SUBSTITUTED PYRAZOLO[1,5-A]PYRIMIDINE-7-AMINE COMPOUNDS AS CDK INHIBITORS AND THEIR THERAPEUTIC USE

RELATED APPLICATION

This application is related to United Kingdom (GB) patent application number 2108572.5 filed 16 June 2021, the contents of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeutic compounds.

More specifically the present invention pertains to certain substituted pyrazolo[1,5-a]pyrimidine-7-amine compounds (referred to herein as “PPA 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 cofactor 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., a DNA repair inhibitor, an immune checkpoint inhibitor, an agent stimulating the immune system, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcriptional inhibitor, a cytotoxic chemotherapeutic agent, 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. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

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.

Cvclin-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 etai, 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 post-transcriptional processes, thereby modulating multiple cellular functions. Studies have characterised CDK12 and CDK13 as transcriptional CDKs that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II (see, e.g., Li et ai, 2016; Greifenberg et ai, 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. 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 ai, 2011; Li etai., 2016). Studies have also implicated CDK12 in regulating mRNA splicing, 3’-end processing, pre-replication complex assembly, and genomic stability (see, e.g., Choi et al., 2020). 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 etai., 2019). CDK13 regulates a different set of genes to CDK12, with CDK13 activity mostly involved in growth signaling pathways, including tyrosine kinase signalling (Greifenberg et al., 2016).

Cyclin K degradation is a property of some, but not all inhibitors of CDK 12 (see, e.g., Stabicki et al., 2020; Lv 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

Schering Corporation has describes certain pyrazolo[1,5-a]pyrimidine-7-amine compounds which allegedly act as CDK inhibitors. See, e.g., Guzi etai, 2004a, 2004b, 2006, 2007, 2008a, 2008b, 2008c. It appears that the following compounds are shown therein:

The 9H-purine-6-amine derivative known as CR8 (or more specifically, as (R)- CR8), shown below) is a CDK1 1215 / 9 / 12 inhibitor, and causes proteosomal dependent degradation of Cyclin K. See, e.g., Slabicki eta!., 2020. Nam et ai, 2019, describes certain compounds of the following formula (wherein X may be CH and R ¹ may be hydrogen) which allegedly inhibit CDK (in particular CDK7) and are useful in the treatment of cell proliferative diseases, inflammatory diseases, etc.

Among the examples provided therein (see, e.g., Table 11 at pages 139-183 therein) are Compounds 1, 47, and 62, shown below. None of the examples provided therein has a -Z group that is permitted by the -Ar ¹ -Ar ² group of the compounds described herein.

Parratt et al., 2019, describes certain compounds of the following formula which allegedly are useful in the treatment of diseases mediated by excessive or in appropriate CDK2, PDK1 , and/or CHK1 activity, including cancer, psoriasis, and restenosis. None of the examples provided therein has an -A-Q group that is permitted by the -Ar ¹ -Ar ² group of the compounds described herein.

Samajdar et ai, 2016, describes certain compounds of the following formula (wherein X may be CH, m may be 1, R ₆ may be hydrogen, and l_2 may be absent) which allegedly are selective transcription CDK inhibitors. None of the examples provided therein has an -A-I_2-B group that is permitted by the -Ar ¹ -Ar ² group of the compounds described herein.

Vankayalapati et ai, 2020, describes certain compounds of the following formula which allegedly inhibit CDK7 are useful in the treatment of cancer. In these compounds, R ² is defined as -C(=O)alkyl, optionally substituted aryl, or optionally substituted alkylaryl (see page 17 therein), including, e.g., benzyl (see pages 19-20 therein). None of the examples provided therein has an R ² group that is permitted by the -Ar ¹ -Ar ² group of the compounds described herein.

Potency / Selectivity The PPA compounds described herein are potent CDK12 and/or CDK13 inhibitors that are also selective for CDK12 and/or CDK13, for example, as compared to CDK7.

In addition to selectively inhibiting CDK12 and/or CDK13, the PPA 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.

SUMMARY OF THE INVENTION

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

Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising a PPA 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 a PPA 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 a PPA 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 a PPA compound, as described herein.

Another aspect of the present invention pertains to a PPA 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 a PPA 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 a PPA compound, as described herein, preferably in the form of a pharmaceutical composition. ln one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., a DNA repair inhibitor, an immune checkpoint inhibitor, an agent stimulating the immune system, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcriptional inhibitor, a cytotoxic chemotherapeutic agent, etc., as described herein.

Another aspect of the present invention pertains to a kit comprising (a) a PPA 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 a PPA 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 a PPA 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.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is shows the effect of THZ-531 , CR8, PPA-005 and PPA-006 on cyclin K degradation in A673 cells, as assessed by Western blotting, as well as the effect of MLN4924 on cytotoxic potency in A673 cells.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

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

Thus, one aspect of the present invention is a compound of the following formula, or a pharmaceutically acceptable salt or solvate thereof, wherein -L ⁷ -, -Ar ¹ -, -Ar ² , -X ⁵ -, -L ⁵ -, -Cy ⁵ , and -R ³ are as defined herein (for convenience, collectively referred to herein as “PPA” compounds”):

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

Note that it is intended that the pyrazolo[1,5-a]pyrimidine ring is unsubstituted at the 2- and 6-positions. Some embodiments include the following:

(1) A compound of the following formula: or a pharmaceutically acceptable salt or solvate thereof; wherein:

-L ⁷ - is independently -CH ₂ -, -CH(R ^L7 )-, or -C(R ^L7 ) ₂ -; each -R ^L7 is independently linear or branched saturated C _1-4 alkyl;

-Ar ¹ - is independently phenylene, Ceheteroarylene, or Csheteroarylene; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N ;

-Ar ² is independently phenyl, Ceheteroaryl, or Csheteroaryl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N ;

-X ⁵ - is independently -NH-, -NR ^X5 -, O -, or a single bond;

-R ^X5 is linear or branched saturated C _1-4 alkyl;

-L ⁵ - is independently -CH ₂ -, -CH(R ^L5 )-, -C(R ^L5 ) ₂ -, or a single bond; each -R ^L5 is independently linear or branched saturated C _1-4 alkyl;

-Cy ⁵ is independently -Cy ^5A or -Cy ^5B ;

-Cy ^5A is non-aromatic C ₄ -ioheterocyclyl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5AN ; -Cy ^5B is C5-6heteroaryl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^cy5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5BN ;

-R ³ is independently -R ^3A , -R ^3B , -R ^3C , or -CN;

-R ^3A is linear or branched saturated C _1-6 alkyl, and is optionally substituted with one or more groups -R ^R3 ;

-R ^3B is saturated C3-6cycloalkyl, and is optionally substituted with one or more groups -R ^R3 ;

-R ^3C is -F, -Cl, -Br, or -I; and each -R ^R3 is independently -F, -OH, or -OMe; and wherein: each -R ^AR1C and each -R ^AR2C is independently selected from: -CN, and -NO ₂ ; each -R ^AR1N and each -R ^AR2N is independently selected from: wherein: each -L ^T - is independently linear or branched saturated C _1-4 alkylene; each -R ^TT is independently -R ^TT1 , -R ^TT2 , -L ^TT -R ^TT2 , -R ^TT3 , or -L ^TT -R ^TT3 ; each -R ^TT1 is independently linear or branched saturated C _1-6 alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^TTT ; each -R ^TT2 is saturated C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -F, -R ^TTT , -OH, and -OR ^TTT ; each -R ^TT3 is independently phenyl or naphthyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^TTT , OH, -OR ^TTT , -OCF ₃ , -NH ₂ , -NHR ^TTT , and -NR ^TTT ₂ ; each -L ^TT - is independently linear or branched saturated C _1-4 alkylene; each -R ^TN is linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; each -R™ is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups selected from: -R ^TMM , -C(=O)R ^TMM , -S(=O) ₂ R ^tmm , -F, -NH ₂ , -NHR ^tmm , -NR ^TMM 2, -OH, and -OR ^TMM ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R ^TMM , -C(=O)R ^TMM , -C(=O)OR ^TMM , and -S(=O) ₂ R ^TMM ; each -R ^TTT is independently linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; and each -R ^TMM is independently linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; and wherein: each -R ^cy5AC and each -R ^cy5BC is independently selected from: wherein: each -L ^J - is independently linear or branched saturated C _1-4 alkylene; each -R ^JJ is independently -R ^JJ1 , -R ^JJ2 , -L ^JJ -R ^JJ2 , -R ^JJ3 , or -L ^JJ -R ^JJ3 ; each -R ^JJ1 is independently linear or branched saturated C _1-6 alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^JJJ ; each -R ^JJ2 is saturated C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -F, -R ^JJJ , -OH, and -OR ^JJJ ; each -R ^JJ3 is independently phenyl or naphthyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^JJJ , OH, -OR ^JJJ , -OCF ₃ , -NH ₂ , -NHR ^JJJ , and -NR ^jjj ₂ ; each -L ^JJ - is independently linear or branched saturated C _1-4 alkylene; each -R ^JN is linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; each -R ^JM is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is: optionally substituted on carbon with one or more groups selected from: -R ^JMM , -C(=O)R ^JMM , -S(=O) ₂ R ^jmm , -F, -NH ₂ , -NHR ^jmm , -NR ^jmm ₂ , -OH, and -OR ^JMM ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R ^JMM , -C(=O)R ^JMM , -C(=O)OR ^JMM , and -S(=O) ₂ R ^JMM ; each -R ^JJJ is independently linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; and each -R ^JMM is independently linear or branched saturated C _1-4 alkyl, phenyl, or benzyl; with the proviso that: if: -X ⁵ - is a single bond, -L ⁵ - is a single bond, and -R ³ is -Br, then: -Ar ² is not oxadiazolyl or thiadiazolyl; and with the proviso that: if: -X ⁵ - is a single bond and -L ⁵ - is a single bond, then: -Ar ² is not pyrazolyl.

For the avoidance of doubt:

The index “C _x-y ” in terms such as “C _9-10 heteroaryl”, “C _3-7 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 ₆ heteroaryl group, and piperidino is an example of a Ceheterocyclyl 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 Ceheteroaryl group, and quinolyl is an example of a Cioheteroaryl group. The term “heterocyclyl” refers to a group that is attached to the rest of the molecule by an atom that is part of a non-aromatic ring, wherein the non-aromatic ring is part of a non aromatic ring system, and the non-aromatic ring system has one or more heteroatoms (e.g., N, O, S, as the case may be). Unless otherwise specified, “heterocyclyl” includes monocyclic heterocyclyl (e.g., piperidinyl, an example of a monocyclic Ceheterocyclyl), fused heterocyclyl (e.g., decahydroquinolinyl, an example of a fused Cioheterocyclyl), bridged heterocyclyl (e.g., 6-azabicyclo[3.1.1]heptanyl, an example of a bridged Cyheterocyclyl), and spiro heterocyclyl (7-azaspiro[3.5]nonyl, an example of a spiro Cgheterocyclyl).

The phrase “one or more groups” in the context of optional substituents (e.g., “one or more groups -R ^{AR1 C} ”, etc.) is necessarily constrained by the parent moiety and the number of positions on it that are suitable for substitution. In some parent moieties (e.g., tetrazolyl) there is only one position available for substitution. However, for other parent moieties, there may be several (e.g., phenyl has five). Except when constrained by the parent moiety, the “one or more groups” may be, e.g., 1, 2, 3, 4, etc., though more preferably is 1, 2, or 3, yet more preferably 1 or 2, still more preferably 1.

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.

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.

Certain groups despite having carbon ring atoms may not have any carbon ring atoms available for substitution. For example, a tetrazolyl group may only permit a “substituent on carbon” or may only permit a “substituent on secondary nitrogen”, as illustrated below. substituent on secondary nitrogen substituent on carbon

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 ( R ) and (S) 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(CH3)CH ₂ CH3 is usually chiral, and so gives rise to stereoisomers, e.g., (R) and (S) enantiomers if it is the only chiral centre, each of which is disclosed and encompassed.

The Group -L ⁷ -

(2) A compound according to (1), wherein -L ⁷ - is independently -CH ₂ - or -CH(R ^L7 )-.

(3) A compound according to (1), wherein -L ⁷ - is -CH ₂ -. The Group -R ^L7

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

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

(6) A compound according to any one of (1) to (3), wherein each -R ^L7 , if present, is -Me. The Group -X ⁵ -

(7) A compound according to any one of (1) to (6), wherein -X ⁵ - is independently -NH-, -NR ^X5 -, or a single bond.

(8) A compound according to any one of (1) to (6), wherein -X ⁵ - is independently -NH- or -NR ^X5 -.

(9) A compound according to any one of (1) to (6), wherein -X ⁵ - is -NH-.

(10) A compound according to any one of (1) to (6), wherein -X ⁵ - is -NR ^X5 -.

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

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

The Group -L ⁵ -

(13) A compound according to any one of (1) to (12), wherein -L ⁵ - is independently -CH _2- or a single bond.

(14) A compound according to any one of (1) to (12), wherein -L ⁵ - is -CH ₂ -.

(15) A compound according to any one of (1) to (12), wherein -L ⁵ - is a single bond. Some Preferred Combinations of -X ⁵ - and -L ⁵ -

(16) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-);

Cy ⁵ -CH ₂ -NR ^X5 - (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NR ^X5 -);

Cy ⁵ -CH ₂ -O- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -O-);

Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

Cy ⁵ -NR ^X5 - (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NR ^X5 -);

Cy ⁵ -O- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -O-); or Cy ⁵ - (i.e., each of -L ⁵ - and -X ⁵ - is a single bond).

(17) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-);

Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

Cy ⁵ -O- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -O-); or Cy ⁵ - (i.e., each of -L ⁵ - and -X ⁵ - is a single bond).

(18) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-);

Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-); or Cy ⁵ -O- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -O-).

(19) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-); or Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-).

(20) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-).

(21) A compound according to any one of (1) to (6), wherein Cy ⁵ -L ⁵ -X ⁵ - is:

Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-). The Group -R ^xs

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

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

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

The Group -R ^L5

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

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

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

The Group -R ³

(28) A compound according to any one of (1) to (27), wherein -R ³ is -R ^3A or -R ^3B .

(29) A compound according to any one of (1) to (27), wherein -R ³ is -R ^3A .

(30) A compound according to any one of (1) to (27), wherein -R ³ is -R ^3B .

(31) A compound according to any one of (1) to (27), wherein -R ³ is -R ^3C .

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

The Group -R ^3A

(33) A compound according to any one of (1) to (32), wherein -R ^3A , if present, is linear or branched saturated C _1-6 alkyl.

(34) A compound according to any one of (1) to (32), wherein -R ^3A , 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.

(35) A compound according to any one of (1) to (32), wherein -R ^3A , if present, is linear or branched saturated C _1-4 alkyl.

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

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

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

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

The Group -R ^3B

(40) A compound according to any one of (1) to (39), wherein -R ^3B , if present, is saturated C3-6cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

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

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

The Group -R ^3C

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

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

The Group -R ^R3

(45) A compound according to any one of (1) to (44), wherein each -R ^R3 , if present, is independently selected from -F and -OH. The Group -Ar ¹ - : When Phenylene

(46) A compound according to any one of (1) to (45), wherein -Ar ¹ - is phenylene; and is optionally substituted with one or more groups -R ^AR1C .

(47) A compound according to any one of (1) to (45), wherein -Ar ¹ - is independently 1 ,4-phenylene, 1,3-phenylene, or 1,2-phenylene; and is optionally substituted with one or more groups -R ^AR1C .

(48) A compound according to any one of (1) to (45), wherein -Ar ¹ - is 1,4-phenylene; and is optionally substituted with one or more groups -R ^AR1C .

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

The Group -Ar ¹ - : When Ceheteroarylene

(50) A compound according to any one of (1) to (49), wherein -Ar ¹ - is Ceheteroarylene; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(51) A compound according to any one of (1) to (49), wherein -Ar ¹ - is independently pyridin-di-yl, pyrimidin-di-yl, pyridazin-di-yl, or pyrazin-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

Pyridin-di-yl:

(52) A compound according to any one of (1) to (49), wherein -Ar ¹ - is pyridin-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(53) A compound according to any one of (1) to (49), wherein -Ar ¹ - is independently pyridin-2,5-di-yl, pyridin-2,4-di-yl, pyridin-2,3-di-yl, pyridin-2,6-di-yl, pyridin-3,4-di-yl or pyridin-3,5-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(54) A compound according to any one of (1) to (49), wherein -Ar ¹ - is independently pyridin-2, 5-di-yl, pyridin-2,4-di-yl, pyridin-2,6-di-yl, or pyridin-3, 5-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(55) A compound according to any one of (1) to (49), wherein -Ar ¹ - is pyridin-2, 5-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(56) A compound according to any one of (1) to (49), wherein -Ar ¹ - is pyridin-2, 5-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and wherein -Ar ² is attached at the 5-position.

(57) A compound according to any one of (1) to (49), wherein -Ar ¹ - is pyridin-2, 5-di-yl; and wherein -Ar ² is attached at the 5-position.

The Group -Ar ¹ - : When Csheteroarylene

(58) A compound according to any one of (1) to (57), wherein -Ar ¹ - is Csheteroarylene; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N (59) A compound according to any one of (1) to (57), wherein -Ar ¹ - is independently pyrrol-di-yl, pyrazol-di-yl, imidazol-di-yl, triazol-di-yl, tetrazol-di-yl, furan-di-yl, thiofuran-di-yl, oxazol-di-yl, isoxazol-di-yl, thiazol-di-yl, isothiazol-di-yl, oxadiazol-di-yl, or thiadiazol-di-yl; and is: optionally substituted on carbon, if present, with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N

(60) A compound according to any one of (1) to (57), wherein -Ar ¹ - is independently pyrrol-di-yl, pyrazol-di-yl, imidazol-di-yl, triazol-di-yl, tetrazol-di-yl, furan-di-yl, thiofuran-di-yl, oxazol-di-yl, isoxazol-di-yl, thiazol-di-yl, isothiazol-di-yl; and is: optionally substituted on carbon, if present, with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N

(61) A compound according to any one of (1) to (57), wherein -Ar ¹ - is independently pyrrol-di-yl, pyrazol-di-yl, imidazol-di-yl, oxazol-di-yl, or isoxazol-di-yl; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N

(62) A compound according to any one of (1) to (57), wherein -Ar ¹ - is independently pyrrol-di-yl, pyrazol-di-yl, or imidazol-di-yl; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N

Imidazol-di-yl:

(63) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-di-yl; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N .

(64) A compound according to any one of (1) to (57), wherein -Ar ¹ - is independently imidazol-2,4-di-yl or imidazol-1 ,4-di-yl; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR1N . imidazol-2,4-di-yl imidazol-1 ,4-di-yl

(65) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-2,4-di-yl; and is: optionally substituted on carbon with one or more groups -R ^AR1C ; and optionally substituted on secondary nitrogen with a group -R ^{AR1 N} ; and wherein -Ar ² is attached at the 4-position.

(66) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-2,4-di-yl; and wherein -Ar ² is attached at the 4-position.

(67) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-1 ,4-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C .

(68) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-1 ,4-di-yl; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and wherein -Ar ² is attached at the 1 -position.

(69) A compound according to any one of (1) to (57), wherein -Ar ¹ - is imidazol-1 ,4-di-yl; and wherein -Ar ² is attached at the 1 -position. The Group -Ar ² : When Phenyl

(70) A compound according to any one of (1) to (69), wherein -Ar ² is phenyl; and is optionally substituted with one or more groups -R ^AR2C .

The Group -Ar ² : When Ceheteroaryl

(71) A compound according to any one of (1) to (70), wherein -Ar ² is Ceheteroaryl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(72) A compound according to any one of (1) to (70), wherein -Ar ² is independently pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

Pyridinyl:

(73) A compound according to any one of (1) to (70), wherein -Ar ² is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . pyridin-2-yl pyridin-3-yl pyridin-4-yl

(74) A compound according to any one of (1) to (70), wherein -Ar ² is pyridin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(75) A compound according to any one of (1) to (70), wherein -Ar ² is pyridin-2-yl.

(76) A compound according to any one of (1) to (70), wherein -Ar ² is pyridin-3-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(77) A compound according to any one of (1) to (70), wherein -Ar ² is pyridin-4-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C . Pyrimidinyl:

(78) A compound according to any one of (1) to (70), wherein -Ar ² is pyrimidinyl

(e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . pyrimidin-2-yl pyrimidin-5-yl pyrimidin-4-yl

(79) A compound according to any one of (1) to (70), wherein -Ar ² is pyrimidin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(80) A compound according to any one of (1) to (70), wherein -Ar ² is pyrimidin-2-yl.

(81) A compound according to any one of (1) to (70), wherein -Ar ² is pyrimidin-3-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(82) A compound according to any one of (1) to (70), wherein -Ar ² is pyrimidin-4-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

Pyridazinyl:

(83) A compound according to any one of (1) to (70), wherein -Ar ² is pyridazinyl (e.g., pyridazin-3-yl or pyridazin-4-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . pyridazin-3-yl pyridazin-4-yl

(84) A compound according to any one of (1) to (70), wherein -Ar ² is pyridazin-3-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(85) A compound according to any one of (1) to (70), wherein -Ar ² is pyridazin-4-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C . Pyrazinyl:

(86) A compound according to any one of (1) to (70), wherein -Ar ² is pyrazinyl (e.g., pyrazin-2-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . pyrazin-2-yl

The Group -Ar ² : When Csheteroaryl

(87) A compound according to any one of (1) to (86), wherein -Ar ² is Csheteroaryl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N .

(88) A compound according to any one of (1) to (86), wherein -Ar ² is independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiofuranyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon, if present, with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N .

(89) A compound according to any one of (1) to (86), wherein -Ar ² is independently pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, or thiazolyl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N .

Pyrrolyl:

(90) A compound according to any one of (1) to (86), wherein -Ar ² is pyrrolyl (e.g., pyrrol-1 -yl, 1 H-pyrrol-2-yl, or 1 H-pyrrol-3-yl); and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N . pyrrol-1 -yl 1 H-pyrrol-2-yl 1 H-pyrrol-3-yl

(91) A compound according to any one of (1) to (86), wherein -Ar ² is pyrrol-1-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(92) A compound according to any one of (1) to (86), wherein -Ar ² is 1 H-pyrrol-2-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

(93) A compound according to any one of (1) to (86), wherein -Ar ² is 1 H-pyrrol-3-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

Pyrazolyl:

(94) A compound according to any one of (1) to (86), wherein -Ar ² is pyrazolyl (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl, 1 H-pyrazol-4-yl, or 1 H-pyrazol-5-yl); and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N . pyrazol-1-yl 1 H-pyrazol-5-yl 1 H-pyrazol-4-yl 1 H-pyrazol-3-yl

(95) A compound according to any one of (1) to (86), wherein -Ar ² is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(96) A compound according to any one of (1) to (86), wherein -Ar ² is pyrazol-1-yl.

(97) A compound according to any one of (1) to (86), wherein -Ar ² is 1 H-pyrazol-3-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N . (98) A compound according to any one of (1) to (86), wherein -Ar ² is 1 H-pyrazol-4-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

(99) A compound according to any one of (1) to (86), wherein -Ar ² is 1 H-pyrazol-5-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

Imidazolyl:

(100) A compound according to any one of (1) to (86), wherein -Ar ² is imidazolyl (e.g., imidazole-1-yl, 1 H-imidazol-2-yl, 1 H-imidazol-4-yl, or 1H-imidazol-5-yl); and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N . imidazol-1-yl 1 H-imidazol-5-yl 1 H-imidazol-4-yl 1 H-imidazol-2-yl

(101) A compound according to any one of (1) to (86), wherein -Ar ² is imidazol-1-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(102) A compound according to any one of (1) to (86), wherein -Ar ² is 1H-imidazol-2-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

(103) A compound according to any one of (1) to (86), wherein -Ar ² is 1H-imidazol-4-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N . (104) A compound according to any one of (1) to (86), wherein -Ar ² is 1H-imidazol-5-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen with a group -R ^AR2N .

Oxazolyl :

(105) A compound according to any one of (1) to (86), wherein -Ar ² is oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, or oxazol-5-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . oxazol-5-yl oxazol-4-yl oxazol-2-yl

(106) A compound according to any one of (1) to (86), wherein -Ar ² is oxazol-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(107) A compound according to any one of (1) to (86), wherein -Ar ² is oxazol-4-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(108) A compound according to any one of (1) to (86), wherein -Ar ² is oxazol-5-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

Thiazolyl:

(109) A compound according to any one of (1) to (86), wherein -Ar ² is thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, or thiazol-5-yl); and is optionally substituted on carbon with one or more groups -R ^AR2C . thiazol-5-yl thiazol-4-yl thiazol-2-yl

(110) A compound according to any one of (1) to (86), wherein -Ar ² is thiazol-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C . (111) A compound according to any one of (1) to (86), wherein -Ar ² is thiazol-2-yl.

(112) A compound according to any one of (1) to (86), wherein -Ar ² is thiazol-4-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(113) A compound according to any one of (1) to (86), wherein -Ar ² is thiazol-5-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

Some Preferred Combinations of Ar ¹ and Ar ²

Ar ^2- Ar ¹ - as Pyridinyl-Phenyl:

(114) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyridinyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(115) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1 ,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyridinyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(116) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1 ,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyridin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(117) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1 ,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyridin-2-yl.

(118) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1 ,4-phenylene; and -Ar ² is pyridin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C . (119) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is pyridin-2-yl.

Ar ² -Ar ¹ - as Pyrimidinyl-Phenyl:

(120) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrimidinyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(121) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrimidinyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(122) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrimidin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(123) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrimidin-2-yl.

(124) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is pyrimidin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(125) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is pyrimidin-2-yl. Ar ² -Ar ¹ - as Thiazolyl-Phenyl:

(126) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is thiazolyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(127) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is thiazolyl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(128) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is thiazol-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(129) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is thiazol-2-yl.

(130) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is thiazol-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(131) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is thiazol-2-yl. Ar ² -Ar ¹ - as Pyrazolyl-Phenyl:

(132) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrazolyl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N .

(133) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrazolyl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N .

(134) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(135) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; and -Ar ² is pyrazol-1-yl;

(136) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is pyrazol-1-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C .

(137) A compound according to any one of (1) to (45), wherein:

-Ar ¹ - is 1,4-phenylene; and -Ar ² is pyrazol-1-yl. Substituents -R ^{AR1 C} and -R ^AR2C

(138) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from:

(139) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from: (140) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from:

(141) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from:

(142) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from:

(143) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, and each -R ^AR2C , if present, is independently selected from:

-F, -Me, -OMe, -CF ₃ , and -OCF ₃ .

(144) A compound according to any one of (1) to (137), wherein each -R ^AR1C , if present, is independently selected from:

-F, -Me, and -OMe. Substituents -R ^{AR1 N} and -R ^AR2N

(145) A compound according to any one of (1) to (144), wherein each -R ^AR1N , if present, and each -R ^AR2N , if present, is independently selected from:

-R ^TT , -C(=O)R ^TT , -C(=O)OR ^TT , and -S(=O) ₂ R ^TT

(146) A compound according to any one of (1) to (144), wherein each -R ^AR1N , if present, and each -R ^AR2N , if present, is independently selected from:

-R ^TT , -C(=O)R ^TT , and -C(=O)OR ^TT

(147) A compound according to any one of (1) to (144), wherein each -R ^AR1N , if present, and each -R ^AR2N , if present, is: -R ^TT .

The Group -R

(148) A compound according to any one of (1) to (147), wherein each -R ^TT , if present, is independently -R ^TT1 , -R ^TT2 , -R ^TT3 , or -L ^TT -R ^TT3 .

(149) A compound according to any one of (1) to (147), wherein each -R ^TT , if present, is independently -R ^TT1 , -R ^TT3 , or -L ^TT -R ^TT3 .

(150) A compound according to any one of (1) to (147), wherein each -R ^TT , if present, is -R ^TT1 .

The Group -R ^TT1

(151) A compound according to any one of (1) to (150), wherein each -R ^TT1 , if present, is independently linear or branched saturated C _1-6 alkyl.

(152) A compound according to any one of (1) to (150), wherein each -R ^TT1 , if present, is independently linear or branched saturated C _1-4 alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^TTT .

(153) A compound according to any one of (1) to (150), wherein each -R ^TT1 , if present, is independently linear or branched saturated C _1-4 alkyl.

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

(155) A compound according to any one of (1) to (150) wherein each -R ^TT1 , if present, is independently -Me, -Et, -nPr, or -iPr. (156) A compound according to any one of (1) to (150), wherein each -R ^TT1 , if present, is -Me.

The Group -R ^TT2

(157) A compound according to any one of (1) to (156), wherein each -R ^TT2 , if present, is saturated C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^TTT

(158) A compound according to any one of (1) to (156), wherein each -R ^TT2 , if present, is saturated C3-6cycloalkyl.

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

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

The Group -R ^TT3

(161) A compound according to any one of (1) to (160), wherein each -R ^TT3 , if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^TTT , OH, -OR ^TTT , -OCF ₃ , -NH ₂ , -NHR ^ttt , and -NR ^TTT ₂ .

(162) A compound according to any one of (1) to (160), wherein each -R ^TT3 , if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^TTT , OH, -OR ^TTT , and -OCF ₃ .

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

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

The Group -L ^T -

(165) A compound according to any one of (1) to (164), wherein each -L ^T -, if present, is independently linear or branched saturated Ci-3alkylene. (166) A compound according to any one of (1) to (164), wherein each -L ^T -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₃ )CH ₂ -, or -CH ₂ CH(CH ₃ )-.

(167) A compound according to any one of (1) to (164), wherein each -L ^T -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(168) A compound according to any one of (1) to (164), wherein each -L ^T -, if present, is -CH ₂ -.

The Group -L ^TT -

(169) A compound according to any one of (1) to (168), wherein each -L ^TT -, if present, is independently linear or branched saturated Ci-3alkylene.

(170) A compound according to any one of (1) to (168), wherein each -L ^TT -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₃ )CH ₂ -, or -CH ₂ CH(CH ₃ )-.

(171) A compound according to any one of (1) to (168), wherein each -L ^TT -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(172) A compound according to any one of (1) to (168), wherein each -L ^TT -, if present, is -CH ₂ -.

The Group -R ^TN

(173) A compound according to any one of (1) to (172), wherein each -R ^TN , if present, is independently linear or branched saturated C _1-4 alkyl.

(174) A compound according to any one of (1) to (172) wherein each -R ^TN , if present, is -Me. The Group -R™

(175) A compound according to any one of (1) to (174), wherein each -R™, 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 ^TMM , -F, -OH, and -OR ^TMM ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R ^TMM , -C(=O)R ^TMM , and -C(=O)OR ^TMM

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

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

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

The Group -

(179) A compound according to any one of (1) to (178), wherein each -R ^TTT , if present, is independently linear or branched saturated C _1-4 alkyl.

(180) A compound according to any one of (1) to (178), wherein each -R ^TTT , if present, is -Me. The Group -R ^TMM

(181) A compound according to any one of (1) to (180), wherein each -R ^TMM , if present, is independently linear or branched saturated C _1-4 alkyl.

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

The Group -Cv ⁵

(183) A compound according to any one of (1) to (182), wherein -Cy ⁵ is -Cy ^5A .

(184) A compound according to any one of (1) to (182), wherein -Cy ⁵ is -Cy ^5B . The Group -Cy ^5A

(185) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is independently: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, tetrahydropyridinyl, dihydropyridinyl,

3.6-diazabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1 ]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl,

2.6-diazaspiro[3.3]heptanyl, 2,7-diazaspiro[3.4]octanyl, 2,7-diazaspiro[3.5]nonanyl,

2.7-diazaspiro[4.4]nonanyl, 2,8-diazaspiro[4.5]decanyl, or 3,9-diazaspiro[5.5]undecanyl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN . azetidine pyrrolidine piperidine piperazine morpholine thiomorpholine azepane 1 ,2-diazepane 1 ,3-diazepane 1 ,4-diazepane

(186) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is non-aromatic C^heterocyclyl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5AN (187) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, dihydropyridinyl, azepanyl, diazepanyl, or

6-diazabicyclo[3.1.1 ]heptanyl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN .

(188) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is non-aromatic C^heterocyclyl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN .

(189) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN .

(190) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is independently azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN Azetidinyl:

(191) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is azetidinyl (e.g., azetidin-1-yl, azetidin-2-yl, azetidin-3-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN . azetidin-1-yl azetidin-2-yl azetidin-3-yl

(azetidino)

(192) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is azetidin-1-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O.

(193) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is azetidin-2-yl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, with a group -R ^cy5AN

(194) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is azetidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, with a group -R ^c y ^5AN .

Pyrrolidinyl:

(195) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN pyrrolidin-1-yl pyrrolidin-2-yl pyrrolidin-3-yl

(pyrrolidino) (196) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is pyrrolidin-1-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O.

(197) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is pyrrolidin-2-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(198) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is pyrrolidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(199) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is pyrrolidin-3-yl.

(200) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is (3S)-pyrrolidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(3S)-pyrrolidin-3-yl

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

(202) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN .

(203) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidin-1-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O.

(204) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidin-2-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN

(205) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(206) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidin-3-yl. (207) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is

(3S)-piperidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(3S)-piperidin-3-yl

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

(209) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperidin-4-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN

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

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

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

(3R,4R)-3-hydroxy-piperidin-4-yl Piperazinyl:

(213) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperazinyl (e.g., piperazin-1-yl, piperazin-2-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN . piperazin-1-yl piperazin-2-yl

(piperazino)

(214) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperazin-1-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN

(215) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is piperazin-2-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

Morpholinyl:

(216) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is morpholinyl (e.g., morpholiny-2-yl, morpholiny-3-yl, morpholiny-4-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5AN morpholin-4-yl morpholin-3-yl morpholin-2-yl

(morpholino)

(217) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is morpholinyl-4-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O.

(218) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is morpholinyl-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

(219) A compound according to any one of (1) to (184), wherein -Cy ^5A , if present, is morpholinyl-2-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^c y ^5AN .

The Group -Cv ^5B

(220) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5BN . CsHeteroaryl:

(221) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is Csheteroaryl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5BN

(222) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is independently pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazole, isoxazole, thiazole, isothiazole, oxadiazolyl, or thiadiazolyl; and is: optionally substituted on carbon with one or more groups -R ^cy5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5BN

(223) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is independently pyrrolyl, pyrazolyl, imidazolyl, oxazole, isoxazole, thiazole, or isothiazole; and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5BN

Pyrazolyl:

(224) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is pyrazolyl (e.g., pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, or 1H-pyrazol-5-yl); and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^c y ^5BN pyrazol-1-yl 1 H-pyrazol-5-yl 1 H-pyrazol-4-yl 1 H-pyrazol-3-yl

(225) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is

1H-pyrazol-4-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen with a group -R ^c y ^5BN (226) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is 1 H-pyrazol-5-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5BC ; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5BN

C ₆ Heteroaryl:

(227) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is Ceheteroaryl having at least one nitrogen ring atom; and is optionally substituted on carbon with one or more groups -R ^cy5BC

(228) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is independently pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl; and is optionally substituted on carbon with one or more groups -R ^c y ^5BC .

Pyridinyl:

(229) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl); and is optionally substituted on carbon with one or more groups -R ^c y ^5BC .

(230) A compound according to any one of (1) to (219), wherein -Cy ^5B , if present, is pyridin-3-yl; and is optionally substituted on carbon with one or more groups -R ^c y ^5BC .

Substituents -R ^c y ^5AC and -R ^c y ^5BC

(231) A compound according to any one of (1) to (230), wherein each -R ^c y ^5AC , if present, and each -R ^cy5BC , if present, is independently selected from:

(232) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, and each -R ^c y ^5BC , if present, is independently selected from:

(233) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, and each -R ^cy5BC , if present, is independently selected from: (234) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, and each -R ^cy5BC , if present, is independently selected from:

(235) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, and each -R ^cy5BC , if present, is independently selected from:

(236) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, and each -R ^cy5BC , if present, is independently selected from:

-F, -Me, -OH, -OMe, and -NH ₂ .

(237) A compound according to any one of (1) to (230), wherein each -R ^cy5AC , if present, is -OH.

(238) A compound according to any one of (1) to (230), wherein each -R ^cy5BC , if present, is -Me.

Substituents -R ^cy5AN and -R ^cy5BN

(239) A compound according to any one of (1) to (238), wherein each -R ^c y ^5AN , if present, and each -R ^c y ^5BN , if present, is independently selected from:

-R ^JJ , -C(=O)R ^JJ , -C(=O)OR ^JJ , and -S(=O) ₂ R ^JJ .

(240) A compound according to any one of (1) to (238), wherein each -R ^c y ^5AN , if present, and each -R ^c y ^5BN , if present, is independently selected from:

-R ^JJ , -C(=O)R ^JJ , and -C(=O)OR ^JJ . (241) A compound according to any one of (1) to (238), wherein each -R ^cy5AN , if present, and each -R ^cy5BN , if present, is: -R ^JJ .

The Group -R ^JJ

(242) A compound according to any one of (1) to (241), wherein each -R ^JJ , if present, is independently -R ^JJ1 , -R ^JJ2 , -R ^JJ3 , or -L ^JJ -R ^JJ3 .

(243) A compound according to any one of (1) to (241), wherein each -R ^JJ , if present, is independently -R ^JJ1 , -R ^JJ3 , or -L ^JJ -R ^JJ3 .

(244) A compound according to any one of (1) to (241), wherein each -R ^JJ , if present, is

_R ^JJ 1

The Group -R ^JJ1

(245) A compound according to any one of (1) to (244), wherein each -R ^JJ1 , if present, is independently linear or branched saturated C _1-6 alkyl.

(246) A compound according to any one of (1) to (244), wherein each -R ^JJ1 , if present, is independently linear or branched saturated C _1-4 alkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^JJJ .

(247) A compound according to any one of (1) to (244), wherein each -R ^JJ1 , if present, is independently linear or branched saturated C _1-4 alkyl.

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

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

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

The Group -R ^JJ2

(251) A compound according to any one of (1) to (250), wherein each -R ^JJ2 , if present, is saturated C3-6cycloalkyl, and is optionally substituted with one or more groups selected from -F, -OH, and -OR ^JJJ . (252) A compound according to any one of (1) to (250), wherein each -R ^JJ2 , if present, is saturated C _3-6 cycloalkyl.

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

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

The Group -R ^JJ3

(255) A compound according to any one of (1) to (254), wherein each -R ^JJ3 , if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^JJJ , OH, -OR ^JJJ , -OCF ₃ , -NH ₂ , -NHR ^jjj , and -NR ^JJJ ₂ .

(256) A compound according to any one of (1) to (254), wherein each -R ^JJ3 , if present, is phenyl, and is optionally substituted with one or more groups selected from -F, -Cl, -Br, -I, -R ^JJJ , OH, -OR ^JJJ , and -OCF ₃ .

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

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

The Group -L ^J -

(259) A compound according to any one of (1) to (258), wherein each -L ^J -, if present, is independently linear or branched saturated Ci-3alkylene.

(260) A compound according to any one of (1) to (258), wherein each -L ^J -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₃ )CH ₂ -, or -CH ₂ CH(CH ₃ )-.

(261) A compound according to any one of (1) to (258), wherein each -L ^J -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(262) A compound according to any one of (1) to (258), wherein each -L ^J -, if present, is -CH ₂ -. The Group -L ^JJ -

(263) A compound according to any one of (1) to (262), wherein each -L ^JJ -, if present, is independently linear or branched saturated Ci-3alkylene.

(264) A compound according to any one of (1) to (262), wherein each -L ^JJ -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )-, -C(CH ₃ ) ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₃ )CH ₂ -, or -CH ₂ CH(CH ₃ )-.

(265) A compound according to any one of (1) to (262), wherein each -L ^JJ -, if present, is independently -CH ₂ -, -CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ -.

(266) A compound according to any one of (1) to (262), wherein each -L ^JJ -, if present, is -CH ₂ -.

The Group -R ^JN

(267) A compound according to any one of (1) to (266), wherein each -R ^JN , if present, is independently linear or branched saturated C _1-4 alkyl.

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

The Group -R ^JM

(269) A compound according to any one of (1) to (268), wherein each -R ^JM , 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 ^JMM , -F, -OH, and -OR ^JMM ; and optionally substituted on secondary nitrogen, if present, with a group selected from: -R ^JMM , -C(=O)R ^JMM , and -C(=O)OR ^JMM

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

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

The Group -R ^JJJ

(273) A compound according to any one of (1) to (272), wherein each -R ^JJJ , if present, is independently linear or branched saturated C _1-4 alkyl.

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

The Group -R ^JMM

(275) A compound according to any one of (1) to (274), wherein each -R ^JMM , if present, is independently linear or branched saturated C _1-4 alkyl.

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

Some Preferred Combinations

(277) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ;

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is non-aromatic C4-6heterocyclyl having at least one nitrogen ring atom; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5AN .

(278) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-);

Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

Cy ⁵ -O- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -O-); or Cy ⁵ - (i.e., each of -L ⁵ - and -X ⁵ - is a single bond);

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is independently azetidinyl, pyrrolidinyl, or piperidinyl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5AN

(279) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ;

-Ar ² is independently pyridinyl, pyrimidinyl, thiazolyl, or pyrazolyl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and optionally substituted on secondary nitrogen, if present, with a group -R ^AR2N . Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-); or Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

-Cy ⁵ is -Cy ^5A ; -Cy ^5A is independently azetidinyl, pyrrolidinyl, or piperidinyl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen, if present, with a group -R ^cy5AN

(280) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ;

-Ar ² is independently pyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, or pyrazol-1-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-); or Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is independently pyrrolidin-3-yl, piperidin-3-yl, or piperidin-4-yl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^cy5AN

(281) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ;

-Ar ² is independently pyridin-2-yl, pyrimidin-2-yl, thiazol-2-yl, or pyrazol-1-yl; and is: optionally substituted on carbon with one or more groups -R ^AR2C ; and Cy ⁵ -L ⁵ -X ⁵ - is independently:

Cy ⁵ -CH ₂ -NH- (i.e., -L ⁵ - is -CH ₂ - and -X ⁵ - is -NH-); or Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is independently pyrrolidin-3-yl, piperidin-3-yl, or piperidin-4-yl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^cy5AN ; and -R ³ is -R ^3B . (282) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene; and is optionally substituted on carbon with one or more groups -R ^AR1C ; -Ar ² is independently pyridin-2-yl or pyrimidin-2-yl; and is optionally substituted on carbon with one or more groups -R ^AR2C ; Cy ⁵ -L ⁵ -X ⁵ - is Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is piperidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^cy5AC ; and optionally substituted on carbon with =O; and optionally substituted on secondary nitrogen with a group -R ^cy5AN ;

-R ³ is -R ^3B ; and -R ^3B is cyclopropyl.

(283) A compound according to (1), wherein:

-L ⁷ - is -CH ₂ -;

-Ar ¹ - is 1,4-phenylene;

-Ar ² is independently pyridin-2-yl or pyrimidin-2-yl;

Cy ⁵ -L ⁵ -X ⁵ - is Cy ⁵ -NH- (i.e., -L ⁵ - is a single bond and -X ⁵ - is -NH-);

-Cy ⁵ is -Cy ^5A ;

-Cy ^5A is piperidin-3-yl; and is: optionally substituted on carbon with one or more groups -R ^c y ^5AC ; and optionally substituted on secondary nitrogen, with a group -R ^cy5AN ;

-R ³ is -R ^3B ; and -R ^3B is cyclopropyl.

Specific Compounds

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

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., -L ⁷ -, -Ar ¹ -, -Ar ² , -X ⁵ -, -L ⁵ -, -Cy ⁵ , -R ³ , 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 PPA 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 l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and b-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., Ci-7alkyl 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, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH ₂ 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. keto enol enolate

For example, 1 H-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.

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 ¹ H, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ O and ¹⁸ 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 ), 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 ⁺ and K ⁺ , alkaline earth cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Al ³⁺ as well as the ammonium ion (i.e. , NhV). Examples of suitable organic cations include, but are not limited to substituted ammonium ions (e.g., NH ₃ R ⁺ , NH ₂ R ₂ +, NHR ₃ ⁺ , NR ₄ ⁺ ), for example, where each R is independently linear or branched saturated C _1-18 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkyl-C _1-6 alkyl, and phenyl-C _1-6 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 ₃ ) ₄ ⁺ .

If the compound is cationic, or has a functional group, which upon protonation may become cationic (e.g., -NH ₂ may become -NH ₃ ⁺ ), then a salt may be formed with a suitable anion.

For example, if a parent structure contains a cationic group (e.g., -NMe ₂ ⁺ ), or has a functional group, which upon protonation may become cationic (e.g., -NH ₂ may become -NH ₃ ⁺ ), 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 ₂ ⁺ , -NH ₃ ⁺ ), 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 -NMe2 ⁺ 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 (-OC(=O)CH _3I -OAC).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R ₂ C(OR) ₂ ), respectively, in which the carbonyl group (>C=O) is converted to a 1,1- diether (>C(OR) ₂ ), by reaction with, for example, a primary alcohol in the presence of an acid. The aldehyde or ketone group is readily regenerated, for example, by hydrolysis 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-CH3); a benzyloxy amide (-NHCO-OCH ₂ C ₆ H ₅ , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH ₃ )3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH ₃ ) ₂ C ₆ H ₄ C ₆ H ₅ , -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 Ci-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a Ci-7haloalkyl ester (e.g., a 2,2,2- trihaloethyl ester); a 2-tri(Ci- ₇ alkyl)silyl-ethyl ester; or a C5-2oaryl-Ci-7alkyl 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 ₂ NHC(=O)CH ₃ ).

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 (LI DEPT), 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 a PPA 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 a PPA compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient. Uses

The PPA 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 a PPA 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 PPA 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 PPA 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 a PPA 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 a PPA 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 PPA 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 a PPA 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 a PPA 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 PPA 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 a PPA 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 eta!., 2016; Choi et a!., 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, 2016). 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.

T reatment

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 PPA compounds described herein include the following: a DNA repair inhibitor; for example, a PARP inhibitor, for example, Olaparib, Niraparib, etc.; an immune checkpoint inhibitor; for example, an inhibitor of PD1, PD1L, CTLA4, etc., for example, pembrolizumab, atezolizumab, ipilimumab, 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 cell cycle checkpoint inhibitor; for example, an inhibitor of ATM, ATR, Wee1, etc., for example, AZD0156, AZD1390, AZD6738, adavosertib, etc.; a Her2 blocker; for example, herceptin, pertuzumab, lapatinib, etc.; a transcriptional inhibitor; for example, an inhibitor of BRD4, BRD2, CDK9, etc., for example, JQ-1, OTX015, AZD4573, etc.; and 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.).

Thus, in one embodiment, the treatment further comprises treatment (e.g., simultaneous or sequential treatment) with a further active agent which is, e.g., a DNA repair inhibitor, an immune checkpoint inhibitor, an agent stimulating the immune system, a cell cycle checkpoint inhibitor, a Her2 blocker, a transcriptional inhibitor, a cytotoxic chemotherapeutic agent, etc.

Further examples of additional agents/therapies that may be co-administered/combined with treatment with the PPA 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.; and an anti-androgen; for example, an anti-androgen used in the treatment of prostate cancer, for example, flutamide, enzalutamide, apalutamide, bicalutamide, nilutamide, etc.

Other Uses

The PPA compounds described herein may also be used as cell culture additives to inhibit CDK (e.g., CDK12 and/or CDK13).

The PPA 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 PPA 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) a PPA compound as described herein, or a composition comprising a PPA 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 PPA compound or pharmaceutical composition comprising the PPA 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 develoμment, for example, a foetus.

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

Formulations

While it is possible for a PPA compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one PPA 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 PPA 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 micro particulate 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 micro particulate). 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 pg/mL, for example from about 10 ng/mL to about 1 pg/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 PPA compounds, and compositions comprising the PPA 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 PPA compound, the route of administration, the time of administration, the rate of excretion of the PPA 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 PPA 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 PPA compound is in the range of about 10 pg to about 250 mg (more typically about 100 pg 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 aq: aqueous;

BOC: tert-butoxycarbonyl;

BoC ₂ O: di-tert-butyl dicarbonate; br: broad; car. circa ; d: doublet;

‘BuBrettPhos Pd G3: [(2-Di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisoprop yl-1,1'- biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(ll) methanesulfonate;

DCM: dichloromethane;

DCE: 1,2-dichloroethane; dioxane: 1,4-dioxane;

DIPEA: diisopropylethylamine;

DMAP: 4-(Dimethylamino)pyridine;

EtOAc: ethyl acetate;

EtOH: ethanol; h: hours;

HPLC: high performance liquid chromatography;

I PA: 2-isopropanol;

LCMS: liquid chromatography - mass spectrometry;

LiHMDS: lithium hexamethyldisilazide; m: multiplet;

M: molar, molecular ion; mCPBA: 3-chloroperbenzoic acid;

MeCN: actetonitrile;

MeOH: methanol; min: minutes;

MS: mass spectrometry;

NCS: N -chlorosuccinimide;

NIS: N -iodosuccinimide;

NMR: nuclear magnetic resonance;

Pd (dppf)Cl2-DCM: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane;

Pd-162: Chloro(crotyl)(tri-tert-butylphosphine) palladium (II);

Pd-171: Chloro(crotyl)(2-Dicyclohexylphosphino-2',6'-diisopropoxy-1, 1 '-biphenyl) palladium(ll) q: quartet;

RT: room temperature ( ca . 20 °C); R _T : retention time;

Ruphos: 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; s: singlet, solid;

SCX: strong cation exchange; t: triplet;

TBME: tert-butyl methyl ether;

TFA: trifluoroacetic acid;

THF: tetrahydrofuran;

UPLC/MS: ultra 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 20 (PerkinElmer).

General Synthetic Methods

Methods for the chemical synthesis of the PPA 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 PPA compounds.

In a first method, the synthesis starts with the 5,7-dichloro-3-pyrazolo[1,5-a]pyrimidine derivative 1-1. 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 with a primary or secondary amine to yield the intermediate I-4. Final global Boc-deprotection yields the target compounds I-5.

This method is illustrated in the following chemical scheme.

Scheme 1

Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 °C to 90 °C; (b) Boc ₂ O, DMAP, THF, RT to 60 °C; (c)

‘BuBrettPhos Pd G3, LiHMDS, THF, 60 °C; or Pd-171, Cs ₂ CO ₃ , dioxane, 90 °C; (d) TFA, DCM, RT; or HCI, dioxane, RT to 40 °C.

In a second method, intermediate I-3 is used in a Buchwald-Hartwig cross-coupling with an alcohol to yield the intermediate I-6. Final global Boc-deprotection yields the target compounds I-7.

This method is illustrated in the following chemical scheme. Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 °C to 90 °C; (b) Boc ₂ O, DMAP, THF, RT to 60 °C; (c) Pd-171, CS2CO3, dioxane, 90 °C; (d) TFA, DCM, RT; or HCI, dioxane, RT to 40 °C. In a third method, intermediate i-2 is used in a Buchwald-Hartwig cross-coupling with a primary or secondary amine to yield the intermediate I-8. Final global Boc-deprotection yields the target compounds I-5.

This method is illustrated in the following chemical scheme.

Scheme 3

Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 °C to 90 °C; (b)‘BuBrettPhos Pd G3, LiHMDS, dioxane, 90 °C; (c) TFA, DCM, RT; or HCI, dioxane, RT to 40 °C.

In a fourth method, intermediate i-2 is used in a nucleophilic aromatic substitution with an amine to yield i-8. Final global Boc-deprotection yields the target compounds i-5.

This method is illustrated in the following chemical scheme. Scheme 4

Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 °C to 90 °C; (b) DIPEA, NMP, 120 °C, microwave; (c) TFA, DCM, RT; or HCI, dioxane, RT to 40 °C.

In a fifth method, intermediate I-3 is used in a Negishi cross-coupling to yield 1-12. Final global Boc-deprotection yields the target compounds 1-13. This method is illustrated in the following chemical scheme. Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH or IPA, 50 °C to 90 °C; (b) Boc ₂ O, DMAP, THF, RT to 60 °C; (c) Pd(dppf)CI ₂ , THF, 50 °C; (d) TFA, DCM, RT; or HCI, dioxane, RT to 40 °C. In a sixth method, intermediate I-3 is used in a Suzuki cross-coupling to yield 1-12. Final global Boc-deprotection yields the target compounds 1-13.

This method is illustrated in the following chemical scheme.

Representative reactions conditions for the above scheme are as follows: (a) RNH2, DIPEA, EtOH , 50 °C to 90 °C; (b) Boc ₂ O, DMAP, THF, RT to 60 °C; (c) Pd(dppf)CI ₂ , potassium phosphate tribasic, dioxane, water, 90 °C; (d) TFA, DCM, RT; or HCI, dioxane, RT to 40 °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.

¹ H NMR spectra were recorded using a Bruker Avance III spectrometer (400 MHz) r 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 or Waters HPLC/UPLC system coupled to a mass spectrometer running Methods 1-8 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, Apparatus: Agilent 1260; Quaternary Pump, HiP Sampler, Column Compartment, DAD:260+/- 90nm, G6150 MSD: ESI; Column: Waters Codecs C18, 30 x 2.1 mm, 2.7μm, Temp: 40°C, Flow: 1.35 ml_/min, Gradient: t0 = 5% B, t2.5min = 100% B, t3.0min = 100% B, Eluent A: 0.1% Formic in water, Eluent B: acetonitrile.

Method 2:

UPLC_Acidic, Apparatus: Waters HCIass; Quaternary Solvent Pump, SM-FTN, CMA, PDA:210-400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30 x 2.1 mm, 1.7μm, Temp: 40°C, Flow: 0.77 mL/min, Gradient: tO = 5% B, t3.0min = 95% B, Eluent A: 0.1% Formic acid in water, Eluent B: acetonitrile.

Method 3:

UPLC_Basic, Apparatus: Waters HCIass; Binary Solvent Pump, SM-FTN, CMA, PDA:210-400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 x 2.1 mm, 1.7μm, Temp: 40°C, Flow: 0.77 mL/min, Gradient: tO = 5% B, t3.0min = 95% B, Eluent A: 0.1% NH3 in water or 10 nM ammonium bicarbonate, Eluent B: acetonitrile.

Method 4:

UPLC_Acid, Apparatus: Waters HCIass; Quaternary Solvent Pump, SM-FTN, CMA, PDA:210-400 nm, QDa: ACQ-QDa ESI; Column: Waters CSH C18, 30 x 2.1 mm, 1.7μm, Temp: 40°C, Flow: 0.77 mL/min, Gradient: tO = 2% B, t2.5min = 100% B, t3.0min = 100% B, Eluent A: 0.1% Formic acid in water, Eluent B: acetonitrile. Method 5:

UPLC_Basic, Apparatus: Waters HCIass; Binary Solvent Pump, SM-FTN, CMA, PDA:210-400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 x 2.1 mm, 1.7μm, Temp: 40°C, Flow: 0.77 mL/min, Gradient: tO = 2% B, t2.5min = 100% B, t3.0min = 100% B, Eluent A: 0.1% NH3 in water or 10 nM ammonium bicarbonate, Eluent B: acetonitrile.

Method 6:

UPLC_Basic, Apparatus: Waters HCIass; Binary Solvent Pump, SM-FTN, CMA, PDA:210-400 nm, QDa: ACQ-QDa ESI; Column: Waters BEH C18, 30 x 2.1 mm, 1.7μm, Temp: 40°C, Flow: 0.77 mL/min, Gradient: tO = 2% B, t9.5min = 100% B, tIO.Omin = 100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

Method 7:

LCMS_Acidic, Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:260+/- 90nm, G6150 MSD: ESI; Column: Waters Codecs C18, 30 x 2.1 mm, 2.7μm, Temp: 40°C, Flow: 1.35 mL/min, Gradient: tO = 5% B, t2.5min = 100% B, t3.0min = 100% B, Eluent A: 0.1% Formic in water, Eluent B: acetonitrile.

Method 8:

LCMS_Basic, Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:260+/- 90nm, G6150 MSD: ESI; Column: Waters XBridge C18, 30 x 2.1 mm, 2.5μm, Temp: 40°C, Flow: 1.35 mL/min, Gradient: tO = 5% B, t2.5min = 100% B, t3.0min = 100% B, Eluent A: 0.1% NH3 in water, Eluent B: acetonitrile.

Synthesis 001

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

Step 1/2 tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrid in-2- yl)benzyl)carbamate DIPEA (0.34 mL, 1.95 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (150 mg, 0.65 mmol) and (4-(pyridin-2- yl)phenyl)methanamine, 2HCI (184 mg, 0.72 mmol) in dioxane (5.0 mL). The reaction mixture was heated to 90 °C for 2 h. At RT, DCM (25 mL) and water (10 mL) were added. The organic layer was separated, dried over Na2SC>4, filtered and concentrated in vacuo. The residue was dissolved in THF (4.0 mL). DMAP (3.9 mg, 33 μmol) and BOC-anhydride (171 mg, 0.78 mmol) were added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-50% EtOAc/isohexane) gave the title compound (219 mg, 0.45 mmol, 69% yield, 99% purity) as a colourless oil.

LCMS (Method 1): m/z 478 (M+H) ⁺ , R _T 2.80 min.

Step 3/4

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

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrid in-2- yl)benzyl)carbamate (100 mg, 210 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (58 mg, 251 μmol) in THF (3.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (8.9 mg, 10.5 μmol) and LiHMDS (1M in THF) (209 pL, 209 μmol). The reaction concentrated in vacuo and the residue dissolved in dioxane (3.0 mL). Hydrogen chloride (4 M in dioxane) (5.0 mL, 20 mmol) was added, and the reaction mixture was stirred at RT for 1 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (28 mg, 59 μmol, 28% yield, 99% purity) as a white solid.

LCMS (Method 1): m/z 472 (M+H) ⁺ , R _T 0.98 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.00 (t, J = 6.5 Hz, 1 H), 7.93 (dt, = 8.1 , 1.2 Hz, 1H), 7.90 - 7.81 (m, 1H), 7.66 (s,

1 H), 7.46 (d, J = 8.3 Hz, 2H), 7.34 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.85 - 6.73 (m, 1 H), 5.62 - 5.48 (m, 1 H), 5.16 (s, 1 H), 4.50 (d, J = 6.5 Hz, 2H), 3.62 - 3.46 (m, 1 H), 3.23 - 3.14 (m, 1H), 3.13 - 3.04 (m, 1H), 3.00 - 2.89 (m, 2H), 2.89 - 2.82 (m, 1 H), 2.44 - 2.35 (m, 1 H), 2.30 - 2.21 (m, 1 H), 1.63 - 1.55 (m, 1 H), 1.45 - 1.31 (m, 1H), 1.23 (dd, J = 6.9, 5.8 Hz, 6H), 1.19 - 1.13 (m, 1H). 1H under water. Synthesis 002

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

Step 1 :

5-chloro-3-isopropyl-N-(4-(pyridin-4-yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine

DIPEA (0.35 L, 2.0 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (80 mg, 0.35 mmol) and (4-(pyridin-4- yl)phenyl)methanamine (77 mg, 0.42 mmol) in EtOH (1.5 mL). The reaction mixture was heated to 65 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (120 mg, 0.25 mmol, 73% yield, 80% purity) as a brown oil.

UPLC/MS (Method 3): m/z 378 (M+H) ⁺ , R _T 0.78 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrid in-4- yl)benzyl)carbamate

DMAP (9 mg, 74.6 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyridin-4- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (120 mg, 255 μmol) and BOC-anhydride (98 mg, 0.45 mmol) in anhydrous THF (5.0 mL). The reaction mixture was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 mL) and washed with brine (3 x 10 mL). The combined organics was filtered through a phase separator, concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (76 mg, 0.15 mmol, 59% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 478 (M+H) ⁺ , R _T 1.57 min. Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-4-yl)benzyl )amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrid in-4- yl)benzyl)carbamate (76 mg, 135 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (38 g, 166 μmol) in THF (3.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (12 mg, 13.5 μmol) and LiHMDS (1M in THF) (195 pL, 195 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 2 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc (15 ml_). The filtrate was diluted with water (10 ml_) and the aq. layer was extracted with EtOAc (3 x 20 ml_). The combined organic was washed with brine (20 ml_), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 30-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (39 mg, 55 μmol, 17% yield, 95% purity) as a colourless glass solid.

UPLC/MS (Method 2): m/z 672 (M+H) ⁺ , R _T 1.48 min.

Step 4:

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

Hydrogen chloride (4 M in dioxane) (0.31 ml_, 1.22 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-4-yl)benzyl )amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (43 mg, 61 μmol) in dioxane (0.5 ml_). The reaction mixture was stirred at 40 °C for 1 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (21 mg, 42 μmol, 69% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 472 (M+H)+, R _T 0.51 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 - 8.58 (m, 2H), 7.96 (t, J = 6.5 Hz, 1 H), 7.81 - 7.75 (m, 2H), 7.71 - 7.67 (m, 2H), 7.65 (s, 1 H), 7.53 - 7.46 (m, 2H), 6.78 - 6.72 (m, 1H), 5.55 - 5.45 (m, 1H), 5.18 (s, 1H), 4.51 (d, J = 6.5 Hz, 2H), 3.63 - 3.43 (m, 1H), 3.27 - 3.18 (m, 1 H), 3.18 - 3.07 (m, 1H), 3.03 - 2.82 (m, 3H), 2.47 - 2.37 (m, 1H), 2.34 - 2.24 (m, 1H), 1.66 - 1.57 (m, 1H), 1.45 - 1.33 (m, 1H), 1.26 - 1.17 (m, 7H). 1 H under water. Synthesis 003

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

Step 1 :

5-chloro-3-isopropyl-N-(4-(pyridin-3-yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine

DIPEA (0.35 ml_, 2.0 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (80 mg, 0.35 mmol) and (4-(pyridin-3- yl)phenyl)methanamine (77 mg, 0.42 mmol) in EtOH (1.5 ml_). The reaction mixture was heated to 65 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (124 mg, 0.26 mmol, 75% yield, 80% purity) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 - 8.95 (m, 1 H), 8.90 - 8.84 (m, 1H), 8.55 (dd, J = 4.7, 1.6 Hz, 1 H), 8.08 - 8.01 (m, 2H), 7.75 - 7.67 (m, 2H), 7.58 - 7.49 (m, 2H), 7.49 - 7.45 (m, 1H), 6.14 (s, 1 H), 4.68 (d, J = 6.1 Hz, 2H), 3.09 (p, J = 6.9 Hz, 1 H), 1.28 (d, J = 6.9 Hz, 6H).

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrid in-3- yl)benzyl)carbamate

DMAP (9 mg, 74.6 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyridin-3- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (124 mg, 255 μmol) and BOC-anhydride (98 mg, 0.45 mmol) in anhydrous THF (5 ml_). The reaction mixture was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 ml_) and washed with brine (3 x 10 ml_). The combined organics was filtered through a phase separator, concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (103 mg, 183 μmol, 66% yield, 85% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 478 (M+H) ⁺ , R _T 1.79 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-3-yl)benzyl )amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(pyridin-3- yl)benzyl)carbamate (103 mg, 183 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (52 mg, 225 μmol) in THF (3.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (15.6 mg, 18.3 μmol) and LiHMDS (1M in THF) (225 pL, 225 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 2 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc (15 ml_). The filtrate was diluted with water (10 ml_) and the aq. layer was extracted with EtOAc (3 x 20 ml_). The combined organic was washed with brine (20 ml_), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 30-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (79 mg, 110 μmol, 33% yield, 90% purity) as a colourless glass solid.

UPLC/MS (Method 2): m/z 672 (M+H) ⁺ , R _T 1.66 min.

Step 4:

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

Hydrogen chloride (4 M in dioxane) (0.47 mL, 1.89 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-3-yl)benzyl )amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (79 mg, 94 μmol) in dioxane (1.0 mL). The reaction mixture was stirred at 40 °C for 2 h and concentrated in vacuo. The solid was triturated in MeCN (3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (38 mg, 76 μmol, 80% yield, 95% purity) as a yellow solid.

LCMS (Method 2): m/z 472 (M+H) ⁺ , R _T 0.58 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 - 8.86 (m, 1H), 8.56 (dd, J = 4.7, 1.6 Hz, 1H), 8.07 - 8.01 (m, 1 H), 7.97 (t, J = 6.5 Hz, 1 H), 7.73 - 7.68 (m, 2H), 7.65 (s, 1 H), 7.53 - 7.43 (m, 3H), 6.79 (t, J = 6.2 Hz, 1 H), 5.64 (s, 1 H), 5.19 (s, 1 H), 4.51 (d, J = 6.5 Hz, 2H), 3.56 - 3.46 (m, 1H), 3.28 - 3.15 (m, 3H), 3.08 - 2.99 (m, 1H), 2.99 - 2.88 (m, 2H), 2.43 - 2.31 (m, 1 H), 1.71 - 1.61 (m, 1H), 1.53 - 1.38 (m, 1H), 1.34 - 1.26 (m, 1H), 1.23 (dd, J = 6.9, 5.2 Hz, 6H). 1H under water.

Synthesis 004

(3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyr imidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

N-([1,T-biphenyl]-4-ylmethyl)-5-chloro-3-isopropylpyrazol o[1,5-a]pyrimidin-7-amine

DIPEA (0.37 ml_, 2.1 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (81 mg, 0.35 mmol) and [1,1'-biphenyl]-4- ylmethanamine (77 mg, 0.42 mmol) in EtOH (1.4 ml_). The reaction mixture was heated to 80 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (95 mg, 0.24 mmol, 68% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 377 (M+H) ⁺ , R _T 1.97 min.

Step 2: tert-butyl ([1 ,T-biphenyl]-4-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5-a] pyrimidin-7- yl)carbamate

DMAP (5.8 mg, 48 μmol) was added to a solution of N-([1 ,T-biphenyl]-4-ylmethyl)-5- chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (95 mg, 239 μmol) and BOC- anhydride (63 mg, 287 μmol) in anhydrous THF (4.8 ml_). The reaction mixture was heated at 65 °C for 2 h then more BOC-anhydride (45 mg, 210 μmol) was added and the reaction mixture was heated at 65 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted in DCM (15 ml_) and washed with brine (3 x 10 ml_). The combined organics was filtered through a phase separator, concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (91 mg, 180 μmol, 75% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 421 (M-‘Bu+H) ⁺ , R _T 2.20 min.

Step 3: tert-butyl (3R,4R)-4-(((7-(([1 , 1 '-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl ([1 ,T-biphenyl]-4-ylmethyl)(5-chloro-3-isopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (91 mg, 180 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (62 mg, 271 μmol) in THF (2.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (15.4 mg, 18.0 μmol) and LiHMDS (1M in THF) (217 pL, 217 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 1.5 h. The reaction mixture was cooled to RT, filtered through celite and washed with EtOAc (15 mL). The filtrate was diluted with water (10 mL) and the aq. layer was extracted with EtOAc (3 x 20 mL). The combined organic was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (95 mg, 130 μmol, 74% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 671 (M+H) ⁺ , R _T 2.10 min.

Step 4:

(3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-isopropylpyrazolo[1,5-a]pyr imidin-5- yl)amino)methyl)piperidin-3-ol

TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-(([1 ,T-biphenyl]-4- ylmethyl)(tert-butoxycarbonyl)amino)-3-isopropylpyrazolo[1,5 -a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (94 mg, 130 μmol) in DCM (2.0 mL). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was triturated in Et ₂ O (2 x 3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (50 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (60 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (43 mg, 90 μmol, 67% yield, 98% purity) as a beige solid.

UPLC/MS (Method 3): m/z 471 (M+H) ⁺ , RT 1.57 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.91 (t, J = 6.5 Hz, 1 H), 7.68 - 7.59 (m, 5H), 7.49 - 7.41

(m, 4H), 7.39 - 7.32 (m, 1 H), 6.74 - 6.68 (m, 1 H), 5.34 - 5.27 (m, 1 H), 5.20 (s, 1 H), 4.49

(d, J = 6.0 Hz, 2H), 3.59 - 3.45 (m, 1H), 3.25 - 3.15 (m, 1H), 3.08 - 2.98 (m, 1H), 2.98 - 2.87 (m, 2H), 2.83 - 2.73 (m, 1H), 2.37 - 2.26 (m, 1H), 2.20 - 2.11 (m, 1 H), 1.62 - 1.51 (m, 1H), 1.37 - 1.28 (m, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.18 - 1.11 (m, 1 H). 1 H under water.

Synthesis 005

(3R,4R)-4-(((3-ethyl-7-((4-(pyridin-2-yl)benzyl)amino)pyr azolo[1 ,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-ethyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a ]pyrimidin-7-amine

DIPEA (0.99 ml_, 5.70 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5- a]pyrimidine (176 mg, 0.81 mmol) and (4-(pyridin-2-yl)phenyl)methanamine (150 mg, 814 μmol) in EtOH (4.0 ml_). The reaction mixture was heated to 50 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (179 mg, 0.48 mmol, 59% yield, 98% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 365 (M+H) ⁺ , R _T 1.58 min.

Step 2: tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2 -yl)benzyl)carbamate

DMAP (11.8 mg, 96 μmol) was added to a solution of 5-chloro-3-ethyl-N-(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (179 mg, 482 μmol) and BOC-anhydride (126 mg, 579 μmol) in anhydrous THF (5.0 ml_). The reaction mixture was stirred at RT overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-5% MeOH/DCM) gave the title compound (95 g, 180 μmol, 38% yield, 90% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 465 (M+H) ⁺ , R _T 1.94 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypi peridine-1-carboxylate

A solution of tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2 - yl)benzyl)carbamate (95 mg, 200 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (57 mg, 250 μmol) in THF (3.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17 mg, 20.0 μmol) and LiHMDS (1M in THF) (270 pL, 270 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 4 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 0-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (76 mg, 110 μmol, 55% yield, 97% purity) a white solid.

UPLC/MS (Method 3): m/z 658 (M+H) ⁺ , R _T 1.80 min.

Step 4:

(3R,4R)-4-(((3-ethyl-7-((4-(pyridin-2-yl)benzyl)amino)pyr azolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

TFA (0.2 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin- 5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (76 mg, 120 μmol) in DCM (0.8 mL). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was triturated in Et ₂ O (2 x 3 mL) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 mL) to give the title compound (38 mg, 83 μmol, 72% yield, 99% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 458 (M+H) ⁺ , RT 1.20 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 (dt, J = 4.6, 1.6 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 - 7.90 (m, 2H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.65 (s, 1 H), 7.46 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 6.74 (t, J = 6.1 Hz, 1H), 5.47 - 5.38 (m, 1H), 5.18 (s, 1 H), 4.51 (d, J = 6.3 Hz, 2H), 3.60 - 3.46 (m, 1H), 3.19 - 3.11 (m, 1H), 3.05 - 2.95 (m, 1H), 2.89 (dd, J = 11.6, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.48 - 2.44 (m, 2H), 2.34 - 2.25 (m, 1H), 2.15 (dd, 1H), 1.57 - 1.49 (m, 1H), 1.35 - 1.26 (m, 1H), 1.17 (t, J = 7.5 Hz, 3H), 1.15 - 1.07 (m, 1 H). 1 H under water.

Synthesis 006

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo [1,5-a]pyrimidin-7-amine

DIPEA (0.99 ml_, 5.70 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (186 mg, 814 μmol) and (4-(pyridin-2- yl)phenyl)methanamine (150 mg, 814 μmol) in EtOH (4.0 ml_). The reaction mixture was heated to 50 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (239 mg, 0.52 mmol, 64% yield, 82% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 376 (M+H) ⁺ , R _T 1.59 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate

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

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (164 g, 345 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (95 mg, 413 μmol) in THF (4.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (29 mg, 34.5 μmol) and LiHMDS (1M in THF) (448 pL, 448 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 0-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (124 mg, 0.17 mmol, 50% yield, 93% purity) a white solid.

UPLC/MS (Method 3): m/z 670 (M+H) ⁺ , R _T 1.80 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

TFA (0.3 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (124 mg, 185 μmol) in DCM (1.2 ml_). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was loaded onto a column of SCX. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (44 mg, 93 μmol, 50% yield, 99% purity) as an off- white solid.

UPLC/MS (Method 3): m/z 470 (M+H) ⁺ , RT 1.22 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.96 - 7.91 (m, 1H), 7.90 - 7.83 (m, 2H), 7.52 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.71 (t, J = 5.8 Hz, 1 H), 5.33 - 5.26 (m, 1H), 5.18 (s, 1 H), 4.50 (d, J = 6.2 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.24 - 3.13 (m, 1 H), 3.06 - 2.97 (m, 1H), 2.90 (dd, J = 11.5, 4.5 Hz, 1 H), 2.81 - 2.73 (m, 1H), 2.33 - 2.24 (m, 1H), 2.21 - 2.08 (m, 1 H), 1.76 - 1.66 (m, 1H), 1.58 - 1.51 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.09 (m, 1H), 0.79 - 0.72 (m, 2H), 0.70 - 0.60 (m, 2H). 1 H under water.

Synthesis 007

(3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-isopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazolo [1,5-a]pyrimidin-7-amine

DIPEA (0.34 ml_, 2.0 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (75 mg, 0.33 mmol) and (4-(pyrimidin-2- yl)phenyl)methanamine (63 mg, 0.34 mmol) in EtOH (3.0 ml_). The reaction mixture was heated to 75 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (120 mg, 0.30 mmol, 92% yield, 95% purity) as an off-white solid

UPLC/MS (Method 3): m/z 401 (M+Na) ⁺ , R _T 1.65 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrim idin-2- yl)benzyl)carbamate

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

1 H), 4.72 (d, J = 5.7 Hz, 2H), 3.09 (p, J = 6.9 Hz, 1 H), 1.28 (d, J = 6.9 Hz, 6H).

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benz yl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrim idin-2- yl)benzyl)carbamate (130 mg, 0.26 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (69 mg, 0.30 mmol) in THF (2.5 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (23 mg, 27.1 μmol) and LiHMDS (1M in THF) (285 pl_, 285 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 1.5 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 15- 75% MeCN/10 mM ammonium bicarbonate) gave the title compound (108 mg, 150 μmol, 56% yield, 95% purity) a colourless oil.

UPLC/MS (Method 3): m/z 673 (M+H) ⁺ , R _T 1.83 min.

Step 4:

(3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.61 ml_, 2.4 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benz yl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (108 mg, 0.16 mmol) in dioxane (1.0 ml_). The reaction mixture was stirred at 35 °C for 2 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (60 mg, 120 μmol, 76% yield, 96% purity) as a pink solid.

LCMS (Method 3): m/z 473 (M+H)+, RT 1.24 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 (d, J = 4.8 Hz, 2H), 8.37 (d, J = 8.4 Hz, 2H), 7.94 (t, J = 6.4 Hz, 1 H), 7.64 (s, 1 H), 7.50 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1 H), 6.70 (t, J = 5.7 Hz, 1 H), 5.31 - 5.24 (m, 1H), 5.16 (s, 1 H), 4.53 (d, J = 6.4 Hz, 2H), 3.59 - 3.43 (m,

1 H), 3.22 - 3.13 (m, 1H), 3.05 - 2.96 (m, 1 H), 2.96 - 2.92 (m, 1H), 2.92 - 2.85 (m, 1H), 2.79 - 2.73 (m, 1H), 2.32 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1 H), 1.56 - 1.49 (m, 1H), 1.36 - 1.27 (m, 1 H), 1.25 - 1.20 (m, 6H), 1.18 - 1.12 (m, 1 H). 1 H under water.

Synthesis 008

(3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-4-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-isopropyl-N-(4-(pyrimidin-4-yl)benzyl)pyrazolo [1,5-a]pyrimidin-7-amine

DIPEA (90 μL_, 520 μmol) was added to a solution of 5,7-dichloro-3-isopropylpyrazolo[1,5- a]pyrimidine (34 g, 150 μmol) and (4-(pyrimidin-4-yl)phenyl)methanamine (29 mg, 74 μmol) in EtOH (1.0 ml_). The reaction mixture was heated to 50 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (32 mg, 73 μmol, 100% yield, 87% purity) as a white solid.

UPLC/MS (Method 3): m/z 379 (M+H) ⁺ , R _T 1.54 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrim idin-4- yl)benzyl)carbamate

DMAP (2.1 mg, 17 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(pyrimidin- 4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (32 mg, 84 μmol) and BOC-anhydride (22 mg, 100 μmol) in anhydrous THF (1.0 mL). The reaction mixture was heated at RT overnight then concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (23 mg, 47 μmol, 55% yield, 97% purity) as a colourless glass solid.

UPLC/MS (Method 3): m/z 379 (M-Boc+H) ⁺ , R _T 1.87 min. Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-4-yl)benz yl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyrim idin-4- yl)benzyl)carbamate (23 mg, 48 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (13 g, 58 μmol) in THF (1.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (4.1 mg, 4.8 μmol) and LiHMDS (1M in THF) (62 pL, 62 μmol). The reaction was degassed for another 5 min before being heated to 75 °C for 2 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (26 mg, 37 μmol, 78% yield, 97% purity) a yellow solid.

UPLC/MS (Method 3): m/z 673 (M+H) ⁺ , R _T 1.76 min.

Step 4:

(3R,4R)-4-(((3-isopropyl-7-((4-(pyrimidin-4-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

TFA (0.10 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)(4-(pyrimidin-4-yl)benzyl)amino)-3-isopropylp yrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (26 mg, 37 μmol) in DCM (0.4 ml_). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid triturated in Et ₂ O (3 x 1 ml_) to give the title compound (16 mg, 32 μmol, 86% yield, 95% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 473 (M+H) ⁺ , RT 1.15 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.23 (d , J = 1.4 Hz, 1 H), 8.84 (d, J = 5.5 Hz, 1H), 8.19 (d, J = 8.4 Hz, 2H), 8.06 (dd, J = 5.4, 1.4 Hz, 1 H), 7.95 (t, J = 6.5 Hz, 1 H), 7.65 (s, 1 H), 7.52 (d, J = 8.2 Hz, 2H), 6.69 (s, 1 H), 5.30 - 5.23 (m, 1H), 5.16 (s, 1 H), 4.54 (d, J = 6.4 Hz, 2H), 3.57 - 3.43 (m, 1 H), 3.22 - 3.14 (m, 1H), 3.06 - 2.97 (m, 1H), 2.97 - 2.92 (m, 1 H), 2.92 - 2.85 (m, 1H), 2.79 - 2.72 (m, 1 H), 2.32 - 2.22 (m, 1H), 2.19 - 2.10 (m, 1H), 1.58 - 1.49 (m, 1H), 1.30 (s, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.14 - 1.07 (m, 1 H). 1 H under water. Synthesis 009

(4-(pyrimidin-4-yl)phenyl)methanamine

Step A:

4-(pyrimidin-4-yl)benzonitrile

4-chloropyrimidine, HCI (100 mg, 662 μmol), Pd(Ph3P)4 (23 g, 19.9 μmol), (4- cyanophenyl)boronic acid (107 mg, 729 μmol) and sodium carbonate (211 mg, 1.99 mmol) were taken up in toluene (5.0 ml_), methanol (2.5 ml_) and water (2.5 ml_). The mixture was sparged with N2 for 15 min then heated to 100 °C for 24 h then allowed to cool to RT. The mixture was diluted with EtOAc (20 ml_) and water (20 ml_). The layers were separated, and the organic layer was washed with brine (10 ml_) then dried over MgSCU, filtered then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (42 mg, 220 μmol, 33% yield, 95% purity) as a white solid.

UPLC/MS (Method 3): m/z 182 (M+H)+, R _T 0.953 min.

Step B:

(4-(pyrimidin-4-yl)phenyl)methanamine

4-(pyrimidin-4-yl)benzonitrile (42 mg, 0.23 mmol) in MeOH (20 ml_) was subjected to hydrogenation in the H-cube for 4 h at RT using a Raney Nickel cartridge, recirculating the mixture through the cartridge (flow rate: 1 mL/min). The solvent was concentrated in vacuo to give the title compound (27 mg, 69 μmol, 30% yield, 47% purity) as a white solid.

UPLC/MS (Method 3): m/z 186 (M+H)+, R _T 0.67 min.

Synthesis 010

(3R,4R)-4-(((7-((4-(1 H-pyrazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyr imidin-

5-yl)amino)methyl)piperidin-3-ol

Step 1 :

N-(4-(1 H-pyrazol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a] pyrimidin-7-amine

DIPEA (0.64 ml_, 3.67 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (120 mg, 0.53 mmol) and (4-(1H-pyrazol-1- yl)phenyl)methanamine (100 mg, 0.58 mmol) in EtOH (3.0 ml_). The reaction mixture was heated to 50 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (170 mg, 0.44 mmol, 84% yield, 95% purity) as a white solid.

UPLC/MS (Method 3): m/z 365 (M+H) ⁺ , R _T 1.54 min.

Step 2: tert-butyl (4-(1 H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5-a] pyrimidin-7- yl)carbamate

DMAP (11 mg, 93 μmol) was added to a solution of N-(4-(1 H-pyrazol-1-yl)benzyl)-5- chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (122 mg, 466 μmol) and BOC- anhydride (122 mg, 559 μmol) in anhydrous THF (4.0 ml_). The reaction mixture was heated at RT overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (158 mg, 290 μmol, 63% yield, 86% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 365 (M-Boc+H) ⁺ , R _T 1.87 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((4-(1 H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (4-(1 H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (158 mg, 340 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (86 g, 374 μmol) in THF (3.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (29 mg, 34 μmol) and LiHMDS (1M in THF) (0.44 ml_, 0.44 mmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (182 mg, 0.26 mmol, 77% yield, 95% purity) a brown glass solid.

UPLC/MS (Method 3): m/z 659 (M+H) ⁺ , R _T 1.76 min.

Step 4:

(3R,4R)-4-(((7-((4-(1 H-pyrazol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyr imidin-

5-yl)amino)methyl)piperidin-3-ol

TFA (0.80 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((4-(1 H-pyrazol-1- yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[ 1,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (182 mg, 276 μmol) in DCM (2.2 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid triturated in Et ₂ O (3 x 1 ml_) to give the title compound (81 mg, 170 μmol, 62% yield, 97% purity) as a cream solid.

UPLC/MS (Method 3): m/z 459 (M+H)+, RT 1.20 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.45 (d, J = 2.5 Hz, 1 H), 7.88 (t, J = 6.5 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 1.8 Hz, 1H), 7.52 (s, 1 H), 7.46 (d, J = 8.6 Hz, 2H), 6.70 (t, J = 6.1 Hz, 1 H), 6.56 - 6.49 (m, 1H), 5.35 - 5.26 (m, 1H), 5.18 (s, 1 H), 4.47 (d, J = 6.4 Hz, 2H), 3.59 - 3.44 (m, 1H), 3.23 - 3.15 (m, 1 H), 3.07 - 2.98 (m, 1H), 2.90 (dd, J = 11.7, 4.5 Hz, 1 H), 2.83 - 2.72 (m, 1H), 2.35 - 2.24 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1 H), 1.77 - 1.67 (m, 1H), 1.59 - 1.51 (m, 1H), 1.40 - 1.26 (m, 1H), 1.20 - 1.11 (m, 1H), 0.76 (dq, J = 8.2, 1.3 Hz, 2H), 0.69 - 0.60 (m, 2H). 1 H under water. Svnthesis 011

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

Step 1 :

5-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a] pyrimidine-3-carbonitrile

DIPEA (0.99 mL, 5.70 mmol) was added to a solution of 5,7-dichloropyrazolo[1,5- a]pyrimidine-3-carbonitrile (173 mg, 0.81 mmol) and (4-(pyridine-2- yl)phenyl)methanamine (150 mg, 0.81 mmol) in EtOH (4.0 mL). The reaction mixture was heated to 50 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (166 mg, 0.45 mmol, 55% yield, 98% purity) as an orange solid.

UPLC/MS (Method 3): m/z 361 (M+H) ⁺ , R _T 1.35 min.

Step 2: tert-butyl (5-chloro-3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2 -yl)benzyl)carbamate

DMAP (10.8 mg, 89 μmol) was added to a solution of 5-chloro-7-((4-(pyridin-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (160 mg, 443 μmol) and BOC- anhydride (116 mg, 532 μmol) in anhydrous THF (4.0 mL). The reaction mixture was heated at RT overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-5% MeOH/DCM) gave the title compound (120 mg,

250 μmol, 56% yield, 95% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 461 (M+H) ⁺ , R _T 1.71 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyanopyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypi peridine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2 - yl)benzyl)carbamate (120 mg, 247 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (72 g, 310 μmol) in THF (3.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (22 mg, 26 μmol) and LiHMDS (1M in THF) (0.34 ml_, 0.34 mmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (24 g cartridge, 20-80% MeCN/10 mM ammonium bicarbonate) gave the title compound (113 mg, 0.16 mmol, 65% yield, 93% purity) a yellow glass solid.

UPLC/MS (Method 3): m/z 655 (M+H) ⁺ , R _T 1.67 min.

Step 4:

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

TFA (0.30 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3-cyanopyrazol o[1,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (113 mg, 173 μmol) in DCM (0.90 ml_). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid triturated in Et ₂ O (3 x 1 ml_). Purification by RP preparative HPLC (45-100% MeCN/0.3% NH3 in water) gave the title compound (22 mg, 46 μmol, 27% yield, 95% purity) as a white solid.

UPLC/MS (Method 3): m/z 455 (M+H) ⁺ , RT 1.12 min.

¹ H was performed at 50 °C.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 (d, J = 4.8 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 8.2 Hz, 2H), 7.99 - 7.91 (m, 1 H), 7.91 - 7.81 (m, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.38 - 7.26 (m,

1 H), 7.03 - 6.94 (m, 1H), 5.47 (s, 1H), 4.62 - 4.53 (m, 3H), 3.50 (dt, J = 13.6, 4.8 Hz, 1H), 3.38 - 3.27 (m, 1 H), 3.26 - 3.17 (m, 1H), 2.91 - 2.83 (m, 1H), 2.41 (td, J = 12.1, 2.9 Hz,

1 H), 2.33 - 2.25 (m, 1H), 1.78 - 1.66 (m, 1 H), 1.54 - 1.43 (m, 1H), 1.24 - 1.11 (m, 1H). 2H under water. Synthesis 012

(3R,4R)-4-(((3-isopropyl-7-((3-methyl-4-(pyridin-2-yl)ben zyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-isopropyl-N-(3-methyl-4-(pyridin-2-yl)benzyl)p yrazolo[1,5-a]pyrimidin-7-amine

DIPEA (0.68 ml_, 3.89 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (128 mg, 217 μmol) and (3-methyl-4-(pyridin-2- yl)phenyl)methanamine (110 mg, 555 μmol) in EtOH (4.0 ml_). The reaction mixture was heated to 50 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (49 mg, 88 μmol, 40% yield, 70% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 392 (M+H) ⁺ , R _T 1.79 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methyl -4-(pyridin-2- yl)benzyl)carbamate

DMAP (2.1 mg, 18 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(3-methyl-4- (pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (49 mg, 88 μmol) and BOC- anhydride (23 mg, 110 μmol) in anhydrous THF (1.0 ml_). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (55 mg, 75 μmol, 86% yield, 67% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 392 (M-Boc+H) ⁺ , R _T 2.03 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methyl-4-(pyridin-2- yl)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-methyl -4- (pyridin-2-yl)benzyl)carbamate (55 mg, 75 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (31 mg, 130 μmol) in THF (1.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (9.5 mg, 11 μmol) and LiHMDS (1M in THF) (0.14 ml_, 0.14 mmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2 h. The reaction mixture was cooled to RT and concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH/DCM) followed by further purification on RP Flash C18 (4 g cartridge, 0-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (33 mg, 48 μmol, 64% yield, 99% purity) a white solid.

UPLC/MS (Method 3): m/z 686 (M+H) ⁺ , R _T 1.89 min.

Step 4:

(3R,4R)-4-(((3-isopropyl-7-((3-methyl-4-(pyridin-2-yl)ben zyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

TFA (0.25 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)(3-methyl-4-(pyridin-2-yl)benzyl)amino)-3-iso propylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (33 mg, 48 μmol) in DCM (0.75 ml_). The reaction mixture was stirred at RT overnight and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid triturated in Et ₂ O (3 x 1 ml_) to give the title compound (13 mg, 25 μmol, 53% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 486 (M+H)+, RT 1.35 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.94 - 7.81 (m, 2H), 7.64 (s, 1H), 7.54 - 7.46 (m, 1 H), 7.39 - 7.31 (m, 2H), 7.31 - 7.21 (m, 2H), 6.78 - 6.68 (m, 1 H), 5.47 - 5.23 (m, 1 H), 5.19 (s, 1 H), 4.47 (d, J = 6.4 Hz, 2H), 3.62 - 3.45 (m, 1H), 3.24 - 3.16 (m, 1H), 3.09 - 2.99 (m, 1 H), 2.99 - 2.87 (m, 2H), 2.83 - 2.75 (m, 1H), 2.36 - 2.25 (m, 4H), 2.17 (t, J = 10.6 Hz, 1H), 1.61 - 1.51 (m, 1 H), 1.40 - 1.29 (m, 1 H), 1.27 - 1.19 (m, 6H), 1.18 - 1.12 (m, 1H). 1H under water. Svnthesis 013

(3-methyl-4-(pyridin-2-yl)phenyl)methanamine

Step A:

3-methyl-4-(pyridin-2-yl)benzonitrile

2-Bromopyridine (250 mg, 1.58 mmol), (4-cyano-2-methylphenyl)boronic acid (331 mg, 2.06 mmol) Pd(dppf)Cl2.DCM (129 mg, 158 μmol) and potassium carbonate (656 mg, 4.75 mmol) were taken up in dioxane (9.0 ml_) and water (1.0 ml_). The reaction mixture was sparged with N2 for 15 min then heated to 90 °C for 2 h then allowed to cool to RT. The mixture was diluted with EtOAc (20 ml_) and water (20 ml_). The layers were separated, and the organic layer was washed with brine (10 ml_) then dried over MgSO4 _, filtered then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (290 mg, 1.3 mmol, 85% yield, 90% purity) as an orange oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.70 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.98 - 7.91 (m, 1H), 7.87 - 7.80 (m, 1 H), 7.76 (dd, J = 8.0, 1.7 Hz, 1 H), 7.63 - 7.54 (m, 2H), 7.44 (ddd, J = 7.6, 4.8, 1.1 Hz, 1 H), 2.35 (s, 3H).

Step B:

(3-methyl-4-(pyridin-2-yl)phenyl)methanamine

3-Methyl-4-(pyridin-2-yl)benzonitrile (143 mg, 736 μmol) in MeOH/0.7M NH3 (20 ml_) was subjected to hydrogenation in the H-cube for 3 h at 40 °C using a Raney Nickel cartridge, recirculating the mixture through the cartridge (flow rate: 1 mL/min). The solvent was concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (128 mg, 250 μmol, 34% yield, 39% purity) as a brown oil.

UPLC/MS (Method 3): m/z 199 (M+H) ⁺ , R _T 0.99 min. Svnthesis 014

(3R,4R)-4-(((3-isopropyl-7-((4-(3-methylpyridin-2-yl)benz yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-isopropyl-N-(4-(3-methylpyridin-2-yl)benzyl)py razolo[1,5-a]pyrimidin-7-amine

DIPEA (0.18 ml_, 1.0 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (40 mg, 0.17 mmol), and (4-(3-methylpyridin-2- yl)phenyl)methanamine (34 mg, 0.17 mmol) in EtOH (3.0 ml_). The reaction mixture was heated to 75 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (59 mg, 150 μmol, 86% yield, 99% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 392 (M+H)+, R _T 1.73 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-met hylpyridin-2- yl)benzyl)carbamate

DMAP (4.0 mg, 33 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(3- methylpyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (59 mg, 150 μmol) and BOC- anhydride (60 mg, 270 μmol) in anhydrous THF (3.0 ml_). The reaction mixture was heated at 65 °C for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (68 mg, 0.13 mmol, 88% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 492 (M+H)+, R _T 2.03 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methylpyridin-2-y l)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- methylpyridin-2-yl)benzyl)carbamate (67 mg, 129 μmol), tert-butyl (3R,4R)-4- (a ino ethyl)-3-hydroxypiperidine-1-carboxylate (36 g, 155 μmol) in THF (2.0 ml_) was degassed in N ₂ for 5 min before adding ‘BuBrettPhos Pd G3 (11.1 mg, 12.9 μmol) and LiHMDS (1M in THF) (155 pL, 0.155 mmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 4 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (67 mg, 84 μmol, 65% yield, 85% purity) as an orange oil.

UPLC/MS (Method 3): m/z 686 (M+H) ⁺ , R _T 1.98 min.

Step 4:

(3R,4R)-4-(((3-isopropyl-7-((4-(3-methylpyridin-2-yl)benz yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.40 ml_, 1.6 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methylpyridin-2-y l)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (65 mg, 81 μmol) in dioxane (1.2 ml_). The reaction mixture was stirred at 40 °C for 1 h and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (1.0 ml_, 1.3 mmol) was added then the reaction mixture was stirred at 40 °C for 1 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_). Further purification by RP preparative HPLC (55-100% MeCN/0.3% NH ₃ in water) gave the title compound (29 mg, 59 μmol, 73% yield, 99% purity) as a white solid.

LCMS (Method 3): m/z 486 (M+H) ⁺ , RT 1.36 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.50 - 8.42 (m, 1H), 7.99 - 7.85 (m, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.64 (s, 1 H), 7.56 - 7.49 (m, 2H), 7.44 (d, J = 7.8 Hz, 2H), 7.31 - 7.22 (m, 1 H), 6.77 - 6.64 (m, 1 H), 5.34 - 5.26 (m, 1 H), 5.23 (s, 1 H), 4.55 - 4.48 (m, 2H), 3.61 - 3.46 (m, 1H), 3.22 - 3.14 (m, 1H), 3.08 - 2.85 (m, 3H), 2.82 - 2.72 (m, 1H), 2.36 - 2.22 (m, 4H), 2.19 - 2.06 (m, 1 H), 1.62 - 1.49 (m, 1 H), 1.40 - 1.28 (m, 1H), 1.27 - 1.17 (m, 6H), 1.18 - 1.08 (m, 1 H). 1H under water. Synthesis 015

(4-(3-methylpyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-methylpyridin-2-yl)phenyl)methanamine

A mixture of 2-chloro-3-methylpyridine (60 g, 470 μmol), (4- (aminomethyl)phenyl)boronic acid, HCI (97 mg, 517 μmol) and Pd(dppf)Cl2 (34.4 mg, 47.0 μmol) in dioxane (2.5 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (399 mg, 1.88 mmol) in water (1.1 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 60 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was diluted with water (3 ml_) and DCM/MeOH 90:10 (10 ml_). The layers were separated, and the aq. layer was extracted with DCM/MeOH 90:10 (5 ml_). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (36 mg, 0.18 mmol, 38% yield, 99% purity) as a brown solid.

UPLC/MS (Method 3): m/z 199 (M+H) ⁺ , R _T 0.93 min.

Synthesis 016

(3R,4R)-4-(((3-isopropyl-7-((4-(3-methoxypyridin-2-yl)ben zyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-isopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl)p yrazolo[1,5-a]pyrimidin-7-amine

DIPEA (0.27 ml_, 1.57 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (60 mg, 0.26 mmol), and (4-(3-methoxypyridin-2- yl)phenyl)methanamine (62 mg, 0.29 mmol) in EtOH (2.0 ml_). The reaction mixture was heated to 75 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (91 mg, 0.19 mmol, 73% yield, 86% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 408 (M+H)+, R _T 1.68 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-met hoxypyridin-2- yl)benzyl)carbamate

DMAP (4.6 mg, 38 μmol) was added to a solution of 5-chloro-3-isopropyl-N-(4-(3- methoxypyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (90 mg, 190 μmol) and BOC-anhydride (53 mg, 240 μmol) in anhydrous THF (3.8 ml_). The reaction mixture was heated at 65 °C for 2 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (80 mg, 160 μmol, 83% yield, 99% purity) as a colourless oil.

UPLC/MS (Method 2): m/z 508 (M+H) ⁺ , R _T 2.01 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2- yl)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- methoxypyridin-2-yl)benzyl)carbamate (80 mg, 157 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (44 mg, 189 μmol) in THF (2.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (13.5 mg, 15.7 μmol) and LiHMDS (1M in THF) (189 pL, 189 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2 h. At RT, the reaction mixture was diluted with EtOAc (10 mL) and filtered through celite, rinsing with EtOAc (15 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25: 75/isohexane) followed by further purification on RP Flash C18 (12 g cartridge, 30-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (83 mg, 110 μmol, 72% yield, 96% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 702 (M+H) ⁺ , R _T 1.86 min.

Step 4:

(3R,4R)-4-(((3-isopropyl-7-((4-(3-methoxypyridin-2-yl)ben zyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol Hydrogen chloride (4 M in dioxane) (0.59 ml_, 2.37 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2- yl)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (83 mg, 118 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1 h and concentrated in vacuo. The solid was triturated in MeCN (2 x 2 ml_) then was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_). Further purification by RP preparative HPLC (55-100% MeCN/0.3% NH3 in water) gave the title compound (53 mg, 100 μmol, 88% yield, 98% purity) as an off-white solid.

LCMS (Method 3): m/z 502 (M+H) ⁺ , RT 1.32 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.23 (dd, J = 4.6, 1.3 Hz, 1 H), 7.90 (t, J = 6.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.64 (s, 1 H), 7.54 (dd, J = 8.4, 1.3 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 2H), 7.34 (dd, J = 8.4, 4.6 Hz, 1H), 6.76 - 6.68 (m, 1H), 5.33 - 5.26 (m, 1H), 5.19 (s, 1 H), 4.50 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.58 - 3.46 (m, 1H), 3.23 - 3.15 (m, 1 H), 3.06 - 2.98 (m, 1H), 2.98 - 2.91 (m, 1H), 2.91 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1 H), 2.32 - 2.25 (m, 1 H), 2.20 - 2.11 (m, 1H), 1.61 - 1.50 (m, 1H), 1.37 - 1.27 (m, 1H), 1.23 (dd, J = 6.9, 5.1 Hz, 6H), 1.19 - 1.11 (m, 1H). 1H under water.

Synthesis 017

(4-(3-methoxypyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-methoxypyridin-2-yl)phenyl)methanamine

A mixture of 2-chloro-3-methoxypyridine (200 mg, 1.39 mmol), (4- (aminomethyl)phenyl)boronic acid, HCI (287 mg, 1.53 mmol) and Pd(dppf)Cl2 (102 mg, 139 μmol) in dioxane (8.0 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (1.18 g, 5.57 mmol) in water (3.4 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with brine (15 ml_) and DCM/IPA 70:30 (30 ml_). The layers were separated, and the aq. layer was extracted with DCM/IPA 70:30 (2 x 30 ml_). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (110 mg, 0.52 mmol, 38% yield, 99% purity) as a red oil. UPLC/MS (Method 3): m/z 215 (M+H) ⁺ , R _T 0.96 min.

Synthesis 018

(3R,4R)-4-(((7-((4-(3-fluoropyridin-2-yl)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-

5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-N-(4-(3-fluoropyridin-2-yl)benzyl)-3-isopropylpy razolo[1,5-a]pyrimidin-7-amine

DIPEA (0.34 ml_, 1.96 mmol) was added to a solution of 5,7-dichloro-3- isopropylpyrazolo[1,5-a]pyrimidine (75 mg, 0.33 mmol), and (4-(3-fluoropyridin-2- yl)phenyl)methanamine (80 mg, 0.38 mmol) in EtOH (2.8 ml_). The reaction mixture was heated to 80 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (111 mg, 0.27 mmol, 82% yield, 96% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 396 (M+H) ⁺ , R _T 1.78 min.

Step 2: tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-flu oropyridin-2- yl)benzyl)carbamate

DMAP (6.8 mg, 56 μmol) was added to a solution of 5-chloro-N-(4-(3-fluoropyridin-2- yl)benzyl)-3-isopropylpyrazolo[1,5-a]pyrimidin-7-amine (110 mg, 278 μmol) and BOC-anhydride (79 mg, 361 μmol) in anhydrous THF (5.4 ml_). The reaction mixture was heated at 65 °C for 2 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (136 mg, 0.25 mmol, 89% yield, 90% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 396 (M-Boc+H) ⁺ , R _T 2.08 min. Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-fluoropyridin-2-y l)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-isopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- fluoropyridin-2-yl)benzyl)carbamate (136 mg, 247 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (68 g, 296 μmol) in THF (3.2 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (21.1 mg, 24.7 μmol) and LiHMDS (1M in THF) (296 pL, 296 μmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 2 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75/isohexane) followed by further purification on RP Flash C18 (12 g cartridge, 30-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (152 mg, 0.20 mmol, 82% yield, 92% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 690 (M+H) ⁺ , R _T 1.92 min.

Step 4:

(3R,4R)-4-(((7-((4-(3-fluoropyridin-2-yl)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-

5-yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (1.10 ml_, 4.41 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-fluoropyridin-2-y l)benzyl)amino)-3- isopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydro xypiperidine-1-carboxylate (152 mg, 220 μmol) in dioxane (2.2 ml_). The reaction mixture was stirred at 40 °C for 1 h then hydrogen chloride (1.25 M in MeOH) (1.0 ml_, 1.3 mmol) was added and the reaction mixture was stirred at 40 °C for 30 min then concentrated in vacuo. The solid was triturated in MeCN (2 x 2 ml_) then was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (83 mg, 0.17 mmol, 75% yield,

98% purity) as a white solid.

UPLC/MS (Method 3): m/z 490 (M+H) ⁺ , RT 1.74 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.53 (dt, J = 4.6, 1.7 Hz, 1H), 7.94 (t, J = 6.5 Hz, 1 H), 7.89 (dd, J = 8.3, 1.7 Hz, 2H), 7.82 (ddd, J = 11.7, 8.3, 1.3 Hz, 1 H), 7.64 (s, 1 H), 7.53 - 7.43 (m, 3H), 6.75 - 6.68 (m, 1H), 5.31 - 5.25 (m, 1H), 5.18 (s, 1 H), 4.52 (d, J = 6.4 Hz, 2H), 3.57 - 3.45 (m, 1H), 3.21 - 3.14 (m, 1 H), 3.06 - 2.98 (m, 1H), 2.97 - 2.91 (m, 1H), 2.91 - 2.85 (m, 1H), 2.81 - 2.73 (m, 1H), 2.31 - 2.23 (m, 1H), 2.14 (t, J = 10.7 Hz, 1H), 1.59 - 1.50 (m, 1H), 1.39 - 1.26 (m, 1H), 1.23 (dd, J = 6.9, 5.0 Hz, 6H), 1.19 - 1.11 (m, 1 H). 1 H under water.

Synthesis 019

(4-(3-fluoropyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-fluoropyridin-2-yl)phenyl)methanamine A mixture of 2-bromo-3-fluoropyridine (200 g, 1.14 mmol), (4-

(aminomethyl)phenyl)boronic acid, HCI (234 mg, 1.25 mmol) and Pd(dppf)Cl2 (83 mg, 114 μmol) in dioxane (6.7 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (965 mg, 4.55 mmol) in water (2.9 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 60 °C overnight. The reaction mixture was concentrated in vacuo. The residue was diluted with water (5 ml_) and DCM/MeOH 90:10 (15 ml_). The layers were separated, and the aq. layer was extracted with DCM/MeOH 90:10 (2 x 10 ml_). The combined organic layers were filtered through a phase separator and concentrated in vacuo. The oil was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_) to give the title compound (165 mg, 0.79 mmol, 61% yield, 97% purity) as a red oil.

UPLC/MS (Method 3): m/z 203 (M+H) ⁺ , R _T 0.93 min.

Synthesis 020

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

(PPA-015)

Step 1 : 5-chloro-3-cyclopropyl-N-(3-methoxy-4-(pyridin-2-yl)benzyl)p yrazolo[1 ,5- a]pyrimidin-7-amine

DIPEA (0.73 mL, 4.16 mmol) was added to a solution of 3-methoxy-4-(pyridin-2- yl)phenyl)methanamine (140 mg, 653 μmol) and 5,7-dichloro-3-cyclopropylpyrazolo[1,5- a]pyrimidine (135 mg, 594 μmol) in EtOH (6.0 mL). The reaction mixture was heated at 50 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (105 mg, 0.25 mmol, 41% yield, 95% purity) as a white crystalline solid.

UPLC/MS (Method 3): m/z 406 (M+H) ⁺ , R _T 1.59 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-meth oxy-4- (pyridin-2-yl)benzyl)carbamate

BOC-anhydride (68 mg, 310 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N- (3-methoxy-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7 -amine (105 mg, 259 μmol) and DMAP (6.3 mg, 52 μmol) in THF (3.0 mL). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (112 mg, 0.21 mmol, 81% yield, 95% purity) as a green oil.

UPLC/MS (Method 3): m/z 506 (M+H) ⁺ , R _T 1.91 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-methoxy-4-(pyridin-2 - yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-meth oxy-4- (pyridin-2-yl)benzyl)carbamate (112 mg, 221 μmol) and tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (61 g, 266 μmol) and in THF (3.0 ml_) was degassed with N2 for 10 min. before adding ‘BuBrettPhos Pd G3 (19 mg, 22 μmol) and LiHMDS (1 M in THF) (288 pL, 288 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (147 mg, 0.18 mmol, 81% yield, 85% purity) as a brown glass.

UPLC/MS (Method 3): m/z 663 (M+H) ⁺ , R _T 1.61 min.

Step 4: (3R,4R)-4-(((3-cyclopropyl-7-((3-methoxy-4-(pyridin-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

TFA (1.0 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3- methoxy-4-(pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[ 1 ,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (147 mg, 210 μmol) in DCM (3.0 ml_). The reaction mixture was stirred at RT for 3 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 ₃ in MeOH (30 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (73 mg, 0.14 mmol, 66 % yield, 95% purity) as a pink solid.

UPLC/MS (Method 3): m/z 500 (M+H)+, R _T 1.59 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 - 8.60 (m, 1H), 7.88 (t, J = 6.4 Hz, 1 H), 7.85 - 7.74 (m, 2H), 7.69 (d, J = 7.9, 2.1 Hz, 1 H), 7.53 (s, 1H), 7.32 - 7.26 (m, 1H), 7.19 (s, 1H), 7.03 (d, J = 7.6 Hz, 1 H), 6.76 - 6.69 (m, 1 H), 5.36 - 5.27 (m, 1 H), 5.21 (s, 1 H), 4.49 (d, J = 6.2 Hz, 2H), 3.82 (s, 3H), 3.58 - 3.45 (m, 1 H), 3.25 - 3.17 (m, 1H), 3.08 - 2.98 (m, 1 H), 2.95 - 2.87 (m, 1H), 2.83 - 2.75 (m, 1H), 2.35 - 2.26 (m, 1H), 2.20 - 2.12 (m, 1H), 1.77 - 1.67 (m, 1H), 1.60 - 1.52 (m, 1H), 1.39 - 1.28 (m, 1H), 1.20 - 1.11 (m, 1H), 0.79 - 0.74 (m, 2H), 0.70 - 0.59 (m, 2H). 1 H under water.

Svnthesis 021

(3-methoxy-4-(pyridin-2-yl)phenyl)methanamine Step A:

4-cyano-2-methoxyphenyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (0.73 ml_, 4.36 mmol) was added to a solution of 3,4- hydroxy-3-methoxybenzonitrile (500 mg, 3.35 mmol) and triethylamine (509 mg, 701 μl_, 1.5 Eq, 5.03 mmol) in DCM (15 ml_) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with aq. sat. NaHCO ₃ (20 ml_) and extracted with DCM (3 x 10 ml_). The combined organic fractions were washed with brine (50 ml_), dried over MgSO _4, filtered, then concentrated in vacuo to give the title compound (938 mg, 3.20 mmol, 95% yield, 95% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.91 (d, J = 1.9 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1 H), 7.60 (dd, J = 8.4, 1.9 Hz, 1H), 3.97 (s, 3H).

Step B:

3-methoxy-4-(pyridin-2-yl)benzonitrile

A solution of 2-(tributylstannyl)pyridine (1.47 g, 4.00 mmol), 4-cyano-2-methoxyphenyl trifluoromethanesulfonate (938 mg, 3.34 mmol), Pd(Ph3P)4 (385 mg, 334 μmol) and lithium chloride (141 mg, 3.34 mmol) in DMF (15.0 ml_) was degassed with N ₂ for 15 min. Bubbling was ceased and the reaction mixture heated to 90 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The mixture was cooled to RT then diluted with water (50 ml_) and brine (50 ml_) and extracted into MTBE (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_) then dried over MgSCU, filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0- 100% EtOAc/isohexane) gave the title compound (233 mg, 0.94 mmol, 28% yield, 85% prity) as a white solid.

UPLC/MS (Method 3): m/z 211 (M+H) ⁺ , R _T 1.16 min.

Step C:

(3-methoxy-4-(pyridin-2-yl)phenyl)methanamine

LiAIH ₄ (4 M in Et ₂ O ) (180 mI_, 720 μmol) was added to a solution of 3-methoxy-4-(pyridin- 2-yl)benzonitrile (155 mg, 627 μmol) in THF (8.0 ml_) at 0 °C. The mixture was stirred for 15 min at 0 °C then allowed to warm to RT and stirred for a further 15 min. The mixture was quenched with methanol until effervescence ceased then the mixture was diluted with water (100 ml_) and extracted with DCM (3 x 50 ml_). The combined organic layers were washed with brine (50 ml_), dried over MgSCU, filtered and concentrated in vacuo to afford the title compound (140 mg, 0.52 mmol, 83% yield, 80% purity) as a brown solid. UPLC/MS (Method 3): m/z 215 (M+H) ⁺ , R _T 0.93 min.

Synthesis 022

(3R,4R)-4-(((3-chloro-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

3,5-dichloro-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyr imidin-7-amine

DIPEA (1.1 ml_, 6.47 mmol) was added to a solution of 3,5,7-trichloropyrazolo[1,5- a]pyrimidine (240 mg, 1.08 mmol) and (4-(pyridin-2-yl)phenyl)methanamine, HCI (238 mg, 1.08 mmol) in EtOH (10.0 ml_). The reaction mixture was heated at 70 °C overnight. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) to give the title compound (206 mg, 0.55 mmol, 51% yield, 99% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 370 (M+H) ⁺ , R _T 1.52 min.

Step 2: tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl) benzyl)carbamate

DMAP (13.7 mg, 0.112 mmol) was added to a solution of 3,5-dichloro-N-(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (207 mg, 560 μmol) and BOC-anhydride (175 mg, 802 μmol) in THF (10 mL). The reaction mixture was heated at 65 °C for 1.5 h and 20 min. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (274 mg, 0.55 mmol, 98% yield, 94% purity) as a yellow gum.

UPLC/MS (Method 3): m/z 470 (M+H) ⁺ , R _T 1.87 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxyp iperidine-1-carboxylate

A solution of tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (270 mg, 574 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (145 g, 631 μmol) in THF (2.5 ml_) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (49 mg, 57 μmol) and LiHMDS (1 M in THF) (603 pL, 603 μmol). The reaction was degassed for another 5 min before being heated to 60 for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (324 mg, 0.46 mmol, 81% yield, 95% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 664 (M+H) ⁺ , R _T 2.15 min.

Step 4:

(3R,4R)-4-(((3-chloro-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

HCI (4 M in dioxane) (1.81 ml_, 7.23 mmol) was added to a solution of tert-butyl (3R,4R)- 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3-chloropyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (320 mg, 482 μmol) in dioxane (3.0 ml_). The reaction mixture was stirred at 35°C for 3 h and 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 ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (87 mg, 0.17 mmol, 36% yield, 93% purity) as a pink solid.

UPLC/MS (Method 3): m/z 464 (M+H) ⁺ , R _T 1.55 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.62 (m, 1H), 8.13 (t, J = 6.4 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 2H), 7.96 - 7.91 (m, 1H), 7.89 (s, 1H), 7.89 - 7.83 (m, 1 H), 7.47 (d, J = 8.1 Hz, 2H), 7.37 - 7.30 (m, 1 H), 6.96 (t, J = 5.9 Hz, 1 H), 5.29 (s, 1 H), 5.08 - 5.00 (m, 1 H), 4.52 (d, J = 6.3 Hz, 2H), 3.46 - 3.35 (m, 1H), 3.29 - 3.22 (m, 1H), 3.07 - 2.99 (m, 1H), 2.94 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.35 - 2.23 (m, 1H), 2.20 - 2.11 (m, 1 H), 1.62 - 1.54 (m, 1 H), 1.38 - 1.27 (m, 1H), 1.17 - 1.03 (m, 1H). 1 H under water. Synthesis 023

(3R,4R)-4-(((7-((4-(1 H-pyrrol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

N-(4-(1 H-pyrrol-1-yl)benzyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]p yrimidin-7-amine

DIPEA (412 μl_, 2.37 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (90.0 mg, 395 μmol) and (4-(1 H-pyrrol-1- yl)phenyl)methanamine (81.6 mg, 474 μmol) in EtOH (2.5 ml_). The reaction mixture was heated at 65 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (135 mg, 0.35 mmol, 88% yield, 93% purity) as a yellow gum.

UPLC/MS (Method 3): m/z 364 (M+H) ⁺ , R _T 2.12 min.

Step 2: tert-butyl (4-(1 H-pyrrol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-7- yl)carbamate

DMAP (8.98 mg, 73.5 μmol) was added to a solution of N-(4-(1 H-pyrrol-1-yl)benzyl)-5- chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (135 mg, 367 μmol) and BOC- anhydride (104 mg, 478 μmol) in THF (6.80 ml_). The reaction mixture was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% 25%EtOH in EtOAc/isohexane) gave the title compound (183 mg, 0.35 mmol, 96% yield, 89% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 408 (M+H-tBu) ⁺ , R _T 2.04 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((4-(1 H-pyrrol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (4-(1 H-pyrrol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (183 mg, 0.351 mmol) and tert-butyl (3R,4R)-4-(aminomethyl)-

3-hydroxypiperidine-1-carboxylate (97 mg, 0.421 mmol) in THF (4.0 ml_) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (30 mg, 35 μmol) and LiHMDS (1 M in THF) (421 μl_, 0.421 mmol). The reaction was degassed for another 5 min before being heated to 60-65 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 75:25/ isohexane) gave the title compound (139 mg, 0.20 mmol, 57% yield, 94% purity) as a brown solid.

UPLC/MS (Method 3): m/z 658 (M+H) ⁺ , R _T 1.91 min.

Step 4:

(3R,4R)-4-(((7-((4-(1 H-pyrrol-1-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5- yl)amino)methyl)piperidin-3-ol

HCI (4 M in dioxane) (1.08 ml_, 4.33 mmol) was added to a solution of tert-butyl (3R,4R)-

4-(((7-((4-(1 H-pyrrol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3-cycloprop ylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (150 mg, 217 μmol) in dioxane (2.80 ml_). The suspension was stirred at 40 °C for 3 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with DCM/MeOH (1:2; 120mL) and the product eluted with DCM/0.7 M NH ₃ in MeOH (1:2; 150ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (71 mg, 0.15 mmol, 69% yield, 97% purity) as a beige solid.

UPLC/MS (Method 3): m/z 458 (M+H) ⁺ , R _T 1.41 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.87 (t, J = 6.5 Hz, 1H), 7.56 - 7.50 (m, 3H), 7.42 (d, J = 8.5 Hz, 2H), 7.32 (t, J = 2.2 Hz, 2H), 6.74 - 6.67 (m, 1H), 6.24 (t, J = 2.2 Hz, 2H), 5.34 - 5.29 (m, 1H), 5.19 (s, 1 H), 4.45 (d, J = 6.4 Hz, 2H), 3.55 - 3.45 (m, 1H), 3.24 - 3.15 (m,

1 H), 3.07 - 2.98 (m, 1H), 2.95 - 2.87 (m, 1 H), 2.83 - 2.75 (m, 1H), 2.32 - 2.26 (m, 1H), 2.16 (t, J = 10.8 Hz, 1H), 1.76 - 1.66 (m, 1H), 1.59 - 1.52 (m, 1 H), 1.40 - 1.27 (m, 1H), 1.20 - 1.11 (m, 1H), 0.79 - 0.72 (m, 2H), 0.68 - 0.59 (m, 2H). 1 H under water. Synthesis 024

(3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(thiazol-2-yl)benzyl)pyrazolo [1 ,5-a]pyrimidin-7-amine

DIPEA (550 μl_, 3.16 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (80.0 mg, 351 μmol) and (4-thiazol-2- ylphenyl)methanamine HCI (95.4 mg, 421 μmol) in EtOH (1.2 ml_). The reaction mixture was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (125 mg, 0.31 mmol, 90% yield, 96% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 382 (M+H) ⁺ , R _T 1.63 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thi azol-2- yl)benzyl)carbamate

DMAP (7.9 mg, 65.0 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4- (thiazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (124 mg, 0.325 mmol) and BOC- anhydride (92 mg, 423 μmol) in THF (6.4 ml_). The reaction mixture was heated at 65 °C for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (151 mg, 0.29 mmol, 90% yield, 93% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 482 (M+H) ⁺ , R _T 2.04 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thi azol-2- yl)benzyl)carbamate (148 mg, 286 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (79 g, 343 μmol) in THF (3.8 ml_) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (24.4 mg, 28.6 μmol) and LiHMDS (1 M in THF) (343 pL, 343 μmol). The reaction was degassed for another 5 min before heating to 60-65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc/ isohexane) gave the title compound (150 mg, 0.21 mmol, 73% yield, 94% purity) as a brown oil.

UPLC/MS (Method 3): m/z 676 (M+H) ⁺ , R _T 1.84 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

HCI (4 M in dioxane) (1.05 ml_, 4.22 mmol) was added to a solution of tert-butyl (3R,4R)- 4-(((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl)amino)- 3-cyclopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (150 mg, 211 μmol) in dioxane (2.80 ml_). The suspension was stirred at 40 °C for 1 h before adding HCI (1.25 M in methanol) (1.00 ml_, 1.25 mmol) and further stirring at 40 °C for 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (150 ml_) and the product eluted with 0.7 M NH ₃ in MeOH (150 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (90 mg, 0.18 mmol, 88% yield, 98% purity) as a beige solid.

UPLC/MS (Method 3): m/z 476 (M+H) ⁺ , R _T 1.42 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95 - 7.88 (m, 4H), 7.77 (d, J = 3.2 Hz, 1 H), 7.53 (s,

1 H), 7.46 (d, J = 8.2 Hz, 2H), 6.70 (t, J = 6.0 Hz, 1 H), 5.32 - 5.26 (m, 1H), 5.15 (s, 1 H), 4.50 (d, J = 6.1 Hz, 2H), 3.56 - 3.43 (m, 1H), 3.23 - 3.14 (m, 1 H), 3.07 - 2.97 (m, 1 H), 2.93 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.34 - 2.23 (m, 1 H), 2.18 - 2.10 (m, 1H), 1.75 - 1.66 (m, 1H), 1.59 - 1.50 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.05 (m, 1 H), 0.81 - 0.71 (m, 2H), 0.70 - 0.60 (m, 2H). 1 H under water. Synthesis 025

(3R,4R)-4-(((3-cyclopropyl-7-((4-(5-fluoropyridin-2-yl)be nzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1/2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(5-f luoropyridin-2- yl)benzyl)carbamate

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

5-chloro-3-cyclopropyl-N-(4-(5-fluoropyridin-2-yl)benzyl) pyrazolo[1,5-a]pyrimidin-7-amine was dissolved in THF (2.5 ml_) then BOC-anhydride (87.3 mg, 400 μmol) and DMAP (3.26 mg, 26.7 μmol) were added. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography silica gel (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (115 mg, 0.22 mmol, 50% yield, 95% purity) as a yellow foam.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.62 (d, J = 2.9 Hz, 1H), 8.10 (s, 1H), 8.00 (dd, J= 8.9, 4.4 Hz, 1H), 7.99 - 7.92 (m, 2H), 7.79 (td, J = 8.8, 3.0 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.18 (s, 1H), 5.05 (s, 2H), 1.96 (tt, J= 8.3, 5.1 Hz, 1H), 1.28 (s, 9H), 0.97 - 0.86 (m, 2H), 0.82 - 0.72 (m, 2H).

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(5-fluoropyridin-2-y l)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(5- fluoropyridin-2-yl)benzyl)carbamate (116 mg, 222 μmol) and tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (61 g, 266 μmol) in THF (3.8 ml_) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (19 mg, 22 μmol) and LiHMDS (1 M in THF) (267 pL, 267 μmol) were added under bubbling N2. The reaction was degassed for another 5 min before heating to 60-65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc/ isohexane) gave the title compound (97 mg, 0.14 mmol, 61% yield, 96% purity) as a brown oil.

UPLC/MS (Method 3): m/z 688 (M+H) ⁺ , R _T 1.88 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(5-fluoropyridin-2-yl)be nzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

HCI (4 M in dioxane) (0.67 ml_, 2.7 mmol) was added to a solution of tert-butyl (3R,4R)-4- (((7-((tert-butoxycarbonyl)(4-(5-fluoropyridin-2-yl)benzyl)a mino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (96 mg, 0.13 mmol) in dioxane (1.8 ml_). The suspension was stirred at 40 °C for 1.5 h before adding HCI (1.25 M in MeOH) (1.00 ml_, 1.25 mmol) and further stirring at 40 °C for 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with DCM/MeOH (1 :2; 120 ml_) and the product eluted with DCM/0.7 M NH3 in MeOH (1:2; 150 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (61.5 mg, 0.12 mmol, 91% yield, 97% purity) as a beige solid.

UPLC/MS (Method 3: m/z 488 (M+H) ⁺ , R _T 1.49 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.63 (d, J = 3.0 Hz, 1 H), 8.05 - 7.97 (m, 3H), 7.90 (t, J = 6.5 Hz, 1H), 7.84 - 7.77 (m, 1 H), 7.52 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2H), 6.74 - 6.68 (m,

1 H), 5.36 - 5.26 (m, 1H), 5.17 (s, 1 H), 4.50 (d, J = 6.2 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.23 - 3.16 (m, 1 H), 3.07 - 2.98 (m, 1H), 2.94 - 2.87 (m, 1H), 2.81 - 2.74 (m, 1H), 2.32 - 2.24 (m, 1H), 2.19 - 2.12 (m, 1H), 1.77 - 1.67 (m, 1H), 1.59 - 1.50 (m, 1H), 1.39 - 1.27 (m,

1 H), 1.19 - 1.11 (m, 1H), 0.79 - 0.73 (m, 2H), 0.69 - 0.60 (m, 2H). 1H under water. Synthesis 026

(3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(pyridin-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(2-fluoro-4-(pyridin-2-yl)benzyl )pyrazolo[1,5-a]pyrimidin-7-amine

DIPEA (0.15 ml_, 0.88 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (38 mg, 0.15 mmol) and (2-fluoro-4-(pyridin-2- yl)phenyl)methanamine (30 mg, 0.15 mmol)in EtOH (3.0 ml_). The reaction mixture was heated at 60 °C overnight. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (40 mg, 96 μmol, 66% yield, 95% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 394 (M+H) ⁺ , R _T 1.68 min.

Step 2: tert-butyl (5-amino-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluor o-4-(pyridin-2- yl)benzyl)carbamate

BOC-anhydride (27 mg, 0.12 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N- (2-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7- amine (40 mg, 0.10 mmol) and DMAP (2.5 mg, 20 μmol) in THF (3.0 ml_). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (43 mg, 86 μmol, 85% yield, 99% purity) as a thick green oil.

UPLC/MS (Method 3): m/z 494 (M+H) ⁺ , R _T 1.99 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2- yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluo ro-4- (pyridin-2-yl)benzyl)carbamate (40.0 mg, 81.0 μmol), tert-butyl (3R,4R)-4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (28.0 g, 121 μmol) and cesium carbonate (79.2 mg, 243 μmol) in dioxane (1.5 ml_) was degassed with N2 for 5 min. Pd-171 (1.6 mg, 2.4 μmol) and Ruphos phosphane (1.3 mg, 2.8 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (39 mg, 50 μmol, 62% yield, 89% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 688 (M+H) ⁺ , R _T 1.92 min.

Step 4:

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

HCI (4 M in dioxane) (126 pL, 505 μmol) was added to a solution of tert-butyl (3R,4R)-4- (((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (39 mg, 50 μmol) in dioxane (2.0 ml_). The suspension was stirred at 35 °C for 4 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (140 ml_) and the product eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (16 mg, 32 μmol, 64% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 488 (M+H) ⁺ , R _T 1.53 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.95 - 7.88 (m, 4H), 7.77 (d, J = 3.2 Hz, 1H), 7.53 (s,

1 H), 7.46 (d, J = 8.2 Hz, 2H), 6.70 (t, J = 6.0 Hz, 1H), 5.32 - 5.26 (m, 1H), 5.15 (s, 1 H), 4.50 (d, J = 6.1 Hz, 2H), 3.56 - 3.43 (m, 1H), 3.23 - 3.14 (m, 1 H), 3.07 - 2.97 (m, 1H), 2.93 - 2.86 (m, 1H), 2.81 - 2.73 (m, 1H), 2.34 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 1.75 - 1.66 (m, 1 H), 1.59 - 1.50 (m, 1H), 1.38 - 1.26 (m, 1H), 1.19 - 1.05 (m, 1 H), 0.81 - 0.71 (m, 2H), 0.70 - 0.60 (m, 2H). 1 H under water. Synthesis 027

(2-fluoro-4-(pyridin-2-yl)phenyl)methanamine

Step A:

(2-fluoro-4-(pyridin-2-yl)phenyl)methanamine

A suspension of 2-bromopyridine (60 μL_, 633 μmol), (4-(aminomethyl)-3- fluorophenyl)boronic acid (118 mg, 696 μmol), Pd(dppf)Cl2.DCM (52 mg, 63 μmol) and cesium carbonate (206 mg, 633 μmol) in dioxane (9.0 ml_) and water (1.0 ml_) was degassed with N2 for 5 min. The reaction mixture was stirred at 90 °C for 2 h. At RT, the reaction mixture was diluted with water (50 ml_) and extracted with EtOAc (2 x 25 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (38 mg, 0.17 mmol, 26% yield, 88% purity) as an orange oil.

UPLC/MS (Method 6): m/z 203 (M+H) ⁺ , R _T 1.98 min.

Synthesis 028

(3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)amino)-3-cy clopropylpyrazolo[1,5-a]pyrimidin-

5-yl)amino)methyl)piperidin-3-ol

Step 1 :

N-([2,3'-bipyridin]-6'-ylmethyl)-5-chloro-3-cyclopropylpy razolo[1,5-a]pyrimidin-7-amine DIPEA (698 mI_, 4.01 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (130 mg, 572 μmol) and [2,3'-bipyridin]-6'- ylmethanamine, 2 HCI, (211 mg, 572 μmol) in EtOH (8.0 ml_). The reaction mixture was heated at 50 °C for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (96 mg, 0.24 mmol, 42% yield, 95% purity) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.25 - 9.20 (m, 1H), 8.82 (t, J = 6.2 Hz, 1 H), 8.73 - 8.66 (m, 1 H), 8.44 (dd, J = 8.2, 2.3 Hz, 1 H), 8.08 - 8.00 (m, 1 H), 7.96 (s, 1 H), 7.92 (td, J = 7.7, 1.8 Hz, 1 H), 7.53 - 7.45 (m, 1 H), 7.41 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.13 (s, 1 H), 4.79 (d, J = 6.2 Hz, 2H), 1.96 - 1.84 (m, 1H), 0.93 - 0.80 (m, 2H), 0.84 - 0.71 (m, 2H).

Step 2: tert-butyl ([2,3'-bipyridin]-6'-ylmethyl)(5-chloro-3-cyclopropylpyrazol o[1,5-a]pyrimidin-7- yl)carbamate

BOC-Anhydride (67 mg, 0.31 mmol) was added to a solution of N-([2,3'-bipyridin]-6'- ylmethyl)-5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-a mine (96 mg, 0.25 mmol), and DMAP (6.2 mg, 51 μmol) in THF (3.0 ml_). The reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (84 mg, 0.16 mmol, 62% yield, 90% purity) as a green solid.

UPLC/MS (Method 3): m/z 477 (M+H) ⁺ , R _T 2.15 min.

Step 3: tert-butyl (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)(tert-butoxyca rbonyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl ([2,3'-bipyridin]-6'-ylmethyl)(5-chloro-3-cyclopropylpyrazol o[1,5- a]pyrimidin-7-yl)carbamate (84 mg, 0.18 mmol) (150 mg, 311 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (49 mg, 0.21 mmol) in THF (2.0 mL) was degassed with N2 for 5 min, before adding ‘BuBrettPhos Pd G3 (15 mg, 18 μmol) and LiHMDS (1 M in THF) (0.23 mL, 0.23 mmol). The reaction was degassed for another 10 min before heating to 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (93 mg, 0.13 mmol, 75% yield, 95% purity) as a brown glass.

UPLC/MS (Method 3): m/z 671 (M+H) ⁺ , R _T 2.03 min. Step 4:

(3R,4R)-4-(((7-(([2,3'-bipyridin]-6'-ylmethyl)amino)-3-cy clopropylpyrazolo[1 ,5-a]pyrimidin-

5-yl)amino)methyl)piperidin-3-ol

TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-(([2,3'-bipyridin]-6'- ylmethyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (93 mg, 0.14 mmol) in DCM (1.5 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (150 mL) and the product eluted with 0.7 M NH3 in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (39.9 mg, 81 μmol, 58% yield, 96% purity) as a beige solid.

UPLC/MS (Method 2): m/z 471 (M+H) ⁺ , R _T 0.62 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.23 (d, J = 2.3 Hz, 1 H), 8.74 - 8.66 (m, 1H), 8.42 (dd, J = 8.2, 2.4 Hz, 1 H), 8.06 - 8.01 (m, 1 H), 7.94 - 7.90 (m, 1 H), 7.90 - 7.82 (m, 1 H), 7.55 (s,

1 H), 7.45 (d, J = 8.2 Hz, 1 H), 7.43 - 7.38 (m, 1 H), 6.79 - 6.72 (m, 1 H), 5.38 - 5.26 (m,

1 H), 5.18 (s, 1 H), 4.66 - 4.56 (m, 2H), 3.60 - 3.43 (m, 1 H), 3.24 - 3.16 (m, 1H), 3.09 - 3.00 (m, 1H), 2.91 (dd, J = 11.5, 4.6 Hz, 1H), 2.83 - 2.75 (m, 1 H), 2.36 - 2.27 (m, 1H), 2.22 - 2.13 (m, 1H), 1.77 - 1.68 (m, 1H), 1.60 - 1.51 (m, 1 H), 1.41 - 1.28 (m, 1H), 1.26 - 1.10 (m, 1H), 0.81 - 0.73 (m, 2H), 0.71 - 0.59 (m, 2H). 1 H under water.

Synthesis 029

[2,3'-bipyridin]-6'-ylmethanamine 2HCI

Step A:

[2,3'-bipyridine]-6'-carbonitrile

2-(tributylstannyl)pyridine (529 μL, 1.64 mmol), 5-bromopicolinonitrile (250 mg, 1.37 mmol), Pd(Ph3P)4 (158 mg, 137 μmol) and lithium chloride (58 mg, 1.37 mmol) were taken up in DMF (5.0 mL). The mixture was sparged with N2 for 10 min then heated to 90 °C for 18 h then allowed to cool to RT. The mixture was diluted with aq. sat. LiCI solution (40 mL) and water (40 mL) then extracted with MTBE (2 x 40 mL). The organic layers were washed with brine (40 mL) then dreid with MgSO4, filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (146 mg, 0.76 mmol, 56% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 182 (M+H)+, R _T 1.23 min. Step B:

[2,3'-bipyridin]-6'-ylmethanamine 2HCI

[2,3'-bipyridine]-6'-carbonitrile (139 mg, 767 μmol) in HCI (1.25 M in MeOH) (20 ml_) was subjected to hydrogenation in the H-cube for 1.5 h at RT using a 10% palladium on carbon cartridge, recirculating the mixture through the cartridge (flow rate: 1 mL/min). The solvent was concentrated in vacuo to give the title compound (211 mg, 0.57 mmol, 75% yield, 70% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 186 (M+H) ⁺ , R _T 0.75 min.

Synthesis 030

(3R,4R)-4-(((3-cyclopropyl-7-((3-fluoro-4-(pyridin-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(3-fluoro-4-(pyridin-2-yl)benzyl )pyrazolo[1,5-a]pyrimidin-7-amine

DIPEA (367 pl_, 2.10 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (80 mg, 351 μmol) and (3-fluoro-4-(pyridin-2- yl)phenyl)methanamine (82 mg, 389 μmol), in EtOH (1.4 ml_). The reaction mixture was heated at 65 °C for 2.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (93 mg, 0.21 mmol, 59% yield, 88% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 394 (M+H) ⁺ , R _T 1.60 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-fluo ro-4-(pyridin-2- yl)benzyl)carbamate

DMAP (5.1 mg, 42 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(3-fluoro-4- (pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (93 g, 208 μmol), and BOC- anhydride (59 mg, 270 μmol) in THF (4.6 ml_). The resulting reaction mixture was heated at 65 °C for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (94 mg, 0.16 mmol, 79% yield, 87% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 494 (M+H) ⁺ , R _T 1.98 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(3-fluoro-4-(pyridin-2- yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(3-fluo ro-4- (pyridin-2-yl)benzyl)carbamate (93 mg, 185 μmol) and tert-butyl (3R,4R)-4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (51 mg, 221 μmol) in THF (2.0 ml_) was degassed with N2 for 5 min, before adding ‘BuBrettPhos Pd G3 (15.8 mg, 18.5 μmol) and LiHMDS (1 M in THF) (221 pL, 221 μmol). The reaction was degassed for another 5 min before heating to 60-65 °C for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (36 mg, 50 μmol, 27% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 688 (M+H) ⁺ , R _T 1.84 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((3-fluoro-4-(pyridin-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

HCI (4 M in dioxane) (244 pL, 974 μmol) was added to a solution of tert-butyl (3R,4R)-4- (((7-((tert-butoxycarbonyl)(3-fluoro-4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (33.5 mg, 48.7 μmol) in dioxane (1.0 mL). The suspension was stirred at 40 °C for 2 h before adding HCI in methanol (1.25 M in MeOH) (1.00 mL, 1.25 mmol) and stirring for further 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (100 mL) and the product eluted with 0.7 M NH ₃ in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (20 g, 40 μmol, 82% yield, 97% purity) as a grey solid.

UPLC/MS (Method 3): m/z 488 (M+H)+, R _T 1.31 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.73 - 8.65 (m, 1H), 7.99 - 7.85 (m, 3H), 7.79 - 7.73 (m, 1 H), 7.53 (s, 1 H), 7.43 - 7.36 (m, 1 H), 7.34 - 7.25 (m, 2H), 6.72 (t, J = 6.0 Hz, 1 H), 5.31 - 5.24 (m, 1H), 5.18 (s, 1 H), 4.51 (d, J = 6.3 Hz, 2H), 3.57 - 3.41 (m, 1H), 3.25 - 3.17 (m,

1 H), 3.08 - 2.98 (m, 1H), 2.94 - 2.86 (m, 1 H), 2.82 - 2.74 (m, 1H), 2.35 - 2.24 (m, 1H), 2.18 - 2.11 (m, 1H), 1.76 - 1.67 (m, 1H), 1.59 - 1.51 (m, 1 H), 1.38 - 1.26 (m, 1H), 1.18 - 1.06 (m, 1 H), 0.79 - 0.73 (m, 2H), 0.70 - 0.60 (m, 2H). 1 H under water.

Synthesis 031

(3-fluoro-4-(pyridin-2-yl)phenyl)methanamine

Step A:

3-fluoro-4-(pyridin-2-yl)benzonitrile

2-Bromopyridine (250 mg, 151 μl_, 1.58 mmol), (4-cyano-2-fluorophenyl)boronic acid (346 mg, 2.06 mmol), and Pd(dppf)CI2 (116 mg, 158 μmol) were taken up in dioxane (7.0 ml_). The mixture was sparged with N2 for 10 min then solution of potassium carbonate (656 mg, 4.75 mmol) in water (778 mI_) was added and N2 was bubbled through the reaction mixture for further 5 min. The mixture was heated to 90 °C ON then allowed to cool to RT. The reaction mixture was diluted in EtOAc (20 ml_) and filtered on celite. The filtrated was further diluted with water (10 ml_) and extracted with EtOAc (2x 15 ml_). The combined organics were washed with brine (2 x 15 ml_), dried with MgSO ₄ , filtered and concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-100% 25% EtOH in EtOAc/isohexane) gave the title compound (297 mg, 1.4 mmol, 89% yield, 94% purity) as a white solid.

UPLC/MS (Method 2): m/z 199 (M+H)+, R _T 1.16 min.

Step B:

(3-fluoro-4-(pyridin-2-yl)phenyl)methanamine

3-Fluoro-4-(pyridin-2-yl)benzonitrile (142 mg, 573 μmol) and acetic acid (1.00 mL, 17.4 mmol) in MeOH (19 mL) was subjected to hydrogenation (hydrogen pressure set to 30 bar) in the H-cube for 2.5 h at 45 °C using a 10% palladium on carbon cartridge, recirculating the mixture through the cartridge (flow rate: 1 mL/min). The reaction mixture was concentrated under reduced pressure (co-evaporation with MeCN). The crude was precipitated and triturated in MeCN in an ice bath. The suspension was filtrated and the solid was dried under reduced pressure to afford the title compound (82 g, 0.33 mmol, 48% yield, 80% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 203 (M+H) ⁺ , R _T 1.12 min.

Synthesis 032

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

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(2-methyl-1 H-imidazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7- amine

DIPEA (367 μL , 2.10 mmol) was added to a solution 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (80.0 mg, 351 μmol) and (4-(2-methyl-1 H-imidazol- 1-yl)phenyl)methanamine (78.8 mg, 421 μmol) in EtOH (1.4 ml_). The reaction mixture was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (121 mg, 0.31 mmol, 89% yield, 97% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 379 (M+H) ⁺ , R _T 1.69 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(2-methyl-1 H-imidazol-1- yl)benzyl)carbamate

DMAP (7.6 mg, 62 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(2- methyl-1H-imidazol-1-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-am ine (121 mg, 310 μmol) and BOC-anhydride (88 g, 403 μmol) in THF (6.2 ml_). The resulting reaction mixture was heated at 65 °C for 4 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (105 mg, 0.21 mmol, 67% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 479 (M+H) ⁺ , R _T 2.04 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(2-methyl-1 H-imidazol-1- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(2-m ethyl- 1 H-imidazol-1-yl)benzyl)carbamate (105 mg, 219 μmol) and tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (60.6 mg, 263 μmol) in THF (2.4 mL) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (18.7 mg, 21.9 μmol) and LiHMDS (1 M in THF) (263 μL, 263 μmol). The reaction was degassed for another 5 min before heating to 60-65 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% (25% EtOH in EtOAc)/isohexane) gave the title compound (90 mg, 0.13 mmol, 59% yield, 96% purity) as an orange oil.

UPLC/MS (Method 2): m/z 673 (M+H) ⁺ , R _T 1.20 min.

Step 4:

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

Hydrogen chloride (4 M in dioxane) (631 pL, 2.52 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(2-methyl-1H-imidazo l-1-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (87 mg, 126 μmol) in dioxane (2.0 mL). The suspension was stirred at 40 °C for 2 h. Hydrogen chloride (1.25 M in MeOH) (0.80 mL, 1.00 mol) was added and the reaction mixture was stirred for 30 min. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (150 mL) and the product eluted with 0.7 M NH ₃ in MeOH (150 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (53 mg, 0.11 mmol, 84% yield, 95% purity) as an orange solid.

UPLC/MS (Method 3): m/z 473 (M+H) ⁺ , R _T 1.12 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.92 (t, J = 6.6 Hz, 1H), 7.52 (s, 1H), 7.51 - 7.47 (m,

2H), 7.43 - 7.39 (m, 2H), 7.24 (d, J = 1.4 Hz, 1 H), 6.89 (d, J = 1.4 Hz, 1 H), 6.71 (t, J = 6.0 Hz, 1 H), 5.32 - 5.25 (m, 1 H), 5.23 (s, 1 H), 4.50 (d, J = 6.3 Hz, 2H), 3.54 - 3.44 (m, 1 H), 3.27 - 3.19 (m, 1H), 3.09 - 2.99 (m, 1H), 2.95 - 2.88 (m, 1 H), 2.83 - 2.75 (m, 1H), 2.35 - 2.23 (m, 4H), 2.21 - 2.12 (m, 1H), 1.76 - 1.66 (m, 1H), 1.62 - 1.54 (m, 1 H), 1.39 - 1.27 (m, 1H), 1.19 - 1.08 (m, 1H), 0.79 - 0.71 (m, 2H), 0.69 - 0.61 (m, 2H). 1H under water.

Synthesis 033

(3R,4R)-4-(((3-cyclopropyl-7-(((1-methyl-4-(pyridin-2-yl) -1 H-imidazol-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-((1-methyl-4-(pyridin-2-yl)-1H-i midazol-2-yl)methyl)pyrazolo[1,5- a]pyrimidin-7-amine

DIPEA (0.32 ml_, 1.8 mmol) was added to a solution 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (70 mg, 0.31 mmol) and (1-methyl-4-(pyridin-2-yl)- 1 H-imidazol-2-yl)methanamine (58 mg, 0.31 mmol) in EtOH (3.0 ml_). The reaction mixture was heated at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (87 mg, 0.23 mmol, 74% yield, 99% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.70 (t, J = 5.5 Hz, 1 H), 8.47 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 7.94 (s, 1H), 7.84 - 7.72 (m, 2H), 7.70 (s, 1H), 7.17 (ddd, J = 6.8, 4.8, 1.7 Hz, 1 H), 6.47 (s, 1H), 4.71 (d, J = 5.3 Hz, 2H), 3.73 (s, 3H), 1.89 (tt, J = 8.4, 5.2 Hz, 1H), 0.92 - 0.83 (m, 2H), 0.78 - 0.70 (m, 2H).

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-met hyl-4-(pyridin-2-yl)- 1 H-imidazol-2-yl)methyl)carbamate BOC-anhydride (73 mg, 0.34 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N- ((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)pyrazolo [1,5-a]pyrimidin-7-amine (85 mg, 0.22 mmol) and DMAP (1.5 mg, 45 μmol) in THF (1.5 ml_). The resulting reaction mixture was heated at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography 12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (105 mg, 0.21 mmol, 95% yield, 97% purity) as a yellow foam.

UPLC/MS (Method 3): m/z 480 (M+H) ⁺ , R _T 1.83 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-methyl-4-(pyridin-2 -yl)-1H-imidazol-2- yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-met hyl-4- (pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (104 mg, 217 μmol), tert-butyl (3R,4R)- 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (55 mg, 238 μmol) and ‘BuBrettPhos Pd G3 (18.5 mg, 21.7 μmol) in THF (2.5 ml_) was degassed with N2 for 5 min. LiHMDS (1 M in THF) (228 pL, 228 μmol) was added in one portion under bubbling N2. Bubbling was ceased after 5 min and the reaction mixture heated to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) followed by purification by RP Flash C18 chromatography (12 g cartridge, 15-80% MeCN/10 mM ammonium bicarbonate) gave the title compound (57 mg, 84 μmol, 39% yield, 99% purity) as a white solid.

UPLC/MS (Method 3): m/z 674 (M+H) ⁺ , R _T 1.88 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((1-methyl-4-(pyridin-2-yl) -1H-imidazol-2- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

HCI (4 M in dioxane) (0.32 mL, 1.3 mmol) was added to a solution of tert-butyl (3R,4R)-4- (((7-((tert-butoxycarbonyl)((1-methyl-4-(pyridin-2-yl)-1H-im idazol-2-yl)methyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (57 mg, 85 μmol) in dioxane (1.0 mL). The suspension was stirred at 35 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (14 mg, 29 μmol, 34% yield, 98% purity) as a white solid.

UPLC/MS (Method 3): m/z 474 (M+H) ⁺ , R _T 1.04 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.50 - 8.42 (m, 1H), 7.90-7.84 (m, 1H), 7.76 (td, J = 7.7, 1.9 Hz, 1 H), 7.69 (s, 1H), 7.66-7.59 (m, 1H), 7.52 (s, 1H), 7.21 -7.12 (m, 1H), 6.89 - 6.74 (m, 1 H), 5.50 (s, 1 H), 5.36 - 5.20 (m, 1 H), 4.55 (d, J = 5.5 Hz, 2H), 3.73 (s, 3H), 3.60-3.45 (m, 1H), 3.28-3.18 (m, 1H), 3.10-3.00 (m, 1H), 2.94-2.86 (m, 1H), 2.82- 2.74 (m, 1H), 2.34-2.25 (m, 1H), 2.20-2.11 (m, 1H), 1.77-1.67 (m, 1H), 1.63-1.55 (m, 1H), 1.42-1.31 (m, 1H), 1.22-1.08 (m, 1H), 0.80-0.71 (m, 2H), 0.71 -0.58 (m, 2H). 1H underwater.

Synthesis 034

(1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methanamine

Step A: tert-butyl ((4-(pyridin-2-yl)-1 H-imidazol-2-yl)methyl)carbamate

A solution of K2CO3 (330 mg, 2.38 mmol) in Water (400 μL) was added to a mixture of tert-butyl (2-amino-2-iminoethyl)carbamate, HCI (100 mg, 477 μmol) and 2-bromo-1- (pyridin-2-yl)ethan-1-one, HBr (134 mg, 477 μmol) in THF (4.0 ml_). The reaction mixture was stirred at 60°C overnight. The reaction mixture was diluted with water (2 ml_) and extracted with EtOAc (10 ml_, 2x5 ml_). The combined organic fractions were washed with brine (50 ml_), dried over Na2SC>4, filtered, then concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM)/DCM) to afford the title compound (80 mg, 0.28 mmol, 58% yield, 95% purity) as a brown oil.

UPLC/MS (Method 3): m/z 275 (M+H) ⁺ , R _T 0.96 min.

Step B: tert-butyl ((1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamat e At 0 °C, sodium hydride (66 g, 1.65 mmol) was added to a solution of tert-butyl ((4- (pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (432 mg, 1.57 mmol) in DMF (4.0 ml_). The reaction mixture was stirred at 0 °C for 1 hour then iodomethane (224 mg, 1.57 mmol) was added. The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (10 ml_) and extracted with DCM/MeOH (90:10) (40 ml). The organic fractions were washed with brine (3 x 15 ml_), dried over Na ₂ SC> ₄ , filtered, then concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (40 g cartridge, 15-50% MeCN/10 mM ammonium bicarbonate) to afford the title compound (204 mg, 0.67 mmol, 43% yield, 95% purity) as a brown solid.

UPLC/MS (Method 3): m/z 289 (M+H) ⁺ , R _T 1.16 min.

Step C:

(1-methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methanamine

HCI (4 M in dioxane) (2.60 ml_, 10.4 mmol) was added to a solution of tert-butyl ((1- methyl-4-(pyridin-2-yl)-1H-imidazol-2-yl)methyl)carbamate (200 mg, 694 μmol) in dioxane (2.0 ml_). The suspension was stirred at 35 °C overnight. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product eluted with 0.7 M NH ₃ in MeOH (30 ml_).

The ammoniacal methanol solution was concentrated in vacuo to give the title (133 mg, 0.64 mmol, 92% yield, 90% purity) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.79 (s, 2H), 8.67 - 8.61 (m, 1H), 8.37 (s, 1H), 8.26 (t, J = 7.8 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 6.4 Hz, 1H), 4.29 (d, J = 5.2 Hz, 2H), 3.85 (s, 3H).

Synthesis 035

(3R,4R)-4-(((3-cyclopropyl-7-(((1-(pyridin-2-yl)-1H-imida zol-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

Step 1 : 5-chloro-3-cyclopropyl-N-((1-(pyridin-2-yl)-1H-imidazol-4-yl )methyl)pyrazolo[1,5- a]pyrimidin-7-amine

DIPEA (0.23 mL, 1.32 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (50 mg, 219 μmol) and (1-(pyridin-2-yl)-1H-imidazol- 4-yl)methanamine (47 mg, 241 μmol) in EtOH (3.0 mL). The reaction mixture was heated at 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (43 mg, 0.12 mmol, 53% yield, 99% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 366 (M+H) ⁺ , R _T 1.32 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1 ,5-a] pyrimidin-7-yl)((1-(pyridin-2-yl)-1 H- imidazol-4-yl)methyl)carbamate

BOC-anhydride (31 mg, 0.14 mmol) was added to a solution of 5-chloro-3-cyclopropyl-N- ((1-(pyridin-2-yl)-1H-imidazol-4-yl)methyl)pyrazolo[1,5-a]py rimidin-7-amine (43 mg, 0.12 mmol) and DMAP (2.9 mg, 24 μmol) in THF (3.0 mL). The resulting reaction mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography 12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (38 mg, 80 μmol, 68% yield, 98% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 466 (M+H) ⁺ , R _T 1.67 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((1-(pyridin-2-yl)-1H-i midazol-4- yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((1-(py ridin-2- yl)-1H-imidazol-4-yl)methyl)carbamate (38 mg, 81.6 μmol) and tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (23 mg, 98 μmol) in THF (2.0 mL) was degassed with N2 for 5 min before adding ‘BuBrettPhos Pd G3 (7.0 mg, 8.2 μmol) and □ HMDS (1 M in THF) (106 pL, 106 μmol). The reaction was degassed for another 10 min before heating to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (46 mg, 56 μmol, 69% yield, 81% purity) as a colourless solid. UPLC/MS (Method 3): m/z 660 (M+H) ⁺ , R _T 1.59 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((1-(pyridin-2-yl)-1H-imida zol-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

HCI (4 M in dioxane) (0.17 ml_, 0.70 mmol) was added to a solution of tert-butyl (3R,4R)- 4-(((7-((tert-butoxycarbonyl)((1-(pyridin-2-yl)-1H-imidazol- 4-yl)methyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (46 mg, 70 μmol) in dioxane (2.0 ml_). The suspension was stirred at 35 °C for 4 h. The reaction mixture was concentrated in vacuo. The residue was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (21 mg, 44 μmol, 63% yield, 96% purity) as a yellow solid.

UPLC/MS (Method 6): m/z 460 (M+H) ⁺ , R _T 2.67 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.52 (d, J = 1.4 Hz, 1H), 8.48-8.45 (m, 1H), 8.00-7.95 (m, 1 H), 7.83 - 7.78 (m, 2H), 7.50 (s, 1 H), 7.47 (t, J = 6.2 Hz, 1 H), 7.40 - 7.32 (m, 1 H), 6.81 -6.73 (m, 1H), 5.36 (s, 1H), 4.44-4.35 (m, 2H), 3.60-3.46 (m, 1H), 3.26-3.17 (m, 1H), 3.10-2.98 (m, 2H), 2.98-2.88 (m, 1H), 2.85-2.76 (m, 1H), 2.33-2.28 (m, 1H), 2.22-2.12 (m, 1H), 1.76-1.68 (m, 1H), 1.62-1.56 (m, 1H), 1.39-1.30 (m, 1H), 1.22-1.13 (m, 1H), 0.80-0.70 (m, 2H), 0.68-0.60 (m, 2H). 1H underwater.

Synthesis 036

(3R,4R)-4-(((3-cyclopropyl-7-(((6-phenylpyridin-3-yl)meth yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-((6-phenylpyridin-3-yl)methyl)py razolo[1,5-a]pyrimidin-7-amine DIPEA (902 μL , 5.18 mmol) was added to a solution 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (169 mg, 740 μmol) and (6-phenylpyridin-3- yl)methanamine (150 mg, 814 μmol) in EtOH (4.0 ml_). The reaction mixture was heated at 50 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title (219 mg, 0.52 mmol, 71% yield, 90% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 376 (M+H) ⁺ , R _T 2.04 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6-phe nylpyridin-3- yl)methyl)carbamate

BOC-anhydride (153 mg, 699 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N- ((6-phenylpyridin-3-yl)methyl)pyrazolo[1 ,5-a]pyrimidin-7-amine (219 mg, 583 μmol), and DMAP (14.2 mg, 117 μmol) in THF (5.0 ml_). The resulting reaction mixture was stirred at RT for 3 h; further BOC-anhydride (153 mg, 699 μmol) was added, and the mixture stirred for further 2 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography 12 g cartridge, 0-10% MeOH/DCM) gave the title compound (200 mg, 0.34 mmol, 58% yield, 80% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 476 (M+H) ⁺ , R _T 1.98 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((6-phenylpyridin-3-yl) methyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (116 mg, 504 μmol) and tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((6- phenylpyridin-3-yl)methyl)carbamate (200 mg, 420 μmol) in THF (5.0 mL) was degassed with N2 for 10 min before adding ‘BuBrettPhos Pd G3 (36 mg, 42 μmol) and LiHMDS (1 M in THF) (546 pL, 546 μmol). The reaction was degassed for another 10 min before heating to 60 °C for 3 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) followed by purification by RP Flash C18 chromatography (12 g cartridge, 25-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (131 mg, 0.19 mmol,

44% yield, 95% purity) as a white solid.

UPLC/MS (Method 3): m/z 670 (M+H) ⁺ , R _T 2.22 min. Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((6-phenylpyridin-3-yl)meth yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((6-phenylpyridin-3-yl)methyl)amino)-3-cyclop ropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (131 mg, 196 μmol) in DCM (1.5 L). The reaction mixture was stirred at RT for 3 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 ₃ in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo then the solid was triturated with Et ₂ O (3 x 2 mL) to give the title compound (75 mg, 0.16 mmol, 80% yield, 98% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 470 (M+H) ⁺ , R _T 1.71 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.68 (d, J = 2.2 Hz, 1 H), 8.09 - 8.02 (m, 2H), 7.97 - 7.90 (m, 2H), 7.84 (dd, J = 8.2, 2.3 Hz, 1H), 7.52 (s, 1H), 7.51 - 7.45 (m, 2H), 7.45 - 7.39 (m,

1 H), 6.72 (t, J = 6.0 Hz, 1 H), 5.32 - 5.19 (m, 2H), 4.50 (d, J = 6.4 Hz, 2H), 3.54 - 3.43 (m, 1 H), 3.26 - 3.18 (m, 1H), 3.07 - 2.98 (m, 1 H), 2.94 - 2.88 (m, 1H), 2.82 - 2.75 (m, 1H), 2.34 - 2.25 (m, 1H), 2.20 - 2.11 (m, 1H), 1.75 - 1.66 (m, 1H), 1.60 - 1.52 (m, 1H), 1.37 - 1.27 (m, 1 H), 1.19 - 1.11 (m, 1H), 0.80 - 0.70 (m, 2H), 0.70 - 0.59 (m, 2H). 1 H under water.

Synthesis 037

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-methoxypyridin-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(3-methoxypyridin-2-yl)benzyl )pyrazolo[1 ,5-a]pyrimidin-7- amine DIPEA (0.26 ml_, 1.50 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (57 mg, 250 μmol), and (4-(3-methoxy)pyridin-2- yl)phenyl)methanamine (57 mg, 250 μmol) in EtOH (1.0 ml_). The reaction mixture was heated to 65 °C for 4 h. The reaction mixture was concentrated in vacuo then the residue re-dissolved in EtOH (1.0 ml_) and more DIPEA (0.17 ml_, 1.00 mmol) and 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (20 mg, 88 μmol) were added. The reaction mixture was heated to 65 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75/isohexane) gave the title compound (126 mg, 0.30 mmol, 90% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 406 (M+H) ⁺ , R _T 1.60 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3-m ethoxypyridin-2- yl)benzyl)carbamate

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

UPLC/MS (Method 3): m/z 506 (M+H) ⁺ , R _T 1.92 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2- yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- methoxypyridin-2-yl)benzyl)carbamate (149 mg, 295 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (81 mg, 353 μmol) in THF (3.3 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (25.2 mg, 29.5 μmol) and LiHMDS (1M in THF) (353 pL, 353 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOH in EtOAc 25:75/isohexane) gave the title compound (114 mg, 0.15 mmol, 52% yield, 95% purity) as a brown oil.

UPLC/MS (Method 3): m/z 700 (M+H) ⁺ , R _T 1.89 min. Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-methoxypyridin-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.77 ml_, 3.07 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-methoxypyridin-2- yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (113 mg, 153 μmol) in dioxane (2.4 ml_). The reaction mixture was stirred at 40 °C for 2 h then Hydrogen chloride (1.25 M in MeOH) (1.0 ml_, 1.3 mmol) was added, and the reaction mixture was stirred at 40 °C for 30 min then concentrated in vacuo. The solid was triturated in MeCN (2 x 2 ml_) then was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (68 mg, 0.13 mmol, 87% yield, 97% purity) as an orange solid.

LCMS (Method 2): m/z 500 (M+H) ⁺ , RT 0.65 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.23 (dd, J = 4.6, 1.3 Hz, 1 H), 7.89 (t, J = 6.5 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.54 (dd, J = 8.4, 1.4 Hz, 1 H), 7.53 (s, 1H), 7.40 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 8.3, 4.6 Hz, 1 H), 6.73 (t, J = 6.0 Hz, 1 H), 5.42 - 5.29 (m, 1H), 5.19 (s,

1 H), 4.49 (d, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.57 - 3.44 (m, 1H), 3.24 - 3.16 (m, 1H), 3.09 - 2.99 (m, 1 H), 2.91 (dd, J = 11.6, 4.6 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.36 - 2.27 (m, 1H), 2.17 (dd, J = 11.6, 9.9 Hz, 1 H), 1.78 - 1.65 (m, 1H), 1.61 - 1.53 (m, 1H), 1.39 - 1.29 (m,

1 H), 1.21 - 1.08 (m, 1 H), 0.83 - 0.71 (m, 2H), 0.70 - 0.59 (m, 2H). 1 H under water.

Synthesis 038

(4-(3-methoxypyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-methoxypyridin-2-yl)phenyl)methanamine

A mixture of 2-chloro-3-methoxypyridine (60 mg, 418 μmol), (4- (aminomethyl)phenyl)boronic acid, HCI (86 mg, 460 μmol) and Pd(dppf)Cl ₂ (31 mg, 42 μmol) in dioxane (2.5 ml_) was sparged with N ₂ for 5 min. A solution of potassium phosphate, tribasic (355 mg, 1.67 mmol) in water (1.1 ml_) was added and the reaction mixture was sparged with N ₂ for 5 min. The mixture was heated to 90 °C for 2 h. The reaction mixture was concentrated in vacuo. The residue was diluted with DCM/MeOH 90:10 (10 ml_) and water (3 ml_). The layers were separated and the aq layer was extracted with more DCM/MeOH 90:10 (5 ml_). The combined organic layers were filtered through a phase separator and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (59 mg, 0.27 mmol, 64% yield, 97% purity) as a brown solid.

UPLC/MS (Method 3): m/z 215 (M+H) ⁺ , R _T 0.87 min.

Synthesis 039

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethoxy)pyr idin-2- yl)benzyl)amino)pyrazolo[1 ,5-a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(3-(trifluoromethoxy)pyridin- 2-yl)benzyl)pyrazolo[1,5- a]pyrimidin-7-amine

DIPEA (0.28 ml_, 1.58 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (60 mg, 263 μmol), and (4-(3- trifluoromethoxy)pyridin-2-yl)phenyl)methanamine (71 mg, 263 μmol) in EtOH (3.0 ml_). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (92 mg, 0.19 mmol, 73% yield, 96% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 460 (M+H) ⁺ , R _T 1.78 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- (trifluoromethoxy)pyridin-2-yl)benzyl)carbamate

DMAP (4.9 mg, 40 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(3- (trifluoromethoxy)pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimid in-7-amine (92 mg, 200 μmol) and BOC-anhydride (52 g, 240 μmol) in anhydrous THF (3.0 ml_). The reaction mixture was heated at RT for 1.5 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (110 mg, 0.19 mmol, 95% yield, 97% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 560 (M+H) ⁺ , R _T 2.05 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-(trifluoromethoxy )pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- (trifluoromethoxy)pyridin-2-yl)benzyl)carbamate (106 mg, 189 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (52 mg, 227 μmol) in THF (3.2 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (16.2 mg, 18.9 μmol) and LiHMDS (1M in THF) (246 pL, 246 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. The reaction mixture concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (135 mg, 0.16 mmol, 85% yield, 90% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 754 (M+H) ⁺ , R _T 2.01 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethoxy)pyr idin-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.84 mL, 3.34 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-(trifluoromethoxy )pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate (134 mg, 167 μmol) in dioxane (2.4 mL). The reaction mixture was stirred at 40 °C for 2 h then hydrogen chloride (1.25 M in MeOH) (1.0 mL, 1.3 mmol) was added and the reaction mixture was stirred at 40 °C for 30 min then concentrated in vacuo. The solid was triturated in MeCN (2 x 2 mL) then was loaded onto a column of SCX. The column was washed with MeOH (80 mL) and the product was eluted with 0.7 M NH3 in MeOH (100 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 mL) to give the title compound (67 mg, 0.11 mmol, 69% yield, 95% purity) as a beige solid.

LCMS (Method 2): m/z 554 (M+H) ⁺ , RT 0.88 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.69 (dd, J = 4.6, 1.4 Hz, 1 H), 7.98 (dt, J = 8.4, 1.5 Hz,

1 H), 7.90 (t, J = 6.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.55 (dd, J = 8.4, 4.6 Hz, 1H), 7.53 (s, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 6.76 - 6.68 (m, 1 H), 5.37 - 5.28 (m, 1 H), 5.21 (s, 1 H), 4.52 (d, J = 6.4 Hz, 2H), 3.60 - 3.42 (m, 1H), 3.25 - 3.16 (m, 1 H), 3.09 - 2.98 (m, 1H), 2.91 (dd, J = 11.5, 4.6 Hz, 1 H), 2.83 - 2.75 (m, 1H), 2.33 - 2.25 (m, 1H), 2.17 (t, J = 10.8 Hz, 1H), 1.75 - 1.67 (m, 1H), 1.61 - 1.51 (m, 1H), 1.38 - 1.28 (m, 1H), 1.18 - 1.11 (m,

1 H), 0.80 - 0.71 (m, 2H), 0.69 - 0.59 (m, 2H). 1 H under water.

Synthesis 040

(4-(3-(trifluoromethoxy)pyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-(trifluoromethoxy)pyridin-2-yl)phenyl)methanamine

A mixture of 2-Chloro-3-(trifluoromethoxy)pyridine (150 g, 759 μmol), (4- (aminomethyl)phenyl)boronic acid (206 mg, 1.37 mmol) and Pd(dppf)Cl2.DCM (62 mg, 76 μmol) in dioxane (9.0 ml_) was sparged with N2 for 5 min. A solution of cesium carbonate (990 mg, 3.04 mmol) in water (1.0 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 90 °C for 2 h. At RT, water (50 ml_) was added, and the mixture was extracted with EtOAc (2 x 25 ml_). The combined organic layers were dried over MgSCU, filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (160 mg, 0.55 mmol, 72% yield, 92% purity) as an orange oil.

UPLC/MS (Method 1): m/z 269 (M+H) ⁺ , R _T 1.15 min.

Synthesis 041

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyrimidin-2-yl)benzyl)a mino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(pyrimidin-2-yl)benzyl)pyrazo lo[1,5-a]pyrimidin-7-amine

DIPEA (0.28 ml_, 1.63 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (62 mg, 272 μmol), and (4-(pyrimidin-2- yl)phenyl)methanamine (60 mg, 324 μmol) in EtOH (3.0 ml_). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (67 mg, 0.18 mmol, 65% yield, 99% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 377 (M+H) ⁺ , R _T 1.56 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr imidin-2- yl)benzyl)carbamate

DMAP (3.9 mg, 32 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4- (pyrimidin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (60 mg, 159 μmol) and BOC- anhydride (42 mg, 191 μmol) in anhydrous THF (3.0 ml_). The reaction mixture was heated at RT for 1.5 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (69 mg, 0.14 mmol, 86% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 477 (M+H) ⁺ , R _T 1.98 min

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benz yl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr imidin- 2-yl)benzyl)carbamate (65 mg, 136 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (38 g, 164 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (11.6 mg, 13.6 μmol) and LiHMDS (1M in THF) (177 pL, 177 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (95 mg, 0.12 mmol, 90% yield, 87% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 671 (M+H) ⁺ , R _T 1.87 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyrimidin-2-yl)benzyl)a mino)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.62 ml_, 2.5 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benz yl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (95 mg, 0.12 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 2 h then hydrogen chloride (1.25 M in MeOH) (1.0 ml_, 1.3 mmol) was added and the reaction mixture was stirred at 40 °C for 30 min then concentrated in vacuo. The solid was triturated in MeCN (2 x 2 ml_) then was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (42 mg, 86 μmol, 69% yield, 96% purity) as a beige solid.

LCMS (Method 2): m/z 471 (M+H) ⁺ , RT 0.68 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 (d, J = 4.8 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H), 7.92 (t, J = 6.5 Hz, 1 H), 7.53 (s, 1 H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1 H), 6.76 - 6.67 (m, 1H), 5.38 - 5.28 (m, 1 H), 5.16 (s, 1H), 4.53 (d, J = 6.3 Hz, 2H), 3.58 - 3.43 (m, 1H), 3.24 - 3.14 (m, 1H), 3.08 - 2.98 (m, 1H), 2.91 (dd, J = 11.5, 4.4 Hz, 1H), 2.82 - 2.74 (m,

1 H), 2.34 - 2.24 (m, 1H), 2.16 (t, J = 10.8 Hz, 1 H), 1.77 - 1.66 (m, 1 H), 1.59 - 1.50 (m,

1 H), 1.39 - 1.26 (m, 1H), 1.21 - 1.06 (m, 1H), 0.80 - 0.72 (m, 2H), 0.69 - 0.59 (m, 2H).

1H under water. Synthesis 042

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

Step 1 :

5-chloro-3-cyclopropyl-N-(2-methoxy-4-(pyridin-2-yl)benzy l)pyrazolo[1,5-a]pyrimidin-7- amine

DIPEA (0.41 mL, 2.4 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (90 mg, 0.39 mmol), and (2-methoxy-4-(pyridin-2- yl)phenyl)methanamine (110 mg, 0.51 mmol) in EtOH (3.0 mL). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (150 mg, 0.33 mmol, 84% yield, 90% purity) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.74 - 8.62 (m, 2H), 7.97 (dt, = 8.1 , 1.1 Hz, 1H), 7.94 (s, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1 H), 7.75 (d, J = 1.6 Hz, 1 H), 7.61 (dd, J = 7.9, 1.6 Hz,

1 H), 7.35 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1 H), 6.05 (s, 1H), 4.61 (d, J = 6.4 Hz, 2H), 3.98 (s, 3H), 1.95 - 1.84 (m, 1H), 0.92 - 0.83 (m, 2H), 0.80 - 0.70 (m, 2H).

Step 2: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-methoxy-4-(pyridin-2 -yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of 5-chloro-3-cyclopropyl-N-(2-methoxy-4-(pyridin-2-yl)benzyl)p yrazolo[1,5- a]pyrimidin-7-amine (130 mg, 320 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (81 mg, 352 μmol) in dioxane (2.5 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (27 mg, 32 μmol) and LiHMDS (1M in THF) (416 pL, 416 μmol). The reaction was degassed for another 5 min before being heated to 90 °C overnight. At RT, the reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 15- 75% MeCN/10 mM ammonium bicarbonate) gave the title compound (94 mg, 150 μmol, 46% yield, 95% purity) as a white solid.

UPLC/MS (Method 3): m/z 600 (M+H) ⁺ , R _T 1.19 min.

Step 3:

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

Hydrogen chloride (4 M in dioxane) (0.59 ml_, 2.4 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-methoxy-4-(pyridin-2 -yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (94 mg, 160 μmol) in dioxane (1.0 ml_). The reaction mixture was stirred at 35 °C for 2 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (61 mg, 0.11 mmol, 73% yield, 94% purity) as a white solid.

LCMS (Method 2): m/z 500 (M+H) ⁺ , RT 0.71 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 (ddd, J = 4.7, 1.9, 0.9 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1 H), 7.74 (d, J = 1.7 Hz, 1 H), 7.71 (t, J = 6.4 Hz, 1 H), 7.61 (dd, J = 8.0, 1.6 Hz, 1H), 7.55 (s, 1 H), 7.35 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 7.22 (d, J = 7.9 Hz,

1 H), 6.82 (t, J = 6.1 Hz, 1 H), 5.89 - 5.79 (m, 1H), 5.10 (s, 1 H), 4.46 (d, J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.59 - 3.48 (m, 1 H), 3.29 - 3.22 (m, 2H), 3.12 (dd, J = 11.8, 4.3 Hz, 1 H), 3.08 - 3.00 (m, 1 H), 2.66 - 2.58 (m, 1 H), 2.49 - 2.44 (m, 1 H), 1.77 - 1.67 (m, 2H), 1.56 - 1.45 (m, 1H), 1.39 - 1.28 (m, 1H), 0.82 - 0.72 (m, 2H), 0.72 - 0.61 (m, 2H). 1H under water.

Synthesis 043

(2-methoxy-4-(pyridin-2-yl)phenyl)methanamine

Step A:

2-methoxy-4-(pyridin-2-yl)benzonitrile

2-Chloropyridine (250 mg, 2.20 mmol), (4-cyano-3-methoxyphenyl)boronic acid (423 mg, 1.98 mmol) Pd(dppf)Cl2 (161 mg, 220 μmol) and potassium phosphate, tribasic (1.87 g, 8.81 mmol) were taken up in dioxane (16 ml_) and water (4.0 ml_). The reaction mixture was sparged with N2 for 15 min then heated to 60 °C for 4 h then allowed to cool to RT. The mixture was diluted with EtOAc (30 ml_) and water (10 ml_). The layers were separated and the aq layer extracted with EtOAc (2 x 15 ml_). The combined organic layer was dried over Na ₂ SO ₄ , filtered then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (320 mg, 1.3 mmol, 63% yield, 85% purity) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.74 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.20 - 8.10 (m, 1H), 7.96 (td, J = 7.8, 1.8 Hz, 1 H), 7.90 (d, J = 1.4 Hz, 1 H), 7.88 - 7.78 (m, 2H), 7.46 (ddd, J = 7.5, 4.8, 1.1 Hz, 1 H), 4.03 (s, 3H).

Step B:

(2-methoxy-4-(pyridin-2-yl)phenyl)methanamine

2-Methoxy-4-(pyridin-2-yl)benzonitrile (200 mg, 951 μmol) was taken up in THF (8.0 ml_) and the solution was cooled to 0 °C. LiAIH ₄ (4M in Et ₂ O ) (238 μl_, 951 μmol) was added and the mixture was stirred for 15 min at 0 °C then at RT for 30 min. The reaction mixture was heated at 50 °C for 1 h before being cooled to 0 °C and quenched with a few drops of aq. sat. Na2SC>4. The mixture was filtered through a short pad of celite, rinsing with THF (30 ml_). The filtrate was concentrated to give the title compound (217 mg, 0.91 mmol, 96% yield, 90% purity) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.03 - 7.93 (m, 1H), 7.86 (td, J = 7.7, 1.8 Hz, 1 H), 7.67 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 7.8, 1.6 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1 H), 7.33 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 3.89 (s, 3H), 3.71 (s, 2H), 1.72 (s (br), 2H).

Synthesis 044

(3R,4R)-4-(((3-cyclopropyl-7-((4-(oxazol-2-yl)benzyl)amin o)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol Step 1 :

5-chloro-3-cyclopropyl-N-(4-(oxazol-2-yl)benzyl)pyrazolo[ 1,5-a]pyrimidin-7-amine

DIPEA (0.22 mL, 1.24 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (42 mg, 186 μmol), and (4-(oxazol-2- yl)phenyl)methanamine (36 mg, 207 μmol) in EtOH (1.0 mL). The reaction mixture was heated to 60 °C for 3 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (62 mg, 0.16 mmol, 75% yield, 92% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 366 (M+H) ⁺ , R _T 1.61 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(oxa zol-2- yl)benzyl)carbamate

DMAP (4.1 mg, 34 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(oxazol- 2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (62 mg, 169 μmol) and BOC-Anhydride (44 mg, 203 μmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at RT for 1 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (52 mg, 0.11 mmol, 63% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 466 (M+H) ⁺ , R _T 1.95 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(oxazol-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(oxa zol-2- yl)benzyl)carbamate (50 mg, 0.11 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (30 mg, 0.13 mmol) in THF (2.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (9.2 mg, 11 μmol) and LiHMDS (1M in THF) (140 pL, 140 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. At RT, the reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (78 mg, 95 μmol, 88% yield, 80% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 660 (M+H) ⁺ , R _T 1.80 min. Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(oxazol-2-yl)benzyl)amin o)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.21 ml_, 0.85 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(oxazol-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (70 mg, 85 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (10 mg, 21 μmol, 25% yield, 97% purity) as a white solid.

LCMS (Method 2): m/z 460 (M+H) ⁺ , RT 0.98 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.20 (d, J = 0.8 Hz, 1 H), 7.96 (d, J = 8.3 Hz, 2H), 7.94 - 7.89 (m, 1 H), 7.52 (s, 1 H), 7.49 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 0.8 Hz, 1 H), 6.71 - 6.67 (m, 1H), 5.30 - 5.25 (m, 1H), 5.14 (s, 1 H), 4.51 (d, J = 6.2 Hz, 2H), 3.53 - 3.43 (m, 1H), 3.23 - 3.15 (m, 1H), 3.06 - 2.95 (m, 1H), 2.89 (dd, J = 11.6, 4.5 Hz, 1H), 2.80 - 2.73 (m,

1 H), 2.33 - 2.22 (m, 1H), 2.14 (t, J = 10.7 Hz, 1 H), 1.77 - 1.65 (m, 1H), 1.58 - 1.50 (m,

1 H), 1.36 - 1.25 (m, 1H), 1.18 - 1.06 (m, 1 H), 0.80 - 0.70 (m, 2H), 0.70 - 0.58 (m, 2H).

1 H under water.

Synthesis 045

(R)-3-cyclopropyl-N ⁵ -(morpholin-2-ylmethyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-2-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)ami no)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)morpho line-4-carboxylate A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (90 mg, 189 μmol) (prepared as described herein), tert-butyl (S)-2- (amino ethyl) orpholine-4-carboxylate (61 g, 284 μmol) and cesium carbonate (185 mg, 567 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (3.8 mg, 5.7 μmol) and Ruphos (3.1 mg, 6.62 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (66 mg, 96 μmol, 51% yield, 95% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 656 (M+H) ⁺ , RT 2.17 min.

Step 4:

(R)-3-cyclopropyl-N ⁵ -(morpholin-2-ylmethyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (252 pL, 1.01 mmol) was added to a solution of tert- butyl (S)-2-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)ami no)-3- cyclopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino)methyl)morpholine-4-carboxylate (66 mg, 101 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (22 mg, 47 μmol, 47% yield, 98% purity) as a white solid.

LCMS (Method 2): m/z 456 (M+H) ⁺ , RT 0.89 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.68 - 8.61 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 - 7.90 (m, 1 H), 7.90 - 7.81 (m, 2H), 7.55 (s, 1 H), 7.45 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.3,

4.8, 1.2 Hz, 1 H), 6.65 (t, J = 5.7 Hz, 1 H), 5.19 (s, 1 H), 4.49 (d, J = 6.3 Hz, 2H), 3.76 - 3.69 (m, 1 H), 3.54 - 3.46 (m, 1H), 3.46 - 3.36 (m, 1H), 3.29 - 3.15 (m, 1 H), 2.87 - 2.79 (m, 1H), 2.73 - 2.59 (m, 2H), 2.45 - 2.35 (m, 1H), 1.82 - 1.71 (m, 1H), 0.80 - 0.73 (m, 4H). 2H under water. Svnthesis 046

3-cyclopropyl-5-morpholino-N-(4-(pyridin-2-yl)benzyl)pyra zolo[1,5-a]pyrimidin-7-amine

Step 3: tert-butyl (3-cyclopropyl-5-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)(4- (pyridin-2- yl)benzyl)carbamate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), morpholine (92 mg, 1.05 mmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.30 μmol) and Ruphos (3.4 mg, 7.35 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min.

The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (105 mg, 0.16 mmol, 76% yield, 80% purity) as a yellow glass solid.

UPLC/MS (Method 2): m/z 527 (M+H) ⁺ , RT 2.00 min.

Step 4:

3-cyclopropyl-5-morpholino-N-(4-(pyridin-2-yl)benzyl)pyra zolo[1,5-a]pyrimidin-7-amine

Hydrogen chloride (4 M in dioxane) (404 pL, 1.61 mmol) was added to a solution of tert- butyl (3-cyclopropyl-5-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)(4- (pyridin-2- yl)benzyl)carbamate (105 mg, 161 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (24 mg, 53 μmol, 33% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 427 (M+H) ⁺ , RT 1.41 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.07 - 7.98 (m, 3H), 7.96 - 7.89 (m, 1H), 7.86 (td, J = 7.7, 1.8 Hz, 1H), 7.63 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J =

7.4, 4.8, 1.2 Hz, 1 H), 5.56 (s, 1 H), 4.62 (d, J = 6.6 Hz, 2H), 3.64 (t, J = 4.8 Hz, 4H), 3.45

(t, J = 4.8 Hz, 4H), 1.84 - 1.73 (m, 1 H), 0.82 - 0.70 (m, 4H).

Synthesis 047

(3R,4R)-4-(((3-cyclopropyl-7-(((5-phenylpyridin-2-yl)meth yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-((5-phenylpyridin-2-yl)methyl)py razolo[1,5-a]pyrimidin-7-amine

DIPEA (902 pl_, 5.18 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (150 mg, 814 mmol), (5-phenylpyridin-2- yl)methanamine (150 mg, 814 μmol) in EtOH (4.0 ml_). The reaction mixture was heated to 60 °C for 3 h. At RT, the resulting solid was collected by filtration, rinsing with EtOH (2 ml_) to give the title compound (237 mg, 0.60 mmol, 81% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 376 (M+H) ⁺ , R _T 2.11 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5-phe nylpyridin-2- yl)methyl)carbamate

DMAP (14.5 mg, 119 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((5- phenylpyridin-2-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (235 mg, 594 μmol) and BOC- anhydride (156 mg, 713 μmol) in anhydrous THF (6.0 ml_). The reaction mixture was heated at RT for 4 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (275 g, 0.46 mmol, 78% yield, 80% purity) as a green oil.

UPLC/MS (Method 3): m/z 476 (M+H) ⁺ , R _T 2.01 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((5-phenylpyridin-2-yl) methyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((5- phenylpyridin-2-yl)methyl)carbamate (275 mg, 462 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (160 mg, 695 μmol) in THF (8.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (60 mg, 70 μmol) and LiHMDS (1M in THF) (753 pL, 753 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (294 mg, 0.37 mmol, 81% yield, 85% purity) as a brown oil.

UPLC/MS (Method 3): m/z 670 (M+H) ⁺ , R _T 1.85 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((5-phenylpyridin-2-yl)meth yl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

TFA (1.0 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((5-phenylpyridin-2-yl)methyl)amino)-3-cyclop ropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (294 mg, 373 μmol) in DCM (3.0 mL). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (114 mg, 0.24 mmol, 64% yield, 99% purity) as a tan solid.

UPLC/MS (Method 3): m/z 470 (M+H) ⁺ , RT 1.34 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.86 (dd, J = 2.4, 0.8 Hz, 1 H), 8.07 (dd, J = 8.2, 2.4 Hz,

1 H), 7.86 (t, J = 6.2 Hz, 1 H), 7.76 - 7.68 (m, 2H), 7.54 (s, 1 H), 7.53 - 7.47 (m, 2H), 7.45 - 7.38 (m, 2H), 6.76 (t, J = 6.0 Hz, 1H), 5.34 - 5.25 (m, 1H), 5.20 (s, 1 H), 4.59 (d, J = 6.1 Hz, 2H), 3.59 - 3.43 (m, 1 H), 3.25 - 3.18 (m, 1H), 3.10 - 2.98 (m, 1H), 2.91 (dd, J = 11.6, 4.5 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.37 - 2.25 (m, 1H), 2.16 (dd, J = 11.6, 9.9 Hz, 1 H), 1.78 - 1.68 (m, 1H), 1.60 - 1.51 (m, 1H), 1.40 - 1.27 (m, 1 H), 1.20 - 1.11 (m, 1H), 0.83 - 0.72 (m, 2H), 0.72 - 0.60 (m, 2H). 1 H under water.

Synthesis 048

(3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-4-yl)benzyl)ami no)pyrazolo[1 ,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(thiazol-4-yl)benzyl)pyrazolo [1,5-a]pyrimidin-7-amine

DIPEA (926 μL , 5.32 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (173 mg, 759 mmol), (4-(thiazol-4- yl)phenyl)methanamine (170 mg, 759 μmol) in EtOH (5.0 ml_). The reaction mixture was heated to 60 °C for 3 h then was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (210 mg, 0.53 mmol, 70% yield, 96% purity) as a white solid.

UPLC/MS (Method 2): m/z 382 (M+H) ⁺ , R _T 2.02 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thi azol-4- yl)benzyl)carbamate

DMAP (6.4 mg, 52 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(thiazol- 4-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (100 mg, 262 μmol) and BOC-anhydride (69 mg, 314 μmol) in anhydrous THF (3.0 mL). The reaction mixture was heated at RT for 4 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 100% EtOAc/isohexane) gave the title compound (136 mg, 0.24 mmol, 92% yield, 85% purity) as a green oil.

UPLC/MS (Method 3): m/z 382 (M-Boc+H) ⁺ , R _T 1.90 min. Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(thiazol-4-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thi azol-4- yl)benzyl)carbamate (136 mg, 240 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (66 g, 288 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (20.5 mg, 24.0 μmol) and LiHMDS (1M in THF) (312 pL, 312 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (113 mg, 0.14 mmol, 59% yield, 85% purity) as a brown oil.

UPLC/MS (Method 3): m/z 676 (M+H) ⁺ , R _T 1.81 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(thiazol-4-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

TFA (0.5 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4- (thiazol-4-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (180 mg, 207 μmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (30 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (50 mg, 0.10 mmol, 71% yield, 96% purity) as a tan solid.

UPLC/MS (Method 3): m/z 476 (M+H) ⁺ , RT 1.25 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (d, J = 1.9 Hz, 1 H), 8.12 (d, J = 1.9 Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 7.87 (t, J = 6.5 Hz, 1 H), 7.52 (s, 1 H), 7.45 - 7.40 (m, 2H), 6.71 (t, J = 6.0 Hz, 1H), 5.38 - 5.27 (m, 1H), 5.18 (s, 1 H), 4.47 (d, J = 6.3 Hz, 2H), 3.57 - 3.44 (m,

1 H), 3.24 - 3.15 (m, 1H), 3.07 - 2.98 (m, 1 H), 2.90 (dd, J = 11.5, 4.5 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.36 - 2.25 (m, 1H), 2.16 (dd, J = 11.6, 9.9 Hz, 1 H), 1.76 - 1.67 (m, 1 H), 1.60 - 1.50 (m, 1H), 1.38 - 1.27 (m, 1H), 1.20 - 1.11 (m, 1H), 0.82 - 0.71 (m, 2H), 0.70 - 0.59 (m, 2H). 1 H under water. Synthesis 049

(4-(thiazol-4-yl)phenyl)methanamine

Step A:

(4-(thiazol-4-yl)phenyl)methanamine

A mixture of 4-bromothiazole (200 g, 1.22 mmol), (4-(aminomethyl)phenyl)boronic acid, HCI (251 mg, 1.34 mmol) and Pd(dppf)Cl2 (89 mg, 122 μmol) in dioxane (9.0 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (1.04 g, 4.88 mmol) in water (1.0 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 70 °C for 2 h. At RT, water (100 ml_) was added, and the mixture was extracted with DCM (3 x 25 ml_). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The oil was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (30 ml_) to give the title compound (170 mg, 0.76 mmol, 62% yield, 85% purity) as a brown solid.

UPLC/MS (Method 3): m/z 191 (M+H) ⁺ , R _T 0.85 min.

Synthesis 050

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethyl)pyri din-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(4-(3-(trifluoromethyl)pyridin-2 -yl)benzyl)pyrazolo[1 ,5- a]pyrimidin-7-amine

DIPEA (1.04 ml_, 5.99 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (195 mg, 0.86 mmol), and (4-(3- (trifluoromethyl)pyridin-2-yl)phenyl)methanamine (240 mg, 0.86 mmol) in EtOH (5.0 ml_). The reaction mixture was heated to 60 °C for 3 h then was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (270 mg, 0.58 mmol, 68% yield, 96% purity) as a white solid.

UPLC/MS (Method 2): m/z 444 (M+H) ⁺ , R _T 2.12 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- (trifluoromethyl)pyridin-2-yl)benzyl)carbamate

DMAP (5.5 mg, 45 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-(4-(3- (trifluoromethyl)pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidi n-7-amine (100 mg, 225 μmol) and BOC-anhydride (59 mg, 270 μmol) in anhydrous THF (3.0 ml_). The reaction mixture was heated at RT for 4 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (128 mg, 0.21 mmol, 93% yield, 89% purity) as a green oil.

UPLC/MS (Method 3): m/z 444 (M-Boc+H) ⁺ , R _T 1.97 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(3-(trifluoromethyl) pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(3- (trifluoromethyl)pyridin-2-yl)benzyl)carbamate (128 mg, 209 μmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (58 mg, 251 μmol) in THF (2.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17.9 mg, 20.9 μmol) and LiHMDS (1M in THF) (272 pL, 272 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (180 mg, 0.21 mmol, 99% yield, 85% purity) as a brown oil.

UPLC/MS (Method 3): m/z 738 (M+H) ⁺ , R _T 1.88 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(3-(trifluoromethyl)pyri din-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol TFA (0.5 mL) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4- (3-(trifluoromethyl)pyridin-2-yl)benzyl)amino)-3-cyclopropyl pyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (180 mg, 207 μmol) in DCM (1.5 L). The reaction mixture was stirred at RT for 16 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 mL) to give the title compound (96 mg, 0.17 mmol, 83% yield, 96% purity) as a tan solid.

UPLC/MS (Method 3): m/z 538 (M+H) ⁺ , RT 1.38 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.91 - 8.87 (m, 1H), 8.29 (dd, = 8.1 , 1.6 Hz, 1H), 7.90 (t, J = 6.5 Hz, 1 H), 7.68 - 7.61 (m, 1 H), 7.53 (s, 1 H), 7.47 - 7.40 (m, 4H), 6.78 - 6.68 (m,

1 H), 5.38 - 5.26 (m, 1 H), 5.22 (s, 1 H), 4.53 (d, J = 6.4 Hz, 2H), 3.59 - 3.43 (m, 1 H), 3.26 - 3.17 (m, 1 H), 3.09 - 2.99 (m, 1H), 2.95 - 2.87 (m, 1H), 2.85 - 2.74 (m, 1H), 2.36 - 2.26 (m, 1H), 2.21 - 2.12 (m, 1H), 1.78 - 1.67 (m, 1H), 1.61 - 1.52 (m, 1H), 1.40 - 1.28 (m,

1 H), 1.22 - 1.11 (m, 1H), 0.80 - 0.71 (m, 2H), 0.71 - 0.60 (m, 2H). 1H under water.

Synthesis 051

(4-(3-(trifluoromethyl)pyridin-2-yl)phenyl)methanamine

Step A:

(4-(3-(trifluoromethyl)pyridin-2-yl)phenyl)methanamine

A mixture of 2-chloro-3-(trifluoromethyl)pyridine (200 mg, 1.10 mmol), (4- (aminomethyl)phenyl)boronic acid, HCI (227 mg, 1.21 mmol) and Pd(dppf)Cl ₂ (81 mg, 110 μmol) in dioxane (9.0 mL) was sparged with N ₂ for 5 min. A solution of potassium phosphate, tribasic (935 mg, 4.41 mmol) in water (1.0 mL) was added and the reaction mixture was sparged with N ₂ for 5 min. The mixture was heated to 70 °C for 2 h. At RT, water (100 mL) was added and the mixture was extracted with DCM (3 x 25 mL). The combined organic layers were dried over MgSCU, filtered and concentrated in vacuo. The oil was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (30 mL) to give the title compound (244 mg, 0.87 mmol, 79% yield, 90% purity) as a red solid.

UPLC/MS (Method 3): m/z 253 (M+H) ⁺ , R _T 1.06 min. Synthesis 052

(S)-3-cyclopropyl-N ⁷ -(4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), tert-butyl (S)-

3-aminopyrrolidine-1-carboxylate (117 mg, 630 μmol) and cesium carbonate (205 mg,

630 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.30 μmol) and Ruphos (3.4 mg, 7.35 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (90 mg, 0.13 mmol, 62% yield, 90% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 626 (M+H) ⁺ , RT 1.94 min.

Step 4:

(S)-3-cyclopropyl-N ⁷ -(4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine- 5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.36 ml_, 1.4 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate (90 mg, 0.14 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (10 mg, 23 μmol, 16% yield, 96% purity) as a white solid.

UPLC/MS (Method 2): m/z 426 (M+H) ⁺ , RT 1.68 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.68 - 8.61 (m, 1 H), 8.08 - 8.01 (m, 2H), 7.92 (d, J = 8.0 Hz, 1 H), 7.91 - 7.80 (m, 2H), 7.55 (s, 1 H), 7.44 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.3,

4.7, 1.2 Hz, 1 H), 6.64 (d, J = 6.5 Hz, 1 H), 5.08 (s, 1 H), 4.50 (d, J = 6.3 Hz, 2H), 4.18 - 4.14 (m, 1H), 2.98 (dd, J = 11.1 , 6.5 Hz, 1H), 2.87 - 2.77 (m, 1 H), 2.75 - 2.69 (m, 1H), 2.00 - 1.83 (m, 1H), 1.81 - 1.70 (m, 1H), 1.55 - 1.44 (m, 1 H), 0.81 - 0.71 (m, 4H). 2H under water.

Synthesis 053

3-cyclopropyl-5-(piperazin-1-yl)-N-(4-(pyridin-2-yl)benzy l)pyrazolo[1 ,5-a]pyrimidin-7- amine

Step 3: tert-butyl 4-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carbox ylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl piperazine- 1-carboxylate (43 mg, 231 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (2.0 mL) was degassed with N2 for 5 min. Pd-171 (7.0 mg, 10.5 μmol) and Ruphos (5.4 mg, 11.6 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C overnight. At RT, the reaction mixture was diluted with EtOAc (10 mL) and filtered through celite, rinsing with EtOAc (20 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 15-75% MeCN/10 mM ammonium bicarbonate) gave the title compound (59 g, 91 μmol, 44% yield, 97% purity) as an off- white solid.

UPLC/MS (Method 3): m/z 626 (M+H) ⁺ , RT 2.02 min.

Step 4:

3-cyclopropyl-5-(piperazin-1-yl)-N-(4-(pyridin-2-yl)benzy l)pyrazolo[1,5-a]pyrimidin-7- amine

Hydrogen chloride (4 M in dioxane) (0.34 ml_, 1.3 mmol) was added to a solution of tert- butyl 4-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5- a]pyrimidin-5-yl)piperazine-1-carboxylate (56 mg, 89 μmol) in dioxane (0.5 ml_). The reaction mixture was stirred at 35 °C for 2 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification on RP Flash C18 (12 g cartridge, 15- 75% MeCN/10 mM ammonium bicarbonate) gave the title compound (15 mg, 33 μmol, 37 yield, 95% purity) as a white solid.

LCMS (Method 2): m/z 426 (M+H) ⁺ , RT 0.79 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.62 (m, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.98 - 7.90 (m, 2H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.60 (s, 1 H), 7.50 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 5.50 (s, 1 H), 4.61 (d, J = 6.5 Hz, 2H), 3.40 (t, J = 5.1 Hz, 4H), 2.75 - 2.67 (m, 4H), 1.83 - 1.72 (m, 1 H), 0.80 - 0.71 (m, 4H). 1 H under water.

Synthesis 054

3-cyclopropyl-N ⁵ -methyl-N ⁵ -(piperidin-4-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl 4-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3 - cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)piper idine-1-carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl 4- (methylamino)piperidine-l-carboxylate (180 g, 840 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 ml_) was degassed with N ₂ ^for 5 min. Pd-171 (4.2 mg, 6.3 μmol) and Ruphos (3.4 mg, 7.4 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (100 mg, 0.13 mmol, 64% yield, 88% purity) as a yellow glass solid.

UPLC/MS (Method 2): m/z 654 (M+H) ⁺ , RT 2.09 min.

Step 4:

3-cyclopropyl-N ⁵ -methyl-N ⁵ -(piperidin-4-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.38 ml_, 1.53 mmol) was added to a solution of tert- butyl 4-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3 -cyclopropylpyrazolo[1 ,5- a]pyrimidin-5-yl)(methyl)amino)piperidine-1-carboxylate (100 mg, 153 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo.

The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by RP preparative HPLC (35- 100% MeCN/0.3% NH3 in water) gave the title compound (11 mg, 24 μmol, 15% yield, 97% purity) as a white solid.

UPLC/MS (Method 4): m/z 454 (M+H) ⁺ , RT 1.70 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.04 (d, J = 8.3 Hz, 2H), 7.95 (t, J = 6.4 Hz, 1 H), 7.93 - 7.90 (m, 1 H), 7.85 (td, J = 7.7, 1.9 Hz, 1 H), 7.59 (s, 1 H), 7.51 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 5.25 (s, 1H), 4.60 (d, J = 6.2 Hz, 2H), 4.25 - 4.12 (m, 1H), 2.98 - 2.90 (m, 2H), 2.79 (s, 3H), 2.56 - 2.52 (m, 1 H), 2.48 - 2.44 (m, 1 H), 1.82 - 1.70 (m, 1 H), 1.55 - 1.35 (m, 4H), 0.83 - 0.70 (m, 4H). 1 H under water. Synthesis 055

3-cyclopropyl-N ⁵ -(piperidin-4-ylmethyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)piperi dine-1-carboxylate

A solution tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl 4- (aminomethyl)piperidine-l-carboxylate (180 g, 840 μmol) in THF (2.0 ml_) was degassed in N2for 5 min before adding tBuBrettPhos Pd G3 (18.0 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h then concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH/DCM) gave the title compound (64 mg, 94 μmol, 45% yield, 96% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 654 (M+H) ⁺ , R _T 1.99 min.

Step 4:

3-cyclopropyl-N ⁵ -(piperidin-4-ylmethyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.23 ml_, 0.92 mmol) was added to a solution of tert- butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino)methyl)piperidine-1-carboxylate (60 mg, 92 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (16 mg, 35 μmol, 38% yield, 99% purity) as a white solid. UPLC/MS (Method 4): m/z 454 (M+H) ⁺ , RT 0.91 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.68 - 8.61 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 - 7.90 (m, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.84 - 7.76 ( , 1 H), 7.54 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 6.61 (t, J = 5.6 Hz, 1 H), 5.13 (s, 1 H), 4.50 (d, J = 6.3 Hz, 2H), 3.07 (t, J = 5.5 Hz, 2H), 2.93 - 2.86 (m, 2H), 2.43 - 2.32 (m, 2H), 1.82 - 1.69 (m, 1 H), 1.58 (d, J = 12.8 Hz, 3H), 1.06 - 0.94 (m, 2H), 0.75 (d, J = 8.1 Hz, 4H). 1H under water.

Synthesis 056

3-cyclopropyl-N ⁵ -((3,3-difluoropiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

Step 3: tert-butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3,3-d ifluoropiperidine-1- carboxylate

A solution tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (175 mg, 368 μmol) (prepared as described herein), tert-butyl 4- (aminomethyl)-3,3-difluoropiperidine-1-carboxylate (147 mg, 588 μmol) in THF (2.0 mL) was degassed in N ₂ ^for 5 min before adding tBuBrettPhos Pd G3 (47.1 mg, 55.1 μmol) and LiHMDS (1M in THF) (386 pL, 386 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h then concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (12 g cartridge, 15- 75% MeCN/10 mM ammonium bicarbonate) gave the title compound (135 mg, 0.18 mmol, 48% yield, 90% purity) as a colourless oil.

UPLC/MS (Method 3): m/z 690 (M+H) ⁺ , R _T 1.99 min. Step 4:

3-cyclopropyl-N ⁵ -((3,3-difluoropiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.62 ml_, 2.47 mmol) was added to a solution of tert- butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3,3-d ifluoropiperidine-1- carboxylate (126 mg, 164 μmol) in dioxane (3.0 ml_). The reaction mixture was stirred at 35 °C for 2 h and concentrated in vacuo. Purification on RP Flash C18 (12 g cartridge, 20-80% MeCN/10 mM ammonium bicarbonate) gave the title compound (20 mg, 39 μmol, 24% yield, 95% purity) as an off-white solid.

LCMS (Method 3): m/z 490 (M+H) ⁺ , RT 1.49 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.62 (m, 1 H), 8.05 (d, J = 8.4 Hz, 2H), 7.93 (dt, J = 8.0, 1.2 Hz, 1 H), 7.89 - 7.83 (m, 2H), 7.57 (s, 1 H), 7.44 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.68 (t, J = 5.8 Hz, 1 H), 5.11 (s, 1H), 4.50 (d, J = 6.4 Hz, 2H), 3.68 - 3.58 (m, 1H), 3.18 - 3.08 (m, 1H), 3.05 - 2.95 (m, 1H), 2.89 - 2.79 (m, 1H), 2.73 - 2.61 (m, 1H), 2.43 - 2.33 (m, 1H), 2.25 - 2.08 (m, 1H), 1.82 - 1.70 (m, 2H), 1.33 - 1.20 (m,

1 H), 0.84 - 0.70 (m, 4H). 1 H under water.

Synthesis 057

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(2,7-diazaspir o[3.5]nonan-2-yl)pyrazolo[1,5- a]pyrimidin-7-amine

Step 3: tert-butyl 2-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-2,7-diazaspiro[3.5 ]nonane-7-carboxylate A solution tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl 2,7- diazaspiro[3.5]nonane-7-carboxylate (71 g, 315 μmol) in dioxane (2.0 ml_) was degassed in N ₂ for 5 min before adding tBuBrettPhos Pd G3 (18.0 mg, 21.0 μmol) and LiHMDS (1M in THF) (221 pL, 221 μmol). The reaction was degassed for another 5 min before being heated to 90 °C for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (68 mg, 98 μmol, 47% yield, 98% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 666 (M+H) ⁺ , R _T 2.51 min.

Step 4:

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(2,7-diazaspir o[3.5]nonan-2-yl)pyrazolo[1,5- a]pyrimidin-7-amine

Hydrogen chloride (4 M in dioxane) (0.38 ml_, 1.5 mmol) was added to a solution of tert- butyl 2-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5- a]pyrimidin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (68 mg, 0.10 mmol) in dioxane (3.0 ml_). The reaction mixture was stirred at 35 °C for 2 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (44 mg, 90 μmol, 88% yield, 95% purity) as an off-white solid.

LCMS (Method 5): m/z 466 (M+H) ⁺ , RT 1.54 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.62 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 8.00 (t, J = 6.5 Hz, 1 H), 7.95 - 7.91 (m, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.57 (s, 1 H), 7.48 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 5.05 (s, 1 H), 4.57 (d, J = 6.5 Hz, 2H), 3.59 (s, 4H), 2.65 - 2.57 (m, 4H), 1.81 - 1.71 (m, 1H), 1.62 - 1.54 (m, 4H), 0.81 - 0.72 (m, 2H), 0.71 - 0.66 (m, 2H). 1 H under water. Synthesis 058

(R)-3-cyclopropyl-N ⁷ -(4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Step 3: tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), tert-butyl (R)-

3-aminopyrrolidine-1-carboxylate (117 mg, 630 μmol) and cesium carbonate (205 mg,

630 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.30 μmol) and Ruphos (3.4 mg, 7.35 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (91 mg, 0.11 mmol, 53% yield, 78% purity) as a yellow glass solid.

UPLC/MS (Method 2): m/z 627 (M+H) ⁺ , RT 2.39 min.

Step 4:

(R)-3-cyclopropyl-N ⁷ -(4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5-a]pyrimidine- 5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.32 ml_, 1.3 mmol) was added to a solution of tert- butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate (80 mg, 128 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (11 mg, 26 μmol, 20% yield, 99% purity) as a white solid.

LCMS (Method 1): m/z 426 (M+H) ⁺ , RT 0.80 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.68 - 8.61 (m, 1 H), 8.08 - 8.01 (m, 2H), 7.92 (d, J = 8.0 Hz, 1 H), 7.90 - 7.80 (m, 2H), 7.55 (s, 1 H), 7.44 (d, J = 8.2 Hz, 2H), 7.37 - 7.29 (m, 1 H), 6.63 (d, J = 6.5 Hz, 1H), 5.09 (s, 1H), 4.50 (d, J = 6.3 Hz, 2H), 4.20 - 4.11 (m, 1H), 2.97 (dd, J = 11.0, 6.4 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.75 - 2.67 (m, 1H), 2.00 - 1.86 (m, 1H), 1.81 - 1.70 (m, 1 H), 1.54 - 1.43 (m, 1 H), 0.80 - 0.72 (m, 4H). 2H under water.

Synthesis 059

(S)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl (S)-

3-aminopiperidine-1-carboxylate (126 mg, 630 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 mL) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.30 μmol) and Ruphos (3.4 mg, 7.35 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 mL) and filtered through celite, rinsing with EtOAc (20 mL). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (90 mg, 0.13 mmol, 60% yield, 90% purity) as a yellow glass solid.

UPLC/MS (Method 2): m/z 641 (M+H) ⁺ , RT 2.44 min. Step 4:

(S)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Hydrogen chloride (4 M in dioxane) (0.35 ml_, 1.4 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate (90 mg, 0.14 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (28 mg, 61 μmol, 43% yield, 95% purity) as a white solid.

LCMS (Method 2): m/z 426 (M+H) ⁺ , RT 0.68 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 - 7.77 (m, 2H), 7.53 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m,

1 H), 6.41 (d, J = 7.7 Hz, 1 H), 5.13 (s, 1 H), 4.49 (d, J = 6.2 Hz, 2H), 3.77 - 3.68 (m, 1H), 3.04 - 2.97 (m, 1H), 2.77 - 2.69 (m, 1H), 2.44 - 2.34 (m, 1 H), 2.29 - 2.19 (m, 1H), 1.86 - 1.69 (m, 2H), 1.61 - 1.51 (m, 1H), 1.43 - 1.21 (m, 2H), 0.79 - 0.69 (m, 4H). 1 H under water.

Synthesis 060

(R)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Step 3: tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (76 mg, 135 μmol) (prepared as described herein), tert-butyl (R)-3- aminopiperidine-1-carboxylate (51 g, 252 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding tBuBrettPhos Pd G3 (18 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 20 h. The reaction mixture was recharged with more tert-butyl (R)-3- aminopiperidine-1-carboxylate (101 mg, 504 μmol), ‘BuBrettPhos Pd G3 (36 mg, 42.0 μmol) and LiHMDS (1M in THF) (0.55 mL, 0.55 mmol). The reaction was degassed for another 5 min before being heated to 60 °C for 3 h. The reaction was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (122 mg, 0.17 mmol, 82% yield, 90% purity) as a brown oil.

UPLC/MS (Method 2): m/z 640 (M+H) ⁺ , R _T 2.45 min.

Step 4:

(R)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

TFA (0.5 mL) was added to a solution of tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5-yl)amino)piperidine-1- carboxylate (120 mg, 178 μmol) in DCM (1.5 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX.

The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH3 in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (45 mg, 98 μmol, 55% yield, 96% purity) as a tan solid.

UPLC/MS (Method 3): m/z 440 (M+H) ⁺ , RT 1.51 min.

¹ H NMR (500 MHz, DMSO-d ₆ ) d 8.64 (ddd, J = 4.8, 1.8, 1.0 Hz, 1H), 8.05 (d, J = 8.3 Hz, 2H), 7.93 (dt, = 8.1 , 1.1 Hz, 1H), 7.86 (td, J = 7.7, 1.8 Hz, 1 H), 7.81 (t, J = 6.5 Hz, 1 H), 7.53 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 6.42 (d, J = 7.7 Hz, 1H), 5.13 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H), 3.79 - 3.69 (m, 1H), 3.05 - 2.98 (m, 1H), 2.78 - 2.71 (m, 1H), 2.45 - 2.37 (m, 1H), 2.29 - 2.22 (m, 1 H), 1.86 - 1.79 (m, 1H), 1.78 - 1.71 (m, 1H), 1.61 - 1.54 (m, 1H), 1.43 - 1.33 (m, 1H), 1.33 - 1.23 (m, 1 H), 0.79 - 0.71 (m, 4H). 1 H under water. Synthesis 061

1-(4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-1-yl)ethan-1-one

Step 3: tert-butyl (5-(((1-acetylpiperidin-4-yl)methyl)amino)-3-cyclopropylpyra zolo[1 ,5-a]pyrimidin- 7-yl)(4-(pyridin-2-yl)benzyl)carbamate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), 1-(4- (aminomethyl)piperidin-1-yl)ethan-1-one (39 g, 252 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (18 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction mixture was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (81 mg, 0.11 mmol, 83% yield, 82% purity) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.69 - 8.62 (m, 1 H), 8.04 (d, J = 8.3 Hz, 2H), 7.94 (dt, J = 8.0, 1.1 Hz, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1 H), 7.62 (s, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.34 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 7.24 (t, J = 5.5 Hz, 1 H), 6.02 (s, 1 H), 4.94 - 4.80 (m, 2H), 4.40 - 4.29 (m, 1H), 3.82 - 3.73 (m, 1 H), 3.24 - 3.15 (m, 2H), 2.99 - 2.89 (m, 1H), 2.48 - 2.41 (m, 1H), 1.95 (s, 3H), 1.84 - 1.61 (m, 3H), 1.32 (s, 9H), 1.15 - 1.08 (m, 1 H),

1.03 - 0.92 (m, 1 H), 0.83 - 0.73 (m, 4H). 1 H under water.

Step 4:

1-(4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-1-yl)ethan-1-one TFA (0.25 mL) was added to a solution of tert-butyl (5-(((1-acetylpiperidin-4- yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl) (4-(pyridin-2- yl)benzyl)carbamate (81 mg, 0.11 mmol) in DCM (0.75 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 mL) to give the title compound (48 mg, 92 μmol, 83% yield, 95% purity) as a tan solid.

UPLC/MS (Method 2): m/z 496 (M+H) ⁺ , RT 1.18 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.93 (dt, J = 8.0, 1.2 Hz, 1 H), 7.89 - 7.79 (m, 2H), 7.54 (s, 1 H), 7.45 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 6.66 (t, J = 5.7 Hz, 1 H), 5.12 (s, 1H), 4.51 (d, J = 6.3 Hz, 2H), 4.37 - 4.26 (m, 1H), 3.11 (t, J = 5.9 Hz, 2H), 2.97 - 2.84 (m, 1 H), 2.47 - 2.38 (m, 1H), 1.93 (s, 3H), 1.80 - 1.58 (m, 4H), 1.11 - 1.03 (m, 1H), 1.01 - 0.88 (m, 1H), 0.75 (d, J = 6.9 Hz, 4H). 1H under water.

Synthesis 062

N ⁵ -(azetidin-3-yl)-3-cyclopropyl-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-5,7 - diamine

Step 3: tert-butyl 3-((7-((tert-butoxycarbonyl)(4-(pyridine-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)azetidine-1-c arboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl 3- aminoazetidine-1-carboxylate (109 mg, 630 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 mL) was degassed with N ₂ for 5 min. Pd-171 (4.2 mg, 6.3 μmol) and Ruphos (3.4 mg, 7.4 μmol) were added and N ₂ was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (90 mg, 0.13 mmol, 63% yield, 90% purity) as a yellow glass solid.

UPLC/MS (Method 2): m/z 612 (M+H) ⁺ , RT 2.36 min.

Step 4:

N ⁵ -(Pyridine-3-yl)-3-cyclopropyl-N ⁷ -(4-(pyridine-2-yl)benzyl)pyrazolo[1 ,5-a]pyrimidine-5,7- diamine

Hydrogen chloride (4 M in dioxane) (0.41 ml_, 1.63 mmol) was added to a solution of tert- butyl 3-((7-((tert-butoxycarbonyl)(4-(pyridine-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)azetidine-1-c arboxylate (100 mg, 0.16 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 30 °C for 3 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (12 mg, 28 μmol, 17% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 412 (M+H) ⁺ , RT 1.02 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.63 (m, 1H), 8.07 - 8.00 (m, 3H), 7.96 - 7.82 (m, 3H), 7.56 (s, 1 H), 7.46 - 7.41 (m, 2H), 7.33 (ddd, J = 7.4, 4.7, 1.2 Hz, 1 H), 7.06 (d, J =

6.9 Hz, 1 H), 5.07 (s, 1 H), 4.62 - 4.53 (m, 1 H), 4.51 (d, J = 6.4 Hz, 2H), 3.55 (t, J = 7.4 Hz, 2H), 1.81 - 1.69 (m, 1 H), 0.76 (d, J = 6.9 Hz, 4H). 2H under water.

Svnthesis 063

3-cyclopropyl-N ⁵ -(piperidin-4-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-5,7 - diamine

Step 3: tert-butyl 4-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3 - cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), tert-butyl 4- aminopiperidine-1-carboxylate (126 mg, 630 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.3 μmol) and Ruphos (3.4 mg, 7.4 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (100 mg, 0.14 mmol, 67% yield, 90% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 640 (M+H) ⁺ , RT 2.48 min.

Step 4:

3-cyclopropyl-N ⁵ -(piperidin-4-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-5,7 - diamine

Hydrogen chloride (4 M in dioxane) (0.39 ml_, 1.56 mmol) was added to a solution of tert- butyl 4-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3 -cyclopropylpyrazolo[1 ,5- a]pyrimidin-5-yl)amino)piperidine-1-carboxylate (100 mg, 0.156 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (24 g, 54 μmol, 34% yield, 98% purity) as a white solid.

UPLC/MS (Method 2): m/z 440 (M+H) ⁺ , RT 0.94 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.05 (d, J = 8.2 Hz, 2H), 7.93 (d, J = 8.1 Hz, 1H), 7.90 - 7.77 (m, 2H), 7.53 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m,

1 H), 6.47 (d, J = 7.4 Hz, 1 H), 5.09 (s, 1 H), 4.49 (d, J = 6.2 Hz, 2H), 3.75 - 3.65 (m, 1 H), 2.92 - 2.84 (m, 2H), 2.49 - 2.41 (m, 1H), 1.81 - 1.75 (m, 1 H), 1.78 - 1.69 (m, 2H), 1.24 - 1.11 (m, 2H), 0.78 - 0.72 (m, 4H). 2H under water.

Synthesis 064

5-(azetidin-3-yloxy)-3-cyclopropyl-N-(4-(pyridin-2-yl)ben zyl)pyrazolo[1,5-a]pyrimidin-7- amine

Step 3: tert-butyl 3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3 - cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)azetidine-1-car boxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (200 mg, 420 μmol) (prepared as described herein), tert-butyl-3- hydroxyazetidine-1-Carboxylate (291 mg, 1.68 mmol) and cesium carbonate (548 mg, 1.68 mmol) in dioxane (5.0 ml_) was degassed with N2 for 5 min. Pd-171 (28 mg, 42 μmol) and Ruphos (20 mg, 42 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (180 mg, 0.27 mmol, 65% yield, 93% purity) as a yellow oil.

UPLC/MS (Method 5): m/z 613 (M+H) ⁺ , RT 2.20 min. Step 4:

5-(azetidin-3-yloxy)-3-cyclopropyl-N-(4-(pyridin-2-yl)ben zyl)pyrazolo[1,5-a]pyrimidin-7- amine

TFA (0.5 ml_) was added to a solution of tert-butyl 3-((7-((tert-butoxycarbonyl)(4-(pyridin- 2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-y l)oxy)azetidine-1-carboxylate (180 g, 294 μmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (50 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (80 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (70 mg, 160 μmol, 55% yield, 96% purity) as a white solid.

UPLC/MS (Method 4): m/z 413 (M+H) ⁺ , RT 1.44 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.61 (m, 1H), 8.41 (t, J = 6.4 Hz, 1 H), 8.08 - 8.01 (m, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.7, 1.8 Hz, 1 H), 7.79 (s, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 7.37 - 7.29 (m, 1 H), 5.38 (s, 1 H), 5.30 - 5.22 (m, 1 H), 4.63 - 4.57 (m, 2H), 4.36 - 4.28 (m, 1 H), 3.67 (dd, J = 9.0, 6.8 Hz, 2H), 3.50 - 3.38 (m, 2H), 1.85 - 1.76 (m,

1 H), 0.84 - 0.77 (m, 4H).

Synthesis 065

1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazol o[1 ,5-a]pyrimidin-5-yl)piperidin-

4-ol

Step 3: tert-butyl (3-cyclopropyl-5-(4-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyr imidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), piperidin-4-ol (64 mg, 630 μmol) and cesium carbonate (205 mg, 630 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.3 μmol) and Ruphos (3.4 mg, 7.4 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 10% MeOH/DCM) gave the title compound (105 mg, 0.19 mmol, 91% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 541 (M+H) ⁺ , RT 1.90 min.

Step 4:

1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazol o[1,5-a]pyrimidin-5-yl)piperidin-4- ol

Hydrogen chloride (4 M in dioxane) (0.49 ml_, 1.94 mmol) was added to a solution of tert- butyl (3-cyclopropyl-5-(4-hydroxypiperidin-1-yl)pyrazolo[1,5-a]pyr imidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (105 mg, 194 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 30 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (35 mg, 78 μmol, 40% yield, 98% purity) as a white solid.

UPLC/MS (Method 3): m/z 441 (M+H) ⁺ , RT 1.14 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.61 (m, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.96 - 7.89 (m, 2H), 7.86 (td, J = 7.7, 1.8 Hz, 1H), 7.59 (s, 1 H), 7.50 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m, 1 H), 5.54 (s, 1 H), 4.63 (d, J = 4.3 Hz, 1 H), 4.61 (d, J = 6.5 Hz, 2H), 4.03 - 3.95 (m, 2H), 3.69 - 3.59 (m, 1 H), 3.11 - 2.99 (m, 2H), 1.85 - 1.63 (m, 3H), 1.33 - 1.21 (m, 2H), 0.81 - 0.71 (m, 4H).

Svnthesis 066

4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyraz olo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-2-one

Step 3: tert-butyl (3-cyclopropyl-5-(((2-oxopiperidin-4-yl)methyl)amino)pyrazol o[1,5-a]pyrimidin-7- yl)(4-(pyridin-2-yl)benzyl)carbamate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), 4- (aminomethyl)piperidin-2-one, HCI (42 g, 252 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (18 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction mixture was degassed for another 5 min before being heated to 60 °C overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (50 mg, 85 μmol, 41% yield, 97% purity) as a brown oil.

UPLC/MS (Method 2): m/z 568 (M+H) ⁺ , RT 1.76 min.

Step 4:

4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyraz olo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-2-one

TFA (0.25 ml_) was added to a solution of tert-butyl (3-cyclopropyl-5-(((2-oxopiperidin-4- yl)methyl)amino)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (50 mg, 88 μmol) in DCM (0.75 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by RP preparative HPLC (25-100% MeCN/0.3% NH3 in water) gave the title compound (11 mg, 22 μmol, 25% yield, 95% purity) as a white solid. UPLC/MS (Method 3): m/z 468 (M+H) ⁺ , RT 1.28 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.62 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.96 - 7.90

(m, 1H), 7.89 - 7.80 (m, 2H), 7.55 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2H), 7.41 - 7.36 (m, 1H),

7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 6.70 (t, J = 5.7 Hz, 1 H), 5.13 (s, 1H), 4.51 (d, J = 6.0 Hz, 2H), 3.23 - 3.11 ( , 3H), 3.04 (td, J = 11.2, 4.3 Hz, 1H), 2.21 (dd, J = 17.0, 5.1 Hz,

1 H), 2.05 - 1.92 (m, 1H), 1.87 - 1.71 (m, 3H), 1.38 - 1.25 (m, 1H), 0.80 - 0.71 (m, 4H).

Synthesis 067

1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazol o[1,5-a]pyrimidin-5-yl)azetidin-

3-ol

Step 3: tert-butyl (3-cyclopropyl-5-(3-hydroxyazetidin-1-yl)pyrazolo[1,5-a]pyri midin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), azetidin-3-ol, HCI (69 mg, 630 μmol) and cesium carbonate (411 mg, 1.26 mmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (4.2 mg, 6.3 μmol) and Ruphos (3.4 mg, 7.4 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (85 mg, 0.17 mmol, 79% yield, 99% purity) as a yellow glass solid.

UPLC/MS (Method 3): m/z 513 (M+H) ⁺ , RT 1.74 min.

Step 4: 1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1 ,5-a]pyrimidin-5-yl)azetidin-3- ol

At 0 °C, hydrogen chloride (4 M in dioxane) (0.41 ml_, 1.7 mmol) was added to a solution of tert-butyl (3-cyclopropyl-5-(3-hydroxyazetidin-1-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate (85 mg, 0.17 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at RT for 1.5 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by RP preparative HPLC (25-100% MeCN/0.3% NH3 in water) gave the title compound (22 mg, 53 μmol, 32% yield, 99% purity) as a white solid.

UPLC/MS (Method 2): m/z 413 (M+H) ⁺ , RT 1.04 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 (d, J = 4.9 Hz, 1 H), 8.08 - 7.98 (m, 3H), 7.93 (d, J = 8.0 Hz, 1H), 7.90 - 7.82 (m, 1H), 7.58 (s, 1 H), 7.48 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m,

1 H), 5.60 - 5.56 (m, 1H), 5.06 (s, 1H), 4.60 - 4.54 (m, 2H), 4.50 - 4.46 (m, 1 H), 4.13 - 4.05 (m, 2H), 3.62 (dd, J = 8.8, 4.6 Hz, 2H), 1.82 - 1.70 (m, 1H), 0.81 - 0.73 (m, 2H), 0.73 - 0.64 (m, 2H).

Synthesis 068

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)(methyl)amino)methyl)piperidin-3-ol

Step A: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-((t ert- butyldimethylsilyl)oxy)piperidine-1-carboxylate

Tert-butylchlorodimethylsilane (47 mg, 311 μmol) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (130 mg, 194 μmol) (prepared as described herein) and 1H-imidazole (26 g, 388 μmol) in DMF (2.0 ml_). The reaction mixture was stirred at RT overnight then recharged with 1H-imidazole (26 mg, 388 μmol) and tert-butylchlorodimethylsilane (47 mg, 311 μmol) and stirred at RT for 24 h. The reaction mixture was diluted with brine (20 ml_) and extracted with TBME (3 x 20 ml_), dried over Na2SC>4, filtered and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (130 mg, 0.16 mmol, 82% yield, 96% purity) as a colourless oil.

UPLC/MS (Method 2): m/z 785 (M+H) ⁺ , RT 2.50 min.

Step B: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methy l)-3-((tert- butyldimethylsilyl)oxy)piperidine-1-carboxylate

To an ice cooled solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3-((tert- butyldimethylsilyl)oxy)piperidine-1-carboxylate (130 mg, 166 μmol) in THF (3.00 ml_) was added LiHMDS (1M in THF) (199 pL, 199 μmol). The reaction mixture was stirred for 10 min then iodomethane (12 pL, 199 μmol) was added and the reaction mixture was stirred at RT for 1 h then poured onto ice water (30 ml_) and extracted into ethyl acetate (2 x 20 ml_). The organics were dried over Na2SC>4, filtered and concentrated in vacuo.

Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (130 mg, 0.15 mmol, 88% yield, 90% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 799 (M+H) ⁺ , RT 1.77 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)ami no)pyrazolo[1,5-a]pyrimidin-5- yl)(methyl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (0.41 mL, 1.63 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)(methyl)amino)methy l)-3-((tert- butyldimethylsilyl)oxy)piperidine-1-carboxylate (130 mg, 0.163 mmol) in dioxane (2.0 mL). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product was eluted with 0.7 M NH3 in MeOH (10 mL). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (28 g, 55 μmol, 34% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 484 (M+H) ⁺ , RT 0.99 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.61 (m, 1 H), 8.04 (d, J = 8.1 Hz, 2H), 7.98 (t, J = 6.5 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.89 - 7.81 (m, 1H), 7.57 (s, 1 H), 7.53 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m, 1 H), 5.36 (s, 1 H), 5.05 - 5.01 (m, 1 H), 4.57 (d, J = 6.4 Hz, 2H), 3.60 - 3.46 (m, 2H), 3.09 - 2.98 (m, 1H), 2.97 (s, 3H), 2.97 - 2.89 (m, 1H), 2.70 - 2.62 (m,

1 H), 2.15 (q, J = 9.9 Hz, 2H), 1.99 - 1.84 (m, 1H), 1.81 - 1.68 (m, 1H), 1.49 - 1.42 (m, 2H), 1.04 - 0.94 (m, 1 H), 0.79 - 0.66 (m, 4H).

Synthesis 069

(3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(thiazol-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-(2-fluoro-4-(thiazol-2-yl)benzyl )pyrazolo[1,5-a]pyrimidin-7-amine

DIPEA (0.20 ml_, 1.20 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (92 mg, 0.40 mmol), and (2-fluoro-4-(thiazol-2- yl)phenyl)methanamine (80 mg, 0.38 mmol) in I PA (1.0 ml_). The reaction mixture was heated to 80 °C for 2 h. At RT, the reaction mixture was partitioned between EtOAc (30 ml_) and water (30 ml_). The organic layer was separated, washed with water (30 ml_), brine (10 ml_), dried over Na2SC>4, filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 50-100% TBM E/isohexane then 0-5% MeOH/TBME) gave the title compound (140 mg, 0.33 mmol, 85% yield, 93% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 400 (M+H) ⁺ , R _T 2.21 min. Step 2: tert-butyl (3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(thiazol-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)- 3-hydroxypiperidine-1- carboxylate

A solution of 5-chloro-3-cyclopropyl-N-(2-fluoro-4-(thiazol-2-yl)benzyl)py razolo[1,5- a]pyrimidin-7-amine (138 mg, 345 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (95 g, 414 mmol) in dioxane (1.2 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (29.5 mg, 34.5 μmol) and LiHMDS (1M in THF) (449 pL, 449 μmol). The reaction mixture was degassed for another 5 min before being heated to 90 °C overnight then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 40-100% TBM E/isohexane) gave the title compound (122 mg, 201 μmol, 58% yield, 98% purity) as an orange solid.

UPLC/MS (Method 2): m/z 594 (M+H) ⁺ , RT 1.61 min.

Step 3:

(3R,4R)-4-(((3-cyclopropyl-7-((2-fluoro-4-(thiazol-2-yl)b enzyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

At 0 °C, TFA (0.5 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((3-cyclopropyl-7- ((2-fluoro-4-(thiazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrim idin-5-yl)amino)methyl)-3- hydroxypiperidine-1 -carboxylate (118 mg, 189 μmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 30 min and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (81 mg, 0.16 mmol, 85% yield, 98% purity) as a tan solid.

UPLC/MS (Method 3): m/z 494 (M+H) ⁺ , RT 1.45 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.94 (d, J = 3.2 Hz, 1 H), 7.85 (d, J = 6.4 Hz, 1H), 7.83 (d, J = 3.2 Hz, 1 H), 7.80 - 7.73 (m, 2H), 7.54 (s, 1 H), 7.42 (t, J = 8.1 Hz, 1 H), 6.73 (t, J = 5.9 Hz, 1H), 5.35 - 5.21 (m, 1H), 5.16 (s, 1 H), 4.54 (d, J = 6.4 Hz, 2H), 3.56 - 3.42 (m,

1 H), 3.25 - 3.14 (m, 1H), 3.11 - 2.96 (m, 1 H), 2.90 (dd, J = 11.5, 4.5 Hz, 1H), 2.84 - 2.71 (m, 1H), 2.37 - 2.23 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1 H), 1.78 - 1.66 (m, 1 H), 1.61 - 1.49 (m, 1H), 1.41 - 1.25 (m, 1H), 1.22 - 1.03 (m, 1H), 0.80 - 0.72 (m, 2H), 0.71 - 0.61 (m, 2H). 1 H under water. Synthesis 070

(2-fluoro-4-(thiazol-2-yl)phenyl)methanamine

Step A: tert-butyl (2-fluoro-4-(thiazol-2-yl)benzyl)carbamate

2-Bromothiazole (62 pL, 683 μmol), (4-(((tert-butoxycarbonyl)amino)methyl)-3- fluorophenyl)boronic acid (175 mg, 650 μmol), Pd(dppf)Cl2.DCM (26.6 g, 32.5 μmol) and potassium phosphate, tribasic (276 mg, 1.30 mmol) were taken up in dioxane (2.0 ml_) and water (0.4 ml_). The reaction mixture was sparged with N2 for 5 min then heated under microwave irradiation at 100°C for 1 h then allowed to cool to RT. The mixture was diluted with EtOAc (20 ml_) and water (20 ml_). The layers were separated, and the organic layer was washed with brine (10 ml_) then dried over Na2SC>4, filtered then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0- 100% TBM E/isohexane) gave the title compound (131 mg, 332 μmol, 51% yield, 78% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 309 (M+H) ⁺ , R _T 1.93 min.

Step B:

(2-fluoro-4-(thiazol-2-yl)phenyl)methanamine

At 0 °C, TFA (0.95 ml_) was added to a solution of tert-butyl (2-fluoro-4-(thiazol-2- yl)benzyl)carbamate (128 mg, 415 μmol) in DCM (1.0 ml_). The reaction mixture was stirred at 0 °C for 30 min and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (80 mg, 361 μmol, 88% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 209 (M+H) ⁺ , RT 0.99 min. Synthesis 071

5-(azetidin-3-ylmethoxy)-3-cyclopropyl-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl 3-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)methyl)azetidin e-1-carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), tert-butyl 3- (hydroxymethyl)azetidine-l-carboxylate (175 mg, 840 μmol) and cesium carbonate (274 mg, 840 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (13.9 mg,

21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/ isohexane) gave the title compound (117 mg, 0.18 mmol, 84% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 627 (M+H) ⁺ , RT 2.23 min.

Step 4:

5-(azetidin-3-ylmethoxy)-3-cyclopropyl-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

At 0 °C, TFA (1.0 ml_) was added to a solution of tert-butyl 3-(((7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5- yl)oxy)methyl)azetidine-1-carboxylate (69 mg, 106 μmol) in DCM (2.0 ml_). The reaction mixture was stirred at 0 °C for 3 h then RT for 1 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 ml_) to give the title compound (33 g, 75 μmol, 71% yield, 97% purity) as a beige solid.

UPLC/MS (Method 3): m/z 427 (M+H) ⁺ , RT 2.00 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.62 (m, 1H), 8.36 (t, J = 6.5 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.6, 1.8 Hz, 1 H), 7.76 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.3, 4.7, 1.2 Hz, 1H), 5.36 (s, 1 H), 4.59 (d, J = 6.2 Hz, 2H), 4.36 (d, J = 7.1 Hz, 2H), 3.50 (t, J = 7.7 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H), 2.99 - 2.88 (m,

1 H), 1.89 - 1.80 (m, 1 H), 0.89 - 0.80 (m, 2H), 0.80 - 0.73 (m, 2H). 1 H under water.

Synthesis 072

3-cyclopropyl-N ⁵ -((1-(methylsulfonyl)piperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (3-cyclopropyl-5-(((1-(methylsulfonyl)piperidin-4-yl)methyl) amino)pyrazolo[1,5- a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), (1- (methylsulfonyl)piperidin-4-yl)methanamine, HCI (58 mg, 252 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (18 mg, 21.0 μmol) and LiHMDS (1M in THF) (546 pL, 546 μmol). The reaction mixture was degassed for another 5 min before being heated to 60 °C for 1 h. The reaction mixture was recharged with more LiHMDS (1M in THF) (546 pL, 546 μmol). The reaction was degassed for another 5 min before being heated to 60 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 100% EtOAc/isohexane) gave the title compound (87 mg, 0.13 mmol, 60% yield, 92% purity) as a tan oil. UPLC/MS (Method 2): m/z 632 (M+H) ⁺ , RT 2.03 min.

Step 4:

3-cyclopropyl-N ⁵ -((1-(methylsulfonyl)piperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

TFA (0.5 ml_) was added to a solution of tert-butyl (3-cyclopropyl-5-(((1- (methylsulfonyl)piperidin-4-yl)methyl)amino)pyrazolo[1,5-a]p yrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (87 mg, 0.13 mmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 ml_) to give the title compound (69 mg, 0.13 mol, 91% yield, 97% purity) as a beige solid.

UPLC/MS (Method 3): m/z 532 (M+H) ⁺ , RT 1.55 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 - 8.62 (m, 1 H), 8.05 (d, J = 8.4 Hz, 2H), 7.93 (dt, J = 8.0, 1.2 Hz, 1 H), 7.89 - 7.81 (m, 2H), 7.55 (s, 1 H), 7.45 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.69 (t, J = 5.8 Hz, 1 H), 5.13 (s, 1H), 4.51 (d, J = 6.4 Hz, 2H), 3.58 - 3.47 (m, 2H), 3.13 (t, J = 6.1 Hz, 2H), 2.78 (s, 3H), 2.59 (t, J = 11.7 Hz, 2H), 1.81 - 1.70 (m, 3H), 1.66 - 1.51 (m, 1H), 1.25 - 1.12 (m, 2H), 0.75 (d, J = 7.4 Hz, 4H).

Synthesis 073

5-(3-aminoazetidin-1-yl)-3-cyclopropyl-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (5-(3-aminoazetidin-1-yl)-3-cyclopropylpyrazolo[1,5-a]pyrimi din-7-yl)(4-(pyridin- 2-yl)benzyl)carbamate A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (120 mg, 252 μmol) (prepared as described herein), tert-butyl azetidin-3-ylcarbamate (174 g, 1.01 mmol), and cesium carbonate (329 mg, 1.01 mmol) in dioxane (3.2 ml_) was degassed with N2 for 5 min. Pd-171 (16.7 mg, 25.2 μmol) and Ruphos (11.8 mg, 25.2 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (122 mg, 0.19 mmol, 76% yield, 87% purity) as an orange oil.

UPLC/MS (Method 5): m/z 512 (M+H) ⁺ , RT 1.74 min.

Step 4:

5-(3-aminoazetidin-1-yl)-3-cyclopropyl-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

At 0 °C, TFA (0.5 ml_) was added to a solution of tert-butyl (5-(3-aminoazetidin-1-yl)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)be nzyl)carbamate (122 mg, 0.19 mmol) in DCM (1.5 ml_). The reaction mixture was stirred at 0 °C for 3 h then at RT for 1 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (42 mg, 98 μmol, 44% yield, 97% purity) as an orange solid.

UPLC/MS (Method 3): m/z 412 (M+H) ⁺ , RT 1.30 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.60 (m, 1 H), 8.04 (d, J = 8.3 Hz, 2H), 7.99 (t, J = 6.6 Hz, 1H), 7.93 (dt, J = 8.0, 1.2 Hz, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.57 (s, 1H), 7.48 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 5.03 (s, 1 H), 4.56 (d, J = 6.5 Hz, 2H), 4.04 (t, J = 7.7 Hz, 2H), 3.75 - 3.65 (m, 1 H), 3.52 - 3.43 (m, 2H), 2.13 - 1.94 (m,

2H), 1.81 - 1.70 (m, 1H), 0.82 - 0.72 (m, 2H), 0.71 - 0.64 (m, 2H). Svnthesis 074

5-(azetidin-3-yl)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl )pyrazolo[1,5-a]pyrimidin-7-amine

Step 3: tert-butyl 3-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)azetidine-1-carboxy late / 5-(azetidin-3-yl)-3- cyclopropyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimid in-7-amine (1/0.94)

A mixture of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (200 g, 420 μmol) (prepared as described herein), (1 -(tert- butoxycarbonyl)azetidin-3-yl)zinc(ll) iodide (0.5M in THF) (2.10 ml_, 1.05 mmol), Pd(dppf)Cl2-DCM (34 mg, 42.0 μmol) in THF (2.0 ml_) was sparged with N2 for 15 min before being heated to 50 °C for 72 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave a mixture of tert-butyl 3-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)azetidine-1-carboxy late / 5-(azetidin-3-yl)-3- cyclopropyl-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine (1/0.94) (140 mg, 175 μmol, 41% yield, 56% purity) as a brown oil.

UPLC/MS (Method 2): m/z 497 (M+H) ⁺ , RT 1.76 min; m/z 397 (M+H) ⁺ , RT 1.03 min Step 4:

5-(azetidin-3-yl)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl )pyrazolo[1,5-a]pyrimidin-7-amine

At 0 °C, TFA (0.5 ml_) was added to a mixture of tert-butyl 3-(7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5-yl)azetidine-1- carboxylate / 5-(azetidin-3-yl)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)py razolo[1 ,5- a]pyrimidin-7-amine (1/0.94) (140 mg, 175 μmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 3 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo. Further purification by RP preparative HPLC (30-100% MeCN/0.3% NH3 in water) gave solid which was dissolved in MeOH (0.50 ml_). The solution was treated with a 2M aq. solution of sodium hydroxide (59 μL, 117 μmol) and the reaction mixture was stirred at RT for 30 min. Sat. aq. NH4CI (0.5 ml_) was added and the solution was loaded onto a column of SCX. The column was washed with MeOH (50 ml_) and the product was eluted with 0.7 M NH3 in MeOH (60 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 ml_) to give the title compound (8 mg, 20 μmol, 20% yield, 97% purity) as a beige solid.

UPLC/MS (Method 2): m/z 397 (M+H) ⁺ , RT 1.03 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.63 (m, 1 H), 8.44 - 8.40 (m, 1 H), 8.04 (d, J = 8.1 Hz, 3H), 7.92 (d, J = 8.0 Hz, 1 H), 7.90 - 7.81 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m, 1 H), 6.01 (s, 1 H), 4.66 (d, J = 6.4 Hz, 2H), 3.83 - 3.70 (m, 2H), 3.63 - 3.55 (m, 2H), 1.99 - 1.90 (m, 1 H), 0.90 - 0.76 (m, 4H). 1 H under water.

Synthesis 075

(3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-cyclopropylpyrazolo[1,5-a]p yrimidin-

5-yl)amino)methyl)piperidin-3-ol

Step 1 :

N-([1,T-biphenyl]-4-ylmethyl)-5-chloro-3-cyclopropylpyraz olo[1,5-a]pyrimidin-7-amine

DIPEA (0.67 mL, 3.82 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (124 mg, 0.55 mmol) and [1,T-biphenyl]-4- ylmethanamine (100 mg, 545 mmol) in EtOH (5.0 mL). The reaction mixture was heated to 50 °C overnight then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 50-100% TBM E/isohexane then 0-10% MeOH/DCM) gave the title compound (182 mg, 0.39 mmol, 71% yield, 80% purity) as a green oil.

UPLC/MS (Method 3): m/z 375 (M+H) ⁺ , R _T 2.06 min. Step 2: tert-butyl ([1,T-biphenyl]-4-ylmethyl)(5-chloro-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-7- yl)carbamate

DMAP (9.5 mg, 78 μmol) was added to a solution of N-([1,T-biphenyl]-4-ylmethyl)-5- chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-amine (182 g, 388 μmol) and BOC-anhydride (127 mg, 583 μmol) in anhydrous THF (4.0 ml_). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (218 mg, 0.39 mmol, 100% yield, 85% purity) as a green oil.

UPLC/MS (Method 3): m/z 419 (M-tBu+H) ⁺ , R _T 2.35 min.

Step 3: tert-butyl (3R,4R)-4-(((7-(([1 , 1 '-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of tert-butyl ([1,T-biphenyl]-4-ylmethyl)(5-chloro-3-cyclopropylpyrazolo[1 ,5- a]pyrimidin-7-yl)carbamate (215 mg, 385 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (98 mg, 423 μmol) in THF (5.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (33 mg, 39 μmol) and LiHMDS (1M in THF) (385 pL, 385 μmol). The reaction mixture was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo.

Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (252 mg, 377 μmol, 97% yield, 99% purity) as a brown oil.

UPLC/MS (Method 2): m/z 669 (M+H) ⁺ , RT 2.53 min.

Step 4:

(3R,4R)-4-(((7-(([1,T-biphenyl]-4-ylmethyl)amino)-3-cyclo propylpyrazolo[1,5-a]pyrimidin-

5-yl)amino)methyl)piperidin-3-ol

TFA (1.0 mL) was added to a mixture of tert-butyl (3R,4R)-4-(((7-(([1,T-biphenyl]-4- ylmethyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (252 mg, 377 μmol) in DCM (3.0 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo. Further purification column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (115 g, 240 mmol, 64% yield, 99% purity) as a white solid.

UPLC/MS (Method 3): m/z 469 (M+H) ⁺ , RT 1.66 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (t, J = 6.5 Hz, 1 H), 7.68 - 7.59 (m, 4H), 7.52 (s,

1 H), 7.48 - 7.40 (m, 4H), 7.38 - 7.32 (m, 1 H), 6.72 (t, J = 6.0 Hz, 1 H), 5.34 - 5.27 (m,

1 H), 5.20 (s, 1 H), 4.48 (d, J = 6.5 Hz, 2H), 3.57 - 3.42 (m, 1H), 3.24 - 3.15 (m, 1H), 3.08 - 2.97 (m, 1 H), 2.90 (dd, J = 11.6, 4.5 Hz, 1H), 2.84 - 2.74 (m, 1H), 2.34 - 2.24 (m, 1 H), 2.16 (dd, J = 11.6, 9.9 Hz, 1 H), 1.78 - 1.65 (m, 1H), 1.61 - 1.51 (m, 1H), 1.38 - 1.26 (m,

1 H), 1.20 - 1.06 (m, 1 H), 0.80 - 0.71 (m, 2H), 0.69 - 0.60 (m, 2H). 1 H under water.

Synthesis 076

(R)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(pyrrolidi n-3-yloxy)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyrrolidine-1-c arboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl (R)-

3-hydroxypyrrolidine-1-carboxylate (162 mg, 840 μmol) and cesium carbonate (274 mg, 840 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (13.9 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (86 mg, 0.13 mmol, 64% yield, 98% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 627 (M+H) ⁺ , RT 2.26 min. Step 4:

(R)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(pyrrolidi n-3-yloxy)pyrazolo[1,5-a]pyrimidin-

7-amine

Hydrogen chloride (4 M in dioxane) (0.68 ml_, 2.7 mmol) was added to a solution of tert- butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyrrolidine-1-c arboxylate (85 mg, 0.14 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 2 h and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (2.0 ml_, 2.50 mmol) was added and the resulting reaction mixture was stirred at 40 °C for 1.5 h then concentrated in vacuo. The solid was triturated in MeCN/Et ₂ O 1 :1 (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (44 mg, 100 μmol, 75% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 427 (M+H) ⁺ , RT 1.61 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.66 - 8.62 (m, 1H), 8.35 (t, J = 6.5 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.78 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 5.34 - 5.28 (m, 2H), 4.59 (d, J = 6.3 Hz, 2H), 3.08 (dd, J = 12.3, 5.7 Hz, 1H), 2.89 - 2.70 (m, 3H), 2.06 - 1.94 (m, 1H), 1.87 - 1.79 (m, 1 H), 1.76 - 1.67 (m, 1 H), 0.89 - 0.76 (m, 4H). 1 H under water.

Synthesis 077

(R)-3-cyclopropyl-5-(piperidin-3-yloxy)-N-(4-(pyridin-2-y l)benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-ca rboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (103 mg, 216 μmol) (prepared as described herein), tert-butyl (R)-

3-hydroxypiperidine-1-carboxylate (183 g, 866 μmol) and cesium carbonate (282 mg, 866 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (14.4 mg, 21.6 μmol) and Ruphos (10.1 mg, 21.6 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/ isohexane) gave the title compound (202 mg, 88 μmol, 41% yield, 28% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 641 (M+H) ⁺ , RT 2.56 min.

Step 4:

(R)-3-cyclopropyl-5-(piperidin-3-yloxy)-N-(4-(pyridin-2-y l)benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Hydrogen chloride (4 M in dioxane) (0.88 ml_, 3.5 mmol) was added to a solution of tert- butyl (R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)oxy)piperidine-1-carboxylate (202 mg, 88 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 2 h and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (2.0 ml_, 2.50 mmol) was added and the resulting reaction mixture was stirred at 40 °C for 1 h then concentrated in vacuo. The solid was triturated in MeCN/Et ₂ O 1:1 (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (37 mg, 82 μmol, 93% yield, 99% purity) as a white solid.

UPLC/MS (Method 3): m/z 441 (M+H) ⁺ , RT 1.68 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.62 (m, 1 H), 8.34 (t, J = 6.4 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.95 - 7.91 (m, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.76 (s, 1 H), 7.48 (d, J = 8.1 Hz, 2H), 7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1H), 5.31 (s, 1H), 4.94 - 4.86 (m, 1H), 4.59 (d, J = 6.5 Hz, 2H), 3.10 (dd, J = 11.9, 3.9 Hz, 1H), 2.79 - 2.71 (m, 1H), 2.48 - 2.39 (m,

1 H), 2.06 - 1.98 (m, 1H), 1.88 - 1.78 (m, 1 H), 1.67 - 1.58 (m, 1H), 1.51 - 1.37 (m, 2H), 0.87 - 0.76 (m, 4H). 2H under water. Synthesis 078

3-cyclopropyl-N ⁵ -((4-fluoropiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-4-flu oropiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (101 mg, 200 μmol) (prepared as described herein), tert-butyl 4- (aminomethyl)-4-fluoropiperidine-1-carboxylate (56 g, 240 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17 mg, 20.0 μmol) and LiHMDS (1M in THF) (240 pL, 240 μmol). The reaction mixture was degassed for another 5 min before being heated to 60 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (92 mg, 0.13 mmol, 65% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 672 (M+H) ⁺ , RT 2.13 min.

Step 4:

3-cyclopropyl-N ⁵ -((4-fluoropiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.64 ml_, 2.6 mmol) was added to a solution of tert- butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-4-flu oropiperidine-1-carboxylate (91 mg, 0.13 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 2 h and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (2.0 ml_, 2.50 mmol) was added and the resulting reaction mixture was stirred at 40 °C for 1.5 h then concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 ml_) to give the title compound (47 mg, 96 μmol, 75% yield, 97% purity) as an off-white solid.

UPLC/MS (Method 3): m/z 472 (M+H) ⁺ , RT 1.48 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.62 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.93 (dt, J = 8.0, 1.2 Hz, 1H), 7.89 - 7.83 (m, 2H), 7.55 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 6.76 (t, J = 6.1 Hz, 1 H), 5.29 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H), 3.51 (dd, J = 21.1 , 6.1 Hz, 2H), 2.78 - 2.60 (m, 4H), 1.81 - 1.70 (m, 1H), 1.67 - 1.45 (m, 4H), 0.80 - 0.70 (m, 4H). 1 H under water.

Synthesis 079

3-cyclopropyl-N ⁵ -((4-methylpiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-4-met hylpiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (101 mg, 200 μmol) (prepared as described herein), tert-butyl 4- (aminomethyl)-4-methylpiperidine-1-carboxylate (57 mg, 240 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17.1 mg, 20.0 μmol) and LiHMDS (1M in THF) (240 pL, 240 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 6 h. The reaction mixture was recharged with more tert-butyl 4-(aminomethyl)-4-methylpiperidine-1-carboxylate (23 mg, 100 μmol), ‘BuBrettPhos Pd G3 (17.1 mg, 20.0 μmol) and LiHMDS (1M in THF) (100 pL, 100 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2.5 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (78 mg, 0.11 mmol, 56% yield, 97% purity) as a tan oil.

UPLC/MS (Method 3): m/z 668 (M+H) ⁺ , R _T 2.22 min.

Step 4:

3-cyclopropyl-N ⁵ -((4-methylpiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.56 ml_, 2.2 mmol) was added to a solution of tert- butyl 4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)- 3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-4-met hylpiperidine-1-carboxylate (77 mg, 0.11 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1.5 h and concentrated in vacuo. Hydrogen chloride (1.25 M in MeOH) (2.0 ml_, 2.50 mmol) was added and the resulting reaction mixture was stirred at 40 °C for 30 min then concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with DCM/MeOH 30/70 (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 ml_) to give the title compound (42 mg, 85 μmol, 76% yield, 96% purity) as a yellow solid.

UPLC/MS (Method 3): m/z 468 (M+H) ⁺ , RT 1.95 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.60 (m, 1 H), 8.05 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.89 - 7.83 (m, 1 H), 7.77 (t, J = 6.6 Hz, 1 H), 7.53 (s, 1 H), 7.45 (d, J = 8.0 Hz, 2H), 7.33 (dd, J = 7.2, 4.9 Hz, 1 H), 6.51 (t, J = 6.1 Hz, 1 H), 5.24 (s, 1H), 4.50 (d, J = 6.4 Hz, 2H), 3.18 (d, J = 5.7 Hz, 2H), 2.80 - 2.65 (m, 2H), 2.63 - 2.54 (m, 2H), 1.81 - 1.71 (m, 1 H), 1.40 - 1.28 (m, 2H), 1.18 - 1.09 (m, 2H), 0.86 (s, 3H), 0.80 - 0.71 (m, 4H). 1H under water.

Synthesis 080

(S)-3-cyclopropyl-5-(piperidin-3-yloxy)-N-(4-(pyridin-2-y l)benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-ca rboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 216 μmol) (prepared as described herein), tert-butyl (S)-

3-hydroxypiperidine-1-carboxylate (178 g, 841 μmol) and cesium carbonate (274 mg, 841 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (13.9 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (110 mg, 140 μmol, 66% yield, 81% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 641 (M+H) ⁺ , RT 2.56 min.

Step 4:

(S)-3-cyclopropyl-5-(piperidin-3-yloxy)-N-(4-(pyridin-2-y l)benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Hydrogen chloride (4 M in dioxane) (1.72 ml_, 6.9 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)piperidine-1-ca rboxylate (110 mg, 172 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (53 mg, 120 μmol, 68% yield, 97% purity) as a white solid.

UPLC/MS (Method 3): m/z 441 (M+H) ⁺ , RT 1.21 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1H), 8.34 (t, J = 6.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.76 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.37 - 7.29 (m, 1H), 5.31 (s, 1H), 4.93 - 4.84 (m, 1 H), 4.59 (d, J = 6.5 Hz, 2H), 3.13 - 3.05 (m, 1H), 2.77 - 2.68 (m, 1H), 2.43 (ddd, J = 16.4, 12.0, 8.9 Hz, 1H), 2.24 - 2.13 (m, 1H), 2.03 - 1.99 (m, 1H), 1.88 - 1.77 (m, 1H), 1.66 - 1.58 (m, 1H), 1.51 - 1.37 (m, 2H), 0.87 - 0.75 (m, 4H). 1H underwater.

Synthesis 081

(S)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(pyrrolidi n-3-yloxy)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyrrolidine-1-c arboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl (S)-

3-hydroxypyrrolidine-1-carboxylate (157 mg, 840 μmol) and cesium carbonate (274 mg, 840 μmol) in dioxane (3.0 ml_) was degassed with N2 for 5 min. Pd-171 (13.9 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (120 mg, 160 μmol, 74% yield, 81% purity) as a yellow oil. UPLC/MS (Method 4): m/z 627 (M+H) ⁺ , RT 2.49 min.

Step 4:

(S)-3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(pyrrolidi n-3-yloxy)pyrazolo[1,5-a]pyrimidin-

7-amine

Hydrogen chloride (4 M in dioxane) (1.91 ml_, 7.7 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)pyrrolidine-1-c arboxylate (120 mg, 191 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (30 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (58 mg, 130 μmol, 69% yield, 97% purity) as an off-white solid.

UPLC/MS (Method 2): m/z 427 (M+H) ⁺ , RT 1.17 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.61 (m, 1H), 8.35 (t, J = 6.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.7, 1.8 Hz, 1 H), 7.78 (s, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.37 - 7.29 (m, 1 H), 5.33 - 5.28 (m, 2H), 4.59 (d, J = 6.4 Hz, 2H), 3.07 (dd, J = 12.3, 5.8 Hz, 1H), 2.88 - 2.78 (m, 1 H), 2.78 - 2.68 (m, 2H), 2.06 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1 H), 1.75 - 1.66 (m, 1 H), 0.86 - 0.79 (m, 4H). 1 H under water.

Synthesis 082

(3R,4R)-4-(((3-cyclopropyl-7-(((3-fluoro-[1,T-biphenyl]-4 -yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 : 5-chloro-3-cyclopropyl-N-((3-fluoro-[1 , T-biphenyl]-4-yl)methyl)pyrazolo[1 ,5-a]pyrimidin-7- amine

DIPEA (1.21 ml_, 6.96 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (227 mg, 0.99 mmol) and (3-fluoro-[1,T-biphenyl]-4- yl)methanamine (200 mg, 0.99 mmol) in EtOH (10 ml_). The reaction mixture was heated to 50 °C for 3 h. The resulting solid was collected by filtration, washing with water (3 x 2 ml_). The solid was dissolved in MeCN (10 ml_) and the solution concentrated in vacuo to give the title compound (346 mg, 0.87 mmol, 88% yield, 99% purity) as a white solid.

UPLC/MS (Method 2): m/z 393 (M+H) ⁺ , R _T 2.45 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-flu oro-[1,T-biphenyl]-4- yl)methyl)carbamate

DMAP (21 mg, 174 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((3-fluoro- [1,T-biphenyl]-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (346 mg, 872 μmol) and BOC-anhydride (228 mg, 1.05 mmol) in anhydrous THF (9.0 mL). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (415 mg, 0.72 mmol, 83% yield, 86% purity) as a green glass solid.

UPLC/MS (Method 2): m/z 437 (M-tBu+H) ⁺ , R _T 2.71 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-fluoro-[1 , 1 '-biphenyl]-4- yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3-flu oro-[1,T- biphenyl]-4-yl)methyl)carbamate (200 mg, 349 μmol), tert-butyl (3R,4R)-4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (88 mg, 384 μmol) in THF (4.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (29.8 mg, 35 μmol) and LiHMDS (1M in THF) (454 pL, 454 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (291 mg, 0.32 mmol, 91% yield, 75% purity) as a brown oil.

UPLC/MS (Method 3): m/z 687 (M+H) ⁺ , R _T 2.19 min. Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((3-fluoro-[1,T-biphenyl]-4 -yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

TFA (1.0 mL) was added to a mixture of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)-3-cyclopropylpyrazolo[1 ,5- a]pyrimidin-5-yl)a ino) ethyl)-3-hydroxypiperidine-1-carboxylate (291 g, 0.32 mmol) in DCM (3.0 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product was eluted with 0.7 M NH3 in MeOH (40 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 mL) to give the title compound (157 mg, 0.32 mmol, 99% yield, 98% purity) as a pink solid.

UPLC/MS (Method 2): m/z 487 (M+H) ⁺ , RT 1.27 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.80 (t, J = 6.5 Hz, 1 H), 7.70 - 7.65 (m, 2H), 7.58 - 7.49 (m, 2H), 7.49 - 7.43 (m, 3H), 7.41 - 7.35 (m, 2H), 6.75 (t, J = 6.0 Hz, 1 H), 5.31 - 5.23 (m, 1 H), 5.20 (s, 1 H), 4.53 (d, J = 6.4 Hz, 2H), 3.56 - 3.44 (m, 1H), 3.26 - 3.18 (m, 1H), 3.09 - 2.97 (m, 1H), 2.90 (dd, J = 11.5, 4.5 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.34 - 2.24 (m, 1H), 2.15 (dd, J = 11.6, 9.9 Hz, 1 H), 1.77 - 1.68 (m, 1 H), 1.60 - 1.51 (m, 1H), 1.37 - 1.27 (m,

1 H), 1.20 - 1.11 (m, 1H), 0.82 - 0.73 (m, 2H), 0.71 - 0.60 (m, 2H). 1H under water.

Synthesis 083

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

Step 1 :

5-chloro-3-cyclopropyl-N-(2-fluoro-4-(pyrimidin-2-yl)benz yl)pyrazolo[1,5-a]pyrimidin-7- amine DIPEA (0.23 ml_, 1.3 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1,5-a]pyrimidine (110 mg, 0.47 mmol) and (2-fluoro-4-(pyrimidin-2- yl)phenyl)methanamine (91 mg, 0.45 mmol) in I PA (3.0 ml_). The reaction mixture was heated to 70 °C for 2 h. At RT, water (1 ml_) was added and the mixture was stirred for 10 min. The resulting precipitate was collected by filtration, washing with IPA/water 2:1 (3 ml_). The solid was dissolved in DCM (15 ml_) and the solution was dried over Na2SC>4, filtered and concentrated in vacuo to give the title compound (127 mg, 0.32 mmol, 70% yield, 98% purity) as a white solid.

UPLC/MS (Method 2): m/z 395 (M+H) ⁺ , R _T 2.14 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyrimidin- 2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate

A solution of 5-chloro-3-cyclopropyl-N-(2-fluoro-4-(pyrimidin-2-yl)benzyl) pyrazolo[1,5- a]pyrimidin-7-amine (125 mg, 317 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (88 mg, 380 μmol) in dioxane (1.0 mL) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (27 mg, 32 μmol) and LiHMDS (1M in THF) (412 pL, 412 μmol). The reaction was degassed for another 5 min before being heated to 90 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 100% TBME) gave the title compound (109 mg, 0.18 mmol, 57% yield, 98% purity) as an orange solid.

UPLC/MS (Method 2): m/z 589 (M+H) ⁺ , R _T 1.58 min.

Step 4:

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

At 0 °C, TFA (0.7 mL) was added to a mixture of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)(2-fluoro-4-(pyrimidin-2-yl)benzyl)amino)-3-c yclopropylpyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (107 mg, 173 μmol) in DCM (1.5 mL). The reaction mixture was stirred at RT for 30 min and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (40 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 mL) to give the title compound (55 mg, 0.11 mmol, 65% yield, 99% purity) as a tan solid.

UPLC/MS (Method 3): m/z 489 (M+H) ⁺ , RT 1.24 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.92 (d, J = 4.9 Hz, 2H), 8.20 (dd, = 8.1 , 1.6 Hz, 1 H), 8.11 (dd, J = 11.5, 1.6 Hz, 1 H), 7.85 (t, J = 6.4 Hz, 1 H), 7.54 (s, 1H), 7.50 - 7.42 (m, 2H), 6.73 (t, J = 6.0 Hz, 1 H), 5.35 - 5.21 (m, 1H), 5.17 (s, 1H), 4.58 (d, J = 6.3 Hz, 2H), 3.49 (s, 1 H), 3.26 - 3.15 (m, 1 H), 3.06 - 2.97 (m, 1 H), 2.90 (dd, J = 11.6, 4.6 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.40 - 2.23 (m, 1 H), 2.15 (dd, J = 11.6, 9.9 Hz, 1 H), 1.77 - 1.68 (m, 1H), 1.61 - 1.49 (m, 1H), 1.38 - 1.27 (m, 1H), 1.18 - 1.06 (m, 1 H), 0.85 - 0.72 (m, 2H), 0.71 - 0.59 (m, 2H).1H under water.

Synthesis 084

(2-fluoro-4-(pyrimidin-2-yl)phenyl)methanamine

Step A: tert-butyl (2-fluoro-4-(pyrimidin-2-yl)benzyl)carbamate

2-Chloropyrimidine (75 mg, 650 μmol), (4-(((tert-butoxycarbonyl)amino)methyl)-3- fluorophenyl)boronic acid (175 g, 650 μmol), Pd(dppf)Cl2.DCM (27 mg, 32.5 μmol) and potassium phosphate, tribasic (276 mg, 1.30 mmol) were taken up in dioxane (2.0 ml_) and water (0.4 ml_). The reaction mixture was sparged with N2 for 5 min then heated under microwave irradiation for 1 h at 100 °C then allowed to cool to RT. The mixture was diluted with EtOAc (25 ml_) and water (25 ml_). The layers were separated and the organic layer was washed with brine (10 ml_) then dried over Na2SC>4, filtered then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0- 100% EtOAc/isohexane) gave the title compound (140 mg, 0.46 mmol, 70% yield, 99% purity) as an off-white solid.

UPLC/MS (Method 2): m/z 248 (M-tBu+H)+, R _T 1.82 min.

Step B:

(2-fluoro-4-(pyrimidin-2-yl)phenyl)methanamine

At 0 °C, TFA (1.05 ml_) was added to a solution of tert-butyl (2-fluoro-4-(pyrimidin-2- yl)benzyl)carbamate (138 mg, 455 μmol) in DCM (1.0 ml_). The reaction mixture was stirred at 0 °C for 30 min and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (91 mg, 0.44 mmol, 97% yield, 99% purity) as an off-white solid. UPLC/MS (Method 3): m/z 204 (M+H) ⁺ , RT 0.90 min.

Synthesis 085

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

Step 1 :

5-chloro-3-ethyl-N-(2-fluoro-4-(pyridin-2-yl)benzyl)pyraz olo[1,5-a]pyrimidin-7-amine

DIPEA (0.56 mL, 3.24 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5- a]pyrimidine (100 mg, 0.46 mmol) and (2-fluoro-4-(pyridin-2-yl)phenyl)methanamine (103 mg, 0.51 mmol) in EtOH (5 mL). The reaction mixture was heated to 50 °C overnight. At RT, water (2 mL) was added and the solid was collected by filtration, washing with water (5 mL) to give the title compound (170 mg, 0.42 mmol, 91% yield, 95% purity) as a brown solid.

UPLC/MS (Method 2): m/z 382 (M+H) ⁺ , R _T 2.08 min.

Step 2: tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-( pyridin-2- yl)benzyl)carbamate

DMAP (10.3 mg, 84.6 μmol) was added to a solution of 5-chloro-3-ethyl-N-(2-fluoro-4- (pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (170 mg, 423 μmol) and BOC- Anhydride (111 mg, 508 μmol) in anhydrous THF (4.0 mL). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (174 mg, 0.34 mmol, 81% yield, 95% purity) as a green oil.

UPLC/MS (Method 2): /z 382 (M-Boc+H) ⁺ , R _T 2.49 min. Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2- yl)benzyl)amino)-3- ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypi peridine-1-carboxylate

A solution of tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-( pyridin-2- yl)benzyl)carbamate (174 mg, 361 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (92 g, 397 μmol) in THF (4.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (30.8 mg, 36 μmol) and LiHMDS (1M in THF) (469 pL, 469 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (217 mg, 321 μmol, 89% yield, 99% purity) as a brown solid.

UPLC/MS (Method 5): m/z 676 (M+H) ⁺ , R _T 2.00 min.

Step 4:

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

TFA (1.0 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2- fluoro-4-(pyridin-2-yl)benzyl)amino)-3-ethylpyrazolo[1,5-a]p yrimidin-5-yl)amino)methyl)-3- hydroxypiperidine-1-carboxylate (214 mg, 317 μmol) in DCM (3.0 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (30 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (136 mg, 0.28 mmol, 89% yield, 98% purity) as a pink solid.

UPLC/MS (Method 5): m/z 476 (M+H) ⁺ , RT 1.29 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.71 - 8.62 (m, 1 H), 7.99 (d, J = 7.9 Hz, 1 H), 7.95 - 7.82 (m, 4H), 7.67 (s, 1 H), 7.42 (t, J = 8.1 Hz, 1 H), 7.38 (ddd, J = 7.5, 4.8, 1.1 Hz, 1 H), 6.76 (t, J = 6.1 Hz, 1 H), 5.48 - 5.34 (m, 1H), 5.18 (s, 1 H), 4.56 (d, J = 6.3 Hz, 2H), 3.60 - 3.46 (m, 1 H), 3.21 - 3.13 (m, 1H), 3.06 - 2.96 (m, 1H), 2.90 (dd, J = 11.5, 4.5 Hz, 1H), 2.84 - 2.73 (m, 1H), 2.48 - 2.44 (m, 2H), 2.37 - 2.26 (m, 1H), 2.16 (dd, J = 11.6, 9.9 Hz, 1 H), 1.59 - 1.50 (m, 1H), 1.37 - 1.26 (m, 1H), 1.18 (t, J = 7.5 Hz, 3H), 1.14 - 1.08 (m, 1H). 1 H under water. Synthesis 086

(3R,4R)-4-(((3-ethyl-7-(((3-fluoro-[1,T-biphenyl]-4-yl)me thyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

Step 1 :

5-chloro-3-ethyl-N-((3-fluoro-[1,T-biphenyl]-4-yl)methyl) pyrazolo[1,5-a]pyrimidin-7-amine

DIPEA (0.56 ml_, 3.24 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5- a]pyrimidine (100 mg, 0.46 mmol) and (3-fluoro-[1,T-biphenyl]-4-yl)methanamine (102 mg, 0.51 mmol) in EtOH (5.0 ml_). The reaction mixture was heated to 50 °C overnight. The resulting solid was collected by filtration, washing with water (3 x 2 ml_). The solid was dissolved in MeCN (10 ml_) and the solution concentrated in vacuo to give the title compound (175 mg, 0.44 mmol, 94% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 381 (M+H) ⁺ , R _T 2.45 min.

Step 2: tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((3-fluoro-[1 ,T-biphenyl]-4- yl)methyl)carbamate

DMAP (10.7 mg, 87 μmol) was added to a solution of 5-chloro-3-ethyl-N-((3-fluoro-[1,T- biphenyl]-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (175 mg, 437 μmol) and BOC- anhydride (114 mg, 524 μmol) in anhydrous THF (4.0 ml_). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (192 mg, 0.35 mmol, 80% yield, 88% purity) as a green oil.

UPLC/MS (Method 2): m/z 425 (M-tBu+H) ⁺ , R _T 2.73 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3-fluoro-[1 , 1 '-biphenyl]-4- yl)methyl)amino)-3-ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino) methyl)-3-hydroxypiperidine-

1-carboxylate

A solution tert-butyl (5-chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-yl)((3-fluoro-[1 ,T- biphenyl]-4-yl)methyl)carbamate (192 mg, 399 μmol), tert-butyl (3R,4R)-4-(aminomethyl)- 3-hydroxypiperidine-1-carboxylate (101 g, 439 μmol) in THF (4.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (34.1 mg, 40 μmol) and LiHMDS (1M in THF) (519 pL, 519 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 4 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (214 mg, 0.30 mmol, 75% yield, 95% purity) as a brown solid.

UPLC/MS (Method 5): m/z 675 (M+H) ⁺ , R _T 2.18 min.

Step 4:

(3R,4R)-4-(((3-ethyl-7-(((3-fluoro-[1,T-biphenyl]-4-yl)me thyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)methyl)piperidin-3-ol

TFA (1.0 ml_) was added to a mixture of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)-3-ethylpyrazolo[1 ,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (217 mg, 305 μmol) in DCM (3.0 ml_). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (30 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (130 mg, 0.26 mmol, 85% yield, 95% purity) as a pink solid.

UPLC/MS (Method 5): m/z 475 (M+H) ⁺ , RT 1.56 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.84 (t, J = 6.5 Hz, 1 H), 7.72 - 7.63 (m, 3H), 7.58 - 7.50 (m, 1H), 7.50 - 7.43 (m, 3H), 7.42 - 7.35 (m, 2H), 6.78 (t, J = 6.1 Hz, 1 H), 5.49 - 5.36 (m, 1 H), 5.20 (s, 1 H), 4.54 (d, J = 6.4 Hz, 2H), 3.62 - 3.46 (m, 1H), 3.23 - 3.13 (m, 1H), 3.08 - 2.97 (m, 1H), 2.91 (dd, J = 11.6, 4.5 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.49 - 2.44 (m, 2H), 2.36 - 2.26 (m, 1H), 2.17 (t, J = 10.7 Hz, 1H), 1.60 - 1.50 (m, 1 H), 1.38 - 1.27 (m, 1H),

1.22 - 1.09 (m, 4H). 1 H under water. Synthesis 087

7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)-5-((((3R,4R)-3-hydroxypiperid in-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Step 1 :

5-chloro-7-(((3-fluoro-[1,T-biphenyl]-4-yl)methyl)amino)p yrazolo[1,5-a]pyrimidine-3- carbonitrile

DIPEA (1.42 L, 8.17 mmol) was added to a solution of 5,7-dichloropyrazolo[1,5- a]pyrimidine-3-carbonitrile (250 mg, 1.17 mmol) and (3-fluoro-[1,1'-biphenyl]-4- yl)methanamine (300 mg, 1.34 mmol) in EtOH (5.0 mL). The reaction mixture was heated to 50 °C overnight then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (270 mg, 0.66 mmol, 57% yield, 93% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 378 (M+H) ⁺ , R _T 2.20 min.

Step 2: tert-butyl (3R,4R)-4-(((3-cyano-7-(((3-fluoro-[1 , 1 '-biphenyl]-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)- 3-hydroxypiperidine-1- carboxylate

A solution of 5-chloro-7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)pyrazolo[1 ,5- a]pyrimidine-3-carbonitrile (50 mg, 0.13 mmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (61 mg, 0.26 mmol) and DIPEA (69 μL, 0.40 mmol) in NMP (1.5 mL) was heated under microwave irradiation at 120 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification on RP Flash C18 (24 g cartridge, 0- 100% 0.1% formic Acid in MeCN/0.1% formic acid in water) gave the title compound (75 mg, 0.12 mmol, 94% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 572 (M+H) ⁺ , R _T 2.23 min. Step 3:

7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)-5-((((3R,4R)-3-hydroxypiperid in-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Hydrogen chloride (4 M in dioxane) (1.6 ml_, 6.4 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((3-cyano-7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)pyrazolo[1 ,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late (75 mg, 0.16 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (28 mg, 59 μmol, 37% yield, 99% purity) as an off-white solid.

UPLC/MS (Method 2): m/z 472 (M+H) ⁺ , RT 1.43 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.28 (s, 1H), 8.26 - 8.22 (m, 1 H), 7.72 - 7.65 (m, 2H), 7.55 (d, J = 11.7 Hz, 1 H), 7.53 - 7.43 (m, 3H), 7.43 - 7.34 (m, 2H), 7.28 - 7.23 (m, 1 H), 5.44 - 5.39 (m, 1 H), 4.76 (d, J = 5.1 Hz, 1H), 4.56 (s, 2H), 3.59 - 3.43 (m, 1 H), 3.14 - 3.02 (m, 1H), 2.97 - 2.88 (m, 1H), 2.81 - 2.74 (m, 1H), 2.30 - 2.25 (m, 2H), 2.15 (t, J = 10.8 Hz, 1 H), 1.68 - 1.60 (m, 1 H), 1.42 - 1.31 (m, 1H), 1.14 - 0.99 (m, 1 H). 1H under water.

Synthesis 088

(S)-7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)-5-(pyrrolidin-3-ylamino)pyraz olo[1 ,5- a]pyrimidine-3-carbonitrile

Step 2: tert-butyl (S)-3-((3-cyano-7-(((3-fluoro-[1 ,T-biphenyl]-4-yl)methyl)amino)pyrazolo[1,5- a]pyrimidin-5-yl)amino)pyrrolidine-1-carboxylate A solution of 5-chloro-7-(((3-fluoro-[1 , 1 '-biphenyl]-4-yl)methyl)amino)pyrazolo[1 ,5- a]pyrimidine-3-carbonitrile (70 mg, 185 μmol) (prepared as described herein), tert-butyl (S)-3-a inopyrrolidine-1-carboxylate (138 g, 741 μmol) and DIPEA (97 pL, 0.56 mmol) in NMP (1.5 ml_) was heated under microwave irradiation at 120 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification on RP Flash C18 (24 g cartridge, 0-100% 0.1% formic Acid in MeCN/0.1% formic acid in water) gave the title compound (80 mg, 0.14 mmol, 78% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 550 (M+Na) ⁺ , R _T 2.33 min.

Step 3:

(S)-7-(((3-fluoro-[1,T-biphenyl]-4-yl)methyl)amino)-5-(py rrolidin-3-ylamino)pyrazolo[1,5- a]pyrimidine-3-carbonitrile

Hydrogen chloride (4 M in dioxane) (1.5 ml_, 6.1 mmol) was added to a solution of tert- butyl (S)-3-((3-cyano-7-(((3-fluoro-[1,T-biphenyl]-4-yl)methyl)ami no)pyrazolo[1,5- a]pyrimidin-5-yl)amino)pyrrolidine-1-carboxylate (80 mg, 0.15 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (26 mg, 58 μmol, 38% yield, 95% purity) as a white solid.

UPLC/MS (Method 2): m/z 428 (M+H) ⁺ , RT 1.42 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.29 (s, 1H), 8.35 - 8.23 (m, 1 H), 7.72 - 7.65 (m, 2H), 7.56 (dd, J = 11.7, 1.7 Hz, 1 H), 7.53 - 7.34 (m, 6H), 5.30 (s, 1 H), 4.61 - 4.51 (m, 2H), 4.45 - 4.13 (m, 1 H), 3.01 (s, 1H), 2.90 - 2.80 (m, 1H), 2.80 - 2.73 (m, 1H), 2.58 - 2.51 (m, 1 H), 2.02 - 1.92 (m, 1 H), 1.58 - 1.46 (m, 1 H). 1 H under water.

Synthesis 089

(S)-3-cyclopropyl-N ⁷ -(2-fluoro-4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)be nzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(2-fluo ro-4- (pyridin-2-yl)benzyl)carbamate (100 mg, 202 μmol) (prepared as described herein), tert- butyl (S)-3-aminopyrrolidine-1-carboxylate (155 g, 810 μmol) and cesium carbonate (264 mg, 810 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (13.4 mg, 20.2 μmol) and Ruphos (9.5 mg, 20.2 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (90 mg, 0.13 mmol, 63% yield, 91% purity) as a yellow oil.

UPLC/MS (Method 4): m/z 644 (M+H) ⁺ , RT 2.49 min.

Step 4:

(S)-3-cyclopropyl-N ⁷ -(2-fluoro-4-(pyridin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (1.4 ml_, 5.6 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)be nzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate (90 mg, 0.14 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (18 mg, 39 μmol, 28% yield, 97% purity) as a white solid.

UPLC/MS (Method 4): m/z 444 (M+H) ⁺ , RT 1.10 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.69 - 8.63 (m, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.95 - 7.86 (m, 3H), 7.84 (t, J = 6.3 Hz, 1 H), 7.58 (s, 1 H), 7.45 - 7.34 (m, 2H), 6.77 (d, J = 5.9 Hz,

1 H), 5.09 (s, 1 H), 4.55 (d, J = 6.3 Hz, 2H), 4.25 - 4.20 (m, 1H), 3.16 - 3.07 (m, 1H), 2.98 - 2.91 (m, 1 H), 2.91 - 2.83 (m, 1 H), 2.73 - 2.65 (m, 1H), 2.06 - 1.96 (m, 1 H), 1.83 - 1.71 (m, 1 H), 1.66 - 1.54 (m, 1 H), 0.83 - 0.71 (m, 4H). 1 H under water.

Synthesis 090

3-cyclopropyl-5-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)-N- (4-(pyridin-2- yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine / 3-cyclopropyl-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)-N-(4- (pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (1 :1)

Step 3: tert-butyl (3R,4R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)oxy)-4-fluoropyrrolidine-1-carboxylate / tert-butyl (3S,4S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-4-fluoropyrrol idine-1-carboxylate (1 :1)

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), racemic trans- tert-butyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (178 mg, 841 μmol) and cesium carbonate (274 mg, 840 μmol) in dioxane (2.6 ml_) was degassed with N ₂ for 5 min. Pd- 171 (13.9 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N ₂ was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (120 g, 0.15 mmol, 73% yield, 82% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 645 (M+H) ⁺ , RT 2.52 min.

Step 4:

3-cyclopropyl-5-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)-N- (4-(pyridin-2- yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine / 3-cyclopropyl-5-(((3S,4S)-4-fluoropyrrolidin- 3-yl)oxy)-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin -7-amine (1:1)

Hydrogen chloride (4 M in dioxane) (1.9 ml_, 7.4 mmol) was added to a solution of tert- butyl (3R,4R)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1 ,5-a]pyrimidin-5-yl)oxy)-4-fluoropyrrolidine-1-carboxylate / tert-butyl (3S,4S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl) amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)-4-fluoropyrrol idine-1-carboxylate (1:1) (120 mg, 186 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (78 mg, 0.17 mmol, 92% yield, 98% purity) as a white solid.

UPLC/MS (Method 4): m/z 445 (M+H) ⁺ , RT 1.20 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 (d, J = 4.8 Hz, 1 H), 8.46 (t, J = 6.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.82 (s, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.37 - 7.29 (m, 1H), 5.36 (s, 1H), 5.34 - 5.26 (m, 1H), 5.19 - 5.02 (m, 1 H), 4.60 (d, J = 6.5 Hz, 2H), 3.36 (dd, J = 12.6, 6.0 Hz, 1 H), 3.00 (d, J = 3.8 Hz, 1 H), 2.92 (d, J = 3.1 Hz, 1 H), 2.70 (dd, J = 12.7, 3.7 Hz, 1H), 1.90 - 1.79 (m, 1H), 0.92 - 0.78 (m, 4H). 1 H under water.

Synthesis 091

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

Step 1 :

3,5-dichloro-N-(2-fluoro-4-(pyridin-2-yl)benzyl)pyrazolo[ 1,5-a]pyrimidin-7-amine

DIPEA (0.30 ml_, 1.71 mmol) was added to a solution of 3,5,7-trichloropyrazolo[1,5- a]pyrimidine (133 mg, 0.60 mmol) and (2-fluoro-4-(pyridin-2-yl)phenyl)methanamine (115 mg, 0.57 mmol) in I PA (2.0 ml_). The reaction mixture was heated to 80 °C under microwave irradiation for 30 min. The reacton mixture was partitioned between EtOAc (20 ml_) and water (20 ml_). The layers were separated and the organic layer was washed with brine (10 ml_), dried over Na2SC>4, filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-5% MeOH/TBME) gave the title compound (173 mg, 0.42 mmol, 73% yield, 95% purity) as a brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.16 - 9.10 (m, 1H), 8.68 - 8.65 (m, 1H), 8.35 (s, 1H), 8.06 - 7.81 (m, 4H), 7.52 - 7.27 (m, 2H), 6.36 (s, 1 H), 4.77 (d, J = 5.0 Hz, 2H).

Step 2: tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-(pyri din-2- yl)benzyl)carbamate

DMAP (5.4 mg, 44 μmol) was added to a solution of 3,5-dichloro-N-(2-fluoro-4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine (170 mg, 438 μmol) and BOC-anhydride (105 mg, 482 μmol) in anhydrous THF (1.5 ml_). The reaction mixture was stirred at RT for 1 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0- 100% TBM E/isohexane) gave the title compound (210 mg, 0.42 mmol, 96% yield, 98% purity) as a yelow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.69 - 8.61 (m, 1H), 8.51 (s, 1H), 7.99 (d, J = 8.0 Hz,

1 H), 7.92 - 7.79 (m, 3H), 7.58 (t, J = 8.0 Hz, 1 H), 7.50 (s, 1 H), 7.39 - 7.36 (m, 1 H), 5.08 (s, 2H), 1.28 (s, 9H).

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(2-fluoro-4-(pyridin-2- yl)benzyl)amino)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxyp iperidine-1-carboxylate

A solution of tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(2-fluoro-4-(pyri din-2- yl)benzyl)carbamate (150 mg, 307 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (85 g, 369 mmol) in dioxane (1.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (26.2 mg, 30.7 μmol) and LiHMDS (1M in THF) (399 pL, 399 μmol). The reaction was degassed for another 5 min before being heated to 60 °C overnight. At RT, brine (2 ml_) and DCM (10 ml_). The layers were separated and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (100 mg, 0.14 mmol, 47% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 683 (M+H) ⁺ , R _T 2.31 min.

Step 4:

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

At 0 °C, TFA (0.66 ml_) was added to a solution of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)(2-fluoro-4-(pyridin-2-yl)benzyl)amino)-3-chl oropyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (86 mg, 0.12 mmol) in DCM (1.5 ml_). The reaction mixture was stirred at RT for 30 min then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (40 mg, 81 μmol, 58% yield, 98% purity) as a tan solid.

UPLC/MS (Method 3): m/z 482 (M+H) ⁺ , RT 1.25 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.72 - 8.62 (m, 1 H), 8.05 (t, J = 6.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1 H), 7.96 - 7.86 (m, 4H), 7.49 - 7.32 (m, 2H), 7.00 (t, J = 5.9 Hz, 1 H), 5.29 (s,

1 H), 5.16 - 4.93 (m, 1H), 4.57 (d, J = 6.2 Hz, 2H), 3.51 - 3.36 (m, 1H), 3.12 - 2.98 (m,

1 H), 2.92 (dd, J = 11.6, 4.6 Hz, 1 H), 2.86 - 2.71 (m, 1H), 2.39 - 2.24 (m, 1H), 2.23 - 2.09 (m, 1 H), 1.66 - 1.52 (m, 1 H), 1.42 - 1.27 (m, 1 H), 1.20 - 1.00 (m, 1 H). 2H under water. Svnthesis 092

(S)-4-((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)pyrrolidin-2-one

Step 3: tert-butyl (S)-(3-cyclopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1 ,5-a]pyrimidin-7- yl)(4-(pyridin-2-yl)benzyl)carbamate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (120 mg, 252 μmol) (prepared as described herein), (S)-4- aminopyrrolidin-2-one (114 g, 1.13 mmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (21.5 mg, 25.2 μmol) and LiHMDS (1M in THF) (378 pL, 378 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 5 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (90 mg, 0.16 mmol, 65% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 540 (M+H) ⁺ , R _T 1.68 min.

Step 4:

(S)-4-((3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)amino)py razolo[1,5-a]pyrimidin-5- yl)amino)pyrrolidin-2-one

Hydrogen chloride (4 M in dioxane) (1.70 ml_, 6.7 mmol) was added to a solution of tert- butyl (S)-(3-cyclopropyl-5-((5-oxopyrrolidin-3-yl)amino)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate (90 mg, 0.17 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 mL) to give the title compound (26 g, 58 μmol, 35% yield, 98% purity) as a white solid.

UPLC/MS (Method 2): m/z 440 (M+H) ⁺ , RT 1.07 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.05 (d, J = 8.1 Hz, 2H), 7.96 - 7.89 (m, 2H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H), 7.59 (s, 1H), 7.56 (s, 1H), 7.44 (d, J = 8.1 Hz, 2H), 7.33 (dd, J = 7.3, 4.8 Hz, 1H), 7.00 (d, J = 5.9 Hz, 1 H), 5.11 (s, 1H), 4.50 (d, J = 6.4 Hz, 2H), 4.48 - 4.40 (m, 1 H), 3.56 (dd, J = 9.9, 6.8 Hz, 1 H), 3.04 (dd, J = 9.9, 4.5 Hz, 1 H), 2.04 (dd, J = 16.7, 5.6 Hz, 1 H), 1.82 - 1.71 (m, 1 H), 0.85 - 0.72 (m, 4H). 1 H under water.

Synthesis 093

(3R,4R)-4-(((3-cyclopropyl-7-(((3,5-difluoro-[1 , 1 '-biphenyl]-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

Step 1 :

5-chloro-3-cyclopropyl-N-((3,5-difluoro-[1,T-biphenyl]-4- yl)methyl)pyrazolo[1,5- a]pyrimidin-7-amine

DIPEA (0.78 mL, 4.46 mmol) was added to a solution of 5,7-dichloro-3- cyclopropylpyrazolo[1 ,5-a]pyrimidine (145 mg, 637 μmol) and (3,5-difluoro-[1,T-biphenyl]- 4-yl)methanamine (160 mg, 701 μmol) in EtOH (7.0 mL). The reaction mixture was heated to 60 °C for 72 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100%0 EtOAc/isohexane) gave the title compound (250 mg, 0.24 mmol, 37% yield, 39% purity) as a brown solid.

UPLC/MS (Method 2): m/z 411 (M+H) ⁺ , R _T 2.51 min.

Step 2: tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3,5-d ifluoro-[1,T- biphenyl]-4-yl)methyl)carbamate DMAP (15 mg, 120 μmol) was added to a solution of 5-chloro-3-cyclopropyl-N-((3,5- difluoro-[1,T-biphenyl]-4-yl)methyl)pyrazolo[1,5-a]pyrimidin -7-amine (250 g, 237 μmol) and BOC-Anhydride (159 mg, 729 μmol) in anhydrous THF (6.0 ml_). The reaction mixture was heated at RT for 3 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) followed by purification on RP Flash C18 (24 g cartridge, 20-80% MeCN/10 nM ammonium bicarbonate) gave the title compound (71 mg, 0.13 mmol, 53% yield, 90% purity) as a green glass solid.

UPLC/MS (Method 2): m/z 455 (M-tBu+H) ⁺ , R _T 2.70 min.

Step 3: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)((3,5-difluoro-[1,T-bip henyl]-4- yl)methyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)((3,5-d ifluoro- [1,T-biphenyl]-4-yl)methyl)carbamate (71 mg, 0.14 mmol), tert-butyl (3R,4R)-4- (aminomethyl)-3-hydroxypiperidine-1-carboxylate (35 mg, 0.15 mmol) in THF (1.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (12 mg, 14 μmol) and LiHMDS (1M in THF) (180 mI_, 180 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2.5 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (89 mg, 0.12 mmol, 88% yield, 97% purity) as a brown glass solid.

UPLC/MS (Method 2): m/z 705 (M+H) ⁺ , R _T 2.53 min.

Step 4:

(3R,4R)-4-(((3-cyclopropyl-7-(((3,5-difluoro-[1,T-bipheny l]-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)p iperidin-3-ol

TFA (0.25 mL) was added to a mixture of tert-butyl (3R,4R)-4-(((7-((tert- butoxycarbonyl)((3,5-difluoro-[1,T-biphenyl]-4-yl)methyl)ami no)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hyd roxypiperidine-1-carboxylate (86 mg, 0.12 mmol) in DCM (0.75 mL). The reaction mixture was stirred at RT for 3 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 mL) to give the title compound (35 mg, 66 μmol, 54% yield, 95% purity) as an off-white solid. UPLC/MS (Method 2): m/z 505 (M+H) ⁺ , RT 1.34 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.80 - 7.72 (m, 2H), 7.52 - 7.38 (m, 7H), 6.90 - 6.81 (m, 1 H), 5.33 (s, 1 H), 5.32 - 5.24 (m, 1 H), 4.54 (d, J = 6.0 Hz, 2H), 3.59 - 3.46 (m, OH), 3.28 - 3.20 (m, 1H), 3.11 - 3.01 (m, 1H), 2.92 (dd, J = 11.8, 4.5 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.40 - 2.26 (m, 1H), 2.17 (t, J = 10.7 Hz, 1H), 1.74 - 1.66 (m, 1 H), 1.65 - 1.55 (m, 1H), 1.43 - 1.32 (m, 1H), 1.23 - 1.12 (m, 1H), 0.80 - 0.70 (m, 2H), 0.68 - 0.58 (m, 2H). 2H under water.

Synthesis 094

(2,6-difluoro-4-(pyridin-2-yl)phenyl)methanamine

Step A:

(2,6-difluoro-4-(pyridin-2-yl)phenyl)methanamine

(4-Bromo-2,6-difluorophenyl)methanamine (210 mg, 946 μmol), phenylboronic acid (138 mg, 1.13 mmol), Pd(dppf)Cl2 (69 mg, 95 μmol) and potassium carbonate (261 mg, 1.89 mmol) were taken up in THF (9.0 ml_) and Water (1.0 ml_). The reaction mixture was sparged with N2 for 5 min then heated at 60 °C for 2 h then allowed to cool to RT. The mixture was diluted with DCM (30 ml_) and water (30 ml_). The layers were separated and the aq. layer was extracted with DCM (2 x 30 ml_). The combined organic layers were dried over MgSCU, filtered then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (160 mg, 0.70 mmol, 74% yield, 96% purity) as a white solid.

UPLC/MS (Method 2): /z 220 (M+H) ⁺ , R _T 1.03 min.

Synthesis 095

3-cyclopropyl- N-(4-(pyridin-2-yl)benzyl)-5-(4,7-diazaspiro[2.5]octan-7-yl) pyrazolo[1, 5- a]pyrimidin-7-amine

Step 3: tert-butyl 7-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-4,7-diazaspiro[2.5 ]octane-4-carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl 4- carbamoylpiperidine-1-carboxylate (48 g, 210 μmol) and cesium carbonate (274 mg,

840 μmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd-171 (13.9 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (60 mg, 88 μmol, 42% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 668 (M+H) ⁺ , RT 2.36 min.

Step 4:

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(4,7-diazaspir o[2.5]octan-7-yl)pyrazolo[1,5- a]pyrimidin-7-amine

Hydrogen chloride (4 M in dioxane) (1.20 ml_, 4.9 mmol) was added to a solution of tert- butyl 7-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5- a]pyrimidin-5-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate (60 mg, 92 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 mL). The ammoniacal methanol solution was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (17 mg, 37 μmol, 40% yield, 97% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 452 (M+H) ⁺ , RT 1.17 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.61 (m, 1 H), 8.03 (d, J = 8.3 Hz, 2H), 7.95 - 7.87 (m, 2H), 7.86 (td, J = 7.6, 1.8 Hz, 1 H), 7.58 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 - 7.29 (m, 1 H), 5.45 (s, 1 H), 4.59 (d, J = 6.4 Hz, 2H), 3.51 - 3.44 (m, 2H), 2.77 - 2.71 (m, 2H), 1.76 (tt, J = 8.1, 5.4 Hz, 1H), 0.80 - 0.68 (m, 4H), 0.42 - 0.32 (m, 4H). 3H under water.

Synthesis 096

(S)-4-amino-1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)a mino)pyrazolo[1,5-a]pyrimidin-5- yl)pyrrolidin-2-one

Step 3: tert-butyl (S)-(5-(4-amino-2-oxopyrrolidin-1-yl)-3-cyclopropylpyrazolo[ 1,5-a]pyrimidin-7- yl)(4-(pyridin-2-yl)benzyl)carbamate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), (S)-4- aminopyrrolidin-2-one (84 mg, 840 μmol) and cesium carbonate (274 mg, 840 μmol) in dioxane (2.6 mL) was degassed with N2 for 5 min. Pd-171 (13.6 mg, 21.0 μmol) and Ruphos (9.8 mg, 21.0 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (40 mg, 73 μmol, 35% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 540 (M+H) ⁺ , RT 1.36 min. Step 4:

(S)-4-amino-1-(3-cyclopropyl-7-((4-(pyridin-2-yl)benzyl)a mino)pyrazolo[1,5-a]pyrimidin-5- yl)pyrrolidin-2-one

Hydrogen chloride (4 M in dioxane) (0.74 ml_, 3.0 mmol) was added to a solution of tert- butyl (S)-(5-(4-amino-2-oxopyrrolidin-1-yl)-3-cyclopropylpyrazolo[ 1,5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate (40 mg, 74 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (18 mg, 41 μmol, 55% yield, 99% purity) as a white solid.

UPLC/MS (Method 2): m/z 440 (M+H) ⁺ , RT 1.07 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.62 (m, 1H), 8.52 (t, J = 6.4 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.87 (dd, J = 7.6, 1.9 Hz, 1 H), 7.83 (s, 1 H), 7.47 (d, J = 8.3 Hz, 2H), 7.36 - 7.30 (m, 1 H), 7.20 (s, 1 H), 4.58 (d, J = 6.3 Hz, 2H), 3.99 (dd, J = 11.4, 6.1 Hz, 1H), 3.71 (dd, J = 11.3, 3.4 Hz, 1H), 3.59 - 3.52 (m, 1H), 2.75 (dd, J = 16.8, 6.9 Hz, 1H), 2.21 (dd, J = 16.8, 3.9 Hz, 1H), 2.09 - 1.93 (m, 2H), 1.92 - 1.83 (m, 1H), 0.84 (d, J = 8.5 Hz, 4H).

Synthesis 097

3-cyclopropyl-5-(1 H-pyrazol-5-yl)-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyr imidin-7- amine

Step 3: tert-butyl (3-cyclopropyl-5-(1 H-pyrazol-5-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate A mixture of 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (44 g, 227 μmol), tert- butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (90 mg, 189 μmol) (prepared as described herein) and Pd(dppf)Cl2 (27.7 mg, 37.8 μmol) in dioxane (3.0 ml_) was sparged with N2 for 5 min. A solution of Potassium phosphate, tribasic (120 mg, 567 μmol) in water (0.75 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (102 mg, 0.19 mmol, 76% yield, 96% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 508 (M+H) ⁺ , R _T 1.79 min.

Step 4:

3-cyclopropyl-5-(1 H-pyrazol-5-yl)-N-(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyr imidin-7- amine

Hydrogen chloride (4 M in dioxane) (0.96 ml_, 3.8 mmol) was added to a solution of tert- butyl (3-cyclopropyl-5-(1 H-pyrazol-5-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (101 mg, 191 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1.5 h then hydrogen chloride (125 M in MeOH) (2.0 ml_, 2.5 mmol) was added and the reaction mixture was stirred at 40 °C for 2 h then concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH3 in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 ml_) to give the title compound (63 mg, 151 μmol, 80% yield, 99% purity) as a tan solid.

UPLC/MS (Method 3): m/z 408 (M+H) ⁺ , RT 1.42 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) - 0.80/0.20 mixture of tautomers - d 13.43 (s, 0.2H), 12.99 (s, 0.8H), 8.69 - 8.59 (m, 1.2H), 8.58 - 8.45 (m, 0.8H), 8.09 - 8.01 (m, 2H), 7.96 - 7.81 (m, 3.2H), 7.78 (s, 0.8H), 7.61 - 7.45 (m, 2H), 7.32 (ddd, J = 7.3, 4.8, 1.2 Hz, 1H), 6.91 - 6.74 (m, 1 H), 6.57 (s, 1 H), 4.72 (d, J = 6.4 Hz, 2H), 2.09 - 1.93 (m, 1 H), 0.97 - 0.79 (m, 4H).

¹ H NMR (400 MHz, DMSO-d ₆ ) - VT at 90 °C - d 13.40 - 12.40 (m, 1 H), 8.69 - 8.59 (m,

1 H), 8.15 - 8.00 (m, 3H), 7.90 - 7.79 (m, 3H), 7.75 - 7.61 (m, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.30 (ddd, J = 7.3, 4.8, 1.4 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1 H), 6.61 (s, 1H), 4.75 (d, J = 6.4 Hz, 2H), 2.09 - 1.98 (m, 1 H), 0.97 - 0.85 (m, 4H). Synthesis 098

5-(3,6-diazabicyclo[3.1.1 ]heptan-3-yl)-3-cyclopropyl-N-(4-(pyridin-2- yl)benzyl)pyrazolo[1 ,5-a]pyrimidin-7-amine

Step 3: tert-butyl 3-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-diazabicyclo[3 .1.1]heptane-6-carboxylate

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (106 mg, 209 μmol) (prepared as described herein), 6-(tert- Butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (87.38 g, 419 μmol) and cesium carbonate (136 mg, 419 μmol) in dioxane (2.7 ml_) was degassed with N2 for 5 min. Pd- 171 (20.8 mg, 31.4 μmol) and Ruphos (14.7 mg, 31.4 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 8 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (20 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (72 mg, 0.11 mmol, 50% yield, 94% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 638 (M+H) ⁺ , RT 2.11 min.

Step 4:

5-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-3-cyclopropyl-N-(4 -(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine

Hydrogen chloride (4 M in dioxane) (0.56 ml_, 2.2 mmol) was added to a solution of tert- butyl 3-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5- a]pyrimidin-5-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxyla te (71 mg, 0.11 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1.5 h then hydrogen chloride (1.25 M in MeOH) (2.0 ml_, 2.5 mmol). The reaction mixture was stirred at 40 °C for 1 h then concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by RP preparative HPLC (30- 100% MeCN/0.3% NH3 in water) gave the title compound (17 mg, 39 μmol, 35% yield, 98% purity) as an off-white solid.

UPLC/MS (Method 5): m/z 438 (M+H) ⁺ , RT 1.22 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.64 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.99 (t, J = 6.6 Hz, 1 H), 7.92 (dt, = 8.1 , 1.2 Hz, 1H), 7.86 (td, J = 7.7, 1.9 Hz, 1 H),

7.60 (s, 1 H), 7.51 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 5.31 (s, 1 H),

4.61 (d, J = 6.4 Hz, 2H), 3.62 (d, J = 6.0 Hz, 2H), 3.59 - 3.48 (m, 4H), 2.47 - 2.40 (m,

1 H), 1.83 - 1.73 (m, 1H), 1.67 - 1.58 (m, 1H), 1.38 (d, J = 8.5 Hz, 1 H), 0.81 - 0.71 (m, 4H).

Synthesis 099

7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-5-((((3R,4R)-3-hydroxypiperid in-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Step 1 :

7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-5-chloropyrazolo[1,5-a]pyrimi dine-3-carbonitrile

DIPEA (1.01 ml_, 5.77 mmol) was added to a solution of 5,7-dichloropyrazolo[1,5- a]pyrimidine-3-carbonitrile (205 mg, 0.96 mmol) and [1,T-biphenyl]-4-ylmethanamine (218 mg, 1.16 mmol) in EtOH (3.6 ml_). The reaction mixture was heated to 65 °C overnight. The solid was collected by filtration and triturated in ice-cold EtOH (5 ml_) then Et ₂ O (3 x 8 ml_) to give the title compound (343 mg, 0.89 mmol, 92% yield, 93% purity) as a beige solid. UPLC/MS (Method 3): m/z 360 (M+H) ⁺ , R _T 1.76 min.

Step 2: tert-butyl (3R,4R)-4-(((7-(([1,T-biphenyl]-4-ylmethyl)amino)-3-cyanopyr azolo[1 ,5- a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxy late

A solution of 7-(([1 , 1 '-biphenyl]-4-ylmethyl)amino)-5-chloropyrazolo[1 ,5-a]pyrimidine-3- carbonitrile (170 g, 444 μmol), tert-butyl (3R,4R)-4-(aminomethyl)-3-hydroxypiperidine- 1-carboxylate (205 mg, 888 μmol) and DIPEA (0.23 ml_, 1.33 mmol) in NMP (2.0 ml_) was heated under microwave irradiation at 120 °C for 2.5 h. At RT, the reaction mixture was precipitated from the addition of water (5 ml_). The solid was collected by filtration rinsing with water (2 x 2 ml_). Purification on RP Flash C18 (24 g cartridge, 0-100% MeCN/10 nM ammonium bicarbonate) gave the title compound (197 mg, 0.34 mmol, 77% yield, 96% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 498 (M-tBu+H) ⁺ , R _T 2.15 min.

Step 3:

7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-5-((((3R,4R)-3-hydroxypiperid in-4- yl)methyl)amino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile

Hydrogen chloride (4 M in dioxane) (1.76 ml_, 7.04 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-(([1,T-biphenyl]-4-ylmethyl)amino)-3-cyanopyr azolo[1,5-a]pyrimidin- 5-yl)amino)methyl)-3-hydroxypiperidine-1-carboxylate (195 mg, 352 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1.5 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 2 ml_) to give the title compound (139 mg, 0.30 mmol,

85% yield, 98% purity) as an off-white solid.

UPLC/MS (Method 4): m/z 454 (M+H) ⁺ , RT 1.37 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.44 - 8.29 (m, 1H), 8.27 (s, 1H), 7.71 - 7.58 (m, 4H), 7.53 - 7.39 (m, 4H), 7.39 - 7.31 (m, 1H), 7.29 - 7.17 (m, 1H), 5.42 (s, 1H), 4.78 (d, J =

5.1 Hz, 1H), 4.59 - 4.42 (m, 2H), 3.55 - 3.43 (m, 1 H), 3.14 - 3.04 (m, 1H), 2.93 (dd, J = 11.5, 4.5 Hz, 1H), 2.84 - 2.72 (m, 1H), 2.34 - 2.22 (m, 1H), 2.16 (t, J = 10.7 Hz, 1H), 1.69 - 1.58 (m, 1H), 1.42 - 1.31 (m, 1H), 1.13 - 0.98 (m, 1H). 2H under water. Synthesis 100

(3R,4R)-4-(((7-(([1 , T-biphenyl]-4-ylmethyl)amino)-3-ethylpyrazolo[1 ,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

N-([1,T-biphenyl]-4-ylmethyl)-5-chloro-3-ethylpyrazolo[1, 5-a]pyrimidin-7-amine

DIPEA (0.99 ml_, 5.70 mmol) was added to a solution of 5,7-dichloro-3-ethylpyrazolo[1,5- a]pyrimidine (205 mg, 0.95 mmol) and [1,T-biphenyl]-4-ylmethanamine (215 mg, 1.14 mmol) in EtOH (3.6 ml_). The reaction mixture was heated to 65 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (329 mg, 0.82 mmol, 86% yield, 90% purity) as a yellow oil.

UPLC/MS (Method 2): m/z 363 (M+H) ⁺ , R _T 2.40 min.

Step 2: tert-butyl ([1 ,T-biphenyl]-4-ylmethyl)(3-ethyl-5-methylpyrazolo[1,5-a]pyri midin-7- yl)carbamate

DMAP (19.9 mg, 163 μmol) was added to a solution of N-([1 ,T-biphenyl]-4-ylmethyl)-5- chloro-3-ethylpyrazolo[1,5-a]pyrimidin-7-amine (329 mg, 816 μmol) and BOC-anhydride (267 mg, 1.22 mmol) in anhydrous THF (4.4 ml_). The reaction mixture was heated at 65 °C for 3 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (358 mg, 0.71 mmol, 87% yield, 92% purity) as a yellow oil.

UPLC/MS (Method 3): m/z 407 (M-tBu+H) ⁺ , R _T 2.30 min.

Step 3: tert-butyl (3R,4R)-4-(((7-(([1 , 1 '-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- ethylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypi peridine-1-carboxylate

A solution of tert-butyl ([1 ,T-biphenyl]-4-ylmethyl)(3-ethyl-5-methylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (170 mg, 338 μmol), (tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (93 g, 405 μmol) in THF (3.8 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (28.9 mg, 33.8 μmol) and LiHMDS (1M in THF) (405 pL, 405 μmol). The reaction was degassed for another 5 min before being heated to 65 °C for 4.5 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (127 mg, 0.18 mmol, 53% yield, 92% purity) as a tan oil.

UPLC/MS (Method 5): m/z 657 (M+H) ⁺ , R _T 2.12 min.

Step 4:

(3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-ethylpyrazolo[1,5-a]pyrimid in-5- yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (1.05 ml_, 4.20 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- ethylpyrazolo[1 ,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxypiperidine-1-carb oxylate (127 mg, 0.18 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 3 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 2 ml_) to give the title compound (78 mg, 0.17 mmol, 94% yield, 98% purity) as a tan solid.

UPLC/MS (Method 4): m/z 457 (M+H) ⁺ , RT 1.16 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.91 (t, J = 6.5 Hz, 1 H), 7.68 - 7.60 (m, 5H), 7.49 - 7.40 (m, 4H), 7.38 - 7.31 (m, 1 H), 6.75 (t, J = 6.2 Hz, 1 H), 5.48 - 5.38 (m, 1 H), 5.20 (s, 1 H), 4.49 (d, J = 6.4 Hz, 2H), 3.63 - 3.46 (m, 1H), 3.21 - 3.11 (m, 1 H), 3.05 - 2.96 (m, 1H), 2.90 (dd, J = 11.5, 4.6 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.48 - 2.43 (m, 2H), 2.30 (dd, J = 13.4, 10.7 Hz, 1 H), 2.20 - 2.11 (m, 1H), 1.61 - 1.50 (m, 1H), 1.39 - 1.25 (m, 1 H), 1.17 (t, J = 7.5 Hz, 3H), 1.14 - 1.09 (m, 1H). 1 H under water. Synthesis 101

(3R,4R)-4-(((7-(([1,T-biphenyl]-4-ylmethyl)amino)-3-chlor opyrazolo[1,5-a]pyrimidin-5- yl)amino)methyl)piperidin-3-ol

Step 1 :

N-([1,T-biphenyl]-4-ylmethyl)-3,5-dichloropyrazolo[1,5-a] pyrimidin-7-amine

DIPEA (0.99 ml_, 5.70 mmol) was added to a solution of 3,5,7-trichloro [1,5-a]pyrimidine (235 mg, 0.95 mmol) and [1,1'-biphenyl]-4-ylmethanamine (215 mg, 1.14 mmol) in EtOH (3.6 ml_). The reaction mixture was heated to 65 °C overnight. The reaction mixture was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (349 mg, 0.88 mmol, 93% yield, 93% purity) as an orange oil.

UPLC/MS (Method 2): m/z 369 (M+H) ⁺ , R _T 2.33 min.

Step 2: tert-butyl ([1,T-biphenyl]-4-ylmethyl)(3,5-dichloropyrazolo[1,5-a]pyrim idin-7-yl)carbamate

DMAP (21.5 mg, 176 μmol) was added to a solution of N-([1,T-biphenyl]-4-ylmethyl)-3,5- dichloropyrazolo[1,5-a]pyrimidin-7-amine (349 mg, 879 μmol) and BOC-Anhydride (288 mg, 1.32 mmol) in anhydrous THF (4.6 ml_). The reaction mixture was heated at 65 °C for 3 h then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0- 100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (315 mg, 0.65 mmol, 74% yield, 97% purity) as a yellow oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.53 (s, 1H), 7.65 - 7.55 (m, 4H), 7.47 - 7.38 (m, 5H), 7.37 - 7.32 (m, 1H), 5.05 (s, 2H), 1.29 (s, 9H).

Step 3: tert-butyl (3R,4R)-4-(((7-(([1 , 1 '-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxyp iperidine-1-carboxylate

A solution of tert-butyl ([1 ,T-biphenyl]-4-ylmethyl)(3,5-dichloropyrazolo[1,5-a]pyrimidi n-7- yl)carbamate (155 mg, 320 μmol), (tert-butyl (3R,4R)-4-(aminomethyl)-3- hydroxypiperidine-1-carboxylate (89 g, 384 μmol) in THF (3.6 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (27.4 mg, 32.0 μmol) and LiHMDS (1M in THF) (384 pL, 384 μmol). The reaction was degassed for another 5 min before being heated to 65 °C for 4.5 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (172 mg, 0.24 mmol, 76% yield, 94% purity) as a brown oil.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 7.96 (s, 1H), 7.65 (td, J = 5.9, 3.1 Hz, 4H), 7.51 (s, 1 H), 7.45 (dd, J = 8.4, 6.9 Hz, 2H), 7.41 - 7.31 (m, 3H), 6.23 (s, 1 H), 5.14 (d, J = 5.0 Hz, 1 H), 4.86 (s, 2H), 4.00 (s, 1 H), 3.86 (s, 1 H), 3.59 (d, J = 13.4 Hz, 1 H), 3.13 (tt, J = 10.0, 5.0 Hz, 1 H), 1.71 (d, J = 13.2 Hz, 1H), 1.50 (d, J = 21.9 Hz, 1H), 1.37 (s, 9H), 1.31 (s, 9H), 1.16 - 1.03 (m, 2H). 2H under water.

Step 4:

(3R,4R)-4-(((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-chloropyrazolo[1,5-a]pyrimi din-5- yl)amino)methyl)piperidin-3-ol

Hydrogen chloride (4 M in dioxane) (1.05 ml_, 4.20 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-(([1 , 1 '-biphenyl]-4-ylmethyl)(tert-butoxycarbonyl)amino)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-hydroxyp iperidine-1-carboxylate (170 mg, 0.24 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 40 °C for 1.5 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 2 ml_) to give the title compound (103 mg, 0.22 mmol, 91% yield, 99% purity) as a beige solid.

UPLC/MS (Method 4): m/z 463 (M+H) ⁺ , RT 1.39 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.11 (t, J = 6.5 Hz, 1 H), 7.89 (s, 1 H), 7.64 (d, J = 8.0 Hz, 4H), 7.49 - 7.40 (m, 4H), 7.39 - 7.32 (m, 1 H), 6.97 (t, J = 5.9 Hz, 1 H), 5.31 (s, 1 H), 5.09 - 4.97 (m, 1 H), 4.50 (d, J = 6.2 Hz, 2H), 3.48 - 3.35 (m, 1H), 3.10 - 2.98 (m, 1H), 2.91 (dd, J = 11.7, 4.6 Hz, 1 H), 2.82 - 2.73 (m, 1H), 2.35 - 2.23 (m, 1H), 2.15 (t, J = 10.7 Hz, 1H), 1.63 - 1.53 (m, 1H), 1.39 - 1.28 (m, 1H), 1.18 - 1.04 (m, 1 H). 2H under water. Synthesis 102

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(2,6-diazaspir o[3.3]heptan-2-yl)pyrazolo[1,5- a]pyrimidin-7-amine

Step 3: tert-butyl (3-cyclopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyrazolo[1, 5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate / tert-butyl 6-(7-((tert-butoxycarbonyl)(4-(pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) -2,6-diazaspiro[3.3]heptane- 2-carboxylate (1:0.24)

A suspension of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin- 2-yl)benzyl)carbamate (80 mg, 168 μmol) (prepared as described herein), tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate, O.5Oxalic acid (164 g, 672 μmol) and cesium carbonate (438 mg, 1.34 mmol) in dioxane (2.6 ml_) was degassed with N2 for 5 min. Pd- 171 (11.2 mg, 16.8 μmol) and Ruphos (7.8 mg, 16.8 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave a mixture of tert-butyl (3-cyclopropyl-5-(2,6-diazaspiro[3.3]heptan-2-yl)pyrazolo[1, 5- a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate / tert-butyl 6-(7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyri midin-5-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate (1 :0.24) (80 mg, 136 μmol, 84% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 2): m/z 638 (M+H) ⁺ , RT 2.32 min; m/z 538 (M+H)+, RT 1.51 min.

Step 4:

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(2,6-diazaspir o[3.3]heptan-2-yl)pyrazolo[1,5- a]pyrimidin-7-amine TFA (0.5 mL) was added to a mixture of tert-butyl (3-cyclopropyl-5-(2,6- diazaspiro[3.3]heptan-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate / tert-butyl 6-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-2,6-diazaspiro[3.3 ]heptane-2-carboxylate (1 :0.24) (80 g, 136 μmol) in DCM (1.5 mL). The reaction mixture was stirred at RT for 4 h and concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (40 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (3 x 1 mL) to give the title compound (30 mg, 68 μmol, 54% yield, 99% purity) as a white solid.

UPLC/MS (Method 4): m/z 438 (M+H) ⁺ , RT 0.88 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.67 - 8.62 (m, 1H), 8.07 - 8.02 (m, 3H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (td, J = 7.6, 1.8 Hz, 1 H), 7.58 (s, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 7.33 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 5.05 (s, 1 H), 4.59 - 4.55 (m, 2H), 3.97 (s, 4H), 3.67 (s, 4H), 1.80 - 1.71 (m, 1 H), 0.80 - 0.73 (m, 2H), 0.72 - 0.66 (m, 2H). 1 H under water.

Synthesis 103

(S)-7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-5-(pyrrolidin-3-ylamino)pyraz olo[1,5- a]pyrimidine-3-carbonitrile

Step 2: tert-butyl (S)-3-((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-cyanopyrazolo[1,5-a]pyrimid in-5- yl)amino)pyrrolidine-1-carboxylate

A solution of 7-(([1 , 1 '-biphenyl]-4-ylmethyl)amino)-5-chloropyrazolo[1 ,5-a]pyrimidine-3- carbonitrile (70 mg, 183 μmol) (prepared as described herein), tert-butyl (S)-3- aminopyrrolidine-1-carboxylate (68 mg, 366 μmol) and DIPEA (50 pL, 0.29 mmol) in NMP (1.0 mL) was heated under microwave irradiation at 120 °C for 3 h. The reaction mixture was recharged with DIPEA (50 pL, 0.29 mmol) and heated under microwave irradiation at 120 °C for 1.5 h. The reaction mixture was recharged with tert-butyl (S)-3- aminopyrrolidine-1-carboxylate (17 g, 91 μmol), DIPEA (50 mI_, 0.29 mmol) and NMP (0.25 ml_) and heated under microwave irradiation at 120 °C for 2 h. At RT, the reaction mixture was precipitated from the addition of water (5 ml_). The solid was collected by filtration rinsing with water (2 x 2 ml_). Purification on RP Flash C18 (12 g cartridge, 0- 100% MeCN/10 nM ammonium bicarbonate) gave the title compound (62 mg, 0.11 mmol, 61% yield, 92% purity) as a tan glass solid.

UPLC/MS (Method 5): m/z 410 (M-Boc+H) ⁺ , R _T 1.89 min.

Step 3:

(S)-7-(([1 , 1 '-biphenyl]-4-ylmethyl)amino)-5-(pyrrolidin-3-ylamino)pyrazo lo[1 ,5- a]pyrimidine-3-carbonitrile

Hydrogen chloride (4 M in dioxane) (0.55 ml_, 2.2 mmol) was added to a solution of tert- butyl (S)-3-((7-(([1 ,T-biphenyl]-4-ylmethyl)amino)-3-cyanopyrazolo[1,5-a]pyrimid in-5- yl)amino)pyrrolidine-1-carboxylate (61 mg, 0.11 mmol) in dioxane (1.0 ml_). The reaction mixture was stirred at 35 °C for 3 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH3 in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (27 mg, 64 μmol, 58% yield, 98% purity) as a beige solid.

UPLC/MS (Method 5): m/z 410 (M+H) ⁺ , RT 1.51 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.42 - 8.30 (m, 1H), 8.28 (s, 1H), 7.68 - 7.61 (m, 5H), 7.48 - 7.41 (m, 5H), 7.40 - 7.32 (m, 2H), 5.30 (s, 1H), 4.58 - 4.44 (m, 2H), 4.39 - 4.15 (m, 1H), 3.02 - 2.90 (m, 1H), 2.86 - 2.77 (m, 1H), 2.77 - 2.68 (m, 1H), 2.00 - 1.89 (m,

1 H), 1.54 - 1.43 (m, 1 H).

Synthesis 104

(S)-7-((4-(pyridin-2-yl)benzyl)amino)-5-(pyrrolidin-3-yla mino)pyrazolo[1,5-a]pyrimidine-3- carbonitrile

Step 2: tert-butyl (S)-3-((3-cyano-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1, 5-a]pyrimidin-5- yl)amino)pyrrolidine-1-carboxylate

A solution of 5-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyr imidine-3- carbonitrile (80 mg, 217 μmol) (prepared as described herein), tert-butyl (S)-3- aminopyrrolidine-1-carboxylate (162 g, 869 μmol) and DIPEA (189 pL, 1.09 mmol) in NMP (1.0 ml_) was heated under microwave irradiation at 120 °C for 1 h. At RT, the reaction mixture was precipitated from the addition of water (5 ml_) to give the title compound (104 mg, 0.19 mmol, 88% yield, 94% purity) as an orange solid.

UPLC/MS (Method 5): m/z 411 (M-Boc+H) ⁺ , R _T 1.62 min.

Step 3:

(S)-7-((4-(pyridin-2-yl)benzyl)amino)-5-(pyrrolidin-3-yla mino)pyrazolo[1,5-a]pyrimidine-3- carbonitrile

Hydrogen chloride (4 M in dioxane) (0.96 ml_, 3.8 mmol) was added to a solution of tert- butyl (S)-3-((3-cyano-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1, 5-a]pyrimidin-5- yl)amino)pyrrolidine-1-carboxylate (104 mg, 191 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 3 h and concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (80 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (100 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification by column chromatography (4 g cartridge, 0-20% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (40 mg, 95 μmol, 50% yield, 98% purity) as an orange solid. UPLC/MS (Method 5): m/z 411 (M+H) ⁺ , RT 1.20 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.69 - 8.62 (m, 1H), 8.45 - 8.32 (m, 1H), 8.29 (s, 1 H), 8.06 (d, J = 8.3 Hz, 2H), 7.97 - 7.91 (m, 1 H), 7.87 (td, J = 7.7, 1.9 Hz, 1 H), 7.46 (d, J =

7.9 Hz, 2H), 7.41 - 7.29 (m, 2H), 5.28 (s, 1H), 4.62 - 4.46 (m, 2H), 4.39 - 4.19 (m, 1H),

3.00 (s, 1 H), 2.89 - 2.80 (m, 1 H), 2.80 - 2.70 (m, 1H), 2.03 - 1.91 (m, 1 H), 1.58 - 1.46 (m, 1 H). 2H under water.

Synthesis 105

3-cyclopropyl-N ⁵ -(((3R,4R)-3-methoxypiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

Step A: tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-met hoxypiperidine-1- carboxylate

To a mixture of tert-butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) amino)methyl)-3- hydroxypiperidine-1-carboxylate (300 mg, 448 μmol) (prepared as described herein) and tetrabutylammonium bromide (14.4 mg, 44.8 μmol) in toluene (3.0 ml_) was added an aq. solution of sodium hydroxide (12.5 M) (322 pL, 4.03 mmol) and iodomethane (252, 4.03 mmol). The reaction mixture was stirred at 50 °C for 3 h. At RT, water (30 ml_) and EtOAc (25 ml_) were added. The layers were separated and aq. layer was extracted with EtOAc (2 x 25 ml_). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (130 mg, 0.19 mmol, 42% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 5): m/z 684 (M+H) ⁺ , RT 2.11 min.

Step 4: 3-cyclopropyl-N ⁵ -(((3R,4R)-3-methoxypiperidin-4-yl)methyl)-N ⁷ -(4-(pyridin-2- yl)benzyl)pyrazolo[1,5-a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.48 ml_, 1.9 mmol) was added to a solution of tert- butyl (3R,4R)-4-(((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl )amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)methyl)-3-met hoxypiperidine-1- carboxylate (130 mg, 0.19 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at RT for 4 h then concentrated in vacuo. The solid was triturated in MeCN (3 ml_) and the solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (40 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (38 mg, 77 μmol, 41% yield, 98% purity) as a white solid.

UPLC/MS (Method 5): m/z 484 (M+H) ⁺ , RT 1.36 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 - 8.61 (m, 1 H), 8.05 (d, J = 8.3 Hz, 2H), 7.92 (dt, J = 8.2, 1.2 Hz, 1 H), 7.86 (td, J = 7.6, 1.8 Hz, 1 H), 7.81 (t, J = 6.4 Hz, 1 H), 7.53 (s, 1 H),

7.45 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.51 (t, J = 5.9 Hz, 1 H), 5.17 (s, 1 H), 4.53 - 4.47 (m, 2H), 3.56 - 3.47 (m, 1H), 3.27 (s, 3H), 3.25 - 3.20 (m, 1H), 3.19 - 3.11 (m, 1H), 2.90 (td, J = 9.2, 4.2 Hz, 1H), 2.84 - 2.77 (m, 1H), 2.39 - 2.28 (m, 1H), 2.19 (dd, J = 11.7, 9.2 Hz, 1 H), 1.81 - 1.64 (m, 2H), 1.59 - 1.48 (m, 1H), 1.19 - 1.06 (m, 1H), 0.80 - 0.70 (m, 4H). 1 H under water.

Synthesis 106

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(1 ,2,5,6-tetrahydropyridin-3-yl)pyrazolo[1,5- a]pyrimidin-7-amine

Step 3: tert-butyl 5-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)-3,6-dihydropyridin e-1(2H)-carboxylate A mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro- 1(2H)- pyridinecarboxylate (78 g, 252 μmol), tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5- a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein) and Pd(dppf)Cl2 (30.8 mg, 39.4 μmol) in dioxane (2.0 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (134 mg, 630 μmol) in water (0.50 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 90 °C for 6 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (137 mg, 0.21 mmol, 99% yield, 95% purity) as a yellow glass solid.

UPLC/MS (Method 4): m/z 623 (M+H) ⁺ , R _T 2.60 min.

Step 4:

3-cyclopropyl-N-(4-(pyridin-2-yl)benzyl)-5-(1 ,2,5,6-tetrahydropyridin-3-yl)pyrazolo[1,5- a]pyrimidin-7-amine

TFA (0.20 ml_) was added to a mixture of tert-butyl 5-(7-((tert-butoxycarbonyl)(4-(pyridin- 2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-y l)-3,6-dihydropyridine-1(2H)- carboxylate (27 mg, 43 μmol) in DCM (0.60 ml_). The reaction mixture was stirred at RT for 3 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (10 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (14 mg, 31 μmol, 73% yield, 95% purity) as a yellow solid.

UPLC/MS (Method 4): m/z 423 (M+H) ⁺ , RT 1.12 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.67 - 8.61 (m, 1 H), 8.35 (t, J = 6.6 Hz, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.92 (dt, J = 8.2, 1.2 Hz, 1 H), 7.89 - 7.82 (m, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.33 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.65 (t, J = 4.1 Hz, 1 H), 6.16 (s, 1H), 4.70 (d, J = 6.4 Hz, 2H), 3.63 - 3.59 (m, 2H), 2.77 (t, J = 5.7 Hz, 2H), 2.20 - 2.09 (m, 2H), 1.93 (p, J = 6.8 Hz, 1 H), 0.90 - 0.80 (m, 4H). 1 H under water. Svnthesis 107

(S)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)am ino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr imidin-

2-yl)benzyl)carbamate (100 g, 210 μmol) (prepared as described herein), tert-butyl (S)-

3-aminopiperidine-1-carboxylate (50 mg, 252 μmol) in THF (2.0 ml_) was degassed in

N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17.9 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction was degassed for another 5 min before being heated to 60 °C overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (59 mg, 92 μmol, 44% yield, 99% purity) as a yellow glass solid.

UPLC/MS (Method 4): m/z 641 (M+H) ⁺ , RT 2.44 min.

Step 4:

(S)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyrimidin-2-yl)benzyl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

TFA (0.25 ml_) was added to a mixture of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4- (pyrimidin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1 ,5-a]pyrimidin-5- yl)amino)piperidine-1-carboxylate (59 mg, 92 μmol) in DCM (0.75 ml_). The reaction mixture was stirred at RT for 4 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 ml_) to give the title compound (16 mg, 35 μmol, 38% yield, 97% purity) as an orange solid. UPLC/MS (Method 4): m/z 441 (M+H) ⁺ , RT 1.08 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 (d, J = 4.8 Hz, 2H), 8.36 (d, J = 8.4 Hz, 2H), 7.83 (t, J = 6.5 Hz, 1 H), 7.53 (s, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 4.9 Hz, 1 H), 6.41 (d, J = 7.8 Hz, 1 H), 5.11 (s, 1 H), 4.52 (d, J = 6.4 Hz, 2H), 3.78 - 3.66 (m, 1H), 3.05 - 2.95 (m,

1 H), 2.79 - 2.69 (m, 1H), 2.43 - 2.35 (m, 1H), 2.23 (dd, J = 11.7, 8.7 Hz, 1H), 1.86 - 1.71 (m, 2H), 1.61 - 1.51 (m, 1H), 1.44 - 1.19 (m, 2H), 0.80 - 0.69 (m, 4H). 1 H under water.

Synthesis 108

(S)-3-cyclopropyl-N ⁷ -(4-(pyrimidin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyrimidin-2-yl)benzyl)am ino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr imidin-

2-yl)benzyl)carbamate (100 mg, 210 μmol) (prepared as described herein), tert-butyl (S)-

3-aminopyrrolidine-1-carboxylate (47 mg, 252 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (17.9 mg, 21.0 μmol) and LiHMDS (1M in THF) (273 pL, 273 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2 h then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (61 mg, 97 μmol, 46% yield, 99% purity) as a yellow glass solid.

UPLC/MS (Method 4): m/z 627 (M+H) ⁺ , RT 2.39 min.

Step 4:

(S)-3-cyclopropyl-N ⁷ -(4-(pyrimidin-2-yl)benzyl)-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine TFA (0.25 mL) was added to a mixture of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4- (pyrimidin-2-yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]py rimidin-5- yl)amino)pyrrolidine-1-carboxylate (61 g, 97 μmol) in DCM (0.75 mL). The reaction mixture was stirred at RT for 3 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH3 in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 1 mL). Purification on RP Flash C18 (12 g cartridge, 20-100% MeCN/10 mM ammonium bicarbonate) gave to give the title compound (7 mg, 20 μmol, 20% yield, 95% purity) as a tan solid.

UPLC/MS (Method 4): m/z 427 (M+H) ⁺ , RT 1.08 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 (d, J = 4.9 Hz, 2H), 8.36 (d, J = 8.3 Hz, 2H), 7.86 (t, J = 6.4 Hz, 1 H), 7.56 (s, 1 H), 7.48 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1 H), 6.63 (d, J = 6.5 Hz, 1H), 5.07 (s, 1H), 4.52 (d, J = 6.3 Hz, 2H), 4.21 - 4.09 (m, 1H), 2.97 (dd, J = 11.1, 6.4 Hz, 1 H), 2.80 (dt, J = 10.8, 7.5 Hz, 1H), 2.75 - 2.69 (m, 1H), 2.01 - 1.87 (m, 1H), 1.81 - 1.70 (m, 1 H), 1.54 - 1.42 (m, 1 H), 0.84 - 0.69 (m, 4H). 2H under water.

Synthesis 109

(S)-N ⁷ -(4-(1 H-pyrazol-1-yl)benzyl)-3-cyclopropyl-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1 ,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-(4-(1 H-pyrazol-1-yl)benzyl)(3-cyclopropyl-5-(pyrrolidin-3- ylamino)pyrazolo[1,5-a]pyrimidin-7-yl)carbamate

A suspension of tert-butyl (4-(1 H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (150 mg, 323 μmol) (prepared as described herein), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (180 mg, 968 μmol) and cesium carbonate (315 mg, 968 μmol) in dioxane (4.0 mL) was degassed with N2 for 5 min. Pd-171 (21.4 mg, 32.3 μmol) and Ruphos (15.1 mg, 32.3 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (30 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) followed by further purification by column chromatography (12 g cartridge, 0-20% EtOAc/DCM) gave the title compound (27 mg, 44 μmol, 14% yield, 99% purity) as a yellow glass solid.

LCMS (Method 7): m/z 615 (M+H) ⁺ , RT 2.72 min.

Step 4:

(S)-N ⁷ -(4-(1 H-pyrazol-1-yl)benzyl)-3-cyclopropyl-N ⁵ -(pyrrolidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

TFA (0.13 ml_) was added to a mixture of tert-butyl (S)-(4-(1 H-pyrazol-1-yl)benzyl)(3- cyclopropyl-5-(pyrrolidin-3-ylamino)pyrazolo[1,5-a]pyrimidin -7-yl)carbamate (27 mg, 44 μmol) in DCM (2.0 ml_). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 2 ml_) to give the title compound (18 mg, 42 μmol, 95% yield, 96% purity) as an off-white solid.

LCMS (Method 7): m/z 415 (M+H) ⁺ , RT 1.02 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.44 (d, J = 2.5 Hz, 1H), 7.92 (t, J = 6.4 Hz, 1 H), 7.81 - 7.77 (m, 2H), 7.71 (d, J = 1.7 Hz, 1 H), 7.56 (s, 1 H), 7.50 (d, J = 8.5 Hz, 2H), 6.54 - 6.49 (m, 1 H), 5.12 (s, 1 H), 4.56 (d, J = 6.5 Hz, 2H), 3.55 - 3.42 (m, 3H), 3.11 - 3.01 (m, 1H), 2.05 - 1.96 (m, 1H), 1.79 - 1.72 (m, 1H), 1.71 - 1.61 (m, 1H), 0.80 - 0.70 (m, 4H). 3H under water.

Synthesis 110

(S)-5-(piperidin-3-ylamino)-7-((4-(pyridin-2-yl)benzyl)am ino)pyrazolo[1,5-a]pyrimidine-3- carbonitrile

Step 2: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- cyanopyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carbox ylate

A suspension of 5-chloro-7-((4-(pyridin-2-yl)benzyl)amino)pyrazolo[1,5-a]pyr imidine-3- carbonitrile (200 mg, 554 μmol) (prepared as described herein), tert-butyl (S)-3- aminopiperidine-1-carboxylate (333 g, 1.66 mmol) and cesium carbonate (542 mg, 1.66 mmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (18.4 mg, 27.7 μmol) and Ruphos (15.5 mg, 33.3 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C overnight then 105 °C for 24 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (60 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (170 mg, 0.31 mmol, 56% yield, 95% purity) as a brown oil.

UPLC/MS (Method 5): m/z 425 (M-Boc+H) ⁺ , R _T 1.69 min.

Step 3:

(S)-5-(piperidin-3-ylamino)-7-((4-(pyridin-2-yl)benzyl)am ino)pyrazolo[1,5-a]pyrimidine-3- carbonitrile

TFA (1.5 ml_) was added to a mixture of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4- (pyridin-2-yl)benzyl)amino)-3-cyanopyrazolo[1,5-a]pyrimidin- 5-yl)amino)piperidine-1- carboxylate (170 mg, 324 μmol) in DCM (6.0 ml_). The reaction mixture was stirred at RT overnight then concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-20% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (15 g cartridge, 15-55% MeCN/10 mM ammonium bicarbonate) gave the title compound (41 mg, 93 μmol, 29% yield, 96% purity) as an off-white solid.

UPLC/MS (Method 5): m/z 425 (M+H) ⁺ , R _T 1.30 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.65 (dt, J = 5.0, 1.3 Hz, 1H), 8.39 - 8.28 (m, 1H), 8.27 (s, 1H), 8.06 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.87 (td, J = 7.7, 1.8 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2H), 7.34 (ddd, J = 7.3, 4.8, 1.2 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 5.33 (s, 1 H), 4.64 - 4.42 (m, 2H), 3.98 - 3.77 (m, 1H), 3.05 - 2.91 (m, 1H), 2.74 (dt, J = 12.1, 3.9 Hz, 1H), 2.35 (s, 1H), 2.26 (dd, J = 11.6, 9.0 Hz, 1H), 1.88 - 1.73 (m, 1H), 1.63 - 1.52 (m, 1 H), 1.45 - 1.21 (m, 2H). 1 H under water.

Synthesis 111

(S)-3-chloro-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-5,7 - diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carbo xylate

A suspension of tert-butyl (3,5-dichloropyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2- yl)benzyl)carbamate (prepared as described herein) (200 mg, 425 μmol), tert-butyl (S)-3- aminopiperidine-1-carboxylate (255 mg, 1.28 mmol) and cesium carbonate (416 mg, 1.28 mmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (14.1 mg, 21.3 μmol) and Ruphos (11.9 mg, 25.5 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C overnight. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (60 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH (containing 0.7 M NH ₃ )/DCM) gave the title compound (220 mg, 0.28 mmol, 67% yield, 82% purity) as a brown oil. UPLC/MS (Method 5): m/z 635 (M+H) ⁺ , R _T 2.11 min.

Step 4:

(S)-3-chloro-N ⁵ -(piperidin-3-yl)-N ⁷ -(4-(pyridin-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-5,7 - diamine

Hydrogen chloride (4 M in dioxane) (1.58 ml_, 6.31 mmol) was added to a solution of of tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amin o)-3- chloropyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1-carbo xylate (400 mg, 631 μmol) in dioxane (2.0 ml_). The reaction was stirred at 35 °C for 9 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (40 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification on RP Flash C18 (15 g cartridge, 0-100% MeCN/10 mM ammonium bicarbonate) followed by purification by chromatography on silica gel (24 g cartridge, 0-10% (0.7 M NH3/MeOH)/TBME) afford the title compound (99 mg, 0.23 mmol, 36% yield, 99% purity) as a white solid.

UPLC/MS (Method 5): m/z 435 (M+H) ⁺ , R _T 1.39 min.

¹ H NMR (500 MHz, DMSO-d ₆ ) d 8.68 - 8.63 (m, 1 H), 8.10 - 8.04 (m, 3H), 7.94 (d, J = 8.0 Hz, 1 H), 7.91 - 7.84 (m, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.34 (dd, J = 7.4, 4.8 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1 H), 5.23 (s, 1 H), 4.52 (d, J = 5.9 Hz, 2H), 3.02 - 2.96 (m, 1 H), 2.78 - 2.70 (m, 1 H), 2.43 - 2.35 (m, 1H), 2.28 - 2.20 (m, 1H), 2.14 - 2.05 (m, 1H), 1.84 - 1.78 (m,

1 H), 1.60 - 1.54 (m, 1 H), 1.41 - 1.22 (m, 2H). 1 H under water.

Synthesis 112

(S)-5-(piperidin-3-ylamino)-7-((4-(pyrimidin-2-yl)benzyl) amino)pyrazolo[1,5-a]pyrimidine-

3-carbonitrile Step 1 :

5-chloro-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1,5- a]pyrimidine-3-carbonitrile

DIPEA (0.40 mL, 2.3 mmol) was added to a solution of 5,7-dichloropyrazolo[1,5- a]pyrimidine-3-carbonitrile (99 mg, 0.46 mmol) and (4-(pyrimidin-2- yl)phenyl)methanamine (86 mg, 0.46 mmol) in EtOH (2.0 mL). The reaction mixture was heated to 50 °C for 2 h. The reaction mixture was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (97 mg, 0.26 mmol, 57% yield, 98% purity) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 9.57 (s, 1H), 8.89 (d, J = 4.9 Hz, 2H), 8.72 (d, J = 1.2 Hz, 1 H), 8.37 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 4.9 Hz, 1H), 6.58 (s,

1 H), 4.77 (s, 2H).

Step 2: tert-butyl (S)-3-((3-cyano-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[ 1,5-a]pyrimidin-5- yl)amino)piperidine-1-carboxylate

A solution 5-chloro-7-((4-(pyrimidin-2-yl)benzyl)amino)pyrazolo[1 ,5-a]pyrimidine-3- carbonitrile (97 mg, 0.26 mmol), tert-butyl (S)-3-aminopiperidine-1-carboxylate (210 mg, 1.1 mmol) and DIPEA (0.18 mL, 1.1 mmol) in NMP (2.0 mL) was heated under microwave irradiation at 120 °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 (77 mg, 0.14 mmol, 54% yield, 97% purity) as a white solid.

UPLC/MS (Method 4): m/z 526 (M+H) ⁺ , R _T 1.99 min.

Step 3:

(S)-5-(piperidin-3-ylamino)-7-((4-(pyrimidin-2-yl)benzyl) amino)pyrazolo[1,5-a]pyrimidine-

3-carbonitrile

TFA (0.5 mL) was added to a mixture of tert-butyl (S)-3-((3-cyano-7-((4-(pyrimidin-2- yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidi ne-1-carboxylate (77 mg,

0.14 mmol) in DCM (1.5 mL). The reaction mixture was stirred at RT for 3 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (30 mL) and the product was eluted with 0.7 M NH ₃ in MeOH (30 mL). The ammoniacal methanol solution was concentrated in vacuo. Further purification on RP Flash C18 (12 g cartridge, 20-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (35 mg, 80 μmol, 57% yield, 97% purity) as a white solid.

UPLC/MS (Method 5): m/z 426 (M+H) ⁺ , R _T 1.17 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.89 (d, J = 4.9 Hz, 2H), 8.37 (d, J = 8.3 Hz, 2H), 8.35 - 8.30 (m, 1H), 8.28 (s, 1 H), 7.50 (d, J = 8.0 Hz, 2H), 7.43 (t, J = 4.8 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 4.60 - 4.48 (m, 2H), 4.03 - 3.71 (m, 1 H), 3.06 - 2.90 (m, 1H), 2.77 - 2.69 (m, 1 H), 2.44 - 2.34 (m, 1H), 2.28 - 2.20 (m, 1 H), 1.87 - 1.73 (m, 1H), 1.63 - 1.49 (m, 1H), 1.45 - 1.19 (m, 2H). 1H under water.

Synthesis 113

3-cyclopropyl-5-(3-methyl-1H-pyrazol-4-yl)-N-(4-(pyridin- 2-yl)benzyl)pyrazolo[1,5- a]pyrimidin-7-amine

Step 3: tert-butyl (3-cyclopropyl-5-(3-methyl-1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyrimidin-7-yl)(4- (pyridin-2-yl)benzyl)carbamate

A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (66 g, 315 μmol), tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (125 mg, 263 μmol) (prepared as described herein) and Pd(dppf)Cl2 (28.8 mg, 39.4 μmol) in dioxane (3.0 ml_) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (167 mg, 788 μmol) in water (0.75 ml_) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-100% (EtOH in EtOAc 25:75)/isohexane) gave the title compound (130 mg, 0.20 mmol, 79% yield, 80% purity) as a yellow oil.

UPLC/MS (Method 5): m/z 522 (M+H) ⁺ , R _T 1.76 min.

Step 4:

3-cyclopropyl-5-(3-methyl-1H-pyrazol-4-yl)-N-(4-(pyridin- 2-yl)benzyl)pyrazolo[1,5- a]pyrimidin-7-amine TFA (1.0 mL) was added to a mixture of tert-butyl (3-cyclopropyl-5-(3-methyl-1 H-pyrazol- 4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)c arbamate (130 g, 249 μmol) in DCM (4.0 mL). The reaction mixture was stirred at RT overnight and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-20% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (49 mg, 0.11 mmol, 44% yield, 95% purity) as a white solid.

UPLC/MS (Method 5): m/z 422 (M+H) ⁺ , RT 1.27 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) - 0.65/0.35 mixture of tautomers - d 12.76 (s, 0.65H), 12.67 (s, 0.35H), 8.66 - 8.60 (m, 1H), 8.41 - 8.29 (m, 1H), 8.25 (s, 0.35H), 8.08 - 8.02 (m, 2H), 7.94 - 7.89 (m, 1.65), 7.88 - 7.81 (m, 2H), 7.60 - 7.46 (m, 2H), 7.32 (ddd, J = 7.4, 4.8, 1.2 Hz, 1 H), 6.29 (s, 0.35H), 6.25 (s, 0.65H), 4.76 - 4.66 (m, 2H), 2.54 (s, 2H), 2.47 (s, 1H), 2.00 - 1.89 (m, 1 H), 0.98 - 0.89 (m, 2H), 0.88 - 0.82 (m, 2H).

Synthesis 114

3-cyclopropyl-5-(2-methylpyridin-3-yl)-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl (3-cyclopropyl-5-(2-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimi din-7-yl)(4-(pyridin-2- yl)benzyl)carbamate

A mixture of 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyri dine (69.0 mg, 315 μmol), tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (125 mg, 263 μmol) (prepared as described herein) and Pd(dppf)Cl2 (28.8 mg, 39.4 μmol) in dioxane (3.0 mL) was sparged with N2 for 5 min. A solution of potassium phosphate, tribasic (167 mg, 788 μmol) in water (0.75 mL) was added and the reaction mixture was sparged with N2 for 5 min. The mixture was heated to 90 °C for 6 h. At RT, the reaction mixture was diluted with EtOAc (10 mL) and filtered through celite, rinsing with EtOAc (15 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH (containing 0.7 M NH3)/DCM) gave the title compound (130 mg, 0.23 mmol, 92% yield, 95% purity) as a yellow oil.

UPLC/MS (Method 5): m/z 533 (M+H) ⁺ , R _T 1.88 min.

Step 4:

3-cyclopropyl-5-(2-methylpyridin-3-yl)-N-(4-(pyridin-2-yl )benzyl)pyrazolo[1,5-a]pyrimidin-

7-amine

TFA (1.0 ml_) was added to a mixture of tert-butyl (3-cyclopropyl-5-(2-methylpyridin-3- yl)pyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyridin-2-yl)benzyl)car bamate (130 mg, 244 μmol) in DCM (4.0 ml_). The reaction mixture was stirred at RT overnight and concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-20% MeOH (containing 0.7 M NH3)/DCM) followed by further purification on RP Flash C18 (15 g cartridge, 30-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (59 mg, 0.13 mmol, 54% yield, 97% purity) as an off-white solid.

UPLC/MS (Method 5): m/z 422 (M+H) ⁺ , RT 1.27 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.69 (t, J = 6.6 Hz, 1 H), 8.66 - 8.62 (m, 1H), 8.48 (dd, J = 4.8, 1.8 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H), 7.92 (dt, = 8.1 , 1.2 Hz, 1H), 7.85 (td, J = 7.7, 1.9 Hz, 1 H), 7.77 (dd, J = 7.8, 1.8 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 2H), 7.35 - 7.28 (m, 2H), 6.22 (s, 1 H), 4.72 (d, J = 6.4 Hz, 2H), 2.43 (s, 3H), 2.02 - 1.92 (m, 1 H), 0.92 - 0.81 (m, 4H).

Synthesis 115

N-(4-(1 H-pyrazol-1-yl)benzyl)-5-(azetidin-3-yloxy)-3-cyclopropylpyr azolo[1,5-a]pyrimidin-

7-amine

Step 3: tert-butyl 3-((7-((4-(1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino )-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)oxy)azetidine-1-car boxylate

A suspension of tert-butyl (4-(1H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1 ,5- a]pyrimidin-7-yl)carbamate (150 mg, 323 μmol) (prepared as described herein), tert-butyl 3-hydroxyazetidine-1-carboxylate (168 g, 968 μmol) and cesium carbonate (315 mg,

968 μmol) in dioxane (4.0 ml_) was degassed with N2 for 5 min. Pd-171 (21.4 mg, 32.3 μmol) and Ruphos (15.1 mg, 32.3 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 5 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (30 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-50% EtOAc/isohexane) gave the title compound (180 mg, 299 μmol, 93% yield, 99% purity) as a yellow glass solid.

LCMS (Method 7): m/z 602 (M+H) ⁺ , RT 2.35 min.

Step 4:

N-(4-(1H-pyrazol-1-yl)benzyl)-5-(azetidin-3-yloxy)-3-cycl opropylpyrazolo[1,5-a]pyrimidin-

7-amine

At 0 °C, TFA (0.9 ml_) was added to a mixture of tert-butyl 3-((7-((4-(1H-pyrazol-1- yl)benzyl)(tert-butoxycarbonyl)amino)-3-cyclopropylpyrazolo[ 1,5-a]pyrimidin-5- yl)oxy)azetidine-1-carboxylate (180 mg, 299 μmol) in DCM (2.0 ml_). The reaction mixture was stirred at 0 °C for 1 h then RT for 4 h. More TFA (0.1 ml_) was added. The reaction mixture was stirred for 30 min then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo and the solid was triturated in Et ₂ O (2 x 2 ml_) to give the title compound (22 mg, 52 μmol, 17% yield, 95% purity) as an off-white solid.

LCMS (Method 7): m/z 402 (M+H) ⁺ , RT 1.25 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.44 (d, J = 2.5 Hz, 1H), 8.39 (t, J= 6.6 Hz, 1H), 7.81 - 7.76 (m, 3H), 7.72 (d, J = 1.8 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 2H), 6.54 - 6.50 (m, 1 H), 5.40 (s, 1 H), 5.28 (p, J = 6.4 Hz, 1 H), 4.56 (d, J = 6.4 Hz, 2H), 3.72 - 3.66 (m, 2H), 3.51 - 3.45 (m, 2H), 1.84 - 1.76 (m, 1 H), 0.83 - 0.78 (m, 4H). 1 H under water. Synthesis 116

(S)-3-cyclopropyl-N ⁵ -(pyrrolidin-3-yl)-N ⁷ -(4-(thiazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine-

5,7-diamine

Step 3: tert-butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate

A solution of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(thi azol-2- yl)benzyl)carbamate (80 g, 166 μmol) (prepared as described herein), tert-butyl (S)-3- aminopyrrolidine-1-carboxylate (62 mg, 332 μmol) in THF (2.0 ml_) was degassed in N2 for 5 min before adding ‘BuBrettPhos Pd G3 (14.2 mg, 16.6 μmol) and LiHMDS (1M in THF) (249 pL, 249 μmol). The reaction was degassed for another 5 min before being heated to 60 °C for 2 h. At RT, the reaction mixture was diluted with EtOAc (5 ml_) and filtered through celite, rinsing with EtOAc (30 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (12 g cartridge, 0-10% MeOH/DCM) gave the title compound (50 mg, 73 μmol, 44% yield, 92% purity) as a yellow solid.

LCMS (Method 8): m/z 632 (M+H) ⁺ , RT 2.26 min.

Step 4:

(S)-3-cyclopropyl-N ⁵ -(pyrrolidin-3-yl)-N ⁷ -(4-(thiazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidine- 5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.79 ml_, 3.17 mmol) was added to a solution of tert- butyl (S)-3-((7-((tert-butoxycarbonyl)(4-(thiazol-2-yl)benzyl)amin o)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)pyrrolidine-1 -carboxylate (50 mg, 79.1 μmol) in dioxane (2.0 ml_). The reaction mixture was stirred at 35 °C for 4 h then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo. Purification on RP Flash C18 (15 g cartridge, 0-100% (0.1 % formic acid in MeCN)/(0.1% formic acid in water)) gave the title compound (25 mg, 57 μmol, 72% yield, 98% purity) as an orange solid.

UPLC/MS (Method 7): m/z 432 (M+H) ⁺ , RT 1.05 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.29 (s, 1H), 8.02 (t, J = 6.6 Hz, 1 H), 7.98 - 7.89 (m,

3H), 7.77 (d, J = 3.3 Hz, 1 H), 7.59 (s, 1H), 7.54 - 7.49 (m, 2H), 7.19 - 6.46 (m, 1H), 5.14 (s, 1 H), 4.60 (d, J = 6.5 Hz, 2H), 3.69 - 3.61 (m, 1 H), 3.59 - 3.52 (m, 1 H), 3.51 - 3.45 (m, 1 H), 3.25 - 3.21 (m, 1H), 2.15 - 2.05 (m, 1 H), 1.84 - 1.73 (m, 2H), 0.81 - 0.73 (m, 4H).

1 H under water.

Synthesis 117

(S)-N ⁷ -(4-(1H-pyrazol-1-yl)benzyl)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Step 3: tert-butyl (S)-3-((7-((4-(1H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)a mino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate

A suspension of tert-butyl (4-(1 H-pyrazol-1-yl)benzyl)(5-chloro-3-cyclopropylpyrazolo[1,5- a]pyrimidin-7-yl)carbamate (140 mg, 256 μmol) (prepared as described herein), tert-butyl (S)-3-aminopiperidine-1-carboxylate (154 mg, 768 μmol) and cesium carbonate (250 mg, 768 μmol) in dioxane (4.0 ml_) was degassed with I ^for 5 min. Pd-171 (17.0 mg, 25.6 μmol) and Ruphos (11.9 mg, 25.6 μmol) were added and N2 was bubbled through the reaction mixture for another 5 min. The reaction mixture was stirred at 90 °C for 2 h. At RT, the reaction mixture was diluted with EtOAc (10 ml_) and filtered through celite, rinsing with EtOAc (30 ml_). The filtrate was concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-10% MeOH/DCM) gave the title compound (140 mg, 0.21 mmol, 84% yield, 96% purity) as a yellow solid. LCMS (Method 8): m/z 629 (M+H) ⁺ , RT 2.27 min.

Step 4:

(S)-N ⁷ -(4-(1 H-pyrazol-1-yl)benzyl)-3-cyclopropyl-N ⁵ -(piperidin-3-yl)pyrazolo[1,5- a]pyrimidine-5, 7-diamine

Hydrogen chloride (4 M in dioxane) (0.56 ml_, 2.23 mmol) was added to a solution of tert- butyl (S)-3-((7-((4-(1 H-pyrazol-1-yl)benzyl)(tert-butoxycarbonyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)amino)piperidine-1- carboxylate (140 mg, 0.22 mmol) in dioxane (2.0 ml_). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (20 ml_) and the product was eluted with 0.7 M NH ₃ in MeOH (20 ml_). The ammoniacal methanol solution was concentrated in vacuo to give the title compound (72 mg, 0.16 mmol, 72% yield, 95% purity) as a yellow solid.

LCMS (Method 7): m/z 429 (M+H) ⁺ , RT 1.05 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.45 (d, J = 2.5 Hz, 1 H), 7.83 - 7.77 (m, 3H), 7.72 (d, J = 1.8 Hz, 1 H), 7.53 (s, 1 H), 7.46 (d, J = 8.5 Hz, 2H), 6.53 (t, J = 2.2 Hz, 1 H), 6.42 (d, J = 7.7 Hz, 1H), 5.14 (s, 1 H), 4.47 (d, J = 6.4 Hz, 2H), 3.79 - 3.68 (m, 1 H), 3.04 - 2.99 (m, 1H), 2.77 - 2.71 (m, 1H), 2.45 - 2.37 (m, 1H), 2.26 (dd, J = 11.6, 8.6 Hz, 1 H), 1.83 (d, J = 12.1 Hz, 1 H), 1.80 - 1.71 (m, 1 H), 1.61 - 1.55 (m, 1H), 1.41 - 1.35 (m, 1H), 1.34 - 1.24 (m,

1 H), 0.81 - 0.70 (m, 4H). 1 H under water.

Synthesis 118

3-cyclopropyl-5-(piperidin-4-yl)-N-(4-(pyridin-2-yl)benzy l)pyrazolo[1,5-a]pyrimidin-7-amine

Step 3: tert-butyl 4-(7-((tert-butoxycarbonyl)(4-(pyridin-2-yl)benzyl)amino)-3- cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carbox ylate A mixture of tert-butyl (5-chloro-3-cyclopropylpyrazolo[1,5-a]pyrimidin-7-yl)(4-(pyr idin-2- yl)benzyl)carbamate (200 g, 420 μmol) (prepared as described herein), 1-(tert- butoxycarbonyl)piperidin-4-yl)zinc(ll) bromide (0.74M in THF) (2.84 ml_, 2.11 mmol), Pd(dppf)Cl ₂ (22.2 mg, 30.3 μmol) in THF (2.0 ml_) was sparged with N2 for 15 min before being heated to 50 °C for 2 h. At RT, the reaction mixture was quenched with MeOH (1 ml_) then concentrated in vacuo. Purification by column chromatography (24 g cartridge, 0-100% EtOAc/isohexane) gave the title compound (250 mg, 0.39 mmol, 92% yield, 98% purity) as a yellow solid.

UPLC/MS (Method 4): m/z 525 (M-Boc+H) ⁺ , RT 2.53 min.

Step 4:

3-cyclopropyl-5-(piperidin-4-yl)-N-(4-(pyridin-2-yl)benzy l)pyrazolo[1,5-a]pyrimidin-7-amine

TFA (1.0 ml_) was added to a mixture of tert-butyl 4-(7-((tert-butoxycarbonyl)(4-(pyridin-2- yl)benzyl)amino)-3-cyclopropylpyrazolo[1,5-a]pyrimidin-5-yl) piperidine-1-carboxylate (250 mg, 400 μmol) in DCM (3.0 ml_). The reaction mixture was stirred at RT overnight then concentrated in vacuo. The solid was loaded onto a column of SCX. The column was washed with MeOH (40 ml_) and the product was eluted with 0.7 M NH3 in MeOH (40 ml_). The ammoniacal methanol solution was concentrated in vacuo. Further purification on RP Flash C18 (24 g cartridge, 20-100% MeCN/10 mM ammonium bicarbonate) gave the title compound (80 mg, 0.18 mmol, 46% yield, 98% purity) as a white solid.

UPLC/MS (Method 4): m/z 425 (M+H) ⁺ , RT 1.01 min.

¹ H NMR (400 MHz, DMSO-d ₆ ) d 8.66 - 8.61 (m, 1 H), 8.35 (t, J = 6.6 Hz, 1 H), 8.08 - 8.01 (m, 2H), 7.93 (d, J = 8.0 Hz, 1 H), 7.86 (td, J = 7.7, 1.9 Hz, 1H), 7.81 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.33 (dd, J = 7.4, 4.8 Hz, 1 H), 5.94 (s, 1H), 4.65 (d, J = 6.3 Hz, 2H), 3.01 - 2.91 (m, 2H), 2.63 - 2.53 (m, 2H), 1.96 - 1.88 (m, 1 H), 1.72 - 1.62 (m, 2H), 1.55 (qd, J = 12.0, 3.9 Hz, 2H), 0.88 - 0.76 (m, 4H). 2H under water.

Biological Methods

IC50 Assay

Materials and solutions:

- HEPES-NaOH (Sigma, H-3375)

- Sodium orthovanadate (Sigma, S-6508)

- DTT (Sigma, D-0632)

- MgCI ₂ (M-3634)

- MnCI ₂ (VWR, 1.05927.1000)

- PEG-20000 (SERVA, 33138)

- ATP (Sigma, A-7699)

- [g-33R]-ATR (Hartmann Analytic, FF301T)

- H3PO4 (VWR, 1.00563.1000)

- NaCI (Merck, 1.06404)

- Human CDK12 wt/CycK (ProQinase, 1483-1484-1 - Lot 2)

- RBER-IRStide (ProQinase, 0863-0000-1 - Lot 036)

- 96-well FlashPlates™ (PerkinElmer, SMP200)

Additionally for the CDK12 assay:

- Human CDK12 wt/CycK (ProQinase, 1483-1484-1 - Lot 2)

- RBER-IRStide (ProQinase, 0863-0000-1 - Lot 036)

Additionally for the CDK7 assay:

- Human CDK7/CycH/MAT1 (ProQinase, 0366-0360-4 - Lot 2).

- RBER-CHKtide (ProQinase, 0581-0000-5 - Lot 106).

Assay procedure:

A radiometric protein kinase assay ( ³³ PanQinase ^® Activity Assay) was used for measuring the kinase activity of the two protein kinases (CDK12 / CDK7). All kinase assays were performed in 96-well FlashPlates™ from PerkinElmer (Boston, MA, USA) in a 50 pL reaction volume.

The reaction cocktail was pipetted in four steps in the following order:

- 20 pL of assay buffer (standard buffer)

- 5 pL of ATP solution (in H2O)

- 5 pL of test compound (in 10 % DMSO)

- 10 pL of substrate / 10 pL of enzyme solution (premixed) Forthe CDK7 assay, a reaction mixture (50 mI_) containing the following components was prepared:

- 70 mM HEPES-NaOH (pH 7.5);

- sodium orthovanadate (3 mM);

- PEG-20000 (50 pg/mL);

- DTT (1.2 mM);

- MgCI ₂ (3 mM);

- MnCI ₂ (3 mM);

- purified human CDK7/CycH/MAT1 (3.3 nM - Lot 02);

- RBER-CHKtide substrate (40 pg/mL - Lot 106);

- ATP (3 mM);

- [y-33P]-ATP (approx. 8 x 10 ⁵ cμm per well); and

- test compound at the appropriate concentration such that the final concentration of DMSO was 10% w/w.

For the CDK7 assay, a reaction mixture (50 pL) containing the following components was prepared:

- 70 mM HEPES-NaOH (pH 7.5);

- sodium orthovanadate (3 mM);

- PEG-20000 (50 pg/mL);

- DTT (1.2 mM);

- MgCI ₂ (3 mM);

- MnCI ₂ (3 mM);

- purified human CDK12 wt/CycK (14.7 nM - Lot 02);

- RBER-IRStide substrate (40 pg/mL - Lot 036);

- ATP (0.3 mM);

- [y-33P]-ATP (approx. 8 x 10 ⁵ cμm per well); and

- test compound at the appropriate concentration such that the final concentration of DMSO was 10% w/w.

The reaction mixture was incubated at 30°C for 60 min and then stopped by the addition of 2 % (v/v) H3PO4. Plates were aspirated and washed two times with 200 pL 0.9 % (w/v) NaCI. Incorporation of ³³ Pi was determined with a microplate scintillation count (Microbeta, Wallac).

The residual activities for each concentration and the compound IC50 values were calculated using Quattro Workflow V3.1.1 (Quattro Research GmbH, Munich, Germany). The fitting model for the IC50 determinations was "Sigmoidal response (variable slope)" with parameters "top" fixed at 100 % and "bottom" at 0 %. The fitting method used was a least-squares fit. Western Blotting Analysis of Cyclin K Depletion in Cell Culture

A673 cells were incubated for 2 hours with of 1 mM compound in presence or in absence of 10 mM of the NAE (NEDD8 activating enzyme) inhibitor MLN4924 (Cell Signalling Technologies). Cells were washed 2x with cold Phosphate Buffered Saline (PBS, Sigma Aldrich), followed by the addition of lysis buffer for 15 minutes on ice before harvesting and centrifugation.

Protein content in the cell lysate was assessed by BCA assay (Thermo Fisher). Samples were then prepared with 4x Laemmlli Buffer (Bio-Rad) and heated to 95°C for 5 minutes. Each sample was loaded onto a Mini-PROTEAN TGX Stain Free Gel (Bio-Rad) at 50 pg protein/well. SDS-PAGE was performed and then protein was transferred onto a PVDF membrane using a Trans-Blot® Turbo™ Midi PVDF Transfer Pack (Bio-Rad. Membranes were blocked in TBS-T (Invitrogen), 5% (w/v) milk powder (Marvel) overnight at 4°C.

Membranes were incubated with anti-CCNK antibody (rabbit) primary antibody (Abeam) and anti-GAPDH antibody (rabbit) in TBS-T for 2 hours. Membranes were then washed three times with TBS-T, before incubation secondary goat anti-rabbit HRP antibody (Cell Signalling Technologies) followed by 3x washing in TBS-T. Blots were imaged using a Chemidoc imager (Bio-Rad). Cyclin K depletion was measured as the observable drop in band intensity in compound treated samples relative to proteasome-inhibitor treated samples.

Cytotoxicity in A673 Cells

Inhibition of cell viability by test compounds was assessed in A673 cells (ATCC CRL-1598) and the compound mode of action was attributed to a “molecular-glue’Vcyclin K-degradation mechanism by probing for a loss of compound potency in the presence of the NEDD8-activating enzyme inhibitor, MLN4924.

Cells were plated in 96-well plates at a density of 1.2 x 10 ⁵ viable cells per well in 200 mI_ fully supplemented growth medium (DM EM + 10% heat inactivated foetal bovine serum) and incubated for 24 hours in standard tissue culture conditions. Compounds, including MLN4924, were solubilised in DMSO and then diluted in fully supplemented growth medium at 2X their final assay concentration such that the final DMSO concentration was 0.1%. Growth medium in the assay plates was replaced with 50 mI_ of growth medium containing 2X MLN4924 (final assay concentration: 30 nM, where tested) or vehicle only and 50 mI_ of growth medium containing a 2X compound concentration series or vehicle only such that each compound was at 1X final assay concentration in 100 mI_. Cells were then incubated for 72 hours in standard tissue culture conditions before viability was assessed using 50 mI_ Cell Titer Glo reagent (Promega) per well and luminescence measured on an EnVision plate reader. Data were normalised to vehicle control (100 %) and cells treated with 0.1% Triton x-100 for 1 hour before viability measurement (0%; full cell kill). IC50 values were determined using a semi-logistic curve fit with parameters “top” fixed at 100% and “bottom” at or below 0%. Viability curves generated in the presence of MLN4924 were normalised and fixed to controls treated with MLN4924.

Biological Data

The PPA compounds were assessed using the biological methods described above. The following reference compound, CR8, was also assessed, for comparison purposes. CR8 acts as a molecular glue degrader that depletes cyclin K. See, e.g., Slabicki et al., 2020. The resulting data are summarized in the following table. A ratio of CDK7 / CDK12 of greater than 1 indicated selectivity for CDK12.

† Pubchem Bioassay ID 1587605, Pubchem SID 103586761 (see https://pubchem.ncbi.nlm.nih. gov/substance/103586761#section=BioAssay-Results). The data demonstrated that the PPA compounds are highly potent inhibitors of CDK12, and, in addition, some also have substantial selectivity for CDK12 as compared to CDK7.

Cvclin K Degradation Many of the compounds described herein are characterised not ony by the ability to inhibit CDK12 but also to cause Cyclin K degradation.

Cyclin K degradation was evaluated by Western blotting for cyclin K in A673 cells exposed to 1 mM test compound for 2 hours in the absence and presence of 10 mM MLN4924 (to inhibit proteosome activity).

Figure 1 is shows the effect of THZ-531 , CR8, PPA-005 and PPA-006 on cyclin K degradation in A673 cells, as assessed by Western blotting, as well as the effect of MLN4924 on cytotoxic potency in A673 cells. As reported by Slabicki etal., 2020, the known CDK12 / 13 inhibitor THZ-531 showed no protesomal dependent Cyclin K degradation, whereas the known CDK1 / 2 / 5 / 9 / 12 inhibitor CR8 did cause proteosomal dependent degradation of Cyclin K. Furthermore, evaluation of cytotoxicity to THZ-531 and CR8 in A673 cells incubated for 72 hours in the presence and absence of 30 nM MLN4924 showed a decrease in potency for CR8, but not for THZ-531 demonstrating Cyclin K degradation is a factor in the cytotoxic potency for CR8 but not THZ-531.

As shown in Figure 1, compounds PPA-005 and PPA-006 were also found to degrade Cyclin K in A673 cells by western blot and a significant decrease in cytotoxic potency in the presence of MLN4924.

Compounds that are cyclin K degraders, such as CR8, were also found to more potent in cellular assays than biochemical assays. In contrast, THZ-531 and Dinaciclib, which are known not to degrade cyclin K despite being potent biochemical inhibitors of cyclin K, have similar potency in cellular assays and biochemical assays.

Data summarising biochemical and cellular potency as well as cyclin K degrader activity as evaluated by a decrease in cytoxic potency in A673 cells in the presence of MLN4924 are shown in the following table. Legend:

(-): < 1 fold change.

(+): > 1 and < 2 fold change.

(++): > 2 and < 5 fold change. (+++): > 5 fold change.

The data show that many of the compounds described herein show enhanced cellular potency compared to biochemical potency, and that their potency is dependent on proteosome activity. Therefore, they act both as direct inhibitors of CDK12 and as inducers of Cyclin K degradation, so as to elicit a cytotoxic effect in cancer cells.

The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive. It should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

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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. Full citations for these references are provided below.

Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

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