Klhdc2 (kelch domain-containing protein 2) ligase ligands

Abstract

The present invention relates to compounds which can bind to KLHDC2 (Kelch Domain-Containing Protein 2) E3 ubiquitin ligase with high-affinity, and bifunctional degraders containing such compounds.

Description

[0001] KLHDC2 (KELCH DOMAIN-CONTAINING PROTEIN 2) LIGASE LIGANDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to compounds which can bind to KLHDC2 (Kelch Domain-Containing Protein 2) E3 ubiquitin ligase with high-affinity, and bifunctional degraders containing such compounds.

[0004] BACKGROUND

[0005] In recent years targeted protein degradation (TPD) has emerged as a new and promising pharmaceutical modality beyond the established occupancy-driven paradigm intrinsic for protein inhibitors. Among others, TPD uses bifunctional molecules consisting of E3 ubiquitin ligase ligand connected to a warhead for degradation of medically relevant proteins. TPD holds great promise to address so far incurable diseases, nevertheless, a paucity of known E3 ligase ligands is a major impediment to advancing the field. From about 600 known E3s expressed in human cells, only a handful have been exploited for TPD applications. Among them, the cereblon (CRBN) and von Hippel-Lindau (VHL) E3 ubiquitin ligases have sparked the most interest due to the availability of chemical probes with favorable physiochemical properties and their well-studied mechanism of target engagement. Besides, both ligases have shown high efficiency and versatility in degrading proteins in the cytoplasm and nucleus. However, the pharmacological intervention by using the CRBN and VHL ligands is associated with certain risks, such as impairment of developmental processes and hematopoiesis in the case of CRBN and dysregulation of cell survival and angiogenesis in the case of VHL. In addition, cells may acquire resistance to CRBN ligands due to mutations in the ligase gene and a broad expression profile of CRBN can lead to unexpected side effects. Therefore, the employment of other E3s for this purpose could expand the therapeutic opportunities offered by TPD by broadening a substrate range, increasing efficacy, and evading drug resistance.

[0006] The Kelch-like family member 2 (KLHDC2) is a BC-box protein and a substrate receptor of the CRL2 E3 complex that is implicated in the regulation of protein stability by destruction via C-end degrons (DesCEND mechanism). A specific degron, or in the other words, destruction motif, recognized by the KLHDC2 contains a diglycine at the C terminus. This kind of sequence has been found in several substrates such as early-terminated selenoproteins (SelK and SelS) and several full-length proteins (Rusnac et al., 2018). Importantly, KLHDC2 emerged as a potent degrader in the proteome-scale induced proximity screens performed by Poirson et al. (2022) and AdPROM screen performed by Roth et al. (2022). Moreover, the utility of KLHDC2 to degrade proteins of interest was shown by using bifunctional compounds based on a degron peptide conjugated with chloroalkane (Roth et al. ,2022) or a promiscuous kinase inhibitor (Kim et al., 2022). Although a degron peptide was utilized to demonstrate a proof-of-concept, it is poorly applicable to act as an actual drug due to its high molecular weight and related bioavailability issues. Recently, the recruitment of the CRL2 KLHDC ligase complex using bifunctional compounds composed of low molecular weight KLHDC2 ligands leading to degradation of model proteins BRD4 and STAT3 (WO2023192578A1) as well as BRD4 and androgen receptor (Hickey et al., 2024) were demonstrated.

[0007] Compounds disclosed herein are characterized by a small size with favorable physicochemical properties and can be used as building blocks of bifunctional degraders for the recruitment of KLHDC2 and degradation of the protein of interest. Furthermore, two distinct classes of compounds have been developed: ligands incorporating carboxylic groups and their corresponding prodrugs designed to enhance cellular membrane permeability.

[0008] References:

[0009] 1. Rusnac D.V., Lin H.C., Canzani D., Tien K.X., Hinds T.R., Tsue A.F., Bush M.F., Yen H.C.S. and Zheng N., 2018. Recognition of the diglycine C-end degron by CRL2KLHDC2 ubiquitin ligase. Mol. cell, 72(5), 813-822.

[0010] 2. Poirson J., Dhillon A., Cho H., Lam M.H.Y., Alerasool N., Lacoste J., Mizan L. and Taipale M., 2022. Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers. bioRxiv.

[0011] 3. Roth S., Carton B., Sathyamurthi P.S., Watt M., Macartney T.J., Chan K.H., Isidro-Llobet A., Konopacka A., Queisser M.A. and Sapkota G., Screening of E3 Ligases Uncovers KLHDC2 as an Efficient Proximity-Induced Degrader of K-RAS, STK33, 0-catenin and FoxP3. STK33, 0-catenin and FoxP3.

[0012] 4. Kim Y., Seo C., Jeon E., You I., Hwang K., Kim N., Choi H.S., Hinshaw S.M., Gray N.S. and Sim T., 2022. Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase. bioRxiv.

[0013] 5. Hickey Ch.M., Digianantonio K.M., Zimmermann K., Harbin A., Quinn C., Patel A., Gareiss P., Chapman A., Tiber! B., Dobrodziej J., Corradi J., Cacace A.M., Longley D.R., Bekes M., 2023. Coopting the E3 ligase KLHDC2 for targeted protein degradation by small molecules. Nat. Struct. Mol. Biol., 31, 311-322. SUMMARY OF INVENTION

[0014] In accordance with a first aspect of the invention, there is provided a compound of formula (la): wherein:

[0015] X2is N or CR3;

[0016] X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;

[0017] R1is H, halogen, haloalkyl, methyl, -OH or -NH2;

[0018] R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl), -NH2or -CN;

[0019] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), and -P(O)(alkyl)2; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl or heteroaryl, each of which is independently unsubstituted or is substituted with at least one of -OH, -NH2, -NH(alkyl) or -N (al kyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -0(CH2)q0Me, -(CHzJqOMe, -(OCHzCFbJrNHR73, -C(O)alkyl and -S(O)2alkyl; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or - C(O)alkyl;

[0020] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2-P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and ^(OjOCHjCHjSOjIVIe; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkyl)2, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; and wherein:

[0021] (a) at least one of R1, R2and R3is not H;

[0022] (b) when R2and R3are each H, then R1is halogen; and

[0023] (c) when R1and R3are each H, then R2is not halogen. In accordance with a second aspect of the invention, there is provided the use of a compound as defined above in a bifunctional protein degrader compound.

[0024] In accordance with a third aspect of the invention, there is provided a bifunctional protein degrader compound comprising a compound as defined above.

[0025] In accordance with a fourth aspect of the invention, there is provided a bifunctional protein degrader compound comprising a compound of formula (la'): wherein:

[0026] X2is N or CR3;

[0027] X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;

[0028] R1is H, halogen, haloalkyl, methyl, -OH or -NH2;

[0029] R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl),- NH2or -CN;

[0030] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)z; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -O(CH2)qOI\ / le, -(CH2)qOI\ / le, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19and -OR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;

[0031] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and -C(O)OCH2CH2SO2l\ / le; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0032] R19is a bond connecting the compound of formula (la') to a Target protein binding moiety or to a linker, wherein the linker is attached to a Target protein binding moiety, and wherein formula (la') contains a single R19; and wherein:

[0033] (a) at least one of R1, R2and R3is not H;

[0034] (b) when R2and R3are each H, then R1is halogen; and

[0035] (c) when R1and R3are each H, then R2is not halogen.

[0036] In accordance with a fifth aspect of the invention, there is provided a compound of formula (II)

[0037] [KLHDC2 ligase binding moiety] - linker - [Target protein binding moiety]

[0038] CD or a salt, solvate, hydrate or isomer thereof, wherein [Target protein binding moiety] is: wherein

[0039] M is O, S or NH, or is absent; indicates attachment to R18of the linker;

[0040] R11is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl; R12is H or Me; and

[0041] L' is H, alkyl, benzyl, acetyl or pivaloyl; or

[0042] (b) wherein indicates attachment to R18of the linker; and k is an integer from 1-10;

[0043] (c)

[0044] wherein

[0045] X4and X5are each independently N or CH;

[0046] X6is N or CH;

[0047] R30is H, halogen, -OMe, -CN, unsubstituted C1-C6 alkyl, -CECH, R40, or -C(O)R40;

[0048] R31is H, -OMe, -heteroaryl, -heteroaryl-R40or R40;

[0049] R32is H, unsubstituted C1-C6 alkyl,

[0050] R33is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH(aryl), or R40;

[0051] R34is -Me or -C(O)R40; and

[0052] R40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; or wherein

[0053] X7is N or CH;

[0054] R35is -heterocycloalkyl-R40, or R40;

[0055] R36is H or -OMe; and R40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; wherein [KLHDC2 ligase binding moiety] is a compound of formula (la'): wherein:

[0056] X2is N or CR3;

[0057] X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;

[0058] R1is H, halogen, haloalkyl, methyl, -OH or -NH2;

[0059] R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl),- NH2or -CN;

[0060] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -0(CH2)q0Me, -(CH2)q0Me, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19, -OR19and -(OCH2CH2)rR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;

[0061] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and -C(O)OCH2CH2SO2Me; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alkylhcycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0062] R19is a bond connected to R14of the linker, wherein formula (la') contains a single R19; and wherein:

[0063] (a) at least one of R1, R2and R3is not H;

[0064] (b) when R2and R3are each H, then R1is halogen; and

[0065] (c) when R1and R3are each H, then R2is not halogen; and wherein [linker] has the following formula wherein

[0066] R14is -Ci-6 alkyl, -C2.6alkenyl, -C2.6alkynyl, C1-6 alkyl-N(C1-6 alkyl)-, -C(O)-, -SO2- or is absent

[0067] R15is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci.g alkyl-NH-, -Ci.g alkyl-N(Ci-6 alkyl)-, - cycloalkyl-NH-, -heterocycloalkyl-NH- or is absent

[0068] R16is -Ci-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O- or is absent

[0069] R17is -CH2(C2H4-O)y, (C2H4-O)X, (CaHg-Ojx, or is absent x is 1-10 y is 2-10; and wherein

[0070] (a) when [Target protein binding moiety] is

[0071] , then R18is -Ci.g alkyl, cycloalkyl,

[0072] CH2-NH-C(0)-, heterocycloalkyl, or is absent; and

[0073] (b) when [Target protein binding moiety] is

[0074] then R18is -C1-6 alkyl-NH-, cycloalkyl-NH, -CH2-NH-C(O)-NH-, heterocycloalkyl, heterocycloalkyl-NH, or is absent.

[0075] The present invention also provides a pharmaceutical composition comprising a compound of the invention.

[0076] The present invention also provides a compound or pharmaceutical composition of the invention, for use in medicine.

[0077] The present invention also provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the invention.

[0078] As used herein the term "alkyl" is intended to include both linear and branched alkyl groups, both of which either may be unsubstituted, or may be substituted by one or more additional groups. In some embodiments, the alkyl group is an unsubstituted alkyl group. In some embodiments, the alkyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkyl group is a C1-C12 alkyl, a C1-C10 alkyl, a Ci-Cg alkyl, a Ci-Cg alkyl, or a C1-C4 alkyl group. In some embodiments the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group. In some embodiments the alkyl group is a linear alkyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, - NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkyl group is a branched alkyl group. In some embodiments the alkyl group is an unsubstituted branched alkyl group. In some embodiments the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0079] As used herein the term "alkenyl" is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups. In some embodiments, the alkenyl group is an unsubstituted alkenyl group. In some embodiments, the alkenyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkenyl group is a C2-C12 alkenyl, a C2-CM alkenyl, a C2-C8 alkenyl, a C2-C6 alkenyl, or a C2-C4alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group. In some embodiments the alkenyl group is an unsubstituted linear alkenyl group. In some embodiments the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, - ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkenyl group is a branched alkenyl group. In some embodiments the alkenyl group is an unsubstituted branched alkenyl group. In some embodiments the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0080] As used herein the term "alkynyl" is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups. In some embodiments, the alkynyl group is an unsubstituted alkynyl group. In some embodiments, the alkynyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the alkynyl group is a C2-C12 alkynyl, a C2-Cio alkynyl, a C2-Cg alkynyl, a C2-Cg alkynyl, or a C2-C4alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group. In some embodiments the alkynyl group is an unsubstituted linear alkynyl group. In some embodiments the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments the alkynyl group is a branched alkynyl group. In some embodiments the alkynyl group is an unsubstituted branched alkynyl group. In some embodiments the alkynyl group is a branched alkynyl group which is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0081] As used herein the term "cycloalkyl" is intended to include both unsubstituted cycloalkyl groups, and cycloalkyl groups which are substituted by one or more additional groups. The term "cycloalkyl" is also intended to include monocyclic and bicyclic ring systems (including spirocyclic ring systems, in which the two rings share a single atom; fused bicyclic ring systems, in which the two rings share two adjacent atoms; and bridged bicyclic ring systems, in which the two rings share three or more atoms). In some embodiments, the cycloalkyl group is an unsubstituted cycloalkyl group. In some embodiments, the cycloalkyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, - SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the cycloalkyl group is a C3-C12 cycloalkyl, a C4-C12 cycloalkyl, a C5-C12 cycloalkyl, a C3-C10 cycloalkyl, a C4-C10 cycloalkyl, a C5-C10 cycloalkyl, a C3-C8 cycloalkyl, a C4-C8 cycloalkyl, a C5-C8 cycloalkyl, a C3-C6 cycloalkyl, a C4-C6 cycloalkyl, a C5-C6 cycloalkyl, a C3-C4 cycloalkyl, or a C4-C5 cycloalkyl group.

[0082] As used herein the term "cycloalkenyl" is intended to include both unsubstituted cycloalkenyl groups, and cycloalkenyl groups which are substituted by one or more additional groups. In some embodiments, the cycloalkenyl group is an unsubstituted cycloalkenyl group. In some embodiments, the cycloalkenyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the cycloalkenyl group is a C4-C12 cycloalkenyl, a C5-C12 cycloalkenyl, a C4-C10 cycloalkenyl, a C5-C10 cycloalkenyl, a C4-C8 cycloalkenyl, a C5-C8 cycloalkenyl, a C4-C6 cycloalkenyl, a C5-C6 cycloalkenyl, or a C4-C5 cycloalkenyl group.

[0083] As used herein the term "heterocycloalkyl" is intended to include both unsubstituted heterocycloalkyl groups, and heterocycloalkyl groups which are substituted by one or more additional groups. The term "heterocycloalkyl" is also intended to include monocyclic and bicyclic ring systems (including spirocyclic ring systems, in which the two rings share a single atom; fused bicyclic ring systems, in which the two rings share two adjacent atoms; and bridged bicyclic ring systems, in which the two rings share three or more atoms). In some embodiments, the heterocycloalkyl group is a monocyclic ring system, a spirocyclic ring system, or a fused bicyclic ring system. In some embodiments, the heterocycloalkyl group is an unsubstituted heterocycloalkyl group. In some embodiments, the heterocycloalkyl group is substituted by one or more groups selected from -Rw, -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, one or more -CH2- groups of the heterocycloalkyl ring may be replaced with a -C(O)- group, In some embodiments, the heterocycloalkyl group is a C3-C12 heterocycloalkyl, a C4-C12 heterocycloalkyl, a C5-C12 heterocycloalkyl, a C3-C10 heterocycloalkyl, a C4-C10 heterocycloalkyl, a C5-C10 heterocycloalkyl, a C3-C8heterocycloalkyl, a C4-C8heterocycloalkyl, a C5-C8heterocycloalkyl, a C3-C6 heterocycloalkyl, a C4-C6 heterocycloalkyl, a C5-C6 heterocycloalkyl, a C3-C4 heterocycloalkyl, or a C4-C5 heterocycloalkyl group.

[0084] As used herein the term "aryl" is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups. In some embodiments, the aryl group is an unsubstituted aryl group. In some embodiments, the aryl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -OC(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, the aryl group is a C6-C10 aryl, a C6-C8 aryl, or a Cg aryl.

[0085] As used herein the term "heteroaryl" is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups. In some embodiments, the heteroaryl group is an unsubstituted heteroaryl group. In some embodiments, the heteroaryl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl. In some embodiments, one or more -NH- groups of the heteroaryl ring may be replaced with a -NRW- group. In some embodiments, the heteroaryl group is a C6-C10 heteroaryl, a C6-C9 heteroaryl, a C6-C8 heteroaryl, or a Cg heteroaryl.

[0086] As used herein the term "fused heterocycloalkyl-heteroaryl" is intended to mean a bicyclic ring system in which one ring is a heterocycloalkyl ring and the other is a heteroaryl ring, and in which the two rings share two adjacent atoms. Of the two adjacent atoms shared by the two rings, both may be carbon atoms; both may be heteroatoms (e. g. independently O, N or S); or one may be a carbon atom and the other a heteroatom (e. g. O, N or S). The fused heterocycloalkyl-heteroaryl may be unsubstituted or may be substituted by one or more additional groups. In some embodiments, the fused heterocycloalkylheteroaryl group is an unsubstituted cycloalkenyl group. In some embodiments, the fused heterocycloalkyl-heteroaryl group is substituted by one or more groups selected from -OH, -ORW, -NH2, - NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0087] As used herein the term "benzyl" is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups. In some embodiments, the benzyl group is an unsubstituted benzyl group. In some embodiments, the benzyl group is substituted by one or more groups selected from -OH, -ORW, -NH2, -NHRW, -NRW2, -SO2RW, -C(O)RW, -CN, and -NO2, wherein each Rwis unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.

[0088] In some embodiments of any of the above aspects of the invention, all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.

[0089] DETAILED DESCRIPTION OF THE INVENTION

[0090] As discussed above, in a first aspect the present invention provides a compound of formula (la): wherein:

[0091] X2is N or CR3;

[0092] X3is N or CR1; wherein when X2 is N, then X3 is CR1; and when X3 is N, then X2 is CR3;

[0093] R1is H, halogen, haloalkyl, methyl, -OH or -NH2;

[0094] R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl), -NH2or -CN;

[0095] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)z, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), and -P(O)(alkyl)2; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl or heteroaryl, each of which is independently unsubstituted or is substituted with at least one of -OH, -NH2, -NH(alkyl) or -N (alkyl >2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -0(CH2)q0Me, -(CH2)q0Me, -(OCH2CH2)rNHR7a, -C(O)alkyl and -S(O)2alkyl; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or - C(O)alkyl;

[0096] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2-P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and -qojOCHjCHjSOjMe; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)( C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH( C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(0)(0H)2, - 0P(0)(0H)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyl)morpholinium cation, and N-(unsubstituted C1-C6alkyl)imidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; and wherein:

[0097] (a) at least one of R1, R2and R3is not H;

[0098] (b) when R2and R3are each H, then R1is halogen; and

[0099] (c) when R1and R3are each H, then R2is not halogen.

[0100] In some embodiments, X2 is N. In other embodiments, X3 is N.

[0101] In other embodiments, X2 is CR3and X3 is CR1.

[0102] In certain embodiments, R1is H, halogen or methyl.

[0103] In some embodiments, R3is H, halogen, unsubstituted alkyl or -CN.

[0104] In certain embodiments, R1is H. In some such embodiments, R1and R3are each H. In other embodiments, R1and R2are each H.

[0105] In certain embodiments, R2and R3are each H.

[0106] In certain embodiments,

[0107] R3is H,

[0108] R1is halogen or methyl, and

[0109] R2is -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0110] In certain embodiments, R2is -B(OH)2, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0111] In certain embodiments, R2is selected from aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl and benzyl; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0112] In some embodiments, R2is selected from:

[0113] n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

[0114] In some embodiments, R2is selected from n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

[0115] In certain embodiments, R2is selected from

[0116] wherein n is 1, 2 or 3; and wherein m is 0 or 1.

[0117] In some embodiments, R2is

[0118]

[0119] In some embodiments, each R4is independently selected from halogen, -CN, alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), and -C(O)OH; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0120] In some embodiments, each R7is independently selected from -Me, -OMe, -O(CH2)qOMe, -CH2OMe, -

[0121] C(O)Me and -S(O)2Me. In some embodiments, each R4is independently selected from -F, -Cl, -lBu, -Me, -CF3, -OH, -OMe, -OCF3,

[0122] -CN, -NH2, -NMe2, , -NHC(O)Me, -S(O)2Me, -S(O)2NMe2, -CH2S(O)2NHMe, cyclopropyl, -C(O)OH,

[0123] In some embodiments, each R6is independently selected from halogen, haloalkyl, -NH2, - C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0124] In some embodiments, each R6is independently selected from -Cl, -CF3, -NH2, -C(O)piperidine, -C(O)Me

[0125] In some embodiments, R2is selected from:

[0126]

[0127]

[0128]

[0129] In some embodiments, when

[0130] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl); then: C4-R4is selected from C-alkynyl, C-S(O)2alkyl, C-S(O)2aryl, C-S(O)2N(alkyl)2, C-CH2S(O)2NH(alkyl), C-S(O)2(heterocycloalkyl), C-CH2heterocycloalkyl, C-CH2C(O)NH(alkyl), C-NHC(O)(alkyl), C-SO(alkyl) and C- P(O)(alkyl)2; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0131] In some embodiments, when

[0132] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl): then: each R4of — ”R4) is independently selected from -CN, alkynyl, cycloalkyl, heterocycloalkyl, - NH2, -N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -COOH, -C(O)NH(alkyl), - SO(alkyl), and -P(O)(alkyl)2; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0133] In some embodiments, when

[0134] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl); then:

[0135] R8is -CH2C(O)OH;

[0136] X2and X3are both CH; and

[0137]

[0138] In some embodiments, when

[0139] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl); then:

[0140] R8is -CH2C(O)OH or -CH^O^CH^CfOfBu;

[0141] X2and X3 are both CH; and

[0142] (i) each R4of — ( '”R4) is -S(O)2(heterocycloalkyl), wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; or

[0143]

[0144] In certain embodiments, R1is methyl.

[0145] In some embodiments, -

[0146] In some embodiments, R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, - CH2(heterocycloalkyl), -CH2(heteroaryl), -CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2. In some such embodiments, R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, CH2(4- or 5-membered heterocycloalkyl), -CH2(5-membered heteroaryl), -CH2B(OH)2, -CH2P(O)(OH)2, - COOR9, -B(OH)2and -P(O)(OH)2. In some embodiments, R8is -CHR9C(O)OR10.

[0147] In some embodiments, R8is selected from -CH2C(O)OH, -CHMeC(O)OH, -CH2C(O)OMe, -CH2C(O)OEt, - CH2S(O)2NH2, -CH^OjOCfWqorBu, -CH2C(O)NH2, -CH2S(O)2NH2, -S(O)2NH2, -CH2-oxetane, -CH2(1,2,3- triazole), -CH2B(OH)2, -CH2P(O)(OH)2, -COOH, -COOMe, -B(OH)2and -P(O)(OH)2. In some such embodiments, R8is selected from -CH2C(O)OCH2OC(O)tBu, -CH2C(O)OH and -CHMeC(O)OH.

[0148] In some embodiments, R8is -CH2C(O)OH. In other embodiments, R8is -CHzCfOjOCHzOCfOfBu.

[0149] In some embodiments, the compound is selected from:

[0150]

[0151]

[0152] In some embodiments, the compound is selected from Compound nos. 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 26, 28, 30, 31, 33, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 80, 81, 82, 84, 86 and 88.

[0153] In some embodiments, R1is H; R3is H or methyl; R2is aryl substituted with one or more R4or is fused bicyclic heteroaryl substituted with one or more R6; and R8is -CH2C(O)OH, -CH(Me)C(O)OH or CHR9(heteroaryl). In some such embodiments, each R4is independently selected from halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -NHz, -N(alkyl)?, -NH(CO)alkyl, - C(O)NHalkyl, -C(O)N(alkyl)?, -S(O)? N(alkyl)2,-S(0)z(aryl), -S(O)2(heterocycloalkyl) and -C(O)OH; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R6is -S(O)z(heterocycloalkyl), alkyl or -NH?; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0154] In some embodiments, the compound is selected from Compound nos. 1, 2, 3, 8, 10, 11, 12, 13, 14, 15, 19, 22, 24, 25, 27 , 34, 37, 38, 39, 41, 44, 45, 46, 47, 48, 50, 53, 56, 59, 64, 72, 73, 75, 76, 77, 78, 79, 81, 82, 84, 86, 90, 91, 92, 94, 96, 101, 102 and 103.

[0155] In some embodiments:

[0156] R3is H; each R4is independently selected from -OH, -NHz, -O(alkyl), -NHC(O)alkyl, -C(O)NHalkyl, - S(O)z(heterocycloalkyl) and -C(O)OH; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from -O(alkyl), -O(CHz)qOI\ / le, -(CHz)qOI\ / le and -(OCH2CHz)rNHR7a; wherein q is 1 or 2, r is 4 and R7ais -C(O)Me.

[0157] In some embodiments, the compound is Compound ID no. 2, 24, 37, 45, 46, 47, 73, 76, 77, 79, 82, 84, 86, 91, 96, 102 or 103.

[0158] In accordance with a second aspect of the invention, there is provided the use of a compound as defined in any of the above embodiments of the first aspect in a bifunctional protein degrader compound.

[0159] In accordance with a third aspect of the invention, there is provided a bifunctional protein degrader compound comprising a compound as defined in any of the above embodiments of the first aspect.

[0160] In accordance with a fourth aspect of the invention, there is provided a bifunctional protein degrader compound comprising a compound of formula (la'): wherein: X2is N or CR3;

[0161] X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;

[0162] R1is H, halogen, haloalkyl, methyl, -OH or -NH2;

[0163] R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl),- NH2or -CN;

[0164] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -O(CH2)qOMe, -(CH2)qOMe, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19and -OR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;

[0165] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)pNMe2, -C(O)O(CH2)pNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CMe2OH, and -C(O)OCH2CH2SO2Me; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkyl)2, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alkyl)2cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;

[0166] R19is a bond connecting the compound of formula (la') to a Target protein binding moiety or to a linker, wherein the linker is attached to a Target protein binding moiety, and wherein formula (la') contains a single R19; and wherein:

[0167] (a) at least one of R1, R2and R3is not H;

[0168] (b) when R2and R3are each H, then R1is halogen; and

[0169] (c) when R1and R3are each H, then R2is not halogen.

[0170] In the fourth embodiment, the Target protein binding moiety is a moiety which binds to a target protein. The target protein may be a protein which mediates a disease or disorder in a subject. The degradation of the target protein may thus result in a therapeutic effect in a subject treated with the bifunctional protein degrader compound. Proteins susceptible to binding with the Target protein binding moiety (and subsequent degradation by the E3 ligase - KLHDC2 ligase associated with the KLHDC2 ligase binding moiety) encompass a broad spectrum, including any protein or peptide, along with their fragments, analogs, or homologs. Target proteins exhibit diverse biological functions or activities, such as structural, regulatory, hormonal, enzymatic, genetic, immunological, contractile, storage, transportation, and signal transduction roles. Specifically, within certain embodiments, these proteins include structural proteins, receptors, enzymes, cell surface proteins, and those integral to overall cell function. This covers proteins involved in catalytic, aromatase, motor, helicase, metabolic, antioxidant, proteolytic, and biosynthetic activities, as well as proteins with kinase, oxidoreductase, transferase, hydrolase, lyase, isomerase, and ligase activities. Other categories involve enzyme regulator, signal transducer, structural molecule, and binding activities, including proteins relevant to cell motility, membrane fusion, cell communication, and the regulation of biological processes, development, cell differentiation, and response to stimuli.

[0171] These target proteins also encompass behavioral proteins, cell adhesion proteins, those involved in cell death, transport proteins, chaperone regulator proteins, nucleic acid binding proteins, transcription regulators, and proteins involved in extracellular organization and biogenesis. The scope extends to proteins from various organisms, including eukaryotes and prokaryotes, such as humans, microbes, viruses, fungi, parasites, and other animals, including domesticated ones.

[0172] Employing these diverse target proteins in screening processes by utilizing target protein binding moieties, coupled to KLHDC2 ligase binding moieties, as outlined in the present disclosure, and placing / presenting that target protein or polypeptide in proximity to an KLHDC2 ligase may lead to ubiquitination and subsequent degradation of the target protein, allows for the modulation of protein activity, bringing on to therapeutic outcomes.

[0173] Target proteins of the Target protein binding moiety according to the present invention include, for example, moieties which bind to Human BET Bromodomain-containing proteins, for example BRD4. Further, kinase warhead TL13-87 targeting 183 kinases (Huang et al., 2018) was utilized in the exemplified bifunctional compounds.

[0174] Table 1. List of kinases targeted by TL13-87 kinase warhead.

[0175] In accordance with a fifth aspect of the invention, there is provided a compound of formula (II)

[0176] [KLHDC2 ligase binding moiety] - linker - [Target protein binding moiety] CD or a salt, solvate, hydrate or isomer thereof, wherein [Target protein binding moiety] is:

[0177] wherein

[0178] M is O, S or NH, or is absent; indicates attachment to R18of the linker;

[0179] R11is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;

[0180] R12is H or Me; and

[0181] L' is H, alkyl, benzyl, acetyl or pivaloyl; or

[0182] (b) wherein indicates attachment to R18of the linker; and k is an integer from 1-10; or

[0183] (c)

[0184] wherein

[0185] X4and X5are each independently N or CH;

[0186] X6is N or CH;

[0187] R30is H, halogen, -OMe, -CN, unsubstituted C1-C6 alkyl, -CECH, R40, or -C(O)R40;

[0188] R31is H, -OMe, -heteroaryl, -heteroaryl-R40or R40;

[0189] R32is H, unsubstituted C1-C6 alkyl, R33is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH(aryl), or R40;

[0190] R34is -Me or -C(O)R40; and

[0191] R40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; or wherein

[0192] X7is N or CH;

[0193] R35is -heterocycloalkyl-R40, or R40;

[0194] R36is H or -OMe; and

[0195] R40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; wherein [KLHDC2 ligase binding moiety] is a compound of formula (la'): wherein:

[0196] X2is N or CR3;

[0197] X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;

[0198] R1is H, halogen, haloalkyl, methyl, -OH or -NH2; R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)z, - NH(alkyl),- NH2or -CN;

[0199] R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -O(CH2)qOMe, -(CH2)qOMe, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19, -OR19and -(OCH2CH2)rR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;

[0200] R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)pNMe2, -C(O)O(CH2)pNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CMe2OH, and -C(O)OCH2CH2SO2Me; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(0)NMe2;

[0201] R19is a bond connected to R14of the linker, wherein formula (la') contains a single R19; and wherein:

[0202] (a) at least one of R1, R2and R3is not H;

[0203] (b) when R2and R3are each H, then R1is halogen; and

[0204] (c) when R1and R3are each H, then R2is not halogen; and wherein [linker] has the following formula

[0205] R14.R15.R16.R17.R18 wherein

[0206] R14is -C1-6 alkyl, -C2-6 alkenyl, -C2-6alkynyl, Ci.g alkyl-N(C1-6 alkyl)-, -C(O)-, -SO2- or is absent

[0207] R15is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-NH-, -Ci.g alkyl-N(Ci-6 alkyl)-, - cycloalkyl-NH-, -heterocycloalkyl-NH- or is absent

[0208] R16is -C1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O- or is absent

[0209] R17is -CH2(C2H4-O)y, (C2H4-O)X, (CaHg-Ojx, or is absent x is 1-10 y is 2-10; and wherein

[0210] (a) when [Target protein binding moiety] is cycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or is absent; and.

[0211] (b) when [Target protein binding moiety] is

[0212]

[0213] C(O)-NH-, heterocycloalkyl, heterocycloalkyl-NH, or is absent.

[0214] In some embodiments of the fourth and fifth aspects, X2is N. In other embodiments, X3is N.

[0215] In other embodiments of the fourth and fifth aspects, X2is CR3and X3is CR1.

[0216] In some embodiments of the fourth and fifth aspects, R1is H, halogen or methyl.

[0217] In some embodiments of the fourth and fifth aspects, R3is H, halogen, unsubstituted alkyl or -CN.

[0218] In some embodiments of the fourth and fifth aspects, R1is H. In some embodiments, R1and R3are each

[0219] H. In other embodiments, R1and R2are each H.

[0220] In some embodiments of the fourth and fifth aspects, R2and R3are each H. In some embodiments of the fourth and fifth aspects,

[0221] R3is H,

[0222] R1is halogen or methyl, and

[0223] R2is -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0224] In some embodiments of the fourth and fifth aspects, R2is -B(OH)2, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0225] In some embodiments of the fourth and fifth aspects, R2is selected from aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

[0226] In some embodiments of the fourth and fifth aspects, R2is selected from

[0227] wherein n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

[0228] In some embodiments of the fourth and fifth aspects, R2is selected from wherein n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

[0229] In some embodiments of the fourth and fifth aspects, R2is selected from wherein n is 1, 2 or 3; and wherein m is 0 or 1. In some embodiments of the fourth and fifth aspects, R2is

[0230]

[0231] In some embodiments of the fourth and fifth aspects, each R4is independently selected from halogen, alkyl, -CN, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), - O(heterocycloalkyl), -NH2, -N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), - S(O)2(heterocycloalkyl), -C(O)(heterocycloalkyl), -C(O)OH, R19and -OR19; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0232] In some embodiments of the fourth and fifth aspects, each R7is independently selected from -Me, - OMe, -O(CH2)qOMe, -CH2OMe, -C(O)Me, -S(O)2Me, R19and -OR19.

[0233] In some embodiments of the fourth and fifth aspects, each R4is independently selected from R19, -OR19, -NHR19-F, -Cl, -lBu, -Me, -CF3, -CN, -OH, -OMe, -OCF3, -NH2, -NMe2, -S(O)2Me, -S(O)2NMe2, - CH2S(O)2NHMe, cyclopropyl, -C(O)OH,

[0234] In some embodiments of the fourth and fifth aspects, each R4is independently selected from R19, -OR19,

[0235] In some embodiments, each R6is independently selected from haloalkyl, -C(O)(heterocycloalkyl), - S(O)2(heterocycloalkyl), -C(O)alkyl, R19and NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7. In some embodiments of the fourth and fifth aspects, each R6is independently selected from -CF3, -

[0236] C(O)piperidine, -

[0237] In some embodiments of the fourth and fifth aspects, R2is selected from:

[0238]

[0239]

[0240] In some embodiments of the fourth and fifth aspects: when

[0241] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl); then

[0242] C4-R4is selected from C-alkynyl, C-S(O)2alkyl, C-S(O)2N(alkyl)2, C-CH2S(O)2NH(alkyl), C- S(O)2(heterocycloalkyl), C-S(O)2aryl, C-CH2heterocycloalkyl, C-CH2C(O)NH(alkyl), C-NHC(O)(alkyl), C- SO(alkyl) and C-P(O)(alkyl)2; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0243] In some embodiments of the fourth and fifth aspects: when

[0244] R8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl), n is 1 or 2, then each R4of - ( '~R4 / )nis independently selected from -CN, alkynyl, cycloalkyl, heterocycloalkyl, - NH2, -N(alkyl)z, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -COOH, -C(O)NH(alkyl), - SO(alkyl), and -P(O)(alkyl)2; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

[0245] In some embodiments of the fourth and fifth aspects: when

[0246] R8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl);

[0247] In some embodiments of the fourth and fifth aspects: when

[0248] R8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl); then:

[0249] R8is -CH2C(O)OH or -CH^O^CH^CfOfBu;

[0250] X2and X3are both CH; and

[0251] (i) each is -S(O)2(heterocycloalkyl), wherein each heterocycloalkyl is

[0252]

[0253] In some embodiments of the fourth and fifth aspects, R1is methyl.

[0254] In some embodiments of the fourth and fifth aspects, -

[0255] In some embodiments of the fourth and fifth aspects, R8is selected from -CHR9C(O)OR10, - CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, -CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, - CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR9, -B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)PNMe2, - C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CI\ / le2OH, and -C(O)OCH2CH2SO2Me

[0256] In some embodiments of the fourth and fifth aspects, R8is selected from -CHR9C(O)OR10, CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, -CH2(heterocycloalkyl), -CH2(heteroaryl), -CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, - B(OH)2and -P(O)(OH)2.

[0257] In some embodiments of the fourth and fifth aspects, R8is selected from -CHR9C(O)OR10, CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, -CH2(4- or 5-membered heterocycloalkyl), -CH2(5-membered heteroaryl), - CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2.

[0258] In some embodiments of the fourth and fifth aspects, R8is selected from -CH2C(O)OH, -CHMeC(O)OH, - CH2C(O)OMe, -CH2C(O)OEt, -CH2C(O)OCH2OC(O)tBu, -CH2C(O)NH2, -CH2S(O)2NH2, -S(O)2NH2, -CH2- oxetane, -CH2(l,2,3-triazole), -CH2B(OH)2, -CH2P(O)(OH)2, -COOH, -COOMe, -B(OH)2and -P(O)(OH)2.

[0259] In some embodiments of the fourth and fifth aspects, R8is -CHR9C(O)OR10. In some embodiments of the fourth and fifth aspects, R8is selected from -CHjCfOjOCHjOCXOfBu, - CH2C(O)OH and -CHMeC(O)OH.

[0260] In some embodiments of the fourth and fifth aspects, R8is selected from

[0261] In some embodiments, R8is -CH2C(O)OH. In other embodiments, R8is -CH2C(O)OCH2OC(O)tBu.

[0262] In some embodiments of the fourth and fifth aspects, R1and R3are each H; R2is selected from aryl, fused aryl / heterocycloalkyl and benzyl; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the fused aryl / heterocycloalkyl is unsubstituted or is substituted with one or more R6; and R8is -CHR9C(O)OR10. In some such embodiments, R2is aryl is substituted with R4and R8is -CHR9C(O)OR10

[0263] In some embodiments of the fourth and fifth aspects, each R4is S(O)2(heterocycloalkyl) substituted with R19.

[0264] In some embodiments of the fifth aspect of the invention, at least one of R14, R15, R16, R17and R18is present.

[0265] In some embodiments of the fifth aspect, R14is absent. In other embodiments, R14is -C(O)-.

[0266] In some embodiments of the fifth aspect, R15is absent. In other embodiments, R15is heterocycloalkyl.

[0267] In some embodiments of the fifth aspect, R16is absent. In other embodiments, R16is -Ci.g alkyl. In other embodiments, R16is -C(O)-. In other embodiments, R16is -C(O)-NH-.

[0268] In some embodiments of the fifth aspect, R17is absent. In other embodiments, R17is (C2H4-O)X. In some embodiments of the fifth aspect, x is 3-9. In some embodiments, x is 3, 5, 7 or 9.

[0269] In some embodiments of the fifth aspect, R18is absent. In other embodiments, R18is -Ci-w alkyl or -Ci-io alkyl-NH-. In some embodiments, R18is -Ci.g alkyl or -Ci.g alkyl-NH-. In some embodiments, R18is - CH2CH2- or -CH2CH2-NH-. In other embodiments, R18is heterocycloalkyl or heterocycloalkyl-NH-.

[0270] In some embodiments of the fifth aspect, R14, R15, R16, R17and R18are each absent.

[0271] In some embodiments of the fifth aspect, [linker] is

[0272] rT' n1rvT wherei indicates attachment to [KLHDC2 ligase binding moiety] and2indicates attachment to [Target protein binding moiety].

[0273] In some embodiments of the fifth aspect, the [Target protein binding moiety] is: wherein

[0274] M is O, S or NH, or is absent; indicates attachment to R18of the linker;

[0275] R11is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;

[0276] R12is H or Me; and

[0277] L' is H, alkyl, benzyl, acetyl or pivaloyl.

[0278] In some embodiments of the fifth aspect, R12is Me. In other embodiments, R12is H.

[0279] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0280]

[0281] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0282] In some embodiments, M is absent.

[0283] In some embodiments, L' is H.

[0284] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0285] In some embodiments of the fifth aspect, [Target protein binding moiety] is: n some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0286] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0287]

[0288] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0289] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0290] In some embodiments of the fifth aspect, [Target protein binding moiety] is:

[0291]

[0292] _,1 wherein indicates attachment to [KLHDC2 ligase binding moiety] indicates attachment to [Target protein binding moiety]. In some embodiments, k is an integer from 3-8; optionally wherein k is 4, 6, or 8; further optionally wherein k is 6.

[0293] In some embodiments of the fifth aspect, the compound is selected from:

[0294]

[0295]

[0296]

[0297] In some embodiments of the fifth aspect, the compound is selected from Compound ID nos. 1001, 1002 and 1003.

[0298] In some embodiments of the fifth aspect, the compound is selected from Compound ID nos. 1002, 1003, 1005, 1007, 1008, 1010, 1013, 1014, 1016, 1019, 1020, 1022, 1024, 1026, 1028, 1031, 1034, 1036 and 1038.

[0299] In some embodiments of the fifth aspect, the compound is selected from Compound ID no. 1003, 1008, 1010, 1012, 1014, 1016, 1020, 1022, 1026, 1028, 1034, 1036 and 1038. In some embodiments of the fifth aspect, the compound is selected from Compound ID no. 1005 and 1007.

[0300] In some embodiments of the fifth aspect, the compound is selected from Compound ID nos. 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018 and 1019.

[0301] In some embodiments of the fifth aspect, the compound is selected from Compound ID nos. 1024 and 1025.

[0302] In some embodiments of the fifth aspect, the compound is selected from Compound ID nos. 1028, 1029, 1030, 1031, 1033, 1034, 1035, 1036 and 1037.

[0303] The present invention also provides a pharmaceutical composition comprising a compound of the invention. In some embodiments, the pharmaceutical composition comprises a bifunctional protein degrader compound of the present invention. In some embodiments, the pharmaceutical composition comprises a compound of any of the above embodiments of the fourth or fifth aspects of the present invention. In some embodiments, the pharmaceutical composition comprises a compound of any of the above embodiments of the fifth aspect of the present invention.

[0304] The present invention also provides a compound or pharmaceutical composition of the invention, for use in medicine. In some embodiments, the compound is a bifunctional protein degrader compound of the present invention. In some embodiments, the compound is a compound of any of the above embodiments of the fourth or fifth aspects of the present invention. In some embodiments, the compound is a compound of any of the above embodiments of the fifth aspect of the present invention.

[0305] The present invention also provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the invention. In some embodiments, the compound is a bifunctional protein degrader compound of the present invention. In some embodiments, the compound is a compound of any of the above embodiments of the fourth or fifth aspects of the present invention. In some embodiments, the compound is a compound of any of the above embodiments of the fifth aspect of the present invention.

[0306] EXAMPLES

[0307] The compounds of the present invention were prepared as described below.

[0308] The reagents and solvents were used as received from the commercial sources. Proton nuclear magnetic resonance (NMR) spectra were recorded on Bruker Avance-lll 400 MHz and Bruker Avance Neo 400 MHz spectrometers. The spectra are reported in terms of chemical shift (6 [ppm]), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = quintet, m= multiplet), coupling constant (J [Hz]), and integration. Chemical shifts are reported in ppm relative to dimethyl sulfoxide-dg (6 2.50), chloroform-d (6 7.26) or methanol-c / 4 (6 3.34) (as indicated in NMR spectra data. The samples were prepared by dissolving a dry sample (0.2 - 2 mg) in an appropriate deuterated solvent (0.7-1 mL).

[0309] GCMS were performed on Agilent Model 7890B GC system with 5977B MSD.

[0310] LCMS were collected using Waters SQD2 or API 2000 Mass Spectrometers. All masses reported are the m / z of the protonated parent ions unless otherwise stated.

[0311] Preparative HPLC was performed using Waters auto purification instrument equipped with Gemini C18 column (100 x 19 mm, 5m), YMC-Actus C18 (250 x 20 mm, 5m), YMC-Triart C18 (250 x 20 mm, 5m), Hydrosphere C18 (250 x 20 mm, 5m).

[0312] The chemical names were generated using ChemDraw Professional v. 18.2.0.48 from PerkinElmer Informatics, Inc.

[0313] Abbreviations used in the following examples are presented below in the alphabetical order:

[0314] ACN Acetonitrile

[0315] AcOH Acetic acid

[0316] Bpin Boronic acid pinacol ester

[0317] BOC tert-Butoxycarbonyl m-CPBA 3-Chlorobenzoperoxoic acid

[0318] DBU l,8-Diazabicyclo[5.4.0]undec-7-ene

[0319] DCM Dichloromethane DIAD Diisopropyl azodicarboxylate

[0320] DIBAL Diisobutylaluminium hydride

[0321] DIPEA / V, / V-Diisopropyl ethylamine

[0322] DMAP Dimethyl(pyridin-4-yl)azane

[0323] DME Dimethoxyethane

[0324] DMF / V, / V-Dimethylformamide

[0325] DMF-DMA l,l-dimethoxy- / V, / V-dimethylmethanamine

[0326] DMSO Dimethyl sulfoxide

[0327] EtOH Ethanol

[0328] FA Formic acid

[0329] GCMS Gas chromatography-mass spectrometry

[0330] HATU l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate

[0331] HPLC High performance liquid chromatography

[0332] LAH Lithium aluminium hydride

[0333] LDA Lithium diisopropylamide

[0334] LCMS Liquid chromatography-mass spectrometry

[0335] M molarity

[0336] Me Methyl

[0337] MeOH Methanol

[0338] NaHMDS Sodium l7l,l-trimethyl- / V-(trimethylsilyl)silanaminide

[0339] NMR Nuclear magnetic resonance

[0340] Pd2(dba)3Tris(dibenzylideneacetone)dipalladium

[0341] Pd(dppf)CI2[l,r-Bis(diphenylphosphino)ferrocene]palladium(ll) dichloride

[0342] Pd(dtbpf)CI2[l,r-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll)

[0343] Pd(PPh3)4Tetrakis(triphenylphosphine)palladium(0)

[0344] Pd(PPh3)2CI2Bis(triphenylphosphine)palladium(ll) dichloride

[0345] PdXphosG3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-

[0346] (2,2'-amino-l,r-biphenyl)]palladium(ll) methanesulfonate

[0347] RT Room temperature

[0348] TBAI Tetrabutylammonium iodide

[0349] TEA Triethylamine

[0350] TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride

[0351] THF Tetrahydrofuran

[0352] XantPhos (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

[0353] General procedures

[0354] The synthesis of the compounds can be summarized in the following general procedures as set out below:

[0355] Example method 1: Ester hydrolysis

[0356] Reaction Scheme 1: Ester hydrolysis

[0357] The ester (1 equiv) was taken in appropriate solvent or in mixture of solvents (e.g. MeOH, THF) and lithium hydroxide monohydrate (1-5 equiv) or sodium hydroxide (1-5 equiv) or cesium carbonate (1-5 equiv) in water was added at temperature between 0°C and RT. The mixture was stirred at temperature between RT and 90°C for 1-18 h. After completion the solvent was removed under reduced pressure, the residue was diluted with water and washed with ether. The aqueous layer was cooled to 0°C, acidified with IM HCI and extracted with ethyl acetate. The organic layer was dried over anhydrous NajSCU and evaporated. The product was purified by flash column chromatography and / or preparative HPLC unless otherwise stated.

[0358] Example method 2: Nitrile hydrolysis

[0359] R^^CN

[0360] Reaction Scheme 2: Nitrile hydrolysis

[0361] The appropriate nitrile was taken up in IM NaOH and THF and refluxed for 1-16 h. The reaction mixture was cooled, acidified with IM HCI and extracted with ethyl acetate. The organic fraction was washed with water, brine, dried over NajSCU and evaporated. The resulting product was purified by flash column chromatography and / or preparative HPLC unless otherwise stated.

[0362] Example method 3: Suzuki reaction

[0363] The solution of appropriate halide (i.e. bromide or iodide) (1-1.6 equiv) in mixture of 1,4-dioxane / water or DME / water or THF / water system was added boronic acid (1-1.6 equiv) or boronic ester (1-1.6 equiv), base (e.g. K3PO4, CS2CO3) (3.5-5.5 equiv), palladium catalyst (0.1-0.4 equiv). The resulting mixture was bubbled with argon or nitrogen for 15 min and stirred at 60-100°C for 4-16 h. The volatiles were removed under reduced pressure and the product was purified by flash column chromatography and / or preparative HPLC unless otherwise stated.

[0364] Example method 4: Synthesis of nitrile from alcohol

[0365] To a stirred solution of triphenylphosphine (1-1.3 equiv) in DCM, cooled in an ice-water bath, was added carbononitridic bromide (1.4-1.9 equiv). The reaction was stirred for 15-30 min at 0°C and solution of appropriate alcohol (0.7-1 equiv) ) in DCM or THF was added slowly and the reaction was stirred at 0°C for 1 h. After full consumption of the starting material DBU (1.5-2 equiv) was added dropwise at 0°C and the resulting solution was stirred at RT for 12-16 h. After completion of the reaction the volatiles were removed under reduced pressure and the product was purified by flash column chromatography.

[0366] Example method 5: BOC removal

[0367] Reaction Scheme 5: BOC removal

[0368] To the ice-cold solution of appropriate BOC-protected amine in DCM was added TFA and the resulting solution was stirred at RT for 1-18 h. Once the reaction was completed the volatiles were removed under reduced pressure and the crude product was used into the next step without additional purification unless otherwise stated.

[0369] Example method 6: Reduction of C=C double bond

[0370] Reaction Scheme 6: Reduction of C=C double bond

[0371] To a solution of the substrate in appropriate solvent or in mixture of solvents (e.g. EtOH, THF) was added palladium on activated carbon (10% wt.) and the reaction mixture was stirred at RT for 1-16 h in Parr shaker under hydrogen atmosphere. After completion of the reaction the solid particles were filtered off, the solvent was removed under reduced pressure. The product was purified by flash column chromatography and / or preparative HPLC unless otherwise stated.

[0372] Example method 7: Reduction of ester to alcohol

[0373] Reaction Scheme 7: Reduction of ester to alcohol

[0374] To a solution of an ester (1 equiv) in THF was slowly added LAH (1.2 equiv) in THF or DIBAL (2 equiv) in THF with cooling between -15°C to -5°C. The reaction mixture was stirred for 1-3 h at temperature between -10°C to RT. After completion the reaction was quenched with Rochelle salt solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous NajSCU and evaporated. The product was purified by flash column chromatography. Example method 8: Sulfonamide synthesis

[0375] Reaction Scheme 8: Sulfonamide synthesis

[0376] To a solution of sulfonyl chloride (1 equiv) in DCM, cooled in an ice-water bath, was added TEA (2-4 equiv) and appropriate amine or amine trifluoroacetate (0.5-3 equiv) and the reaction mixture was stirred at RT for 1-4 h. After completion, the volatiles were removed under reduced pressure and the product was purified by flash column chromatography unless otherwise stated.

[0377] Example method 9: Miyaura borylation reaction

[0378] R'X

[0379] X = Br, OTf

[0380] Reaction Scheme 9: Miyaura borylation reaction

[0381] The solution of appropriate bromide or triflate (1 equiv), potassium acetate (2.5-3.5 equiv) and bis(pinacolato)diboron (1.5-2.5 equiv) in 1,4-dioxane was bubbled with argon for 15 min. Pd(dppf)CI2(0.08-0.12 equiv) was added and the reaction mixture was stirred at 80-100°C for 4-18 h in a sealed tube. The volatiles were removed under reduced pressure and the product was purified by flash column chromatography.

[0382] Example method 10: Buchwald-Hartwig cross coupling

[0383] R^ R'N'R2

[0384] Reaction Scheme 10: Buchwald-Hartwig cross coupling The suspension of appropriate aryl iodide (1 equiv), amine (0.8-2.5 equiv), CS2CO3 (2-2.5 equiv), Xantphos (0.1-0.2 equiv) and Pd2(dba)3 (0.08-0.12 equiv) in DMF was stirred at 90-110°C for 5-18 h. The volatiles were removed under reduced pressure and the product was purified by flash column chromatography unless otherwise stated.

[0385] Example method 11: Acylation of amine

[0386] Reaction Scheme 11: Acylation of amine

[0387] To a solution of appropriate amine trifluoroacetate (1 equiv) in DCM, cooled in an ice-water bath, was added TEA (2-4 equiv) followed by acetyl anhydride (1.5-3 equiv) or acetyl chloride (1.2-1.7 equiv). The resulting solution was stirred at RT for 1-4 h and the volatiles were removed under reduced pressure. The product was purified by flash column chromatography unless otherwise stated.

[0388] Example 1-001: Synthesis of 2-(5-(2-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound

[0389] 71)

[0390] Step 1: Ethyl 5-(2-methoxyphenyl)pyrazolo[l,5-a]pyridine-3-carboxylate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (60% yield), using ethyl 5- bromopyrazolo[l,5-a]pyridine-3-carboxylate [commercial] (300 mg, 1.11 mmol, 1 equiv) and (2- methoxyphenyl)boronic acid [commercial] (1.2 equiv) as starting materials, K3PO4 (5 equiv) as base, PdXphosG3 as catalyst (0.1 equiv). After completion the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over NajSCU and evaporated. The product was purified by flash column chromatography.

[0391] LCMS (ESI+) m / z 297.2 [M+H]+

[0392] Step 2: (5-(2-Methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)methanol was synthesized using the general procedure shown in Reaction Scheme 7 and Example Method 7, above (49% yield), using ethyl 5-(2- methoxyphenyl)pyrazolo[l,5-o]pyridine-3-carboxylate (290 mg, 1.03 mmol, 1 equiv) as starting material and LAH (1.2 equiv, IM in THF) as reducing agent.

[0393] LCMS (ESI+) m / z 255.1 [M+H]+

[0394] Step 3: 2-(5-(2-Methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 4 and Example Method 4, above (48% yield), using (5-(2- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)methanol (100 mg, 0.4 mmol, 1 equiv) as starting material.

[0395] LCMS (ESI+) m / z 264.2 [M+H]+

[0396] Step 4: 2-(5-(2-Methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (27% yield), using 2-(5-(2- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile (50 mg, 0.19 mmol, 1 equiv) as starting material. After extraction, the residue was triturated with 50% ether in pentane to afford pure product.

[0397] LCMS (ESI+) m / z 283.1 [M+H]+

[0398] NMR (400 MHz, DMSO-d6) δ 12.93 - 11.79 (m, 1H), 8.60 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.70 (s, 1H), 7.45 - 7.33 (m, 2H), 7.15 (d, J = 8.3 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 7.00 (dd, J = 1.9, 7.3 Hz, 1H), 3.80 (s, 3H), 3.73 (s, 2H). Example 1-002: Synthesis of 2-(5-(2-(( / V-methylsulfamoyl)methyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 67)

[0399] Step 1: Methyl 2-(4-bromopyridin-2-yl)acetate [commercial] (5.6 g, 24.3 mmol, 1 equiv) and DMF-DMA [commercial] (46 mL) were stirred at 80°C for 16 h under nitrogen. After consumption of the starting material the reaction mixture was evaporated under reduced pressure and the residue was triturated with ether to afford crude methyl (Z)-2-(4-bromopyridin-2-yl)-3-(dimethylamino)acrylate (5.0 g) which was forwarded directly for the next step.

[0400] LCMS (ESI+) m / z 284.8 [M+H]+

[0401] Step 2: To a solution of methyl (Z)-2-(4-bromopyridin-2-yl)-3-(dimethylamino)acrylate (5.0 g, 17.5 mmol, 1 equiv, crude after Step 1) in DCM (50 mL) was added O-(mesitylsulfonyl)hydroxylamine [commercial] (4.53 g, 21 mmol, 1.2 equiv) and the reaction mixture was stirred at RT for 16 h. After completion the reaction was quenched with water and extracted with ethyl acetate. The combined organic fractions were washed with brine and evaporated. Methyl 5-bromopyrazolo[l,5-o]pyridine-3-carboxylate (2.2 g, 8.63 mmol, 35% yield over two steps) was purified by flash column chromatography.

[0402] GCMS (ESI+) m / z 254.0 [M+H] Step 3: (5-Bromopyrazolo[l,5-a]pyridin-3-yl)methanol was synthesized using the general procedure shown in Reaction Scheme 7 and Example Method 7 , above (56% yield), using methyl 5- bromopyrazolo[l,5-a]pyridine-3-carboxylate (1.0 g, 3.92 mmol, 1 equiv) as starting material and DIBAL (15.6 mL, 15.6 mmol, 4 equiv, IM solution in toluene) as reducing agent.

[0403] LCMS (ESI+) m / z 227.0, 229.0 [M+H]+

[0404] Step 4: 2-(5-Bromopyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 4 and Example Method 4, above (49% yield) using (5-bromopyrazolo[l,5- o]pyridin-3-yl)methanol (250 mg, 1.1 mmol, 1 equiv) as starting material.

[0405] GCMS (ESI+) m / z 235.0 [M+H]+

[0406] Step 5: 2-(5-Bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (61% yield), using 2-(5-bromopyrazolo[l,5- o]pyridin-3-yl)acetonitrile (75 mg, 0.32 mmol) as a starting material. After completion, the acidified reaction mixture was extracted with ethyl acetate, the combined organic fractions were dried over Na2SO4and evaporated. The residue was triturated with 50% (v / v) mixture of ether and pentane to afford the target compound.

[0407] LCMS (ESI+) m / z 254.9 [M+H]+

[0408] Step 6: [TLS-364, step 1] To a solution of 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (1.7 g, 6.67 mmol, 1 equiv) in MeOH (20 mL) was added concentrated H2SO4(0.5 mL) and the mixture was refluxed for 6 h. After completion the volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate, washed with water, saturated NaHCOs solution, dried over Na2SO4and evaporated to afford methyl 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetate (1.4 g, 5.2 mmol, 78% yield).

[0409] LCMS (ESI+) m / z 270.9 [M+H] Step 7: Methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 9 and Example Method 9, above (42% yield), using methyl 2-(5-bromopyrazolo[l,5-a]pyridin-3-yl)acetate (700 mg, 2.612 mmol, 1 equiv) as starting material.

[0410] LCMS (ESI+) m / z 317.3 [M+H]+

[0411] Step 8: Methyl 2-(5-(2-(( / V-methylsulfamoyl)methyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (258.3 mg, 0.817 mmol, 1.3 equiv) and l-(2-bromophenyl)- / V-methylmethanesulfonamide [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.2 equiv). After completion of the reaction the solution was filtered, the volatiles were removed under reduced pressure and the resulting crude was used in the next step without purification.

[0412] LCMS (ESI+) m / z 374.2 [M+H]+

[0413] Step 9: 2-(5-(2-(( / V-Methylsulfamoyl)methyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (59% yield over two steps), using methyl 2-(5-(2-(( / V-methylsulfamoyl)methyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate as starting material.

[0414] LCMS (ESI+) m / z 360.1 [M+H]+

[0415] TH NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.1 Hz, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.62 - 7.55 (m, 1H), 7.49 - 7.41 (m, 2H), 7.43 - 7.36 (m, 1H), 6.88 (d, J = 7.0 Hz, 1H), 4.37 (s, 2H), 3.60 (s, 2H), 2.42 (s, 3H).

[0416] Example 1-003: Synthesis of 2-(5-(2-chlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 69 ) Step 1: 2-(5-(2-Chlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-(5-bromopyrazolo[l,5- o]pyridin-3-yl)acetonitrile (35 mg, 0.15 mmol, 1 equiv) and (2-chlorophenyl)boronic acid [commercial] (1.2 equiv) as starting materials, CS2CO3 (5 equiv) as base, Pd(dppf)Ck as catalyst (0.1 equiv). After completion the solution was diluted with ethyl acetate, washed with water, brine, dried over NajSCU and evaporated to give crude product which was forwarded to the next step without purification.

[0417] Step 2: 2-(5-(2-Chlorophenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 1, above (46% yield over two steps), using 2-(5-(2-chlorophenyl)pyrazolo[l,5-a]pyridin-3-yl)acetonitrile (200 mg, 0.75 mmol) as a starting material.

[0418] LCMS (ESI+) m / z 287.1 [M+H]+

[0419] 'H NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.64 - 7.55 (m, 1H), 7.54- 7.49 (m, 1H), 7.47 - 7.40 (m, 2H), 6.90 (d, J = 7.1 Hz, 1H), 3.60 (s, 2H).

[0420] Example 1-004: Synthesis of 2-(5-(2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound

[0421] 70)

[0422] Step 1: 2-(5-(2,6-Dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)acetonitrile (150 mg, 0.63 mmol, 1 equiv) and (2,6- dichlorophenyl)boronic acid [commercial] (1.2 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over Na2SO4and evaporated to give crude product which was used in the next step without further purification.

[0423] LCMS (ESI+) m / z 301.9 [M+H]+ Step 2: 2-(5-(2,6-Dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (17% yield over two steps), using 2-(5-(2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile (200 mg, 0.66 mmol) as a starting material.

[0424] LCMS (ESI+) m / z 321.0 [M+H]+

[0425] !H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 7.1 Hz, 1H), 7.92 (s, 1H), 7.63 (m, 1H), 7.60 (m, 2H), 7.52 - 7.43 (m, 1H), 6.71 (dd, J = 1.9, 7.1 Hz, 1H), 3.58 (s, 2H).

[0426] Example 1-005: Synthesis of 2-(5-(m-tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 68)

[0427] Step 1: 2-(5-(m-Tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-(5-bromopyrazolo[l,5-o]pyridin-3- yl)acetonitrile (20 mg, 0.08 mmol, 1 equiv) and m-tolylboronic acid [commercial] (1.2 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.11 equiv). After completion the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over NajSCU and evaporated to give crude product which was used in the next step without further purification.

[0428] LCMS (ESI+) m / z 248.2 [M+H]+

[0429] Step 2: 2-(5-(m-Tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (8% yield over two steps), using 2-(5-(m- tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile (100 mg, 0.4 mmol) as a starting material.

[0430] LCMS (ESI+) m / z 267.1 [M+H]+

[0431] !H NMR (400 MHz, DMSO-d6) δ 13.21 - 11.52 (m, 1H), 8.67 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.91 (s, 1H), 7.63 (s, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.26 - 7.16 (m, 2H), 3.78 (s, 2H), 2.40 (s, 3H). Example 1-006: Synthesis of 2-(5-(2-(methylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0432] (Compound 65)

[0433] Step 1: 2-(5-(2-(Methylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (62% yield), using 2-(5- bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (80 mg, 0.315 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(2- (methylsulfonyl)phenyl)-l,3,2-dioxaborolane (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0434] LCMS (ESI+) m / z 331.0 [M+H]+

[0435] NMR (400 MHz, DMSO-d6) δ 12.75 - 11.90 (s, 1H), 8.63 (d, J = 7.1 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.80 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.49 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 3.68 (s, 2H), 3.06 (s, 3H).

[0436] Example 1-007: Synthesis of 2-(5-(4-(l-methylpiperidin-4-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 66)

[0437] Step 1: 2-(5-(4-(l-Methylpiperidin-4-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (61% yield), using 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (50 mg, 0.197 mmol, 1 equiv) and (4-(l- methylpiperidin-4-yl)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dppf)CI2as catalyst (0.1 equiv). LCMS (ESI+) m / z 350.2 [M+H]+

[0438] XH NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 6.9 Hz, 1H), 3.77 (s, 2H), 2.90 (d, J = 11.4 Hz, 2H), 2.22 (s, 3H), 2.01 (t, J = 11.1 Hz, 2H), 1.86 - 1.61 (m, 4H).

[0439] Example 1-008: Synthesis of 2-(5-benzylpyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 63)

[0440] Step 1: 2-(5-Benzylpyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (55% yield), using 2-(5-bromopyrazolo[l,5- o]pyridin-3-yl)acetic acid (60 mg, 0.236 mmol, 1 equiv) and 2-benzyl-4,4,5,5-tetramethyl-l,3,2- dioxaborolane [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.1 equiv).

[0441] LCMS (ESI+) m / z 267.1 [M+H]+

[0442] NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 7.1 Hz, 1H), 7.81 (s, 1H), 7.48 (s, 1H), 7.35 - 7.24 (m, 4H), 7.25 - 7.16 (m, 1H), 6.63 (dd, J = 2.0, 7.2 Hz, 1H), 3.96 (s, 2H), 3.55 (s, 2H).

[0443] Example 1-009: Synthesis of 2-(5-(2-(piperidin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0444] (Compound 60)

[0445] Step 1: Methyl 2-(5-(2-(piperidin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (171 mg, 0.541 mmol, 1.3 equiv) and l-(2-bromophenyl)piperidine [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.2 equiv). After completion the solvents were removed under reduced pressure and the obtained crude was used in the next step without further purification.

[0446] LCMS (ESI+) m / z 350.3 [M+H]+

[0447] Step 2: 2-(5-(2-(Piperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (34% yield over two steps), using methyl 2-(5-(2-(piperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0448] LCMS (ESI+) m / z 336.2 [M+H]+

[0449] 1H NMR (400 MHz, DMSO-d6) δ 12.66 - 11.93 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.37 - 7.24 (m, 3H), 7.15 - 7.05 (m, 2H), 3.73 (s, 2H), 2.84 - 2.69 (m, 4H), 1.58 - 1.34 (m, 6H).

[0450] Example 1-010: Synthesis of 2-(5-(2,3-dihydrobenzo[b][l,4]dioxin-5-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 62)

[0451] Step 1: 2-(5-(2,3-Dihydrobenzo[b][l,4]dioxin-5-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (27% yield), using 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (100 mg, 0.394 mmol, 1 equiv) and (2,3- dihydrobenzo[b][l,4]dioxin-5-yl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0452] LCMS (ESI+) m / z 311.1 [M+H]+

[0453] XH NMR (400 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.71 (s, 1H), 7.03 (dd, J = 1.3, 7.2 Hz, 1H), 7.02 - 6.88 (m, 3H), 4.29 (m, 4H), 3.74 (s, 2H). Example 1-011: Synthesis of 2-(5-(2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0454] (Compound 64)

[0455] Step 1: Methyl 2-(5-(2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, using methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (135 mg, 0.43 mmol, 1.3 equiv) and l-((2-bromophenyl)sulfonyl)piperidine [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.15 equiv). After completion the solvents were removed under reduced pressure and the resulting crude was used in the next step without purification.

[0456] LCMS (ESI+) m / z 414.0 [M+H]+

[0457] Step 2: 2-(5-(2-(Piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (13% yield over two steps), using methyl 2-(5-(2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0458] LCMS (ESI+) m / z 400.1 [M+H]+

[0459] NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.0 Hz, 1H), 7.98 (d, J = 7.5 Hz, 1H), 7.92 (s, 1H), 7.74 (t, J = 6.9 Hz, 1H), 7.66 (t, J = 7.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.1 Hz, 1H), 3.65 (s, 2H), 2.91 - 2.71 (m, 4H), 1.45 - 1.16 (m, 6H).

[0460] Example 1-012: Synthesis of 2-(5-(2,6-dimethoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0461] (Compound 61)

[0462] Step 1: 2-(5-(2,6-Dimethoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (24% yield), using 2-(5- bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (100 mg, 0.39 mmol, 1 equiv) and (2,6- dimethoxyphenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.2 equiv).

[0463] LCMS (ESI+) m / z 313.1 [M+H]+

[0464] NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 8.56 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.44 (s, 1H), 7.35 (t, J = 8.3 Hz, 1H), 6.77 (d, J = 8.4 Hz, 2H), 6.68 (dd, J = 1.2, 7.0 Hz, 1H), 3.69 (m, 8H).

[0465] Example 1-013: Synthesis of 2-(5-(2-(trifluoromethoxy)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0466] (Compound 58)

[0467] Step 1: 2-(5-(2-(Trifluoromethoxy)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (31% yield), using 2- (5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (60 mg, 0.23 mmol, 1 equiv) and (2- (trifluoromethoxy)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0468] LCMS (ESI+) m / z 337.1 [M+H]+

[0469] XH NMR (400 MHz, DMSO-d6) δ 12.54 - 12.15 (s, 1H), 8.71 (d, J = 7.1 Hz, 1H), 7.97 (s, 1H), 7.79 (s, 1H), 7.66

[0470] (dd, J = 2.3, 7.0 Hz, 1H), 7.63 - 7.49 (m, 3H), 6.97 (d, J = 7.1 Hz, 1H), 3.76 (s, 2H). Example 1-014: Synthesis of 2-(5-(2-methoxy-6-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 59)

[0471] Step 1: 2-(5-(2-Methoxy-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (32% yield), using 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (100 mg, 0.39 mmol, 1 equiv) and (2- methoxy-6-(trifluoromethyl)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Ck as catalyst (0.1 equiv).

[0472] (2-Methoxy-6-(trifluoromethyl)phenyl)boronic acid was synthesized according to procedure described in Kopka, I.E. et al., Biomol

[0473] LCMS (ESI+) m / z 351.1 [M+H]+

[0474] NMR (400 MHz, DMSO-d6) δ 12.76 - 11.89 (s, 1H), 8.62 (d, J = 7.0 Hz, 1H), 7.93 (s, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.49 - 7.40 (m, 3H), 6.67 (d, J = 7.0 Hz, 1H), 3.74 (s, 3H), 3.69 (s, 2H).

[0475] Example 1-015: Synthesis of 2-(5-pp(4-(4-methylpiperazin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 57)

[0476] Step 1: 2-(5-(4-(4-Methylpiperazin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (48% yield), using 2-(5-bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (60 mg, 0.23 mmol, 1 equiv) and l-methyl-4-(4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)piperazine [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0477] LCMS (ESI+) m / z 351.2 [M+H]+

[0478] NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.62 (d, J = 7.3 Hz, 1H), 7.89 (d, J = 4.8 Hz, 2H), 7.74 (d, J = 8.4 Hz, 2H), 7.24 - 7.16 (m, 1H), 7.13 (d, J = 8.3 Hz, 2H), 3.95 (d, J = 10.7 Hz, 2H), 3.78 (s, 2H), 3.51 (d, J = 9.6 Hz, 2H), 3.14 (m, 4H), 2.88 - 2.79 (m, 3H).

[0479] Example 1-016: Synthesis of 2-(5-(2-methoxyphenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0480] (Compound 9)

[0481] Step 1: To a solution of 4-bromo-2,3-dimethylpyridine (5.0 g, 26.9 mmol, 1 equiv) in THF (75 mL), cooled to -78°C, was added LDA (41 mL, 80.6 mmol, 3 equiv, 2M solution in THF) and the resulting mixture was stirred at that temperature for 1 h. Dimethyl carbonate (5 mL, 53.8 mmol, 2 equiv) was added and the reaction was stirred at -78°C for 1 h. The reaction was then quenched with saturated NH4CI solution and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over Na2SO4and evaporated to yield crude product. Methyl 2-(4-bromo-3-methylpyridin-2-yl)acetate (4.0 g, 16.4 mmol, 61% yield) was purified by flash column chromatography.

[0482] LCMS (ESI+) m / z 244.0, 246.0 [M+H]+

[0483] Step 2: Methyl 2-(4-bromo-3-methylpyridin-2-yl)acetate (4.0 g, 16.46 mmol, 1 equiv) and DMF-DMA (40 mL) were stirred at 140°C for 16 h under nitrogen. After consumption of the starting material the reaction mixture was evaporated under reduced pressure and the residue was triturated with ether to afford crude methyl (Z)-2-(4-bromo-3-methylpyridin-2-yl)-3-(dimethylamino)acrylate which was forwarded directly for the next step. LCMS (ESI+) m / z 299.2 [M+H]

[0484] Step 3: To a solution of methyl (Z)-2-(4-bromo-3-methylpyridin-2-yl)-3-(dimethylarriino)acrylate (5.0 g, 16.7 mmol, 1 equiv, crude after Step 2) in DCM (40 mL) was added O-(mesitylsulfonyl)hydroxylamine (4.3 g, 20.04 mmol, 1.2 equiv) and the reaction mixture was stirred at RT for 16 h. After completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic fractions were washed with brine and evaporated. Methyl 5-bromo-4-methylpyrazolo[l,5-a]pyridine-3-carboxylate (2.5 g, 9.3 mmol, 57% yield over two steps) was purified by flash column chromatography.

[0485] LCMS (ESI+) m / z 269.2, 271.2 [M+H]+

[0486] Step 4: (5-Bromo-4-methylpyrazolo[l,5-a]pyridin-3-yl)methanol was synthesized using the general procedure shown in Reaction Scheme 7 and Example Method 7, above (58% yield), using methyl 5-bromo- 4-methylpyrazolo[l,5-o]pyridine-3-carboxylate (2.5 g, 9.3 mmol, 1 equiv) as starting material and DIBAL (2 equiv) as reducing agent.

[0487] LCMS (ESI+) m / z 241.2, 243.2 [M+H]+

[0488] Step 5: 2-(5-Bromo-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 4 and Example Method 4, above (38% yield), using (5-bromo-4- methylpyrazolo[l,5-o]pyridin-3-yl)methanol (1.0 g, 4.15 mmol, 1 equiv) as starting material.

[0489] LCMS (ESI+) m / z 250.2 [M+H]+

[0490] Step 6: 2-(5-(2-Methoxyphenyl)-4-methylpyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (67% yield), using 2- (5-bromo-4-methylpyrazolo[l,5-o]pyridin-3-yl)acetonitrile (200 mg, 0.8 mmol, 1 equiv) and (2- methoxyphenyl)boronic acid (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0491] LCMS (ESI+) m / z 278.4 [M+H]+ Step 7: 2-(5-(2-Methoxyphenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 1, above (48% yield), using 2-(5-(2- methoxyphenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetonitrile (75 mg, 0.32 mmol) as starting material. After completion, the reaction mixture was cooled and washed with ether. Aqueous layer was separated and slowly acidified with IM HCI. Solid was precipitated and filtered and triturated with 50% ether in pentane to obtain the product.

[0492] LCMS (ESI+) m / z 297.2 [M+H]+

[0493] TH NMR (400 MHz, DMSO-d6) δ 12.48 - 12.15 (s, 1H), 8.44 (d, J = 7.0 Hz, 1H), 7.86 (s, 1H), 7.46 - 7.36 (m, 1H), 7.20 - 7.10 (m, 2H), 7.05 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.1 Hz, 1H), 3.88 (s, 2H), 3.73 (s, 3H), 2.25 (s, 3H).

[0494] Example 1-017: Synthesis of 2-(5-(2,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 50)

[0495] Step 1: 4-(4-Bromo-3,5-dichlorophenyl)-3,6-dihydro-2H-pyran was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (50% yield), using 2-bromo-l,3- dichloro-5-iodobenzene [commercial] (250 mg, 0.715 mmol, l.l equiv) and 2-(3,6-dihydro-2H-pyran-4- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [commercial] (1 equiv) as starting materials, K3PO4 (3.33 equiv) as base and Pd(dppf)CL as catalyst (0.11 equiv). After completion, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4and evaporated under reduced pressure. The crude product was purified by flash column chromatography.

[0496] GCMS (ESI+) m / z 307.9 [M+H]+

[0497] Step 2: Methyl 2-(5-(2,6-dichloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (45% yield), using 4-(4-bromo-3,5-dichlorophenyl)-3,6-dihydro-2H-pyran (130 mg, 0.41 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetate (1.1 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv). After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4and evaporated. The resulting crude was purified by flash column chromatography.

[0498] LCMS (ESI+) m / z 416.9, 418.8 [M+H]+

[0499] Step 3: 2-(5-(2,6-Dichloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above, using methyl 2-(5-(2,6-dichloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (120 mg, 0.288 mmol) as starting material and lithium hydroxide as base. After completion, the reaction mixture was diluted with water and washed with 30% ethyl acetate in hexanes. The aqueous layer was acidified with IM HCI and extracted with ethyl acetate, dried over Na2SO4and evaporated to yield crude product which was used to the next step without additional purification.

[0500] LCMS (ESI+) m / z 403.0 [M+H]+

[0501] Step 4: 2-(5-(2,6-Dichloro-4-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (10% yield over two steps), using 2-(5-(2,6-dichloro-4-(3,6-dihydro-2H-pyran-4-yl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid as starting material.

[0502] LCMS (ESI-) m / z 403.1 [M-H]’1H NMR (400 MHz, DMSO-d6) δ 12.81 - 11.92 (s, 1H), 8.71 (d, J = 7.0 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.52 (s, 2H), 6.75 (d, J = 7.8 Hz, 1H), 3.97 (d, J = 10.4 Hz, 2H), 3.72 (s, 2H), 3.49 - 3.39 (m, 2H), 3.03 - 2.80 (m, 1H), 1.85 - 1.60 (m, 4H).

[0503] Example 1-018: Synthesis of 2-(5-(2-(piperidine-l-carbonyl)-lH-pyrrol-l-yl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 4)

[0504] Step 1: To a stirred solution of piperidin-l-yl(lH-pyrrol-2-yl)methanone (70 mg, 0.393mmol, 1 equiv) in DMSO (2 mL) was added 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (1 equiv) and the suspension was purged with argon for 10 min. CuO (0.2 equiv) and K2CO3 (3 equiv) were added, the reaction mixture was purged with argon for 5 min and stirred at 140°C for 16 h. After completion, the solvent was removed under reduced pressure and the crude was purified by preparative HPLC affording 2-(5-(2-(piperidine-l- carbonyl)-lH-pyrrol-l-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (10 mg, 7% yield).

[0505] Piperidin-l-yl(lH-pyrrol-2-yl)methanone was synthesized as described in Gao, S. et al., J. Org. Chem. 2018, 83, 9250.

[0506] LCMS (ESI-) m / z 351.1 [M-H]’

[0507] XH NMR (400 MHz, DMSO-d6, 373K) 6 8.61 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 2.0, 2.8 Hz, 1H), 6.80 (dd, J = 2.4, 7.6 Hz, 1H), 6.46 (dd, J = 1.6, 4.0 Hz, 1H), 6.30 (t, J = 3.2 Hz, 1H), 3.67 (s, 2H), 3.55 - 3.43 (m, 4H), 1.61 - 1.53 (m, 2H), 1.50 - 1.39 (m, 4H).

[0508] Example 1-019: Synthesis of 2-(5-(2,6-dichlorophenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0509] (Compound 54) Step 1: 2-(5-(2,6-Dichlorophenyl)-4-methylpyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (31% yield), using 2- (5-bromo-4-methylpyrazolo[l,5-o]pyridin-3-yl)acetonitrile (20 mg, 0.08 mmol, 1 equiv) and (2,6- dichlorophenyl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0510] LCMS (ESI+) m / z 316.1 [M+H]+

[0511] Step 2: 2-(5-(2,6-Dichlorophenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 1, above (37% yield), using 2- (5-(2,6-dichlorophenyl)-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetonitrile (15 mg, 0.047 mmol). After completion the cooled solution was diluted with water, washed with ether, acidified with IM HCI. The precipitation was filtered and dried to give the pure product.

[0512] LCMS (ESI+) m / z 335.1, 337.1 [M+H]+

[0513] NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 6.58 (d, J = 7.0 Hz, 1H), 3.90 (s, 2H), 2.21 (s, 3H).

[0514] Example 1-020: Synthesis of 2-(5-(4-(l-acetylpiperidin-4-yl)-2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 41) Step 1: tert-Butyl 4-(4-bromo-3,5-dichlorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (93% yield), using 2-bromo-l,3-dichloro-5-iodobenzene (500 mg, 1.42 mmol, l.l equiv) and tert-butyl 4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate [commercial] (1 equiv) as starting materials, K3PO4 (3.33 equiv) as base and Pd(dppf)CL as catalyst (0.11 equiv).

[0515] LCMS (ESI+) m / z 305.4 [M-BOC+H]+

[0516] Step 2: 4-(4-Bromo-3,5-dichlorophenyl)-l,2,3,6-tetrahydropyridine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (73% yield), using tert-butyl 4-(4-bromo-3,5-dichlorophenyl)-3,6-dihydropyridine-l(2H)-carboxylate (400 mg, 0.988 mmol) as starting material.

[0517] LCMS (ESI+) m / z 307.9, 309.9 [M+H]+

[0518] Step 3: l-(4-(4-Bromo-3,5-dichlorophenyl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above (89% yield), using 4-(4-bromo-3,5-dichlorophenyl)-l,2,3,6-tetrahydropyridine trifluoroacetate (300 mg, 0.72 mmol, 1 equiv) and acetic anhydride (2.7 equiv) as starting materials.

[0519] LCMS (ESI+) m / z 347.9, 350.0 [M+H]+

[0520] Step 4: Methyl 2-(5-(4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2,6-dichlorophenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-(4-bromo-3,5-dichlorophenyl)-3,6-dihydropyridin-l(2H)-yl)ethan-l- one (150 mg, 0.43 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Ck as catalyst (0.1 equiv). After completion the solvents were evaporated, the residue was quenched with IM HCI and extracted with DCM. The organic layer was evaporated to afford crude product (220 mg) which was used directly in the next step.

[0521] LCMS (ESI+) m / z 458.3 [M+H] Step 5: 2-(5-(4-(l-Acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example

[0522] Method 1, above, using methyl 2-(5-(4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2,6- dichlorophenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate. After completion, the crude product was used directly in the next step.

[0523] LCMS (ESI+) m / z 444.1 [M+H]+

[0524] Step 6: 2-(5-(4-(l-Acetylpiperidin-4-yl)-2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (22 mg, 10% yield over three steps), using 2-(5-(4-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2,6- dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid as starting material.

[0525] LCMS (ESI+) m / z 446.0, 448.0 [M+H]+

[0526] NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 7.0 Hz, 1H), 7.93 (s, 1H), 7.60 (s, 1H), 7.52 (s, 2H), 6.72 (d, J = 7.0 Hz, 1H), 4.55 (d, J = 12.3 Hz, 1H), 3.94 (d, J = 14.4 Hz, 1H), 3.62 (s, 2H), 3.12 (t, J = 12.4 Hz, 1H), 2.99 - 2.81 (m, 1H), 2.64 - 2.54 (m, 1H), 2.03 (s, 3H), 1.90 - 1.74 (m, 2H), 1.78 - 1.58 (m, 1H), 1.64 - 1.37 (m, 1H), 1.24 - 1.13 (m, 1H).

[0527] Example 1-021: Synthesis of 2-(5-(2,6-dichloro-4-(4-(2-methoxyethoxy)cyclohexyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 10)

[0528]

[0529] Step 1: To a stirred solution of l,4-dioxaspiro[4.5]decan-8-ol [commercial] (500 mg, 3.163 mmol, 1 equiv) in dry THF (10 mL) was added sodium hydride (60% suspension in mineral oil, 380 mg, 9.488 mmol, 3 equiv) at 0°C and stirred for 10 min. l-Bromo-2-methoxyethane (1.6 mL, 15.814 mmol, 5 equiv) was added at 0°C and the reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was cooled, quenched with cold water and extracted with ethyl acetate. Organic layer was washed with brine, dried over Na2SO4and evaporated. 8-(2-Methoxyethoxy)-l,4-dioxaspiro[4.5]decane (300 mg, 43% yield) was purified by flash column chromatography.

[0530] NMR (400 MHz, Chloroform-d) 6 4.00 - 3.83 (m, 4H), 3.58 (dd, J = 5.8, 3.4 Hz, 4H), 3.46 - 3.24 (m, 4H), 1.91 - 1.60 (m, 6H), 1.60 - 1.41 (m, 2H).

[0531] Step 2: To a stirred solution of 8-(2-methoixyethoxy)-l,4-dioxaspiro[4.5]decane (500 mg, 2.313 mmol, 1 equiv) in THF (12 mL) was added 5M HCI (6 mL, 30 mmol, 13 equiv) at 0°C. Then the reaction mixture was stirred at RT for 5 h. After completion, the reaction mixture was quenched with cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over NazSCU and evaporated to obtain 4-(2-methoxyethoxy)cyclohiexan-l-one (250 mg, 62% yield).

[0532] GCMS (ESI+) m / z 172.2 [M+H] NMR (400 MHz, Chloroform-d) 6 3.75 (tt, J = 6.0, 3.1 Hz, 1H), 3.66 (dd, J = 5.8, 3.5 Hz, 2H), 3.57 (dd, J =

[0533] 5.8, 3.5 Hz, 2H), 3.40 (s, 3H), 2.58 (ddd, J = 15.2, 9.9, 5.7 Hz, 2H), 2.25 (dt, J = 14.6, 6.0 Hz, 2H), 2.09 (q, J =

[0534] 6.3, 5.8 Hz, 2H), 2.02 - 1.89 (m, 2H).

[0535] Step 3: To a stirred solution of 4-(2-methoxyethoxy)cyclohexan-l-one (250 mg, 1.453 mmol, 1 equiv) in dry THF (10 mL) was added 2M LDA in THF (1.45 ml, 2.907 mmol, 2 equiv) at -78°C and stirred at that temperature for 1 h. Bis(trifluoromethanesulfonyl)aniline (624 mg, 1.744 mmol, 2 equiv) in THF was added and stirred at -78°C for 1 h, then at RT for 16 h. After completion, the reaction mixture was quenched with saturated NH4CI and extracted with ethyl acetate. The organic layer was dried over Na2SO4and evaporated. 4-(2-Methoxyethoxy)cyclohex-l-en-l-yl trifluoromethanesulfonate (150 mg, 34% yield) was purified by flash column chromatography.

[0536] XH NMR (400 MHz, Chloroform-d) 6 5.64 (s, 1H), 3.75 - 3.58 (m, 3H), 3.57 - 3.45 (m, 2H), 3.39 (s, 3H), 2.54 - 2.11 (m, 4H), 2.12 - 1.78 (m, 2H).

[0537] Step 4: 2-(4-(2-Methoxyethoxy)cyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane was synthesized using the general procedure shown in Reaction Scheme 9 and Example Method 9, above, using 4-(2-methoxyethoxy)cyclohex-l-en-l-yl trifluoromethanesulfonate (380 mg, 1.25 mmol) as starting material. After completion, the reaction mixture was filtered through Celite®, evaporated and the obtained crude was used directly in the next step.

[0538] Step 5: 4'-Bromo-3',5'-dichloro-4-(2-methoxyethoxy)-2,3,4,5-tetrahydro-l,l'-biphenyl was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (12% yield over two steps), using 2-bromo-l,3-dichloro-5-iodobenzene (291 mg, 1.029 mmol, 1 equiv) and 2-(4-(2- methoxyethoxy)cyclohex-l-en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.11 equiv) as starting materials, KaPO4(3.33 equiv) as base and Pd(dppf)CI2as catalyst (0.14 equiv).

[0539] XH NMR (400 MHz, Chloroform-d) 6 7.36 (s, 2H), 6.10 - 6.02 (m, 1H), 3.74 - 3.61 (m, 3H), 3.61 - 3.52 (m, 2H), 3.40 (s, 3H), 2.62 - 2.44 (m, 2H) 2.42 - 2.31 (m, 1H), 2.29 - 2.19 (m, 1H), 2.12 - 2.00 (m, 1H), 1.90 - 1.74 (m, 1H). Step 6: Methyl 2-(5-(3,5-dichloro-4'-(2-methoxyethoxy)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 4'-bromo-3',5'-dichloro-4-(2-methoxyethoxy)-2, 3,4,5- tetrahydro-l,l'-biphenyl (40 mg, 0.106 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.11 equiv) as starting materials, K3PO4 (3.33 equiv) as base and Pd(dppf)CI2as catalyst (0.12 equiv). After completion the obtained crude mixture of methyl 2-(5-(3,5-dichloro-4'-(2-methoxyethoxy)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate and 2-(5-(3,5-dichloro-4'-(2-methoxyethoxy)-2',3',4',5'-tetrahydro- [l,l'-biphenyl]-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was used for the next step.

[0540] LCMS (ESI+) m / z 489.1, 491.0 [M+H]+

[0541] Step 7: 2-(5-(3,5-Dichloro-4'-(2-methoxyethoxy)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4-yl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above, using mixture of methyl 2-(5-(3,5-dichloro-4'-(2-methoxyethoxy)-2',3',4',5'- tetrahydro-[l,l'-biphenyl]-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate and 2-(5-(3,5-dichloro-4'-(2- methoxyethoxy)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid as starting materials. The crude product was used for the next step.

[0542] LCMS (ESI+) m / z 475.0 [M+H]

[0543] Step 8: 2-(5-(2,6-Dichloro-4-(4-(2-methoxyethoxy)cyclohexyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (17% yield over three steps), using 2-(5-(3,5-dichloro-4'-(2-methoxyethoxy)-2',3',4',5'-tetrahydro- [l,l'-biphenyl]-4-yl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid as starting material.

[0544] LCMS (ESI+) m / z 477.0 [M+H]+

[0545] NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.56 (s, 1H), 7.40 (s, 2H), 6.68 (d, J = 7.0 Hz, 1H), 3.65 - 3.55 (m, 2H), 3.54 - 3.44 (m, 5H), 3.27 (s, 3H), 2.76 - 2.58 (m, 1H), 1.99 - 1.88 (m, 2H), 1.76 - 1.63 (m, 2H), 1.62 - 1.55 (m, 2H), 1.54 - 1.44 (m, 2H). Example 1-022: Synthesis of 2-(5-(2,6-dichloro-4-(4-methoxycyclohexyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 27)

[0546] Step 1: 4'-Bromo-3',5'-dichloro-4-methoxy-2,3,4,5-tetrahydro-l,r-biphenyl was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (42% yield), using methyl 2-bromo-l,3-dichloro-5-iodobenzene (100 mg, 0.286 mmol, 1.11 equiv) and 2-(4-methoxycyclohex-l-en- l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [commercial] (1 equiv) as starting materials, K3PO4 (2.3 equiv) as base, Pd(dppf)CL as catalyst (0.12 equiv). Reaction was quenched with water and extracted with ethyl acetate, organic layer was washed with brine, dried over NajSCU and concentrated under reduced pressure. The product was purified by flash column chromatography.

[0547] GCMS (ESI+) m / z 333.9, 335.9 [M+H]+

[0548] Step 2: 2-(5-(3,5-Dichloro-4'-methoxy-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-4-yl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 4'-bromo-3',5'-dichloro-4-methoxy-2,3,4,5-tetrahydro-l,l'-biphenyl (100 mg, 0.299 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate (1 equiv) as starting materials, K3PO4 (3.5 equiv) as base, Pd(dppf)CL as catalyst (0.1 equiv). Reaction was quenched with water and extracted with ethyl acetate. Organic layer was washed with brine, dried over Na?SO4 and concentrated under reduced pressure to obtain crude which was used directly in the next step. LCMS (ESI+) m / z 431.1, 433.1 [M+H]

[0549] Step 3: 2-(5-(2,6-Dichloro-4-(4-methoxycyclohexyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (29% yield over two steps), using methyl 2-(5-(3,5-dichloro-4'-methoxy-2',3',4',5'-tetrahydro-[l,r-biphenyl]-4- yl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid as starting material.

[0550] LCMS (ESI+) m / z 433.0, 435.0 [M+H]+

[0551] 1H NMR (400 MHz, DMSO-d6) δ 12.77 - 11.88 (s, 1H), 8.70 (d, J = 7.0 Hz, 1H), 7.97 (s, 1H), 7.62 (s, 1H), 7.43 (s, 2H), 6.75 (d, J = 7.0 Hz, 1H), 3.72 (s, 2H), 3.48 (s, 1H), 3.25 (s, 3H), 2.06 - 1.88 (m, 2H), 1.74 - 1.54 (m, 4H), 1.51 - 1.47 (m, 2H).

[0552] Example 1-023: Synthesis of 2-(5-(2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0553] (Compound 55)

[0554] Step 1: 2-(5-(2-(Trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (48% yield), using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid [commercial] (150 mg, 0.591 mmol, 1 equiv) and (2- (trifluoromethyl)phenyl)boronic acid (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0555] LCMS (ESI+) m / z 321.2 [M+H]+

[0556] XH NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 6.9 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.76 (t, J = 7.7 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.57 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 3.48 (s, 2H).

[0557] Example 1-024: Synthesis of 2-(5-(2-chloro-6-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0558] (Compound 56)

[0559] Step 1: 2-(5-(2-Chloro-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (50% yield), using 2-(5- bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (70 mg, 0.276 mmol, 1 equiv) and (2-chloro-6- methoxyphenyl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0560] LCMS (ESI+) m / z 317.1, 319.1 [M+H]+

[0561] NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.50 (s, 1H), 7.41 (t, J = 8.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 3.72 (s, 3H), 3.60 (s, 2H).

[0562] Example 1-025: Synthesis of 2-(5-(4-(4-acetylpiperazin-l-yl)-2,6-dichlorophenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 15)

[0563] Step 1: tert-Butyl 4-(4-bromo-3,5-dichlorophenyl)piperazine-l-carboxylate was synthesized using the general procedure shown in Reaction Scheme 10 and Example Method 10, above (85% yield), using 2- bromo-l,3-dichloro-5-iodobenzene (500 mg, 1.429 mmol, 1.25 equiv) and tert-butyl piperazine-1- carboxylate [commercial] (1 equiv) as starting materials. After completion the solution was filtered through Celite®, evaporated and the resulting crude was used in the next step.

[0564] LCMS (ESI+) m / z 410.9, 412.9 [M+H]+ Step 2: l-(4-Bromo-3,5-dichlorophenyl)piperazine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl 4-(4-bromo-3,5- dichlorophenyl)piperazine-l-carboxylate (500 mg, 1.21 mmol) as starting material. After completion the volatiles were removed under reduced pressure and the crude product was used directly in the next step.

[0565] Step 3: l-(4-(4-Bromo-3,5-dichlorophenyl)piperazin-l-yl)ethan-l-one was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above (93% yield over two steps), using l-(4-bromo-3,5-dichlorophenyl)piperazine trifluoroacetate and acetic anhydride as starting materials.

[0566] LCMS (ESI+) m / z 350.8, 352.8 [M+H]+

[0567] Step 4: Methyl 2-(5-(4-(4-acetylpiperazin-l-yl)-2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-(4-bromo-3,5-dichlorophenyl)piperazin-l-yl)ethan-l-one (80 mg, 0.229 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0568] LCMS (ESI+) m / z 461.2 [M+H]+

[0569] Step 5: 2-(5-(4-(4-Acetylpiperazin-l-yl)-2,6-dichlorophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (10 mg, 10% yield two steps), using methyl 2-(5-(4-(4-acetylpiperazin-l-yl)-2,6-dichlorophenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0570] LCMS (ESI+) m / z 447.1, 449.1 [M+H]+

[0571] NMR (400 MHz, DMSO-d6, 373K) 6 8.60 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.50 (s, 1H), 7.08 (s, 2H), 6.67 (d, J = 7.2 Hz, 1H), 3.67 (s, 2H), 3.61 (t, J = 5.6 Hz, 4H), 3.33 (t, J = 5.4 Hz, 4H), 2.05 (s, 3H). Example 1-026: Synthesis of 2-(5-(pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 26)

[0572] Step 1: Methyl 2-(5-(pyridin-4-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (100 mg, 0.317 mmol, 1 equiv) and 4-bromopyridine [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0573] LCMS (ESI+) m / z 268.0 [M+H]+

[0574] Step 2: 2-(5-(Pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (7 mg, 11% yield over two steps), using methyl 2-(5-(pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0575] LCMS (ESI+) m / z 254.1 [M+H]+

[0576] TH NMR (400 MHz, DMSO-d6) δ 12.73 - 12.10 (s, 1H), 8.76 (d, J = 7.2 Hz, 1H), 8.71 (d, J = 4.6 Hz, 2H), 8.29 (s, 1H), 7.99 (s, 1H), 7.92 (d, J = 5.2 Hz, 2H), 7.34 (d, J = 7.3 Hz, 1H), 3.84 (s, 2H).

[0577] Example 1-027: Synthesis of 2-(5-(lH-benzo[d]imidazol-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 51)

[0578] Step 1: Methyl 2-(5-(lH-benzo[d]imidazol-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (150 mg, 0.765 mmol, 1 equiv) and 4-bromo-lH-benzo[d]imidazole [commercial] (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0579] LCMS (ESI+) m / z 307.0 [M+H]+

[0580] Step 2: 2-(5-(lH-Benzo[d]imidazol-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (20 mg, 9% yield over two steps), using methyl 2-(5-(lH-benzo[d]imidazol-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material. After completion the solvents were removed under reduced pressure and the residue was taken up in water, washed with ethyl acetate, acidified with IM HCI and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4and evaporated to obtain pure product.

[0581] LCMS (ESI+) m / z 293.1 [M+H]+

[0582] NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.2 Hz, 1H), 8.56 - 8.35 (m, 1H), 8.33 (s, 1H), 7.89 (s, 1H), 7.74 - 7.47 (m, 3H), 7.32 (t, J = 7.8 Hz, 1H), 3.65 (s, 2H).

[0583] Example 1-028: Synthesis of 2-(5-(2-( / V, / V-dimethylsulfamoyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 53)

[0584] Step 1: Methyl 2-(5-(2-( / V, / V-dimethylsulfamoyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (180 mg, 0.57 mmol, 1.5 equiv) and 2-bromo- / V, / V-dimethylbenzenesulfonamide [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dppf)Ck as catalyst (0.1 equiv). After completion the reaction mixture was evaporated to give crude product which was used directly in the next step.

[0585] LCMS (ESI+) m / z 374.1 [M+H]+ Step 2: 2-(5-(2-( / V, / V-Dimethylsulfamoyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (35 mg, 25% yield over two steps), using methyl 2-(5-(2-( / V, / V-dimethylsulfamoyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate as starting material.

[0586] LCMS (ESI+) m / z 360.1 [M+H]+

[0587] TH NMR (400 MHz, Methanol-d4) 6 8.42 (d, J = 7.0 Hz, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.47 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 3.58 (s, 2H), 2.48 (s, 6H).

[0588] Example 1-029: Synthesis of 2-(5-(2-chloro-6-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 42)

[0589] Step 1: 2-(5-(2-Chloro-6-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (14% yield), using 2-(5-bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (50 mg, 0.197 mmol, 1 equiv) and (2-chloro-6- (trifluoromethyl)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0590] LCMS (ESI+) m / z 355.0, 357.0 [M+H]+

[0591] NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 9.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.2 Hz, 1H), 7.54 (s, 1H), 6.70 (d, J = 7.0 Hz, 1H), 3.52 (s, 2H).

[0592] Example 1-030: Synthesis of 2-(5-(2-chloro-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 39)

[0593] Step 1: To the stirred solution of 2-bromo-l-chloro-3-iodobenzene [commercial] (120 mg, 0.342 mmol, 1.11 equiv), Xantphos (0.22 equiv), Pd?(dba)3 (0.011 equiv) and DIPEA (3.33 equiv) in dioxane (2 mL) was added (4-methoxyphenyl)methanethiol (0.044 mL, 0.308 mmol, 1 equiv). The suspension was purged with argon for 15 min and the reaction mixture was stirred at 90°C for 5 h in a sealed tube. After completion of the reaction, the solvent was evaporated and (2-bromo-3-chlorophenyl)(4-methoxybenzyl)sulfane (90 mg, 69% yield) was purified by flash column chromatography.

[0594] GCMS (ESI+) m / z 344.0 [M+H]+

[0595] Step 2: To a stirred solution of (2-bromo-3-chlorophenyl)(4-methoxybenzyl)sulfane (420 mg, 1.22 mmol, 1 equiv) in ACN (15 mL), cooled in an ice-water bath, were added acetic acid (0.5 mL) and water (0.5 mL). l,3-Dichloro-5,5-dimethylimidazolidine-2, 4-dione (3 equiv) was added and the resulting mixture was stirred at 0°C for 1 h. After completion, the reaction was quenched with cold water and extracted with DCM. The organic fraction was washed with brine, dried over NajSCU and evaporated to afford crude 2- bromo-3-chlorobenzenesulfonyl chloride (400 mg) which was used directly in the next step.

[0596] Step 3: l-((2-Bromo-3-chlorophenyl)sulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (43% yield over two steps), using 2-bromo-3- chlorobenzenesulfonyl chloride (781 mg, 2.69 mmol, 1 equiv) and piperidine (1.1 equiv) as starting materials.

[0597] LCMS (ESI+) m / z 338.0, 339.8 [M+H]+

[0598] Step 4: Methyl 2-(5-(2-chloro-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromo-3-chlorophenyl)sulfonyl)piperidine (100 mg, 0.295 mmol, 1.11 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, Cs2CO3(4.4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.36 equiv). After completion of the reaction, the solvent was evaporated to give crude product which was used directly in the next step.

[0599] LCMS (ESI+) m / z 448.0 [M+H]+

[0600] Step 5: 2-(5-(2-Chloro-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (8% yield over three steps), using methyl 2-(5-(2-chloro-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate.

[0601] LCMS (ESI+) m / z 434.0 [M+H]+

[0602] 'H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.2 Hz, 1H), 8.00 - 7.85 (m, 3H), 7.67 (t, J = 8.0 Hz, 1H), 7.45 (s, 1H), 6.67 (d, J = 7.2 Hz, 1H), 3.62 (d, J = 3.6 Hz, 2H), 2.93 - 2.70 (m, 4H), 1.40 - 1.34 (m, 6H).

[0603] Example 1-031: Synthesis of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 47) Step 1: l-((2-Bromophenyl)sulfonyl)-4-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (46% yield), using 2-bromobenzenesulfonyl chloride (532 mg, 2.09 mmol, 1 equiv) and 4-methoxypiperidine (1.25 equiv) as starting materials.

[0604] LCMS (ESI+) m / z 334.0 [M+H]+

[0605] Step 2: Methyl 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-4-methoxypiperidine (100 mg, 0.3 mmol, 1 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.5 equiv) as starting materials, CS2CO3 (5 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion of the reaction, solvent was evaporated, quenched with IM HCI and extracted with dichloromethane to give crude product which was used directly in the next step.

[0606] LCMS (ESI+) m / z 443.7 [M+H]+

[0607] Step 3: 2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (13% yield over two steps), using methyl 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0608] LCMS (ESI+) m / z 430.1 [M+H]+

[0609] TH NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.75 (t, J = 6.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 6.9 Hz, 1H), 6.81 (d, J = 7.4 Hz, 1H), 3.65 (s, 2H), 3.28 - 3.17 (m, 1H), 3.14 (s, 3H), 3.06 - 2.94 (m, 2H), 2.79 - 2.63 (m, 2H), 1.72 - 1.48 (m, 2H), 1.43 - 1.14 (m, 2H).

[0610] Example 1-032: Synthesis of 2-(5-(2-((3-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 44)

[0611] Step 1: l-((2-Bromophenyl)sulfonyl)-3-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (46% yield), using 2-bromobenzenesulfonyl chloride (1.1 g, 4.17 mmol, 1 equiv) and 3-methoxypiperidine (1.25 equiv) as starting materials.

[0612] LCMS (ESI+) m / z 333.9, 335.9 [M+H]+

[0613] Step 2: Methyl 2-(5-(2-((3-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-3-methoxypiperidine (100 mg, 0.3 mmol, 1 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (5 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion, the reaction mixture was acidified with IM HCI and extracted with ethyl acetate to give crude product which was used directly for the next step.

[0614] LCMS (ESI+) m / z 444.2 [M+H]+

[0615] Step 3: 2-(5-(2-((3-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (28% yield over two steps), using methyl 2-(5-(2-((3-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0616] LCMS (ESI+) m / z 430.1 [M+H]+

[0617] NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.2 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.58 (s, 1H), 7.46 (d, J = 7.4 Hz, 1H), 6.83 (d, J = 7.0 Hz, 1H), 3.60 (s, 2H), 3.14 - 3.07 (m, 1H), 3.05 (s, 3H), 2.98 - 2.82 (m, 2H), 2.77 - 2.57 (m, 1H), 2.58 - 2.51 (m, 1H), 1.72 - 1.60 (m, 1H), 1.56 - 1.46 (m, 1H), 1.28 - 1.13 (m, 2H). Example 1-033: Synthesis of 2-(5-(2-((4-(2-methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 45)

[0618] Step 1: l-((2-Bromophenyl)sulfonyl)-4-(2-methoxyethoxy)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (28% yield), using 2- bromobenzenesulfonyl chloride (385 mg, 1.50 mmol, 1 equiv) and 4-(2-methoxyethoxy)piperidine [commercial] (1.25 equiv) as starting materials.

[0619] LCMS (ESI+) m / z 378.0, 380.0 [M+H]+

[0620] Step 2: Methyl 2-(5-(2-((4-(2-methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-4-(2-methoxyethoxy)piperidine (100 mg, 0.265 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base and Pd(dppf)CI2as a catalyst (0.1 equiv). After completion of the reaction, solvent was evaporated, quenched with IM HCI and extracted with dichloromethane to give crude product which was used directly in the next step.

[0621] LCMS (ESI+) m / z 488.0 [M+H]+

[0622] Step 3: 2-(5-(2-((4-(2-Methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (8% yield over two steps), using methyl 2-(5-(2-((4-(2-methoxyethoxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0623] LCMS (ESI+) m / z 474.2 [M+H]+

[0624] NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.75 (t, J = 7.3 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 6.7 Hz, 1H), 3.57 (s, 2H), 3.46 - 3.34 (m, 5H), 3.20 (s, 3H), 3.09 - 2.96 (m, 2H), 2.76 - 2.59 (m, 2H), 1.76 - 1.51 (m, 2H), 1.40 - 1.16 (m, 2H).

[0625] Example 1-034: Synthesis of 2-(5-(2-((4-(methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 37)

[0626] Step 1: l-((2-Bromophenyl)sulfonyl)-4-(methoxymethyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (59% yield), using 2- bromobenzenesulfonyl chloride (300 mg, 1.176 mmol, 1 equiv) and 4-(methoxymethyl)piperidine [commercial] (1.25 equiv) as starting materials.

[0627] LCMS (ESI+) m / z 348.0, 350.2 [M+H]+

[0628] Step 2: Methyl 2-(5-(2-((4-(methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-4-(methoxymethyl)piperidine (88 mg, 0.253 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.5 equiv) as starting materials, Cs2CO3(5 equiv) as base and Pd(dtbpf)CI2as a catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0629] LCMS (ESI+) m / z 458.1 [M+H]+

[0630] Step 3: 2-(5-(2-((4-(Methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (6% yield over two steps), using methyl 2-(5-(2-((4-(methoxymethyl)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate as starting material.

[0631] LCMS (ESI+) m / z 444.1 [M+H]+

[0632] NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 7.2 Hz, 1H), 7.99 (dd, J = 7.9, 1.4 Hz, 1H), 7.95 (s, 1H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.67 (td, J = 7.7, 1.5 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.47 (dd, J = 7.6, 1.4 Hz, 1H), 3.71 (s, 2H), 3.32 (s, 4H), 3.27 - 3.23 (m, 1H), 3.16 (s, 3H), 3.02 (d, J = 6.0 Hz, 2H), 2.38 (td, J = 12.3, 1.8 Hz, 2H), 1.50 (dd, J = 9.7, 5.6 Hz, 3H), 0.82 (q, J = 12.5 Hz, 2H).

[0633] Example 1-035: Synthesis of 2-(5-(4-(piperidin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0634] (Compound 29)

[0635] Step 1: 2-(5-(4-(Piperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (36% yield), using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (60 mg, 0.236 mmol, 1 equiv) and l-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)piperidine [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0636] LCMS (ESI+) m / z 336.1 [M+H]+

[0637] TH NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.4 Hz, 1H), 7.83 (s, 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.13 (dd, J = 2.0, 7.3 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 3.66 (s, 2H), 3.22 (t, J = 5.6 Hz, 4H), 1.74 - 1.48 (m, 6H).

[0638] Example 1-036: Synthesis of 2-(5-(2,6-dichloro-4-(piperidin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 34) Step 1: l-(4-Bromo-3,5-dichlorophenyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 10 and Example Method 10, above (38% yield), using 2-bromo-l,3-dichloro-5- iodobenzene (300 mg, 0.853 mmol, 1 equiv) and piperidine [commercial] (1.6 equiv) as starting materials.

[0639] GCMS (ESI+) m / z 307.9 [M+H]+

[0640] Step 2: Methyl 2-(5-(2,6-dichloro-4-(piperidin-l-yl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-bromo-3,5-dichlorophenyl)piperidine (100 mg, 0.324 mmol, 1 equiv) and methyl 2-(5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0641] LCMS (ESI+) m / z 418.0, 419.9 [M+H]+

[0642] Step 3: 2-(5-(2,6-Dichloro-4-(piperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (7% yield over two steps), using methyl 2-(5-(2,6-dichloro-4-(piperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0643] LCMS (ESI+) m / z 404.2, 406.2 [M+H]+

[0644] NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.1 Hz, 1H), 7.91 (s, 1H), 7.52 (s, 1H), 7.08 (s, 2H), 6.67 (dd, J = 1.6, 7.0 Hz, 1H), 3.64 (s, 2H), 3.31 - 3.12 (m, 4H), 1.58 (m, 6H).

[0645] Example 1-037: Synthesis of 2-(5-(3-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound

[0646] 33) Step 1: 2-(5-(3-Methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (36% yield), using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (70 mg, 0.276 mmol, 1 equiv) and (3- methoxyphenyl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0647] LCMS (ESI+) m / z 283.1[M+H]+

[0648] TH NMR (400 MHz, DMSO-d6) δ 8.67 (dd, J = 7.3, 0.9 Hz, 1H), 8.01 (dd, J = 2.1, 0.9 Hz, 1H), 7.92 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.37 (dt, J = 7.7, 1.4 Hz, 1H), 7.34 (t, J = 2.1 Hz, 1H), 7.22 (dd, J = 7.3, 2.1 Hz, 1H), 6.99 (ddd, J = 8.0, 2.6, 1.2 Hz, 1H), 3.85 (s, 3H), 3.80 (s, 2H).

[0649] Example 1-038: Synthesis of 2-(5-(3-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0650] (Compound 31)

[0651] Step 1: 2-(5-(3-(Trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (40% yield), using 2-(5- bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (70 mg, 0.276 mmol, 1 equiv) and (3- (trifluoromethyl)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0652] LCMS (ESI+) m / z 321.2 [M+H]+

[0653] NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 7.2 Hz, 1H), 8.16 - 8.07 (m, 3H), 7.90 (s, 1H), 7.80 - 7.68 (m, 2H), 7.26 (dd, J = 2.0, 7.3 Hz, 1H), 3.66 (s, 2H).

[0654] Example 1-039: Synthesis of 2-(5-(2,6-dichloro-4-(3-methoxypiperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-

[0655] 3-yl)acetic acid (Compound 13)

[0656] Step 1: l-(4-Bromo-3,5-dichlorophenyl)-3-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 10 and Example Method 10, above (62% yield), using 2-bromo-l,3- dichloro-5-iodobenzene (500 mg, 1.421 mmol, 1 equiv) and 3-methoxypiperidine [commercial] (1.6 equiv) as starting materials.

[0657] NMR (400 MHz, Chloroform-d) 6 6.96 - 6.78 (s, 2H), 3.56 - 3.47 (m, 1H), 3.44 - 3.38 (s, 3H), 3.40 - 3.27 (m, 2H), 3.00 - 2.79 (m, 2H), 2.05 - 1.95 (m, 1H), 1.92 - 1.81 (m, 1H), 1.65 - 1.50 (m, 2H).

[0658] Step 2: Methyl 2-(5-(2,6-dichloro-4-(3-methoxypiperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-bromo-3,5-dichlorophenyl)-3-methoxypiperidine (200 mg, 0.59 mmol, 1 equiv) and methyl 2- (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product which was used directly in the next step.

[0659] Step 3: 2-(5-(2,6-Dichloro-4-(3-methoxypiperidin-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (10% yield over two steps), using methyl 2-(5-(2,6-dichloro-4-(3-methoxypiperidin-l-yl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0660] LCMS (ESI+) m / z 434.3, 436.3 [M+H]+

[0661] NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H), 7.48 (s, 1H), 7.06 (s, 2H), 6.67 (d, J = 7.0 Hz, 1H), 3.67 - 3.56 (m, 2H), 3.49 - 3.34 (m, 1H), 3.28 (s, 3H), 3.12 - 2.84 (m, 2H), 2.00 - 1.81 (m, 2H), 1.79 - 1.66 (m, 2H), 1.59 - 1.32 (m, 2H).

[0662] Example 1-040: Synthesis of 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 28)

[0663] Step 1: Methyl 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(6-bromo-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one [commercial] (80 mg, 0.316 mmol, 1.0 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion, the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0664] LCMS (ESI+) m / z 364.3 [M+H]+

[0665] Step 2: 2-(5-(2-Acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (24% yield over two steps), using methyl 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-6-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0666] LCMS (ESI+) m / z 350.1 [M+H]+

[0667] TH NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.72 - 7.53 (m, 2H), 7.30 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 6.9 Hz, 1H), 4.69 (s, 1H), 4.63 (s, 1H), 3.73 - 3.63 (m, 4H), 2.99 - 2.92 (m, 1H), 2.90 - 2.80 (m, 1H), 2.10 (s, 3H).

[0668] Example 1-041: Synthesis of 2-(5-(3-(piperidine-l-carbonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 30) Step 1: Methyl 2-(5-(3-(piperidine-l-carbonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2- (5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (100 mg, 0.316 mmol, 1.25 equiv) and (3-bromophenyl)(piperidin-l-yl)methanone [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion, the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0669] LCMS (ESI+) m / z 378.1 [M+H]+

[0670] Step 2: 2-(5-(3-(Piperidine-l-carbonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (23% yield over two steps), using methyl 2-(5-(3-(piperidine-l-carbonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0671] LCMS (ESI+) m / z 364.1 [M+H]+

[0672] NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.3 Hz, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 3.72 (s, 2H), 3.67 - 3.56 (m, 2H), 3.53 - 3.11 (m, 2H), 1.71 - 1.35 (m, 6H).

[0673] Example 1-042: Synthesis of 2-(5-(4-(tert-butyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 36)

[0674] Step 1: 2-(5-(4-(tert-Butyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (44% yield), using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (100 mg, 0.394 mmol, 1 equiv) and (4-(tert- butyl)phenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0675] LCMS (ESI+) m / z 309.2 [M+H]+

[0676] XH NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1H), 3.68 (s, 2H), 1.32 (s, 9H).

[0677] Example 1-043: Synthesis of 2-(5-(4-cyclopropylphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound

[0678] Step 1: 2-(5-(4-Cyclopropylphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (63% yield), using 2-(5- bromopyrazolo[l,5-a]pyridin-3-yl)acetic acid (70 mg, 0.276 mmol, 1 equiv) and (4- cyclopropylphenyl)boronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0679] LCMS (ESI+) m / z 293.1 [M+H]+

[0680] NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 3.60 (s, 2H), 2.03 - 1.91 (m, 1H), 1.04 - 0.94 (m, 2H), 0.77 - 0.68 (m, 2H).

[0681] Example 1-044: Synthesis of 2-(5-(2-methoxy-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 24)

[0682] Step 1: l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (28% yield), using 2-bromo-3- methoxybenzenesulfonyl chloride [commercial] (400 mg, 1.404 mmol, 1 equiv) and piperidine (2 equiv) as starting materials.

[0683] LCMS (ESI+) m / z 334.0 [M+H]+

[0684] Step 2: 2-(5-(2-Methoxy-6-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (29% yield), using l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidine (120 mg, 0.36 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0685] LCMS (ESI+) m / z 430.1 [M+H]+

[0686] NMR (400 MHz, DMSO-d6, 373K) 6 8.51 (d, J = 7.2 Hz, 1H), 7.89 (s, 1H), 7.66 - 7.55 (m, 2H), 7.50 - 7.31 (m, 2H), 6.63 (d, J = 7.2 Hz, 1H), 3.74 (s, 3H), 3.64 (s, 2H), 2.91 - 2.76 (m, 4H), 1.54 - 1.30 (m, 6H).

[0687] Example 1-045: Synthesis of 2-(5-(2,6-dichloro-4-(dimethylamino)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 22)

[0688] Step 1: 4-Bromo-3,5-dichloro- / V, / V-dimethylaniline was synthesized using the general procedure shown in

[0689] Reaction Scheme 10 and Example Method 10, above (43% yield), using 2-bromo-l,3-dichloro-5- iodobenzene (300 mg, 0.853 mmol, 1 equiv) and dimethylamine (2.5 equiv, 2M solution in THF) as starting materials.

[0690] GCMS (ESI+) m / z 267.9 [M+H]+

[0691] Step 2: 2-(5-(2,6-Dichloro-4-(dimethylamino)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (39% yield), using 4-bromo-3,5-dichloro- / V, / \ / -dimethylaniline (60 mg, 0.3 mmol, 1.33 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv).

[0692] LCMS (ESI+) m / z 364.0, 366.0 [M+H]+

[0693] NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H), 7.51 (s, 1H), 6.84 (s, 2H), 6.66 (d, J = 6.9 Hz, 1H), 3.63 (s, 2H), 2.97 (s, 6H).

[0694] Example 1-046: Synthesis of 2-(5-(4-(prop-l-yn-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0695] (Compound 23)

[0696] Step 1: 2-(5-(4-(Prop-l-yn-l-yl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (27% yield), using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (100 mg, 0.309 mmol, 1.03 equiv) and l-bromo-4-(prop-l-yn-l-yl)benzene (1 equiv) as starting materials, Cs2CO3(4.1 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv). l-Bromo-4-(prop-l-yn-l-yl)benzene was synthesized as described in Fujihara, T. et al., Angew. Chem. Int. Ed. 2012, 51, 11487.

[0697] LCMS (ESI+) m / z 291.1 [M+H]+ NMR (400 MHz, DMSO-d6) δ 8.65 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H),

[0698] 7.49 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.2 Hz, 1H), 3.70 (s, 2H), 2.08 (s, 3H).

[0699] Example 1-047: Synthesis of 2-(5-(2-((l-acetylpiperidin-4-yl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 6)

[0700] Step 1: 4-(2-Bromo-3-(trifluoromethyl)phenoxy)piperidine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl 4-(2- bromo-3-(trifluoromethyl)phenoxy)piperidine-l-carboxylate (600 mg, 1.415 mmol) as starting material. After completion of the reaction the volatiles were removed under reduced pressure and the crude product was forwarded into the next step. tert-Butyl 4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidine-l-carboxylate was prepared according to the procedure described in WO2018217809A1.

[0701] LCMS (ESI+) m / z 323.6, 325.8 [M+H]+

[0702] Step 2: l-(4-(2-Bromo-3-(trifluoromethyl)phenoxy)piperidin-l-yl)ethan-l-one was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above (46% yield over two steps), using 4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidine trifluoroacetate (300 mg, 0.68 mmol, 1 equiv) and acetyl chloride (1.5 equiv) as starting materials. LCMS (ESI+) m / z 366.2 [M+H]

[0703] Step 3: Methyl 2-(5-(2-((l-acetylpiperidin-4-yl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-(2-bromo-3-(trifluoromethyl)phenoxy)piperidin-l-yl)ethan-l-one (110 mg, 0.328 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate (1 equiv) as starting materials, Cs2CO3(4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.11 equiv). After completion of the reaction the solvent was evaporated to give crude product which was used directly in the next step.

[0704] LCMS (ESI+) m / z 476.0 [M+H]+

[0705] Step 4: 2-(5-(2-((l-Acetylpiperidin-4-yl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (23% yield over two steps), using methyl 2-(5-(2-((l-acetylpiperidin-4-yl)oxy)-6- (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0706] LCMS (ESI+) m / z 462.1 [M+H]+

[0707] NMR (400 MHz, DMSO-d6, 373K) 6 8.57 (d, J = 7.6 Hz, 1H), 7.90 (s, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 7.2 Hz, 2H), 6.68 (d, J = 7.2 Hz, 1H), 4.72 - 4.58 (m, 1H), 3.65 (s, 2H), 3.41 - 3.16 (m, 4H), 1.90 (s, 3H), 1.86 - 1.67 (m, 2H), 1.58 - 1.36 (m, 2H).

[0708] Example 1-048: Synthesis of 2-(5-(2-((4-methoxycyclohexyl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 17) Step 1: To a stirred solution of 2-bromo-3-(trifluoromethyl)phenol [commercial] (600 mg, 2.5 mmol, 1 equiv) in THF were added 4-methoxycyclohexan-l-ol [commercial] (391 mg, 3.0 mmol, 1.2 equiv) and PPha (980 mg, 3.75 mmol, 1.5 equiv) at 0°C and the suspension was stirred for 10 min. DIAD (1 mL, 5.0 mmol, 2 equiv) was added and the reaction mixture was stirred at RT for 16 h. After completion, the resulting mixture was quenched with water, extracted with ethyl acetate, then organic layer was washed with brine, dried over Na2SO4and evaporated under reduced pressure. The crude product was purified by flash column chromatography to obtain 2-bromo-l-((4-methoxycyclohexyl)oxy)-3-(trifluoromethyl)benzene (400 mg, 45% yield).

[0709] TH NMR (400 MHz, Chloroform-d) 6 7.40 - 7.26 (m, 2H), 7.07 (t, J = 6.9 Hz, 1H), 4.52 - 4.39 (m, 1H), 3.36 (s, 3H), 2.12 - 1.96 (m, 4H), 1.87 (t, J = 9.4 Hz, 1H), 1.75 - 1.64 (m, 4H).

[0710] Step 2: Methyl 2-(5-(2-((4-methoxycyclohexyl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-bromo-l-((4-methoxycyclohexyl)oxy)-3-(trifluoromethyl)benzene (55 mg, 0.156 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.1 equiv). After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4and concentrated to afford crude product which was used directly in the next step.

[0711] LCMS (ESI+) m / z 463.2 [M+H]+

[0712] Step 3: 2-(5-(2-((4-Methoxycyclohexyl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (31% yield over two steps), using methyl 2-(5-(2-((4-methoxycyclohexyl)oxy)-6- (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0713] LCMS (ESI+) m / z 449.6 [M+H]+

[0714] 'H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 7.0 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.46 - 7.36 (m, 2H), 6.67 (d, J = 6.9 Hz, 1H), 4.58 - 4.38 (m, 1H), 3.64 (s, 2H), 3.25 - 2.97 (m, 5H), 1.92 - 1.73 (m, 1H), 1.70 - 1.42 (m, 3H), 1.42 - 1.18 (m, 3H). Example 1-049: Synthesis of 2-(5-(2-((l-(methylsulfonyl)piperidin-4-yl)oxy)-6-

[0715] (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 7)

[0716] Step 1: 4-(2-Bromo-3-(trifluoromethyl)phenoxy)-l-(methylsulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (64% yield), using 4-(2- bromo-3-(trifluoromethyl)phenoxy)piperidine trifluoroacetate (300 mg, 0.69 mmol, 1 equiv) and methanesulfonyl chloride (2 equiv) as starting materials.

[0717] LCMS (ESI+) m / z 401.9, 403.8 [M+H]+

[0718] Step 2: Methyl 2-(5-(2-((l-(methylsulfonyl)piperidin-4-yl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 4-(2-bromo-3-(trifluoromethyl)phenoxy)-l-(methylsulfonyl)piperidine (130 mg, 0.323 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the solvent was evaporated to give crude product which was used directly in the next step.

[0719] LCMS (ESI+) m / z 512.2 [M+H]+

[0720] Step 3: 2-(5-(2-((l-(Methylsulfonyl)piperidin-4-yl)oxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin- 3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (16% yield over two steps), using methyl 2-(5-(2-((l-(methylsulfonyl)piperidin-4-yl)oxy)- 6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0721] LCMS (ESI+) m / z 498.0 [M+H]+XH NMR (400 MHz, DMSO-d6, 373K) 6 8.60 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.47 - 7.42 (m, 2H), 6.72 (d, J = 7.6 Hz, 1H), 4.86 - 4.50 (m, 1H), 3.68 (s, 2H), 3.20 - 3.02 (m, 2H), 2.81 - 2.67 (m, 2H), 2.45 (s, 3H), 1.93 - 1.53 (m, 4H).

[0722] Example 1-050: Synthesis of 2-(5-(5-methoxy-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid (Compound 12)

[0723] Step 1: Methyl 2-(5-(5-methoxy-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-bromo-4-methoxy-l-(trifluoromethyl)benzene [commercial] (150 mg, 0.588 mmol, 1.0 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion, the reaction mixture was filtered through Celite®, the solvent was evaporated and the crude product was used in the next step without additional purification.

[0724] LCMS (ESI+) m / z 365.2 [M+H]+

[0725] Step 2: 2-(5-(5-Methoxy-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (23% yield over two steps), using methyl 2-(5-(5-methoxy-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate as starting material.

[0726] LCMS (ESI+) m / z 351.2 [M+H]+

[0727] NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.17 (dd, J = 2.6, 8.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 3.87 (s, 3H), 3.57 (s, 2H). Example 1-051: Synthesis of 2-(5-(4-(trifluoromethyl)pyridin-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0728] (Compound 20)

[0729] Step 1: Methyl 2-(5-(4-(trifluoromethyl)pyridin-3-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 3-bromo- 4-(trifluoromethyl)pyridine [commercial] (150 mg, 0.664 mmol, 1 equiv) and methyl 2-(5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, Cs2CO3(2.7 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv). After completion, the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0730] LCMS (ESI+) m / z 336.3 [M+H]+

[0731] Step 2: 2-(5-(4-(Trifluoromethyl)pyridin-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (20% yield over two steps), using methyl 2-(5-(4-(trifluoromethyl)pyridin-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0732] LCMS (ESI+) m / z 322.1 [M+H]+

[0733] NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 5.1 Hz, 1H), 8.79 (s, 1H), 8.72 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.72 (s, 1H), 6.87 (d, J = 7.3 Hz, 1H), 3.69 (s, 2H).

[0734] Example 1-052: Synthesis of 2-(5-(5-(l-acetylpiperidin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 11)

[0735]

[0736] Step 1: tert-Butyl 4-(3-bromo-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (86% yield), using 2-bromo-4-iodo-l-(trifluoromethyl)benzene [commercial] (2.5 g, 7.143 mmol, l.ll equiv) and tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (1 equiv) as starting materials, K3PO4(3.33 equiv) as base and Pd(PPh3)2Cl2 as catalyst (0.11 equiv).

[0737] TH NMR (400 MHz, Chloroform-d) 6 7.69 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.22 - 6.07 (m, 1H), 4.15 - 4.07 (m, 2H), 3.64 (t, J = 5.7 Hz, 2H), 2.55 - 2.43 (m, 2H), 1.49 (s, 9H).

[0738] Step 2: 4-(3-Bromo-4-(trifluoromethyl)phenyl)-l,2,3,6-tetrahydropyridine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl 4-(3-bromo-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-l(2H)-carboxylate (500 mg, 1.232 mmol) as starting material. After completion of the reaction the volatiles were removed under reduced pressure, the residue was washed with ether and dried to afford crude product which was directly forwarded into the next step.

[0739] LCMS (ESI+) m / z 306.0, 308.0 [M+H]+

[0740] Step 3: l-(4-(3-Bromo-4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-l(2H)-yl)ethan-l-one was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above (70% yield over two steps), using 4-(3-bromo-4-(trifluoromethyl)phenyl)-l,2,3,6-tetrahydropyridine trifluoroacetate (350 mg, 0.835 mmol, 1 equiv) and acetyl anhydride (1.5 equiv) as staring materials.

[0741] LCMS (ESI+) m / z 347.9 [M+H]+

[0742] Step 4: Methyl 2-(5-(5-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-(4-(3-bromo-4-(trifluoromethyl)phenyl)-3,6-dihydropyridin-l(2H)- yl)ethan-l-one (110 mg, 0.316 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, Cs2CO3(4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.1 equiv). After completion of the reaction the solvent was evaporated to give crude product which was used directly in the next step.

[0743] LCMS (ESI+) m / z 458.2 [M+H]+

[0744] Step 5: 2-(5-(5-(l-Acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (57% yield over two steps), using methyl 2-(5-(5-(l-acetyl-l,2,3,6- tetrahydropyridin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (100 mg, 0.219 mmol) as starting material. After completion the solvents were removed under reduced pressure, the residue was triturated with diluted HCI and dried to afford pure product.

[0745] LCMS (ESI+) m / z 444.2 [M+H]+

[0746] Step 6: 2-(5-(5-(l-Acetylpiperidin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (7% yield), using 2-(5-(5-(l-acetyl-l,2,3,6-tetrahydropyridin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (80 mg, 0.181 mmol) as starting material.

[0747] LCMS (ESI+) m / z 446.1 [M+H]+

[0748] NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 6.80 (d, J = 6.8 Hz, 1H), 4.69 - 4.37 (m, 1H), 4.00 - 3.82 (m, 1H), 3.69 (s, 2H), 3.21 - 2.99 (m, 1H), 3.01 - 2.81 (m, 1H), 2.64 - 2.51 (m, 1H), 2.01 (s, 3H), 1.93 - 1.76 (m, 2H), 1.74

[0749] - 1.59 (m, 1H), 1.58 - 1.41 (m, 1H).

[0750] Example 1-053: Synthesis of 2-(5-(5-(l-(methylsulfonyl)piperidin-4-yl)-2-

[0751] (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 8)

[0752] Step 1: 4-(3-Bromo-4-(trifluoromethyl)phenyl)-l-(methylsulfonyl)-l,2,3,6-tetrahydropyridine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (64% yield), using 4-(3-bromo-4-(trifluoromethyl)phenyl)-l,2,3,6-tetrahydropyridine trifluoroacetate (350 mg,

[0753] 1.144 mmol, 1 equiv) and methanesulfonyl chloride (2 equiv) as starting materials.

[0754] LCMS (ESI+) m / z 382.0, 384.0 [M+H]+

[0755] Step 2: Methyl 2-(5-(5-(l-(methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-

[0756] (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 4-(3-bromo-4-(trifluoromethyl)phenyl)- l-(methylsulfonyl)-l,2,3,6-tetrahydropyridine (120 mg, 0.313 mmol, 1 equiv) and methyl 2-(5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion of the reaction the solvent was evaporated to give crude product which was used in the next step.

[0757] LCMS (ESI+) m / z 494.1 [M+H]+

[0758] Step 3: 2-(5-(5-(l-(Methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-

[0759] (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (53% yield over two steps), using methyl 2-(5-(5-(l-(methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-

[0760] (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material. After completion the solvents were removed under reduced pressure, the residue was triturated with diluted HCI and dried to afford pure product.

[0761] LCMS (ESI+) m / z 480.1 [M+H]+

[0762] Step 4: 2-(5-(5-(l-(Methylsulfonyl)piperidin-4-yl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (27% yield), using 2-(5-(5-(l-(methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2- (trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (80 mg, 0.167 mmol) as starting material.

[0763] LCMS (ESI+) m / z 482.1 [M+H]+

[0764] TH NMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.40 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.69 (d, J = 10.8 Hz, 2H), 3.60 (s, 2H), 2.90 (s, 3H), 2.81 (t, J = 11.2 Hz, 3H), 2.02 - 1.89 (m, 2H), 1.86 - 1.65 (m, 2H).

[0765] Example 1-054: Synthesis of 2-(5-(5-chloro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 19) Step 1: Methyl 2-(5-(5-chloro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (135 mg, 0.425 mmol, 1.1 equiv) and 2-bromo-4-chloro-l-(trifluoromethyl)benzene [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0766] LCMS (ESI+) m / z 369.2 [M+H]+

[0767] Step 2: 2-(5-(5-Chloro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (25% yield over 2 steps), using methyl 2-(5-(5-chloro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate as a starting material.

[0768] LCMS (ESI+) m / z 355.1, 357.1 [M+H]+

[0769] 'H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.3 Hz, 1H), 7.96 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 9.6 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 3.66 (s, 2H).

[0770] Example 1-055: Synthesis of 2-(5-(5-fluoro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 21)

[0771] Step 1: 2-(5-(5-Fluoro-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (65% yield), using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (79 mg, 0.247 mmol, 1 equiv) and 2-bromo-4-fluoro-l-(trifluoromethyl)benzene [commercial] (1 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv). LCMS (ESI+) m / z 339.0 [M+H]

[0772] 1H NMR (400 MHz, DMSO-cfe) 6 8.64 (d, J = 7.0 Hz, 1H), 7.99 - 7.89 (m, 2H), 7.62 (s, 1H), 7.51 (t, J = 8.6 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 6.8 Hz, 1H), 3.49 (s, 2H).

[0773] Example 1-056: Synthesis of 2-(5-(5-methyl-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 18)

[0774] Step 1: Methyl 2-(5-(5-methyl-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (100 mg, 0.315 mmol, 1 equiv) and 2-bromo-4-methyl-l-(trifluoromethyl)benzene [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0775] LCMS (ESI+) m / z 349.2 [M+H]+

[0776] Step 2: 2-(5-(5-Methyl-2-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (15% yield over two steps), using methyl 2-(5-(5-methyl-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate as starting material.

[0777] LCMS (ESI-) m / z 333.1 [M-H]’

[0778] TH NMR (400 MHz, DMSO-d6, 373K) 6 8.61 (d, J = 7.2 Hz, 1H), 7.94 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 6.78 (d, J = 6.8 Hz, 1H), 3.71 (s, 2H), 2.44 (s, 3H). Example 1-057: Synthesis of 2-(5-(3-(trifluoromethyl)pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid

[0779] (Compound 16)

[0780] Step 1: Methyl 2-(5-(3-(trifluoromethyl)pyridin-4-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, using methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (105 mg, 0.332 mmol, 1 equiv) and 4-bromo-3-(trifluoromethyl)pyridine [commercial] (1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.1 equiv). After completion the solvent was evaporated and the crude product was used in the next step without additional purification.

[0781] LCMS (ESI+) m / z 336.1 [M+H]+

[0782] Step 2: 2-(5-(3-(Trifluoromethyl)pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (22% yield over two steps), using methyl 2-(5-(3-(trifluoromethyl)pyridin-4-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate as a starting material.

[0783] LCMS (ESI-) m / z 320.0 [M-H]’

[0784] NMR (400 MHz, DMSO-d6, 373K) 69.03 (s, 1H), 8.92 (d, J = 5.2 Hz, 1H), 8.67 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.57 (d, J = 5.2 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H), 3.70 (s, 2H).

[0785] Example 1-058: Synthesis of 2-(5-(5-(4-methoxycyclohexyl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 14)

[0786] Step 1: 3'-Bromo-4-methoxy-4'-(trifluoromethyl)-2,3,4,5-tetrahydro-l,l'-biphenyl was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (41% yield), using 2- bromo-4-iodo-l-(trifluoromethyl)benzene (280 mg, 0.8 mmol, 1.11 equiv) and 2-(4-methoxycyclohex-l- en-l-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane [commercial] (1 equiv) as starting materials, K3PO4(3.33 equiv) as base and Pd(PPh3)2Cl2 as catalyst (0.11 equiv).

[0787] GCMS (ESI+) m / z 335.9 [M+H]+

[0788] Step 2: Methyl 2-(5-(4'-methoxy-4-(trifluoromethyl)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-3- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 3'-bromo-4-methoxy-4'-(trifluoromethyl)-2, 3,4,5- tetrahydro-l,l'-biphenyl (120 mg, 0.359 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Ch as catalyst (0.1 equiv). After completion of the reaction the solvent was evaporated to give crude mixture of product and 2-(5-(4'-methoxy-4-(trifluoromethyl)-2',3',4',5'-tetrahydro-[l,l'- biphenyl]-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid which was used directly in the next step.

[0789] LCMS (ESI+) m / z 445.1 [M+H] Step 3: 2-(5-(4'-Methoxy-4-(trifluoromethyl)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-3-yl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above, using mixture of methyl 2-(5-(4'-methoxy-4-(trifluoromethyl)-2',3',4',5'- tetrahydro-[l,l'-biphenyl]-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate and 2-(5-(4'-methoxy-4- (trifluoromethyl)-2',3',4',5'-tetrahydro-[l,l'-biphenyl]-3-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid as starting materials. After completion the solvents were removed under reduced pressure and crude product was used directly in the next step.

[0790] LCMS (ESI+) m / z 431.2 [M+H]+

[0791] Step 4: 2-(5-(5-(4-Methoxycyclohexyl)-2-(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 6 and Example Method 6, above (16% yield over three steps), using 2-(5-(4'-methoxy-4-(trifluoromethyl)-2',3',4',5'-tetrahydro-[l,r- biphenyl]-3-yl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid as starting material.

[0792] LCMS (ESI+) m / z 433.2 [M+H]+

[0793] NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.2 Hz, 1H), 7.96 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.30 (s, 1H), 6.81 (d, J = 7.1 Hz, 1H), 3.71 (s, 2H), 3.51 - 3.44 (m, 1H), 3.23 (s, 3H), 2.82 - 2.58 (m, 1H), 2.01 - 1.92 (m, 2H), 1.79 - 1.45 (m, 6H).

[0794] Example 1-059: Synthesis of 2-(5-(2-(cyclohexyloxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 5)

[0795] Step 1: To a stirred solution of 2-bromo-3-(trifluoromethyl)phenol (200 mg, 0.83 mmol, 1 equiv) in THF (3 mL), cooled in an ice-water bath, were added PPh3(1.5 equiv), DIAD (1.5 equiv) and cyclohexanol (1 equiv) and the resulting mixture was stirred at RT for 16 h. After completion, the reaction was quenched with saturated NaHCO3solution and extracted with ethyl acetate. The combined organic fractions were washed with brine, dried over NajSCU and evaporated to give crude product. 2-Bromo-l-(cyclohexyloxy)-3- (trifluoromethyl)benzene (160 mg, 0.49 mmol, 59% yield) was purified by flash column chromatography.

[0796] NMR (400 MHz, CDCI3) 6 7.36 - 7.22 (m, 2H), 7.07 (d, J = 8.1 Hz, 1H), 4.44 - 4.28 (m, 1H), 1.91 (d, J = 10.8 Hz, 2H), 1.87 (m, 2H), 1.76 - 1.62 (m, 2H), 1.41 (d, J = 8.4 Hz, 4H).

[0797] Step 2: Methyl 2-(5-(2-(cyclohexyloxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-bromo-l-(cyclohexyloxy)-3-(trifluoromethyl)benzene (100 mg, 0.311 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, CS2CO3 (3 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion, the solvents were evaporated, the residue was quenched with water, extracted with ethyl acetate and dried over Na2SO4. The organic layer was concentrated to afford crude product which was used directly in the next step.

[0798] LCMS (ESI+) m / z 432.8 [M+H]+

[0799] Step 3: 2-(5-(2-(Cyclohexyloxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (23% yield over two steps), using methyl 2-(5-(2-(cyclohexyloxy)-6-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0800] LCMS (ESI+) m / z 419.1 [M+H]+

[0801] TH NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.1 Hz, 1H), 7.91 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 6.67 (dd, J = 1.2, 7.1 Hz, 1H), 4.49 - 4.38 (m, 1H), 3.65 (s, 2H), 1.92 - 1.59 (m, 2H), 1.53 - 1.04 (m, 8H).

[0802] Example 1-060: Synthesis of 2-(5-(2,5-bis((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 2)

[0803] Step 1: To a stirred solution of 2-bromo-l,4-diiodobenzene (1.0 g, 2.45 mmol, 1 equiv) in dioxane (5 mL) were added (4-methoxyphenyl)methanethiol (1.9 equiv) and DIPEA (6 equiv). The mixture was then bubbled with argon for 10 min and XantPhos (0.2 equiv) and Pd?(dba)3 (0.1 equiv) were added and the mixture was further bubbled with argon for 5 min and stirred in a sealed tube at 90°C for 3 h. After completion the volatiles were removed under reduced pressure and (2-bromo-l,4-phenylene)bis((4- methoxybenzyl)sulfane) (400 mg, 0.87 mmol, 35% yield) was purified by flash column chromatography.

[0804] GCMS (ESI+) m / z 462.1 [M+H]+

[0805] Step 2: To a stirred solution of (2-bromo-l,4-phenylene)bis((4-methoxybenzyl)sulfane) (340 mg, 0.74 mmol, 1 equiv) in ACN (5 mL) were added AcOH (0.3 mL), water (0.3 mL) and the solution was cooled to 0°C. After 10 min l,3-dichloro-5,5-dimethylhydantoin (6 equiv) was added and the reaction was stirred at RT for 1 h. After completion, the reaction was quenched with water and extracted with DCM. The combined organic fractions were washed with brine, dried over NajSCU and evaporated to afford crude 2- bromobenzene-l,4-disulfonyl dichloride, which was forwarded directly for the next step.

[0806] Step 3: l,l'-(2-Bromo-l,4-phenylenedisulfonyl)bis(4-methoxypiperidine) was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (43% yield over two steps), using 2-bromobenzene-l,4-disulfonyl dichloride (260 mg, 0.739 mmol, 1 equiv) and 4-methoxypiperidine (37 equiv) as starting materials.

[0807] LCMS (ESI+) m / z 511.0, 513.0 [M+H]+ Step 4: 2-(5-(2,5-Bis((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (50% yield), using l,l'-(2-bromo-l,4-phenylenedisulfonyl)bis(4-methoxypiperidine) (100 mg, 0.196 mmol,

[0808] 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3- yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0809] LCMS (ESI+) m / z 607.1 [M+H]+

[0810] TH NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.1 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 8.08 - 7.90 (m, 2H), 7.69 (d, J = 13.2 Hz, 2H), 6.89 (d, J = 6.9 Hz, 1H), 3.73 (s, 2H), 3.29-3.11 (m, 10H), 3.14 - 2.99 (m, 2H), 2.88 (t, J = 4.9 Hz, 2H), 2.80 - 2.69 (m, 2H), 1.95 - 1.76 (m, 2H), 1.72 - 1.43 (m, 4H), 1.38 - 1.20 (m, 2H).

[0811] Example 1-061: Synthesis of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)-4-methylpyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 3)

[0812] Step 1: 2-(5-Bromo-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (73% yield), using 2-(5-bromo-4- methylpyrazolo[l,5-o]pyridin-3-yl)acetonitrile (700 mg, 2.789 mmol) as starting material. After completion the reaction mixture was diluted with cold water, washed with ether and acidified with IM HCI. The precipitated product was filtered and dried to afford pure product.

[0813] LCMS (ESI+) m / z 269.1 [M+H]+ Step 2: To a stirred solution of 2-(5-bromo-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetic acid (550 mg, 2.157 mmol) in methanol (10 mL) was added H2SO4 (0.5 mL) at RT and the solution was heated at 85°C for 6 h. After completion the solvent was evaporated and the residue was taken up in water and extracted with ethyl acetate. The organic layer was dried over NazSCU and concentrated to give pure methyl 2-(5-bromo- 4-methylpyrazolo[l,5-o]pyridin-3-yl)acetate (520 mg, 85% yield).

[0814] LCMS (ESI+) m / z 283.2, 285.0 [M+H]+

[0815] Step 3: Methyl 2-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 9 and Example Method 9, above (46% yield), using methyl 2-(5-bromo-4-methylpyrazolo[l,5-a]pyridin-3-yl)acetate (500 mg, 1.943 mmol, 1 equiv) as starting material.

[0816] LCMS (ESI+) m / z 331.33 [M+H]+

[0817] Step 4: 2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)-4-methylpyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (3.8% yield), using l-((2-bromophenyl)sulfonyl)-4-methoxypiperidine (100 mg, 0.299 mmol, 1 equiv) and methyl 2-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3- yl)acetate as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 (0.1 equiv) as catalyst.

[0818] LCMS (ESI+) m / z 444.1 [M+H]+

[0819] TH NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 7.1 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.83 (s, 1H), 7.78 - 7.70 (m, 1H), 7.70 - 7.62 (m, 1H), 7.33 (dd, J = 7.4, 1.4 Hz, 1H), 6.56 (d, J = 7.0 Hz, 1H), 3.73 (s, 2H), 3.28 - 3.20 (m, 1H), 3.17 (s, 3H), 3.08 - 2.95 (m, 2H), 2.76 - 2.64 (m, 2H), 2.18 (s, 3H), 1.77 - 1.64 (m, 2H), 1.44 - 1.28 (m, 2H).

[0820] Example 1-062: Synthesis of 2-(5-(2,5-bis((4-methoxypiperidin-l-yl)sulfonyl)phenyl)-4- methylpyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1)

[0821] Step 1: 2-(5-(2,5-Bis((4-methoxypiperidin-l-yl)sulfonyl)phenyl)-4-methylpyrazolo[l,5-a]pyridin-3- yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (26% yield), using l,l'-(2-bromo-l,4-phenylenedisulfonyl)bis(4-methoxypiperidine) (120 mg, 0.235 mmol, 1 equiv) and methyl 2-(4-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0822] LCMS (ESI+) m / z 621.1 [M+H]+

[0823] NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 6.9 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.60 (s, 1H), 6.65 (d, J = 7.1 Hz, 1H), 3.82 (s, 2H), 3.28 - 3.23 (m, 2H), 3.18 - 3.14 (m, 8H), 3.08 - 2.99 (m, 2H), 2.94 - 2.83 (m, 2H), 2.78 - 2.69 (m, 2H), 2.19 (s, 3H), 1.85 - 1.79 (m, 2H), 1.75 - 1.69 (m, 2H), 1.53 - 1.44 (m, 2H), 1.39 - 1.32 (m, 2H).

[0824] Example 1-063: Synthesis of 2-(5-(2,6-bis(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 43)

[0825] Step 1: Methyl 2-(5-(2,6-bis(trifluoromethyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-bromo- l,3-bis(trifluoromethyl)benzene [commercial] (100 mg, 0.316 mmol, 1.25 equiv) and methyl 2-(5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (5 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.23 equiv). After completion, the reaction mixture was filtered through Celite® and solvent was evaporated. The crude product was used in the next step without additional purification.

[0826] LCMS (ESI+) m / z 403.2 [M+H]+

[0827] Step 2: 2-(5-(2,6-Bis(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (27% yield over 2 steps), using methyl 2-(5-(2,6-bis(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0828] LCMS (ESI+) m / z 389.1 [M+H]+

[0829] NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 7.1 Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.97 (s, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.61 (s, 1H), 6.80 (d, J = 6.9 Hz, 1H), 3.66 (s, 2H).

[0830] Example 1-064: Synthesis of 2-(5-(p-tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 35)

[0831] Step 1: 2-(5-(p-Tolyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (48% yield), using 2-(5-bromopyrazolo[l,5- o]pyridin-3-yl)acetic acid (70 mg, 0.276 mmol, 1 equiv) and p-tolylboronic acid [commercial] (1.5 equiv) as starting materials, Cs2CO3(4 equiv) as base, Pd(dtbpf)CI2as catalyst (0.3 equiv).

[0832] LCMS (ESI+) m / z 267.2 [M+H]+

[0833] TH NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.3 Hz, 1H), 7.92 (s, 1H), 7.85 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 6.3 Hz, 1H), 3.58 (s, 2H), 2.36 (s, 3H). Example 1-065: Synthesis of 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 52)

[0834] Step 1: Methyl 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (100 mg, 0.316 mmol, 1.25 equiv) and l-(7-bromo-3,4-dihydroisoquinolin-2(lH)-yl)ethan-l-one [commercial] (1 equiv) as starting materials, CS2CO3 (5 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.125 equiv). After completion the solvents were evaporated, the residue was quenched with IM HCI and extracted with DCM. The organic layer was evaporated to afford crude product which was used directly in the next step.

[0835] LCMS (ESI+) m / z 364.0 [M+H]+

[0836] Step 2: 2-(5-(2-Acetyl-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (43% yield over two steps), using methyl 2-(5-(2-acetyl-l,2,3,4-tetrahydroisoquinolin-7-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0837] LCMS (ESI+) m / z 350.1 [M+H]+

[0838] TH NMR (400 MHz, DMSO-d6) δ 8.64 (dd, J = 7.3, 5.6 Hz, 1H), 7.97 (dd, J = 8.9, 2.0 Hz, 1H), 7.87 (s, 1H), 7.69 - 7.64 (m, 1H), 7.61 (dt, J = 8.1, 2.6 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.17 (ddd, J = 7.4, 5.3, 2.0 Hz, 1H), 4.73 (s, 1H), 4.69 (s, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.63 (d, J = 6.8 Hz, 2H), 2.91 (t, J = 6.0 Hz, 1H), 2.79 (t, J = 6.0 Hz, 1H), 2.10 (d, J = 3.5 Hz, 3H).

[0839] Example 1-066: Synthesis of 2-(5-(2-(piperidin-l-ylsulfonyl)-6-(trifluoromethyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 40)

[0840] Step 1: l-((2-Bromo-3-(trifluoromethyl)phenyl)sulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (47% yield), using 2-bromo-3- (trifluoromethyl)benzenesulfonyl chloride [commercial] (185 mg, 0.572 mmol, 1 equiv) and piperidine (3 equiv) as starting materials.

[0841] GCMS (ESI+) m / z 372.0 [M+H]+

[0842] Step 2: Methyl 2-(5-(2-(piperidin-l-ylsulfonyl)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromo-3-(trifluoromethyl)phenyl)sulfonyl)piperidine (50 mg, 0.135 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the solvent was evaporated and the resulting crude was forwarded into the next step.

[0843] LCMS (ESI+) m / z 482.3 [M+H]+

[0844] Step 3: 2-(5-(2-(Piperidin-l-ylsulfonyl)-6-(trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (8% yield over two steps), using methyl 2-(5-(2-(piperidin-l-ylsulfonyl)-6- (trifluoromethyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0845] LCMS (ESI+) m / z 468.0 [M+H]+

[0846] NMR (400 MHz, DMSO-d6) δ 12.41 - 12.17 (s, 1H), 8.60 (d, J = 7.2 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H), 8.17 (t, J = 7.2 Hz, 1H), 7.95 (s, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.51 (d, J = 11.8 Hz, 1H), 6.76 (d, J = 6.5 Hz, 1H), 3.69 (s, 2H), 2.90 - 2.75 (m, 4H), 1.40 (s, 6H). Example 1-067: Synthesis of 2-(5-(4-methyl-2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (Compound 25)

[0847] Step 1: l-((2-Bromo-5-methylphenyl)sulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (67% yield), using 2-bromo-5- methylbenzenesulfonyl chloride [commercial] (150 mg, 0.557 mmol, 1 equiv) and piperidine (2 equiv) as starting materials. After completion the reaction mixture was diluted with cold water and extracted with DCM. The organic fraction was dried over NajSCU and evaporated to give crude product.

[0848] LCMS (ESI+) m / z 317.9 [M+H]+

[0849] Step 2: Methyl 2-(5-(4-methyl-2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromo-5-methylphenyl)sulfonyl)piperidine (60 mg, 0.189 mmol, 1 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dppf)Ck as catalyst (0.1 equiv). After completion the solvent was evaporated and the resulting crude was forwarded into the next step.

[0850] LCMS (ESI+) m / z 427.7 [M+H]+

[0851] Step 3: 2-(5-(4-Methyl-2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (44% yield over two steps), using methyl 2-(5-(4-methyl-2-(piperidin-l-ylsulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetate as starting material.

[0852] LCMS (ESI+) m / z 414.1 [M+H] NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 7.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 1H), 7.54 (d, J = 9.3 Hz, 2H), 7.34 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.61 (s, 2H), 2.78 (d, J = 6.2 Hz, 4H), 2.46 (s, 3H), 1.53 - 1.16 (m, 6H).

[0853] Example 1-068: Synthesis of 2-(5-(2-((3-(2-methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 46)

[0854] Step 1: To a stirred solution of tert-butyl 3-hydroxypiperidine-l-carboxylate (1.0 g, 4.97 mmol, 1 equiv) in THF (6 mL), cooled in an ice-water bath, was added NaH (2 equiv, 60% suspension in mineral oil) followed by l-bromo-2-methoxyethane (1.2 equiv). The reaction mixture was stirred at RT for 3 h, quenched with cold water and extracted with DCM. Combined organic fractions were dried over NajSCU and evaporated. tert-Butyl 3-(2-methoxyethoxy)piperidine-l-carboxylate (800 mg, 3.1 mmol, 62% yield) was purified by flash column chromatography.

[0855] XH NMR (400 MHz, DMSO-d6) δ 4.81 (d, J = 4.2 Hz, 1H), 4.03 (qd, J = 7.1, 1.9 Hz, 1H), 3.74 (s, 1H), 3.64 - 3.54 (m, 1H), 3.37 (d, J = 7.2 Hz, 1H), 2.77 (s, 1H), 2.61 (s, 2H), 1.98 (d, J = 2.0 Hz, 3H), 1.80 (q, J = 5.8 Hz, 1H), 1.67 - 1.55 (m, 1H), 1.38 (d, J = 2.1 Hz, 9H), 1.27 (dq, J = 10.5, 6.7 Hz, 2H), 1.17 (td, J = 7.1, 2.0 Hz, 1H). Step 2: 3-(2-Methoxyethoxy)piperidine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (47% yield), using tert-butyl 3-(2- methoxyethoxy)piperidine-l-carboxylate (300 mg, 1.15 mmol) as starting material. After completion of the reaction the volatiles were removed under reduced pressure to afford crude product which was directly forwarded to the next step.

[0856] Step 3: l-((2-Bromophenyl)sulfonyl)-3-(2-methoxyethoxy)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (76% yield), using 3-(2- methoxyethoxy)piperidine trifluoroacetate (700 mg, 2.76 mmol, 1 equiv) and 2-bromobenzenesulfonyl chloride (1.2 equiv) as starting materials.

[0857] LCMS (ESI+) m / z 378.0, 380.0 [M+H]+

[0858] Step 4: Methyl 2-(5-(2-((3-(2-methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-3-(2-methoxyethoxy)piperidine (100 mg, 0.265 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetate (1.5 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dppf)Ck as catalyst (0.1 equiv). After completion the reaction was quenched with IM HCI and the volatiles were removed under reduced pressure. The obtained crude product was forwarded into the next step.

[0859] LCMS (ESI+) m / z 487.9 [M+H]+

[0860] Step 5: 2-(5-(2-((3-(2-Methoxyethoxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (27% yield over two steps), using methyl 2-(5-(2-((3-(2-methoxyethoxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate as starting material.

[0861] LCMS (ESI+) m / z 474.2 [M+H]+

[0862] NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 7.2 Hz, 1H), 8.01 (dd, J = 7.9, 1.4 Hz, 1H), 7.90 (s, 1H), 7.75 (td, J = 7.5, 1.4 Hz, 1H), 7.66 (td, J = 7.7, 1.5 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 7.5, 1.4 Hz, 1H), 6.83 (dd, J = 7.2, 2.0 Hz, 1H), 3.56 (s, 2H), 3.32 - 3.31 (m, 4H), 3.17 (s, 3H), 3.17 - 3.11 (m, 1H), 3.10 - 3.02 (m, 2H), 2.91 (d, J = 12.3 Hz, 1H), 2.64 - 2.56 (m, 1H), 1.78 - 1.65 (m, 1H), 1.65 - 1.49 (m, 1H), 1.30 - 1.12 (m,

[0863] 2H).

[0864] Example 1-069: Synthesis of 2-(5-(2-((3-(methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 38)

[0865] Step 1: l-((2-Bromophenyl)sulfonyl)-3-(methoxymethyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (51% yield), using 2- bromobenzenesulfonyl chloride (200 mg, 0.784 mmol, 1 equiv) and 3-(methoxymethyl)piperidine (1.2 equiv) as starting materials.

[0866] LCMS (ESI+) m / z 348.0, 349.8 [M+H]+

[0867] Step 2: 2-(5-(2-((3-(Methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (32% yield), using l-((2-bromophenyl)sulfonyl)-3-(methoxymethyl)piperidine (88 mg, 0.253 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetate (1.25 equiv) as starting materials, CS2CO3 (5 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.126 equiv).

[0868] LCMS (ESI+) m / z 444.1 [M+H]+

[0869] TH NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 7.2 Hz, 1H), 7.97 (d, J = 6.7 Hz, 1H), 7.93 (s, 1H), 7.78 - 7.72 (m, 1H), 7.70 - 7.65 (m, 1H), 7.57 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 3.67 (s, 2H), 3.26 - 3.15 (m, 3H), 3.10 (s, 3H), 3.02 - 2.93 (m, 1H), 2.40 - 2.32 (m, 1H), 2.22 - 2.12 (m, 1H), 1.51 (m, 3H), 1.23 - 1.09 (m, 1H), 0.96 - 0.89 (m, 1H). Example 1-070: Synthesis of 3-((lH-tetrazol-5-yl)methyl)-5-(2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a] pyridine (Compound 72)

[0870] Step 1: 4-Methoxy-l-((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 9 and Example Method 9, above (98% yield), using l-((2-bromophenyl)sulfonyl)-4-methoxypiperidine (3 g, 9.009 mmol, 1 equiv) as starting material.

[0871] LCMS (ESI+) m / z 382.1 [M+H]+

[0872] Step 2: 2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetonitrile was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (37% yield), using 4-methoxy-l-((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine (100 mg, 0.262 mmol, 1 equiv) and 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetonitrile (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv).

[0873] LCMS (ESI+) m / z 411.1 [M+H]+

[0874] Step 3: To a stirred solution of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin- 3-yl)acetonitrile (40 mg, 0.097 mmol, 1 equiv) in DMF (1 mL) were added sodium azide (20 mg, 0.292 mmol, 3 equiv) and zinc bromide (65 mg, 0.292 mmol, 3 equiv) and the reaction mixture was stirred at 140°C for 16 h. After completion, 3-((lH-tetrazol-5-yl)methyl)-5-(2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridine (24 mg, 54% yield) was purified by preparative HPLC.

[0875] LCMS (ESI+) m / z 454.2 [M+H] NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.1 Hz, 1H), 4.27 (s, 2H), 3.14 (m, 4H), 3.02 - 2.88 (m, 2H), 2.61 (d, J = 10.2 Hz, 2H), 1.59 (s, 2H), 1.26 (d, J = 13.7 Hz, 2H).

[0876] Example 1-071: Synthesis of 2-(5-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1002)

[0877] Step 1: 2-(5-(2-((4-(tert-Butoxycarbonyl)piperazin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using tert-butyl 4-((2-bromophenyl)sulfonyl)piperazine-l-carboxylate (500 mg, 1.235 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetate (1.1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the solvent was evaporated and the resulting crude was forwarded into the next step.

[0878] LCMS (ESI+) m / z 501.0 [M+H]+ Step 2: 2-(5-(2-(Piperazin-l-ylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using 2-(5-(2-((4-(tert-butoxycarbonyl)piperazin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid as starting material. After completion of the reaction the volatiles were removed under reduced pressure and the crude product was directly forwarded into the next step.

[0879] LCMS (ESI+) m / z 401.2 [M+H]+

[0880] Step 3: To a stirred solution of 2-(5-(2-(piperazin-l-ylsulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid trifluoroacetate (200 mg, 0.39 mmol, 1 equiv) in DMSO (2 mL) were added 2-(2,6-dioxopiperidin-3- yl)-5,6-difluoroisoindoline-l, 3-dione (1.1 equiv) and DIPEA (2 equiv) at RT. The reaction mixture was stirred at 110°C for 6 h. After completion 2-(5-(2-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (30 mg, 3.6% yield over three steps) was purified by preparative HPLC.

[0881] LCMS (ESI-) m / z 673.0 [M-H]’

[0882] NMR (400 MHz, DMSO-d6) δ 13.31 - 11.63 (s, 1H), 11.30 - 10.81 (s, 1H), 8.63 (d, J = 7.1 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.94 (s, 1H), 7.84 - 7.67 (m, 3H), 7.64 (s, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 5.10 (dd, J = 5.4, 12.8 Hz, 1H), 3.70 (s, 2H), 3.21 - 2.96 (m, 8H), 2.95 - 2.81 (m, 1H), 2.74 - 2.54 (m, 2H), 2.10 - 1.99 (m, 1H).

[0883] Example 1-072: Synthesis of 2-(5-(2-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1003)

[0884]

[0885] Step 1: tert-Butyl 4-(l-((2-bromophenyl)sulfonyl)piperidin-4-yl)piperazine-l-carboxylate was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (68% yield), using 2-bromobenzenesulfonyl chloride (500 mg, 1.961 mmol, 1 equiv) and tert-butyl 4-(piperidin-4- yl)piperazine-l-carboxylate [commercial] (1.1 equiv) as starting materials.

[0886] NMR (400 MHz, DMSO-d6) δ 8.05 - 7.95 (m, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 9.0 Hz, 2H), 3.71 - 3.67 (m, 2H), 3.27-3.22 (m, 4H) 2.79 - 2.61 (m, 2H), 2.41 - 2.30 (m, 6H), 1.79 - 1.69 (m, 2H), 1.38 (s, 9H).

[0887] Step 2: tert-Butyl 4-(l-((2-(3-(2-methoxy-2-oxoethyl)pyrazolo[l,5-o]pyridin-5- yl)phenyl)sulfonyl)piperidin-4-yl)piperazine-l-carboxylate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using tert-butyl 4-(l-((2- bromophenyl)sulfonyl)piperidin-4-yl)piperazine-l-carboxylate (150 mg, 0.308 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (4 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the solvent was evaporated and the resulting crude was forwarded into the next step.

[0888] LCMS (ESI+) m / z 598.4 [M+H]+

[0889] Step 3: 2-(5-(2-((4-(4-(tert-Butoxycarbonyl)piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above, using tert-butyl 4-(l-((2-(3-(2-methoxy-2-oxoethyl)pyrazolo[l,5-o]pyridin-5- yl)phenyl)sulfonyl)piperidin-4-yl)piperazine-l-carboxylate as starting material.

[0890] LCMS (ESI+) m / z 584.2 [M+H]+

[0891] Step 4: 2-(5-(2-((4-(Piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using 2-(5-(2-((4-(4-(tert-butoxycarbonyl)piperazin-l-yl)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid as starting material. After completion of the reaction the volatiles were removed under reduced pressure and the crude product was directly forwarded into the next step.

[0892] LCMS (ESI+) m / z 484.6 [M+H]+

[0893] Step 5: To a stirred solution of 2-(5-(2-((4-(piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid trifluoroacetate (130 mg, 0.218 mmol, 1.11 equiv) in DMSO (3 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-l, 3-dione (1 equiv) and DIPEA (3 equiv) at RT. The reaction mixture was stirred at 110°C for 2 h. After completion 2-(5-(2-((4-(4-(2-(2,6-dioxopiperidin-3-yl)- 6-fluoro-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetic acid (16 mg, 6.85% yield over four steps) was purified by preparative HPLC.

[0894] LCMS (ESI+) m / z 758.1 [M+H]+

[0895] NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.96 (s, 1H), 7.82 - 7.64 (m, 3H), 7.60 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 7.3 Hz, 1H), 6.89 (dd, J = 1.5, 7.1 Hz, 1H), 5.10 (dd, J = 5.3, 12.8 Hz, 1H), 3.72 (s, 2H), 3.22 - 3.09 (m, 4H), 3.15 - 2.74 (m, 4H), 2.63 - 2.51 (m, 1H), 2.47 - 2.39 (m, 6H), 2.35 - 2.29 (m, 1H), 2.10 - 1.95 (m, 1H), 1.66 - 1.57 (m, 2H), 1.18 - 0.93 (m, 2H). Example 1-073: Synthesis of (2-(5-(2-((4-(4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5- yl)piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate

[0896] (Compound 1001)

[0897] Step 1: To a stirred solution of 2-(5-(2-((4-(4-(tert-butoxycarbonyl)piperazin-l-yl)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (150 mg, 0.257 mmol, 1 equiv) in DMF (4 mL), cooled in an ice-water bath, were added chloromethyl pivalate (1.5 equiv) and KHCO3(2 equiv). The reaction mixture was stirred at RT for 2 h. After completion the solution was diluted with cold water and extracted with ethyl acetate. The organic fraction was dried over NajSCU and evaporated to give crude tert-butyl 4-(l-((2-(3-(2-oxo-2-((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5-o]pyridin-5- yl)phenyl)sulfonyl)piperidin-4-yl)piperazine-l-carboxylate which was used in the next step.

[0898] LCMS (ESI+) m / z 698.3 [M+H]+

[0899] Step 2: (2-(5-(2-((4-(Piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl 4-(l-((2-(3-(2-oxo-2- ((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5-o]pyridin-5-yl)phenyl)sulfonyl)piperidin-4-yl)piperazine-l- carboxylate as starting material. After completion of the reaction the volatiles were removed under reduced pressure and the crude product was directly forwarded into the next step.

[0900] LCMS (ESI+) m / z 598.4 [M+H]+

[0901] Step 3: To a stirred solution of (2-(5-(2-((4-(piperazin-l-yl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate trifluoroacetate (130 mg, 0.183 mmol, 1.11 equiv) in DMSO (3 mL) were added 2-(2,6-dioxopiperidin-3-yl)-5,6-difluoroisoindoline-l, 3-dione (1 equiv) and DIPEA (3 equiv) at RT. The reaction mixture was stirred at 110°C for 2 h. After completion of the reaction (2-(5-(2-((4-(4-(2- (2,6-dioxopiperidin-3-yl)-6-fluoro-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (12 mg, 5.4% yield over three steps) was purified by preparative HPLC.

[0902] LCMS (ESI+) m / z 872.2 [M+H]+

[0903] 'H NMR (400 MHz, DMSO-d6) δ 11.33 - 10.97 (m, 1H), 8.66 (d, J = 7.0 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.77 (t, J = 7.4 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.60 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 5.71 (s, 2H), 5.14 - 5.06 (m, 1H), 3.91 (s, 2H), 3.30 - 3.28 (m, 5H), 3.19 - 3.14 (m, 4H), 3.00 - 2.78 (m, 1H), 2.78 - 2.59 (m, 1H), 2.48 - 2.37 (m, 4H), 2.37 - 2.24 (m, 1H), 2.12 - 1.97 (m, 2H), 1.98 - 1.88 (m, 1H), 1.71 - 1.56 (m, 2H), 1.21 - 0.96 (s, 9H).

[0904] Example 1-074: Synthesis of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)propanoic acid (Compound 49, S (left) | | | Compound 48, R (right)) Step 1: To a stirred solution of 2-(5-bromopyrazolo[l,5-a]pyridin-3-yl)acetonitrile (500 mg, 2.1 mmol, 1 equiv) in THF (5 mL), cooled to -78°C, was added NaHMDS (3.2 mL, 3.2 mmol, 1.5 equiv, IM solution in THF) and the reaction was stirred for 40 min at the same temperature, lodomethane (1.5 equiv) was added and the reaction mixture was stirred for 1 h at RT, then quenched with water and extracted with ethyl acetate. 2-(5-Bromopyrazolo[l,5-o]pyridin-3-yl)propanenitrile (150 mg, 0.6 mmol, 28% yield) was purified by flash column chromatography.

[0905] TH NMR (400 MHz, DMSO) δ 8.69 (dd, J = 13.7, 7.2 Hz, 1H), 8.12 (d, J = 19.5 Hz, 2H), 7.10 (dd, J = 15.4, 7.7 Hz, 1H), 1.79 (s, 3H), 1.63 (d, J = 7.2 Hz, 1H).

[0906] Step 2: 2-(5-Bromopyrazolo[l,5-o]pyridin-3-yl)propanoic acid was synthesized using the general procedure shown in Reaction Scheme 2 and Example Method 2, above (86% yield), using 2-(5- bromopyrazolo[l,5-o]pyridin-3-yl)propanenitrile (150 mg, 0.6 mmol) as a starting material.

[0907] LCMS (ESI+) m / z 267.0 [M+H]+

[0908] Step 3: 2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)propanoic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)propanoic acid (150 mg, 0.56 mmol, 1 equiv) and 4-methoxy- l-((2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperidine (1 equiv) as starting materials, Cs2CO3(4 equiv) as base and Pd(dtbpf)CI2as catalyst (0.1 equiv). The product (mixture of stereoisomers) was purified by preparative HPLC.

[0909] Separation of the stereoisomers by preparative HPLC: Chiral separation was done on Agilent 1200 series instrument. Column name : CHIRALPAK IG (250 x 21 mm) 5p. Operating at ambient temperature and flow rate 21.0 mL / min. Mobile phase: mixture of 60% hexane, 20% DCM and 20% ethanol.

[0910] Absolute configuration of the stereoisomers was assigned based on crystal structure.

[0911] (S)-2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)propanoic acid

[0912] (Compound 49) (7 mg, 2.8% yield) LCMS (ESI+) m / z 444.1 [M+H]+

[0913] NMR (400 MHz, DMSO-d6) δ 12.83 - 11.77 (s, 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.76 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 3.93 (q, J = 7.2 Hz, 1H), 3.23 - 3.14 (m, 1H), 3.13 (s, 3H), 3.04 - 2.94 (m, 2H), 2.73 - 2.62 (m, 2H), 1.65 - 1.53 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H), 1.38 - 1.17 (m, 2H).

[0914] (R)-2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)propanoic acid (Compound 48) (6 mg, 2.4% yield)

[0915] LCMS (ESI+) m / z 444.1 [M+H]+

[0916] XH NMR (400 MHz, DMSO-d6) δ 12.82 - 11.81 (s, 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.03 - 7.94 (m, 2H), 7.76 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.4 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.0 Hz, 1H), 3.93 (q, J = 7.2 Hz, 1H), 3.19 (dt, J = 4.2, 8.0 Hz, 1H), 3.14 (s, 3H), 3.04 - 2.94 (m, 2H), 2.74 - 2.62 (m, 2H), 1.68 - 1.52 (m, 2H), 1.46 (d, J = 7.1 Hz, 3H), 1.38 - 1.17 (m, 2H).

[0917] Example 1-075: Synthesis of 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidin- l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1007)

[0918]

[0919] Step 1: To a stirred suspension of sodium hydride (173 mg, 60% in mineral oil, 7.2 mmol, 1.5 equiv) in THF (3 mL) and DCM (3 mL), cooled to 0°C, was added l-phenyl-2,5,8,ll,14,17,20-heptaoxadocosan-22-ol [commercial] (2 g, 4.802 mmol, 1 equiv) and the resulting mixture was stirred at RT for 30 min. 1-Chloro- 6-iodohexane (2.36 g, 9.604 mmol, 2 equiv) was added at 0°C and the reaction mixture was stirred at RT for 16 h. After completion, the mixture was quenched with cold water, extracted with ethyl acetate, the organic fraction was dried over Na2SO4and evaporated. 29-Chloro-l-phenyl-2,5,8,ll,14,17,20,23- octaoxanonacosane (1.1 g, 42% yield) was purified by flash column chromatography.

[0920] Step 2: To a solution of 29-chloro-l-phenyl-2,5,8,ll,14,17,20,23-octaoxanonacosane (2 g, 3.73 mmol) in methanol (5 mL) was added Pd / C (280 mg, 10% wt.) and the reaction mixture was stirred at RT under hydrogen atmosphere for 16 h. After completion the solution was filtered through Celite® and evaporated to yield 27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosan-l-ol (1.58 g, 94% yield). Step 3: To a solution of 27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosan-l-ol (180 mg, 0.405 mmol, 1 equiv) in DCM (2 mL), cooled in an ice-water bath, were added TEA (0.17 mL, 1.216 mmol, 3 equiv), DMAP (catalytic) and 4-methylbenzene-l-sulfonyl chloride (115 mg, 0.608 mmol, 1.5 equiv) and the resulting solution was stirred at RT for 3 h. After completion the reaction was diluted with water and extracted with DCM. The organic fraction was dried over Na2SO4and evaporated to give crude product. 27-Chloro- 3,6,9,12,15,18,21-heptaoxaheptacosyl 4-methylbenzenesulfonate (220 mg, 90% yield) was purified by flash column chromatography.

[0921] !H NMR (400 MHz, Chloroform-d) 6 7.85 - 7.75 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.20 - 4.11 (m, 2H), 3.71 - 3.54 (m, 26H), 3.53 (t, J = 6.7 Hz, 2H), 3.45 (t, J = 6.6 Hz, 2H), 2.45 (s, 3H), 1.77 (p, J = 6.9 Hz, 2H), 1.58 (q, J = 7.1 Hz, 2H), 1.49 - 1.35 (m, 4H).

[0922] Step 4: To a suspension of sodium hydride (10 mg, 60% in mineral oil, 0.417 mmol, 2.5 equiv) in DMF (2 mL), cooled in an ice-water bath, was added tert-butyl 4-hydroxypiperidine-l-carboxylate [commercial] (100 mg, 0.167 mmol, 1 equiv) and the mixture was stirred at 0°C for 30 min. 27-Chloro-3,6,9,12,15,18,21- heptaoxaheptacosyl 4-methylbenzenesulfonate (100 mg, 0.167 mmol, 1 equiv) was added and the reaction mixture was stirred at RT for 16 h. After completion, cold water was added and the solution was extracted with ethyl acetate, the organic fraction was dried over Na2SO4and evaporated to yield tert-butyl 4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine-l-carboxylate (52 mg, 49% yield).

[0923] Step 5: 4-((27-Chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (97% yield), using tert-butyl 4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine-l-carboxylate (1 g, 1.59 mmol). After completion the volatiles were removed under reduced pressure and the product was purified by multiple azeotropic evaporation with toluene.

[0924] LCMS (ESI+) m / z 528.3, 530.2 [M+H]+

[0925] Step 6: l-((2-Bromophenyl)sulfonyl)-4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (56% yield), using 4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine trifluoroacetate

[0926] (70 mg, 0.109 mmol, 1 equiv) and 2-bromobenzenesulfonyl chloride (1.2 equiv) as starting materials.

[0927] 1H NMR (400 MHz, Chloroform-d) 6 8.09 (dd, J = 7.8, 1.8 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 (td, J = 7.6, 1.4 Hz, 1H), 7.38 (td, J = 7.6, 1.8 Hz, 1H), 3.69 - 3.54 (m, 24H), 3.51 - 3.41 (m, 11H), 3.21-3.1 (m, 2H), 1.92-1.83 (m, 2H), 1.81-1.73 (m, 2H), 1.61 - 1.53 (m, 4H), 1.49 - 1.31 (m, 4H).

[0928] Step 7: Methyl 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-4-((27- chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidine (200 mg, 0.268 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, CS2CO3 (3 equiv) as base and Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction was diluted with cold water, extracted with ethyl acetate, the organic layer was dried over Na2SO4and evaporated. The crude product was directly used into the next step.

[0929] LCMS (ESI+) m / z 856.0 [M+H]+

[0930] Step 8: 2-(5-(2-((4-((27-Chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (51 mg, 22% yield over two steps), using methyl 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (250 mg, 0.292 mmol) as starting material.

[0931] LCMS (ESI+) m / z 842.3 [M+H]+

[0932] XH NMR (400 MHz, DMSO-d6) δ 12.08 - 11.10 (s, 1H), 8.55 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 3.70 (s, 2H), 3.60 (t, J = 6.4 Hz, 2H), 3.56 - 3.44 (m, 28H), 3.44 - 3.34 (m, 3H), 3.17 - 3.05 (m, 2H), 2.82 - 2.70 (m, 2H), 1.81 - 1.69 (m, 2H), 1.69 - 1.58 (m, 2H), 1.58 - 1.29 (m, 8H). Example 1-076: Synthesis of methyl 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21- heptaoxaheptacosyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (Compound 1006)

[0933] Step 1: To a stirred solution of 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21- heptaoxaheptacosyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (35 mg, 0.042 mmol, 1 equiv) in methanol (1 mL) and ethyl acetate (1 mL) was added trimethylsilyldiazomethane (2M solution in hexanes, 5 equiv) at -10°C and stirred at RT for 1 h. After completion the reaction was quenched with cold water, extracted with ethyl acetate, the organic layer was dried over NajSCU and evaporated. Methyl 2-(5-(2-((4-((27-chloro-3,6,9,12,15,18,21-heptaoxaheptacosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (14 mg, 39% yield) was purified by preparative TLC.

[0934] LCMS (ESI+) m / z 856.6 [M+H]+

[0935] NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.80 (s, 2H), 3.66 - 3.54 (m, 4H), 3.56 - 3.44 (m, 22H), 3.44 - 3.31 (m, 3H), 3.14 - 3.01 (m, 6H), 2.79 - 2.68 (m, 2H), 1.80 - 1.69 (m, 2H), 1.68 - 1.59 (m, 3H), 1.57 - 1.45 (m, 2H), 1.47 - 1.22 (m, 8H).

[0936] Example 1-077: Synthesis of methyl 2-(5-(2-((4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidin- l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (Compound 1004) and 2-(5-(2-((4-((21-chloro- 3,6,9,12,15-pentaoxahenicosyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid

[0937] (Compound 1005)

[0938] Step 1: To a solution of 21-chloro-3,6,9,12,15-pentaoxahenicosan-l-ol [commercial] (700 mg, 1.96 mmol, 1 equiv) in DCM (12 mL), cooled in an ice-water bath, were added TEA (794 mg, 7.86 mmol, 4 equiv), DMAP (catalytic) and 4-methylbenzene-l-sulfonyl chloride (1.3 g, 6.69 mmol, 3.4 equiv) and the reaction mixture was stirred at RT for 3 h. After completion the solution was diluted with water and extracted with ethyl acetate. The organic fraction was dried over Na2SO4and evaporated to give crude product. 21- Chloro-3,6,9,12,15-pentaoxahenicosyl 4-methylbenzenesulfonate (370 mg, 37% yield) was purified by flash column chromatography.

[0939] LCMS (ESI+) m / z 511.2, 513.1 [M+H]+ Step 2: To a solution of tert-butyl 4-hydroxypiperidine-l-carboxylate (124 mg, 0.62 mmol, 1 equiv) in DMF (4 mL), cooled in an ice-water bath, were added sodium hydride (25 mg, 60% suspension in mineral oil, 1.02 mmol, 1.65 equiv) and the mixture was stirred at 0°C for 30 min. 21-Chloro-3,6,9,12,15- pentaoxahenicosyl 4-methylbenzenesulfonate (350 mg, 0.67 mmol, 1.08 equiv) was added at 0°C and the reaction mixture was stirred at RT for 3 h. The solution was diluted with cold water and extracted with ethyl acetate. The organic fraction was evaporated to dryness and the crude tert-butyl 4-((21-chloro- 3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine-l-carboxylate (300 mg) was forwarded into the next step.

[0940] LCMS (ESI+) m / z 540.1 [M+H]+

[0941] Step 3: 4-((21-Chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl 4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine-l-carboxylate (300 mg, 0.55 mmol). After completion the volatiles were removed under reduced pressure and the residue was triturated with pentane to provide crude product which was used directly in the next step.

[0942] LCMS (ESI+) m / z 440.0 [M+H]+

[0943] Step 4: l-((2-Bromophenyl)sulfonyl)-4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (38% yield over three steps), using 4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine trifluoroacetate (300 mg, 0.54 mmol, 1 equiv) and 2-bromobenzenesulfonyl chloride (1.18 equiv) as starting materials.

[0944] LCMS (ESI+) m / z 658.4, 660.2 [M+H]+

[0945] Step 5: Methyl 2-(5-(2-((4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate and 2-(5-(2-((4-((21-chloro-3,6,9,12,15- pentaoxahenicosyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid were synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromophenyl)sulfonyl)-4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidine (120 mg, 0.18 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin- 3-yl)acetate (1.2 equiv) as starting materials, K3PO4 (2 equiv) as base and Pd(dppf)CL as catalyst (0.1 equiv). After completion the products were separated using preparative HPLC.

[0946] Methyl 2-(5-(2-((4-((21-chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate (Compound 1004) (24 mg, 17% yield)

[0947] LCMS (ESI+) m / z 768.4, 770.2 [M+H]+

[0948] TH NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.76 (t, J = 7.4 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.58 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 7.1 Hz, 1H), 3.82 (s, 2H), 3.66 - 3.57 (m, 4H), 3.55 - 3.40 (m, 20H), 3.40 - 3.27 (m, 3H), 3.06 - 2.96 (m, 2H), 2.72 - 2.62 (m, 2H), 1.77 - 1.57 (m, 4H), 1.53 - 1.43 (m, 2H), 1.43 - 1.20 (m, 7H).

[0949] 2-(5-(2-((4-((21-Chloro-3,6,9,12,15-pentaoxahenicosyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 1005) (40 mg, 29% yield)

[0950] LCMS (ESI+) m / z 754.4, 756.2 [M+H]+

[0951] XH NMR (400 MHz, DMSO-d6) δ 13.02 - 11.66 (s, 1H), 8.61 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.75 (t, J = 7.5 Hz, 1H), 7.70 - 7.66 (m, 1H), 7.56 (s, 1H), 7.47 (d, J = 7.4 Hz, 1H), 6.83 (dd, J = 1.8, 7.2 Hz, 1H), 3.71 (s, 2H), 3.61 (t, J = 6.6 Hz, 2H), 3.54 - 3.41 (m, 20H), 3.40 - 3.31 (m, 3H), 3.09 - 2.98 (m, 2H), 2.71 - 2.60 (m, 2H), 1.75 - 1.55 (m, 4H), 1.53 - 1.41 (m, 2H), 1.43 - 1.21 (m, 6H).

[0952] Example 1-078: Synthesis of 2-(5-(2-cyanophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 88)

[0953] Step 1: 2-(5-(2-Cyanophenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (30% yield), using methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (15 mg, 0.047 mmol, 1 equiv) and 2-bromobenzonitrile [commercial] (1 equiv) as starting materials, PdfPPhah (0.1 equiv) as catalyst and sodium carbonate (2 equiv) as base. Once the reaction was completed, IM LiOH aqueous solution (0.95 mL, 0.95 mmol, 20 equiv) was added and the reaction mixture was stirred at RT for 2 h. The solution was neutralized by addition of IM HCI and the product was purified by preparative HPLC.

[0954] LCMS (ESI+) m / z 278.0 [M+H]+

[0955] NMR (500 MHz, DMSO-d6) δ 8.77 (dd, J = 7.2, 1.0 Hz, 1H), 7.99 (d, J = 6.9 Hz, 2H), 7.92 - 7.87 (m, 1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.73 (dd, J = 7.9, 1.2 Hz, 1H), 7.64 (td, J = 7.7, 1.3 Hz, 1H), 7.08 (dd, J = 7.2, 2.1 Hz, 1H), 3.76 (s, 2H).

[0956] Example 1-079: Synthesis of (2-(5-(4-hydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 87)

[0957] Step 1: l-((2-Bromo-5-methoxyphenyl)sulfonyl)-4-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (59% yield), using 2-bromo-5- methoxybenzenesulfonyl chloride [commercial] (8 g, 28.07 mmol, 1 equiv) and 4-methoxypiperidine (1 equiv) as starting materials.

[0958] LCMS (ESI+) m / z 364.0, 366.0 [M+H]+

[0959] Step 2: To a stirred solution of l-((2-bromo-5-methoxyphenyl)sulfonyl)-4-methoxypiperidine (1.5 g, 4.12 mmol, 1 equiv) in DMF (15 mL) was added LiCI (10 equiv) and the reaction mixture was stirred at 150°C for 30 h. The reaction was cooled, quenched with ice-water and extracted with ethyl acetate. The organic fractions were combined, washed with brine, dried over NajSCU and concentrated under reduced pressure. 4-Bromo-3-((4-methoxypiperidin-l-yl)sulfonyl)phenol (700 mg, 2 mmol, 48% yield) was purified by flash column chromatography.

[0960] LCMS (ESI+) m / z 350.1 [M+H]+

[0961] Step 3: (TLS-561, lnt-8, step 5A) To a stirred solution of 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetic acid (6.5 g, 25.59 mmol, 1 equiv) in DMF (5 mL) were added KHCO3(2 equiv) and chloromethyl pivalate (1.5 equiv) and the resulting solution was stirred at RT for 16 h. After completion, the reaction mixture was quenched with ice-water and extracted with ethyl acetate to provide (2-(5-bromopyrazolo[l,5-o]pyridin- 3-yl)acetoxy)methyl pivalate (7.5 g, 20.3 mmol, 79% yield).

[0962] LCMS (ESI+) m / z 368.8, 371.0 [M+H]+

[0963] Step 4: (TLS-561, lnt-8, step 6A) (2-(5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate was synthesized using the general procedure shown in Reaction Scheme 9 and Example Method 9, above (86% yield), using (2-(5-bromopyrazolo[l,5-o]pyridin-3- yl)acetoxy)methyl pivalate (8.2 g, 22.22 mmol, 1 equiv) as starting material.

[0964] LCMS (ESI+) m / z 417.2 [M+H]+

[0965] Step 5: (2-(5-(4-Hydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3- yl)acetoxy)methyl pivalate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (15% yield), using 4-bromo-3-((4-methoxypiperidin-l-yl)sulfonyl)phenol (400 mg, 1.14 mmol, 1 equiv) and (2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3- yl)acetoxy)methyl pivalate (1.2 equiv) as starting materials, Pd(dtbpf)CI2(0.1 equiv) as catalyst and Cs2CO3(2 equiv) as base.

[0966] LCMS (ESI+) m / z 560.1 [M+H]+

[0967] NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.58 (d, J = 7.2 Hz, 1H), 7.92 (s, 1H), 7.50 (s, 1H), 7.36 (s, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 5.70 (s, 2H), 3.88 (s, 2H), 3.15 (m, 4H), 3.02 - 2.94 (m, 2H), 2.73 - 2.63 (m, 2H), 1.60 (s, 2H), 1.33 - 1.26 (m, 2H), 1.05 (s, 9H). Example 1-080: Synthesis of 2-(5-(4-hydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 86)

[0968] Step 1: 2-(5-(4-Hydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (83% yield), using (2-(5-(44iydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (17.5 mg, 0.031 mmol, 1 equiv) as starting material.

[0969] LCMS (ESI+) m / z 446.2 [M+H]+

[0970] NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.91 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.10 (dd, J = 8.4, 2.6 Hz, 1H), 6.78 (dd, J = 7.2, 1.9 Hz, 1H), 3.69 (s, 2H), 3.19 (tt, J = 7.5, 3.5 Hz, 1H), 3.15 (s, 3H), 2.99 (ddd, J = 11.6, 7.1, 3.8 Hz, 2H), 2.67 (ddd, J = 12.2, 8.3, 3.5 Hz, 2H), 1.60 (ddt, J = 13.8, 7.2, 3.6 Hz, 2H), 1.29 (dtd, J = 12.1, 8.0, 3.7 Hz, 2H).

[0971] Example 1-081: Synthesis of 3-((4-methoxypiperidin-l-yl)sulfonyl)-4-(3-(2-oxo-2-

[0972] ((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (Compound 85)

[0973] Step 1: Methyl 4-bromo-3-((4-methoxypiperidin-l-yl)sulfonyl)benzoate was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (93% yield), using methyl 4-bromo- 3-(chlorosulfonyl)benzoate [commercial] (2.5 g, 7.97 mmol, 1 equiv) and 4-methoxypiperidine (1.2 equiv) as starting materials.

[0974] LCMS (ESI+) m / z 392.0, 394.1 [M+H]+ Step 2: 4-Bromo-3-((4-methoxypiperidin-l-yl)sulfonyl)benzoic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (98% yield), using methyl 4-bromo- 3-((4-methoxypiperidin-l-yl)sulfonyl)benzoate (2 g, 1.51 mmol, 1 equiv) as starting material.

[0975] LCMS (ESI+) m / z 376.0, 378.0 [M+H]+

[0976] Step 3: 3-((4-Methoxypiperidin-l-yl)sulfonyl)-4-(3-(2-oxo-2-((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5- o]pyridin-5-yl)benzoic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (35% yield), using 4-bromo-3-((4-methoxypiperidin-l-yl)sulfonyl)benzoic acid (550 mg, 1.45 mmol, 1 equiv) and (2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (1 equiv) as starting materials, Pd(dtbpf)Ck (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[0977] LCMS (ESI+) m / z 588.3 [M+H]+

[0978] NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 7.2 Hz, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.25 (dd, J = 7.9, 1.7 Hz, 1H), 7.97 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 6.89 (dd, J = 7.2, 1.9 Hz, 1H), 5.70 (s, 2H), 3.91 (s, 2H), 3.25 - 3.15 (m, 1H), 3.14 (s, 3H), 3.04 - 2.93 (m, 2H), 2.73 - 2.62 (m, 2H), 1.60 (m, J = 8.8 Hz, 2H), 1.34 - 1.20 (m, 2H), 1.04 (s, 9H).

[0979] Example 1-082: Synthesis of 4-(3-(carboxymethyl)pyrazolo[l,5-a]pyridin-5-yl)-3-((4-methoxypiperidin-l- yl)sulfonyl)benzoic acid (Compound 84)

[0980] Step 1: 4-(3-(Carboxymethyl)pyrazolo[l,5-a]pyridin-5-yl)-3-((4-methoxypiperidin-l-yl)sulfonyl)benzoic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (83% yield), using 3-((4-methoxypiperidin-l-yl)sulfonyl)-4-(3-(2-oxo-2- ((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5-o]pyridin-5-yl)benzoic acid (10 mg, 0.017 mmol, 1 equiv) as starting material.

[0981] LCMS (ESI+) m / z 474.1 [M+H]+

[0982] NMR (500 MHz, DMSO-d6) δ 12.35 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 8.16 (dd, J = 7.9, 1.3 Hz, 1H), 7.94 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 7.2, 1.9 Hz, 1H), 6.73 (s, 1H), 3.72 (s, 2H), 3.20 - 3.18 (m, 1H), 3.14 (s, 3H), 2.99 (ddd, J = 11.6, 7.1, 3.8 Hz, 2H), 2.67 (ddd, J = 12.3, 8.4, 3.7 Hz, 2H), 1.60 (ddt, J = 13.6, 7.1, 3.6 Hz, 2H), 1.29 (dp, J = 12.8, 4.0 Hz, 2H).

[0983] Example 1-083: Synthesis of (2-(5-(4-amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 83)

[0984] Step 1: l-((2-Bromo-5-nitrophenyl)sulfonyl)-4-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (78% yield), using 2-bromo-5- nitrobenzenesulfonyl chloride [commercial] (3.5 g, 11.66 mmol, 1 equiv) and 4-methoxypiperidine (1.5 equiv) as starting materials.

[0985] LCMS (ESI+) m / z 379.0, 380.8 [M+H]+

[0986] Step 2: (2-(5-(2-((4-Methoxypiperidin-l-yl)sulfonyl)-4-nitrophenyl)pyrazolo[l,5-o]pyridin-3- yl)acetoxy)methyl pivalate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (50% yield), using l-((2-bromo-5-nitrophenyl)sulfonyl)-4-methoxypiperidine (400 mg, 1.06 mmol, 1 equiv) and (2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (1.82 equiv) as starting materials, Pd(dtbpf)Ck (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[0987] LCMS (ESI+) m / z 589.3 [M+H] Step 3: To a stirred solution of (2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)-4-nitrophenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (250 mg, 0.42 mmol, 1 equiv) in THF / water system (5 / 2, v / v, 1.4 mL) were added zinc dust (5 equiv) and NH4CI (5 equiv) and the reaction mixture was stirred at 70°C for 2 h. After completion, the solid particles were filtered off and the filtrate was concentrated under reduced pressure. (2-(5-(4-Amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (80 mg, 0.14 mmol, 34% yield) was purified by flash column chromatography.

[0988] LCMS (ESI+) m / z 559.2 [M+H]+

[0989] TH NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 7.3 Hz, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.87 - 6.76 (m, 2H), 5.70 (s, 2H), 3.87 (s, 2H), 3.21 (d, J = 26.2 Hz, 1H), 3.15 (s, 3H), 2.97 (m, 2H), 2.65 (d, J = 13.6 Hz, 2H), 1.60 (m, 2H), 1.29 (m, 2H), 1.05 (s, 9H).

[0990] Example 1-084: Synthesis of 2-(5-(4-amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 82)

[0991] Step 1: 2-(5-(4-Amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (75% yield), using (2-(5-(4-amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (12 mg, 0.021 mmol, 1 equiv) as starting material.

[0992] LCMS (ESI+) m / z 445.1 [M+H]+

[0993] TH NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H), 8.54 (d, J = 7.1 Hz, 1H), 7.91 (s, 1H), 7.49 - 7.45 (m, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.85 (dd, J = 8.3, 2.4 Hz, 1H), 6.78 (dd, J = 7.2, 1.9 Hz, 1H), 5.79 (s, 2H), 3.69 (s, 2H), 3.21 - 3.18 (m, 1H), 3.17 (s, 3H), 3.00 (ddd, J = 11.6, 7.4, 3.9 Hz, 2H), 2.68 (ddd, J = 12.3, 8.3, 3.5 Hz, 2H), 1.60 (ddt, J = 13.7, 7.1, 3.5 Hz, 2H), 1.29 (dtd, J = 12.0, 8.0, 3.8 Hz, 2H). Example 1-085: Synthesis of 2-(5-(2-methoxy-6-((4-methoxy-4-(methoxymethyl)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 77)

[0994] Step 1: To a suspension of NaH (30 mg, 0.81 mmol, 2 equiv, 60% in mineral oil) in DMF (2 mL), cooled in an ice-water bath, was added tert-butyl 4-hydroxy-4-(methoxymethyl)piperidine-l-carboxylate (100 mg, 0.407 mmol, 1 equiv) and stirred for 30 min. lodomethane (1.2 equiv) was added and the reaction mixture was stirred at RT for 1 h. After completion, the reaction was quenched with cold water and extracted with ethyl acetate. The organic phase was dried over NajSCU and evaporated. tert-Butyl 4-methoxy-4- (methoxymethyl)piperidine-l-carboxylate (80 mg, 0.308 mmol, 76% yield) was purified by flash column chromatography.

[0995] TH NMR (400 MHz, Chloroform-d) 6 3.78 (d, J = 12.9 Hz, 2H), 3.37 (s, 3H), 3.31 (s, 2H), 3.25 (s, 3H), 3.14 - 3.03 (m, 2H), 1.76 (dd, J = 12.3, 3.4 Hz, 2H), 1.45 (m, 11H).

[0996] Step 2: 4-Methoxy-4-(methoxymethyl)piperidine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (84% yield), using tert-butyl 4- methoxy-4-(methoxymethyl)piperidine-l-carboxylate (80 mg, 0.173 mmol) as starting material.

[0997] LCMS (ESI+) m / z 160.0 [M+H]+

[0998] Step 3: l-((2-Bromo-3-methoxyphenyl)sulfonyl)-4-methoxy-4-(rnethoxymethyl)piperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (41% yield), using 4-methoxy-4-(methoxymethyl)piperidine trifluoroacetate (80 mg, 0.293 mmol, 1 equiv) and 2-bromo-3-methoxybenzenesulfonyl chloride [commercial] (1.1 equiv) as starting materials.

[0999] LCMS (ESI+) m / z 408.0, 410.0 [M+H] Step 4: 2-(5-(2-Methoxy-6-((4-methoxy-4-(methoxymethyl)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (9% yield), using l-((2-bromo-3-methoxyphenyl)sulfonyl)-4-methoxy-4- (methoxymethyl)piperidine (50 mg, 0.123 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, Pd(dtbpf)CI2(0.1 equiv) as catalyst and Cs2CO3(4 equiv) as base.

[1000] LCMS (ESI+) m / z 504.1 [M+H]+

[1001] TH NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 7.2 Hz, 1H), 7.87 (s, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 6.60 (dd, J = 7.2, 1.9 Hz, 1H), 3.72 (s, 3H), 3.62 - 3.50 (m, 2H), 3.22 (s, 3H), 3.19 (s, 2H), 3.07 - 2.94 (m, 2H), 3.03 (s, 3H), 2.72 - 2.54 (m, 2H), 1.61 (t, J = 12.4 Hz, 2H), 1.36 - 1.14 (m, 2H).

[1002] Example 1-086: Synthesis of 2-(5-(7-((4-methoxypiperidin-l-yl)sulfonyl)quinolin-8-yl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 73)

[1003] Step 1: To a stirred solution of 8-bromoquinolin-7-amine [commercial] (500 mg, 2.2 mmol, 1 equiv) in acetonitrile (5 mL) was added p-toluenesulfonic acid monohydrate (3.1 equiv) and the mixture was cooled in ice-water bath. The solutions of NaNO2(2.05 equiv) in water (1.2 mL) and KI (2.55 equiv) in water (1.2 mL) were slowly added over the period of 5 min. The reaction mixture was stirred for 30 min at RT, then diluted with water (10 mL), neutralized with saturated NaHCOs solution and extracted with ethyl acetate. The combined organic fractions were washed with saturated NaHCOs solution, then 10% Na2S2C>3 and brine. After drying over Na2SO4the solvent was evaporated and 8-bromo-7-iodoquinoline (550 mg, 1.65 mmol, 75% yield) was purified by flash column chromatography.

[1004] LCMS (ESI+) m / z 333.6, 335.7 [M+H]+

[1005] Step 2: To a stirred solution of 8-bromo-7-iodoquinoline (550 mg, 1.65 mmol, 1 equiv) in dioxane were added (4-methoxyphenyl)methanethiol (0.91 equiv) and DIPEA (3 equiv). The mixture was purged with argon for 5 min, followed by addition of XantPhos (0.2 equiv.) and Pd2(dba)3(0.1 equiv). The reaction was stirred at 90°C for 16 h. After completion, the solid particles were filtered off and the filtrate was evaporated. 8-Bromo-7-((4-methoxybenzyl)thio)quinoline (490 mg, 1.36 mmol, 82% yield) was purified by flash column chromatography.

[1006] LCMS (ESI+) m / z 359.8, 361.8 [M+H]+

[1007] Step 3: To a stirred solution of 8-bromo-7-((4-methoxybenzyl)thio)quinoline (200 mg, 0.56 mmol, 1 equiv) in ACN (4 mL) were added AcOH (0.1 mL), water (0.2 mL) and the solution was cooled to 0°C. After 10 min l,3-dichloro-5,5-dimethylhydantoin (2 equiv) was added and the reaction was stirred at 0°C for 1 h. After completion, the reaction was quenched with water and extracted with DCM. The combined organic fractions were washed with brine, dried over Na2SO4and evaporated to afford crude 8-bromoquinoline-

[1008] 7-sulfonyl chloride, which was forwarded directly for the next step.

[1009] Step 4: 8-Bromo-7-((4-methoxypiperidin-l-yl)sulfonyl)quinoline was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (55% yield over two steps), using

[1010] 8-bromoquinoline-7-sulfonyl chloride (170 mg, 0.56 mmol, 1 equiv) and 4-methoxypiperidine (1.5 equiv) as starting materials.

[1011] LCMS (ESI+) m / z 385.0, 387.0 [M+H]+

[1012] Step 5: 2-(5-(7-((4-Methoxypiperidin-l-yl)sulfonyl)quinolin-8-yl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (20% yield), using 8-bromo-7-((4-methoxypiperidin-l-yl)sulfonyl)quinoline (100 mg, 0.26 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-3-yl)acetate (1.2 equiv) as starting materials, Pd(dtbpf)CL (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[1013] LCMS (ESI+) m / z 481.3 [M+H]+

[1014] NMR (400 MHz, DMSO-d6) δ 8.95-8.89 (m, 1H), 8.58 (dd, J = 7.0, 12.4 Hz, 2H), 8.29 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.74-7.66 (m, 1H), 7.49 (s, 1H), 6.75 (d, J = 6.9 Hz, 1H), 3.68-3.58 (m, 2H), 3.26-3.19 (m, 1H), 3.16 (s, 3H), 3.12-3.02 (m, 2H), 2.91-2.70 (m, 2H), 1.86-1.59 (m, 2H), 1.56-1.16 (m, 2H).

[1015] Example 1-087: Synthesis of (2-(5-(7-((4-methoxypiperidin-l-yl)sulfonyl)quinolin-8-yl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 74)

[1016] Step 1: To a stirred solution of 2-(5-(7-((4-methoxypiperidin-l-yl)sulfonyl)quinolin-8-yl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (10 mg, 0.021 mmol, 1 equiv) in dry ACN (0.54 mL) were added chloromethyl pivalate (1.5 equiv) and TEA (3 equiv) and the reaction was carried at 55°C for 24 h. (2-(5-(7-((4- Methoxypiperidin-l-yl)sulfonyl)quinolin-8-yl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (7.0 mg, 0.012 mmol, 56% yield) was purified by preparative HPLC.

[1017] LCMS (ESI+) m / z 595.2 [M+H]+

[1018] XH NMR (500 MHz, DMSO-d6) δ 8.92 (dd, J = 4.1, 1.8 Hz, 1H), 8.62 (dd, J = 7.1, 1.0 Hz, 1H), 8.56 (dd, J = 8.4, 1.8 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J = 8.3, 4.1 Hz, 1H), 7.49 (dd, J = 1.9, 1.0 Hz, 1H), 6.79 (dd, J = 7.1, 1.9 Hz, 1H), 5.68 (s, 2H), 3.92 - 3.81 (m, 2H), 3.23 (dq, J = 7.4, 3.7 Hz, 1H), 3.16 (s, 3H), 3.12 (dd, J = 7.1, 4.1 Hz, 1H), 3.06 (ddd, J = 11.5, 6.7, 3.7 Hz, 1H), 2.82 (ddd, J = 12.1, 8.4, 3.5 Hz, 1H), 2.76 (ddt, J = 12.3, 8.5, 4.1 Hz, 1H), 1.72 (ddt, J = 9.9, 6.2, 3.4 Hz, 2H), 1.39 (tdd, J = 17.0, 8.3, 4.1 Hz, 2H), 1.00 (s, 9H). Example 1-088: Synthesis of 2-(5-(2-methoxy-6-((4-methoxyphenyl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 75)

[1019] Step 1: To a stirred solution of 2-bromo-l-iodo-3-methoxybenzene [commercial] (500 mg, 1.6 mmol, 1 equiv) in dioxane (30 mL) were added 4-methoxybenzenethiol (3 equiv) and DIPEA (4.9 equiv). The mixture was purged with argon for 10 min, followed by addition of XantPhos (0.2 equiv.) and Pd2(dba)3(0.1 equiv). The reaction was stirred at 90°C for 16 h. After completion, the volatiles were evaporated and (2-bromo-3-methoxyphenyl)(4-methoxyphenyl)sulfane (200 mg, 0.615 mmol, 38% yield) was purified by flash column chromatography.

[1020] LCMS (ESI+) m / z 325.0, 326.8 [M+H]+

[1021] Step 2: To a stirred solution of (2-bromo-3-methoxyphenyl)(4-methoxyphenyl)sulfane (200 mg, 0.615 mmol, 1 equiv) in DCM (5 mL) was added m-CPBA (2 equiv) and the reaction was carried at RT for 5 h. After completion, the reaction was quenched with ice-cold water and extracted with DCM. The combined organic fractions were washed with saturated aqueous NaHCO3solution, dried over Na2SO4and evaporated to afford 2-bromo-l-methoxy-3-((4-methoxyphenyl)sulfonyl)benzene (110 mg, 0.308 mmol, 50% yield) as white solid.

[1022] LCMS (ESI+) m / z 356.9, 358.8 [M+H]+

[1023] Step 3: 2-(5-(2-Methoxy-6-((4-methoxyphenyl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (41% yield), using 2-bromo-l-methoxy-3-((4-methoxyphenyl)sulfonyl)benzene (100 mg, 0.281 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.1 equiv) as starting materials, Pd(dtbpf)CI2(0.1 equiv) as catalyst and Cs2CO3(4 equiv) as base.

[1024] LCMS (ESI+) m / z 453.1 [M+H] 'H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 7.2 Hz, 1H), 7.94 - 7.84 (m, 2H), 7.70 (t, J = 8.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 6.85 - 6.75 (m, 3H), 6.30 (dd, J = 1.6, 7.1 Hz, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.58 - 3.54 (m, 1H), 3.42 - 3.38 (m, 1H).

[1025] Example 1-089: Synthesis of 2-(5-(2-methoxy-6-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetic acid (Compound 76)

[1026] Step 1: l-((2-Bromo-3-methoxyphenyl)sulfonyl)-4-methoxypiperidine was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above, using 2-bromo-3- methoxybenzenesulfonyl chloride (100 mg, 0.35 mmol, 1 equiv) and 4-methoxypiperidine (5 equiv) as starting materials. After completion, the reaction mixture was evaporated and the resulting crude was directly forwarded into the next step.

[1027] LCMS (ESI+) m / z 364.0, 365.8 [M+H]+

[1028] Step 2: Methyl 2-(5-(2-methoxy-6-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using l-((2-bromo-3-methoxyphenyl)sulfonyl)-4-methoxypiperidine (100 mg, 0.27 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1.12 equiv) as starting materials, Pd(dtbpf)Cl2 (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base. After completion, the volatiles were removed under reduced pressure and the resulting crude was forwarded directly into the next step.

[1029] LCMS (ESI+) m / z 473.8 [M+H]+

[1030] Step 3: 2-(5-(2-Methoxy-6-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (14% yield over three steps), using methyl 2-(5-(2-methoxy-6-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate (50 mg, 0.106 mmol, 1 equiv) as starting material.

[1031] LCMS (ESI+) m / z 460.2 [M+H]+

[1032] NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 7.1 Hz, 1H), 7.82 (s, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 6.55 (d, J = 7.0 Hz, 1H), 3.72 (s, 3H), 3.39 - 3.36 (m, 2H), 3.16 (s, 3H), 3.07 - 2.86 (m, 2H), 2.77 - 2.59 (m, 2H), 1.81 - 1.59 (m, 2H), 1.48 - 1.09 (m, 2H).

[1033] Example 1-090: Synthesis of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetamide (Compound 80)

[1034] Step 1: To a stirred solution of 2-(5-(2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin- 3-yl)acetic acid (9.7 mg, 0.023 mmol, 1 equiv) in dry DMF (1 mL) were added HATU (1.5 equiv), DIPEA (5 equiv) and NH4CI (5 equiv). The reaction mixture was stirred at RT for 30 min and 2-(5-(2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetamide (6.5 mg, 0.015 mmol, 67% yield) was purified by preparative HPLC.

[1035] LCMS (ESI+) m / z 429.1 [M+H]+

[1036] XH NMR (500 MHz, DMSO-d6) δ 8.64 - 8.59 (m, 1H), 8.01 (dd, J = 8.0, 1.3 Hz, 1H), 7.93 (s, 1H), 7.78 (td, J = 7.5, 1.4 Hz, 1H), 7.70 (td, J = 7.7, 1.4 Hz, 1H), 7.62 - 7.61 (m, 1H), 7.49 (dd, J = 7.6, 1.4 Hz, 1H), 7.42 (br s, 1H, NH), 6.86 (br s, 1H, NH), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 3.52 (s, 2H), 3.23 (tt, J = 7.4, 3.5 Hz, 1H), 3.17 (s, 3H), 3.02 (ddd, J = 11.7, 7.1, 3.8 Hz, 2H), 2.71 (ddd, J = 12.1, 8.3, 3.5 Hz, 2H), 1.64 (ddt, J = 13.7, 7.1, 3.6 Hz, 2H), 1.33 (dtd, J = 12.0, 8.0, 3.7 Hz, 2H). Example 1-091: Synthesis of (S)-2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1037] / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1008)

[1038] Step 1: l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidin-4-ol was synthesized using the general procedure shown in Reaction Scheme 8 and Example Method 8, above (57% yield), using 2-bromo-3- methoxybenzenesulfonyl chloride (425 mg, 1.5 mmol, 1 equiv) and piperidin-4-ol (1.5 equiv) as starting materials.

[1039] LCMS (ESI+) m / z 349.6, 351.9 [M+H]+

[1040] Step 2: To a solution of l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4-ol (300 mg, 0.86 mmol, 1 equiv) in DMF (3 mL), cooled in an ice-water bath, was added NaH (52 mg, 1.29 mmol, 1.5 equiv, 60% suspension in mineral oil) and the reaction mixture was stirred at RT for 30 min, then again cooled in an ice-water bath. 2,2-Dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl 4-methylbenzenesulfonate (1.28 equiv) was added and the reaction mixture was stirred at RT for 16 h. After completion, the reaction was diluted with water and extracted with ethyl acetate. The combined organic fractions were evaporated and tert-butyl (2-(2-(2-(2-((l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (200 mg, 0.32 mmol, 37% yield) was purified by flash column chromatography.

[1041] LCMS (ESI+) m / z 625.2 [M+H]+

[1042] Step 3: Methyl 2-(5-(2-((4-((2,2-dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl)oxy)piperidin- l-yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (51% yield), using tert-butyl (2-(2- (2-(2-((l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (250 mg, 0.4 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, Pd(dtbpf)Cl2 (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[1043] LCMS (ESI+) m / z 735.3 [M+H]+

[1044] Step 4: Methyl 2-(5-(2-((4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (50% yield), using methyl 2-(5-(2- ((4-((2,2-dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl)oxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (30 mg, 0.04 mmol, 1 equiv) as starting material.

[1045] LCMS (ESI+) m / z 635.4 [M+H]+

[1046] Step 5: To a solution of methyl 2-(5-(2-((4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate trifluoroacetate (28 mg, 0.038 mmol, 1 equiv) in DMF (1 mL) were added HATU (1.5 equiv) and DIPEA (2.9 equiv) and the resulting mixture was stirred at RT for 30 min. (S)-2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- o][l,4]diazepin-6-yl)acetic acid (1.2 equiv) in DMF (3 mL) and DIPEA (2.9 equiv) was added and the reaction mixture was stirred at RT for 1 h. After completion, the reaction was diluted with water and extracted with ethyl acetate. The combined organic fractions were dried over NajSCU and evaporated. The crude methyl (S)-2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate was forwarded directly into the next step.

[1047] LCMS (ESI+) m / z 1017.6 [M+H]+

[1048] Step 6: (S)-2-(5-(2-((4-((l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (50% yield over two steps), using methyl (S)- 2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate (50 mg, crude) as starting material.

[1049] LCMS (ESI+) m / z 1003.2 [M+H]+

[1050] NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.1 Hz, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.91 (s, 1H), 7.68-7.53 (m, 2H), 7.52-7.39 (m, 6H), 6.63 (dd, J = 1.6, 7.1 Hz, 1H), 4.66-4.40 (m, 1H), 3.72 (s, 3H), 3.67 (d, J = 5.3 Hz, 2H), 3.55-3.42 (m, 16H), 3.30-3.15 (m, 3H), 3.10-2.95 (m, 2H), 2.72-2.60 (m, 3H), 2.60 (s, 3H), 2.42 (s, 3H), 1.75-1.55 (m, 5H), 1.37-1.22 (m, 2H).

[1051] Example 1-092: Synthesis of (S)-(2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1052] / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1009)

[1053]

[1054] Step 1: To a stirred solution of (S)-2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (60 mg, 0.06 mmol, 1 equiv) in DMF (1 mL) were added KHCO3 (3 equiv) and chloromethyl pivalate (1.5 equiv) at 0°C. The resulting solution was stirred at RT for 2 h. After completion the reaction was quenched with ice-water and extracted with ethyl acetate. The combined organic fractions were dried over NajSCU and evaporated. The residue was triturated with pentane / ether (3 / 1, v / v) to afford (S)-(2-(5-(2-((4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl- 6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)oxy)piperidin-l-yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (30 mg, 0.027 mmol, 44% yield) in form of white solid.

[1055] LCMS (ESI+) m / z 1117.2, 1119.1 [M+H]+

[1056] TH NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 7.1 Hz, 1H), 8.26 (t, J = 5.6 Hz, 1H), 7.90 (s, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.56 (d, J = 7.4 Hz, 1H), 7.47 (t, J = 5.0 Hz, 2H), 7.41 (d, J = 8.2 Hz, 3H), 6.65 (dd, J = 1.8, 7.1 Hz, 1H), 5.70 (s, 2H), 4.50 (dd, J = 6.1, 8.0 Hz, 1H), 3.94 - 3.79 (m, 2H), 3.71 (s, 3H), 3.54 - 3.40 (m, 13H), 3.30 - 3.14 (m, 5H), 3.11 - 2.91 (m, 3H), 2.67 - 2.59 (m, 1H), 2.59 (s, 3H), 2.40 (s, 3H), 1.75 - 1.62 (m, 2H), 1.61 (s, 3H), 1.36 - 1.21 (m, 3H), 1.13 (s, 1H), 1.05 (s, 9H).

[1057] Example 1-093: Synthesis of 2-(5-(2-((4-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 78)

[1058]

[1059] Step 1: 2-(5-(2-((4-((2,2-Dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl)oxy)piperidin-l- yl)sulfonyl)-6-methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (27% yield), using methyl 2-(5-(2- ((4-((2,2-dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl)oxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetate (150 mg, 0.204 mmol, 1 equiv) as starting material.

[1060] LCMS (ESI+) m / z 721.4 [M+H]+

[1061] Step 2: 2-(5-(2-((4-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethoxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (as trifluoroacetic acid salt) was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (95% yield), using 2- (5-(2-((4-((2,2-dimethyl-4-oxo-3,8,ll,14-tetraoxa-5-azahexadecan-16-yl)oxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (30 mg, 0.04 mmol, 1 equiv) as starting material.

[1062] LCMS (ESI+) m / z 621.4 [M+H]+

[1063] NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 7.1 Hz, 1H), 7.91 (s, 1H), 7.87-7.68 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 6.63 (dd, J = 1.7, 7.1 Hz, 1H), 3.72 (s, 3H), 3.68 (d, J = 5.0 Hz, 2H), 3.61-3.52 (m, 6H), 3.49 (s, 4H), 3.45 (s, 4H), 3.39 - 3.28 (m, 1H), 3.11-2.91 (m, 4H), 2.67 - 2.50 (m, 2H), 1.72-1.61 (m, 2H), 1.38-1.21 (m, 2H).

[1064] Example 1-094: Synthesis of 2-(5-(2-methoxy-6-((4-((2-oxo-6,9,12-trioxa-3-azatetradecan-14- yl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 79)

[1065]

[1066] Step 1: 2-(2-(2-(2-((l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethan-l-amine trifluoroacetate was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above, using tert-butyl (2-(2-(2-(2-((l-((2- bromo-3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate (70 mg, 0.12 mmol) as starting material. After completion, the volatiles were removed under reduced pressure. The residue was twice co-evaporated with DCM and then lyophilized to afford crude material, which was directly forwarded into the next step.

[1067] LCMS (ESI+) m / z 524.9 [M+H]+

[1068] Step 2: / V-(2-(2-(2-(2-((l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidin-4- yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)acetamide was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above, using 2-(2-(2-(2-((l-((2-bromo-3- methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethan-l-amine trifluoroacetate (90 mg, 0.14 mmol, 1 equiv) as starting material. After completion, the reaction was quenched with ice-cold water and extracted with DCM. The combined organic fractions were dried over NajSCU, evaporated and the resulting crude was used directly for the next step.

[1069] LCMS (ESI+) m / z 566.9, 569.0 [M+H]+

[1070] Step 3: 2-(5-(2-Methoxy-6-((4-((2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (4% yield over three steps), using / V-(2-(2-(2- (2-((l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)acetamide (70 mg, 0.124 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- o]pyridin-3-yl)acetate (1.2 equiv) as starting materials, Pd(dtbpf)Cl2 (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[1071] LCMS (ESI+) m / z 663.2 [M+H]+

[1072] NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 7.1 Hz, 1H), 8.07-7.84 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 6.62 (dd, J = 1.3, 7.1 Hz, 1H), 3.72 (s, 3H), 3.71-3.57 (m, 2H), 3.54-3.43 (m, 13H), 3.38 (t, J = 5.9 Hz, 2H), 3.17 (q, J = 5.7 Hz, 2H), 3.10-2.94 (m, 2H), 2.72-2.58 (m, 2H), 1.78 (s, 3H), 1.71-1.61 (m, 2H), 1.40-1.20 (m, 2H).

[1073] Example 1-095: Synthesis of (S)-(2-(5-(4-(l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-amido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1011)

[1074] Step 1: To a stirred solution of (S)-l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-oic acid (12 mg, 0.019 mmol, 1 equiv), (2-(5-(4-amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin- 3-yl)acetoxy)methyl pivalate (1 equiv) and pyridine (5 equiv) in THF (1 mL), cooled to 0°C, was added solution of 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.056 mL, 50% in THF, 5 equiv) and the reaction mixture was stirred at 65°C for 18 h. After completion, the volatiles were removed under reduced pressure and (S)-(2-(5-(4-(l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-amido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (11 mg, 0.006 mmol, 30% yield) was purified by preparative HPLC.

[1075] (S)-l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo- 6,9,12,15-tetraoxa-3-azaoctadecan-18-oic acid was prepared as described in Chen, H. et al., J. Am. Chem. Soc. 2021, 143, 15073.

[1076] LCMS (ESI+) m / z 1188.2 [M+H]+

[1077] TH NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.62 (dd, J = 7.3, 1.0 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.28 (t, J = 5.7 Hz, 1H), 7.98 - 7.92 (m, 2H), 7.56 (dd, J = 2.0, 1.0 Hz, 1H), 7.52 - 7.48 (m, 2H), 7.46 - 7.43 (m, 2H), 7.41 (s, 1H), 6.85 (dd, J = 7.2, 2.0 Hz, 1H), 5.72 (s, 2H), 4.52 (dd, J = 8.1, 6.0 Hz, 1H), 3.91 (s, 2H), 3.74 (t, J = 6.2 Hz, 2H), 3.57 - 3.51 (m, 12H), 3.47 (t, J = 5.9 Hz, 2H), 3.38 (s, 2H), 3.30 (s, 2H), 3.26 - 3.18 (m, 1H), 3.17 (s, 3H), 3.03 (ddd, J = 11.6, 7.0, 3.7 Hz, 2H), 2.72 (ddd, J = 12.2, 8.2, 3.4 Hz, 2H), 2.63 (t, J = 6.2 Hz, 2H), 2.61 (s, 3H), 2.42 (d, J = 1.0 Hz, 3H), 1.68 - 1.60 (m, 5H), 1.37 - 1.24 (m, 2H), 1.06 (s, 9H).

[1078] Example 1-096: Synthesis of (S)-2-(5-(4-(l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1079] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-amido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1010)

[1080] Step 1: (S)-2-(5-(4-(l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12,15-tetraoxa-3-azaoctadecan-18-amido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (30% yield), using (S)-(2-(5-(4-(l-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12,15- tetraoxa-3-azaoctadecan-18-amido)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin- 3-yl)acetoxy)methyl pivalate (10 mg, 0.008 mmol, 1 equiv) as starting material.

[1081] LCMS (ESI+) m / z 1074.2 [M+H]+

[1082] TH NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (d, J = 7.1 Hz, 1H), 8.25 - 8.22 (m, 1H), 8.21 (t, J = 5.7 Hz, 1H), 7.88 - 7.83 (m, 2H), 7.46 (d, J = 1.9 Hz, 1H), 7.43 - 7.39 (m, 2H), 7.37 - 7.33 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 6.72 (dd, J = 7.1, 2.0 Hz, 1H), 4.43 (dd, J = 8.1, 6.0 Hz, 1H), 3.65 (t, J = 6.2 Hz, 2H), 3.58 (s, 2H), 3.47 - 3.41 (m, 12H), 3.38 (t, J = 5.9 Hz, 2H), 3.17 - 3.10 (m, 5H), 3.07 (s, 3H), 2.98 - 2.91 (m, 3H), 2.62 (ddd, J = 12.2, 8.2, 3.5 Hz, 2H), 2.54 (t, J = 6.3 Hz, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 1.58 - 1.49 (m, 5H), 1.22 (dtd, J = 12.1, 8.0, 3.7 Hz, 2H).

[1083] Example 1-097: Synthesis of (S)-(2-(5-(4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1013)

[1084] Step 1: 3-((4-Methoxypiperidin-l-yl)sulfonyl)-4-(3-(2-oxo-2-((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5- o]pyridin-5-yl)benzoic acid (34.9 mg, 0.059 mmol, 1.1 equiv) and HATU (1.2 equiv) were dissolved in dry DMF (0.25mL) and stirred at RT for 10 min. Then (S)- / V-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2- (4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamide hydrochloride (33 mg, 0.054 mmol, 1 equiv) was added followed by DIPEA (2 equiv) and the reaction mixture was stirred at RT for 3 h. After completion, the solvent was removed in vacuo and (S)-(2-(5-(4-((l- (4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo- 6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (31 mg, 0.026 mmol, 49% yield) was purified by preparative HPLC.

[1085] (S)- / V-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamide hydrochloride was prepared as described in WO2019238816A1.

[1086] LCMS (ESI+) m / z 1144.3 [M+H]+

[1087] 1H NMR (500 MHz, DMSO-d6) δ 8.93 (t, J = 5.6 Hz, 1H), 8.65 (dd, J = 7.3, 0.9 Hz, 1H), 8.45 (d, J = 1.9 Hz, 1H), 8.26 (t, J = 5.7 Hz, 1H), 8.19 (dd, J = 8.0, 1.9 Hz, 1H), 7.96 (s, 1H), 7.61 (dd, J = 2.0, 1.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.45 - 7.39 (m, 2H), 6.86 (dd, J = 7.1, 1.9 Hz, 1H), 5.70 (s, 2H), 4.50 (dd, J = 8.0, 6.1 Hz, 1H), 3.90 (s, 2H), 3.61 - 3.50 (m, 10H), 3.46 (dt, J = 13.7, 5.9 Hz, 4H), 3.29 - 3.15 (m, 6H), 3.13 (s, 3H), 2.99 (ddd, J = 15.2, 6.8, 3.8 Hz, 2H), 2.66 (ddd, J = 12.4, 8.5, 3.6 Hz, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 1.61 (s, 3H), 1.60 - 1.56 (m, 1H), 1.32 - 1.22 (m, 2H), 1.04 (s, 9H).

[1088] Example 1-098: Synthesis of (S)-2-(5-(4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1012) Step 1: (S)-2-(5-(4-((l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)carbamoyl)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (88% yield), using (S)-(2-(5-(4-((l-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12- trioxa-3-azatetradecan-14-yl)carbamoyl)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5- o]pyridin-3-yl)acetoxy)methyl pivalate (15 mg, 0.013 mmol, 1 equiv) as starting material.

[1089] LCMS (ESI+) m / z 1030.3 [M+H]+

[1090] 'H NMR (500 MHz, DMSO-d6) δ 8.93 (t, J = 5.6 Hz, 1H), 8.63 (d, J = 7.2 Hz, 1H), 8.45 (d, J = 1.8 Hz, 1H), 8.26 (t, J = 5.7 Hz, 1H), 8.18 (dd, J = 7.9, 1.9 Hz, 1H), 7.95 (s, 1H), 7.62 - 7.59 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.45 - 7.39 (m, 2H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 4.50 (dd, J = 8.0, 6.1 Hz, 1H), 3.70 (s, 2H), 3.61 - 3.50 (m, 10H), 3.46 (dt, J = 12.3, 5.8 Hz, 6H), 3.30 - 3.14 (m, 4H), 3.13 (s, 3H), 2.99 (ddd, J = 11.5, 6.9, 3.8 Hz, 2H), 2.70 - 2.60 (m, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 1.61 (s, 3H), 1.57 (dq, J = 10.7, 3.6 Hz, 2H), 1.31 - 1.19 (m, 2H).

[1091] Example 1-099: Synthesis of 2-(5-(2-((4-((14-(4-(4-((5-chloro-4-((2-

[1092] (isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-l-yl)-3,6,9,12- tetraoxatetradecyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1024)

[1093]

[1094] Step 1: To a stirred solution of 14-(piperidin-4-yloxy)-3,6,9,12-tetraoxatetradecan-l-ol hydrochloride (600 mg, 1.67 mmol, 1 equiv) in DCM (10 mL), cooled to 0°C, were added 2-bromobenzenesulfonyl chloride (3 equiv) and TEA (6.45 equiv) and the reaction mixture was stirred at RT for 16 h. After completion the reaction was quenched with cold water and extracted with DCM. The combined organic fractions were washed with brine, dried over NajSCU and evaporated. 14-((l-((2-Bromophenyl)sulfonyl)piperidin-4- yl)oxy)-3,6,9,12-tetraoxatetradecyl 2-bromobenzenesulfonate (400 mg, 0.53 mmol, 31% yield) was purified by flash column chromatography.

[1095] 14-(Piperidin-4-yloxy)-3,6,9,12-tetraoxatetradecan-l-ol hydrochloride was prepared as described in W02021077010A1 and US2014031559A1.

[1096] LCMS (ESI+) m / z 761.8 [M+H]

[1097] Step 2: To a solution of 2,5-dichloro- / V-(2-(isopropylsulfonyl)phenyl)pyrimidin-4-amine (2.5 g, 7.2 mmol, 1 equiv) in isopropanol (25 mL) and 6M HCI (25 mL) was added tert-butyl 4-(4-aminophenyl)piperazine-l- carboxylate (1.2 equiv) and stirred at 95°C for 16 h. The volatiles were removed under reduced pressure, the residue was triturated with ether, taken up in saturated NaHCOs solution and extracted with ethyl acetate. The organic fraction was then evaporated and 5-chloro- / V4-(2-(isopropylsulfonyl)phenyl)- / V2-(4- (piperazin-l-yl)phenyl)pyrimidine-2,4-diamine (1.0 g, 2.05 mmol, 28% yield) was purified by flash column chromatography.

[1098] LCMS (ESI+) m / z 487.0, 489.0 [M+H]+

[1099] Step 3: To a solution of 5-chloro- / V4-(2-(isopropylsulfonyl)phenyl)- / V2-(4-(piperazin-l- yl)phenyl)pyrimidine-2,4-diamine (35 mg, 0.071 mmol, 1.2 equiv) in DMF (3 mL) was added K2CO3(2.5 equiv) at RT and the resulting mixture was stirred at the same temperature for 30 min. Then 14-((l-((2- bromophenyl)sulfonyl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl 2-bromobenzenesulfonate (45 mg, 0.059 mmol, 1 equiv) was added and the reaction mixture was stirred at 70°C for 16 h. After completion, the reaction was diluted with water and extracted with ethyl acetate. / V2-(4-(4-(14-((l-((2- Bromophenyl)sulfonyl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperazin-l-yl)phenyl)-5-chloro- / V4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (30 mg, 0.03 mmol, 49% yield) was purified by flash column chromatography.

[1100] LCMS (ESI+) m / z 1008.1, 1010.3 [M+H]+

[1101] Step 4: 2-(5-(2-((4-((14-(4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)phenyl)piperazin-l-yl)-3,6,9,12-tetraoxatetradecyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (9% yield), using / V2-(4-(4-(14-((l-((2- bromophenyl)sulfonyl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperazin-l-yl)phenyl)-5-chloro- / V4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (50 mg, 0.05 mmol, 1 equiv) and methyl 2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, Pd(dppf)CI2(0.1 equiv) as catalyst and K3PO4 (3.5 equiv) as base.

[1102] LCMS (ESI+) m / z 1104.7 [M+H]+

[1103] 4H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.43 - 9.27 (m, 1H), 8.77 - 8.64 (m, 1H), 8.61 (d, J = 6.8 Hz, 1H), 8.24 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 6.4 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.46 (d, J = 7.5 Hz, 3H), 7.36 (t, J = 8.3 Hz, 1H), 7.00 - 6.85 (m, 2H), 6.82 (d, J = 7.7 Hz, 1H), 3.90 - 3.66 (m, 6H), 3.65 - 3.33 (m, 20H), 3.18 - 2.90 (m, 8H), 2.80 - 2.58 (m, 2H), 1.68 - 1.54 (m, 2H), 1.38 - 1.21 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H). Example 1-100: Synthesis of (2-(5-(2-((4-((14-(4-(4-((5-chloro-4-((2-

[1104] (isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)piperazin-l-yl)-3,6,9,12- tetraoxatetradecyl)oxy)piperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1025)

[1105] Step 1: (2-(5-(2-((4-((14-(4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2- yl)amino)phenyl)piperazin-l-yl)-3,6,9,12-tetraoxatetradecyl)oxy)piperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above (4.5% yield), using / V2-(4-(4-(14- ((l-((2-bromophenyl)sulfonyl)piperidin-4-yl)oxy)-3,6,9,12-tetraoxatetradecyl)piperazin-l-yl)phenyl)-5- chloro- / V4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (140 mg, 0.139 mmol, 1 equiv) and (2-(5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (1.1 equiv) as starting materials, Pd(dtbpf)Cl2 (0.1 equiv) as catalyst and CS2CO3 (2 equiv) as base.

[1106] LCMS (ESI+) m / z 1218.4, 1220.3 [M+H]+

[1107] 4H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.31 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 8.23 (s, 1H), 8.06 - 7.92 (m, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.74 (q, J = 7.7 Hz, 2H), 7.67 (t, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.52 - 7.40 (m, 3H), 7.36 (t, J = 7.6 Hz, 1H), 6.95 - 6.79 (m, 3H), 5.70 (s, 2H), 3.89 (s, 2H), 3.49 (q, J = 19.6, 16.2 Hz, 22H), 3.03 (d, J = 12.4 Hz, 7H), 2.66 (d, J = 9.4 Hz, 3H), 1.60 (s, 2H), 1.28 (dd, J = 25.4, 14.8 Hz, 4H), 1.16 (d, J = 6.8 Hz, 6H), 1.03 (s, 9H). Example 1-101: Synthesis of (S)-(2-(5-(4-(l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-amido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1017)

[1108] Step 1: To the solution of (S)-l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-oic acid (19 mg, 0.031 mmol, 1 equiv), (2- (5-(4-amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (1.02 equiv) and pyridine (2 equiv) in THF (0.32 mL) was added solution of 2,4,6-tripropyl- 1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.028 mL, 50% in THF, 1.5 equiv) and the reaction mixture was stirred at 60°C for 24 h. After completion, the volatiles were removed under reduced pressure. The residue was taken up in ethyl acetate, washed with water, saturated NaHCOs, brine, dried over MgSO4and evaporated. (S)-(2-(5-(4-(l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-amido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (6.5 mg, 0.006 mmol, 17% yield) was purified by preparative HPLC.

[1109] (S)-l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-

[1110] 6,9,12-trioxa-3-azapentadecan-15-oic acid was prepared as described in Chen, H. et al., J. Am. Chem. Soc.

[1111] 2021, 143, 15073. LCMS (ESI+) m / z 1144.3 [M+H]+

[1112] NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.60 (dd, J = 7.2, 1.0 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (dd, J = 2.0, 1.0 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.44 - 7.38 (m, 3H), 6.83 (dd, J = 7.2, 2.0 Hz, 1H), 5.70 (d, J = 1.4 Hz, 2H), 4.50 (dd, J = 8.0, 6.1 Hz, 1H), 3.88 (s, 2H), 3.73 (t, J = 6.2 Hz, 2H), 3.56 - 3.49 (m, 6H), 3.45 (q, J = 6.1 Hz, 2H), 3.29 - 3.16 (m, 5H), 3.14 (s, 3H), 3.01 (ddd, J = 11.5, 7.0, 3.7 Hz, 2H), 2.78 - 2.65 (m, 2H), 2.61 (t, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.40 (d, J = 0.9 Hz, 3H), 1.65 - 1.59 (m, 4H), 1.29 (dtd, J = 12.1, 8.0, 3.7 Hz, 3H), 1.24 (s, 2H), 1.04 (s, 9H).

[1113] Example 1-102: Synthesis of (S)-2-(5-(4-(l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1114] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-amido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1016)

[1115] Step 1: (S)-2-(5-(4-(l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azapentadecan-15-amido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (75% yield), using (S)-(2-(5-(4-(l-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12- trioxa-3-azapentadecan-15-amido)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin- 3-yl)acetoxy)methyl pivalate (4 mg, 0.003 mmol, 1 equiv) as starting material.

[1116] LCMS (ESI+) m / z 1030.3 [M+H]+ 'H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.56 (d, J = 7.2 Hz, 1H), 8.32 - 8.25 (m, 2H), 7.92 (dd, J = 8.4, 2.3 Hz, 1H), 7.90 (s, 1H), 7.55 - 7.51 (m, 1H), 7.50 - 7.45 (m, 2H), 7.44 - 7.40 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 7.2, 2.0 Hz, 1H), 4.50 (dd, J = 8.0, 6.1 Hz, 1H), 3.73 (t, J = 6.2 Hz, 2H), 3.60 (s, 2H), 3.57 - 3.48 (m, 8H), 3.44 (t, J = 5.9 Hz, 2H), 3.28 - 3.16 (m, 4H), 3.14 (s, 3H), 3.02 (ddd, J = 11.8, 7.0, 3.6 Hz, 2H), 2.69 (ddd, J = 12.1, 8.2, 3.5 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 1.65 - 1.51 (m, 5H), 1.34 - 1.25 (m, 2H), 1.25 - 1.22 (m, 2H).

[1117] Example 1-103: Synthesis of (S)-(2-(5-(4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1018)

[1118] Step 1: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetic acid (50 mg, 0.125 mmol, 1 equiv) and HATU (1.5 equiv) in dry DMF (2.5 mL) was added DIPEA (3 equiv) and the mixture was stirred at RT for 15 min. 2-(2-(2-(2- Aminoethoxy)ethoxy)ethoxy)ethan-l-ol (3 equiv) was added and the reaction mixture was stirred at RT for 20 h. After completion, the solution was concentrated under reduced pressure, diluted with saturated NajCOs aqueous solution and extracted with DCM. The combined organic fractions were washed with water, brine, dried over Na2SO4and concentrated. (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)- / V-(2-(2-(2-(2- hydroxyethoxy)ethoxy)ethoxy)ethyl)acetamide (35 mg, 0.06 mmol, 47% yield) was purified by flash column chromatography. LCMS (ESI+) m / z 576.2 [M+H]

[1119] Step 2: To a solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)- / V-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)acetamide (30 mg, 0.052 mmol, 1 equiv), 4-methylbenzenesulfonyl chloride (1.5 equiv) and DMAP (0.1 equiv) in DCM (0.52 mL) was added TEA (4 equiv) and the resulting mixture was stirred at RT for 24 h. Then the reaction was diluted with pyridine (1 mL) and cut filter paper was added to remove excess of 4-methylbenzenesulfonyl chloride. The reaction mixture was sonicated for 1 h and filtered. The filtrate was diluted with 10% KHSO4aqueous solution and extracted with DCM. The combined organic fractions were washed with water, brine, dried over NajSCU and concentrated. (S)-l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl 4- methylbenzenesulfonate (12 mg, 0.016 mmol, 30% yield) was purified by flash column chromatography.

[1120] LCMS (ESI+) m / z 730.0 [M+H]+

[1121] Step 3: To a stirred solution of (S)-l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl 4- methylbenzenesulfonate (11.5 mg, 0.016 mmol, 1 equiv) and (2-(5-(4-hydroxy-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (1.05 equiv) in ACN (0.16 mL) was added K2CO3(5 equiv) and the reaction mixture was stirred at 60°C for 24 h. The volatiles were then removed in vacuo and (S)-(2-(5-(4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (9 mg, 0.008 mmol, 50% yield) was purified by preparative HPLC.

[1122] LCMS (ESI+) m / z 1117.3 [M+H]+

[1123] NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.60 (dd, J = 7.2, 1.0 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.93 (s, 1H), 7.93 (dd, J = 8.4, 2.2 Hz, 1H), 7.54 (dd, J = 2.0, 1.0 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.45 - 7.37 (m, 3H), 6.83 (dd, J = 7.2, 2.0 Hz, 1H), 5.70 (d, J = 1.4 Hz, 2H), 4.50 (dd, J = 8.0, 6.1 Hz, 1H), 3.88 (s, 2H), 3.73 (t, J = 6.2 Hz, 2H), 3.56 - 3.49 (m, 8H), 3.44 (t, J = 5.9 Hz, 2H), 3.27 - 3.16 (m, 4H), 3.14 (s, 3H), 3.01 (ddd, J = 11.5, 7.0, 3.7 Hz, 2H), 2.69 (ddd, J = 12.1, 8.2, 3.5 Hz, 2H), 2.61 (t, J = 6.2 Hz, 2H), 2.59 (s, 3H), 2.40 (d, J = 0.9 Hz, 3H), 1.66 - 1.60 (m, 4H), 1.29 (dtd, J = 12.1, 8.0, 3.7 Hz, 1H), 1.24 (s, 2H), 1.04 (s, 9H). Example 1-104: Synthesis of (S)-2-(5-(4-((l-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1124] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1019)

[1125] Step 1: (S)-2-(5-(4-((l-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)-2-oxo-6,9,12-trioxa-3-azatetradecan-14-yl)oxy)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (44% yield), using (S)-(2-(5-(4-((l-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)-2-oxo-6,9,12- trioxa-3-azatetradecan-14-yl)oxy)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (5 mg, 0.004 mmol, 1 equiv) as starting material.

[1126] LCMS (ESI+) m / z 1003.3 [M+H]+

[1127] NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.57 (dd, J = 7.1, 0.9 Hz, 1H), 8.25 (t, J = 5.7 Hz, 1H), 7.92 (s, 1H), 7.52 (dd, J = 2.0, 1.0 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.45 - 7.39 (m, 3H), 7.36 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.5, 2.6 Hz, 1H), 6.78 (dd, J = 7.2, 2.0 Hz, 1H), 4.51 (dd, J = 8.1, 6.0 Hz, 1H), 4.26 - 4.20 (m, 2H), 3.82 - 3.77 (m, 2H), 3.69 (s, 2H), 3.65 - 3.58 (m, 2H), 3.60 - 3.52 (m, 2H), 3.55 (s, 3H), 3.46 (t, J = 5.9 Hz, 2H), 3.24 (dt, J = 13.4, 5.3 Hz, 2H), 3.21 - 3.12 (m, 1H), 3.14 (s, 3H), 3.00 (ddd, J = 11.7, 7.2, 3.8 Hz, 2H), 2.67 (td, J = 8.6, 4.2 Hz, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 1.62 - 1.61 (m, 3H), 1.59 (dd, J = 6.6, 3.2 Hz, 1H), 1.32 - 1.24 (m, 3H), 1.26 - 1.22 (m, 3H). Example 1-105: Synthesis of (S)-(2-(5-(4-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1128] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethoxy)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1015)

[1129] Step 1: (2-(5-(4-Hydroxy-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (25 mg, 0.045 mmol, 1 equiv) and K2CO3 (5 equiv) were stirred in ACN (5 mL) at RT for 5 min. (S)-2-(2-(2-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- o][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.1 equiv) was added and the reaction mixture was stirred at 70°C for 10 h. (S)-(2-(5-(4-(2-(2-(2-(2-(4-(4-Chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethoxy)-2- ((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (4.5 mg, 0.004 mmol, 9.4% yield) was purified by preparative HPLC.

[1130] (S)-2-(2-(2-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate was synthesized according to procedure described in W02017011590A1.

[1131] LCMS (ESI+) m / z 1073.3 [M+H]+

[1132] NMR (500 MHz, DMSO-d6) δ 8.59 (dd, J = 7.2, 0.9 Hz, 1H), 8.27 (t, J = 5.7 Hz, 1H), 7.93 (s, 1H), 7.52 (dd, J = 2.0, 1.0 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.44 - 7.41 (m, 3H), 7.37 (t, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.5, 2.6 Hz, 1H), 6.81 (dd, J = 7.2, 1.9 Hz, 1H), 5.70 (s, 2H), 4.51 (dd, J = 8.1, 6.0 Hz, 1H), 4.27 - 4.21 (m, 2H), 3.88 (s, 2H), 3.83 - 3.79 (m, 2H), 3.66 - 3.62 (m, 2H), 3.61 - 3.57 (m, 2H), 3.48 (t, J = 5.9 Hz, 2H), 3.28 - 3.16 (m, 5H), 3.13 (s, 3H), 2.99 (ddd, J = 11.3, 6.7, 3.7 Hz, 2H), 2.66 (ddd, J = 12.4, 8.6, 3.5 Hz, 2H), 2.58 (s, 3H), 2.40 (s, 3H), 1.63 - 1.52 (m, 5H), 1.30 - 1.25 (m, 2H), 1.04 (s, 9H).

[1133] Example 1-106: Synthesis of (S)-2-(5-(4-(2-(2-(2-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethoxy)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1014)

[1134] Step 1: (S)-2-(5-(4-(2-(2-(2-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3- a][l,4]diazepin-6-yl)acetamido)ethoxy)ethoxy)ethoxy)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (27% yield), using (S)-(2-(5-(4-(2-(2-(2-(2-(4- (4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)ethoxy)ethoxy)ethoxy)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin- 3-yl)acetoxy)methyl pivalate (4.5 mg, 0.004 mmol, 1 equiv) as starting material.

[1135] LCMS (ESI+) m / z 959.2 [M+H]+

[1136] NMR (500 MHz, DMSO-d6) δ 8.58 (d, J = 7.1 Hz, 1H), 8.30 (t, J = 5.7 Hz, 1H), 7.93 (s, 1H), 7.53 (d, J = 1.7 Hz, 1H), 7.51 - 7.48 (m, 2H), 7.46 - 7.42 (m, 3H), 7.37 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.5, 2.6 Hz, 1H), 6.78 (dd, J = 7.2, 2.0 Hz, 1H), 4.53 (dd, J = 8.1, 6.0 Hz, 1H), 4.27 - 4.23 (m, 2H), 3.84 - 3.81 (m, 2H), 3.67 - 3.64 (m, 4H), 3.62 - 3.60 (m, 2H), 3.50 (t, J = 5.8 Hz, 2H), 3.27 - 3.23 (m, 5H), 3.15 (s, 3H), 3.04 - 2.99 (m, 2H), 2.68 (ddd, J = 12.4, 8.5, 3.6 Hz, 2H), 2.60 (s, 3H), 2.42 (s, 3H), 1.63 (s, 3H), 1.63 - 1.57 (m, 2H), 1.29 (ddd, J = 12.7, 8.3, 4.0 Hz, 2H). Example 1-107: Synthesis of (S)-(2-(5-(4-((10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1137] / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)decyl)carbamoyl)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1023)

[1138] Step 1: (ALMA-273-01) The solution of (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetic acid (30 mg, 0.075 mmol, 1 equiv) and HATU (1.5 equiv) in DMF (1.1 mL) was stirred at RT for 10 min. tert-Butyl (lO-aminodecyl)carbamate (1.2 equiv) was added followed by DIPEA (5 equiv) and the reaction mixture was stirred at RT for 3 h, until complete conversion was indicated by LCMS. tert-Butyl (S)-(10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)decyl)carbamate (32.9 mg, 0.049 mmol, 66% yield) was purified by flash column chromatography.

[1139] LCMS (ESI+) m / z 655.3 [M+H]+

[1140] Step 2: (ALMA-274-01) (S)- / V-(10-Aminodecyl)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamide hydrochloride was synthesized using the general procedure shown in Reaction Scheme 5 and Example Method 5, above (100% yield), using tert-butyl (S)- (10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)decyl)carbamate (32 mg, 0.049 mmol) as starting material.

[1141] LCMS (ESI+) m / z 554.8 [M+H]+ Step 3: (ALMA-276-01) The solution of 3-((4-methoxypiperidin-l-yl)sulfonyl)-4-(3-(2-oxo-2- ((pivaloyloxy)methoxy)ethyl)pyrazolo[l,5-a]pyridin-5-yl)benzoic acid (34.9 mg, 0.059 mmol, 1.1 equiv) and HATU (1.2 equiv) in DMF (0.25 mL) was stirred at RT for 10 min. (S)- / V-(10-Aminodecyl)-2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamide hydrochloride (31.6 mg, 0.054 mmol, 1 equiv) and DIPEA (2 equiv) were added and the reaction was stirred at RT for 3 h, until full conversion was indicated by LCMS. (S)-(2-(5-(4-((10-(2-(4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)decyl)carbamoyl)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (12.5 mg, 0.011 mmol, 20% yield) was purified by preparative HPLC.

[1142] LCMS (ESI+) m / z 1124.4 [M+H]+

[1143] 1H NMR (500 MHz, DMSO-d6) δ 8.81 (t, J = 5.6 Hz, 1H), 8.66 (dd, J = 7.1, 1.0 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.18 (dd, J = 8.0, 1.9 Hz, 1H), 8.14 (t, J = 5.7 Hz, 1H), 7.97 (s, 1H), 7.61 (dd, J = 2.0, 1.0 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 7.45 - 7.40 (m, 2H), 6.87 (dd, J = 7.2, 1.9 Hz, 1H), 5.71 (s, 2H), 4.50 (dd, J = 8.4, 5.8 Hz, 1H), 3.90 (s, 2H), 3.28 (s, 3H), 3.25 (m, 2H), 3.24 - 3.08 (m, 2H), 3.14 (s, 3H), 3.06 (p, J = 6.4 Hz, 2H), 3.01 - 2.95 (m, 2H), 2.70 - 2.63 (m, 2H), 2.59 (s, 3H), 2.42 - 2.39 (m, 3H), 1.62 (s, 3H), 1.61 - 1.51 (m, 4H), 1.45 - 1.40 (m, 2H), 1.27 (s, 12H), 1.04 (s, 9H).

[1144] Example 1-108: Synthesis of (S)-2-(5-(4-((10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1145] / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)decyl)carbamoyl)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetic acid (Compound 1022)

[1146]

[1147] Step 1: (ALMA-277-01) (S)-2-(5-(4-((10-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1148] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)decyl)carbamoyl)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (60% yield), using (S)-(2-(5-(4-((10-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)decyl)carbamoyl)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (8 mg, 0.007 mmol) as starting material.

[1149] LCMS (ESI+) m / z 1010.3 [M+H]+

[1150] 'H NMR (500 MHz, DMSO-d6) δ 8.80 (t, J = 5.6 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H), 8.43 (d, J = 1.9 Hz, 1H), 8.17 (s, 1H), 8.17 (dd, J = 8.0, 1.9 Hz, 1H), 7.91 (s, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.44 - 7.41 (m, 2H), 6.79 (dd, J = 7.1, 2.0 Hz, 1H), 4.50 (dd, J = 8.4, 5.7 Hz, 1H), 3.53 (s, 2H), 3.24 - 3.16 (m, 4H), 3.14 (s, 3H), 3.05 (td, J = 13.0, 6.8 Hz, 1H), 2.99 (dd, J = 9.7, 4.9 Hz, 2H), 2.72 - 2.63 (m, 2H), 2.59 (s, 3H), 2.41 (s, 3H), 1.62 (s, 3H), 1.60 - 1.51 (m, 4H), 1.43 (d, J = 7.6 Hz, 2H), 1.30 - 1.24 (m, 16H).

[1151] Example 1-109: Synthesis of (S)-(2-(5-(4-(8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1152] / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)octanamido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (Compound 1021)

[1153]

[1154] Step 1: (ALMA-280-01) To a solution of (S)-8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)octanoic acid (30 mg, 0.055 mmol, 1 equiv), (2-(5-(4- amino-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-o]pyridin-3-yl)acetoxy)methyl pivalate (1.02 equiv) and pyridine (2 equiv) in THF (0.55 mL) was added 2,4,6-tripropyl-l,3,5,2,4,6- trioxatriphosphinane 2,4,6-trioxide (0.05 mL, 50% in THF, 1.5 equiv). The reaction mixture was stirred at 60°C for 20 h until complete conversion was indicated by LCMS. The volatiles were removed in vacuo, the residue was taken up in ethyl acetate and washed with water, NaHCOs saturated solution and brine. The organic phase was dried over MgSO4and evaporated. (S)-(2-(5-(4-(8-(2-(4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6-yl)acetamido)octanamido)-2-((4- methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetoxy)methyl pivalate (11.5 mg, 0.011 mmol, 19% yield) was purified by preparative HPLC.

[1155] (S)-8-(2-(4-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-o][l,4]diazepin-6- yl)acetamido)octanoic acid was prepared as described in W02017197051A1.

[1156] LCMS (ESI+) m / z 1082.3 [M+H]+

[1157] TH NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.63 - 8.58 (m, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.16 (t, J = 5.7 Hz, 1H), 7.95 (d, J = 7.8 Hz, 2H), 7.53 (dd, J = 2.0, 0.9 Hz, 1H), 7.51 - 7.46 (m, 2H), 7.45 - 7.38 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 7.1, 2.0 Hz, 1H), 5.70 (s, 2H), 4.50 (dd, J = 8.1, 6.0 Hz, 1H), 3.89 (s, 2H), 3.29 - 3.16 (m, 2H), 3.15 (s, 3H), 3.17 - 3.04 (m, 2H), 3.00 (ddd, J = 11.7, 7.0, 3.8 Hz, 2H), 2.69 (ddd, J = 12.2, 8.3, 3.6 Hz, 2H), 2.59 (s, 3H), 2.40 (d, J = 1.0 Hz, 3H), 2.37 - 2.32 (m, 2H), 1.64 - 1.58 (m, 6H), 1.47 - 1.42 (m, 2H), 1.33 - 1.30 (m, 6H), 1.30 - 1.22 (m, 4H), 1.04 (s, 9H).

[1158] Example 1-110: Synthesis of (S)-2-(5-(4-(8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1159] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)octanamido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 1020)

[1160] Step 1: (ALMA-281-01) (S)-2-(5-(4-(8-(2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-

[1161] / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6-yl)acetamido)octanamido)-2-((4-methoxypiperidin-l- yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid was synthesized using the general procedure shown in Reaction Scheme 1 and Example Method 1, above (93% yield), using (S)-(2-(5-(4-(8-(2-(4-(4- chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2- / ][l,2,4]triazolo[4,3-a][l,4]diazepin-6- yl)acetamido)octanamido)-2-((4-methoxypiperidin-l-yl)sulfonyl)phenyl)pyrazolo[l,5-a]pyridin-3- yl)acetoxy)methyl pivalate (8 mg, 0.007 mmol) as starting material.

[1162] LCMS (ESI+) m / z 968.3 [M+H]+

[1163] TH NMR (500 MHz, DMSO-d6) δ 12.33 (s, 1H), 10.33 (s, 1H), 8.59 (dd, J = 7.1, 0.9 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.16 (t, J = 5.6 Hz, 1H), 7.97 - 7.91 (m, 1H), 7.93 (s, 1H), 7.53 (dd, J = 2.0, 1.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.49 - 7.39 (m, 2H), 7.38 (d, J = 8.3 Hz, 1H), 6.80 (dd, J = 7.2, 2.0 Hz, 1H), 4.50 (dd, J = 8.1, 6.0 Hz, 1H), 3.68 (s, 2H), 3.26 - 3.17 (m, 2H), 3.15 (s, 3H), 3.10 (dq, J = 13.0, 6.3 Hz, 1H), 3.01 (td, J = 7.3, 3.5 Hz, 2H), 2.69 (ddd, J = 12.1, 8.4, 3.6 Hz, 2H), 2.59 (s, 3H), 2.40 (s, 3H), 2.37 - 2.32 (m, 2H), 1.62 (s, 3H), 1.59 (m, 2H), 1.45 (s, 2H), 1.36 - 1.20 (m, 12H).

[1164] Example 1-111: Synthesis of 2-(5-(2-((4-(2-(2-acetamidoethoxy)ethoxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-a]pyridin-3-yl)acetic acid (Compound 81)

[1165] Step 1: To a solution of l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4-ol (215 mg, 0.616 mmol, 1 equiv) in DMF (2 mL), cooled in an ice-water bath, was added NaH (2 equiv, 60% suspension in mineral oil) and the resulting mixture was stirred for 15 min. 2-(2-Azidoethoxy)ethyl 4-methylbenzenesulfonate (1 equiv) was then added and the reaction mixture was stirred at RT for 16 h, quenched with ice-cold water and extracted with diethyl ether. The combined organic fractions were dried over NajSCU and evaporated yielding crude 4-(2-(2-azidoethoxy)ethoxy)-l-((2-bromo-3- methoxyphenyl)sulfonyl)piperidine (300 mg) which was directly forwarded to the next step. 2-(2-Azidoethoxy)ethyl 4-methylbenzenesulfonate was prepared as described in Abellan-Flos, M. et al., Org. Biomol. Chem. 2015, 27, 7445

[1166] LCMS (ESI+) m / z 465.0 [M+H]+

[1167] Step 2: To a stirred solution of crude 4-(2-(2-azidoethoxy)ethoxy)-l-((2-bromo-3- methoxyphenyl)sulfonyl)piperidine (300 mg) in THF (5 mL) and water (1 mL) was added triphenylphosphine (340 mg, 1.296 mmol) and the reaction mixture was stirred at 60°C for 4 h and quenched with water. The resulting mixture was extracted with DCM, the combined organic fractions were dried over Na2SO4and evaporated. 2-(2-((l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidin-4- yl)oxy)ethoxy)ethan-l-amine (160 mg, 0.37 mmol, 59% yield over two steps) was purified by flash column chromatography.

[1168] LCMS (ESI+) m / z 439.0 [M+H]+

[1169] Step 3: / V-(2-(2-((l-((2-Bromo-3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethyl)acetamide was synthesized using the general procedure shown in Reaction Scheme 11 and Example Method 11, above, using 2-(2-((l-((2-bromo-3-methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethan-l-amine (70 mg, 0.161 mmol) as starting material. After completion the crude product was directly forwarded into the next step.

[1170] LCMS (ESI+) m / z 481.0 [M+H]+

[1171] Step 4: Methyl 2-(5-(2-((4-(2-(2-acetamidoethoxy)ethoxy)piperidin-l-yl)sulfonyl)-6- methoxyphenyl)pyrazolo[l,5-o]pyridin-3-yl)acetate was synthesized using the general procedure shown in Reaction Scheme 3 and Example Method 3, above, using / V-(2-(2-((l-((2-bromo-3- methoxyphenyl)sulfonyl)piperidin-4-yl)oxy)ethoxy)ethyl)acetamide (70 mg, 0.146 mmol, 1 equiv) and methyl 2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-o]pyridin-3-yl)acetate (1 equiv) as starting materials, CS2CO3 (2 equiv) as base, Pd(dtbpf)Cl2 as catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite®, the filtrate was evaporated to give crude product which was used in the next step without further purification.

[1172] LCMS (ESI+) m / z 589.4 [M+H] Step 5: 2-(5-(2-((4-(2-(2-Acetamidoethoxy)eth...

Claims

CLAIMS1. A compound of formula (la):wherein:X2is N or CR3;X3is N or CR1; wherein when X2is N, then X3 is CR1; and when X3 is N, then X2is CR3;R1is H, halogen, haloalkyl, methyl, -OH or -NH2;R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, -NH(alkyl), -NH2or -CN;R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), and -P(O)(alkyl)2; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl or heteroaryl, each of which is independently unsubstituted or is substituted with at least one of -OH, -NH2, -NH(alkyl) or -N (alkyl )2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; andeach R7is independently selected from unsubstituted alkyl, -O(alkyl), -0(CH2)q0Me, -(CFbJqOIVIe, -(OCHzCFbJrNHR73, -C(O)alkyl and -S(O)2alkyl; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or - C(O)alkyl;R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2-P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and ^(OjOCHjCHjSOjIVIe; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkyl)2, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2; and wherein:(a) at least one of R1, R2and R3is not H;(b) when R2and R3are each H, then R1is halogen; and(c) when R1and R3are each H, then R2is not halogen.

2. The compound of claim 1, wherein X2is N.

3. The compound of claim 1, wherein X3 is N.

4. The compound of claim 1, wherein X2is CR3and X3is CR1.

5. The compound of any preceding claim, wherein R1is H, halogen or methyl.

6. The compound of any preceding claim, wherein R3is H, halogen, unsubstituted alkyl or -CN.

7. The compound of any preceding claim, wherein R1is H.

8. The compound of claim 7, wherein R1and R3are each H.

9. The compound of claim 7, wherein R1and R2are each H.

10. The compound of any one of claims 1-6, wherein R2and R3are each H.

11. The compound of any one of claims 1-6, whereinR3is H,R1is halogen or methyl, andR2is -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

12. The compound of any one of claims 1-8 and 11, wherein R2is -B(OH)2, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl or benzyl; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; andwherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

13. The compound of any one of claims 1-8, 11 and 12, wherein R2is selected from aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl and benzyl; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

15. The compound of claim 14, wherein R2is selected fromwherein n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

16. The compound of claim 15, wherein R2is selected fromwherein n is 1, 2 or 3; and wherein m is 0 or 1.

17. The compound of claim 16, wherein R2is18. The compound of any preceding claim, wherein each R4is independently selected from halogen, -CN, alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), - O(heterocycloalkyl), -NH2, -N(alkyl)z, -S(O)zalkyl, -S(O)zaryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), - S(O)2(heterocycloalkyl), -C(O)(heterocycloalkyl), and -C(O)OH; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

19. The compound of any preceding claim, wherein each R7is independently selected from -Me, - OMe, -O(CH2)qOMe, -CH2OMe, -C(O)Me and -S(O)2Me.

20. The compound of any preceding claim, wherein each R4is independently selected from -F, -Cl, -lBu, -Me, -CF3, -OH, -OMe, -OCF3, -CN, -NH2, -NMe2, -NHC(O)Me, -S(O)2Me, -S(O)2NMe2, -CH2S(O)2NHMe, cyclopropyl, -C(O)OH,21. The compound of any preceding claim, wherein each R6is independently selected from haloalkyl, halogen, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

22. The compound of any preceding claim, wherein each R6is independently selected from -CF3, -Cl,-NH2, -C(O)piperidine, -23. The compound of any preceding claim, wherein R2is selected from:

24. The compound of any preceding claim, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl);then:C4-R4is selected from C-alkynyl, C-S(O)2alkyl, C-S(O)2N(alkyl)2, C-CH2S(O)2NH(alkyl), C- S(O)2(heterocycloalkyl), C-S(O)2aryl, C-CH2heterocycloalkyl, C-CH2C(O)NH(alkyl), C-NHC(O)(alkyl), C- SO(alkyl) and C-P(O)(alkyl)2; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

25. The compound of any one of claims 1-23, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl);then: each R4of — r 'R4) is independently selected from -CN, alkynyl, cycloalkyl, heterocycloalkyl, -NH2, -N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, -C(O)NH(alkyl), -SO(alkyl), and -P(O)(alkyl)2; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

26. The compound of any one of claims 1-25, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl);27. The compound of any one of claims 1-25, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl);n is 1 or 2; then:R8is -CH2C(O)OH or -CH^O^CH^CfOfBu;X2and X3 are both CH; and(i) eachis -S(O)2(heterocycloalkyl), wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; or28. The compound of any one of claims 1-6 and 10-27, wherein R1is methyl.

29. The compound of any preceding claim, wherein -30. The compound of any preceding claim, wherein R8is selected from -CHR9C(O)OR10, - CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, -CH2(heterocycloalkyl), -CH2(heteroaryl), -CH2B(OH)2, - CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2.

31. The compound of claim 30, wherein R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, - CH2S(O)2NR92, -S(O)2NR92, -CH2(4- or 5-membered heterocycloalkyl), -CH2(5-membered heteroaryl), - CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2.

32. The compound of claim 31, wherein R8is -CHR9C(O)OR10.

33. The compound of claim 31, wherein R8is selected from - -CH2C(O)OH, -CHMeC(O)OH, - CH2C(O)OMe, -CH2C(O)OEt, -CH^fOjOCH^CfOfBu, -CH2C(O)NH2, -CH2S(O)2NH2, -S(O)2NH2, -CH2- oxetane, -CH2(l,2,3-triazole), -CH2B(OH)2, -CH2P(O)(OH)2, COOH, -COOMe, -B(OH)2and -P(O)(OH)2.

34. The compound of claim 32 or 33, wherein R8is selected from -CH2C(O)OCH2OC(O)tBu, -CH2C(O)OH and -CHMeC(O)OH.

35. The compound of claim 34, wherein R8is selected from36. The compound of claim 35, wherein R8is -CH2C(O)OH.

37. The compound of any preceding claim, wherein the compound is selected from:

38. The compound of claim 37, wherein the compound is selected from:R1is H;R3is H or methyl;R2is aryl substituted with one or more R4or is fused bicyclic heteroaryl substituted with one or more R6; andR8is -CH2C(O)OH, -CH(Me)C(O)OH, or CHR9(heteroaryl).

40. The compound of claim 39, wherein: each R4is independently selected from halogen, unsubstituted alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -NH2, -N(alkyl)z, -NHC(O)alkyl, -C(O)NHalkyl, -C(O)N(alkyl)2, - S(O)2N(alkyl)2, -S(0)2(aryl), -S(O)2(heterocycloalkyl) and -C(O)OH; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R6is -S(O)2(heterocycloalkyl), alkyl or -NH2; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R71. The compound of claim 40, wherein the compound is selected from:

42. The compound of claim 40, whereinR3is H; each R4is independently selected from -OH, -NHz, -O(alkyl), -NHC(O)alkyl, -C(O)NHalkyl, - S(O)z(heterocycloalkyl) and -C(O)OH; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from -O(alkyl), -O(CHz)qOI\ / le, -(CHz)qOI\ / le, and - (OCH2CHz)rNHR7a; wherein q is 1 or 2, r is 4 and R7ais -C(O)Me.

43. The compound of claim 42, wherein the compound is:

44. Use of a compound of any one of claims 1-43 in a bifunctional protein degrader compound.

45. A bifunctional protein degrader compound comprising a compound of any one of claims 1-43.

46. A bifunctional protein degrader compound comprising a compound of formula (la'):wherein:X2is N or CR3;X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;R1is H, halogen, haloalkyl, methyl, -OH or -NH2;R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl), -NH2or -CN;R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl,fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)z, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -O(CH2)qOMe, -(CH2)qOMe, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19and -OR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)PNMe2, -C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CI\ / le2OH, and -qojOCHjCHjSOjMe; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; and each R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkylsubstituted with 0P(0)(0H)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - 0C(0)0(CH2)mS(0)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - 0C(0)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alkyl)2cycloalkyl, N-(unsubstituted C1-C6alkyl)piperidinium cation, N- (unsubstituted C1-C6alkyl)morpholinium cation, and N-(unsubstituted C1-C6alkyl)imidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(O)NMe2;R19is a bond connecting the compound of formula (la') to a Target protein binding moiety or to a linker, wherein the linker is attached to a Target protein binding moiety, and wherein formula (la') contains a single R19; and wherein:(a) at least one of R1, R2and R3is not H;(b) when R2and R3are each H, then R1is halogen; and(c) when R1and R3are each H, then R2is not halogen.

47. A compound of formula (II)[KLHDC2 ligase binding moiety] - linker - [Target protein binding moiety] CD or a salt, solvate, hydrate or isomer thereof, wherein [Target protein binding moiety] is:(a)whereinM is O, S or NH, or is absent; indicates attachment to R18of the linker;R11is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;R12is H or Me; andL' is H, alkyl, benzyl, acetyl or pivaloyl;(b)wherein indicates attachment to R18of the linker; and k is an integer from 1-10;(c)whereinX4and X5are each independently N or CH;X6is N or CH;R30is H, halogen, -OMe, -CN, unsubstituted C1-C6 alkyl, -CECH, R40, or -C(O)R40;R31is H, -OMe, -heteroaryl, -heteroaryl-R40or R40;R32is H, unsubstituted C1-C6 alkyl,R33is -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -NH(aryl), or R40;R34is -Me or -C(O)R40; andR40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; orwhereinX7is N or CH;R35is -heterocycloalkyl-R40, or R40;R36is H or -OMe; andR40is a bond connected to R18of the linker, wherein the [Target protein binding moiety] contains a single R40; wherein [KLHDC2 ligase binding moiety] is a compound of formula (la'):wherein:X2is N or CR3;X3is N or CR1; wherein when X2is N, then X3is CR1; and when X3is N, then X2is CR3;R1is H, halogen, haloalkyl, methyl, -OH or -NH2;R3is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)z, - NH(alkyl),- NH2or -CN;R2is H, -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6; each R4is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH2, - N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2O(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -C(O)OH, - C(O)NH(alkyl), -C(O)N(alkyl)2, -SO(alkyl), -P(O)(alkyl)2, R19, -NHR19and -OR19; wherein each aryl, cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; each R5is independently selected from alkyl, aryl, heteroaryl and R19, wherein the alkyl, aryl and heteroaryl are independently unsubstituted or are substituted with at least one of -OH, -NH2, -NH(alkyl) or -N(alkyl)2; each R6is independently selected from halogen, unsubstituted alkyl, haloalkyl, unsubstituted aryl, -NH2, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and -NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; and each R7is independently selected from unsubstituted alkyl, -O(alkyl), -O(CH2)qOMe, -(CH2)qOMe, -(OCH2CH2)rNHR7a, -C(O)alkyl, -S(O)2alkyl, R19, -OR19and -(OCH2CH2)rR19; wherein q is 1 or 2; r is 0, 1, 2, 3, 4 or 5; and R7ais H or -C(O)alkyl;R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, - CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, -CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR10, - B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)pNMe2, -C(O)O(CH2)pNHMe, -C(O)OCH2CH(OH)CH2OH, - C(O)OCH2CH2CMe2OH, and -C(O)OCH2CH2SO2Me; wherein each Rpis independently -(CH2)mOC(O)(unsubstituted C1-C6alkyl), wherein each m is independently 1, 2, 3 or 4; each p is independently 2, 3, 4, 5, or 6; each R9is independently H or unsubstituted alkyl; andeach R10is independently H, unsubstituted alkyl, or C1-C6alkyl substituted by one or more groups selected from -OC(O)(unsubstituted C1-C6alkyl), -OC(O)(C1-C6alkyl substituted with at least one R10a), - OC(O)cycloalkyl, -OC(O)heterocycloalkyl, -OC(O)aryl, -OC(O)heteroaryl, - OC(O)(CH2)mO(CH2)mO(unsubstituted C1-C6alkyl), -OC(O)(CH2)mO(CH2CH2O)m(unsubstituted C1-C6alkyl), - OC(O)O(unsubstituted C1-C6alkyl), -OC(O)O(C1-C6alkyl substituted with at least one R10a), - OC(O)Ocycloalkyl, -OC(O)O(CH2CH2O)m(unsubstituted C1-C6alkyl), -OC(O)O(CH2CH2O)m(C1-C6alkyl substituted with OP(O)(OH)2), -OC(O)O(CH2CH2S)m(unsubstituted C1-C6alkyl), - OC(O)O(CH2)mS(O)(unsubstituted C1-C6alkyl), -OC(O)O(CH2)mS(O)2(unsubstituted C1-C6alkyl), - OC(O)NH(C1-C6alkyl substituted with OMe), -OC(O)NMe(C1-C6alkyl substituted with OMe), -P(O)(OH)2, - OP(O)(OH)2, -C(O)heterocycloalkyl, -C(O)N(unsubstituted C1-C6alkylh, heteroaryl, heterocycloalkyl, - S(unsubstituted C1-C6alkyl), -S(O)(unsubstituted C1-C6alkyl), -N+(unsubstituted C1-C6alkyljs, - N+(unsubstituted C1-C6alky^cycloalkyl, N-(unsubstituted C1-C6alkyljpiperidinium cation, N- (unsubstituted C1-C6alkyljmorpholinium cation, and N-(unsubstituted C1-C6alkyljimidazolium cation; wherein each R10ais independently -OH, -O(unsubstituted C1-C6alkyl), -OBn, -NH2, -NMe2, - NHC(O)(unsubstituted C1-C6alkyl), -NHC(O)O(unsubstituted C1-C6alkyl), heterocycloalkyl, heteroaryl, aryl, -C(0)NMe2;R19is a bond connected to R14of the linker, wherein formula (la') contains a single R19; and wherein:(a) at least one of R1, R2and R3is not H;(b) when R2and R3are each H, then R1is halogen; and(c) when R1and R3are each H, then R2is not halogen; and wherein [linker] has the following formulaR14.R15.R16.R17.R18 whereinR14is -C1-6 alkyl, -C2-6 alkenyl, -C2-6alkynyl, Ci.g alkyl-N(Ci-6 alkyl)-, -C(O)-, -SO2- or is absentR15is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci.g alkyl-NH-, -Ci.g alkyl-N(Ci-6 alkyl)-, - cycloalkyl-NH-, -heterocycloalkyl-NH- or is absentR16is -C1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH2-C(O)-, -CH2-C(O)-NH-, -CH2-C(O)O- or is absentR17is -CH2(C2H4-O)y, (C2H4-O)X, (CaHg-Ojx, or is absent x is 1-10 y is 2-10;and wherein(a) when [Target protein binding moiety] iscycloalkyl, CH2-NH-C(O)-, heterocycloalkyl, or is absent; and(b) when [Target protein binding moiety] isC(O)-NH-, heterocycloalkyl, heterocycloalkyl-NH, or is absent.

48. The compound of any one of claims 46-47, wherein X2is N.

49. The compound of any one of claims 46-47, wherein X3is N.

50. The compound of any one of claims 46-47, wherein X2is CR3and X3is CR1.

51. The compound of any one of claims 46-50, wherein R1is H, halogen or methyl.

52. The compound of any one of claims 46-51, wherein R3is H, halogen, unsubstituted alkyl or -CN.

53. The compound of any one of claims 46-52, wherein R1is H.

54. The compound of claim 53, wherein R1and R3are each H.

55. The compound of claim 53, wherein R1and R2are each H.

56. The compound of any one of claims 46-52, wherein R2and R3are each H.

57. The compound of any one of claims 46-51, whereinR3is H,R1is halogen or methyl, andR2is -B(OH)2, halogen, -CN, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

58. The compound of any one of claims 46-54 and 57, wherein R2is -B(OH)2, -NR52, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

59. The compound of any one of claims 46-5457 and 58, wherein R2is selected from aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl / heterocycloalkyl, benzyl or R19; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl / heterocycloalkyl are unsubstituted or are substituted with one or more R6.

60. The compound of claim 59, wherein R2is selected fromwherein n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

61. The compound of claim 60, wherein R2is selected fromn is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; and p is 0, 1, 2 or 3.

62. The compound of claim 61, wherein R2is selected fromwherein n is 1, 2 or 3; and wherein m is 0 or 1.

63. The compound of claim 62, wherein R2is64. The compound of any one of claims 46-63, wherein each R4is independently selected from halogen, -CN, alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), - O(cycloalkyl), -O(heterocycloalkyl), -NH2, -N (a lkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, - CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), -C(O)(heterocycloalkyl), -C(O)OH, R19and -OR19; whereineach cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

65. The compound of any one of claims 46-64, wherein each R7is independently selected from -Me, -OMe, -O(CH2)qOMe, -CH2OMe, -C(O)Me, -S(O)2Me, R19and -OR19.

66. The compound of any one of claims 46-65, wherein each R4is independently selected from R19, - OR19, -NHR19, -F, -Cl, -lBu, -Me, -CF3, -CN, -OH, -OMe, -OCF3, -NH2, -NMe2, -S(O)2Me, -S(O)2NMe2, -CH2S(O)2NHMe, cyclopropyl, -C(O)OH,67. The compound of claim 66, wherein each R4is independently selected from R19, -NHR19, -OR19,68. The compound of any one of claims 46-67, wherein each R6is independently selected from haloalkyl, -C(O)(heterocycloalkyl), -S(O)2(heterocycloalkyl), -C(O)alkyl, R19and NHR19; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

69. The compound of any one of claims 46-68, wherein each R6is independently selected from -CF3,-C(O)piperidine, -70. The compound of any one of claims 46-69, wherein R2is selected from:

71. The compound of claim 70, wherein R2is selected from:

72. The compound of any one of claims 46-70, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl),then:C4-R4is selected from C-alkynyl, C-S(O)2alkyl, C-S(O)2N(alkyl)2, C-CH2S(O)2NH(alkyl), C- S(O)2(heterocycloalkyl), C-S(O)2aryl, C-CH2heterocycloalkyl, C-CH2C(O)NH(alkyl), C-NHC(O)(alkyl), C- SO(alkyl) and C-P(O)(alkyl)2; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

73. The compound of any one of claims 46-70, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl),then: each R4of - (~R4 / )nis independently selected from -CN, alkynyl, cycloalkyl, heterocycloalkyl, - NH2, -N(alkyl)2, -S(O)2alkyl, -S(O)2aryl, -S(O)2N(alkyl)2, -CH2S(O)2NH(alkyl), -S(O)2(heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH2heterocycloalkyl, -CH2C(O)NH(alkyl), -COOH, -C(O)NH(alkyl), - SO(alkyl), and -P(O)(alkyl)2; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one R7.

74. The compound of any one of claims 46-73, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92 or -CHR9(heterocycloalkyl);then:R8is -CH2C(O)OH;X2 and X3 are both CH; and75. The compound of any one of claims 46-73, wherein: whenR8is -CHR9C(O)OR10, -CHR9C(O)NR92or -CHR9(heterocycloalkyl);then:R8is -CH2C(O)OH or -CH^O^CH^CfOfBu;X2and X3 are both CH; andis -S(O)2(heterocycloalkyl), wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R7; or76. The compound of any one of claims 46-52 and 72-75, wherein R1is methyl.

11. The compound of any one of claims 46-76, wherein -CHR9C(O)OR10is78. The compound of any one of claims 46-74, wherein R8is selected from -CHR9C(O)OR10, - CHR9C(O)NR92, -CHR9S(O)2NR92, -S(O)2NR92, -CHR9(heterocycloalkyl), -CHR9(heteroaryl), -CHR9B(OH)2, CHR9P(O)(OH)2, -CHR9P(O)(ORP)2, -COOR9, -B(OH)2, -P(O)(OH)2, -P(O)(ORP)2, -C(O)O(CH2)PNMe2, - C(O)O(CH2)PNHMe, -C(O)OCH2CH(OH)CH2OH, -C(O)OCH2CH2CI\ / le2OH, and -C(O)OCH2CH2SO2l\ / le; or wherein R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, - CH2(heterocycloalkyl), -CH2(heteroaryl), -CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2.

79. The compound of claim 78, wherein R8is selected from -CHR9C(O)OR10, -CHR9C(O)NR92, -CH2S(O)2NR92, -S(O)2NR92, -CH2(4- or 5-membered heterocycloalkyl), -CH2(5-membered heteroaryl), - CH2B(OH)2, -CH2P(O)(OH)2, -COOR9, -B(OH)2and -P(O)(OH)2.

80. The compound of claim 79, wherein R8is -CHR9C(O)OR10,81. The compound of claim 80, wherein R8is selected from -CH2C(O)OH, -CHMeC(O)OH, - CH2C(O)OMe, -CH2C(O)OEt, -CH2C(O)OCH2OC(O)tBu, -CH2C(O)NH2, -CH2S(O)2NH2, -S(O)2NH2, -CH2- oxetane, -CH2(l,2,3-triazole), -CH2B(OH)2, -CH2P(O)(OH)2, -COOH, -COOMe, -B(OH)2and -P(O)(OH)2.

82. The compound of claim 80 or 81, wherein R8is selected from -CH2C(O)OCH2OC(O)lBu, -CH2C(O)OH and -CHMeC(O)OH.

83. The compound of claim 82, wherein R8is selected from84. The compound of claim 82, wherein R8is -CH2C(O)OH.

85. The compound of any one of claims 46-84, wherein:R1and R3are each H;R2is selected from aryl, fused aryl / heterocycloalkyl and benzyl; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R4; and wherein the fused aryl / heterocycloalkyl is unsubstituted or is substituted with one or more R6; andR8is -CHR9C(O)OR10.

86. The compound of claim 85, wherein R2is aryl substituted with R4and R8is -CH2C(O)OR1087. The compound of claim 85 or 86, wherein each R4is S(O)2(heterocycloalkyl) substituted with R19or OR19.

88. The compound of any one of claims 47-88, wherein at least one of R14, R15, R16, R17and R18is present.

89. The compound of any one of claims 47-88, wherein R14is absent.

90. The compound of any one of claims 47-88, wherein R14is -C(O)-.

91. The compound of any one of claims 47-90, wherein R15is absent.

92. The compound of any one of claims 47-90, wherein R15is heterocycloalkyl.

93. The compound of any one of claims 47-92, wherein R16is absent.

94. The compound of any one of claims 47-92, wherein R16is -Ci.g alkyl.

95. The compound of any one of claims 47-92, wherein R16is -C(O)-.

96. The compound of any one of claims 47-92, wherein R16is -C(O)-NH-.

97. The compound of any one of claims 47-96, wherein R17is absent.

98. The compound of any one of claims 47-96, wherein R17is (C2H4-O)x.

99. The compound of any one of claims 47-96and 98, wherein x is 3-9.

100. The compound of claim 99, wherein x is 3, 5, 7 or 9.

101. The compound of any one of claims 47-100, wherein R18is absent.

102. The compound of any one of claims 47-100, wherein R18is -Ci-io alkyl or -Ci-w alkyl-N H-.

103. The compound of claim 102, wherein R18is -Ci.g alkyl or -Ci.g alkyl-N H-; optionally wherein R18is -CH2CH2- or -CH2CH2-NH-.

104. The compound of any one of claims 47-100, wherein R18is heterocycloalkyl or heterocycloalkyl-NH-.

105. The compound of any one of claims 47-87, wherein R14, R15, R16, R17and R18are each absent.

106. The compound of any one of claims 47-104, wherein [linker] isrT' ein1rvT wher indicates attachment to [KLHDC2 ligase binding moiety] and2indicates attachment to [Target protein binding moiety].

107. The compound of any one of claims 47-106, wherein the [Target protein binding moiety] is:whereinM is O, S or NH, or is absent; indicates attachment to R18of the linker;R11is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;R12is H or Me; andL' is H, alkyl, benzyl, acetyl or pivaloyl.

108. The compound of any one of claims 47-107, wherein R12is Me.

109. The compound of any one of claims 47-107, wherein R12is H.

110. The compound of claim 107, wherein [Target protein binding moiety] is:

111. The compound of claim 110, wherein [Target protein binding moiety] is:

112. The compound of any one of claims 47-111, wherein M is absent.

113. The compound of any one of claims 47-112, wherein L' is H.

114. The compound of claim 113, wherein [Target protein binding moiety] is:

115. The compound of any one of claims 47-106, wherein [Target protein binding moiety] is:

116. The compound of any one of claims 47-106, wherein [Target protein binding moiety] is:

117. The compound of any one of claims 47-106, wherein [Target protein binding moiety] is:

118. The compound of claim 117, wherein [Target protein binding moiety] is:

119. The compound of claim 118, wherein [Target protein binding moiety] is:

120. The compound of claim 118, wherein [Target protein binding moiety] is:

121. The compound of any one of claims 117-120, wherein [linker] is~,1 2 wherein indicates attachment to [KLHDC2 ligase binding moiety]indicates attachment to [Target protein binding moiety].

122. The compound of any one of claims 47-121, wherein k is an integer from 3-8; optionally wherein k is 4, 6, or 8; further optionally wherein k is 6.

123. The compound of any one of claims 47-123, wherein the compound is selected from:

124. The compound of claim 123, wherein the compound is selected from:

125. The compound of claim 123, wherein the compound is selected from:

26. The compound of claim 125, wherein the compound is selected from:

27. The compound of claim 125, wherein the compound is selected from:

129. The compound of claim 123, wherein the compound is selected from130. The compound of claim 123, wherein the compound is selected from131. A pharmaceutical composition comprising a compound of any one of claims 1-130.

132. The compound of any one of claims 1-130 or the pharmaceutical composition of claim 131 for use in medicine.

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