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WO2025231112A1 - Modulateurs de sik2 et leurs utilisations - Google Patents

Modulateurs de sik2 et leurs utilisations

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Publication number
WO2025231112A1
WO2025231112A1 PCT/US2025/027058 US2025027058W WO2025231112A1 WO 2025231112 A1 WO2025231112 A1 WO 2025231112A1 US 2025027058 W US2025027058 W US 2025027058W WO 2025231112 A1 WO2025231112 A1 WO 2025231112A1
Authority
WO
WIPO (PCT)
Prior art keywords
independently selected
nitrogen
sulfur
oxygen
optionally substituted
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/US2025/027058
Other languages
English (en)
Inventor
Nathan E. GENUNG
Neelu Kaila
Alan Graves
Scott D. Edmondson
Derun Li
Russell George Dushin
Bruce Lefker
Steffen GRESSIES
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.)
Nimbus Salacia Inc
Original Assignee
Nimbus Salacia Inc
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Filing date
Publication date
Application filed by Nimbus Salacia Inc filed Critical Nimbus Salacia Inc
Publication of WO2025231112A1 publication Critical patent/WO2025231112A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compounds and methods useful for inhibiting saltinducible kinase 2 (SIK2).
  • the invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.
  • a protein kinase is an enzyme that catalyzes the transfer of phosphate groups to proteins or other organic molecules. Consequently, defective control of protein phosphorylation leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.
  • SIKs The salt-inducible kinases
  • AMPK adenosine monophosphate-activated kinase
  • three isoforms have been described, i.e., SIK1, SIK2 (QIK), and SIK3 (QSK).
  • the SIKs play a number of roles in different cell types have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins, and also histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes.
  • CRTC CREB-responsive transcriptional co-activator
  • HDAC histone de-acetylase
  • SIK2 is known to play a role in the secretion of high levels of anti- inflammatory cytokines such as interleukin-10 (IL-10), very low levels of pro-inflammatory cytokines such as TNF- ⁇ , and in the regulation of IFN ⁇ and IL-12 signaling, suggesting SIK2 may be an interesting target for inflammatory diseases.
  • IL-10 interleukin-10
  • TNF- ⁇ very low levels of pro-inflammatory cytokines
  • IFN ⁇ and IL-12 signaling suggesting SIK2 may be an interesting target for inflammatory diseases.
  • IL-10 interleukin-10
  • TNF- ⁇ regulatory factor- ⁇
  • the aim of the present invention is to provide new compounds which are potent SIK2 inhibitors, and which also show selectivity over SIK1 and SIK2.
  • SUMMARY OF THE INVENTION [0008] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as inhibitors of SIK2.
  • the invention provides for compounds of the formulae presented herein.
  • the disclosure provides a compound of formula I, or a pharmaceutically acceptable salt thereof: wherein X, Y, X 1 , X 2 , X 3 , Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , Ring C and Ring D are as described and defined herein.
  • Compounds of the present invention, and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions, associated with modulating SIK2. Such diseases, disorders, or conditions include those described herein.
  • Compounds provided by this invention are also useful for the study of SIK2 kinase in biological and pathological phenomena; the study of intracellular signal transduction pathways occurring in bodily tissues; and the comparative evaluation of new SIK2 inhibitors or other regulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; a is 1, 2, or 3; b is 1, 2, or 3; X 1 , X 2 , and X 3 are independently selected from N and CR 2 provided that none are N or only one of X 1 , X 2 , and X 3 may be N; each R 2 is independently selected from hydrogen, OH, C 1–3 alkyl, C 1–3 alkoxy, or halogen, provided at least one R 2 is halogen; or when Y is C, X is N, and X 3 is N, each R 2 may be independently selected from hydrogen or halogen; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 hetero
  • the present invention provides a compound of formula Io: or a pharmaceutically acceptable salt thereof, wherein: X is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; a is 1, 2, or 3; b is 1, 2, or 3; X 1 , X 2 , and X 3 are independently selected from N and CR 2 provided that none are N or only one of X 1 , X 2 , and X 3 may be N; each R 2 is independently selected from hydrogen, OH, C 1–3 alkyl, C 1–3 alkoxy, or halogen, provided at least one R 2 is halogen; or when Y is C, X is N, and X 3 is N, each R 2 may be independently selected from hydrogen or halogen; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or Io and a pharmaceutically acceptable carrier, adjuvant, or diluent.
  • the present invention provides a method of treating a SIK2- mediated disease, disorder, or condition comprising administering to a patient in need thereof, a compound of formula I or Io, or a pharmaceutically acceptable salt thereof.
  • Stereocenters marked with “&1” or “and1” indicate that the compound material has a mixture of R and S-configured stereoisomers with respect to the marked stereocenter and is in the same relative configuration to each other if they share the same label such as “and1” or “&1” as in compound I-3.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 carbon atoms.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • cycloaliphatic refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.
  • Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • alkyl refers to a C 1-12 straight or branched saturated aliphatic group. In certain instances, alkyl refers to a C 1-8 straight or branched saturated aliphatic group or a C 1-6 straight or branched saturated aliphatic group.
  • the term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl (also referred to interchangeably herein as 2-propyl, iPr, i Pr and i-Pr), butyl, isobutyl (also referred to interchangeably herein as 2-butyl, iBu, i Bu and i-Bu) and tert-butyl (also referred to interchangeably herein as 2-methyl-2-butyl, tBu, t Bu and t-Bu).
  • alkenyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • alkenyl refers to a C 2-8 or a C 1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • lower alkenyl refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon double bond.
  • Alkenyl groups include both cis (Z) and trans (E) regioisomers.
  • alkynyl refers to a C 2-12 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond. In certain instances, alkynyl refers to a C 2-8 or a C 1-6 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond.
  • lower alkynyl refers to a C 2-4 straight or branched partially unsaturated aliphatic group comprising at least one unsaturated carbon carbon triple bond.
  • Exemplary lower alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, and 3-butynyl.
  • haloalkyl refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • heteroatom refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.
  • Heteroaryl groups include, without limitation, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, triazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (i.e., 1,2,3-triazolyl), 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, indolizinyl, isoindolin-1-only, 1,2-dihydro-3H- pyrrolo[3,4-c]pyridin-3-onyl, 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-only, imidazo[1,2- a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[1,2- a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinn
  • heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heterocycle As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N–substituted pyrrolidinyl).
  • a heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl.
  • heterocycle used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • Suitable monovalent substituents on Ro are independently halogen, —(CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(OR ⁇ ) 2 ; –O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0– 2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH 2 ) 0–2 NH 2 , – (CH 2 ) 0–2
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2– 3 O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, –R ⁇ , -(haloR ⁇ ), -OH, – OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above,
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, –R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term "pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2– hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E conformational isomers and R a (or M) and S a (or P) atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • the structures as drawn represent absolute configurations unless indicated otherwise.
  • SIK2 inhibitor is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of SIK2 (e.g., protein phosphorylation). Inhibition using the SIK2 inhibitor does not necessarily indicate a total elimination of the SIK2 activity.
  • a compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents.
  • a detectable moiety may be attached to a provided compound via a suitable substituent.
  • suitable substituent refers to a moiety that is capable of covalent attachment to a detectable moiety.
  • Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst.
  • the term “detectable moiety” is used interchangeably with the term "label” and relates to any moiety capable of being detected, e.g., primary labels and secondary labels.
  • Primary labels such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass-tags, and fluorescent labels are signal generating reporter groups which can be detected without further modifications.
  • Detectable moieties also include luminescent and phosphorescent groups.
  • the term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal.
  • the secondary intermediate may include streptavidin-enzyme conjugates.
  • antigen labels secondary intermediates may include antibody-enzyme conjugates.
  • Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.
  • FRET nonradiative fluorescent resonance energy transfer
  • fluorescent label refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
  • fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G, carboxy
  • mass-tag refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques.
  • mass-tags include electrophore release tags such as N-[3-[4’-[(p- Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2,3,5,6- Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives.
  • mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers of varying length and monomer composition.
  • nucleotides dideoxynucleotides
  • oligonucleotides of varying length and base composition oligopeptides, oligosaccharides
  • other synthetic polymers of varying length and monomer composition.
  • a large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.
  • measurable affinity and “measurably inhibit,” as used herein, means a measurable change in a SIK2 protein kinase activity between a sample comprising a compound of the present invention, or composition thereof, and a SIK2 protein kinase , and an equivalent sample comprising a SIK2 protein kinase, in the absence of said compound, or composition thereof.
  • the present invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; a is 1, 2, or 3; b is 1, 2, or 3; X 1 , X 2 , and X 3 are independently selected from N and CR 2 provided that none are N or only one of X 1 , X 2 , and X 3 may be N; each R 2 is independently selected from hydrogen, OH, C 1–3 alkyl, C 1–3 alkoxy, or halogen, provided at least one R 2 is halogen; or when Y is C, X is N, and X 3 is N, each R 2 may be independently selected from hydrogen or halogen; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3
  • the present invention provides a compound of formula Io: or a pharmaceutically acceptable salt thereof, wherein: X is N or C; Y is N or C, where one of X and Y is N and the other of X and Y is C; is a single or double bond; a is 1, 2, or 3; b is 1, 2, or 3; X 1 , X 2 , and X 3 are independently selected from N and CR 2 provided that none are N or only one of X 1 , X 2 , and X 3 may be N; each R 2 is independently selected from hydrogen, OH, C 1–3 alkyl, C 1–3 alkoxy, or halogen, provided at least one R 2 is halogen; or when Y is C, X is N, and X 3 is N, each R 2 may be independently selected from hydrogen or halogen; Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen,
  • the compound of formula I or Io is a compound of formula I’ or I’’: or a pharmaceutically acceptable salt thereof, wherein each of X 1 , X 2 , X 3 , Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , Ring C and Ring D are as described and defined herein, both singly and in combination, and Ring C is a 5-membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the compound of formula I or Io is a compound of formula I’ or I’’: or a pharmaceutically acceptable salt thereof, wherein each of X 1 , X 2 , X 3 , Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , Ring C and Ring D are as described and defined herein, both singly and in combination, and Ring C is a 6-membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the compound of formula I or Io is a compound of formula I’ or I’’: or a pharmaceutically acceptable salt thereof, wherein each of X 1 , X 2 , X 3 , Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , Ring C and Ring D are as described and defined herein, both singly and in combination, and Ring C is an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the compound of formula I or Io is a compound of formula I’ or I’’: or a pharmaceutically acceptable salt thereof, wherein each of X 1 , X 2 , X 3 , Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , Ring C and Ring D are as described and defined herein, both singly and in combination, and Ring C is a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1– 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • X is N or C.
  • X is N.
  • X is C. [0061] As defined generally above, Y is N or C. [0062] In some embodiments, X is N. In some embodiments, X is C. [0063] In certain embodiments, one of X and Y is N and the other of X and Y is C; [0064] In some embodiments, X and Y are as depicted in the compounds of Table 1, below. As defined generally above, is a single or double bond. In some embodiments, is a single bond. In some embodiments, s a double bond. [0065] In some embodiments, is as depicted in the compounds of Table 1, below.
  • X 1 , X 2 and X 3 are independently selected from N and CR 2 provided that none are N or only one of X 1 , X 2 and X 3 may be N.
  • X 1 is N.
  • X 1 is CR 2 .
  • X 2 is N.
  • X 2 is CR 2 .
  • X 3 is N.
  • X 3 is CR 2 .
  • X 1 , X 2 and X 3 are CR 2 .
  • X 1 is N, and X 2 and X 3 are CR 2 . In some embodiments, X 2 is N, and X 1 and X 3 are CR 2 . In some embodiments, X 3 is N, and X 1 and X 2 are CR 2 . [0071] In some embodiments, X 1 is as depicted in the compounds of Table 1, below. [0072] In some embodiments, X 2 is as depicted in the compounds of Table 1, below. [0073] In some embodiments, X 3 is as depicted in the compounds of Table 1, below. [0074] As defined generally above, each R 2 is independently selected from hydrogen, OH, C 1–3 alkyl, C 1–3 alkoxy, and halogen.
  • each R 2 may be independently selected from hydrogen or halogen.
  • R 2 is hydrogen. In some embodiments, R 2 is OH. In some embodiments, R 2 is C 1–3 alkyl. In some embodiments, R 2 is C 1–3 alkoxy. In some embodiments, R 2 is halogen. [0077] In some embodiments, R 2 is hydrogen, F, Cl, CH 3 , OCH 3 , or CH 2 CH 3 . [0078] In some embodiments, R 2 is F. [0079] In some embodiments, R 2 is Cl. [0080] In some embodiments, R 2 is CH 3 .
  • R 2 is OCH 3 .
  • R 2 is CH 2 CH 3 .
  • R 2 is as depicted in the compounds of Table 1, below.
  • R 6 is independently selected from hydrogen, halogen, C 1–4 alkyl, or C 1–4 haloalkyl, or two R 6 groups may combine to form oxo.
  • R 6 is hydrogen.
  • R 6 is C 1–4 alkyl.
  • R 6 is C 1–4 haloalkyl.
  • R 6 is two R 6 groups form oxo.
  • R 6 is hydrogen, F, Cl, CH 3 , or two R 6 form oxo. [0087] In some embodiments, two R 6 form oxo. [0088] In some embodiments, R 6 is F. [0089] In some embodiments, R 6 is Cl. [0090] In some embodiments, R 6 is CH 3 . [0091] In some embodiments, R 6 is as depicted in the compounds of Table 1, below.
  • Z is a bond, #C(R 6 ) 2 -[C(R 7 )2] 0-2 -, #C(R 6 ) 2 -[C(R 7 ) 2 ] 0-2 -O-, #O- [C(R 7 ) 2 ] 0-2 -, or #NR 6 -[C(R 8 ) 2 ] 0-2 -, provided that # is a direct bond to Ring C.
  • Z is a bond.
  • Z is #C(R 6 ) 2 -[C(R 7 ) 2 ] 0-2 -.
  • Z is #C(R 6 ) 2 -[C(R 7 ) 2 ] 0-2 -O-. In some embodiments, Z is #O-[C(R 7 ) 2 ] 0-2 -. In some embodiments, Z is #NR 6 -[C(R 8 ) 2 ] 0-2 -.
  • Z is a bond, -CH 2 -CH 2 -, -CH 2 -, -C(O)-CH 2 -, -O-, -O-CH 2 -, -O- CH 2 -CH 2 -, -NH-CH 2 -, -NH-CH 2 -CH 2 -,-CH 2 -O-, -CH 2 -CH 2 -O-, -NH-, -N(CH) 3 -CH 2 -,-N(CH) 3 -, or -N(CH) 3 -CH 2 -CH 2 -.
  • Z is -O-CH 2 -.
  • Z is -O-. [0097] In some embodiments, Z is -O-CH 2 -CH 2 -. [0098] In some embodiments, Z is -CH 2 -O-. [0099] In some embodiments, Z is -CH 2 -CH 2 -O-. [0100] In some embodiments, Z is -NH-CH 2 -. [0101] In some embodiments, Z is -NH-. [0102] In some embodiments, Z is -NH-CH 2 -CH 2 -. [0103] In some embodiments, Z is -N(CH 3 )-CH 2 -. [0104] In some embodiments, Z is -N(CH 3 )-.
  • Z is -N(CH 3 )-CH 2 -CH 2 -. [0106] In some embodiments, Z is -CH 2 -CH 2 -. [0107] In some embodiments, Z is -CH 2 -. [0108] In some embodiments, Z is -C(O)-CH 2 -. [0109] In some embodiments, Z is -O-CH 2 -. [0110] In some embodiments, Z is -O-CH 2 -CH 2 -. [0111] In some embodiments, Z is -NH-CH 2 -. [0112] In some embodiments, Z is -NH-CH 2 -CH 2 -.
  • Z is -N(CH 3 )-CH 2 -.
  • Z is -N(CH 3 )-CH 2 -CH 2 -.
  • Z is as depicted in the compounds of Table 1, below.
  • each R 7 is independently selected from hydrogen, halogen, C 1–4 alkyl, or two R 7 groups may combine to form oxo.
  • R 7 is hydrogen.
  • R 7 is halogen.
  • R 7 is C 1–4 alkyl.
  • two R 7 groups combine to form oxo.
  • R 7 is hydrogen, methyl, or two R 7 groups combine to form oxo.
  • R 7 is as depicted in the compounds of Table 1, below.
  • each R8 is independently selected from hydrogen and C 1–4 alkyl.
  • R8 is hydrogen.
  • R8 is C 1–4 alkyl.
  • R8 is hydrogen.
  • R8 is as depicted in the compounds of Table 1, below.
  • Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is a 5–6 membered monocyclic heteroaryl ring having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring C is 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0126] In some embodiments, Ring C is
  • Ring C is [0128] In some embodiments, Ring C is as depicted in the compounds of Table 1, below. [0129] In some embodiments, Ring D is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic. In some embodiments, Ring D is 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • Ring D is [0131]
  • R 3A is a C 1-6 aliphatic-cyclic group or a cyclic group, wherein the cyclic group selected from: ⁇ a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, ⁇ phenyl; ⁇ a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, wherein the cyclic group selected
  • R 3A is substituted with y instances of R A ; [0132]
  • R 3A is C 1-6 aliphatic-cyclic group.
  • R 3A is a cyclic group.
  • the R 3A cyclic group is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • the R 3A cyclic group is phenyl.
  • the R 3A cyclic group is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the R 3A cyclic group is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the R 3A cyclic group is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the R 3A cyclic group is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the R 3A cyclic group is a 5-12 membered saturated or partially unsaturated bicyclic carbocyclic ring that is optionally bridged or spirocyclic.
  • the R 3A cyclic group is a 5-12 membered saturated or partially unsaturated bicyclic heterocyclic ring that is optionally bridged or spirocyclic having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3A is substituted with y instances of R A . [0133] In some embodiments, R 3A is a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with y instances of R A . In some embodiments, R 3A is a 5-6 membered monocyclic heteroaromatic ring having 1-3 nitrogen atoms, substituted with y instances of R A .
  • R 3A is a 5-membered monocyclic heteroaromatic ring having 1-3 nitrogen atoms, substituted with y instances of R A . In some embodiments, R 3A is a 6-membered monocyclic heteroaromatic ring having 1-2 nitrogen atoms, substituted with y instances of R A . [0134] In some embodiments, R 3A is a 9-membered bicyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with y instances of R A .
  • R 3A is a 9-membered bicyclic heteroaromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with y instances of R A . [0135] In some embodiments, R 3A is [0136] In some embodiments, R 3A is as depicted in the compounds of Table 1, below.
  • R 3B is hydrogen. In some embodiments, R 3B is halogen. In some embodiments, R 3B is oxo. In some embodiments, R 3B is –OR. In some embodiments, R 3B is –SR. In some embodiments, R 3B is –NR 2 . In some embodiments, R 3B is –SO 2 R. In some embodiments, R 3B is –SO 2 NR 2 . In some embodiments, R 3B is –S(O)R. In some embodiments, R 3B is –S(O)NR 2 . In some embodiments, R 3B is –C(O)R. In some embodiments, R 3B is –CO 2 R.
  • R 3B is –C(O)NR 2 . In some embodiments, R 3B is –C(O)N(R)OR. In some embodiments, R 3B is –OC(O)R. In some embodiments, R 3B is –OC(O)NR 2 . In some embodiments, R 3B is –N(R)CO 2 R. In some embodiments, R 3B is –N(R)C(O)R. In some embodiments, R 3B is – N(R)C(O)NR 2 . In some embodiments, R 3B is –N(R)C(NR)R. In some embodiments, R 3B is – N(R)C(NR)NR 2 .
  • R 3B is an optionally substituted C 1–6 aliphatic. In some embodiments, R 3B is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 3B is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 3B is an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0139] In some embodiments, R 3B is as depicted in the compounds of Table 1, below.
  • each instance of R A is independently selected from hydrogen; a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1–3 alkyl, C 1–3 haloalkyl, -CN, -NR 2 , and -OR; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1–3 alkyl, C 1–3 haloalkyl, -CN, -NR 2 , and -OR; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally
  • R A is hydrogen. In some embodiments, R A is a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR. In some embodiments, R A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1–3 alkyl, C 1–3 haloalkyl, -CN, -NR 2 , and -OR.
  • R A is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1–3 alkyl, C 1–3 haloalkyl, -CN, -NR 2 , and -OR.
  • R A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1–3 alkyl, C 1–3 haloalkyl, -CN, -NR 2 , and -OR.
  • R A is halogen.
  • R A is a 4-12 membered saturated or partially unsaturated bicyclic ring system that is fused, bridged, or spirocyclic selected from carbocyclyl or heterocyclyl (having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein said carbocyclyl or heterocyclyl is substituted with 0-3 independently selected C 1–3 alkyl, C 1–3 alkoxy, C 1–3 haloalkyl, C 1–3 hydroxyalkyl, halogen, -CN, -OR, and -NR 2 .
  • R A is –CN.
  • R A is –NO 2 .
  • R A is –OR.
  • R A is -SR. In some embodiments, R A is -NR 2 . In some embodiments, R A is -S(O) 2 R. In some embodiments, R A is -S(O) 2 NR 2 . In some embodiments, R A is -S(O)R. In some embodiments, R A is -S(O)NR 2 . In some embodiments, R A is -C(O)R. In some embodiments, R A is -C(O)OR. In some embodiments, R A is –C(O)NR 2 . In some embodiments, R A is -C(O)N(R)OR. In some embodiments, R A is -OC(O)R.
  • R A is -OC(O)NR 2 . In some embodiments, R A is -N(R)C(O)OR; -N(R)C(O)R. In some embodiments, R A is -N(R)C(O)NR 2 . In some embodiments, R A is -N(R)C(NR)NR 2 . In some embodiments, R A is -N(R)S(O) 2 NR 2 . In some embodiments, R A is –N(R)S(O) 2 R. In some embodiments, two instances of R A on the same atom together form oxo.
  • two instances of R A on the same atom together form a cyclic group selected from 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; and a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the cyclic group formed by two instances of R A on the same atom is substituted with 1, 2, or 3 groups independently selected from a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; -SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; –C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR;
  • two instances of R A on adjacent atoms optionally form a cyclic group selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl; and an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • the cyclic group formed by two instances of R A on adjacent atoms is substituted with 1, 2, or 3 groups independently selected from a C 1-6 aliphatic group optionally substituted with 1, 2, or 3 groups independently selected from halogen, -CN, -NR 2 , and -OR; halogen; –CN; –NO 2 ; –OR; -SR; -NR 2 ; -S(O) 2 R; -S(O) 2 NR 2 ; -S(O)R; -S(O)NR 2 ; -C(O)R; -C(O)OR; –C(O)NR 2 ; -C(O)N(R)OR; -OC(O)R; -OC(O)NR 2 ; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR; -N(R)C(O)R; -N(R)C(O)OR;
  • Ring R A is as depicted in the compounds of Table 1, below.
  • y is 0, 1, 2, or 3.
  • y is 0. In some embodiments, y is 1. In some embodiments, a is 2. In some embodiments, a is 3. In some embodiments, y is 0 or 1. In some embodiments, y is 1 or 2. In some embodiments, y is 2 or 3. [0149] In some embodiments, y is depicted in the compounds of Table 1, below.
  • R 1A is CH 2 CH 3 . In some embodiments, R 1A is CH 3 . In some embodiments, R 1A is CF 3 . In some embodiments, R 1A is CHF 2 . In some embodiments, R 1A is CH 2 CF 3 . In some embodiments, R 1A is CH 2 CHF 2 .
  • Ring R 1A is as depicted in the compounds of Table 1, below.
  • Ring C together with its R 1A and R 4 substituents is as depicted in the compounds of Table 1, below.
  • R 1A is halogen. In some embodiments, R 1A is –CN.
  • R 1A is oxo. In some embodiments, R 1A is –OR. In some embodiments, R 1A is –SR. In some embodiments, R 1A is –NR 2 . In some embodiments, R 1A is –SO 2 R. In some embodiments, R 1A is –SO 2 NR 2 . In some embodiments, R 1A is –S(O)R. In some embodiments, R 1A is –S(O)NR 2 . In some embodiments, R 1A is –C(O)R. In some embodiments, R 1A is –CO 2 R. In some embodiments, R 1A is –C(O)NR 2 .
  • R 1A is –C(O)N(R)OR. In some embodiments, R 1A is –OC(O)R. In some embodiments, R 1A is –OC(O)NR 2 . In some embodiments, R 1A is –N(R)CO 2 R. In some embodiments, R 1A is –N(R)C(O)R. In some embodiments, R 1A is –N(R)C(O)NR 2 . In some embodiments, R 1A is –N(R)C(NR)R. In some embodiments, R 1A is –N(R)C(NR)NR 2 . In some embodiments, R 1A is –N(R)NR 2 . In some embodiments, R 1A is –N(R)NR 2 . In some embodiments, R 1A is –N(R)NR 2 .
  • R 1A is an optionally substituted phenyl. In some embodiments, R 1A is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1A is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1A is an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1A is halogen, –CN, oxo, –OR, –SO 2 R, –C(O)NR 2 , an optionally substituted C 1–6 alkyl, a 3–7 membered saturated monocyclic carbocyclic ring, or an optionally substituted 3–7 membered saturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1A is halogen, –CN, –C(O)NR 2 , an optionally substituted C 1–6 alkyl, a 3–7 membered saturated monocyclic carbocyclic ring, or an optionally substituted 3–7 membered saturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1A is fluoro, chloro, –CN, oxo, –OMe, –O(CH 2 ) 2 NMe 2 , – O(CH 2 ) 2 NEt 2 , –O(CH 2 ) 2 pyrrolidinyl, –O(CH 2 ) 2 piperidinyl, –SO 2 cyclopropyl, –SO 2 Ph, – C(O)NH(CH 2 ) 2 NMe 2 , –C(O)NH(CH 2 ) 3 NMe 2 , methyl, ethyl, propyl, isopropyl, isobutyl, tert- butyl, isopentyl, cyclopentyl, cyclobutyl, methyloxycyclobutyl, –CHF 2 , –CF 3 , –CH 2 CH 2 F, – CH 2 CHF 2 , –CH 2 CF 3 , —CHCHF 2 , –CF
  • R 1A is fluoro, chloro, –CN, –C(O)NH(CH 2 ) 2 NMe 2 , – C(O)NH(CH 2 ) 3 NMe 2 , methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, isopentyl, cyclopentyl, cyclobutyl, –CHF 2 , –CF 3 , piperazinyl, or N-methylpiperazinyl.
  • R 1A are as depicted in the compounds of Table 1, below.
  • a is 1, 2, or 3.
  • a is 1. In some embodiments, a is 2. In some embodiments, a is 3. [0162] In some embodiments, a is 1 or 2. In some embodiments, a is 2 or 3. [0163] In some embodiments, a is depicted in the compounds of Table 1, below. [0164] As defined generally above, b is 1, 2, or 3. [0165] In some embodiments, b is 1. In some embodiments, b is 2. In some embodiments, b is 3. [0166] In some embodiments, b is 1 or 2. In some embodiments, b is 2 or 3. [0167] In some embodiments, b is depicted in the compounds of Table 1, below. [0168] In some embodiments, Ring C together with its R 1A , Z, and R 4 substituents is ,
  • Ring C together with its R 1A , Z, and R 4 substituents is [0170] In some embodiments, Ring C together with its R 1A , Z, and R 4 substituents is as depicted in the compounds of Table 1, below.
  • R 4 is an optionally substituted cyclic group, or an optionally substituted C 1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ⁇ phenyl; ⁇ an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; ⁇ an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an optionally substituted 7–12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an optionally substituted 5–8 membered saturated or partially unsaturated
  • R 4 an optionally substituted cyclic group selected from cyclobutyl, cyclohexyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, 3-oxa-8-azabicyclo[3.3.1]octane, quinuclidinyl, phenyl, pyridyl, N- acet
  • R 4 is wherein: W is –CHR 2B –, –O–, or –NR 2C —;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic; each R 1B are independently hydrogen, halogen, –CN, –OR, –SR, –NR 2 , –SO 2 R, –SO 2 NR 2 , – S(O)R, – S(O)NR 2 , –C(O)R, –CO 2 R, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)R, – OC
  • R 4 is wherein: W 1 and W 2 are independently –CHR 2B –, –O–, or –NR 2C —;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic; each R 1B are independently hydrogen, halogen, –CN, –OR, –SR, –NR 2 , –SO 2 R, –SO 2 NR 2 , – S(O)R, – S(O)NR 2 , –C(O)R, –CO 2 R, –C(O)NR 2 , –C(O)N(R)OR, –OC(O)R
  • W is –CHR 2B –, –O–, or –NR 2C –.
  • W is –CHR 2B –.
  • W is –NR 2C –.
  • W is –O–.
  • W1 is –CHR 2B –, –O–, or –NR 2C –.
  • W1 is –CHR 2B –.
  • W1 is –NR 2C –.
  • W 1 is –O–.
  • W2 is –CHR 2B –, –O–, or –NR 2C –.
  • W2 is –CHR 2B –.
  • W2 is –NR 2C –.
  • W 2 is –O–.
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 2B is halogen. In some embodiments, R 2B is C 1-6 alkyl. In some embodiments, R 2B is –NH 2 . In some embodiments, R 2B is –NHC 1-6 alkyl. In some embodiments, R 2B is –N(C 1-6 alkyl) 2 . In some embodiments, R 2B is a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. [0183] In some embodiments, W is –CH 2 –. In some embodiments, W is –CH(NH 2 )–. In some embodiments, W is –CH(NHMe)–.
  • W is –CH(NMe 2 )–.
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic.
  • R 2C is hydrogen.
  • R 2C is an optionally substituted C 1–6 aliphatic.
  • R 2C is C 1-6 alkyl.
  • W is —NH–.
  • W is –NMe–.
  • W is –O–.
  • W1 is –NH–.
  • W1 is –NMe–.
  • W1 is –O–.
  • W2 is —NH–.
  • W2 is –NMe–.
  • W2 is –O–.
  • W, W1, W2, R 2B , and R 2C is as depicted in the compounds of Table 1, below.
  • R 1B is hydrogen. In some embodiments, R 1B is halogen. In some embodiments, R 1B is –CN. In some embodiments, R 1B is –OR. In some embodiments, R 1B is – SR. In some embodiments, R 1B is –NR 2 . In some embodiments, R 1B is –SO 2 R. In some embodiments, R 1B is –SO 2 NR 2 . In some embodiments, R 1B is –S(O)R. In some embodiments, R 1B is –S(O)NR 2 . In some embodiments, R 1B is –C(O)R. In some embodiments, R 1B is –CO 2 R.
  • R 1B is –C(O)NR 2 . In some embodiments, R 1B is –C(O)N(R)OR. In some embodiments, R 1B is –OC(O)R. In some embodiments, R 1B is –OC(O)NR 2 . In some embodiments, R 1B is –N(R)CO 2 R. In some embodiments, R 1B is –N(R)C(O)R. In some embodiments, R 1B is –N(R)C(O)NR 2 . In some embodiments, R 1B is –N(R)C(NR)R. In some embodiments, R 1B is –N(R)C(NR)NR 2 .
  • R 1B is C 1-4 alkyl. In some embodiments, R 1B is C 1-4 alkoxy. In some embodiments, R 1B is C 1-4 haloalkyl. In some embodiments, R 1B is an optionally substituted C 1–6 aliphatic. In some embodiments, R 1B is an optionally substituted phenyl. In some embodiments, R 1B is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R 1B is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R 1B is an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R 1B together form oxo. In some embodiments, two R 1B are taken together with the atoms that connect them to form a 4-7 membered carbocyclic or heterocyclic ring. [0195] In some embodiments, two R 1B are taken together with the atoms that connect them to form a 5-6 membered carbocyclic or heterocyclic ring. In some embodiments, two R 1B are taken together with the atoms that connect them to form a 4-membered carbocyclic or heterocyclic ring.
  • two R 1B are taken together with the atoms that connect them to form a 5-membered carbocyclic or heterocyclic ring. In some embodiments, two R 1B are taken together with the atoms that connect them to form a 6-membered carbocyclic or heterocyclic ring. [0196] In some embodiments, R 1B is as depicted in the compounds of Table 1, below. [0197] As defined generally above, d is 0, 1, 2, 3, or 4. [0198] In some embodiments, d is 0. In some embodiments, d is 1. In some embodiments, d is 2. In some embodiments, d is 3. In some embodiments, d is 4. In some embodiments, d is 0 or 1.
  • d is 1 or 2. In some embodiments, d is 2 or 3. [0199] In some embodiments, d is depicted in the compounds of Table 1, below. [0200] As defined generally above, p and q are each independently 0, 1, or 2 such that p + q is an integer of between 1 and 4. [0201] In some embodiments, p is 0 and q is 1. In some embodiments, p is 0 and q is 2. In some embodiments, p is 0 and q is 3. In some embodiments, p is 0 and q is 4. In some embodiments, p is 1 and q is 0. In some embodiments, p is 2 and q is 0. In some embodiments, p is 3 and q is 0.
  • p is 4 and q is 0. In some embodiments, p is 1 and q is 1. In some embodiments, p is 1 and q is 2. In some embodiments, p is 2 and q is 1. In some embodiments, p is 2 and q is 2. In some embodiments, p is 3 and q is 1. In some embodiments, p is 1 and q is 3. [0202] In some embodiments, p and q are as depicted in the compounds of Table 1, below. [0203] In some embodiments, R 4 together with its R 1B and R 2C substituents is
  • R 4 together with its R 1B and R 2C substituents is [0204] In some embodiments, R 4 is
  • R 4 is [0207] In some embodiments, R 4 substituents is as depicted in the compounds of Table 1, below. [0208] As generally defined above, each R is independently hydrogen, -C(O)N(CH 3 ) 2 , -C(O) 2 CH 3 , -C(O) 2 C(CH 3 ) 3 , -C(O) 2 CH(CH 3 ) 2 , -S(O) 2 CH 3 , an optionally substituted C 1-6 aliphatic group, an optionally substituted cyclic group, or an optionally substituted C 1-6 alkyl-cyclic group, wherein the cyclic group is optionally selected from: ⁇ phenyl; ⁇ an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring; ⁇ an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ⁇ an optionally substituted
  • each R is independently hydrogen, or an optionally substituted group selected from C 1–6 aliphatic; phenyl; naphthyl; a 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7–12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5–8 membered saturated or partially unsaturated bridged bicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6–10
  • R is hydrogen. In some embodiments, R is an optionally substituted C 1–6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted naphthyl. In some embodiments, R is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is an optionally substituted 5–6 membered monocyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 8–10 membered bicyclic heteroaryl ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 7–12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5–8 membered saturated or partially unsaturated bridged bicyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is an optionally substituted 6–10 membered saturated or partially unsaturated spirocyclic ring having 0–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is an optionally substituted 6–11 membered saturated or partially unsaturated bicyclic ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R groups on the same atom are taken together with the atom to form an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic carbocyclic ring.
  • two R groups on the same atom are taken together with the atom to form an optionally substituted 3–7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is as depicted in the compounds of Table 1, below.
  • the compound of formula I or Io is a compound of formulae I-a, I- b, I-c, or I-d: or a pharmaceutically acceptable salt thereof, wherein: each of R 1A , R 3A , R 3B , Z, R 4 , a, b, and Ring D are as described and defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, CH 3 , and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; Ring C is a 5–6 membered monocyclic heteroaryl having 1–3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R 2 is independently selected from hydrogen, F, CH 3 and Cl.
  • the present invention provides a compound formula I or Io is a compound of formulae I-a, I-b, I-c, or I-d, or a pharmaceutically acceptable salt thereof, wherein: each of R 1A , R 3A R 3B , Z, R 4 , b, a, and Ring D are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, CH 3 and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; Ring C is an 8–10 membered bicyclic heteroaryl having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R 2 is independently selected from hydrogen, F, CH 3 , and Cl.
  • the present invention provides a compound formula I or Io is a compound of formulae I-a, I-b, I-c, or I-d, or a pharmaceutically acceptable salt thereof, wherein: wherein each of R 1A , R 3A R 3B , Z, R 4 , b, a, and Ring D are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, CH 3 and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; Ring C is a 7–12 membered saturated or partially unsaturated bicyclic heterocyclyl having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and each R 2 is independently selected from hydrogen, F, CH 3 , and Cl.
  • the compound of formula I or Io is a compound of formulae II-a, II-b, II-c, II-d, II-e, or II-f: or a pharmaceutically acceptable salt thereof, wherein: each of Z, R 1A , R 3A , R 3B , b, R 4 , and Ring D are as described and defined herein, both singly and in combination; and X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N.
  • the compound of formula I or Io is a compound of formulae II-a, II-b, II-c, II-d, II-e, or II-f: or a pharmaceutically acceptable salt thereof, wherein: each of R 1A , R 3A , R 3B , b, R 4 , and Ring D are as described and defined herein, both singly and in combination; and Z is a bond; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N.
  • the compound of formula I or Io is a compound of formulae II-a, II-b, II-c, II-d, II-e, or II-f, or a pharmaceutically acceptable salt thereof, wherein: wherein each of R 3A R 3B , Z, R 4 , b, and Ring D are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; and R 1A is independently C 1-3 alkyl or C 1-3 haloalkyl.
  • the compound of formula I or Io is a compound of formulae III-a, III-b, or III-c: or a pharmaceutically acceptable salt thereof, wherein: each of Z, R 1A , R 2 , R 3A , R 3B , a, b, R 4 , and Ring D are as described and defined herein, both singly and in combination; and X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N. [0219] In some embodiments, the compound of formula I or Io is a compound of formulae IV-a, IV-b, or IV-c:
  • each of a, b, R 2 , R 3B , Ring D, and R 3A are as defined herein, both singly and in combination;
  • X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N;
  • W is –CHR 2B –, –O–, or –NR 2C –;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic;
  • R 1A is independently
  • the compound of formula I or Io is a compound of formulae V-a, V-b, V-c, V-d, V-e, or V-f: or a pharmaceutically acceptable salt thereof, wherein wherein each of b, Ring D, R 3A , and R 3B , are as defined herein, both singly and in combination;
  • X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N;
  • W is –CHR 2B –, –O–, or –NR 2C –;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic hetero
  • the compound of formula I or Io is a compound of formulae V-a, V-b, V-c, V-d, V-e, or V-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –CHR 2B –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C
  • the compound of formula I or Io is a compound of formulae V-a, V-b, V-c, V-d, V-e, or V-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –O–; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C 1-4 alk
  • the compound of formula I or Io is a compound of formulae V-a, V-b, V-c, V-d, V-e, or V-f: or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C
  • each of b, R 3A , Ring D and R 3B are as defined herein, both singly and in combination;
  • X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N;
  • W is –CHR 2B –, –O–, or –NR 2C –;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic;
  • R 1A is independently C 1-3 alkyl
  • the compound of formula I or Io is a compound of formulae VI-a, VI-b, VI-c, VI-d, VI-e, or VI-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –CHR 2B –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C
  • the compound of formula I or Io is a compound of formulae VI-a, VI-b, VI-c, VI-d, VI-e, or VI-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –O–; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C 1-4 alk
  • the compound of formula I or Io is a compound of formulae VI-a, VI-b, VI-c, VI-d, VI-e, or VI-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C
  • the compound of formula I or Io is a compound of formulae VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f: or a pharmaceutically acceptable salt thereof, wherein: each of b, Ring D, R 3A , and R 3B are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –CHR 2B –, –O–, or –NR 2C –; R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having
  • the compound of formula I or Io is a compound of formulae VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –CHR 2B –; R 2B is halogen, or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4
  • the compound of formula I or Io is a compound of formulae VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –O–; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl, C
  • the compound of formula I or Io is a compound of formulae VII-a, VII-b, VII-c, VII-d, VII-e, or VII-f, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W is –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –OR, C 1-4 alkyl
  • the compound of formula I or Io is a compound of formulae IV-d, IV-e, or IV-f: or a pharmaceutically acceptable salt thereof, wherein: each of a, b, R 2 , R 3B , Ring D and R 3A are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B –, –O–, or –NR 2C –; R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having
  • the compound of formula I or Io is a compound of formulae V-g, V-h, V-i, V-j, V-k, or V-l: or a pharmaceutically acceptable salt thereof, wherein: each of b, Ring D, R 3A , and R 3B , are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B –, –O–, or –NR 2C –; R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated
  • the compound of formula I or Io is a compound of formulae V-g, V-h, V-i, V-j, V-k, or V-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B – or –O–; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –
  • the compound of formula I or Io is a compound of formulae V-g, V-h, V-i, V-j, V-k, or V-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –O– or –NR 2C –; R 2B is halogen, or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen, –
  • the compound of formula I or Io is a compound of formulae V-g, V-h, V-i, V-j, V-k, or V-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B – or –NR 2C —; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen
  • the compound of formula I or Io is a compound of formulae VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l: or a pharmaceutically acceptable salt thereof, wherein: each of b, R 3A , Ring D and R 3B , are as defined herein, both singly and in combination; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B –, –O–, or –NR 2C –; R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated mono
  • the compound of formula I or Io is a compound of formulae VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –O– or –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen
  • the compound of formula I or Io is a compound of formulae VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –O– or –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen
  • the compound of formula I or Io is a compound of formulae VI-g, VI-h, VI-i, VI-j, VI-k, or VI-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B – or –NR 2C —; R 2B is halogen, or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently
  • each of b, Ring D, R 3A , and R 3B are as defined herein, both singly and in combination;
  • X 1 , X 2 , and X 3 are independently selected from N, CF, CCl and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N;
  • W 1 and W 2 are independently –CHR 2B –, –O–, or –NR 2C –;
  • R 2B is halogen, C 1-6 alkyl, –NH 2 , –NHC 1-6 alkyl, –N(C 1-6 alkyl) 2 , or a 3–7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
  • R 2C is hydrogen or an optionally substituted C 1–6 aliphatic;
  • R 1A is independently C 1-3
  • the compound of formula I or Io is a compound of formulae VII-g, VII-h, VII-i, VII-j, VII-k, or VII-l: or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B – or –O–; R 2B is halogen, or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen,
  • the compound of formula I or Io is a compound of formulae VII-g, VII-h, VII-i, VII-j, VII-k, or VII-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –O– or –NR 2C –; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen, halogen
  • the compound of formula I or Io is a compound of formulae VII-g, VII-h, VII-i, VII-j, VII-k, or VII-l, or a pharmaceutically acceptable salt thereof, wherein: each of b, R 6 , R 3A , and R 3B are as defined herein, both singly and in combination; Ring D is a carbon linked 3-8 membered saturated monocyclic carbocyclic ring; X 1 , X 2 , and X 3 are independently selected from N, CF, CCl, and CH, provided that none of X 1 , X 2 , and X 3 are N or only one of X 1 , X 2 , and X 3 may be N; W 1 and W 2 are independently –CHR 2B – or –NR 2C —; R 2B is halogen or C 1-6 alkyl; R 1A is independently C 1-3 alkyl or C 1-4 haloalkyl; each R 1B are independently hydrogen
  • Exemplary compounds of the invention are set forth in Table 1, or a pharmaceutically acceptable salt thereof.
  • Table 1 identifies compounds by their IUPAC name and Table 2 lists the same compounds and shows their chemical structure.
  • the chemical names in the present application are generated from the corresponding structures using either CHEMDRAW, or CHEMAXON. In some instances, chemical names generated from the structures may give a different structure when using the “Convert Name to Structure” function in CHEMDRAW. In the event of any discrepancy between Table 1’s name for a compound and Table 2’s structure for that same compound, Table 2’s compound structures will dominate and identify the compound corresponding to each respective compound number (I-#) in Table 1.
  • the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, above. [0247] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound disclosed herein (described in embodiments herein, both singly and in combination), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent. For example, in some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I or Io as defined above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound of formula I or Io as defined above, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, together with a pharmaceutically acceptable carrier, excipient, or diluent. 4.
  • the compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.
  • compositions are provided.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions of this invention is such that is effective to measurably inhibit SIK2, or a mutant thereof, in a biological sample or in a patient.
  • a composition of this invention is formulated for administration to a patient in need of such composition.
  • a composition of this invention is formulated for oral administration to a patient.
  • patient means an animal, preferably a mammal, and most preferably a human.
  • compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxyprop
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitory active metabolite or residue thereof.
  • active metabolite or residue thereof' means that a metabolite or residue thereof is also an inhibitor of SIK2, or a mutant thereof.
  • Metabolites include compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid
  • an inorganic acid such as hydro
  • the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • a compound of the invention can be in the form of a "prodrug,” which includes compounds with moieties which can be metabolized in vivo.
  • the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e g., di methyl ami noethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol.
  • a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxy ethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • sterilizing agents in order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection.
  • Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
  • the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
  • Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • buffering agents include polymeric substances and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include
  • the compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • Vascular stents for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury).
  • patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • compositions should be formulated so that a dosage of between 0.01 and 100 mg/kg, 0.01 and 50 mg/kg, or 1 and 25 mg/kg, body weight/day of the compound can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • Dosage unit form refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • Compounds and compositions described herein are generally useful for the inhibition of kinase activity of one or more enzymes.
  • the kinase inhibited by the compounds and methods of the invention is SIK2
  • the presently disclosed compounds find use in inhibiting SIK2 protein kinase.
  • the subject matter disclosed herein is directed to a method of inhibiting SIK2, the method comprising contacting SIK2 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.
  • the presently disclosed compounds can be used in a method for inhibiting SIK2. Such methods comprise contacting SIK2 with an effective amount of a presently disclosed compound. By “contact” is intended bringing the compound within close enough proximity to an isolated SIK2 kinase or a cell expressing SIK2 such that the compound is able to bind to and inhibit the SIK2.
  • the compound can be contacted with SIK2 in vitro or in vivo via administration of the compound to a subject.
  • a method of inhibiting SIK2 in a biological sample is provided herein.
  • the method comprises contacting the sample with a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of formula I
  • a pharmaceutical composition disclosed herein such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • any method known in the art to measure the kinase activity of SIK2 may be used to determine if SIK2 has been inhibited, including in vitro assays, immunoblots with antibodies specific for phosphorylated targets of SIK2, or the measurement of a downstream biological effect of SIK2 kinase activity.
  • Provided herein are compounds and pharmaceutical compositions that inhibit SIK2 protein kinase, as well as methods of treatment using such compounds and pharmaceutical compositions.
  • the compounds and compositions can be used in methods of modulating the immune system, for treatment of diseases, and for treatment of cells in vivo, in vitro, or ex vivo.
  • the present disclosure provides methods of inhibiting SIK2 in a patient.
  • the method comprises administering to a patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of formula I
  • a pharmaceutical composition disclosed herein such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • SIK2-mediated disorder is a pathological condition in which SIK2 activity is necessary for the genesis or maintenance of the pathological condition.
  • the method comprises administering to said patient a compound disclosed herein (such as a compound of formula I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein (such as a composition comprising a compound disclosed herein [such as a compound of formula I] and a pharmaceutically acceptable carrier, adjuvant, or vehicle).
  • a compound disclosed herein such as a compound of formula I
  • a pharmaceutically acceptable salt thereof such as a pharmaceutical composition disclosed herein for use in medicine.
  • the SIK2-mediated disorder is selected from inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of TNF ⁇ , interferons, IL-6, IL-12 and/or IL-23, respiratory diseases, endocrine and/or metabolic diseases, cardiovascular diseases, dermatological diseases, and abnormal angiogenesis associated diseases.
  • the present invention provides a method of treating an inflammatory disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating an autoinflammatory disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating an autoimmune disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the cancer is selected from solid tumors (e.g., bone cancer, skin cancer, prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, kidney cancer, bladder cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bile duct cancer, bladder cancer), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), D
  • ALL acute lymphoblastic leukemia
  • the SIK2-mediated disorder is a cancer selected from ovarian cancer, breast cancer, acute myeloid leukemia, and multiple myeloma.
  • the present invention provides a method of treating ovarian cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating breast cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating acute myeloid leukemia in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating multiple myeloma in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating fibrotic diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating transplantation rejection diseases involving impairment of cartilage turnover in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating congenital cartilage malformation in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating diseases involving impairment of bone turnover in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating diseases associated with hypersecretion of TNF ⁇ , interferons, IL-6, IL-12 and/or IL-23 in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating respiratory diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating endocrine and/or metabolic diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating cardiovascular diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating dermatological diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating abnormal angiogenesis associated diseases in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the SIK2-mediated disorder is inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, diabetes, a skin pigmentation disease, osteoporosis, osteoarthritis, lupus (systemic lupus erythematosus), a musculoskeletal disease, or rheumatoid arthritis.
  • inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis
  • diabetes a skin pigmentation disease, osteoporosis, osteoarthritis, lupus (systemic lupus erythematosus), a musculoskeletal disease, or rheumatoid arthritis.
  • the SIK2-mediated disorder is Bone-mineral disorders, including chronic kidney disease.
  • the SIK2-mediated disorder is a mineral bone disorder.
  • the SIK2-mediated disorder is a mineral loss disorder, such as Malignancy-related and oncology drug-related bone loss, and osteoporosis (post-menopausal, glucocorticoid-induced, hypogonadal).
  • the SIK2-mediated disorder is Ankylosing Spondylitis, Psoriatic Arthritis, Crohn's Disease (Active and Maintenance), Plaque Psoriasis, Juvenile Idiopathic Arthritis, Ulcerative Colitis, Hidradenitis Suppurativa, Uveitis, and non-radiographic axial spondyloarthritis.
  • the present invention provides a method of treating inflammatory bowel disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating diabetes in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating a skin pigmentation disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating osteoporosis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating osteoarthritis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating a musculoskeletal disease in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method of treating rheumatoid arthritis in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein (such as a compound of formula I) or a pharmaceutically acceptable salt thereof.
  • appropriate doses of the active compound depends upon a number of factors within the knowledge of the ordinarily skilled physician or veterinarian.
  • the dose(s) of the active compound will vary, for example, depending upon the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, and any drug combination.
  • the effective dosage of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used for treatment may increase or decrease over the course of a particular treatment. Changes in dosage may result and become apparent from the results of diagnostic assays.
  • the SIK2 inhibitor is administered to the subject at a dose of between about 0.001 ⁇ g/kg and about 1000 mg/kg, including but not limited to about 0.001 ⁇ g/kg, 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 25 ⁇ g/kg, 50 ⁇ g/kg, 100 ⁇ g/kg, 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 100 mg/kg, and 200 mg/kg.
  • the SIK2 inhibitor is administered to the subject at a dose of between about 0.1 mg and about 10 g, including but not limited to about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 500 mg, 750 mg, 1 g, 2 g, 5 g, and 10 g.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • SIK2 inhibitors for use as therapeutic active substances.
  • administration includes routes of introducing the compound(s) to a subject to perform their intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal), topical, oral, inhalation, rectal and transdermal.
  • an effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result.
  • An effective amount of compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • systemic administration means the administration of a compound(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.
  • terapéuticaally effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human. 5.
  • additional therapeutic agents which are normally administered to treat that condition, may be administered in combination with compounds and compositions of this invention.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as “appropriate for the disease, or condition, being treated.”
  • a provided combination, or composition thereof is administered in combination with another therapeutic agent.
  • Those additional agents may be administered separately from a provided combination therapy, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another.
  • the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.
  • the present invention provides a composition comprising a compound of formula I or Io and one or more additional therapeutic agents.
  • the therapeutic agent may be administered together with a compound of formula I or Io, or may be administered prior to or following administration of a compound of formula I or Io.
  • a compound of formula I or Io may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent.
  • a compound of formula I or Io may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours following the therapeutic agent.
  • a compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation.
  • a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • a compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.
  • the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
  • Proton NMR 1 H NMR was conducted in deuterated solvent. In certain compounds disclosed herein, one or more 1 H shifts overlap with residual proteo solvent signals; these signals have not been reported in the experimental provided hereinafter.
  • LCMS was conduct using the following methods: General synthetic methods of producing compounds of the disclosure
  • Compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying synthetic schemes.
  • Step 1 4-bromo-2-(bromomethyl)-5-fluoropyridine: To a solution of 4-bromo-5-fluoro-2- methyl-pyridine (20 g, 105.3 mmol) in DCE (400 mL) was added NBS (28.1 g, 157.9 mmol) and AIBN (5.19 g, 31.6 mmol). The mixture was stirred at 75 °C for 3 hours. The reaction mixture was quenched by addition of H 2 O 200 mL and extracted with DCM 300 mL (100 mL x 3). The combined organic layers were washed with aq.
  • Step 2 2-(4-bromo-5-fluoropyridin-2-yl)acetonitrile: To a solution of 4-bromo-2- (bromomethyl)-5-fluoro-pyridine (14.5 g, 53.9 mmol) in ACN (150 mL) was added TMSCN (9.57 g, 96.5 mmol). To the mixture was added TBAF (1 M in THF, 80.9 mL) under N 2 atmosphere. The mixture was stirred at 80 °C for 0.5 hour.
  • the reaction was quenched by H 2 O (200 mL) and then extracted with EA (100 mL x 3) and the combined organic phase was washed with brine (100 mL x 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo.
  • the residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to afford the title compound.
  • Step 3 1-amino-4-bromo-2-(cyanomethyl)-5-fluoropyridin-1-ium: To a solution of TFA (138.2 g, 1.21 mol) was added (tert-butoxycarbonylamino) 2, 4, 6 -trimethylbenzenesulfonate (30 g, 95.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The reaction mixture was quenched by addition H 2 O 100 mL at 25 °C. The mixture was filtered to remove the insoluble and the filter liquor was concentrated in vacuo.
  • Step 4 5-bromo-6-fluoropyrazolo[1,5-a]pyridin-2-amine: To a solution of 2 -(1-amino- 4- bromo-5-fluoro-pyridin-1-ium-2-yl) acetonitrile (20 g, 86.6 mmol) in MeOH (400 mL) was added K 2 CO 3 (23.9 g, 173 mmol). The mixture was stirred at 40 °C for 1 hour. To the mixture was added water (300 mL), and the resulting mixture was filtered, and the filter cake was washed with water (50 mL*3) to afford the title compound (6.5 g) which used into the next step without further purification.
  • Step 2 Ethyl 6-bromo-7-fluoroimidazo[1,2-a]pyridine-2-carboxylate: To a solution of 5- bromo-4-fluoropyridin-2-amine (149 g, 780.1 mmol) in dioxane (2000 mL) was added ethyl 3- bromo-2-oxo-propanoate (190.2 g, 780.1 mmol) and the mixture was stirred at 25 °C for 1.5 hours and further stirred at 95 °C for 12 hours. The mixture was concentrated in vacuo to afford the title compound (252.5 g). LCMS: 288.9 [M+H + ], Rt: 0.441 min.
  • Step 3 6-bromo-7-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid: To a solution of ethyl 6-bromo-7-fluoroimidazo[1,2-a]pyridine-2-carboxylate (197 g, 686.2 mmol) in THF (800 mL) and H 2 O (800 mL) was added the LiOH ⁇ H 2 O (57.6 g, 1.37 mol) at 25 °C, then the mixture was stirred at 25 °C for 3 hours.
  • Step 4 tert-butyl (6-bromo-7-fluoroimidazo[1,2-a]pyridin-2-yl)carbamate: To a solution of 6-bromo-7-fluoroimidazo[1,2-a]pyridine-2-carboxylic acid (50 g, 193.0 mmol) in t-BuOH (1500 mL) was added dropwise DIEA (49.9 g, 386 mmol) and Boc 2 O (42.1 g, 193.0 mmol) at 25 °C.
  • Step 5 6-bromo-7-fluoroimidazo[1,2-a]pyridin-2-amine: To a solution of tert-butyl N-(6- bromo-7-fluoro-imidazo[1, 2-a]pyridin-2-yl) carbamate (3.0 g, 9.1 mmol) in EtOAc (10.0 mL) was added HCl/EtOAc (2.0 M, 45.0 mL). The mixture was stirred at 40 °C for 2 hours.
  • Step 1 tert-butyl (R)-(6-(4-((1-ethylazetidin-2-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-7- fluoroimidazo[1,2-a]pyridin-2-yl)carbamate: To a solution of tert-butyl N-(6-bromo-7-fluoro- imidazo[1, 2-a]pyridin-2-yl) carbamate (2.00 g, 6.06 mmol, 1.00 eq), 5-bromo-4-[[(2R)-1- ethylazetidin-2-yl]methoxy]-1-methyl-pyrazole (1.66 g, 6.06 mmol, 1.00 eq) and 4, 4, 5, 5- tetramethyl-2-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1, 3, 2-dioxaborolane (2.31
  • Step 2 (R)-6-(4-((1-ethylazetidin-2-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-7- fluoroimidazo[1,2-a]pyridin-2-amine: To a solution of tert-butyl N-[6-[4-[[(2R)-1-ethylazetidin- 2-yl]methoxy]-2-methyl-pyrazol-3-yl]-7-fluoro-imidazo[1, 2-a]pyridin-2-yl]carbamate (170 mg, 0.382 mmol) in ethyl acetate (0.50 mL) was added HCl in ethyl acetate (2 M, 2.00 mL).
  • Step 2 tert-butyl (2R) -2-[(1-methylpyrazol-4-yl)carbamoyl]azetidine-1-carboxylate: To (2R)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (10.0 g, 49.7 mmol), 1-methylpyrazol-4- amine (5.31 g, 54.7 mmol) and DIEA (19.3 g, 149.1 mmol, 26.0 mL) in dichloromethane (200 mL) was added T 3 P (53.7 g, 74.5 mmol) at 0 °C, the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated.
  • Step 3 tert-butyl (2R)-2-[[(1-methylpyrazol-4-yl)amino]methyl]azetidine-1-carboxylate tert-butyl: To (2R)-2-[(1-methylpyrazol-4-yl)carbamoyl]azetidine-1-carboxylate (10.0 g, 35.7 mmol) in THF (150 mL) was added BH 3 -Me 2 S (10 M, 10.7 mL) at 0 °C, the mixture was stirred at 60 °C under N 2 for 2 hours. The reaction mixture was diluted into MeOH (100 mL) at 0 °C and concentrated.
  • Step 4 tert-butyl (2R)-2-[[methyl-(1-methylpyrazol-4-yl)amino]methyl] azetidine-1- carboxylate: tert-butyl (2R)-2-[[(1-methylpyrazol-4-yl)amino]methyl]azetidine-1-carboxylate (2.0 g, 7.51 mmol) and HCHO (0.609 g, 7.51 mmol, 0.559 mL, 37% purity) in MeOH (20 mL) were stirred at 25 °C for 0.5 hour. NaBH 3 CN (1.42 g, 22.5 mmol) was added to the mixture and stirred at 25 °C for 12 hours.
  • Step 5 tert-butyl(2R)-2-[[(5-bromo-1-methyl-pyrazol-4-yl)-methyl-amino]methyl] azetidine-1-carboxylate: tert-butyl(2R)-2-[[methyl-(1-methylpyrazol-4-yl) amino]methyl]azetidine-1-carboxylate (2.00 g, 7.13 mmol) in DCM (20 mL) was added NBS (1.27 g, 7.13 mmol,) in dichloromethane (20 mL) at 0 °C, the mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated.
  • Step 6 N-[[ (2R) -azetidin-2-yl]methyl]-5-bromo-N, 1-dimethyl-pyrazol-4-amine: To tert- butyl (2R)-2-[[(5-bromo-1-methyl-pyrazol-4-yl)-methyl-amino]methyl]azetidine-1-carboxylate (0.60 g, 1.67 mmol) in dichloromethane (1 mL) was added HCl/dioxane (2 M, 10.0 mL) and stirred at 25 °C for 12 hours. The mixture was concentrated to afford the title compound (500 mg, HCl).
  • Step 7 5-bromo-N-[[ (2R) -1-ethylazetidin-2-yl]methyl]-N, 1-dimethyl-pyrazol-4-amine: To N-[[(2R)-azetidin-2-yl]methyl]-5-bromo-N,1-dimethyl-pyrazol-4-amine (0.500 mg, 1.69 mmol, HCl) in MeCN (10 mL) was added TEA (1.18 mL, 8.46 mmol), then K 2 CO 3 (0.701 g, 5.07 mmol) and CH 3 CH 2 I (0.162 mL, 2.03 mmol) was added and the mixture was stirred at 60 °C for 12 hours.
  • Step 1 tert-butyl (2R)-2-[[benzyl-(1-methylpyrazol-4-yl)amino]methyl]azetidine-1- carboxylate: tert-butyl (2R)-2-[[(1-methylpyrazol-4-yl)amino]methyl]azetidine-1-carboxylate (2.00 g, 7.51 mmol) and benzaldehyde (0.797 g, 7.51 mmol) were dissolved in THF (30 mL) and stirred at 25 °C for 0.5 hour. Then NaBH 3 CN (1.42 g, 22.5 mmol) was added to the mixture and stirred at 25 °C for 12 hours.
  • Step 2 tert-butyl (2R)-2-[[benzyl-(5-bromo-1-methyl-pyrazol-4-yl)amino]methyl] azetidine-1-carboxylate: To tert-butyl (2R)-2-[[benzyl-(1-methylpyrazol-4- yl)amino]methyl]azetidine-1-carboxylate (1.63 g, 4.57 mmol) in DCM (50 mL) was added NBS (0.814 g, 4.57 mmol,) in DCM (50 mL) at -20 °C, the mixture was stirred at -20 °C for 1 hour.
  • Step-3 N-[[ (2R) -azetidin-2-yl]methyl]-N-benzyl-5-bromo-1-methyl-pyrazol-4-amine: To tert-butyl (2R)-2-[[benzyl-(5-bromo-1-methyl-pyrazol-4-yl)amino]methyl]azetidine-1- carboxylate (1.70 g, 3.90 mmol) in DCM (1 mL) was added HCl/dioxane (2 M, 20 mL), the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated to afford the title compound (1.5 g, HCl) which was carried on further without purification.
  • Step 4 N-benzyl-5-bromo-N-[[(2R)-1-ethylazetidin-2-yl]methyl]-1-methyl-pyrazol-4- amine: To N-[[(2R)-azetidin-2-yl]methyl]-N-benzyl-5-bromo-1-methyl-pyrazol-4-amine (1.50 g, 4.04 mmol, HCl) in MeCN (20 mL) was added TEA (2.81 mL, 20.2 mmol), then K 2 CO 3 (1.67 g, 12.1 mmol) and CH 3 CH 2 I (0.692 g, 4.44 mmol) was added the mixture and stirred at 60 °C for 4 hours.
  • Step 1 tert-butyl (R)-2-((tosyloxy)methyl)azetidine-1-carboxylate: To a stirred solution of tert-butyl (R)-2-(hydroxymethyl)azetidine-1-carboxylate (18 g, 96 mmol) and triethylamine (33.5 ml, 240 mmol) in CH 2 Cl 2 (100 mL) was added p-toluene sulfonyl chloride (20.16 g, 106 mmol) at 0 °C. The reaction mixture was allowed to stir at room temperature for 16 h.
  • Step 2 tert-butyl (R)-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate: To a solution of tert-butyl (R)-2-((tosyloxy)methyl)azetidine-1-carboxylate (26.3 g, 77 mmol) and 1-methyl-1H-pyrazol-4-ol (6.3 g, 64.2 mmol) in DMSO (150 mL) was added cesium carbonate (62.8 g, 193 mmol) at room temperature and the mixture was stirred for 16 h.
  • cesium carbonate 62.8 g, 193 mmol
  • reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (3 x 100 mL). The combined organic extract was dried over anhydrous Na 2 SO 4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography using 30% EtOAc in petroleum ether to afford tert-butyl (R)-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate (14.6 g).
  • Step 3 tert-butyl (R)-2-(((5-bromo-1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidine-1- carboxylate: To a stirred solution of tert-butyl (R)-2-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate (7.6 g, 28.4 mmol) in acetonitrile (75 mL) was added NBS (5.06 g, 28.4 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h.
  • reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic extract was dried over anhydrous Na 2 SO 4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography using 40% EtOAc in petroleum ether to afford tert-butyl (R)-2-(((5-bromo-1-methyl-1H-pyrazol-4-yl)oxy)methyl)azetidine-1- carboxylate (7.68 g).
  • Step 4 Intermediate-1 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-2-amine: To a stirred solution of 5-bromopyrazolo[1,5-a]pyridin-2-amine (7 g, 33.0 mmol) and bis(pinacolato)diboron (16.77 g, 66.0 mmol) in 1,4-dioxane (10 mL)) was added potassium acetate (9.72 g, 99.0 mmol). The reaction mixture was purged with N 2 for 10 min.
  • Step 5a Intermediate-2 tert-butyl (R)-2-(((5-(2-aminopyrazolo[1,5-a]pyridin-5-yl)-1- methyl-1H-pyrazol-4-yl)oxy)methyl)azetidine-1-carboxylate: To a stirred solution of 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-2-amine (4.12 g, 15.9 mmol) in 1,4- dioxane (40 mL) were added tert-butyl (R)-2-(((5-bromo-1-methyl-1H-pyrazol-4- yl)oxy)methyl)azetidine-1-carboxylate (5 g, 14.4 mmol) and tripotassium phosphate (in water) (28.9 mL, 14.4 mmol, 0.5 M).
  • the reaction mixture was degassed with N 2 for 10 min and then PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.038 g, 0.046 mmol) was added.
  • the reaction mixture was purged with N 2 for another 5 min and then stirred at 80 °C for 16 h.
  • the reaction mixture diluted with water and extracted with EtOAc (3 x 150 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated.
  • Step 5b Intermediate-3 (R)-5-(4-((1-ethylazetidin-2-yl)methoxy)-1-methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-amine: A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridin-2-amine (0.71 g, 2.74 mmol,), and (R)-5-bromo-4-((1-ethylazetidin-2- yl)methoxy)-1-methyl-1H-pyrazole (0.50 g, 1.82 mmol), Pd(dppf)Cl 2 (0.11 g, 0.146 mmol), K 3 PO 4 (1.16 g, 5.47 mmol) in dioxane (10 mL) and H 2 O (1 mL) was degassed and purged with N 2 three times, and then
  • Step 1 ethyl (cis)-2-(imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate: To a solution of 2-bromoimidazo[1,2-a]pyridine (2 g, 10.2 mmol) and ethyl 2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (4.39 g, 18.3 mmol) in 2-methylbutan-2-ol (30 mL) was added Ad2nBuP Pd G3(cataCXium®APdG3) (739 mg, 1.02 mmol) and Cs 2 CO 3 (1.5 M in water, 13.5 mL) under N 2 atmosphere.
  • Ad2nBuP Pd G3 catalogaCXium®APdG3
  • Step 2 (cis)-2-(imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylic acid: To a solution of ethyl 2-imidazo[1,2-a]pyridin-2-ylcyclopropanecarboxylate (150 mg, 0.65 mmol) in THF (1 mL) and H 2 O (1 mL) was added LiOH (94 mg, 3.91 mmol). The mixture was stirred at 25 °C for 1 hour.
  • Step 3 rac-N-(5-(4-(((R)-1-ethylazetidin-2-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6- fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide (racemic mixture, cis): To a solution of 2-imidazo[1,2-a]pyridin-2-ylcyclopropanecarboxylic acid (90 mg, 0.38 mmol, HCl) and DIEA (197 ⁇ L, 1.13 mmol) in DMF (2 mL) was added HATU (215 mg, 0.57 mmol).
  • Step 1 Rel-ethyl (1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylate: To a stirred solution of 2-bromo-5-chloropyridine (4.5 g, 23.38 mmol) in anhydrous toluene (100 mL) were added rac-ethyl (rel-1R,2S)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1- carboxylate (8.42 g, 35.1 mmol) and cesium carbonate (22.86 g, 70.2 mmol) at room temperature and degassed with N 2 for 10 min.
  • 2-bromo-5-chloropyridine 4.5 g, 23.38 mmol
  • Step 2 Ethyl (1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylate: Rac-ethyl (rel- 1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylate (3.2 g, 14.18 mmol, was purified by SFC chiral purification [Chiral SFC Column: Chiralpak IG, flow rate 5 mL/min, mobile phase: CO 2 , co-solvent-30% MeOH] and two fractions were obtained.
  • Ethyl (1R,2S)-2- (5-chloropyridin-2-yl)cyclopropane-1-carboxylate The second fraction was concentrated under vacuum afford enantiomeric enriched ethyl (1R,2S)-2-(5-chloropyridin-2-yl)cyclopropane-1- carboxylate (1.2 g, 5.27 mmol, 37% yield) as off-white solid.
  • Step 3 (1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylic acid: To a stirred solution of ethyl (1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylate (0.530 g, 2.349 mmol) in a mixture of THF (3 mL), methanol (1.5 mL) and water (0.6 mL) was added LiOH ⁇ H 2 O (0.084 g, 3.52 mmol) and the mixture was stirred at room temperature for 16 h.
  • reaction mass was concentrated under reduced pressure and diluted with water (10 mL), acidified with citric acid till pH ⁇ 2.5 to afford a solid which was separated by filtration, dried under reduced pressure to afford (1S,2R)-2-(5-chloropyridin-2- yl)cyclopropane-1-carboxylic acid (0.34 g, 1.696 mmol, 72% yield) as yellow solid.
  • Step 4 tert-butyl (R)-2-((tosyloxy)methyl)morpholine-4-carboxylate: To a stirred solution of tert-butyl (R)-2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23.01 mmol) in dichloromethane (50 mL) was added TEA (9.62 mL, 69.0 mmol) at 0 °C and stirred for 10 min. Then p-toluene sulphonyl chloride (6.58 g, 34.5 mmol) was added, and the resulting reaction mixture was warmed to room temperature and stirred for 2 h.
  • Step 5 tert-butyl (R)-2-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylate: To a solution of 1-methyl-1H-pyrazol-4-ol (1.5 g, 15.29 mmol) in DMSO (50 mL) was added cesium carbonate (14.95 g, 45.9 mmol) at room temperature and the mixture was stirred for 20 min. Then tert-butyl (R)-2-((tosyloxy)methyl)morpholine-4-carboxylate (5.96 g, 16.05 mmol) was added at room temperature under N 2 . The resulting reaction mixture was allowed to stir for 16 h.
  • reaction mass was diluted with ice water (20 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the crude product.
  • the obtained crude was purified by column chromatography in Biotage-Isolera using 230 – 400 mesh silica gel. The product was eluted at 80-90% ethyl acetate in petroleum ether.
  • Step 6 tert-butyl (R)-2-(((5-bromo-1-methyl-1H-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylate: To a stirred solution of tert-butyl (R)-2-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate (4.13 g, 13.89 mmol) in acetonitrile (75 mL) was added N-bromo succinimide (2.72 g, 15.28 mmol) at 0 oC and stirred for 6 h. Upon completion of the reaction as monitored by TLC & LCMS, the reaction mixture was concentrated as such.
  • the obtained residue was diluted with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the crude.
  • the obtained crude residue was purified by flash column chromatography in Biotage-Isolera using 230-400 mesh silica gel. The product was eluted at 55-60% EtOAc in petroleum ether to afford tert-butyl (R)-2-(((5-bromo-1-methyl- 1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (4.7 g, 11.99 mmol, 86% yield) as pale yellow solid.
  • Step 7 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-2- amine: To a stirred solution of 5-bromo-6-fluoropyrazolo[1,5-a]pyridin-2-amine (1.0 g, 4.35 mmol) and Bis(pinacolato)diboron (1.656 g, 6.52 mmol) in 1,4-dioxane (30 mL) was added potassium acetate (1.280 g, 13.04 mmol) under nitrogen atmosphere.
  • reaction mixture was purged with nitrogen for 10 min and PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.355 g, 0.435 mmol) was added. The resulting mixture was purged with nitrogen for further 5 min and then stirred at 80 °C for 16 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was cooled to room temperature and diluted with tert-butyl methyl ether (5 mL) and filtered through celite bed.
  • Step 8 tert-butyl (R)-2-(((5-(2-amino-6-fluoropyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H- pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate: To a stirred solution of tert-butyl (R)-2-(((5- bromo-1-methyl-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (1.0 g, 2.66 mmol) and 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridin-2-amine (1.105 g, 3.99 mmol) in a mixture of 1,4-dioxane (20 mL) and water (2 mL) was added tripotassium phosphate (1.7 g, 7.97 mmol) under
  • reaction mixture was purged with nitrogen for a period of 10 min, and PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.217 g, 0.266 mmol) was added.
  • the resulting mixture was purged with nitrogen for further 5 min and then stirred at 85 °C for 16 h.
  • LCMS LCMS.
  • the reaction mixture was purified by reverse phase (Biotage, C18 column, 10 mM ammonium bicarbonate in water/acetonitrile as mobile phase), the product fraction was extracted with dichloromethane (2 x 100 mL).
  • Step 9 tert-butyl (R)-2-(((5-(2-((1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1- carboxamido)-6-fluoropyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate: To a stirred solution of tert-butyl (R)-2-(((5-(2-amino- 6-fluoropyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylate (0.3 g, 0.672 mmol) and (1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1-carboxylic acid (0.133 g, 0.672 mmol) in an
  • reaction mixture was allowed to warm to room temperature and was stirred for 16 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2 x 20 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated under vacuum to afford the crude product.
  • Step 10 (1S,2R)-2-(5-chloropyridin-2-yl)-N-(6-fluoro-5-(1-methyl-4-(((R)-morpholin-2- yl)methoxy)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1-carboxamide, TFA: To a stirred solution of tert-butyl (R)-2-(((5-(2-((1S,2R)-2-(5-chloropyridin-2-yl)cyclopropane-1- carboxamido)-6-fluoropyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate (0.23 g, 0.367 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (
  • Step 12 (1S,2R)-N-(6-fluoro-5-(1-methyl-4-(((R)-4-methylmorpholin-2-yl)methoxy)-1H- pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide: To a stirred solution of (1S,2R)-2-(5-chloropyridin-2-yl)-N-(6-fluoro-5-(1-methyl-4-(((R)-4- methylmorpholin-2-yl)methoxy)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1- carboxamide (0.1 g, 0.185 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2 mL) was added potassium methyltrifluorobo
  • reaction mixture was degassed with N 2 for 10 min, followed by the addition of palladium(II) acetate (4.16 mg, 0.019 mmol).
  • the resulting reaction mixture was heated to 120 °C and allowed to stir for 5 h.
  • the reaction mixture was cooled to room temperature, diluted with dichloromethane (25 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford the crude compound.
  • the reaction mixture was purged with nitrogen for 10 min, then XPhos (0.018 g, 0.037 mmol) was added followed by Pd(OAc) 2 (4.17 mg, 0.019 mmol).
  • the resulting mixture was purged with nitrogen for further 5 min and heated at 100 °C for 3 h.
  • the reaction mixture was filtered through celite bed, and the filtrate was concentrated under vacuum to afford crude product.
  • the obtained crude product was purified by RP-preparative HPLC [Column: Xselect C18 x 250 mm, 500 uL, mobile phase: 10 mM ammonium bicarbonate in water/MeCN].
  • the crude product was purified by reverse phase (Grace column: C1840 ⁇ m, 120 g; flow rate: 20 mL/min; 0.1% ammonium bicarbonate in water/acetonitrile), the product fraction was lyophilized to afford (1S,2R)-2-(5-(azetidin-1- yl)pyridin-2-yl)-N-(6-fluoro-5-(1-methyl-4-(((R)-4-methylmorpholin-2-yl)methoxy)-1H-pyrazol- 5-yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1-carboxamide (0.026 g, 0.046 mmol, 41% yield) as white solid.
  • reaction mixture was quenched by saturated aq. NH4Cl (50 mL) and extracted with ethyl acetate (40 mL *3).
  • the combined organic layers were washed with brine 50 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 10% Ethyl acetate/Petroleum ether gradient @ 20 mL/min).
  • Step 2 (4S,5S)-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one: A solution of tert-butyl (2S,3S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-ethyl-5-oxo-pyrrolidine-1-carboxylate (1.80 g, 5.03 mmol, 1.00 eq) in HCl/dioxane (2.00 M, 31.92 mL, 12.68 eq) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was used without further purification.
  • Step 3 [(2S,3S)-3-ethyl-5-oxo-pyrrolidin-2-yl]methyl 4-methylbenzenesulfonate: To a solution of (4S,5S)-4-ethyl-5-(hydroxymethyl)pyrrolidin-2-one (800.00 mg, 5.59 mmol, 1.00 eq), TEA (1.13 g, 11.17mmol, 1.56 mL, 2.00 eq) and DMAP (68.26 mg, 558.73 ⁇ mol, 0.10 eq) in DCM (15.00 mL) was added 4-methylbenzenesulfonyl chloride (1.28 g, 6.70 mmol, 1.20 eq).
  • the mixture was stirred at 25 °C for 0.5 hours.
  • the reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL ⁇ 3). The combined organic layers were washed with brine 50 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 25% MeOH/DCM gradient @ 20 mL/min). The collected mixture was concentrated in vacuo.
  • Step 4 (1R*,2S*)-N-(5-(4-(((2S,3S)-3-ethyl-5-oxopyrrolidin-2-yl)methoxy)-1-methyl-1H- pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1- carboxamide: To a solution of rel-(1R,2S)-N-(6-fluoro-5-(4-hydroxy-1-methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide (105.00 mg, 103.34 ⁇ mol, 1.00 eq) in DMF (2.00 mL) was added Cs 2 CO 3 (101.01 mg, 310.03 ⁇ mol, 3.00
  • Step 1 rel-(1R,2S)-N-(5-bromo-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(imidazo[1,2- a]pyridin-2-yl)cyclopropane-1-carboxamide: A solution of rel-ethyl (1S, 2R) -2-imidazo[1, 2-a] pyridin-2-ylcyclopropanecarboxylate (1.00 g, 4.34 mmol, 1.00 eq.) and 5-bromo-6-fluoro- pyrazolo[1, 5-a] pyridin-2-amine (1.10 g, 4.78 mmol, 1.10 eq.) in toluene (10.00 mL) was stirred at 20 °C for 5 minutes, then LiHMDS (1.00 M, 6.50 mL, 1.50 eq.) was added and the mixture was stirred at 40 °C for 1 hour.
  • the reaction mixture was diluted into sat. aq. NH4Cl (30 mL) and extracted with ethyl acetate 60.00 mL (20 mL ⁇ 3). The combined organic layers were washed with brine 20 mL (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 100 % Ethyl acetate/Petroleum ether, then 0 ⁇ 12 % Methanol/Dichloromethane gradient @ 60 mL/min).
  • ISCO® 40 g SepaFlash® Silica Flash Column
  • Step 2 Rel-(1S, 2R) -N-[6-fluoro-5-(4-hydroxy-2-methyl-pyrazol-3-yl) pyrazolo[1, 5- a]pyridin-2-yl]-2-imidazo[1, 2-a]pyridin-2-yl-cyclopropanecarboxamide: To a solution of rel-(1S, 2R)-N-(5-bromo-6-fluoro-pyrazolo[1, 5-a]pyridin-2-yl) -2-imidazo[1, 2-a]pyridin-2-yl- cyclopropanecarboxamide (650.00 mg, 1.57 mmol, 1.00 eq.), (5-bromo-1-methyl-pyrazol-4-yl) oxy-tert-butyl-dimethyl-silane (600.00 mg, 2.06 mmol, 1.31 eq.) and 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl
  • Step 3 tert-butyl (2R)-2-(p-tolylsulfonyloxymethyl)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl (2R)-2-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (80.00 mg, 345.89 ⁇ mol, 1.00 eq.) in dichloromethane (1.00 mL) was added DMAP (4.23 mg, 34.59 ⁇ mol, 0.10 eq.), TEA (105.00 mg, 1.04 mmol, 144.43 ⁇ L, 3.00 eq.) and TosCl (69.24 mg, 363.18 ⁇ mol, 1.05 eq.) and the mixture and stirred at 25 °C for 2 hours.
  • DMAP 4.23 mg, 34.59 ⁇ mol, 0.10 eq.
  • TEA 105.00 mg, 1.04 mmol, 144.43 ⁇ L, 3.00 eq
  • Step 4 tert-butyl (R)-2-(((5-(6-fluoro-2-((1R*,2S*)-2-(imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamido)pyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H-pyrazol-4- yl)oxy)methyl)-1,4-oxazepane-4-carboxylate: To a solution of tert-butyl (2R) -2-(p- tolylsulfonyloxymethyl) -1, 4-oxazepane-4-carboxylate (66.00 mg, 171.22 ⁇ mol, 1.06 eq.) and rel- (1S, 2R) -N-[6-fluoro-5-(4-hydroxy-2-methyl-pyrazol-3-yl) pyrazolo[1, 5-a]pyridin-2-yl]-2- imi
  • the mixture was filtered to get the filtrate.
  • the filtrate was purified by flash silica gel chromatography (ISCO®; 8 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 100 % Ethyl acetate/Petroleum ether, then 0 ⁇ 15 % Methanol/Dichloromethane gradient @ 36 mL/min).
  • Step 5 (1R*,2S*)-N-(5-(4-(((R)-1,4-oxazepan-2-yl)methoxy)-1-methyl-1H-pyrazol-5- yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(imidazo[1,2-a]pyridin-2-yl)cyclopropane-1- carboxamide: To a solution of tert-butyl (R)-2-(((5-(6-fluoro-2-((1R*,2S*)-2-(imidazo[1,2- a]pyridin-2-yl)cyclopropane-1-carboxamido)pyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H-pyrazol- 4-yl)oxy)methyl)-1,4-oxazepane-4-carboxylate (130.00 mg, 201.65 ⁇ mol, 1.00
  • Step 6 (1R*,2S*)-N-(6-fluoro-5-(1-methyl-4-(((R)-4-methyl-1,4-oxazepan-2- yl)methoxy)-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(imidazo[1,2-a]pyridin-2- yl)cyclopropane-1-carboxamide: To a solution of (1R*,2S*)-N-(5-(4-(((R)-1,4-oxazepan-2- yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(imidazo[1,2- a]pyridin-2-yl)cyclopropane-1-carboxamide (132.00 mg, 200.42 ⁇ mol, 1.00 eq., TFA) in
  • the resulting reaction mixture was purged with N 2 for 5 min, then RuPhos Pd G3 (0.028 g, 0.033 mmol) was added and again purged with N 2 for 2 min, then the resultant reaction mixture was heated at 100 °C for 2 h.
  • the reaction mixture was filtered through a celite bed, and washed with 20% dichloromethane in methanol (20 mL), the filtrate was concentrated under reduced pressure.
  • the obtained crude product was purified by RP Prep HPLC, [Column: XBridge C1819 x 250 mm, 500 uL, mobile phase: 10 mM ammonium bicarbonate in water/MeCN].
  • Step 2 (1S,2R)-2-(5-(azetidin-1-yl)pyridin-2-yl)-N-(5-(4-((4,4-difluorotetrahydrofuran-3- yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1- carboxamide.
  • reaction mixture was irradiated at 100 °C in microwave for 75 min. Upon completion of the reaction as confirmed by LCMS, then reaction mixture was concentrated under reduced pressure to afford the crude product.
  • the obtained crude product was purified by RP Prep HPLC [Column: XBridge C1819 x 250 mm, 500 uL, mobile phase: 10 mM ammonium bicarbonate in water/acetonitrile].
  • Step 3 (1S,2R)-2-(5-(azetidin-1-yl)pyridin-2-yl)-N-(5-(4-(((R*)-4,4- difluorotetrahydrofuran-3-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5- a]pyridin-2-yl)cyclopropane-1-carboxamide
  • Isomer 1 and Isomer 2 The racemic mixture of (1S,2R)-2-(5-(azetidin-1-yl)pyridin-2-yl)-N-(5-(4-((4,4-difluorotetrahydrofuran-3-yl)methoxy)-1- methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1-carboxamide (0.060 g) was
  • Step 2 (1R*,2S*)-N-(6-fluoro-5-(1-methyl-4-(((S)-2-oxooxazolidin-4-yl)methoxy)-1H- pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide: To a solution of [(4R)-2-oxooxazolidin-4-yl]methyl 4-methylbenzenesulfonate (35.38 mg, 130.41 ⁇ mol, 1.06 eq) and (1S,2R)-N-[6-fluoro-5-(4-hydroxy-2-methyl-pyrazol-3-yl
  • Step 1 (1S,2R)-N-(5-(4-(((2RS,3RS)-2-ethyloxetan-3-yl)methoxy)-1-methyl-1H-pyrazol- 5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1- carboxamide: A solution of (1S,2R)-N-(6-fluoro-5-(4-hydroxy-1-methyl-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide (0.1 g, 0.246 mmol) and rac-((2R,3S)-2-ethyloxetan-3-yl)methanol (0.029 g, 0.246 mmol) in toluene (2 mL
  • cyanomethylenetributylphosphorane (0.258 mL, 0.984 mmol) was added, and the mixture was heated at 100 °C for 90 min in microwave reactor. The progress of the reaction was monitored by LCMS and the reaction mixture was concentrated under reduced pressure to get the crude product.
  • Isomer 1 The first fraction was concentrated under reduced pressure and the residue was dissolved in 10% methanol in dichloromethane, washed with water (3 x 15 mL). The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure followed by lyophilization to afford (1S,2R)-N-(5-(4-(((2R*,3R*)-2-ethyloxetan-3-yl)methoxy)-1-methyl-1H- pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1- carboxamide (4.93 mg, 9.67 ⁇ mol, 30% yield) as white solid.
  • Step 1 2-[[tert-butyl (diphenyl) silyl]oxymethyl]-1-ethyl-cyclobutanol: To a solution of 2- [[tert-butyl (diphenyl) silyl]oxymethyl]cyclobutanone (2.00 g, 5.91 mmol, 1.00 eq) in THF (30.00 mL) was added EtMgBr (3.00 M, 3.94 mL, 2.00 eq) at 0 °C under N 2 and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was quenched by addition sat.
  • Step 2 1-ethyl-2-(hydroxymethyl) cyclobutanol: To a solution of 2-[[tert-butyl (diphenyl) silyl]oxymethyl]-1-ethyl-cyclobutanol (2.20 g, 5.97 mmol, 1.00 eq) in tetrahydrofuran (22.00 mL) was added TBAF (1.00 M, 7.16 mL, 1.20 eq). The mixture was stirred at 45 °C for 1 hour. The reaction mixture concentrated under reduced pressure.
  • Step 4 (1R*,2S*)-N-(5-(4-(((1RS,2RS)-2-ethyl-2-hydroxycyclobutyl)methoxy)-1- methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2- yl)cyclopropane-1-carboxamide: To a solution of (2-ethyl-2-hydroxy-cyclobutyl) methyl 4- methylbenzenesulfonate (80.00 mg, 281.32 ⁇ mol, 1.00 eq), rel-(1R,2S)-N-(6-fluoro-5-(4- hydroxy-1-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2- yl)cyclopropane-1-carboxamide (114.33 mg,
  • Step 5 rel-(1R,2S)-N-(5-(4-(((1S,2S)-2-ethyl-2-hydroxycyclobutyl)methoxy)-1-methyl- 1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1- carboxamide
  • Isomer 1 & Isomer 2 The mixture of step 4 was separated by SFC (column: DAICEL CHIRALCEL OD (250mm*30mm,10um); mobile phase: [CO 2 -ACN/EtOH (0.1% NH 4 OH)]; B%:38%, isocratic elution mode).
  • Step 2 [4-[ (4-bromo-6-methyl-3-pyridyl) oxy]cyclohexoxy]-tert-butyl-dimethyl-silane: To a mixture of 4-bromo-5-fluoro-2-methyl-pyridine (3.00 g, 15.79 mmol, 1.00 eq), 4-[tert-butyl (dimethyl) silyl]oxycyclohexanol (4.00 g, 17.37 mmol, 1.10 eq) in N,N-dimethylpropionamide (40.00 mL) was added NaH (3.16 g, 78.94 mmol, 60.00 % purity, 5.00 eq) at 0 °C under N 2 for 1 hour, and then the mixture was stirred at 40 °C for 2 hours under N 2 atmosphere.
  • Step 3 N-[5-[5-[4-[tert-butyl (dimethyl) silyl]oxycyclohexoxy]-2-methyl-4-pyridyl]-6- fluoro-pyrazolo[1,5-a]pyridin-2-yl]-2-(5-methylpyrimidin-2-yl) cyclopropane carboxamide: A mixture of [4-[ (4-bromo-6-methyl-3-pyridyl) oxy]cyclohexoxy]-tert-butyl-dimethyl-silane (287.33 mg, 717.56 ⁇ mol, 1.00 eq), N-(5-bromo-6-fluoro-pyrazolo[1, 5-a]pyridin-2-yl) -2-(5- methylpyrimidin-2-yl) cyclopropanecarboxamide (280.00 mg, 717.56 ⁇ mol, 1.00 eq), 4, 4, 5, 5- tetramethyl-2-(
  • Step 4 N-[6-fluoro-5-[5-(4-hydroxycyclohexoxy)-2-methyl-4-pyridyl]pyrazolo[1,5- a]pyridin-2-yl]-2-(5-methylpyrimidin-2-yl)cyclopropanecarboxamide: To a solution of N-[5-[5- [4-[tert-butyl (dimethyl) silyl]oxycyclohexoxy]-2-methyl-4-pyridyl]-6-fluoro-pyrazolo[1, 5- a]pyridin-2-yl]-2-(5-methylpyrimidin-2-yl) cyclopropane carboxamide (200.00 mg, 317.04 ⁇ mol, 1.00 eq) in tetrahydrofuran (4.00 mL) was added HCl (1.00 M, 634.09 ⁇ L, 2.00 eq).
  • Step 5 (1R*,2S*)-N-(6-fluoro-5-(5-(((1r,4R)-4-hydroxycyclohexyl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyrimidin-2-yl)cyclopropane-1- carboxamide
  • Isomer 1 & (1R*,2S*)-N-(6-fluoro-5-(5-(((1r,4R)-4-hydroxycyclohexyl)oxy)-2- methylpyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyrimidin-2-yl)cyclopropane-1- carboxamide
  • Isomer 2 The crude product was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10um) ; mobile phase: [CO
  • Example 15 (1S,2R)-N-(6-fluoro-5-(2-methyl-5-(((1R,5S,7s)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)oxy)pyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5- methylpyridin-2-yl)cyclopropane-1-carboxamide: (I-37) [0429] Step 1: tert-butyl (1R,5S,7s)-7-((4-bromo-6-methylpyridin-3-yl)oxy)-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylateA solution of tert-butyl (1R,5S,7s)-7-hydroxy-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (300.00 mg, 1.23 mmol, 1.00
  • the reaction mixture was quenched by saturated aq. NH 4 Cl solution (10 mL at 0 °C), and then diluted with water 10 mL and extracted with ethyl acetate 30 mL (10 mL ⁇ 3). The combined organic layers were washed with brine 10 mL (5 mL ⁇ 2), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the title compound (350.00 mg, 846.83 ⁇ mol, 68.68% yield) was obtained as colorless oil after column.
  • Step 2 (1R,5S,7s)-7-((4-bromo-6-methylpyridin-3-yl)oxy)-3-oxa-9- azabicyclo[3.3.1]nonane: To a solution of tert-butyl (1R,5S,7s)-7-hydroxy-3-oxa-9- azabicyclo[3.3.1]nonane-9-carboxylate (300.00 mg, 725.86 ⁇ mol, 1.00 eq) in dichloromethane (3.00 mL) was added TFA (2.30 g, 20.19 mmol, 1.50 mL, 27.82 eq). The mixture was stirred at 25 °C for 0.5 hour.
  • Step 3 (1R,5S,7s)-7-((4-bromo-6-methylpyridin-3-yl)oxy)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonane: To a solution of (1R,5S,7s)-7-((4-bromo-6-methylpyridin-3-yl)oxy)-3- oxa-9-azabicyclo[3.3.1]nonane (300.00 mg, 702.23 ⁇ mol, 1.00 eq, TFA) in methanol (3.00 mL) was added Cs 2 CO 3 (686.40 mg, 2.11 mmol, 3.00 eq) at 25 °C, the mixture was stirred at 25 °C for 0.5 hour.
  • Step 4 (1S,2R)-N-(6-fluoro-5-(2-methyl-5-(((1R,5S,7s)-9-methyl-3-oxa-9- azabicyclo[3.3.1]nonan-7-yl)oxy)pyridin-4-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin- 2-yl)cyclopropane-1-carboxamide: A mixture of (1R,5S,7s)-7-((4-bromo-6-methylpyridin-3- yl)oxy)-9-methyl-3-oxa-9-azabicyclo[3.3.1]nonane (200.00 mg, 611.22 ⁇ mol, 1.00 eq), (1S, 2R) - N-(5-bromo-6-fluoro-pyrazolo[1, 5-a]pyridin-2-yl) -2-(5-methyl-2-pyridyl) cyclopropane
  • the reaction solution was filtered and the filtrate was concentrated under reduced pressure to give the crude product.
  • the residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10um; mobile phase: [water (NH 4 HCO 3 ) -ACN]; gradient: 28%-58% B over 10 min) to give crude product (50.00 mg, 71% purity, by HPLC).
  • the crude product was second purified by prep-HPLC (column: Phenomenex Luna C18150*25 mm*10um; mobile phase: [water (FA) -ACN]; gradient: 1%-30% B over 10 min).
  • Example 16 (1S,2R)-N-(6-(4-(((R)-4,4-difluoropyrrolidin-3-yl)oxy)-1-methyl-1H-pyrazol-5- yl)imidazo[1,2-b]pyridazin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide (I- 38a) and (1S,2R)-2-(5-(bicyclo[1.1.1]pentan-1-yl)-6-(difluoromethyl)pyridin-2-yl)-N-(6- fluoro-5-(1-methyl-4-(((R)-4-methylmorpholin-2-yl)methoxy)-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropane-1-carboxamide) (I-38b):
  • Step 1 (1S,2R)-N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-(5-methylpyridin-2- yl)cyclopropane-1-carboxamide: To a mixture of 6-chloroimidazo[1,2-b]pyridazin-2-amine (0.594 g, 3.52 mmol), (1S,2R)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxylic acid (0.52 g, 2.93 mmol) in dichloromethane (5 mL) was added DIPEA (1.705 g, 13.21 mmol), followed by T3P (2.80 g, 8.80 mmol) dropwise under N 2 atmosphere.
  • DIPEA 1.705 g, 13.21 mmol
  • Step 2 (1S,2R)-N-(6-(4-hydroxy-1-methyl-1H-pyrazol-5-yl)imidazo[1,2-b]pyridazin-2- yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide: To a mixture of (1S,2R)-N-(6- chloroimidazo[1,2-b]pyridazin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide (0.8 g, 2.441 mmol), 5-bromo-4-((tert-butyldimethylsilyl)oxy)-1-methyl-1H-pyrazole (1.066 g, 3.66 mmol) and bis pinacolborane (3.10 g, 12.20 mmol) in 1,4-dioxane (60 mL) and water (15 mL) was added potassium fluoride (1.416 g, 24.
  • the resultant reaction mixture was purged N 2 for 5 min, then added Pd(Amphos)Cl 2 (0.173 g, 0.244 mmol) was added and the reaction mixture was purged N 2 for 5 min and then heated at 120 °C for 16 h.
  • the reaction mixture was filtered, and the obtained residue was washed with ethyl acetate (50 mL). The filtrate was concentrated under reduced pressure to get the crude product.
  • Step 2a tert-Butyl (S)-3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)pyrrolidine-1- carboxylate: To a stirred solution of tert-butyl (S)-3,3-difluoro-4-hydroxypyrrolidine-1- carboxylate (0.23 g, 1.030 mmol) in CH 2 Cl 2 (5 mL), pyridine (0.41 mL, 5.15 mmol) and trifluoromethanesulfonic anhydride (0.43 ml, 2.58 mmol) were added at -10 °C under nitrogen atmosphere.
  • the resultant reaction mixture was heated at 90 °C for 16 h. Upon completion of the reaction as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure to get the crude product.
  • the crude product was purified by Reverse phase column chromatography. (Grace column: RediSep gold, C18, 40 ⁇ m, 120 g; flow rate: 20 mL/min; 0.1% aqueous NH 4 HCO 3 /MeCN mobile phase).
  • the resultant reaction mixture was stirred at rt for 16 h. Upon completion of the reaction as confirmed by LCMS, the reaction mixture was concentrated under reduced pressure to get the crude product.
  • the crude product (70 mg of TFA salt) was purified by Preparative HPLC [column: X-bridge, (50 x 4.6) mm, 3.5 ⁇ m, flow rate: 1.2 mL/min; 5 mM ammonium bicarbonate in water/MeCN as mobile phase).
  • Step 5 (1S,2R)-2-(5-(bicyclo[1.1.1]pentan-1-yl)-6-(difluoromethyl)pyridin-2-yl)-N-(6- fluoro-5-(1-methyl-4-(((R)-4-methylmorpholin-2-yl)methoxy)-1H-pyrazol-5-yl)pyrazolo[1,5- a]pyridin-2-yl)cyclopropane-1-carboxamide: To a cooled solution of (-15 °C) (1S,2R)-N-(6-(4- (((R)-4,4-difluoro-1-(2,2,2-trifluoroacetyl)pyrrolidin-3-yl)oxy)-1-methyl-1H-pyrazol-5- yl)imidazo[1,2-b]pyridazin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide.
  • Example 17 (1S,2R)-N-(6-fluoro-5-(1-methyl-4-(4-methylpiperazin-1-yl)-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide: (I- 39) [0439]
  • Step 1 1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperazine: To a stirred solution of 4- bromo-1-methyl-1H-pyrazole (1 g, 6.21 mmol) and 1-methylpiperazine (0.622 g, 6.21 mmol) in dioxane (30 mL) was added sodium tert-butoxide (1.791 g, 18.63 mmol) under nitrogen atmosphere.
  • Step 2 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-methylpiperazine: To a stirred solution of 1-methyl-4-(1-methyl-1H-pyrazol-4-yl)piperazine (206 mg, 1.143 mmol) in acetonitrile (4 mL) was added NBS (203 mg, 1.143 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was allowed to stir at room temperature for 12 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was diluted with water (20 mL) and extracted with 10% methanol in dicloromethane (3 x 30 mL).
  • the combined organic layer was washed with brine (30 mL) then dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford the crude product.
  • the crude product was purified by reverse-phase column chromatography (Grace column: RediSep gold, C18, 40 ⁇ m, 120 g; flow rate: 20 mL/min; 10 mM ammonium bicarbonate in water / MeCN as mobile phase). The product containing fractions were mixed and concentrated under reduced pressure to afford 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-methylpiperazine (115 mg, 0.426 mmol, 37% yield) as pale yellow liquid.
  • Step-3 (1S,2R)-N-(6-fluoro-5-(1-methyl-4-(4-methylpiperazin-1-yl)-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide): To a stirred solution of 1-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-methylpiperazine (115 mg, 0.444mmol) and (1S,2R)-N-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide (232 mg, 0.533 mmol) in dioxane (3 mL) and water
  • Step 1 5-Bromo-4-(chloromethyl)-1-methyl-1H-pyrazole: To a stirred solution of (5- bromo-1-methyl-1H-pyrazol-4-yl)methanol (1.5 g, 7.85 mmol) in dichloromethane (15 mL) was added SOCl 2 (1.139 ml, 15.70 m mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at rt for 1 h. Upon completion of the reaction as monitored by LCMS, the reaction mixture was concentrated under reduced pressure to get the crude product.
  • Step 3 6-Fluoro-5-(1-methyl-4-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-amine: To a stirred solution of 1-((5-bromo-1-methyl-1H-pyrazol-4- yl)methyl)-4-methylpiperazine (0.3 g, 1.098 mmol) in a mixture of 1,4-dioxane (10 mL) and water (2.0 mL) were added 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-2-amine (0.609 g, 2.196 mmol) and tripotassium phosphate (0.699 g, 3.29 mmol).
  • the reaction mixture was degassed with N 2 for 10 min followed by the addition of PdCl 2 (dppf) ⁇ CH 2 Cl 2 (0.090 g, 0.110 mmol). The resulting reaction mixture was stirred at 100 °C for 4 h. Upon completion of the reaction, as monitored by TLC, the reaction mixture was cooled to room temperature, diluted with dichloromethane (50 mL), dried over Na 2 SO 4 , filtered through celite bed and the filtrate was concentrated under vacuum to afford the crude compound. The crude product was purified by flash column chromatography (Silica gel 100-200 mesh) eluting with 15% MeOH in dichloromethane.
  • Step 4 (1S,2R)-N-(6-fluoro-5-(1-methyl-4-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol- 5-yl)pyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamide: To a stirred solution of 6-fluoro-5-(1-methyl-4-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-5- yl)pyrazolo[1,5-a]pyridin-2-amine (250 mg, 0.189 mmol) in dichloromethane (10 mL) were added (1S,2R)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxylic acid (50.3 mg, 0.284 mmol) and DIPEA (0.165 mL, 0.946 mmol) at rt under nitrogen atmosphere.
  • reaction mixture was cooled to 0 °C.
  • T3P 50% in EtOAc
  • 0.167 ml, 0.568 mmol was added under nitrogen atmosphere and the reaction mixture was stirred at rt for 16 h.
  • the reaction mixture was concentrated under reduced pressure to get the crude product.
  • the crude product was purified by prep HPLC (Column: X-Select C18(19*250), mobile phase: 10mM ammonium bicarbonate in water / acetonitrile).
  • Step 2 tert-Butyl (R)-4-((5-(2-amino-6-fluoropyrazolo[1,5-a]pyridin-5-yl)-1-methyl-1H- pyrazol-4-yl)methoxy)-3,3-difluoropyrrolidine-1-carboxylate: To a stirred solution of tert-butyl (R)-4-((5-bromo-1-methyl-1H-pyrazol-4-yl)methoxy)-3,3-difluoropyrrolidine-1-carboxylate (90 mg, 0.227 mmol) and 6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5- a]pyridin-2-amine (126 mg, 0.454 mmol) in a mixture of dioxane (4 ml) and water (0.4 mL) was added tripotassium phosphat
  • Step 4 (1S,2R)-N-(5-(4-((((R)-4,4-difluoropyrrolidin-3-yl)oxy)methyl)-1-methyl-1H- pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(5-methylpyridin-2-yl)cyclopropane-1- carboxamide, di HCl salt: To a stirred solution of tert-butyl (R)-3,3-difluoro-4-((5-(6-fluoro-2- ((1S,2R)-2-(5-methylpyridin-2-yl)cyclopropane-1-carboxamido)pyrazolo[1,5-a]pyridin-5-yl)-1- methyl-1H-pyrazol-4-yl)methoxy)pyrrolidine-1-carboxylate (10 mg, 0.016 mmol) in anhydrous dichloride,
  • Example 20 rel-(1R,2S)-N-(5-(4-(((S)-4,4-difluorotetrahydrofuran-3-yl)methoxy)-1-methyl- 1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(1-isopropyl-6-oxo-1,6- dihydropyrimidin-4-yl)cyclopropane-1-carboxamide: (I-42a) & (I-42b):
  • Step 1 Chiral separation of racemic 5-bromo-4-((4,4-difluorotetrahydrofuran-3- yl)methoxy)-1-methyl-1H-pyrazole to yield rel-(R)-5-bromo-4-((4,4-difluorotetrahydrofuran-3- yl)methoxy)-1-methyl-1H-pyrazole (single isomer, first eluting compound as isomer 1): Racemic 5-bromo-4-((4,4-difluorotetrahydrofuran-3-yl)methoxy)-1-methyl-1H-pyrazole was separated by chiral SFC (SFC Preparative Method: Instrument Waters 350 Preparative SFC system; Column: Daicel Chiralpak IG column, 250 ⁇ 50 mm I.D., 10 ⁇ m particle size; Mobile phase A: CO 2 , Mobile Phase B: EtOH (0.1% NH 4 OH); Isocratic elution: 40% Phase B in
  • Step 2 Synthesis of 6-bromo-3-isopropylpyrimidin-4(3H)-one: To a solution of 6- bromopyrimidin-4(3H)-one (2.00 g, 11.43 mmol, 1.0 eq.) in MeOH (20.00 mL) were added K 2 CO 3 (4.74 g, 34.29 mmol, 3.0 eq.) and 2-iodopropane (3.89 g, 22.86 mmol, 2.28 mL, 2.0 eq.). The mixture was stirred at 80 °C for 10 hours. The reaction mixture was quenched by H 2 O addition (50 mL), and then extracted with EtOAc (30 mL * 3).
  • Step 3 Synthesis of rac-ethyl (1R,2S)-2-(1-isopropyl-6-oxo-1,6-dihydropyrimidin-4- yl)cyclopropane-1-carboxylate (mix of two enantiomers, cis): A mixture of 6-bromo-3- isopropylpyrimidin-4(3H)-one (150 mg, 691 ⁇ mol, 1.0 eq.), rac-ethyl (1S,2R)-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (mix of two enantiomers, cis) (199 mg,
  • Step 4 Synthesis of rac-(1R,2S)-N-(5-bromo-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(1- isopropyl-6-oxo-1,6-dihydropyrimidin-4-yl)cyclopropane-1-carboxamide (mix of two enantiomers, cis): To a solution of rac-ethyl (1R,2S)-2-(1-isopropyl-6-oxo-1,6-dihydropyrimidin- 4-yl)cyclopropane-1-carboxylate (mix of two enantiomers, cis) (331 mg, 1.44 mmol, 1.2 eq.) in toluene (3.00 mL) was added LiHMDS (1 M, 1.80 mL, 1.5 eq.).
  • Step 5 Synthesis of (1RS,2SR)-N-(5-(4-(((S*)-4,4-difluorotetrahydrofuran-3- yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(1-isopropyl-6- oxo-1,6-dihydropyrimidin-4-yl)cyclopropane-1-carboxamide (mixture of two diastereomers, both cis at cyclopropyl): A mixture of rel-(R)-5-bromo-4-((4,4-difluorotetrahydrofuran-3-yl)methoxy)- 1-methyl-1H-pyrazole (isomer 1) (100 mg, 337 ⁇ mol, 1.0 eq.), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5- tetramethyl-1, 3, 2-dio
  • Step 6 Chiral separation of (1RS,2SR)-N-(5-(4-(((S*)-4,4-difluorotetrahydrofuran-3- yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)-2-(1-isopropyl-6- oxo-1,6-dihydropyrimidin-4-yl)cyclopropane-1-carboxamide (mixture of two diastereomers, both cis at cyclopropyl) to yield first eluting compound rel-(1R,2S)-N-(5-(4-(((S)-4,4- difluorotetrahydrofuran-3-yl)methoxy)-1-methyl-1H-pyrazol-5-yl)-6-fluoropyrazolo[1,5- a]pyridin-2-yl)-2-(1-is
  • Step 1 Synthesis of tert-butyl (2S,4R)-2-methyl-4-(tosyloxy)pyrrolidine-1-carboxylate: To a solution of tert-butyl (2S,4R)-4-hydroxy-2-methyl-pyrrolidine-1-carboxylate (4.00 g, 19.87 mmol, 1.00 eq.) in DCM (80.00 mL) were added TEA (4.02 g, 39.75 mmol, 5.53 mL, 2.00 eq.), TosCl (4.17 g, 21.86 mmol, 1.10 eq.), DMAP (242.81 mg, 1.99 mmol, 0.1 eq) at 0 °C.
  • AMARAtide was purchased from Biopeptide (San Diego, CA) and SIK2-FLAG (UniProt ID Q9H0K1) (G13-L350) was codon optimized for expression in SF21 cells and lysed in a buffer containing 50 mM Tris- HCl (pH 7.5), 500 mM NaCl, 5% glycerol, 0.5% Tween-20, 1 mM TCEP and purified over Glutathione Sepharose FF cartridge and Size Exclusion Chromatography (HiLoad 16/600 Superdex 200pg) into a final storage buffer of 50mM Tris-HCl (pH 7.5), 300mM NaCl, 10% glycerol, 1mM TCEP.
  • the final protein stored at -80 °C, contains a single Glycine cloning artifact at the N-terminus and retains a c-terminal FLAG tag and consists of an amino acid sequence of SEQ ID NO: 1.
  • Compounds (60 nL) in 100% DMSO were added to the assay plate (AlphaPlate- 384, Cat# 6005359 Perkin Elmer) using a LabCyte Echo 550.
  • DMSO (60 nL) was added to maximum signal control (MAX) wells and a reference compound producing 100% inhibition was added to minimum signal control (MIN) wells.
  • SIK2 was diluted to 2X final concentration in 1X assay buffer and 3 ⁇ L was added to the compounds/DMSO in the assay plate. After incubation for 20 minutes at RT, 3 ⁇ L substrate mix containing 2X ATP and 2X AMARAtide in 1X assay buffer was added to the assay plate. After incubation for 60 minutes, the reaction was stopped by the addition of the ADP-Glo Kit components as directed and the relative luminescence units (RLU) were read on an Envision 2104. The final concentrations of the assay components were 3 nM SIK2-FLAG, 50 ⁇ M AMARAtide, 1 mM ATP, and 1% DMSO.
  • Compound activity designations have the following values: A ( ⁇ 10 nM); B (10 nM to ⁇ 100 nM); C (100 nM to 500 nM); D (> 500 nM); and “-” (not tested). Table 3. Biochemical Assays Results

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Abstract

La présente invention concerne des composés de formule I, des compositions de ceux-ci, et des méthodes d'utilisation de ceux-ci pour l'inhibition de SIK2 et le traitement de troubles médiés par SIK2.
PCT/US2025/027058 2024-05-01 2025-04-30 Modulateurs de sik2 et leurs utilisations Pending WO2025231112A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058126A2 (fr) * 2006-11-06 2008-05-15 Supergen, Inc. Dérivés d'imidazo[1,2-b]pyridazine et de pyrazolo[1,5-a]pyrimidine et utilisation de ceux-ci comme inhibiteurs de protéines kinases
US20150344481A1 (en) * 2012-12-21 2015-12-03 Bristol-Myers Squibb Company Novel substituted imidazoles as casein kinase 1 d/e inhibitors
WO2022165529A1 (fr) * 2021-02-01 2022-08-04 Janssen Biotech, Inc. Inhibiteurs à petites molécules de kinases inductibles par le sel
US20220340581A1 (en) * 2017-12-02 2022-10-27 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of diseases
US20240025892A1 (en) * 2020-08-05 2024-01-25 The General Hospital Corporation Salt inducible kinase inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008058126A2 (fr) * 2006-11-06 2008-05-15 Supergen, Inc. Dérivés d'imidazo[1,2-b]pyridazine et de pyrazolo[1,5-a]pyrimidine et utilisation de ceux-ci comme inhibiteurs de protéines kinases
US20150344481A1 (en) * 2012-12-21 2015-12-03 Bristol-Myers Squibb Company Novel substituted imidazoles as casein kinase 1 d/e inhibitors
US20220340581A1 (en) * 2017-12-02 2022-10-27 Galapagos Nv Compounds and pharmaceutical compositions thereof for the treatment of diseases
US20240025892A1 (en) * 2020-08-05 2024-01-25 The General Hospital Corporation Salt inducible kinase inhibitors
WO2022165529A1 (fr) * 2021-02-01 2022-08-04 Janssen Biotech, Inc. Inhibiteurs à petites molécules de kinases inductibles par le sel

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