>1H<annotation encoding="application / x-tex">1H< / annotation>< / semantics>< / com:Math>), <com:Math><semantics>1.37−1.49<annotation encoding="application / x-tex">1.37 - 1.49< / annotation>< / semantics>< / com:Math> 1.27 (m, 1H), 1.23 (dd, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, 4.9 Hz, 6H), 1.19 – 1.11 (m, 1H). 1H under water. Intermediate Synthesis A4 Imidazo[1,2-a]pyridin-2-ylmethan-d2-amine [Image disponible dans le document PDF, Image available in the PDF document] Step A: imidazo[1,2-a]pyridin-2-ylmethan-d2-ol Lithium aluminium 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 for 15 min at 0 °C then water (0.1 mL) was added followed by 2M aq. NaOH solution (0.1 mL) then water (0.3 mL). The solution was warmed to RT, stirred for 15 min then anhydrous MgSO<com:Sub>4< / com:Sub> was added and the mixture was stirred for a further 15 min. The mixture was concentrated under reduced pressure. 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. UPLC / MS (Method 4): m / z 151 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 0.47 min. Step B: 2-(chloromethyl-d2)imidazo[1,2-a]pyridine, HCl Thionyl chloride (205 µL, 2.81 mmol) was added dropwise to a solution of imidazo[1,2- a]pyridin-2-ylmethan-d2-ol (211 mg, 1.40 mmol) in DCM (14 mL) at 0 °C. The mixture was stirred at 0 °C for 2 h 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. UPLC / MS (Method 3): m / z 169 (M+H)+, R<com:Sub>T< / com:Sub> 0.16 min. Step C: 2-(azidomethyl-d2)imidazo[1,2-a]pyridine A solution of 2-(chloromethyl-d2)imidazo[1,2-a]pyridine, HCl (278 mg, 1.36 mmol) and DIPEA (708 µL, 4.07 mmol) in DMF (14 mL) was treated with sodium azide (132 mg, 2.03 mmol). The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to RT, diluted with water (100 mL). Extraction with TBME (3 x 25 mL). The combined organic layers were dried over MgSO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by chromatography (12 g cartridge,0-100% (3:1) EtOAc / EtOH) / isohexane) gave the title compound (150 mg, 0.66 mmol, 49% yield, 77% purity) as a yellow oil. UPLC / MS (Method 4): m / z 176 (M+H)+, R<com:Sub>T< / com:Sub> 0.77 min. Step D: imidazo[1,2-a]pyridin-2-ylmethan-d2-amine 2-(Azidomethyl-d2)imidazo[1,2-a]pyridine (150 mg, 659 µmol) and triphenylphosphine (208 mg, 791 µmol) were dissolved in THF (8.0 mL) and water (0.8 mL). The mixture was heated to 50 °C and stirred for 1 h before removal of the solvent in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (102 mg, 0.65 mmol, 99% yield, 95%) purity) as a white solid. <com:Sup>1< / com:Sup>H NMR in DMSO-d<com:Sub>6< / com:Sub> was consistent with product structure. Synthesis 19 (3R,4R)-4-(((7-((1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-019) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-N-(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)-3-isopropylpyrazolo[1,5- a]pyrimidin-7-amine 1-(Imidazo[1,2-a]pyridin-2-yl)ethan-1-amine (133 mg, 782 µmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 435 µmol) and DIPEA (0.38 mL, 2.17 mmol) in EtOH (3.0 mL). The reaction mixture was heated at 90 °C for 1 h. The reaction mixture was concentrated in vacuo. Purification by chromatography (12 g cartridge,0-100% EtOAc / isohexane) gave the title compound (158 mg, 0.42 mmol, 97% yield, 95% purity) as a white solid. UPLC / MS (Method 4): m / z 355 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.47 min. Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(1-(imidazo[1,2- a]pyridin-2-yl)ethyl)carbamate BOC-Anhydride (136 mg, 623 µmol) was added to a solution of 5-chloro-N-(1- (imidazo[1,2-a]pyridin-2-yl)ethyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (158 mg, 445 µmol) and DMAP (5.4 mg, 44.5 µmol) in THF (2.5 mL). The reaction mixture was stirred at 50 °C overnight. More BOC-Anhydride (136 mg, 623 µmol) was added and the reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (171 mg, 0.36 mmol, 80% yield, 95% purity) as a yellow oil. UPLC / MS (Method 3): m / z 455 (M+H)+, R<com:Sub>T< / com:Sub> 1.79 min. 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(1-(imidazo[1,2- a]pyridin-2-yl)ethyl)carbamate (171 mg, 376 µmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (95 mg, 413 µmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (32 mg, 37.6 μmol) in THF (3.2 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (0.49 mL, 489 µmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 2 h. At RT, water (15 mL) and EtOAc (25 mL) were added. The layers were separated, and the aq. layer extracted with EtOAc (2 x 15 mL). The combined organic layers were filtered through a phase separator and concentrated. Purification by column chromatography (12 g cartridge, 0-10% MeOH / DCM) gave the title compound (168 mg, 0.24 mmol, 64% yield, 93% purity) as a yellow oil. UPLC / MS (Method 4): m / z 649 (M+H)+, R<com:Sub>T< / com:Sub> 1.68 min. Step 4: (3R,4R)-4-(((7-((1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (1.17 mL, 4.69 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(1-(imidazo[1,2-a]pyridin-2-yl)ethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (160 mg, 234 µmol) in dioxane (1.2 mL). The reaction mixture was stirred at 35 °C for 1 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (40 mL). The ammoniacal methanol 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<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 449 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.02 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.49 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.8 Hz, 1H), 7.80 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 4.9 Hz, 1H), 7.62 (s, 1H), 7.52 (d, <com:Math><semantics>J=9.1<annotation encoding="application / x-tex">J = 9.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.26 – 7.18 (m, 1H), 7.13 (d, <com:Math><semantics>J=7.8<annotation encoding="application / x-tex">J = 7.8< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.85 (t, <com:Math><semantics>J=6.7<annotation encoding="application / x-tex">J = 6.7< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>6.76−6.68<annotation encoding="application / x-tex">6.76 - 6.68< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>5.32<annotation encoding="application / x-tex">5.32< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=2.0<annotation encoding="application / x-tex">J = 2.0< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>5.31−5.23<annotation encoding="application / x-tex">5.31 - 5.23< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>4.87−4.81<annotation encoding="application / x-tex">4.87 - 4.81< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,1H),3.60−3.43(m,1H),3.27−3.17(m,1H),3.08−2.98(m,1H),2.99−2.86(m,1H)<annotation encoding="application / x-tex">(m, 1H), 3.60 - 3.43 (m, 1H), 3.27 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1H), 2.99 - 2.86 (m, 1H)< / annotation>< / semantics>< / com:Math> 2H), <com:Math><semantics>2.82−2.73<annotation encoding="application / x-tex">2.82 - 2.73< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.35−2.25<annotation encoding="application / x-tex">2.35 - 2.25< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.16<annotation encoding="application / x-tex">2.16< / annotation>< / semantics>< / com:Math> (td, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>4.3<annotation encoding="application / x-tex">4.3< / annotation>< / semantics>< / com:Math> Hz, 1H), <com:Math><semantics>1.66<annotation encoding="application / x-tex">1.66< / annotation>< / semantics>< / com:Math> (d, <com:Math><semantics>J=10.8<annotation encoding="application / x-tex">J = 10.8< / annotation>< / semantics>< / com:Math>) 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 under water. Intermediate Synthesis A5 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-amine [Image disponible dans le document PDF, Image available in the PDF document] Step A: 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-ol Methylmagnesium bromide (3M in Et<com:Sub>2< / com:Sub>O) (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 RT and stirred overnight. Water (50 mL) was added and the aq. layer was extracted with EtOAc (3 x 50 mL). The combined organic layer was collected, dried over sodium sulfate, filtered and concentrated in vacuo to give the title (350 mg, 2.1 mmol, 61% yield, 96% purity) as a white solid. UPLC / MS (Method 3): m / z 163 (M+H)+, R<com:Sub>T< / com:Sub> 0.15 min. Step B: 2-(1-chloroethyl)imidazo[1,2-a]pyridine, HCl Thionyl chloride (675 µL, 9.25 mmol) was added dropwise to a solution of 1-(imidazo[1,2- a]pyridin-2-yl)ethan-1-ol (300 mg, 1.85 mmol) in DCE (5.0 mL) at RT. The mixture was stirred at 45 °C for 3 h then concentrated to dryness under reduced pressure to give the title compound (300 mg, 1.4 mmol, 74% yield, 82% purity) as a colourless oil. UPLC / MS (Method 3): m / z 181 (M+H)+, R<com:Sub>T< / com:Sub> 0.15 min. Step C: 2-(1-azidoethyl)imidazo[1,2-a]pyridine A solution of 2-(1-chloroethyl)imidazo[1,2-a]pyridine, HCl (200 mg, 921 µmol) and DIPEA (390 μL, 2.76 mmol) in DMF (14 mL) was treated with sodium azide (90 mg, 1.38 mmol). The mixture was heated to 60 °C and stirred for 6 h. The mixture was cooled to RT, diluted with water (40 mL) and brine (60 mL). Extraction with TBME (3 x 50 mL) and EtOAc (50 mL). The combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by chromatography (12 g cartridge,0- 100% EtOAc / isohexane) gave the title compound (190 mg, 0.81 mmol, 88% yield, 80% purity) as a brown oil. UPLC / MS (Method 4): m / z 188 (M+H)+, R<com:Sub>T< / com:Sub> 0.90 min. Step D: 1-(imidazo[1,2-a]pyridin-2-yl)ethan-1-amine 2-(1-Azidoethyl)imidazo[1,2-a]pyridine (190 mg, 913 µmol) and triphenylphosphine (287 mg, 1.10 mmol) were dissolved in THF (4.5 mL) and water (0.5 mL). The mixture was stirred at RT for 1 h then at 50 °C and stirred for 1 h before removal of the solvent in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (144 mg, 0.85 mmol, 93% yield, 95% purity) as a yellow oil. UPLC / MS (Method 4): m / z 162 (M+H)+, R<com:Sub>T< / com:Sub> 0.48 min. Synthesis 20 (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol (H-APPAMP-020) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: N-(benzofuran-2-ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine Benzofuran-2-ylmethanamine hydrochloride (100 mg, 0.547 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (105 mg, 0.456 mmol) and DIPEA (0.48 mL, 2.74 mmol) in EtOH (1.9 mL). The reaction mixture was heated at 90 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-30% EtOAc / heptane) gave the title compound (157 mg, 0.42 mmol, 91% yield, 90% purity) as a yellow oil. UPLC / MS (Method 4): m / z 341 (M+H)+, R<com:Sub>T< / com:Sub> 1.82 min Step 2: tert-butyl (benzofuran-2-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7- yl)carbamate BOC-Anhydride (109 mg, 0.498 mmol) was added to a solution of N-(benzofuran-2- ylmethyl)-5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (157 g, 0.415 mmol) and DMAP (10 mg, 83 µmol) in THF (8.0 mL). The reaction mixture was stirred at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (15 mL) and water (30 mL). The aq. layer was extracted with DCM (2 x 30 mL) and the combined organic layers were washed with brine (30 mL), filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-20% EtOAc / isohexane) gave the title compound (164 mg, 0.37 mmol, 89% yield, 99% purity) as a cream solid. UPLC / MS (Method 4): m / z 385 (M+H-tBu)+, R<com:Sub>T< / com:Sub> 2.10 min. 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 A solution of tert-butyl (benzofuran-2-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (164mg, 0.372 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (94 mg, 0.409 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (31.8 mg, 37.2 <com:Math><semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>< / com:Math>mol) in THF (3.6 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (0.48 mL, 0.48 mmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 2 h. At RT, the mixture was filtered through celite, rinsing with EtOAc (15 mL). The filtrate was washed with water (15 mL) and the aq. layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (235 mg, 0.33 mmol, 89 yield, 90% purity) as an orange solid. UPLC / MS (Method 4): m / z 635 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.96 min. Step 4: (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)amino)-3-isopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (2.0 mL, 8.0 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((benzofuran-2-ylmethyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (233 mg, 0.367 mmol) in dioxane (2.5 mL). The reaction mixture was stirred at 35 °C for 2 h then more 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 h then concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (20) mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (88 mg, 0.20 mmol, 54%) yield, 97% purity) as a beige solid after trituration from Et<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 4): m / z 435 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.37 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 7.81 (t, <com:Math><semantics>J=6.3<annotation encoding="application / x-tex">J = 6.3< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.63 (s, 1H), 7.58 (dd, <com:Math><semantics>J=7.5<annotation encoding="application / x-tex">J = 7.5< / annotation>< / semantics>< / com:Math>, 1.6 Hz, 1H), 7.53 (d, <com:Math><semantics>J=8.0<annotation encoding="application / x-tex">J = 8.0< / annotation>< / semantics>< / com:Math> Hz, 1H), 7.30 – 7.17 (m, 2H), 6.78 (s, 1H), 6.74 (t, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.37 (s, 1H), 5.28 – 5.20 (m, 1H), 4.62 (d, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.56−3.45<annotation encoding="application / x-tex">3.56 - 3.45< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.27<annotation encoding="application / x-tex">3.27< / annotation>< / semantics>< / com:Math> <com:Math><semantics>−3.17<annotation encoding="application / x-tex">-3.17< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.08−2.98<annotation encoding="application / x-tex">3.08 - 2.98< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.98−2.87<annotation encoding="application / x-tex">2.98 - 2.87< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>2.82−2.72<annotation encoding="application / x-tex">2.82 - 2.72< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.36−2.23<annotation encoding="application / x-tex">2.36 - 2.23< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(m,1H),2.15(dd,J=11.5,10.0Hz,1H),1.62−1.52(m,1H),1.39−1.29(m,1H),1.23<annotation encoding="application / x-tex">(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< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(dd,J=6.9,4.7Hz,6H),1.18−1.09(m,1H).1Hunderwater<annotation encoding="application / x-tex">(dd, J = 6.9, 4.7 Hz, 6H), 1.18 - 1.09 (m, 1H). 1H under water< / annotation>< / semantics>< / com:Math> Synthesis 21 (3R,4R)-4-(((3-isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol (H-APPAMP-021) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-3-isopropyl-N-(quinolin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine Quinolin-3-ylmethanamine dihydrochloride (121 mg, 0.522 mmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5-a]pyrimidine (100 mg, 0.435 mmol) and DIPEA (0.68 mL, 3.92 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 90 °C overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (20 mL) and aq. sat. NaHCO<com:Sub>3< / com:Sub> (10 mL). The organic layer was washed with aq. sat. NaHCO<com:Sub>3< / com:Sub> (3 x 10 mL), filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (80 g cartridge, 0-30% EtOAc / isohexane) gave the title compound (109 mg, 0.29 mmol, 66% yield, 93% purity) as a yellow solid. UPLC / MS (Method 3): m / z 352 (M+H)+, R<com:Sub>T< / com:Sub> 1.56 min Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3- ylmethyl)carbamate BOC-Anhydride (80 mg, 0.368 mmol) was added to a solution of 5-chloro-3-isopropyl-N- (quinolin-3-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (108 mg, 0.307 mmol) and DMAP (7.5 mg, 61.4 μmol) in THF (6.0 mL). The reaction mixture was stirred at 65 °C for 2.5 h. More BOC-Anhydride (34 mg, 0.154 mmol) was added and the reaction mixture was stirred at 65 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure and the residue partitioned between DCM (15 mL) and water (30 mL). The aq. layer was extracted with DCM (2 x 30 mL) and the combined organic layers were washed with brine (30 mL), filtered through a phase separator and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc / isohexane) gave the title compound (143 mg, 0.29 mmol, 94% yield, 91% purity) as a yellow oil. UPLC / MS (Method 4): m / z 452 (M+H)+, R<com:Sub>T< / com:Sub> 1.91 min. 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 A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(quinolin-3- ylmethyl)carbamate (139 mg, 0.308 mmol), (3R,4R)-tert-butyl 4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (78 mg, 0.339 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (26.3 mg, 30.8 µmol) in THF (3.0 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (399 μl, 0.399 mmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 1.5 h. At RT, the mixture was filtered through celite, rinsing with EtOAc (15 mL). The filtrate was washed with water (15 mL) and the aq. layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100%) EtOAc / isohexane) gave the title compound (146 mg, 0.18 mmol, 67% yield, 80% purity) as a brown oil. UPLC / MS (Method 4): m / z 646 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.80 min. Step 4: (3R,4R)-4-(((3-isopropyl-7-((quinolin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.90 mL, 3.60 mmol) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(quinolin-3-ylmethyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (116 mg, 0.18 mmol) in dioxane (2.6 mL). The reaction mixture was stirred at 35 °C for 3 h. More 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 h then concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product eluted with 0.7 M NH<com:Sub>3< / com:Sub> in MeOH (60 mL). The ammoniacal methanol 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<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 3): m / z 446 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 0.67 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.96 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 2.2 Hz, 1H), 8.24 (s, 1H), 8.07 – 7.99 (m, 2H), <com:Math><semantics>7.99−7.95<annotation encoding="application / x-tex">7.99 - 7.95< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>7.80−7.71<annotation encoding="application / x-tex">7.80 - 7.71< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>7.66<annotation encoding="application / x-tex">7.66< / annotation>< / semantics>< / com:Math> (s, 1H), <com:Math><semantics>7.60<annotation encoding="application / x-tex">7.60< / annotation>< / semantics>< / com:Math> (ddd, <com:Math><semantics>J=1.2<annotation encoding="application / x-tex">J = 1.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>6.8<annotation encoding="application / x-tex">6.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>8.1<annotation encoding="application / x-tex">8.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 6.66 (t, <com:Math><semantics>J=6.1<annotation encoding="application / x-tex">J = 6.1< / annotation>< / semantics>< / com:Math> Hz, 1H), 5.23 (s, 2H), 4.68 (d, <com:Math><semantics>J=6.2<annotation encoding="application / x-tex">J = 6.2< / annotation>< / semantics>< / com:Math> Hz, 2H), 3.59 <com:Math><semantics>−3.41<annotation encoding="application / x-tex">- 3.41< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.22−3.13<annotation encoding="application / x-tex">3.22 - 3.13< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.05−2.84<annotation encoding="application / x-tex">3.05 - 2.84< / annotation>< / semantics>< / com:Math> (m, 3H), <com:Math><semantics>2.79−2.70<annotation encoding="application / x-tex">2.79 - 2.70< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.30−2.21<annotation encoding="application / x-tex">2.30 - 2.21< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>2.18−2.05<annotation encoding="application / x-tex">2.18 - 2.05< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.59−1.46<annotation encoding="application / x-tex">1.59 - 1.46< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.37−1.26<annotation encoding="application / x-tex">1.37 - 1.26< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>1.23<annotation encoding="application / x-tex">1.23< / annotation>< / semantics>< / com:Math> (dd, <com:Math><semantics>J=5.3<annotation encoding="application / x-tex">J = 5.3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>6.9<annotation encoding="application / x-tex">6.9< / annotation>< / semantics>< / com:Math> Hz, 6H), 1.17 – 1.04 (m, 1H). 1H under water. Synthesis 22 (3R,4R)-4-(((3-cyclopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol (H-APPAMP-022) [Image disponible dans le document PDF, Image available in the PDF document] Step 1: 5-chloro-3-cyclopropyl-N-((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (8-Methylimidazo[1,2-a]pyridin-2-yl)methanamine, 2HCl (101 mg, 0.432 mmol) was added to a solution of 5,7-dichloro-3-cyclopropylpyrazolo[1,5-a]pyrimidine (83.0 mg, 0.364) mmol) and DIPEA (0.57 mL, 3.28 mmol) in EtOH (2.0 mL). The reaction mixture was heated at 65 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue was diluted with DCM (20 mL) then the solution washed with aq. sat. NaHCO<com:Sub>3< / com:Sub> (20 mL) then brine (20 mL). The organic layer was filtered through a phase separator and concentrated under reduced pressure to give the title compound (129 mg, 0.36 mmol, 99% yield, 99% purity) as an off-white solid. UPLC / MS (Method 5): m / z 353 (M+H)+, R<com:Sub>T< / com:Sub> 1.37 min Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((8- methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate BOC-Anhydride (94.50 mg, 0.433 mmol) was added to a solution of 5-chloro-3- cyclopropyl-N-((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7- amine (128.6 mg, 0.361 mmol) and DMAP (8.8 mg, 0.072 mmol) in THF (10 mL). The reaction mixture was stirred at 65 °C for 3 h then more BOC-Anhydride (94.50 mg, 0.433 mmol). The reaction mixture was stirred at 65 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with DCM (20 mL). The solution was washed with water (15 mL) then brine (15 mL). The organic layer was filtered through a phase separator 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. UPLC / MS (Method 5): m / z 452 (M+H)+, R<com:Sub>T< / com:Sub> 1.73 min. 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 A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((8- methylimidazo[1,2-a]pyridin-2-yl)methyl)carbamate (150.2 mg, 0.332 mmol), (3R,4R)-tert- butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (84.02 mg, 0.3645 mmol) and <com:Sup>t< / com:Sup>BuBrettPhos Pd G3 (28.33 mg, 0.033 mmol) in THF (3.2 mL) was degassed with N<com:Sub>2< / com:Sub> for 10 min. LiHMDS (1M in THF) (0.37 g, 0.431 mL, 431.1 µmol) was added in one portion under bubbling N<com:Sub>2< / com:Sub>. Bubbling was ceased and the reaction mixture heated to 60 °C for 1.5 h. At RT, the reaction mixture was filtered through celite and washed with EtOAc (15) mL). The filtrate was diluted with water and the aq. layer was extracted with EtOAc (3 x 20 mL), dried over Na<com:Sub>2< / com:Sub>SO<com:Sub>4< / com:Sub> and concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (3:1 EtOAc / EtOH) / isohexane) gave the title compound (221 mg, 0.30 mmol, 92% yield, 89% purity) as a beige solid. UPLC / MS (Method 5): m / z 647 (M+H)+, <com:Math><semantics>RT<annotation encoding="application / x-tex">R_T< / annotation>< / semantics>< / com:Math> 1.62 min. Step 4: (3R,4R)-4-(((3-cyclopropyl-7-(((8-methylimidazo[1,2-a]pyridin-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol TFA (0.6 mL) was added to a suspension of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((8-methylimidazo[1,2-a]pyridin-2-yl)methyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (77 mg, 0.115 mmol) in DCM (2.4 mL). The reaction mixture was stirred at RT for 18 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product eluted with 0.7 M NH₃ in MeOH (50 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (42 mg, 90 µmol, 78% yield, 95% purity) as a white solid after trituration from Et<com:Sub>2< / com:Sub>O and drying overnight at 40 °C under vacuum. UPLC / MS (Method 5): m / z 447 (M+H)+, R<com:Sub>T< / com:Sub> 1.09 min. <com:Sup>1< / com:Sup>H NMR (400 MHz, DMSO-<com:Math><semantics>d6<annotation encoding="application / x-tex">d_6< / annotation>< / semantics>< / com:Math>) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math> 8.32 (d, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.7 Hz, 1H), 7.73 (s, 1H), 7.64 (t, <com:Math><semantics>J<annotation encoding="application / x-tex">J< / annotation>< / semantics>< / com:Math> = 6.1 Hz, 1H), 7.52 (s, 1H), 7.01 (dt, <com:Math><semantics>J=6.9<annotation encoding="application / x-tex">J = 6.9< / annotation>< / semantics>< / com:Math>, 1.3 Hz, 1H), <com:Math><semantics>6.78−6.69<annotation encoding="application / x-tex">6.78 - 6.69< / annotation>< / semantics>< / com:Math> (m, 2H), <com:Math><semantics>5.36−5.30<annotation encoding="application / x-tex">5.36 - 5.30< / annotation>< / semantics>< / com:Math> (m, 1H), 5.27 (s, 1H), 4.56 (d, <com:Math><semantics>J=5.8<annotation encoding="application / x-tex">J = 5.8< / annotation>< / semantics>< / com:Math> Hz, 2H), <com:Math><semantics>3.57−3.46<annotation encoding="application / x-tex">3.57 - 3.46< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.25−3.15<annotation encoding="application / x-tex">3.25 - 3.15< / annotation>< / semantics>< / com:Math> (m, 1H), <com:Math><semantics>3.10−3.15<annotation encoding="application / x-tex">3.10 - 3.15< / annotation>< / semantics>< / com:Math> 2.97 (m, 1H), 2.91 (dd, <com:Math><semantics>J=11.6<annotation encoding="application / x-tex">J = 11.6< / annotation>< / semantics>< / com:Math>, 4.5 Hz, 1H), 2.83 – 2.73 (m, 1H), 2.47 (s, 3H), 2.35 – 2.24 (m, 1H), 2.20 – 2.12 (m, 1H), 1.78 – 1.67 (m, 1H), 1.61 – 1.51 (m, 1H), 1.40 – 1.26 (m, 1H), 1.22 – 1.11 (m, 1H), 0.79 – 0.73 (m, 2H), 0.70 – 0.59 (m, 2H). 1H under water. Synthesis 23 (3R,4R)-4-(((3-isopropyl-7-(((3-(trifluoromethyl)imidazo[1,2-a]pyridin-2- yl)meth...

Claims

1. A compound of the following formula: [Image disponible dans le document PDF, Image available in the PDF document] or a pharmaceutically acceptable salt or solvate thereof; wherein: -R 7 is 2-imidazo[1,2-a]pyridinyl, and is optionally substituted on carbon with one or more groups -R SC ; each -R SC is independently -R TT , -F, -Cl, -Br, -I, -OH, -OR TT , -CF 3 , -CHF 2 , -OCF 3 , or -OCHF 2 ; each -R TT is independently -R TT1 or -R TT2 ; each -R TT1 is independently linear or branched saturated C 1-6 alkyl; each -R TT2 is saturated C 3-6 cycloalkyl; -L 7 - is -CH 2 -; and -R 3 is saturated C 3-7 cycloalkyl.

2. The compound according to claim 1, wherein: each -R SC , if present, is independently -R TT , -F, -Cl, -Br, or -I.

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

4. The compound according to claim 1 or 2, wherein: each -R TT1 , if present, is -Me.

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

6. The compound according to any one of claims 1-4, wherein: each -R TT2 , if present, is cyclopropyl.

7. The compound according to any one of claims 1-6, wherein: -R 3 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

8. The compound according to any one of claims 1-6, wherein: -R 3 is independently cyclopropyl or cyclobutyl.

9. The compound according to any one of claims 1-6, wherein: -R 3 is cyclopropyl.

10. The compound according to claim 1, which is a compound having one of the following formulae, or pharmaceutically acceptable salt or solvate thereof: [Image disponible dans le document PDF, Image available in the PDF document] - [Image disponible dans le document PDF, Image available in the PDF document]11. A composition comprising the compound according to any one of claims 1-10, and a pharmaceutically acceptable carrier or diluent.

12. A method of preparing a composition comprising the step of mixing the compound according to any one of claims 1-10, and a pharmaceutically acceptable carrier or diluent.

13. A method of inhibiting cyclin-dependent protein kinase function in a cell, in vitro, comprising contacting the cell with an effective amount of the compound according to any one of claims 1-10.

14. A method of inhibiting cyclin-dependent protein kinase 12 function in a cell, in vitro, comprising contacting the cell with an effective amount of the compound according to any one of claims 1-10.

15. The compound according to any one of claims 1-10 for use to treat a proliferative disorder; cancer; a viral infection; a neurodegenerative disorder; ischaemia; a renal disease; a cardiovascular disorder; an autoimmune disorder; or a disorder caused by dysfunction of translation in cells.

16. The compound according to any one of claims 1-10 for use to treat a proliferative disorder.

17. The compound according to any one of claims 1-10 for use to treat cancer.

18. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a further active agent which is an aromatase inhibitor.

19. The compound for use according to claim 18, wherein: the aromatase inhibitor is exemestane, letrozole, or anastrozole.

20. The compound for use according to claim 18 or 19, wherein: the disorder is breast cancer.

21. The compound for use according to claim 18 or 19, wherein: the disorder is breast cancer which is resistant to said aromatase inhibitor.

22. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a further active agent which is an anti-estrogen.

23. The compound for use according to claim 22, wherein: the anti-estrogen is faslodex, tamoxifen, or hydroxytamoxifen.

24. The compound for use according to claim 22 or 23, wherein: the disorder is breast cancer.

25. The compound for use according to claim 22 or 23, wherein: the disorder is breast cancer which is resistant to said anti-estrogen.

26. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a further active agent which is an anti-androgen.

27. The compound for use according to claim 26, wherein: the anti-androgen is flutamide, enzalutamide, apalutamide, bicalutamide, or nilutamide.

28. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a further active agent which is a Her2 blocker.

29. The compound for use according to claim 28, wherein: the Her2 blocker is herceptin, pertuzumab, or lapatinib.

30. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a further cytotoxic chemotherapeutic agent.

31. The compound for use according to claim 30, wherein: the further cytotoxic chemotherapeutic agent is a taxane, cyclophosphamide, or an antimetabolite.

32. The compound for use according to claim 30, wherein: the further cytotoxic chemotherapeutic agent is paclitaxel, docetaxel, cyclophosphamide, carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, or 5-fluorouracil.

33. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with an agent stimulating the immune system.

34. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a checkpoint inhibitor.

35. The compound for use according to any one of claims 15-17, wherein: the treatment further comprises treatment with a DNA repair inhibitor.

36. Use of the compound according to any one of claims 1-10 in the manufacture of a medicament for treating a proliferative disorder; cancer; a viral infection; a neurodegenerative disorder; ischaemia; a renal disease; a cardiovascular disorder; an autoimmune disorder; or a disorder caused by dysfunction of translation in cells.

37. Use of the compound according to any one of claims 1-10 in the manufacture of a medicament for treating a proliferative disorder.

38. Use of the compound according to any one of claims 1-10 in the manufacture of a medicament for treating cancer.

39. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a further active agent which is an aromatase inhibitor.

40. Use according to claim 39, wherein: the aromatase inhibitor is exemestane, letrozole, or anastrozole.

41. Use according to claim 39 or 40, wherein: the disorder is breast cancer.

42. Use according to claim 39 or 40, wherein: the disorder is breast cancer which is resistant to said aromatase inhibitor.

43. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a further active agent which is an anti-estrogen.

44. Use according to claim 43, wherein: the anti-estrogen is faslodex, tamoxifen, or hydroxytamoxifen.

45. Use according to claim 43 or 44, wherein: the disorder is breast cancer.

46. Use according to claim 43 or 44, wherein: the disorder is breast cancer which is resistant to said anti-estrogen.

47. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a further active agent which is an anti-androgen.

48. Use according to claim 47, wherein: the anti-androgen is flutamide, enzalutamide, apalutamide, bicalutamide, or nilutamide.

49. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a further active agent which is a Her2 blocker.

50. Use according to claim 49, wherein: the Her2 blocker is herceptin, pertuzumab, or lapatinib.

51. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a further cytotoxic chemotherapeutic agent.

52. Use according to claim 51, wherein: the further cytotoxic chemotherapeutic agent is a taxane, cyclophosphamide, or an antimetabolite.

53. Use according to claim 51, wherein: the further cytotoxic chemotherapeutic agent is paclitaxel, docetaxel, cyclophosphamide, carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, or 5-fluorouracil.

54. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with an agent stimulating the immune system.

55. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a checkpoint inhibitor.

56. Use according to any one of claims 36-38, wherein: the treatment further comprises treatment with a DNA repair inhibitor.

57. Use of the compound according to any one of claims 1-10 to treat a proliferative disorder; cancer; a viral infection; a neurodegenerative disorder; ischaemia; a renal disease; a cardiovascular disorder; an autoimmune disorder; or a disorder caused by dysfunction of translation in cells.

58. Use of the compound according to any one of claims 1-10 to treat a proliferative disorder.

59. Use of the compound according to any one of claims 1-10 to treat cancer.

60. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a further active agent which is an aromatase inhibitor.

61. Use according to claim 60, wherein: the aromatase inhibitor is exemestane, letrozole, or anastrozole.

62. Use according to claim 60 or 61, wherein: the disorder is breast cancer.

63. Use according to claim 60 or 61, wherein: the disorder is breast cancer which is resistant to said aromatase inhibitor.

64. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a further active agent which is an anti-estrogen.

65. Use according to claim 64, wherein: the anti-estrogen is faslodex, tamoxifen, or hydroxytamoxifen.

66. Use according to claim 64 or 65, wherein: the disorder is breast cancer.

67. Use according to claim 64 or 65, wherein: the disorder is breast cancer which is resistant to said anti-estrogen.

68. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a further active agent which is an anti-androgen.

69. Use according to claim 68, wherein: the anti-androgen is flutamide, enzalutamide, apalutamide, bicalutamide, or nilutamide.

70. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a further active agent which is a Her2 blocker.

71. Use according to claim 70, wherein: the Her2 blocker is herceptin, pertuzumab, or lapatinib.

72. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a further cytotoxic chemotherapeutic agent.

73. Use according to claim 72, wherein: the further cytotoxic chemotherapeutic agent is a taxane, cyclophosphamide, or an antimetabolite.

74. Use according to claim 72, wherein: the further cytotoxic chemotherapeutic agent is paclitaxel, docetaxel, cyclophosphamide, carboplatin, capecitabine, gemcitabine, doxorubicin, epirubicin, or 5-fluorouracil.

75. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with an agent stimulating the immune system.

76. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a checkpoint inhibitor.

77. Use according to any one of claims 57-59, wherein: the treatment further comprises treatment with a DNA repair inhibitor.