[go: up one dir, main page]

WO2025219579A1 - Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch) - Google Patents

Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)

Info

Publication number
WO2025219579A1
WO2025219579A1 PCT/EP2025/060749 EP2025060749W WO2025219579A1 WO 2025219579 A1 WO2025219579 A1 WO 2025219579A1 EP 2025060749 W EP2025060749 W EP 2025060749W WO 2025219579 A1 WO2025219579 A1 WO 2025219579A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heterocycloalkyl
compound
unsubstituted
chr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/060749
Other languages
English (en)
Inventor
Michał BIŚTA
Sylvain Cottens
Katarzyna Dudek
Daria GOŁĘBIOWSKA
Arnaud MATHIEU
Ziemowit Pokładek
Bartosz WOŹNIAK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Captor Therapeutics SA
Original Assignee
Captor Therapeutics SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Captor Therapeutics SA filed Critical Captor Therapeutics SA
Publication of WO2025219579A1 publication Critical patent/WO2025219579A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • KLHDC2 KELCH DOMAIN-CONTAINING PROTEIN 2
  • 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.
  • KLHDC2 Kelch Domain-Containing Protein 2
  • E3 ubiquitin ligase with high-affinity and bifunctional degraders containing such compounds.
  • TPD protein degradation
  • CRBN cereblon
  • VHL von Hippel-Lindau
  • CRBN and VHL ligands have sparked the most interest due to the availability of chemical probes with favorable physiochemical properties and their well-studied mechanism of target engagement.
  • both ligases have shown high efficiency and versatility in degrading proteins in the cytoplasm and nucleus.
  • 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.
  • 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.
  • KLHDC2 The Kelch-like family member 2
  • 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.
  • KLHDC2 AdPROM screen performed by Roth et al. (2022).
  • 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).
  • 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.
  • 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.
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X 2 is N, then X 3 is CR 1 ; and when X 3 is N, then X 2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH 2 ;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl) 2 , - NH(alkyl), -NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , 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 R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycl
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2, -S(O) 2 NR 9 2, - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH)2, -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 -P(O)(OR P ) 2 , -C(O)O(CH 2 ) P NMe 2 , -C(O)O(CH 2 ) P NHMe, -C(O)OCH 2 CH(OH)CH 2 OH, - C(O)OCH2CH 2 CI ⁇ /le2OH, and ⁇ (OjOCHjCHjSOjIVI
  • a bifunctional protein degrader compound comprising a compound as defined above.
  • a bifunctional protein degrader compound comprising a compound of formula (la'): wherein:
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X 2 is N, then X 3 is CR 1 ; and when X 3 is N, then X 2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH 2 ;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl) 2 , - NH(alkyl),- NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl),
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2, -S(O) 2 NR 9 2, - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 , -P(O)(OR P ) 2 , -C(O)O(CH 2 ) P NMe 2 , -C(O)O(CH 2 ) P NHMe, -C(O)OCH2CH(OH)CH 2 OH, - C(O)OCH2CH 2 CI ⁇ /le2OH, and -C(O)OCH2CH
  • R 19 is 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 R 19 ; and wherein:
  • M is O, S or NH, or is absent; indicates attachment to R 18 of the linker;
  • R 11 is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;
  • R 12 is H or Me;
  • L' is H, alkyl, benzyl, acetyl or pivaloyl; or
  • X 4 and X 5 are each independently N or CH;
  • X 6 is N or CH
  • R 30 is H, halogen, -OMe, -CN, unsubstituted C1-C6 alkyl, -CECH, R 40 , or -C(O)R 40 ;
  • R 31 is H, -OMe, -heteroaryl, -heteroaryl-R 40 or R 40 ;
  • R 32 is H, unsubstituted C1-C6 alkyl
  • R 33 is -N(C1-C6 alkyl) 2 , -NH(C1-C6 alkyl), -NH(aryl), or R 40 ;
  • R 34 is -Me or -C(O)R 40 ;
  • R 40 is a bond connected to R 18 of the linker, wherein the [Target protein binding moiety] contains a single R 40 ; or wherein
  • X 7 is N or CH
  • R 35 is -heterocycloalkyl-R 40 , or R 40 ;
  • R 36 is H or -OMe; and R 40 is a bond connected to R 18 of the linker, wherein the [Target protein binding moiety] contains a single R 40 ; wherein [KLHDC2 ligase binding moiety] is a compound of formula (la'): wherein:
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X 2 is N, then X 3 is CR 1 ; and when X 3 is N, then X 2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH 2 ;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl) 2 , - NH(alkyl),- NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl),
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2, -S(O) 2 NR 9 2, - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 , -P(O)(OR P ) 2 , -C(O)O(CH 2 ) P NMe 2 , -C(O)O(CH 2 ) P NHMe, -C(O)OCH2CH(OH)CH 2 OH, - C(O)OCH2CH 2 CI ⁇ /le2OH, and -C(O)OCH 2 CH
  • R 19 is a bond connected to R 14 of the linker, wherein formula (la') contains a single R 19 ; and wherein:
  • R 14 is -Ci-6 alkyl, -C 2.6 alkenyl, -C 2.6 alkynyl, C1-6 alkyl-N(C1-6 alkyl)-, -C(O)-, -SO 2 - or is absent
  • R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Ci.g alkyl-NH-, -Ci.g alkyl-N(Ci-6 alkyl)-, - cycloalkyl-NH-, -heterocycloalkyl-NH- or is absent
  • R 16 is -Ci-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O)O- or is absent
  • R 17 is -CH 2 (C 2 H4-O)y, (C 2 H 4 -O) X , (CaHg-Ojx, or is absent x is 1-10 y is 2-10; and wherein
  • R 18 is -Ci.g alkyl, cycloalkyl
  • R 18 is -C1-6 alkyl-NH-, cycloalkyl-NH, -CH 2 -NH-C(O)-NH-, heterocycloalkyl, heterocycloalkyl-NH, or is absent.
  • the present invention also provides a pharmaceutical composition comprising a compound of the invention.
  • the present invention also provides a compound or pharmaceutical composition of the invention, for use in medicine.
  • 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.
  • 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.
  • the alkyl group is an unsubstituted alkyl group.
  • the alkyl group is substituted by one or more groups selected from -OH, -OR W , -NH2, -NHR W , -NR W 2, -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • the alkyl group is a linear alkyl group. In some embodiments the alkyl group is an unsubstituted linear alkyl group.
  • the alkyl group is a linear alkyl group which is substituted by one or more groups selected from -OH, -OR W , -NH2, - NHR W , -NR W 2, -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkyl group is a branched alkyl group.
  • the alkyl group is an unsubstituted branched alkyl group.
  • the alkyl group is a branched alkyl group which is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • alkenyl is intended to include both unsubstituted alkenyl groups, and alkenyl groups which are substituted by one or more additional groups.
  • the alkenyl group is an unsubstituted alkenyl group.
  • the alkenyl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkenyl group is a C2-C12 alkenyl, a C 2 -CM alkenyl, a C2-C8 alkenyl, a C2-C6 alkenyl, or a C 2 -C 4 alkenyl group.
  • the alkenyl group is a linear alkenyl group.
  • the alkenyl group is an unsubstituted linear alkenyl group.
  • the alkenyl group is a linear alkenyl group which is substituted by one or more groups selected from -OH, - OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkenyl group is a branched alkenyl group.
  • the alkenyl group is an unsubstituted branched alkenyl group.
  • the alkenyl group is a branched alkenyl group which is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • alkynyl is intended to include both unsubstituted alkynyl groups, and alkynyl groups which are substituted by one or more additional groups.
  • the alkynyl group is an unsubstituted alkynyl group.
  • the alkynyl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkynyl group is a C2-C12 alkynyl, a C 2 -Cio alkynyl, a C 2 -Cg alkynyl, a C 2 -Cg alkynyl, or a C 2 -C 4 alkynyl group.
  • the alkynyl group is a linear alkynyl group.
  • the alkynyl group is an unsubstituted linear alkynyl group.
  • the alkynyl group is a linear alkynyl group which is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the alkynyl group is a branched alkynyl group.
  • 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, -OR W , -NH2, -NHR W , -NR W 2, -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • cycloalkyl is intended to include both unsubstituted cycloalkyl groups, and cycloalkyl groups which are substituted by one or more additional groups.
  • 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).
  • the cycloalkyl group is an unsubstituted cycloalkyl group.
  • the cycloalkyl group is substituted by one or more groups selected from -OH, -OR W , -NH2, -NHR W , -NR W 2, - SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • cycloalkenyl is intended to include both unsubstituted cycloalkenyl groups, and cycloalkenyl groups which are substituted by one or more additional groups.
  • the cycloalkenyl group is an unsubstituted cycloalkenyl group.
  • the cycloalkenyl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • 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.
  • heterocycloalkyl is intended to include both unsubstituted heterocycloalkyl groups, and heterocycloalkyl groups which are substituted by one or more additional groups.
  • 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).
  • 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.
  • the heterocycloalkyl group is substituted by one or more groups selected from -R w , -OH, -OR W , -NH2, -NHR W , -NR W 2, -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • one or more -CH 2 - groups of the heterocycloalkyl ring may be replaced with a -C(O)- group
  • 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 C 3 -C 8 heterocycloalkyl, a C 4 -C 8 heterocycloalkyl, a C 5 -C 8 heterocycloalkyl, a C3-C6 heterocycloalkyl, a C4-C6 heterocycloalkyl, a C5-C6 heterocycloalkyl, a C3-C4 heterocycloalkyl, or a C4-C5 heterocycloalkyl group.
  • aryl is intended to include both unsubstituted aryl groups, and aryl groups which are substituted by one or more additional groups.
  • the aryl group is an unsubstituted aryl group.
  • the aryl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -OC(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • the aryl group is a C6-C10 aryl, a C6-C8 aryl, or a Cg aryl.
  • heteroaryl is intended to include both unsubstituted heteroaryl groups, and heteroaryl groups which are substituted by one or more additional groups.
  • the heteroaryl group is an unsubstituted heteroaryl group.
  • the heteroaryl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • one or more -NH- groups of the heteroaryl ring may be replaced with a -NR W - group.
  • the heteroaryl group is a C6-C10 heteroaryl, a C6-C9 heteroaryl, a C6-C8 heteroaryl, or a Cg heteroaryl.
  • 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.
  • the fused heterocycloalkylheteroaryl group is an unsubstituted cycloalkenyl group.
  • the fused heterocycloalkyl-heteroaryl group is substituted by one or more groups selected from -OH, -OR W , -NH2, - NHR W , -NR W 2, -SO2R W , -C(O)R W , -CN, and -NO2, wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • benzyl is intended to include both unsubstituted benzyl groups, and benzyl groups which are substituted by one or more additional groups.
  • the benzyl group is an unsubstituted benzyl group.
  • the benzyl group is substituted by one or more groups selected from -OH, -OR W , -NH 2 , -NHR W , -NR W 2 , -SO 2 R W , -C(O)R W , -CN, and -NO 2 , wherein each R w is unsubstituted and is independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl, or benzyl.
  • all alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl and benzyl groups in the compounds are unsubstituted.
  • the present invention provides a compound of formula (la): wherein:
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X2 is N, then X3 is CR 1 ; and when X3 is N, then X2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH2;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)2, - NH(alkyl), -NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , 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 R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycl
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2, -S(O) 2 NR 9 2 , - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 -P(O)(OR P ) 2 , -C(O)O(CH 2 ) P NMe 2 , -C(O)O(CH 2 ) P NHMe, -C(O)OCH2CH(OH)CH 2 OH, - C(O)OCH2CH 2 CI ⁇ /le2OH, and -qojOCHjCHj
  • X2 is N. In other embodiments, X3 is N.
  • X2 is CR 3 and X3 is CR 1 .
  • R 1 is H, halogen or methyl.
  • R 3 is H, halogen, unsubstituted alkyl or -CN.
  • R 1 is H. In some such embodiments, R 1 and R 3 are each H. In other embodiments, R 1 and R 2 are each H.
  • R 2 and R 3 are each H.
  • R 3 is H
  • R 1 is halogen or methyl
  • R 2 is -B(OH)2, halogen, -CN, -NR 5 2, 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 R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is -B(OH)2, -NR 5 2, 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 R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is 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 R 4 ; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is selected from:
  • R 2 is 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.
  • R 2 is selected from
  • n 1, 2 or 3; and wherein m is 0 or 1.
  • R 2 is
  • each R 4 is independently selected from halogen, -CN, alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), -O(heterocycloalkyl), -NH 2 , - N(alkyl) 2 , -S(O) 2 alkyl, -S(O) 2 aryl, -S(O) 2 N(alkyl) 2 , -CH 2 S(O) 2 NH(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 R 7 .
  • each R 7 is independently selected from -Me, -OMe, -O(CH 2 ) q OMe, -CH 2 OMe, -
  • each R 4 is independently selected from -F, -Cl, - l Bu, -Me, -CF3, -OH, -OMe, -OCF3,
  • each R 6 is independently selected from halogen, haloalkyl, -NH 2 , - C(O)(heterocycloalkyl), -S(O) 2 (heterocycloalkyl) and -C(O)alkyl; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R 7 .
  • each R 6 is independently selected from -Cl, -CF 3 , -NH 2 , -C(O)piperidine, -C(O)Me
  • R 2 is selected from:
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl); then: C 4 -R 4 is selected from C-alkynyl, C-S(O) 2 alkyl, C-S(O) 2 aryl, C-S(O) 2 N(alkyl) 2 , C-CH 2 S(O) 2 NH(alkyl), C-S(O) 2 (heterocycloalkyl), C-CH 2 heterocycloalkyl, C-CH 2 C(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 R 7 .
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl): then: each R 4 of — ” R4 ) is independently selected from -CN, alkynyl, cycloalkyl, heterocycloalkyl, - NH 2 , -N(alkyl) 2 , -S(O) 2 alkyl, -S(O) 2 aryl, -S(O) 2 N(alkyl) 2 , -CH 2 S(O) 2 NH(alkyl), -S(O) 2 (heterocycloalkyl), - C(O)(heterocycloalkyl), -NHC(O)(alkyl), -CH 2 heterocycloalkyl, -CH 2 C(O)NH(alkyl), -COOH, -C(O)NH(alkyl), - SO(alkyl),
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl); then:
  • R 8 is -CH 2 C(O)OH
  • X 2 and X 3 are both CH;
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl); then:
  • R 8 is -CH 2 C(O)OH or -CH ⁇ O ⁇ CH ⁇ CfOfBu;
  • X 2 and X3 are both CH;
  • each R 4 of — ( '” R4 ) is -S(O) 2 (heterocycloalkyl), wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R 7 ; or
  • R 1 is methyl
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CH 2 S(O) 2 NR 9 2 , -S(O) 2 NR 9 2 , - CH 2 (heterocycloalkyl), -CH 2 (heteroaryl), -CH 2 B(OH) 2 , -CH 2 P(O)(OH) 2 , -COOR 9 , -B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CH 2 S(O) 2 NR 9 2 , -S(O) 2 NR 9 2 , CH 2 (4- or 5-membered heterocycloalkyl), -CH 2 (5-membered heteroaryl), -CH 2 B(OH) 2 , -CH 2 P(O)(OH) 2 , - COOR 9 , -B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is -CHR 9 C(O)OR 10 .
  • R 8 is selected from -CH 2 C(O)OH, -CHMeC(O)OH, -CH 2 C(O)OMe, -CH 2 C(O)OEt, - CH 2 S(O) 2 NH 2 , -CH ⁇ OjOCfWqorBu, -CH 2 C(O)NH 2 , -CH 2 S(O) 2 NH 2 , -S(O) 2 NH 2 , -CH 2 -oxetane, -CH 2 (1,2,3- triazole), -CH 2 B(OH) 2 , -CH 2 P(O)(OH) 2 , -COOH, -COOMe, -B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is selected from -CH 2 C(O)OCH 2 OC(O) t Bu, -CH 2 C(O)OH and -CHMeC(O)OH.
  • R 8 is -CH2C(O)OH. In other embodiments, R 8 is -CHzCfOjOCHzOCfOfBu.
  • the compound is selected from:
  • 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.
  • R 1 is H; R 3 is H or methyl; R 2 is aryl substituted with one or more R 4 or is fused bicyclic heteroaryl substituted with one or more R 6 ; and R 8 is -CH2C(O)OH, -CH(Me)C(O)OH or CHR 9 (heteroaryl).
  • each R 4 is 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)?
  • 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.
  • R 3 is H; each R 4 is 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 R 7 ; and each R 7 is independently selected from -O(alkyl), -O(CHz) q OI ⁇ /le, -(CHz) q OI ⁇ /le and -(OCH2CHz) r NHR 7a ; wherein q is 1 or 2, r is 4 and R 7a is -C(O)Me.
  • the compound is Compound ID no. 2, 24, 37, 45, 46, 47, 73, 76, 77, 79, 82, 84, 86, 91, 96, 102 or 103.
  • a bifunctional protein degrader compound comprising a compound as defined in any of the above embodiments of the first aspect.
  • a bifunctional protein degrader compound comprising a compound of formula (la'): wherein: X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X 2 is N, then X 3 is CR 1 ; and when X 3 is N, then X 2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH 2 ;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl) 2 , - NH(alkyl),- NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl),
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2 , -S(O) 2 NR 9 2 , - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 , -P(O)(OR P ) 2 , -C(O)O(CH 2 )pNMe 2 , -C(O)O(CH 2 ) p NHMe, -C(O)OCH 2 CH(OH)CH 2 OH, - C(O)OCH 2 CH 2 CMe 2 OH, and -C(O)OC
  • R 19 is 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 R 19 ; and wherein:
  • 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.
  • 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.
  • 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.
  • 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.
  • Target proteins of the Target protein binding moiety 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.
  • Table 1 List of kinases targeted by TL13-87 kinase warhead.
  • M is O, S or NH, or is absent; indicates attachment to R 18 of the linker;
  • R 11 is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;
  • R 12 is H or Me
  • L' is H, alkyl, benzyl, acetyl or pivaloyl; or
  • X 4 and X 5 are each independently N or CH;
  • X 6 is N or CH
  • R 30 is H, halogen, -OMe, -CN, unsubstituted C1-C6 alkyl, -CECH, R 40 , or -C(O)R 40 ;
  • R 31 is H, -OMe, -heteroaryl, -heteroaryl-R 40 or R 40 ;
  • R 32 is H, unsubstituted C1-C6 alkyl, R 33 is -N(C1-C6 alkyl) 2 , -NH(C1-C6 alkyl), -NH(aryl), or R 40 ;
  • R 34 is -Me or -C(O)R 40 ;
  • R 40 is a bond connected to R 18 of the linker, wherein the [Target protein binding moiety] contains a single R 40 ; or wherein
  • X 7 is N or CH
  • R 35 is -heterocycloalkyl-R 40 , or R 40 ;
  • R 36 is H or -OMe
  • R 40 is a bond connected to R 18 of the linker, wherein the [Target protein binding moiety] contains a single R 40 ; wherein [KLHDC2 ligase binding moiety] is a compound of formula (la'): wherein:
  • X 2 is N or CR 3 ;
  • X 3 is N or CR 1 ; wherein when X 2 is N, then X 3 is CR 1 ; and when X 3 is N, then X 2 is CR 3 ;
  • R 1 is H, halogen, haloalkyl, methyl, -OH or -NH 2 ;
  • R 3 is H, halogen, haloalkyl, unsubstituted alkyl, -OH, -O(alkyl), -C(O)NH(alkyl), -N (alkyl)z, - NH(alkyl),- NH 2 or -CN;
  • R 2 is H, -B(OH) 2 , halogen, -CN, -NR 5 2 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 ; each R 4 is independently selected from halogen, -CN, unsubstituted alkyl, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl),
  • R 8 is selected from -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2 , -S(O) 2 NR 9 2 , - CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , -CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 10 , - B(OH) 2 , -P(O)(OH) 2 , -P(O)(OR P ) 2 , -C(O)O(CH 2 )pNMe 2 , -C(O)O(CH 2 ) p NHMe, -C(O)OCH 2 CH(OH)CH 2 OH, - C(O)OCH 2 CH 2 CMe 2 OH, and -C(O)OC
  • R 19 is a bond connected to R 14 of the linker, wherein formula (la') contains a single R 19 ; and wherein:
  • R 14 is -C1-6 alkyl, -C2-6 alkenyl, -C2-6alkynyl, Ci.g alkyl-N(C1-6 alkyl)-, -C(O)-, -SO2- or is absent
  • R 15 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-6 alkyl-NH-, -Ci.g alkyl-N(Ci-6 alkyl)-, - cycloalkyl-NH-, -heterocycloalkyl-NH- or is absent
  • R 16 is -C1-6 alkyl, -C(O)-, -C(O)-NH-, -C(O)O-, -CH 2 -C(O)-, -CH 2 -C(O)-NH-, -CH 2 -C(O)O- or is absent
  • R 17 is -CH2(C2H 4 -O) y , (C 2 H4-O) X , (CaHg-Ojx, or is absent x is 1-10 y is 2-10; and wherein
  • X 2 is N. In other embodiments, X 3 is N.
  • X 2 is CR 3 and X 3 is CR 1 .
  • R 1 is H, halogen or methyl.
  • R 3 is H, halogen, unsubstituted alkyl or -CN.
  • R 1 is H. In some embodiments, R 1 and R 3 are each
  • R 1 and R 2 are each H.
  • R 2 and R 3 are each H. In some embodiments of the fourth and fifth aspects,
  • R 3 is H
  • R 1 is halogen or methyl
  • R 2 is -B(OH)2, halogen, -CN, -NR 5 2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is -B(OH)2, -NR 5 2, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the cycloalkyl, aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heterocycloalkyl, heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is selected from aryl, heteroaryl, fused bicyclic heteroaryl, fused aryl/heterocycloalkyl, benzyl or R 19 ; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the heteroaryl, fused bicyclic heteroaryl, and fused aryl/heterocycloalkyl are unsubstituted or are substituted with one or more R 6 .
  • R 2 is selected from
  • R 2 is 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.
  • R 2 is 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, R 2 is
  • each R 4 is independently selected from halogen, alkyl, -CN, haloalkyl, alkynyl, cycloalkyl, heterocycloalkyl, -OH, -O(alkyl), -O(haloalkyl), -O(cycloalkyl), - O(heterocycloalkyl), -NH 2 , -N(alkyl) 2 , -S(O) 2 alkyl, -S(O) 2 aryl, -S(O) 2 N(alkyl) 2 , -CH 2 S(O) 2 NH(alkyl), - S(O) 2 (heterocycloalkyl), -C(O)(heterocycloalkyl), -C(O)OH, R 19 and -OR 19 ; wherein each cycloalkyl and heterocycloalkyl is independently unsubstituted or is substituted with at least one
  • each R 7 is independently selected from -Me, - OMe, -O(CH 2 ) q OMe, -CH 2 OMe, -C(O)Me, -S(O) 2 Me, R 19 and -OR 19 .
  • each R 4 is independently selected from R 19 , -OR 19 , -NHR 19 -F, -Cl, - l Bu, -Me, -CF 3 , -CN, -OH, -OMe, -OCF 3 , -NH 2 , -NMe 2 , -S(O) 2 Me, -S(O) 2 NMe 2 , - CH 2 S(O) 2 NHMe, cyclopropyl, -C(O)OH,
  • each R 4 is independently selected from R 19 , -OR 19 ,
  • each R 6 is independently selected from haloalkyl, -C(O)(heterocycloalkyl), - S(O) 2 (heterocycloalkyl), -C(O)alkyl, R 19 and NHR 19 ; wherein each heterocycloalkyl is independently unsubstituted or is substituted with at least one R 7 .
  • each R 6 is independently selected from -CF3, -
  • R 2 is selected from:
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl); then
  • C 4 -R 4 is selected from C-alkynyl, C-S(O) 2 alkyl, C-S(O) 2 N(alkyl) 2 , C-CH 2 S(O) 2 NH(alkyl), C- S(O) 2 (heterocycloalkyl), C-S(O) 2 aryl, C-CH 2 heterocycloalkyl, C-CH 2 C(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 R 7 .
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl), n is 1 or 2, then each R 4 of - ( ' ⁇ R4 / ) n is 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
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl);
  • R 8 is -CHR 9 C(O)OR 10 , -CHR 9 C(O)NR 9 2 or -CHR 9 (heterocycloalkyl); then:
  • R 8 is -CH 2 C(O)OH or -CH ⁇ O ⁇ CH ⁇ CfOfBu;
  • X 2 and X 3 are both CH;
  • each is -S(O) 2 (heterocycloalkyl), wherein each heterocycloalkyl is
  • R 1 is methyl
  • R 8 is selected from -CHR 9 C(O)OR 10 , - CHR 9 C(O)NR 9 2 , -CHR 9 S(O) 2 NR 9 2 , -S(O) 2 NR 9 2, -CHR 9 (heterocycloalkyl), -CHR 9 (heteroaryl), -CHR 9 B(OH) 2 , - CHR 9 P(O)(OH) 2 , -CHR 9 P(O)(OR P ) 2 , -COOR 9 , -B(OH) 2 , -P(O)(OH) 2 , -P(O)(OR P ) 2 , -C(O)O(CH 2 ) P NMe 2 , - C(O)O(CH 2 ) P NHMe, -C(O)OCH2CH(OH)CH 2 OH, -C(O)OCH2CH 2 CI ⁇ /le2OH
  • R 8 is selected from -CHR 9 C(O)OR 10 , CHR 9 C(O)NR 9 2, -CH 2 S(O)2NR 9 2, -S(O) 2 NR 9 2, -CH 2 (heterocycloalkyl), -CH 2 (heteroaryl), -CH 2 B(OH)2, -CH 2 P(O)(OH)2, -COOR 9 , - B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is selected from -CHR 9 C(O)OR 10 , CHR 9 C(O)NR 9 2, -CH 2 S(O)2NR 9 2, -S(O) 2 NR 9 2, -CH2(4- or 5-membered heterocycloalkyl), -CH2(5-membered heteroaryl), - CH 2 B(OH)2, -CH 2 P(O)(OH)2, -COOR 9 , -B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is selected from -CH 2 C(O)OH, -CHMeC(O)OH, - CH 2 C(O)OMe, -CH 2 C(O)OEt, -CH2C(O)OCH 2 OC(O) t Bu, -CH 2 C(O)NH2, -CH 2 S(O)2NH2, -S(O) 2 NH2, -CH 2 - oxetane, -CH 2 (l,2,3-triazole), -CH 2 B(OH)2, -CH 2 P(O)(OH)2, -COOH, -COOMe, -B(OH) 2 and -P(O)(OH) 2 .
  • R 8 is -CHR 9 C(O)OR 10 . In some embodiments of the fourth and fifth aspects, R 8 is selected from -CHjCfOjOCHjOCXOfBu, - CH 2 C(O)OH and -CHMeC(O)OH.
  • R 8 is selected from
  • R 8 is -CH 2 C(O)OH. In other embodiments, R 8 is -CH 2 C(O)OCH 2 OC(O) t Bu.
  • R 1 and R 3 are each H;
  • R 2 is selected from aryl, fused aryl/heterocycloalkyl and benzyl; wherein the aryl and benzyl are unsubstituted or are substituted with one or more R 4 ; and wherein the fused aryl/heterocycloalkyl is unsubstituted or is substituted with one or more R 6 ; and R 8 is -CHR 9 C(O)OR 10 .
  • R 2 is aryl is substituted with R 4 and R 8 is -CHR 9 C(O)OR 10
  • each R 4 is S(O) 2 (heterocycloalkyl) substituted with R 19 .
  • At least one of R 14 , R 15 , R 16 , R 17 and R 18 is present.
  • R 14 is absent. In other embodiments, R 14 is -C(O)-.
  • R 15 is absent. In other embodiments, R 15 is heterocycloalkyl.
  • R 16 is absent. In other embodiments, R 16 is -Ci.g alkyl. In other embodiments, R 16 is -C(O)-. In other embodiments, R 16 is -C(O)-NH-.
  • R 17 is absent. In other embodiments, R 17 is (C 2 H 4 -O) X . In some embodiments of the fifth aspect, x is 3-9. In some embodiments, x is 3, 5, 7 or 9.
  • R 18 is absent. In other embodiments, R 18 is -Ci-w alkyl or -Ci-io alkyl-NH-. In some embodiments, R 18 is -Ci.g alkyl or -Ci.g alkyl-NH-. In some embodiments, R 18 is - CH 2 CH 2 - or -CH 2 CH 2 -NH-. In other embodiments, R 18 is heterocycloalkyl or heterocycloalkyl-NH-.
  • R 14 , R 15 , R 16 , R 17 and R 18 are each absent.
  • the [Target protein binding moiety] is: wherein
  • M is O, S or NH, or is absent; indicates attachment to R 18 of the linker;
  • R 11 is H, halogen, -OMe, an amino group, heterocycloalkyl, or unsubstituted C1-C6 alkyl;
  • R 12 is H or Me
  • L' is H, alkyl, benzyl, acetyl or pivaloyl.
  • R 12 is Me. In other embodiments, R 12 is H.
  • [Target protein binding moiety] is:
  • [Target protein binding moiety] is:
  • M is absent.
  • L' is H.
  • [Target protein binding moiety] is:
  • [Target protein binding moiety] is: n some embodiments of the fifth aspect, [Target protein binding moiety] is:
  • [Target protein binding moiety] is:
  • [Target protein binding moiety] is:
  • [Target protein binding moiety] is:
  • [Target protein binding moiety] is:
  • k is an integer from 3-8; optionally wherein k is 4, 6, or 8; further optionally wherein k is 6.
  • the compound is selected from:
  • the compound is selected from Compound ID nos. 1001, 1002 and 1003.
  • 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.
  • 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.
  • the compound is selected from Compound ID nos. 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018 and 1019.
  • the compound is selected from Compound ID nos. 1024 and 1025.
  • the compound is selected from Compound ID nos. 1028, 1029, 1030, 1031, 1033, 1034, 1035, 1036 and 1037.
  • the present invention also provides a pharmaceutical composition comprising a compound of the invention.
  • the pharmaceutical composition comprises a bifunctional protein degrader compound of the present invention.
  • the pharmaceutical composition comprises a compound of any of the above embodiments of the fourth or fifth aspects of the present invention.
  • the pharmaceutical composition comprises a compound of any of the above embodiments of the fifth aspect of the present invention.
  • the present invention also provides a compound or pharmaceutical composition of the invention, for use in medicine.
  • the compound is a bifunctional protein degrader compound of the present invention.
  • the compound is a compound of any of the above embodiments of the fourth or fifth aspects of the present invention.
  • the compound is a compound of any of the above embodiments of the fifth aspect of the present invention.
  • 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.
  • the compound is a bifunctional protein degrader compound of the present invention.
  • the compound is a compound of any of the above embodiments of the fourth or fifth aspects of the present invention.
  • the compound is a compound of any of the above embodiments of the fifth aspect of the present invention.
  • the compounds of the present invention were prepared as described below.
  • 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).
  • PdXphosG3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,r-biphenyl)[2-
  • 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.
  • solvents e.g. MeOH, THF
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Na 2 SO 4 and evaporated. The residue was triturated with 50% (v/v) mixture of ether and pentane to afford the target compound.
  • 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 H 2 SO 4 (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 Na 2 SO 4 and evaporated to afford methyl 2-(5-bromopyrazolo[l,5-o]pyridin-3-yl)acetate (1.4 g, 5.2 mmol, 78% yield).
  • 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.
  • 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.
  • 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
  • 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.
  • 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 Na2SO 4 and evaporated to give crude product which was used in the next step without further purification.
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dppf)CI 2 as catalyst (0.1 equiv). LCMS (ESI+) m/z 350.2 [M+H] +
  • 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.2 equiv).
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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).
  • 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).
  • 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 NH 4 CI solution and extracted with ethyl acetate.
  • LDA 41 mL, 80.6 mmol, 3 equiv, 2M solution in THF
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv). After completion, the reaction mixture was quenched with water and extracted with e
  • 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.
  • 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 Na 2 SO 4 and evaporated to yield crude product which was used to the next step without additional purification.
  • 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.
  • 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.
  • Piperidin-l-yl(lH-pyrrol-2-yl)methanone was synthesized as described in Gao, S. et al., J. Org. Chem. 2018, 83, 9250.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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).
  • 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 NH 4 CI and extracted with ethyl acetate.
  • 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.
  • 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, KaPO 4 (3.33 equiv) as base and Pd(dppf)CI 2 as catalyst (0.14 equiv).
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 Na2SO 4 and evaporated to obtain pure product.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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.
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4.4 equiv) as base and Pd(dtbpf)CI 2 as 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base and Pd(dppf)CI 2 as a catalyst (0.1 equiv). After completion of the reaction, solvent was evaporated, quenched with
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (5 equiv) as base and Pd(dtbpf)CI 2 as a catalyst (0.1 equiv). After completion the reaction mixture was filtered through Celite® and evaporated to give crude product
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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(dtbp
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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.
  • 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).
  • Step 1 4-Bromo-3,5-dichloro-/V,/V-dimethylaniline was synthesized using the general procedure shown in
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv).
  • 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, Cs 2 CO 3 (4.1 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv). l-Bromo-4-(prop-l-yn-l-yl)benzene was synthesized as described in Fujihara, T. et
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base and Pd(dtbpf)CI 2 as catalyst (0.11 equiv). After completion of the reaction the solvent was evaporated to give crude
  • 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.
  • 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.
  • 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)CI 2 as catalyst (0.1 equiv). After completion, the reaction mixture was quenched with water and extracted with ethy
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (2.7 equiv) as base, Pd(dtbpf)CI 2 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.
  • 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.
  • 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, K 3 PO 4 (3.33 equiv) as base and Pd(PPh 3 ) 2 Cl2 as catalyst (0.11 equiv).
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base and Pd(dtbpf)CI
  • 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.
  • 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.
  • 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,
  • Step 2 Methyl 2-(5-(5-(l-(methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-
  • Step 3 2-(5-(5-(l-(Methylsulfonyl)-l,2,3,6-tetrahydropyridin-4-yl)-2-
  • 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.
  • 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(d
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.1 equiv). LCMS (ESI+) m/z 339.0 [M+H]
  • 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.
  • 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.
  • 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)CI 2 as catalyst (0.1 equiv). After completion the solvent was evaporated and the crude product was used in the next step without additional purification.
  • 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.
  • 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, K 3 PO 4 (3.33 equiv) as base and Pd(PPh 3 ) 2 Cl2 as catalyst (0.11 equiv).
  • 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
  • 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.
  • 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 PPh 3 (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 NaHCO 3 solution 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base, Pd(dtbpf)CI 2 as catalyst (0.3 equiv).
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 volatile
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • 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.
  • 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)
  • 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
  • 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.
  • 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)
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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
  • 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 KHCO 3 (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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • 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, Cs 2 CO 3 (4 equiv) as base and Pd(dtbpf)CI 2 as catalyst (0.1 equiv). The product (mixture of stereoisomers) was purified by preparative HPLC.
  • Absolute configuration of the stereoisomers was assigned based on crystal structure.
  • 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)
  • 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.
  • 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 Na 2 SO 4 and 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.
  • 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.
  • 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.
  • 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
  • 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,
  • 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.
  • 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)
  • 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.
  • 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
  • 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 Na 2 SO 4 and 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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.
  • 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.
  • 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 KHCO 3 (2 equiv) and chloromethyl pivalate (1.5 equiv) and the resulting solution was stirred at RT for 16 h.
  • 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).
  • 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.
  • 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)CI 2 (0.1 equiv) as catalyst and Cs 2 CO 3 (2 equiv) as base.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés qui peuvent se lier à l'ubiquitine ligase E3 de KLHDC2 (protéine 2 contenant un domaine Kelch) avec une affinité élevée, et des agents de dégradation bifonctionnels contenant de tels composés.
PCT/EP2025/060749 2024-04-17 2025-04-17 Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch) Pending WO2025219579A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLPCT/PL2024/000014 2024-04-17
PCT/PL2024/000014 WO2025221154A1 (fr) 2024-04-17 2024-04-17 Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)

Publications (1)

Publication Number Publication Date
WO2025219579A1 true WO2025219579A1 (fr) 2025-10-23

Family

ID=91301990

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/PL2024/000014 Pending WO2025221154A1 (fr) 2024-04-17 2024-04-17 Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)
PCT/EP2025/060749 Pending WO2025219579A1 (fr) 2024-04-17 2025-04-17 Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/PL2024/000014 Pending WO2025221154A1 (fr) 2024-04-17 2024-04-17 Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)

Country Status (1)

Country Link
WO (2) WO2025221154A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140031559A1 (en) 2011-12-16 2014-01-30 State of Oregon, acting by and through the State Board of Higher Education on Behalf of University Tunable phenylacetylene hosts
US20150259357A1 (en) 2013-02-04 2015-09-17 Janssen Pharmaceutica Nv Flap modulators
US20170008904A1 (en) 2015-07-10 2017-01-12 Arvinas, Inc. Mdm2-based modulators of proteolysis and associated methods of use
WO2017011590A1 (fr) 2015-07-13 2017-01-19 Arvinas, Inc. Modulateurs de protéolyse à base d'alanine et procédés d'utilisation associés
WO2017197051A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères de c3-glutarimide liés à une amine pour la dégradation de protéines cibles
WO2018217809A1 (fr) 2017-05-23 2018-11-29 Abide Therapeutics, Inc. Inhibiteurs de magl à base de pyrazole
WO2019238816A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler l'uchl5
WO2021077010A1 (fr) 2019-10-17 2021-04-22 Arvinas Operations, Inc. Molécules bifonctionnelles contenant une fraction de liaison à l'ubiquitine ligase e3 liée à une fraction ciblant bcl6
WO2023192578A1 (fr) 2022-03-31 2023-10-05 Kymera Therapeutics, Inc. Agents de dégradation de protéines et leurs utilisations

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3026051A4 (fr) * 2013-07-24 2017-03-08 Takeda Pharmaceutical Company Limited Composé hétérocyclique
WO2020264499A1 (fr) * 2019-06-28 2020-12-30 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140031559A1 (en) 2011-12-16 2014-01-30 State of Oregon, acting by and through the State Board of Higher Education on Behalf of University Tunable phenylacetylene hosts
US20150259357A1 (en) 2013-02-04 2015-09-17 Janssen Pharmaceutica Nv Flap modulators
US20170008904A1 (en) 2015-07-10 2017-01-12 Arvinas, Inc. Mdm2-based modulators of proteolysis and associated methods of use
WO2017011590A1 (fr) 2015-07-13 2017-01-19 Arvinas, Inc. Modulateurs de protéolyse à base d'alanine et procédés d'utilisation associés
WO2017197051A1 (fr) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Dégronimères de c3-glutarimide liés à une amine pour la dégradation de protéines cibles
WO2018217809A1 (fr) 2017-05-23 2018-11-29 Abide Therapeutics, Inc. Inhibiteurs de magl à base de pyrazole
WO2019238816A1 (fr) 2018-06-13 2019-12-19 University Of Dundee Molécules bifonctionnelles pour cibler l'uchl5
WO2021077010A1 (fr) 2019-10-17 2021-04-22 Arvinas Operations, Inc. Molécules bifonctionnelles contenant une fraction de liaison à l'ubiquitine ligase e3 liée à une fraction ciblant bcl6
WO2023192578A1 (fr) 2022-03-31 2023-10-05 Kymera Therapeutics, Inc. Agents de dégradation de protéines et leurs utilisations

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEN, H ET AL., J. AM. CHEM. SOC, vol. 143, 2021, pages 15073
CHEN, H ET AL., J. AM. CHEM. SOC., vol. 143, 2021, pages 15073
FUJIHARA, T ET AL., ANGEW. CHEM. INT. ED, vol. 51, 2012, pages 11487
GAO, S ET AL., J. ORG. CHEM., vol. 83, 2018, pages 9250
HICKEY CH.M.DIGIANANTONIO K.M.ZIMMERMANN K.HARBIN A.QUINN C.PATEL A.GAREISS P.CHAPMAN A.TIBERI B.DOBRODZIEJ J.: "Co-opting the E3 ligase KLHDC2 for targeted protein degradation by small molecules", NAT. STRUCT. MOL. BIOL., vol. 31, 2023, pages 311 - 322, XP093256737, DOI: 10.1038/s41594-023-01146-w
KIM Y.SEO CJEON E.YOU I.HWANG K.KIM N.CHOI H.S.HINSHAW S.M.GRAY N.SSIM T.: "Targeted Kinase Degradation via the KLHDC2 Ubiquitin E3 Ligase", BIORXIV, 2022
KOPKA, I.E ET AL., BIOMOL
POIRSON J.DHILLON A.CHO H.LAM M.H.Y.ALERASOOL NLACOSTE J.MIZAN LTAIPALE M.: "Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers", BIORXIV, 2022
RÖTH S.CARTON B.SATHYAMURTHI P.S.WATT M.MACARTNEY T.J.CHAN K.H.ISIDRO-LLOBET A.KONOPACKA A.QUEISSER M.ASAPKOTA G: "Screening of E3 Ligases Uncovers KLHDC2 as an Efficient Proximity-Induced Degrader of K-RAS, STK33, β-catenin and FoxP3", STK33, Β-CATENIN AND FOXP3
RUSNAC D.V.LIN H.C.CANZANI D.TIEN K.X.HINDS T.R.TSUE A.F.BUSH M.F.YEN H.C.SZHENG N.: "Recognition of the diglycine C-end degron by CRL2KLHDC2 ubiquitin ligase", MOL. CELL, vol. 72, no. 5, 2018, pages 813 - 822

Also Published As

Publication number Publication date
WO2025221154A1 (fr) 2025-10-23

Similar Documents

Publication Publication Date Title
AU2008296974B2 (en) Soluble guanylate cyclase activators
JP4423043B2 (ja) Ｒｈｏ−キナーゼ阻害剤
KR102400920B1 (ko) 리신 특이적 데메틸라제-1의 억제제
CA3009669C (fr) Inhibiteurs de la tyrosine kinase de bruton
RU2734760C2 (ru) Противоинфекционные соединения
ES2821821T3 (es) Derivados de tetrahidroisoquinolina
US20050245520A1 (en) 2-Phenylpyridin-4-yl derivatives as alk5 inhibitors
KR101721739B1 (ko) 키나제 조절 화합물, 이를 함유하는 조성물 및 그의 용도
JP7299167B2 (ja) Ｓｙｋ阻害薬及びその使用方法
CN111196804B (zh) TGF-βR1抑制剂及其应用
CA2908098A1 (fr) Inhibiteurs mk2 et utilisations associees
FR3000492A1 (fr) Nouveaux derives azaindole en tant qu'inhibiteurs multikinases
US10550080B2 (en) Acyl sulfonamide NaV1.7 inhibitors
US20060058329A1 (en) Pyrazole inhibitors of the transforming growth factor
MX2010010018A (es) Nuevos derivados de carbazol inhibidores de hsp90, composiciones que los contienen y su uso.
WO2012159557A1 (fr) Dérivé substitué de triazine phénylurée et son utilisation contre des tumeurs
ES2468221T3 (es) Derivados de bencimidazol y composiciones farmacéuticas del mismo
US20230227429A1 (en) Sulphonamide compounds
TW201319063A (zh) 以四氫噻唑衍生物或其鹽為有效成分之醫藥品
KR20250112837A (ko) TNF-α 활성의 조절제
CN109641909A (zh) 雷帕霉素信号通路抑制剂的机理靶标及其治疗应用
US20190142810A1 (en) Mitochondrial inhibitors for the treatment of proliferation disorders
KR20240151737A (ko) 이작용성 설폰아미드 화합물
WO2025219579A1 (fr) Ligands de ligase de klhdc2 (protéine 2 contenant un domaine kelch)
JP6167465B2 (ja) イミダゾ−オキサジアゾール及びイミダゾ−チアジアゾール誘導体

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25719437

Country of ref document: EP

Kind code of ref document: A1