WO2025166319A1 - Complement cascade inhibitors - Google Patents

Complement cascade inhibitors

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Publication number
WO2025166319A1
WO2025166319A1 PCT/US2025/014236 US2025014236W WO2025166319A1 WO 2025166319 A1 WO2025166319 A1 WO 2025166319A1 US 2025014236 W US2025014236 W US 2025014236W WO 2025166319 A1 WO2025166319 A1 WO 2025166319A1
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WO
WIPO (PCT)
Prior art keywords
imidazo
methyl
biphenyl
pyridine
dimethyl
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/US2025/014236
Other languages
French (fr)
Inventor
Christopher Meyer
Alexandra GOULD
Michel WEÏWER
Horia PRIBIAG
Morgan Sheng
Thomas ATACK
David Charles Mckinney
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.)
Massachusetts Institute of Technology
Broad Institute Inc
Original Assignee
Massachusetts Institute of Technology
Broad Institute Inc
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Application filed by Massachusetts Institute of Technology, Broad Institute Inc filed Critical Massachusetts Institute of Technology
Publication of WO2025166319A1 publication Critical patent/WO2025166319A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the Complement system is a phylogenetically old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault. Complement activation is a prominent feature of the inflammatory response in a variety of diseases, disorders, and conditions such as Alzheimer's disease ansd schizophrenia, and is apparently- triggered by the presence of senile plaques.
  • the triggering of the Complement system involves the sequential activation of numerous proteins by a cascade effect.
  • the Complement cascade is best defined as a series of binding and cleavage events wherein active forms of Complement proteins are produced, which in turn act upon each other, often by proteolysis, to produce further active proteins and protein fragments, and complexes thereof. These produced active proteins, protein fragments, and complexes then interact with immune system components, or with cellular debris, endogenous or foreign macromolecules, or invading cells which are then targeted for destruction.
  • Complement protein C3 is proteolytically cleaved, resulting in a large fragment (C3b) and the smaller 77 residue peptide, C3a.
  • C3a is known to regulate vasodilation increasing the permeability of small blood vessels, induce contraction of smooth muscles, induce oxidative burst, regulate cytokine release, and stimulate chemotaxis, depending on the involved cells, all inflammation related events.
  • Target cells- include macrophages, neutrophils, eosiniphils, basophils, T-lyphocytes and mast cells, all having important immune and inflammation related functions.
  • Receptors for C3a are expressed on a variety of macrophages and macrophage cell lines. Functionally, C3a binding to C3a receptors in macrphages causes a mobilization of intracellular calcium ions, and leads to both chemotaxis and respiratory burst, which are both host defense mechanism that generate high levels of cytotoxic superoxide. Again, although such mechanisms are useful in protecting against invading bacterial cells, for example, the triggering of such defense mechanism against normal cells (such as brain neurons that happen to be proximal to the site of plaque formation) is devastating to normal brain function. Similar disadvantageous results operate in regard of other inflammatory’ conditions.
  • the Complement system can be activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway.
  • the classical pathway is usually triggered by antibody bound to a foreign particle (i.e., an antigen) and thus requires prior exposure to that antigen for the generation of specific antibody. Since activation of the classical pathway is associated with development of an immune response, the classical pathway is part of the acquired immune system. In contrast, both the lectin and alternative pathways are independent of clonal immunity and are part of the innate immune system.
  • the first step in activation of the classical pathway is the binding of a specific recognition molecule, Clq, to antigen-bound IgG and IgM.
  • Clq specific recognition molecule
  • Clq is associated with the Clr and Cis serine protease proenzymes as a complex called Cl and. upon binding of Clq to an immune complex, autoproteolytic cleavage of the Arg-Ile site of Clr is followed by Clr activation of Cis, which thereby acquires the ability to cleave C4 and C2.
  • the cleavage of C4 into two fragments, designated C4a and C4b, allows the C4b fragments to form covalent bonds vxi th adjacent hydroxy or amino groups and the subsequent generation of C3 convertase (C4b2b) through noncovalent interaction with the C2b fragment of activated C2.
  • C3 convertase activates C3 leading to generation of the C5 convertase (C4b2b3b) and formation of the membrane attack complex (C5b-9) that can cause microbial lysis.
  • the activated forms of C3 and C4 are covalently deposited on the foreign target surfaces, which are recognized by Complement receptors on multiple phagocytes.
  • Complement components also include cell-bound receptors for soluble complement components.
  • Such receptors include, e.g., C5a receptor (C5aR), C3a receptor (C3aR), Complement Receptor 1 (CR1), Complement Receptor 2 (CR2), Complement Receptor 3 (CR3), etc.
  • the C3a receptor belongs to the rhodopsin family of G protein-coupled receptors. Traditionally. C3aR was thought to be present only on myeloid cells, such as macrophages, eosiniphils and mast cells. However, the demonstration that C3aR receptor messenger RNA is expressed throughout the body (and in particular in the adrenal gland, pituitary gland, and the central nervous system) is consistent with participation of C3a in a wide variety of cellular process and mediate numerous disease states. Recently, C3a receptor- immunoreactivity has been detected in areas of inflammation in multiple sclerosis and bacterial meningitis patients.
  • the Complement system has been implicated as contributing to the pathogenesis of numerous acute and chronic disease states, including Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury', epilepsy, haemolytic uraemic syndrome.
  • Complement is not the cause but is one of several factors involved in pathogenesis. Nevertheless, Complement activation may be a major pathological mechanism and represents an effective point for clinical control in many of these disease states.
  • Complement-mediated tissue injury' in a variety of disease states underscores the need for effective complement inhibitory drugs.
  • the present disclosure provides compounds which inhibit the Complement cascade (e.g., by inhibiting C3aR).
  • the compound may have the structure of formula (I): wherein A is C, CR, CR2, ary l (e.g., C6-C10 ary l), heteroaryl (e.g.. 5-10 membered heteroaryl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl); X1 is CR or N;
  • X 2 is CR or N
  • X 3 is CR 2 or NR
  • Ri and R2 are independently hydrogen or alkyl (e.g., C1-C8 alkyl, C1-C4 alkyl, methyl), and wherein Ri and R2 may together (with X3) form an optionally aromatic five or six membered fused ring (cycloalkyl (e.g., C5-Ce membered cycloalkyl ring), aryl (e.g., phenyl), heterocycloalkyl or heteroaryl ring (e.g., 5 to 6 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring)), wherein R1, R2, and the fused ring may be optionally substituted (e.g..).
  • cycloalkyl e.g., C5-Ce membered cycloalkyl ring
  • aryl e.g., phenyl
  • heterocycloalkyl or heteroaryl ring e.g., 5 to 6 membered heterocycl
  • heteroaryl e.g., 5-10 membered heteroaryl such as triazolyl
  • heterocycloalkyl e.g., 5-10 membered heterocycloalkyl
  • R3 is independently at each occurrence hy drogen or R, and two Rs groups may together form an optionally substituted spiro, fused, or bridged ring (e.g., 3 to 6 membered cycloalkyl ring), wherein R3 and the spiro, fused, or bridged ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR, -NHC(O)R, -NRR, -(CRR)i- 4NHCOR;
  • R4 is hydrogen, alkyl (e.g.. C1-C8 alkyl, C1-C5 alkyl, lower alkyl such as C1-C4 alkyl, methyl, ethyl, propyl such as isopropyl, butyl, pentyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), aryl (e.g., C6-C10 aryl, phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, pyridinyl, pyrazolyl, indazolyl), cycloalkyl (e.g., C3-C10 cycloalky l, saturated cycloalky l, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl.
  • alkyl e.g.. C1-C8 alkyl, C1-C5 alkyl, lower alkyl such as C1-C4
  • C3-C10 cycloalkyl unsaturated C3-C10 cycloalkyl. cyclopropyl, cyclobutyl, cyclopenyl. cyclohexyl
  • heterocycloalkyl e.g.. C3-C10 heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl, pyranyl, piperidinyl, pyrrolidinyl, azetidinyl
  • R4 may be optionally substituted (e.g., from one to three times) with, for example, - R, -C(O)R, -C(O)OR.
  • the compound may have the structure of formula (la): wherein the dotted circle indicates optional aromaticity; and
  • X4 is CR or N.
  • the compound may have the structure of formula (lai) or (Ia2): wherein the dotted circle indicates optional aromaticity.
  • the compound has the structure of formula (lb): wherein the dotted circle indicates optional aromaticity; and X4 is CR or N. In some embodiments, the compound has the structure of formula (Ic): wherein the dotted circle indicates optional aromaticity;
  • X4 is CR or N; and optionally R4 is hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl.
  • the compound has the structure of formula (Id): wherein the dotted circle indicates optional aromaticity; X4 is CR or N; and optionally R4 is hydrogen, alkyl, ary l, cycloalkyl, heterocycloalkyl, or heteroaryl.
  • Ri and R2 may be independently alkyl (e.g., lower alkyl such as C1-C4 alkyl, methyl, ethyl, butyl) optionally having one, two or three independent points of substitution such as R which may be independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halo, alkoxy, perfluoroalkoxy, amino, fluoroalkyl such as perfluoroalkyl, acyl (e.g., -COOR* where R* is lower alkyl, hydroxy),.
  • R e.g., lower alkyl such as C1-C4 alkyl, methyl, ethyl, butyl
  • R which may be independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halo, alkoxy, perfluoroalkoxy, amino, fluoroalkyl such as perfluoroalkyl,
  • R4 is cycloalkyl (e.g., C3-C10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally having one, two or three points of substitution (e.g., monosubstitution, geminal substitution, vicinal substitution) such as R which may include alkyl (e.g., lower alkyl substitution such as C1-C4 alkyl, methyl) substitution.
  • R is cycloalkyl (e.g., C3-C10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally having one, two or three points of substitution (e.g., monosubstitution, geminal substitution, vicinal substitution) such as R which may include alkyl (e.g., lower alkyl substitution such as C1-C4 alky
  • R4 is and (e.g., phenyl) optionally having one, two or three points of substitution (e.g., monosubstitution, geminal substitution, vicinal substitution) such as R which may include alkyl (e.g., lower alkyl such as C1-C4 alkyd, methyl) substitution.
  • R4 is independently substituted one or more times (e.g., one, two, three) with R, C(O)R, C(O)OR, NHC(O)R, NRR, (CRR)I- 4 NHC(O)R, wherein R is independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halo, alkoxy, perfluoroalkoxy, amino, fluoroalkyl such as perfluoroalkyd, or acyl (e.g., -COOR* where R* is lower alkyl, hydroxy).
  • at least one of Li or L2 is not absent. In certain instances, Li is absent.
  • the fused ring formed by Ri and R2 contains only one N (e.g., when X3 is NR and the remaining members of the fused ring are all C).
  • the compound may be:
  • the compound has an EC 50 such as IC50 (e.g., as measured in a P-arrestin assay or Calcium Flux assay) of human Complement Component 3a Receptor (C3aR) and/or mouse C3aR of less than (or from 1 nM to) 20pM (e.g., less than 10 pM, less than 5 pM, less than 2 pM, less than 1 pM, less than 500 nM, less than 200 nM).
  • IC50 e.g., as measured in a P-arrestin assay or Calcium Flux assay
  • C3aR human Complement Component 3a Receptor
  • mouse C3aR of less than (or from 1 nM to) 20pM (e.g., less than 10 pM, less than 5 pM, less than 2 pM, less than 1 pM, less than 500 nM, less than 200 nM).
  • compositions comprising a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), Compound 1- 170) comprising a pharmaceutically acceptable excipient and the compound.
  • the pharmaceutical composition may be an injectable composition or an oral composition.
  • a method of inhibiting the Complement Component 3a Receptor (C3aR) (or inhibiting the Complement cascade) in a cell may comprise contacting the cell with the compound of the present disclosure (e.g., a compound of formula (I), (la), (lai), (Ia2) (lb), (Ic), (Id), Compound 1- 170) or a pharmaceutically acceptable salt thereof.
  • the cell is a plasma cell, brain cell, or cerebral spinal fluid (CSF) cell.
  • the cell is in vivo, ex vivo, or in vitro.
  • a method of treating the excessive Complement activation (or inhibiting C3aR) in a subject in need thereof comprising administering a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1- 170) to the subject.
  • a compound of the present disclosure e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1- 170
  • the subject may have a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory' disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis.
  • Schizophrenia amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions.
  • the subject has a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s chorea, Pick’s disease, Guillian Barre syndrome, encephalitis, meningitis, stroke.
  • Schizophrenia amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection and hemorrhagic stroke.
  • methods of treating Alzheimer’s disease in a subject in need thereof comprising administering a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1-170) or a pharmaceutically acceptable salt thereof (or the pharmaceutical composition) to the subject.
  • a compound of the present disclosure e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1-170
  • a pharmaceutically acceptable salt thereof or the pharmaceutical composition
  • the compound e.g., a compound of formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), Compound 1-170
  • the pharmaceutical composition comprising the compound may be administered by intraperitoneal (IP) injection, intravenous (IV) injection, subcutaneous (SC) injection, or orally (PO).
  • IP intraperitoneal
  • IV intravenous
  • SC subcutaneous
  • PO subcutaneous
  • the compound is administered in an amount of from 1 mg/kg-40 mg/kg (e.g., from 3 mg/kg to 30 mg/kg, from 5 mg/kg-15 mg/kg).
  • numeric values include the endpoints and all possible values disclosed between the disclosed values.
  • the exact values of all half-integral numeric values are also contemplated as specifically disclosed and as limits for all subsets of the disclosed range.
  • a range of from 0.1% to 3% specifically discloses a percentage of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%.
  • a range of 0.1 to 3% includes subsets of the original range including from 0.5% to 2.5%, from 1% to 3%. or from 0.1% to 2.5%. It will be understood that the sum of all weight % of individual components will not exceed 100%.
  • agent is meant a compound (e.g., small compound), polypeptide or polynucleotide.
  • ameliorate is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
  • ingredients include only the listed components along with the normal impurities present in commercial materials and with any other additives present at levels which do not affect the operation of the disclosure, for instance at levels less than 5% by weight or less than 1% or even 0.5% by weight.
  • disease is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • diseases, disorders, or conditions described are those associated with excessive Complement activation. Examples include Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Bane syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory' demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions.
  • complement C3a receptor polypeptide or “C3aR polypeptide” is meant a protein or fragment thereof having at least about 85% amino acid sequence identity to NCBI Reference Sequence NP_001313404.1 and/or being an anaphylatoxin released during activation of the complement system.
  • the protein encoded by this gene is an orphan G protein-coupled receptor for C3a.
  • An exemplary C3aR amino acid sequence follows:
  • an effective amount or “therapeutically effective amount” of an agent is meant the amount of an agent (e.g, a compound described herein) required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active compound(s) used for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian may decide the appropriate amount and dosage regimen. Such amount is generally referred to as an “effective” amount.
  • Agents described herein include compounds having the structure of Formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id) one or more of Compounds 1-170. In some embodiments, the compounds are administered in an effective amount for the treatment of a disease disorder or condition.
  • composition represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gel cap); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g, as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein (see below).
  • the phrase “pharmaceutically acceptable’' indicates a component generally safe for ingestion or contact with biologic tissues at the levels employed.
  • Pharmaceutically acceptable is used interchangeably with physiologically compatible. It will be understood that the pharmaceutical compositions of the disclosure include nutraceutical compositions (e.g, dietary supplements) unless otherwise specified.
  • Ranges provided herein are understood to be shorthand for all of the values within the range including the endpoints of the range.
  • a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
  • the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • subject is meant a mammal, including, but not limited to, a human or nonhuman mammal, such as a bovine, equine, canine, ovine, or feline. Typical subjects include any animal (e.g, mammals such as mice, rats, rabbits, non-human primates, and humans).
  • a subject in need thereof is typically a subject for whom it is desirable to treat a disease, disorder, or condition as described herein.
  • a subject in need thereof may seek or be in need of treatment, require treatment, be receiving treatment, may be receiving treatment in the future, or a human or animal that is under care by a trained professional for a particular disease, disorder, or condition.
  • substituted refers to a group “substituted” on a hydrocarbon, e g, an alkyl, at any atom of that group, replacing one or more atoms therein (e.g., the point of substitution) including hydrogen atoms.
  • the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent.
  • a substituent may itself be substituted with any one of the substituents described herein. Substituents may be located pendant to the hydrocarbon chain.
  • substituted with a[n] means the specified group may be substituted with one or more of any combination substituents as described in the present application.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
  • Compounds of the present disclosure may exhibit activity to inhibit C3aR (and affect the Complement cascade typically reducing activity thereof) and administration thereof may result in the ability to decrease diseases, disorders, or conditions as described herein.
  • the compounds of the present disclosure are C3aR inhibitors.
  • the C3aR inhibitors of the present disclosure may be a compound having the structure of formula (I): wherein A is C, CR, CR2, aryl (e.g., C6-C10 ary l), heteroaryl (e.g..
  • cycloalkyl e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl
  • heterocycloalkyl e.g., 3 to 10 membered heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl
  • Xi is CR or N
  • X 2 is CR or N
  • Ri and R2 are independently hydrogen or alkyl (e.g., C1-C8 alkyl, C1-C4 alkyl, methyl), and wherein Ri and R2 may together (with X3) form an optionally aromatic five or six membered fused ring (e.g. cycloalkyl (e.g., C-Ce membered cycloalkyl ring)), aryl (e.g., phenyl), heterocycloalkyl or heteroaryl ring (e.g., 3 to 6 membered heterocycloalkyl ring), 5 to 6 membered heteroaryl ring)), wherein Ri, R2, and the fused ring may be optionally substituted (e.g...
  • cycloalkyl e.g., C-Ce membered cycloalkyl ring
  • aryl e.g., phenyl
  • heterocycloalkyl or heteroaryl ring e.g., 3 to 6 member
  • heteroaryl e.g., 5-10 membered heteroaryl such as triazolyl
  • heterocycloalkyl e.g., 5-10 membered heterocycloalkyl
  • R3 is independently at each occurrence hydrogen or R, and two R3 groups may together form an optionally substituted spiro, fused, or bridged ring (e.g., 3 to 6 membered cycloalkyd ring), wherein R3 and the spiro, fused, or bridged ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR, -NHC(O)R. -NRR, and/or - (CRR)I- 4 NHCOR;
  • R 4 is hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), aryl (e.g., C6-C10 aryl), heteroaryl (e.g., 5-10 membered heteroary l), cycloalkyl (e.g., C3-C10 cycloalkyd, saturated cycloalkyl, saturated Cs- C10 cycloalkyd, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g...).
  • alkyl e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,
  • aryl e.g., C
  • C3-C10 heterocycloalkyl saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl), wherein Ri may be optionally substituted (e.g., from one to three times) with, for example, - R, C(O)R, C(O)OR, NHC(O)R, NRR, and/or (CRR)I- 4 NHC(O)R; and
  • the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-43 W02007034278A2, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-43.
  • the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-166 W02007034282A2. which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-166.
  • the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-51 W02007034277A1, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-51.
  • the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-47 W02007034279A2, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-47.
  • Cycloalkyl or cycloalkylene groups described may refer to cyclic aliphatic hydrocarbon radical of 3-15 carbon atoms (e.g., 3-12 carbon atoms. 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms, 3-4 carbon atoms).
  • the cycloalkyl group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • Cycloalkyl groups may have from 3-12 carbon atoms in the carbon ring. Cycloalkyl groups include monocyclic and multicyclic ring systems such as bicyclic and tricyclic groups.
  • cyclalkyl groups will have from 3-8 or from from 3-6 or from 3-4 or 3 carbon atoms, including for example, embodiments having three, four, five, six, seven, eight, nine, or ten carbon atoms. Any cycloalkyl or cycloalkydene group may be substituted or unsubstituted.
  • Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy l, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • Multicyclic groups include, for example, bridged and/or fused ring systems, such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclofl. l. l]pentan-l-yl, adamantyl, norbomyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Heterocycloalky l groups or heterocycloalkylene may to cycloalkyl groups (e.g., saturated aliphatic hydrocarbon radicals) with one or more heteroatoms (e.g., N, O. S) in the ring.
  • Heterocycloalkyl groups or heterocycloalkylene groups may have 3-15 atoms in the ring (e.g., 3-12 atoms, 3-8 atoms, 3-6 atoms, or 3-5 atoms, 3-4 atoms).
  • the hetercyclooalkyl group or heterocycloalkylene group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
  • Aryl or aryelene groups may be aromatic mono-or polycyclic radicals of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and IH-indenyl.
  • heteroaryls or heteroary clones include mono-or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O. and S, with the remaining ring atoms being C.
  • One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group.
  • heteroaryl groups are pyridyl, benzooxazolyl, benzoimidazolyl, and benzothiazolyl.
  • heterocycloalkyl or heteroaryl groups include: These groups may include one or more substituents as described herein (e.g., R substituted, alkyl substituted, halogen substituted, hydroxy substituted, amino substituted, alkoxysubstituted, each of which may be further substituted one or more times).
  • a substituted hydrocarbon group may have as a substituent one or more hydrocarbon radicals, substituted hydrocarbon radicals, or may comprise one or more heteroatoms.
  • substituted hydrocarbon radicals include, without limitation, heterocycles, such as heteroaryls.
  • a hydrocarbon substituted with one or more heteroatoms will comprise from 1-20 heteroatoms.
  • a hydrocarbon substituted with one or more heteroatoms will comprise from 1-12 or from 1-8 or from 1-6 or from 1-4 or from 1-3 or from 1-2 heteroatoms.
  • heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorous, halogen (e.g, F, Cl, Br, I), boron, or silicon.
  • heteroatoms will be selected from the group consisting of oxygen, nitrogen, sulfur, phosphorous, and halogen (e.g., F. Cl. Br. I).
  • a heteroatom or group may substitute a carbon (e.g., substituted alkyl may include heteroalkyl).
  • a heteroatom or group may substitute a hydrogen.
  • a substituted hydrocarbon may comprise one or more heteroatoms in the backbone or chain of the molecule (e.g.. interposed between two carbon atoms, as in "oxa'’).
  • a substituted hydrocarbon may comprise one or more heteroatoms pendant from the backbone or chain of the molecule (e.g., covalently bound to a carbon atom in the chain or backbone, as in "oxo").
  • all groups described herein e.g., alkyl, cycloalkyd, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, cylcoalkylene, heterocycloalkylene.
  • R1-R4, R. A, Li, L2 may optionally contain one or more substituents, to the extent permitted by valency.
  • Substituents include halogen (e.g., F, Cl), C1-12 straight chain or branched chain alky l, C2-12 alkeny l, C2-i2 alkynyl, C3-12 cycloalky l, Ce-naryl, C3-12 heteroaryl, C3-i2heterocyclyl, C1-12 alkylsulfony l, nitro, cyano, -COOR, -C(O)NRR’, -OR, - SR, -NRR’, and oxo, such as mono-or di-or tri-substitutions with moieties such as halogen, fluoroalkyl, perfluoroalkyl, perfluroalkoxy, trifluoromethoxy, chlorine, bromine, fluorine, methyl, methoxy, pyridyl, furyl, triazyd, piperazinyl, pyrazoyl, imidazoyl, and the like, each
  • R and R’ are independently hydrogen.
  • the phrase optionally substituted indicates the designated hydrocarbon group may be unsubstituted (e.g. substituted with H) or substituted.
  • substituted hydrocarbons are hydrocarbons with a hydrogen atom removed and replaced by a substituent (e.g., a common substituent).
  • a substituent e.g., a common substituent.
  • Any hydrocarbon in the present disclosure may be considered substituted or “optionally substituted” with, for example, alky l (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, ethyl, propyl including isopropyl ('Pr). deuterated alkyl or deuterated lower alkyl such as -CD3,).
  • heteroalkyl e.g., C1-C8 heteroalkyl, lower heteroalkyl such as C1-C4 heteroalkyl
  • alkoxy substituted alkyl e.g., Ci-Ce alkyl substituted with Ci-Ce alkoxy such as methoxy
  • cycloalkyl e.g., C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl
  • alkoxy e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy
  • alkoxy substituted with, for example, aryl e.g...
  • benzyloxy spiro cycloalkyl (C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethy l, perfluoroalky l, C1-C8 perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br).
  • halogen e.g., F, Cl, Br
  • a group described herein may be substituted with a protecting group such as tert-butyloxy carbonyl (Boc).
  • substitution at a given atom is limited by valency.
  • a substituent (radical) prefix names such as alkyl or alkylene without the modifier optionally substituted or substituted is understood to mean that the particular substituent is unsubstituted unless otherwise indicated.
  • haloalkyl without the modifier optionally substituted or substituted is still understood to mean an alkyl group, in which at least one hydrogen atom is replaced by halo. Where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding with regard to valencies, and to give compounds which are not inherently unstable.
  • any carbon atom will be bonded to two, three, or four other atoms, consistent with the four valence electrons of carbon. Additionally, when a structure has less than the required number of functional groups indicated, those carbon atoms without an indicated functional group are bonded to the requisite number of hydrogen atoms to satisfy the valency of that carbon unless otherwise indicated.
  • Compounds provided herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
  • the optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant).
  • certain of the disclosed compounds may exist in various stereoisomeric forms including stereoisomers, enantiomers, diastereomers, or racemates (z.e., the compound exists as a mixture containing two enantiomers and does not rotate polarized light).
  • Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well- known techniques and methods, such as chiral chromatography and separation methods based thereon.
  • the appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
  • the compound provided herein may also be present as geometric isomer which differ in the orientation of substituent atoms (e.g, to a carbon-carbon double bond, to a cycloalkyl ring, to a bridged bicyclic system).
  • Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration.
  • “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “‘trans,” indicate configurations relative to the core molecule and may be used to indicate the geometric configuration of the presently disclosed compounds. Certain of the disclosed compounds may exist in atropisomeric forms.
  • Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers.
  • a compound having a stereocenter is provided without indication of its chirality, it will be understood that all specific configurations (e.g., (R), (S)) are included as well as mixtures thereof (e.g., racemates).
  • the compounds disclosed herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods.
  • the named or depicted stereoisomer may be typically more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) relative to the other stereoisomers.
  • the depicted or named enantiomer is more than 50% (e.g.. at least 55%. 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) optically pure.
  • the depicted or named diastereomer is more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) pure.
  • Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer.
  • Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers.
  • Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer.
  • percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer.
  • Solvates of the compounds described herein may form the aggregate of the compound or an ion of the compound with one or more solvents. Such solvents may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH.
  • Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
  • the compounds described herein may be present as a pharmaceutically acceptable salt.
  • salts are composed of a related number of cations and anions (at least one of which is formed from the compounds described herein) coupled together (e.g., the pairs may be bonded ionically) such that the salt is electrically neutral.
  • Pharmaceutically acceptable salts may retain or have similar activity to the parent compound (e.g.. an ED50 within 10%) and have a toxicity profile within a range that affords utility in pharmaceutical compositions.
  • pharmaceutically acceptable salts may be suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio.
  • Salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19. 1977 and in Pharmaceutically acceptable salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley -VCH, 2008. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases including inorganic and organic acids and bases.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, dichloroacetate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glycerophosphate, hemisulfate, heptonate, hexanoate, hippurate, hydrobromide, hydrochloride, hydroiodide.
  • 2-hydroxy -ethanesulfonate isethionate, lactobionate.
  • lactate laurate, lauryl sulfate, malate, maleate, malonate.
  • mandelate methanesulfonate, mucate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts.
  • Representative basic salts include alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, aluminum salts, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, caffeine, and ethylamine.
  • Pharmaceutically acceptable acid addition salts of the disclosure can be formed by the reaction of a compound of the disclosure with an equimolar or excess amount of acid.
  • hemi -salts can be formed by the reaction of a compound of the disclosure with the desired acid in a 2: 1 ratio, compound to acid.
  • the reactants are generally combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, /.so-propanol. benzene, or the like.
  • the salts normally precipitate out of solution within, e.g. one hour to ten days and can be isolated by filtration or other conventional methods.
  • the compounds of the present invention include the compounds themselves, as well as their salts and their prodrugs, if applicable.
  • a salt for example, can be formed between an anion (e.g., halide such as chloride, fluoride, bromide, optionally substituted phosphate, optionally substituted sulfonate, optionally substituted acetate) and a positively charged substituent (e.g., optionally substituted ammonium) on a compound described herein.
  • Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate.
  • a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein.
  • Suitable cations include sodium ion, potassium ion. magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion.
  • a prodrug generally converts into an active compound following administration to a subject, for example through in vivo hydrolysis.
  • Examples of prodrugs include Ci-e alkyl esters of carboxylic acid groups, which, upon administration to a subject, are typically capable of providing active compounds.
  • the identified hydrocarbon groups in the compounds of the present disclosure may be optionally substituted one or more times with a substituent as described herein.
  • R4 is aryl optionally substituted one or more times with a substituent selected from alkyl, alkoxy, halogen, -NRR, -C(O)R, -NRC(O)R, and -C(O)NRR; and any two vicinal substituents may together form a five or six membered ring.
  • the alkyl group may be optionally unsaturated (e.g., alkenyl).
  • the compound may be any one of Compounds 1-170 as disclosed in Table 1. or pharmaceutically acceptable salts and/or prodrugs thereof.
  • the compound is any Compound in Table 1 including a compound selected from Compounds 1-170, or a pharmaceutically salt or prodrug thereof. Tautomeric, enantiomeric, and diastereomic forms of these compounds, as well as mixtures thereof, are included within the disclosure.
  • the compounds described herein e.g.. C3aR agonists, C3aR inhibitors.
  • Compounds having the structure of Formula (I), (la), (lai), (Ia2) (lb), (Ic), (Id), one or more of Compounds 1-170) are useful for the treatment of a disease, disorder, or condition in a subject in need thereof.
  • the compounds described herein may also be compounds for use in the preparation of a medicament for the treatment of (e.g., a disease caused by) in a subject in need thereof.
  • Pharmaceutical dosage forms are provided as well, which may comprise a compound of the present disclosure (e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170) and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a compound of the present disclosure e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170
  • pharmaceutically acceptable carriers diluents, or excipients.
  • Unit dosage forms also referred to as unitary dosage forms, often denote those forms of medication supplied in a manner that does not require further weighing or measuring to provide the dosage (e.g.. tablet, capsule, caplet).
  • the compositions of the present disclosure may be present as unit dosage forms.
  • a unit dosage form may refer to a physically discrete unit suitable as a unitary 7 dosage for human subjects and other species, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients.
  • Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, and gel cap.
  • the compounds described herein may be present in a unit dosage form.
  • Useful pharmaceutical carriers, excipients, and diluents for the preparation of the compositions hereof can be solids, liquids, or gases. These include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, and aerosols.
  • the carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g.. peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, aqueous dextrose, and glycols are examples of liquid carriers, particularly (when isotonic with the blood) for injectable solutions.
  • formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution and rendering the solution sterile.
  • suitable pharmaceutical excipients include starch, cellulose, chitosan, talc, glucose, lactose, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol.
  • compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, and buffers.
  • suitable pharmaceutical carriers and their formulation are described in Remington’s Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for administration to the recipient.
  • Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate: powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository' waxes; oils such as peanut oil, cottonseed oil, safflower oil. sesame oil.
  • glycols such as polyethylene glycol and propylene glycol
  • esters such as ethyl oleate and ethyl laurate
  • agar buffering agents such as magnesium hydroxide and aluminum hydroxide
  • alginic acid isotonic saline
  • Ringer's solution ethyl alcohol
  • phosphate buffer solutions non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate
  • coloring agents releasing agents: coating agents; sweetening, flavoring and perfuming agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine;
  • SEDDS self-emuls
  • Cyclodextrins such as a-, fy, and y-cyclodextrin. or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of the compounds described herein.
  • the compositions of the invention are formulated in pellets or tablets for an oral administration. According to this type of formulation, they comprise lactose monohydrate, cellulose microcrystalline, crospovidone/povidone, aroma, compressible sugar and magnesium stearate as excipients.
  • the compositions are in the form of pellets or tablets, they are for instance 1 mg, 2 mg, or 4 mg pellets or tablets. Such pellets or tablets are divisible so that they can be cut to suit the posology according to the invention in one or two daily takes.
  • the compositions of the disclosure are formulated in injectable solutions or suspensions for a parenteral administration.
  • the injectable compositions are produced by mixing therapeutically efficient quantity of torasemide with a pH regulator, a buffer agent, a suspension agent, a solubilization agent, a stabilizer, a tonicity agent and/or a preservative, and by transformation of the mixture into an intravenous, sub-cutaneous, intramuscular injection or perfusion according to a conventional method. Possibly, the injectable compositions may be lyophilized according to a conventional method.
  • suspension agents include methylcellulose, polysorbate 80. hydroxy ethylcellulose, xanthan gum, sodic carboxymethylcellulose and poly ethoxylated sorbitan monolaurate.
  • solubilization agent examples include polyoxy ethylene- solidified castor oil, polysorbate 80, nicotinamide, poly ethoxylated sorbitan monolaurate, macrogol and ethyl ester of caste oil fatty acid.
  • the stabilizer includes sodium sulfite, sodium metalsulfite and ether, while the preservative includes methyl p-hydroxy benzoate, ethyl p- hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • An example of tonicity agent is mannitol.
  • the pharmaceutical composition further comprises a viscosity enhancing agent.
  • the viscosity enhancing agent includes methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and smart hydrogel.
  • the viscosity enhancing agent is hydroxyethylcellulose.
  • the pharmaceutical composition comprises 0.01-1.0% (w/v) viscosity enhancing agent.
  • the intranasal pharmaceutical composition comprises 0.05% (w/v) hydroxyethylcellulose.
  • the pH of the pharmaceutical composition is from 4.0 to 7.5. In other embodiments, the pH of the pharmaceutical composition is from 4.0 to 6.5. In another embodiment the pharmaceutical composition has a pH of from 5.5 to 6.5. In further embodiments, the pharmaceutical composition has a pH of from 6.0 to 6.5. In various implementations, the pH of said aqueous solution or liquid formulation is from pH 3 to pH 7, from pH 3 to pH 6. from pH 4 to pH 6, or from pH 5 to pH 6. These pH ranges may be achieved through the incorporation of one or more pH modifying agents, buffers, and the like. In some embodiments, a pH modifier such as acetic acid, is present in a final concentration of at least 0.001%, preferably at least 0.01%, more preferably between 0.01%- 0.2% by weight of the composition.
  • a pH modifier such as acetic acid
  • compositions of this invention may include solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, powders, or other typical solid or liquid compositions used for application to skin and other tissues where the compositions may be used.
  • compositions may contain: antimicrobials, moisturizers and hydration agents, penetration agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, gelling agents, emollients, antioxidants, fragrances, fillers, thickeners, waxes, odor absorbers, dyestuffs, coloring agents, powders, viscosity -controlling agents and water, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals.
  • the composition of the invention is formulated with the above ingredients so as to be stable for a long period of time, as may be beneficial where continual or long-term treatment is intended.
  • beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable.
  • a disease, disorder, or condition may be palliated which includes that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
  • the method of treatment of a subject in need thereof may comprise administration to the subject a compound (e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170) or composition of the present disclosure.
  • a compound e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170
  • a compound e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170
  • the compounds of the present disclosure may selectively modulate C3aR (and produce a decreased Complement cascade).
  • the compounds or compositions of the present disclosure may be administered at least once a day for at least one week.
  • the composition is administered at least twice a day for at least two days. In certain embodiments, the composition is administered approximately daily, at least daily, twice a week, weekly, or for once a month. In certain embodiments, the composition of the invention is administered for several months, such as at least two months, six months, or one year or longer.
  • the invention is further suited for long-term use, which may be particularly beneficial for preventing recurring infection, or for preventing infection or conditions in at-risk or susceptible patients, including immune compromised patients. Such long-term use may involve treatment for at least two years, three years, four years, or even five or more years.
  • Examples of other drugs to combine with the compounds described herein include pharmaceuticals for the treatment of schizophrenia or conditions or disorders associated therewith.
  • Combination methods can involve the use of the two (or more) agents formulated together or separately, as determined to be appropriate.
  • two or more drugs are formulated together for the simultaneous or near simultaneous administration of the agents.
  • the composition of the invention is a kit, which contains the compositions of the present disclosure packaged to facilitate dispensing and/or administration of the compositions disclosed herein (e.g., compositions comprising one or more C3aR inhibitors, compositions comprising one or more compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), or (Id), compositions comprising one or more of Compounds 1-170).
  • the packaging or dispenser may include a bottle, tube, spray bottle, or other dispenser.
  • the composition is packaged in a concentrated form, and diluted to a desired concentration upon use by the end user.
  • the composition may be formulated and packaged in a manner suitable for long-term storage to maintain efficacy of the composition.
  • kits may include instructions for using the compounds (e.g., for treatment of a disease disorder or condition) or include an internet link to such instructions (e g., which may be a pharmaceutical label).
  • the present disclosure also provides synthetic methods for preparing the active compounds of the present disclosure (e.g., compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), or (Id), Compounds 1-170) as well as compounds useful as intermediates in those synthetic methods.
  • the method for producing a compound of Formula (I) may comprise reacting a first compound having a boron containing coupling moiety (e.g., dioxaborolanes, dioxaborinanes), or boronic acid or boronic ester such as a group selected from: with a second compound having a halide (e.g., Cl, Br, I); to produce a compound coupling the first and second compound.
  • the coupling may involve reacting a compound having the structure of formula (II):
  • the method may involve reacting a compound having the structure of formula (IV): with a compound having the structure of formula (V):
  • the method may involve reacting a compound having the structure of formula (VIII): with a compound having the structure of formula (IX):
  • the method may involve the removal of a protecting group.
  • Pg is a protecting group and, prior to contacting the compounds or while contacting the compounds, deprotection occurs.
  • Pg is a silyl ether such as trimethysilyl (which may be deprotected with, for example. Procedure A).
  • the coupling may occur via Chan-Lam, Ullman, or Buchwal-Hartwig reactions.
  • the method may involve reacting a compound having the structure of formula (X): with a compound having the structure of formula (XI):
  • one of Z1 and Z2 is boronic acid (-B(OH)2) or halide and the other of Z1 and Z2 is hydroxy or amine to form a compound having the structure of Formula (I).
  • the coupling may occur via Grignard or organolithium addition to an aldehyde, each of which may be followed by alcohol hydrogenation with H2 and suitable catalyst (e.g., Pd/C) reactions.
  • the method may involve reacting a compound having the structure of formula (X): with a compound having the structure of formula (XI):
  • one of Z1 and Z2 is a ketone (e.g., -C(O)R) and the other of Z1 and Z2 is a Grignard coupling agent such as magnesium halide (e.g., MgCl) or an Organolithium Li to form a compound having the structure of Formula (XII):
  • a Grignard coupling agent such as magnesium halide (e.g., MgCl) or an Organolithium Li
  • Compounds having the structure of Formula (XII) may be subsequently dehydrogenated (e.g., with H2 and a catalyst such as Pd/C) to form compounds having the structure of Formula (I) (or intermediates useful for production of compounds having the structure of Formula (I).
  • the coupling may occur via aromatic substitution (e.g., nucleophilic aromatic substitution (SxAr). electrophilic aromatic substation (Si: Ar)).
  • aromatic substitution e.g., nucleophilic aromatic substitution (SxAr). electrophilic aromatic substation (Si: Ar)
  • the coupling may involve reacting a compound having the structure of formula (XIII) wherein A is ring comprising a nucleophilic moiety (e.g.
  • the coupling may occur under transmateal catalyzed coupling conditions such as Buchwald- Hartwig couplings (e.g., with tBuXPhos, Pd2(dba)s. CuO. and combinations thereof), Negishi couplings, Suzuki couplings, Kumada coupldings, or Stille couplings.
  • the intermediates may be reacted under alkaline conditions (e.g., basic conditions as produced from an organic base or inorganic base in solvent) in the presence of a metal catalyst.
  • the metal catalyst may be Pd(dppf)ChCH2C12, Pd(OAc)2, Pd(PPhs)4, Ni(cod2), or Ni(dppf)C12.
  • the coupling may occur in a solvent seletcted from toluene, tetrahydrofuran, N,N-dimethylformamide, dioxane, water, and mixtures thereof.
  • the alkaline conditions may be established through the use of a base dissolved in the solvent, where the base may be, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, and sodium tert-butoxide.
  • Exemplary chemical synthetic steps include:
  • the syntheses and intermediates associated therewith may include one or more reaction additional steps.
  • compounds having the structures of Formulas (I), (II), (IV), (VI), (VIII), (X), (XII), or (XIII), wherein Ri and R2 together form a fused ring may be formed by amidine cyclization and/or Pd/C reduction, to result in the substitution groups for compounds having the structure of Formula (I).
  • the method may involve modifications involving the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, or substitution. These transformations include those which introduce a functionality which allows for further interconversion of substituents.
  • the method may comprise alkylation (e.g., amine alky lation), acetyl deprotection (e.g., conversion of an -OAc to -OH), deoxygenation (e.g., removal of a hydroxyl group), carbonyl reduction (e.g., conversion of a -C(O)OR group to -CH2-OH), tetrazole installation (e.g., via a cyano group), sulfonylation, or saponification.
  • alkylation e.g., amine alky lation
  • acetyl deprotection e.g., conversion of an -OAc to -OH
  • deoxygenation e.g., removal of a hydroxyl group
  • carbonyl reduction e.g., conversion of a -C(O)OR group to -CH2-OH
  • tetrazole installation e.g., via a cyano group
  • syntheses may proceed in a manner similar to as disclosed in W02007034278A2, W02007034282A2, W02007034277A1, W02007034279A2, each of which are hereby incorporated by reference in their entirety and particularly in relation to the synthetic schema provided therein.
  • C3aR activity was measured by the detection of the interaction of P- arrestin with C3aR, using enzyme fragment complementation, in mammalian cells.
  • C3aR was fused to a small, optimized alpha fragment peptide derived from beta-galactosidase, while P- arrestin was fused to an N-terminal deletion mutant of beta-galactosidase (the enzyme acceptor).
  • P-arrestin recruitment to C3aR drives enzyme fragment complementation, resulting in an active beta-galactosidase enzyme.
  • C3aR activation can then be determined by quantifying beta-galactosidase activity.
  • An exemplary assay is also disclosed in U.S. Pub. No. 2008/0274913, which is hereby incorporated by reference in its entirey.
  • P-arrestin recruitment may be induced using human or mouse C3aR and enzy me activity can be measured using chemiluminescent detection reagents.
  • Activation of C3aR can be driven by a small molecule agonist of C3aR (BR103, CAS No. : 1434873-26-3) or C3a peptide.
  • Compounds of the present disclosure were applied to the cells 1-2 minutes prior to application of C3aR agonist.
  • C3aR activity was also measured by calcium flux detection in primary mouse brain-derived macrophages (microglia) similarly to the assays described in Hansen, Kasper B., and Hans Brauner-Osbome. "FLIPR® assays of intracellular calcium in GPCR drug discovery .” G Protein-Coupled Receptors in Drug Discovery (2009): 269-278, which is hereby incorporated by reference in its entirety and particularly in relation to intracellular calcium assays. Briefly, microglia endogenously express C3aR and are the main target cell type for C3aR inhibition in neurodegenerative conditions such as Alzheimer’s.
  • Mouse microglia were obtained by 7 dissociating early postnatal (P0-P5) mouse brains and culturing mixed glia for two weeks in DMEM supplemented with heat-inactivated 10% fetal bovine serum (Thermo Fisher Scientific). Microglia were then detached from the astrocyte monolayer by shaking for 4 hours, re-seeded at 15,000 cells/well in 384-well plates, and cultured for a further 1-3 days in NbActiv4 media (Fisher Scientific) supplemented with mouse macrophage colony-stimulating factor (MCSF, 40 ng/rnL). Calcium flux assays were then performed using a high-throughput fluorometric imaging plate reader (Molecular Devices).
  • Table 2 lists the ICso for various compounds of the present disclosure as measured by C3aR P-arrestin recruitment assays.
  • the ICso and Emax expressed as a percentage reduction of the maximum value of the agonist effect, were determined for inhibtion of both human (h C3aR) and mouse (m C3aR) C3aR for Compounds as well as the similar values determined for the mouse Calcium flux assay (m C3aR Ca Flux) .
  • m C3aR Ca Flux mouse Calcium flux assay
  • Table 2 tit will be understood that in the event of any inconsistency in the smiles string, compound number, compound structure or 1UPAC nomenclature, each compound will be embraced by the disclosure. Unless otherwise indicated, the data in Table 2 relates to the compound having the indicated smiles string (and any specific stereoisomeric forms associated such structure).
  • COMPOUND 29 Synthesized according to procedure B, title compound was afforded as a light brown solid (70 mg, 30% yield) as a racemic mixture.
  • COMPOUND 75 (Isomer 1): white solid (11.1 mg, 99.55% purity, 22% yield).
  • COMPOUND 75 (Isomer 2): white solid (13 mg, 99.55% purity, 26% yield).
  • COMPOUND 43 Synthesized according to procedure B, title compound was afforded as a white solid (7.0 mg, 99.27% purity, 3% yield).
  • reaction progress was monitored by LCMS and TLC (5% MeOH/DCM), after completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution, diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate, fdter and concentrated under reduced pressure to get crude.
  • COMPOUND 58 Synthesized according to procedure carb red, title compound was afforded as a white solid (42 mg, 99.78% purity, 18% yield).
  • COMPOUND 82 Synthesized according to procedure carb red, title compound was afforded as a white solid (14 mg, 99.11% purity, 53% yield).
  • COMPOUND 102 Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (25.4 mg, 98.13% purity, 28.4% yield).
  • COMPOUND 103 Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (26.3 mg, 96.16% purity, 29.4% yield).
  • Reaction mixture was cooled to ambient temperature, filtered through celite, and washed with methanol (50 mL). The solvent was removed under reduced pressure and obtained residue was dissolved in water (30 mL) and extracted with EtOAc (30x3 mL). The organic layers were combined and dried over sodium sulphate and concentrated under vacuum.
  • the crude product was purified by column chromatography using 230-400 mesh size silica (Column size; 50 g, Flow rate; 40 mL/min, UV; 254 nm) and 0 to 60% EtOAc in hexane as a mobile phase to give title compound N-(4- imidazo[l,2-a]pyridin-2-ylphenyl)-3,4-dimethyl-aniline, (450 mg, 1.37 mmol, 95.71% purity, 75% yield) as an off-white solid.
  • COMPOUND 158 Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (27.3 mg, 99.26% purity, 28% yield).
  • HATU 160 mg, 0.420 mmol, 1.50 eq
  • DIPEA 0.15 mL, 0.841 mmol, 3.00 eq
  • 2- methoxy-5-(trifluoromethoxy)benzoic acid 66 mg, 0.280 mmol, 1.00 eq
  • 4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2- yl)aniline:hydrochloride 70 mg, 0.280 mmol, 1.00 eq
  • the reaction mixture was concentrated under reduced pressure and purified directly by prep HPLC to afford the title compound, (52 mg. 0. 120 mmol, 99.89% purity. 43% yield) as white solid.
  • COMPOUND 129 Synthesized according to HATU procedure to furnish the title compound as a white solid (52 mg, 99.87% purity, 53% yield).
  • reaction mixture 100 eq
  • Ruphos 1362 mg, 2.92 mmol, 0.200 eq
  • reaction mixture was filtered through cehte and the filtrate was evaporated under reduced pressure to get crude, which was purified with silica gel column chromatography to get N-(6-imidazo[l,2- a] pyri din-2-yl-3 -pyridyl)- 1,1 -di phenyl-methanimine, (2.50 g, 6.68 mmol, 46% yield).

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Abstract

Compounds which effect the Complement cascade by, for example, inhibition of the C3aR receptor are provided. The compound may have the structure of Formula (I). The disclosure further provides methods of use of these compounds, kits and compositions comprising these compounds, and synthetic methods involving these compounds.

Description

COMPLEMENT CASCADE INHIBITORS
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims priority to and the benefit of U.S. App. No. 63/549,379, filed February 2, 2024, which is hereby incorporated by reference in its entirety.
SEQUENCE LISTING
This application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The Sequence Listing XML file, created on January 31, 2025, is named ''167741-027001PCT-SL.xml” and is 4,096 bytes in size.
BACKGROUND
The Complement system is a phylogenetically old system of enzymes and other proteins that most likely evolved to protect organisms against microbial assault. Complement activation is a prominent feature of the inflammatory response in a variety of diseases, disorders, and conditions such as Alzheimer's disease ansd schizophrenia, and is apparently- triggered by the presence of senile plaques. The triggering of the Complement system involves the sequential activation of numerous proteins by a cascade effect. The Complement cascade is best defined as a series of binding and cleavage events wherein active forms of Complement proteins are produced, which in turn act upon each other, often by proteolysis, to produce further active proteins and protein fragments, and complexes thereof. These produced active proteins, protein fragments, and complexes then interact with immune system components, or with cellular debris, endogenous or foreign macromolecules, or invading cells which are then targeted for destruction.
During Complement activation, Complement protein C3 is proteolytically cleaved, resulting in a large fragment (C3b) and the smaller 77 residue peptide, C3a. C3a is known to regulate vasodilation increasing the permeability of small blood vessels, induce contraction of smooth muscles, induce oxidative burst, regulate cytokine release, and stimulate chemotaxis, depending on the involved cells, all inflammation related events. Target cells- include macrophages, neutrophils, eosiniphils, basophils, T-lyphocytes and mast cells, all having important immune and inflammation related functions.
Receptors for C3a are expressed on a variety of macrophages and macrophage cell lines. Functionally, C3a binding to C3a receptors in macrphages causes a mobilization of intracellular calcium ions, and leads to both chemotaxis and respiratory burst, which are both host defense mechanism that generate high levels of cytotoxic superoxide. Again, although such mechanisms are useful in protecting against invading bacterial cells, for example, the triggering of such defense mechanism against normal cells (such as brain neurons that happen to be proximal to the site of plaque formation) is devastating to normal brain function. Similar disadvantageous results operate in regard of other inflammatory’ conditions.
The Complement system can be activated through three distinct pathways: the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is usually triggered by antibody bound to a foreign particle (i.e., an antigen) and thus requires prior exposure to that antigen for the generation of specific antibody. Since activation of the classical pathway is associated with development of an immune response, the classical pathway is part of the acquired immune system. In contrast, both the lectin and alternative pathways are independent of clonal immunity and are part of the innate immune system. The first step in activation of the classical pathway is the binding of a specific recognition molecule, Clq, to antigen-bound IgG and IgM. The activation of the Complement system results in the sequential activation of serine protease zymogens. Clq is associated with the Clr and Cis serine protease proenzymes as a complex called Cl and. upon binding of Clq to an immune complex, autoproteolytic cleavage of the Arg-Ile site of Clr is followed by Clr activation of Cis, which thereby acquires the ability to cleave C4 and C2. The cleavage of C4 into two fragments, designated C4a and C4b, allows the C4b fragments to form covalent bonds vxi th adjacent hydroxy or amino groups and the subsequent generation of C3 convertase (C4b2b) through noncovalent interaction with the C2b fragment of activated C2. C3 convertase (C4b2b) activates C3 leading to generation of the C5 convertase (C4b2b3b) and formation of the membrane attack complex (C5b-9) that can cause microbial lysis. The activated forms of C3 and C4 (C3b and C4b) are covalently deposited on the foreign target surfaces, which are recognized by Complement receptors on multiple phagocytes. Complement components also include cell-bound receptors for soluble complement components. Such receptors include, e.g., C5a receptor (C5aR), C3a receptor (C3aR), Complement Receptor 1 (CR1), Complement Receptor 2 (CR2), Complement Receptor 3 (CR3), etc.
The C3a receptor (C3aR) belongs to the rhodopsin family of G protein-coupled receptors. Traditionally. C3aR was thought to be present only on myeloid cells, such as macrophages, eosiniphils and mast cells. However, the demonstration that C3aR receptor messenger RNA is expressed throughout the body (and in particular in the adrenal gland, pituitary gland, and the central nervous system) is consistent with participation of C3a in a wide variety of cellular process and mediate numerous disease states. Recently, C3a receptor- immunoreactivity has been detected in areas of inflammation in multiple sclerosis and bacterial meningitis patients.
The Complement system has been implicated as contributing to the pathogenesis of numerous acute and chronic disease states, including Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury', epilepsy, haemolytic uraemic syndrome. C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions In almost all of these conditions, Complement is not the cause but is one of several factors involved in pathogenesis. Nevertheless, Complement activation may be a major pathological mechanism and represents an effective point for clinical control in many of these disease states. The importance of Complement-mediated tissue injury' in a variety of disease states underscores the need for effective complement inhibitory drugs.
SUMMARY
In accordance with the foregoing objectives and others, the present disclosure provides compounds which inhibit the Complement cascade (e.g., by inhibiting C3aR).
The compound may have the structure of formula (I): wherein A is C, CR, CR2, ary l (e.g., C6-C10 ary l), heteroaryl (e.g.. 5-10 membered heteroaryl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl); X1 is CR or N;
X2 is CR or N;
X3 is CR2 or NR;
Li is absent (i.e., it is a bond) or -C=C-;
L2 is absent (i.e., it is a bond), -C=C-, -(C(R)2)I-4 - NR-, or -O-: n is an integer from 0-16 (e.g.. 1, 2, 3. 4. 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16);
Ri and R2 are independently hydrogen or alkyl (e.g., C1-C8 alkyl, C1-C4 alkyl, methyl), and wherein Ri and R2 may together (with X3) form an optionally aromatic five or six membered fused ring (cycloalkyl (e.g., C5-Ce membered cycloalkyl ring), aryl (e.g., phenyl), heterocycloalkyl or heteroaryl ring (e.g., 5 to 6 membered heterocycloalkyl ring, 5 to 6 membered heteroaryl ring)), wherein R1, R2, and the fused ring may be optionally substituted (e.g.. from one to three times) with, for example, -R, -C(O)R, -C(O)OR. -NHC(O)R. - NRR, -(CRR)I-4NHCOR, -(CRR)I-4NHS(O)2R, heteroaryl (e.g., 5-10 membered heteroaryl such as triazolyl) optionally substituted with R, heterocycloalkyl (e.g., 5-10 membered heterocycloalkyl) optionally substituted with R;
R3 is independently at each occurrence hy drogen or R, and two Rs groups may together form an optionally substituted spiro, fused, or bridged ring (e.g., 3 to 6 membered cycloalkyl ring), wherein R3 and the spiro, fused, or bridged ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR, -NHC(O)R, -NRR, -(CRR)i- 4NHCOR;
R4 is hydrogen, alkyl (e.g.. C1-C8 alkyl, C1-C5 alkyl, lower alkyl such as C1-C4 alkyl, methyl, ethyl, propyl such as isopropyl, butyl, pentyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), aryl (e.g., C6-C10 aryl, phenyl), heteroaryl (e.g., 5-10 membered heteroaryl, pyridinyl, pyrazolyl, indazolyl), cycloalkyl (e.g., C3-C10 cycloalky l, saturated cycloalky l, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl. unsaturated C3-C10 cycloalkyl. cyclopropyl, cyclobutyl, cyclopenyl. cyclohexyl), or heterocycloalkyl (e.g.. C3-C10 heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl, pyranyl, piperidinyl, pyrrolidinyl, azetidinyl), wherein R4 may be optionally substituted (e.g., from one to three times) with, for example, - R, -C(O)R, -C(O)OR. -NHC(O)R, -NRR, -(CRR)I-4NHC(0)R; and
R is independently at each occurrence hydrogen, halo (e.g., F, Cl), cyano, -NH2, hydroxy, =0, alkoxy (e.g.. C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkyl (e.g., C1- Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), aryl (e.g., C6-C10 and), or perhaloalkyl (e.g, C1-C4 perhaloalkyl such as C1-C4 perfluoroalkyl including perfluoromethyl), wherein R may be optionally substituted (e.g., from one to three times) with halo (e.g., F, Cl), hydroxy, cyano, -NH2, alkyl (e.g., C1-C8 alkyl, lower alkyd such as C1-C4 alkyl, methyl) and/or alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy , methoxy ); or a pharmaceutically acceptable salt thereof (e.g, p-toluenesulfonic acid salt, hydrochloride salt, dihydrochloride salt, methylbenzenesulfonate salt, lithium salt). In some embodiments, the compound or pharmaceutically acceptable salt thereof is not
N-[5-(3',4'-Dimethylbiphenyl-4-yl)-2-methyl-2H-pyrazol-3-yl]methylamine,
2-Methyl-5-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-2H-pyrazol-3- ylamine,
6-(3',4'-Dimethylbiphenyl-4-yl)-2,3-dihydro-lH-imidazo[1.2-b]pyrazole,
3-(3',4'-Dimethylbiphenyl-4-yl)-l,5-dimethyl-lH-pyrazole
3-(3',4'-Dimethylbiphenyl-4-yl)-l-methyl-lH-pyrazole
5-(3',4'-Dimethylbiphenyl-4-yl)-2-methyl-2H-pyrazol-3-ylamine
3-(4'-ethyl[ 1, 1 '-biphenyl]-4-yl)-l-methyl-lH-Pyrazol-5-amine l-[4-(5, 6,7, 8-Tetrahydroimidazo[l,2-a]pyri din-2 -yl)phenyl]-3-(trifluoromethyl)-lH- pyrazole-4-methanol, ethyl 1 -(4-imidazo[l ,2-a]pyridin-2-ylphenyl)-3-(trifluoromethyl)-l H-pyrazole-4- carboxylate,
(7S)-5,6,7,8-Tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridine-7-methanol,
5,6,7,8-Tetrahydro-2-[4-[4-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]phenyl]imidazo[l,2-a]pyridine, 2-[4-[4-Methyl-5-(trifluoromethyl)-2-oxazolyl]phenyl]imidazo[l,2-a]pyridine,
1 -Methyl-6- [4-[ 1 -methyl-5-(trifluoromethyl)- 1 H-py razol-3-y 1] phenyl] - 1 H- imidazo[l,2-a]imidazole-2-methanol,
1-methyl-6-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]- 1H- imidazo[ 1 ,2-a] imidazole,
3-Methyl-5-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-3H- imidazof 1,2-b] [ 1 ,2,4]triazole-2-methanol,
6-(2,5-Dimethyl-lH-pyrrol-l-yl)-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazoll,2-ajpyridine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-6-(2H-tetrazol-5- yl)imidazo[ 1 ,2-b]py ridazine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[1.2- b]pyridazine-6-carbonitrile,
3-[2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridin-
6-y 1] - 1 ,2,4-oxadi azol -5 (2H)-one,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-6-(2H-tetrazol-5- yl)imidazo[l,2-a]pyridine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine-
6-carbonitrile,
2,3-Dihydro-6-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[2,l- b] thiazole, a-Methy l-2-[4-[ 1 -methy l-5-(trifluoromethy 1)- 1 H-py razol-3 -y 1] pheny l]imidazo [1,2- a]pyridine-7-methanol.
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine-
7-methanol,
5.6.7,8-Tetrahydro-a-methyl-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[1.2-a]pyridine-6-methanol. a-Methyl-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[1.2- aJpyridine-6-methanol, 2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine- 6-carboxaldehyde,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-b]pyridazin-
6-amine,
6-Chloro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2- b]pyridazine,
5.6.7.8-Tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridine-6-methanol,
2-[4-tl-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazoll,2-aJpyridine-
6-methanol,
2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridine-6- carboxylic acid ethyl ester,
5-(4-(imidazo[l,2-a]pyridin-2-yl)phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester
2-[4-[l-ethyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-5,6,7,8-tetrahydro- imidazo[l,2-a]pyridine,
2-[4-[l-ethyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-imidazo[l,2-a]pyridine,
5.6.7.8-Tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridine,
2-[4-[5-(Trifluoromethyl)-4-methyloxazol-2-yl]phenyl]-imidazo[l,2-a]pyridine,
2-[4-(5-Methylthien-2-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
2-[4-(5-Ethylthien-2-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
2-[4-(4-Ethylthien-2-yl)phenyl]-5.6.7.8-tetrahydroimidazo[l,2-a]pyridine,
[ 1 -Methy 1-6- [4-( 1 -methy 1-5-trifluoromethyl- lH-pyrazol-3-yl)phenyl]- 1 H- imidazo[l,2-a]imidazol-2-yl]methanoL l-Methyl-6-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-lH-imidazo[l,2- a]imidazole,
[3-Methyl-5-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-3H- imidazo[l,2-b]-[l,2,4]triazol-2-yl]methanol, tetr ahydro-N-[[5, 6,7, 8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[1.2-a]pyridin-6-yl]methyl]- 3 -thiopheneacetamide,
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[1.2-a]pyridin-6-yl]methyl]- 3-pyridinecarboxamide
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridin-6-yl]methyl]-lH-Pyrrole-2-carboxamide, 4- methylbenzenesulfonate (1:2)
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridin-6-yl]methyl]-cyclopropanecarboxamide,
[[2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5,6,7,8- tetrahydroimidazo[l,2-a]pyridin-6-yl]methyl]amine,
N-[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridin-6-yl]-acetamide,
5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]- imidazo[l,2-a]pyridin-6-amine,
2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-imidazo[l,2-a]pyridin-6- amine,
N-[2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridin- 6-yl]acetamide
[2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyri din-7- yl] methanol,
2-[4-(l -Methyl-5-trifluoromethyl- lH-pyrazol-3-yl)phenyl]-5, 6,7,8- tetrahy droimidazo[ 1 ,2-b]pyridazine,
2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[1.2-b]pyridazine.
6-Amino-2-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[1.2- b]pyridazine,
2-[4-(l-Ethyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5.6.7.8- tetrahy droimidazo[ 1 ,2-a]pyridine,
2-[4-(l-Ethyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazoll,2-a]pyridine, 2-[4-(l -Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5, 6,7,8- tetrahy droimidazo[ 1.2-a]pyridine, or
2-[4-[l-Methyl-5-lrifluoromelhyl-lH-pyrazol-3-yl]phenyl]imidazo[1.2-a]pyridine;
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-lH-imidazo[l,2-a]imidazole,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine-6- methanamine,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine-6- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6.7.8-tetrahydroimidazo[l,2-a]pyridine-7- methanol,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine-6-carboxamide,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine-7-methanol,
2-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y l)imidazo[ 1 ,2-a] pyridine-6-methanol,
2- [ 1 , 1 '-Biphenyl] -4-y 1-7 -(methoxy methy l)imidazo [ 1 ,2-a] pyridine,
2-[l,r-Biphenyl]-4-ylimidazo[l,2-a]pyridine-7-methanol,
2-[l,l'-Biphenyl]-4-yl-7-ethylimidazo[l,2-a]pyridine,
Ethyl 6-(3 '.4'-dimethyl [1,1 '-biphenyl] -4-yl )imidazo[2.1 -b] thiazole-3-acetate.
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[2,l-b]thiazole-3-ethanol,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-2,3-dihydroimidazo[2,l-b]thi azole,
2-[l,r-Biphenyl]-4-ylimidazo[l,2-a]pyridine-7-carbonitrile,
2-[l,l'-Biphenyl]-4-yl-7-(2H-tetrazol-5-yl)imidazo[l,2-a]pyridine,
3-[2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridin-6-yl]-l,2,4-oxadiazol-
5(2H)-one,
2-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y l)imidazo[ 1 ,2-a] pyridine,
3-Ethyl-6-(4-imidazo[l, 2-a]pyri din-2 -ylphenyl)-l-methyl-lH-indazole,
2-[4-(3,4-Dihydro-lH-2-benzopyran-7-yl)phenyl]imidazo[l,2-a]pyridine,
2-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridine, 2-[4-(2,3-Dihydro-l,4-benzodioxin-6-yl)phenyl]imidazo[l,2-a]pyridine,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-6-(2H-tetrazol-5-yl)imidazo[l,2-a]pyridine,
2-[l,l'-Biphenyl]-4-yl-6-(2H-tetrazol-5-yl)imidazo[l,2-a]pyridine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine-6-carbonitrile,
2-[l,r-Biphenyl]-4-ylimidazo[l,2-a]pyridine-6-carbonitrile,
6-Bromo-2-(3'.4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[1.2-a]pyridine.
2-[ 1, 1 '-Biphenyl]-4-yl-7-(4-morpholinyl)imidazo[ 1.2-a]pyridine,
2-[(2-[l J'-Biphenyl]-4-ylimidazo[1.2-a]pyridin-6-yl)amino]ethanol,
6-(l-Aziridinyl)-2-[l,r-biphenyl]-4-ylimidazo[l,2-a]pyridine,
2-[l, l'-Biphenyl]-4-yl-N-(2 -methoxy ethyl)imidazo[l,2-a]pyridin-6-amine,
2-[l J'-Biphenyl]-4-yl-6-bromoimidazo[l,2-a]pyridine,
2- [ 1 , 1 '-Biphenyl] -4-y l-6-(4-morpholinyl)imidazo[ 1 ,2-a]pyridine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazol-2- amine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- carboxamide,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- carboxylic acid,
2-[5-(3',4'-Dimethylbiphenyl-4-yl)-3-methyl-377-imidazo[l,2-6]-[l,2,4]triazol-2- yl]propan-2-ol,
1-[5-(3 ',4'-Dimethylbiphenyl-4-yl)-3-methyl-3/7-imidazo[l,2-Z>]-[l, 2, 4]tri azoleyl] ethanol,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- methanamine,
2-(3-Fluoro-3',4'-dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[1.2- b]pyridazine-7-methanol,
2-[6-(3.4-Dimethylphenyl)-3-pyridazinyl]imidazo[l,2-b]pyridazin-6-amine,
2-[2-(3.4-Dimethylphenyl)-5-pyrimidinyl]imidazo[l,2-b]pyridazin-6-amine, 5-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- methanol,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-a-methylimidazo[l,2-b]pyridazine-6-methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-6-(4-methyl-l-piperazinyl)imidazo[l,2- b]pyridazine.
2-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-y l)-6-( 1 -piperidinyl)imidazo[ 1 ,2-b] py ridazine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-(4-morpholinyl)imidazo[l,2-b]pyridazine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-hydrazinylimidazo[l,2-b]pyridazine,
N-[(2,4-Dimethoxyphenyl)methyl]-2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2- b] pyridazin-6-amine,
6-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-l-ethyl-lH-imidazo[l,2-a]imidazole,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridin-6-amine,
2-(3',4'-Dimethyl[l ,1 '-biphenyl]-4-yl)-a,a-dimethylimidazo[l ,2-a]pyridine-6- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- a]pyridine,
2-[3',4'-Bis(trifluoromethyl)[l,l'-biphenyl]-4-yl]-5,6,7,8-tetrahydroimidazo[l,2- a]pyridine,
5.6.7.8-Tetrahydro-2-[4'-methyl-3'-(trifluoromethyl)[l,r-biphenyl]-4-yl]imidazo[l,2- a]pyridine,
5.6.7.8-Tetrahydro-2-[3'-methyl-4'-(trifluoromethyl)[l,r-biphenyl]-4-yl]imidazo[l,2- a]pyridine,
6-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-yl)- 1 -methyl- IH-imidazo [2, 1 -c] - 1 ,2,4-triazole,
2-(3-Fluoro-3',4'-dimethyl[l,r-biphenyl]-4-yl)-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- a]pyridine,
5-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole,
5-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-2,3-dimethyl-3H-imidazo[l,2-b][l,2,4]triazole,
2-[4-(2,3-Dihydro-lH-inden-5-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine, 2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-c]pyrimidin-7-amine,
2-(3'.4'-Dimethyl| I . I '-biphenyl |-4-yl)-a-methylimidazo| l.2-b|pyridazinc-7-mcthanol.
2-(3 \4'-Dimethyl [ 1 , l'-bipheny 1] -4-y l)imidazo [ 1 ,2-b] pyridazine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[l,2-b]pyridazine-6- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyrimidin-7-amine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[l,2-b]pyridazine-7- methanol,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-7,8-dihydro-6-methylimidazo[l,2-c]pyrimidin-
5(6H)-one,
6-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y l)imidazo[ 1 ,2-b] [ 1 ,2,4]triazine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-8-fluoroimidazo[l,2-c]pyrimidin-5(6H)-one,
2-(3-Fluoro-3',4'-dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-b]pyridazin-6-amine,
6-Chloro-2-(3'.4'-dimethyl[l,r-biphenyl]-4-yl)imidazo[1.2-b|pyridazine.
2-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y l)imidazo [ 1 ,2-b] pyridazin-6-amine,
6-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-y 1)- IH-imidazo [ 1 ,2-a] imidazole- 1 -ethanol,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6-dihydro-3-methylimidazo[5,l-b]oxazole,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[2,l-b]-l,3,4-thiadiazole,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[2,l-b]thiazole,
6-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-l-methyl-lH-imidazo[2,l-c]-l,2,4- tri azole,
5-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-2,3-dimethyl-3H-imidazo[l,2- b][l,2,4]triazole,
6-(3-Fluoro-3 ',4'-dimethyl [1,1 '-biphenyl] -4-y 1)- 1 -methy 1- lH-imidazo[ 1 ,2- a]imidazole,
5-(3-Fluoro-3',4'-dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2- b][l,2,4]triazole,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-2-methylimidazo[2,l-b]-l,3,4-thiadiazole, Ethyl 2-(3',4'-dimethyl[l,T-biphenyl]-4-yl)imidazo[1.2-a]pyridine-6-carboxylate,
2-[l,r-Biphenyl]-4-yl-7-chloroimidazo[l,2-a]pyridine,
N-[[2-(3',4'-dimethyl[l,T-biphenyl]-4-yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-6- y 1] methyl] - Acetami de, 6-(3',4'-dimethyl[l,r-biphenyl]-4-yl)-imidazo[2,l-b]thiazole-3-ethanol
6-(3',4'-dimethyl[l,r-biphenyl]-4-yl)-2,3-dihydro-imidazo[2,l-b]thiazole,
2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)- imidazo[l,2-a]pyridine-6-carboxylic acid,
2-(3'-fluoro-4'-methyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-(2'-fluoro-4'-methyl[ 1 , 1 '-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l ,2-a]pyridine
5,6,7, 8-tetrahydro-2-(3'-methyl[l,T-biphenyl]-4-yl)-imidazo[l,2-a]pyri dine,
2-(3'-fluoro-4',5'-dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-(4'-chloro-3'-methylll.l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-[4-(l,3-benzodioxol-5-yl)phenyl]-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridine,
2-(3'-ethyl[l.l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro-imidazo[1.2-a]pyridine,
2-[2'-fluoro-4'-(l-methylethyl)[l,T-biphenyl]-4-yl]-5.6.7.8-tetrahydro-imidazo[l,2- a]pyridine, or a pharmaceutically acceptable salt (e.g., p-toluenesulfonic acid salt, hydrochloride salt, dihydrochloride salt, methylbenzenesulfonate salt, lithium salt) thereof.
The compound may have the structure of formula (la): wherein the dotted circle indicates optional aromaticity; and
X4 is CR or N. For example, the compound may have the structure of formula (lai) or (Ia2): wherein the dotted circle indicates optional aromaticity.
In some embodiments, the compound has the structure of formula (lb): wherein the dotted circle indicates optional aromaticity; and X4 is CR or N. In some embodiments, the compound has the structure of formula (Ic): wherein the dotted circle indicates optional aromaticity;
X4 is CR or N; and optionally R4 is hydrogen, alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl. In certain aspects, the compound has the structure of formula (Id): wherein the dotted circle indicates optional aromaticity; X4 is CR or N; and optionally R4 is hydrogen, alkyl, ary l, cycloalkyl, heterocycloalkyl, or heteroaryl. Ri and R2 may be independently alkyl (e.g., lower alkyl such as C1-C4 alkyl, methyl, ethyl, butyl) optionally having one, two or three independent points of substitution such as R which may be independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halo, alkoxy, perfluoroalkoxy, amino, fluoroalkyl such as perfluoroalkyl, acyl (e.g., -COOR* where R* is lower alkyl, hydroxy),. In some embodiments, R4 is cycloalkyl (e.g., C3-C10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) optionally having one, two or three points of substitution (e.g., monosubstitution, geminal substitution, vicinal substitution) such as R which may include alkyl (e.g., lower alkyl substitution such as C1-C4 alkyl, methyl) substitution. In some implementations, R4 is and (e.g., phenyl) optionally having one, two or three points of substitution (e.g., monosubstitution, geminal substitution, vicinal substitution) such as R which may include alkyl (e.g., lower alkyl such as C1-C4 alkyd, methyl) substitution. In various implementations R4 is independently substituted one or more times (e.g., one, two, three) with R, C(O)R, C(O)OR, NHC(O)R, NRR, (CRR)I-4NHC(O)R, wherein R is independently alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, halo, alkoxy, perfluoroalkoxy, amino, fluoroalkyl such as perfluoroalkyd, or acyl (e.g., -COOR* where R* is lower alkyl, hydroxy). In some aspects, at least one of Li or L2 is not absent. In certain instances, Li is absent. In certain embodiments, the fused ring formed by Ri and R2 contains only one N (e.g., when X3 is NR and the remaining members of the fused ring are all C).
The compound may be:
a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound has an EC 50 such as IC50 (e.g., as measured in a P-arrestin assay or Calcium Flux assay) of human Complement Component 3a Receptor (C3aR) and/or mouse C3aR of less than (or from 1 nM to) 20pM (e.g., less than 10 pM, less than 5 pM, less than 2 pM, less than 1 pM, less than 500 nM, less than 200 nM).
Pharmaceutical compositions are also provided comprising a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), Compound 1- 170) comprising a pharmaceutically acceptable excipient and the compound. The pharmaceutical composition may be an injectable composition or an oral composition.
Methods of using the compounds are also provided. In some embodiments, a method of inhibiting the Complement Component 3a Receptor (C3aR) (or inhibiting the Complement cascade) in a cell may comprise contacting the cell with the compound of the present disclosure (e.g., a compound of formula (I), (la), (lai), (Ia2) (lb), (Ic), (Id), Compound 1- 170) or a pharmaceutically acceptable salt thereof. In certain aspects, the cell is a plasma cell, brain cell, or cerebral spinal fluid (CSF) cell. In some embodiments, the cell is in vivo, ex vivo, or in vitro.
A method of treating the excessive Complement activation (or inhibiting C3aR) in a subject in need thereof is also provided comprising administering a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1- 170) to the subject. The subject may have a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory' disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis. Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions. In certain aspects, the subject has a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s chorea, Pick’s disease, Guillian Barre syndrome, encephalitis, meningitis, stroke. Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection and hemorrhagic stroke.
For example, methods of treating Alzheimer’s disease in a subject in need thereof are provided comprising administering a compound of the present disclosure (e.g., a compound of formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id), Compound 1-170) or a pharmaceutically acceptable salt thereof (or the pharmaceutical composition) to the subject.
The compound (e.g., a compound of formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), Compound 1-170) or the pharmaceutical composition comprising the compound may be administered by intraperitoneal (IP) injection, intravenous (IV) injection, subcutaneous (SC) injection, or orally (PO). In certain aspects, the compound is administered in an amount of from 1 mg/kg-40 mg/kg (e.g., from 3 mg/kg to 30 mg/kg, from 5 mg/kg-15 mg/kg).
Definitions
All terms used herein are intended to have their ordinary meaning in the art unless otherwise provided. All concentrations are in terms of percentage by weight of the specified component relative to the entire weight of the topical composition, unless otherwise defined.
As used herein, “a” or “an” shall mean one or more. As used herein when used in conjunction with the word “comprising,” the words “a” or “an” mean one or more than one. As used herein “another"’ means at least a second or more. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive.
As used herein, all ranges of numeric values include the endpoints and all possible values disclosed between the disclosed values. The exact values of all half-integral numeric values are also contemplated as specifically disclosed and as limits for all subsets of the disclosed range. For example, a range of from 0.1% to 3% specifically discloses a percentage of 0.1%, 1%, 1.5%, 2.0%, 2.5%, and 3%. Additionally, a range of 0.1 to 3% includes subsets of the original range including from 0.5% to 2.5%, from 1% to 3%. or from 0.1% to 2.5%. It will be understood that the sum of all weight % of individual components will not exceed 100%.
Throughout this description, various components may be identified having specific values or parameters, however, these items are provided as exemplary embodiments. Indeed, the exemplary embodiments do not limit the various aspects and concepts of the present disclosure as many comparable parameters, sizes, ranges, and/or values may be implemented. Unless otherwise specified, the terms “first,” “second,” and the like, “primary,” “secondary,” and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another.
By “agent” is meant a compound (e.g., small compound), polypeptide or polynucleotide.
By “ameliorate” is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.
By “consist essentially” it is meant that the ingredients include only the listed components along with the normal impurities present in commercial materials and with any other additives present at levels which do not affect the operation of the disclosure, for instance at levels less than 5% by weight or less than 1% or even 0.5% by weight.
By “disease” is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Typically, the diseases, disorders, or conditions described are those associated with excessive Complement activation. Examples include Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Bane syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory' demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions.
By “complement C3a receptor polypeptide” or “C3aR polypeptide” is meant a protein or fragment thereof having at least about 85% amino acid sequence identity to NCBI Reference Sequence NP_001313404.1 and/or being an anaphylatoxin released during activation of the complement system. The protein encoded by this gene is an orphan G protein-coupled receptor for C3a. An exemplary C3aR amino acid sequence follows:
1 masfsaetns tdllsqpwne ppvilsmvil sltf llglpg nglvlwvagl kmqrtvntiw
61 flhltladll cclslpf sla hlalqgqwpy grflcklips iivlnmfasv f lltaisldr 121 clvvfkpiwc qnhrnvgmac sicgciwvva fvmcipvfvy reif ttdnhn rcgykfglss 181 sldypdfygd plenrsleni vqppgemndr Idpssfqtnd hpwtvptvfq pqtfqrpsad 241 slprgsarlt sqnlysnvfk padwspkip sgfpiedhet spldnsdafl sthlklfpsa 301 ssnsfyesel pqgfqdyynl gqftdddqvp tplvaititr Ivvgfllpsv imiacysfiv 361 frmqrgrfak sqsktfrvav vvvavflvcw tpyhifgvls lltdpetplg ktlmswdhvc 421 ialasanscf npf lyallgk dfrkkarqsi qgileaaf se eltrsthcps nnvisernst 481 tv
(SEQ ID 1).
The term “effective amount” or “therapeutically effective amount” of an agent is meant the amount of an agent (e.g, a compound described herein) required to ameliorate the symptoms of a disease relative to an untreated patient. The effective amount of active compound(s) used for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian may decide the appropriate amount and dosage regimen. Such amount is generally referred to as an “effective” amount. Agents described herein include compounds having the structure of Formula (I), (la), (lai ), (Ia2), (lb), (Ic), (Id) one or more of Compounds 1-170. In some embodiments, the compounds are administered in an effective amount for the treatment of a disease disorder or condition.
The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein formulated with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gel cap); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g, as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein (see below).
As used herein, the phrase “pharmaceutically acceptable’' indicates a component generally safe for ingestion or contact with biologic tissues at the levels employed. Pharmaceutically acceptable is used interchangeably with physiologically compatible. It will be understood that the pharmaceutical compositions of the disclosure include nutraceutical compositions (e.g, dietary supplements) unless otherwise specified.
By “reference” is meant a standard or control condition.
Ranges provided herein are understood to be shorthand for all of the values within the range including the endpoints of the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.
As used herein, the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
By “subject” is meant a mammal, including, but not limited to, a human or nonhuman mammal, such as a bovine, equine, canine, ovine, or feline. Typical subjects include any animal (e.g, mammals such as mice, rats, rabbits, non-human primates, and humans). A subject in need thereof is typically a subject for whom it is desirable to treat a disease, disorder, or condition as described herein. For example, a subject in need thereof may seek or be in need of treatment, require treatment, be receiving treatment, may be receiving treatment in the future, or a human or animal that is under care by a trained professional for a particular disease, disorder, or condition.
The term “substituent” refers to a group “substituted” on a hydrocarbon, e g, an alkyl, at any atom of that group, replacing one or more atoms therein (e.g., the point of substitution) including hydrogen atoms. In some aspects, the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent. In another aspect, a substituent may itself be substituted with any one of the substituents described herein. Substituents may be located pendant to the hydrocarbon chain. In addition, the phrase “substituted with a[n],” as used herein, means the specified group may be substituted with one or more of any combination substituents as described in the present application. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C 1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl,” the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. Moreover, where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R- substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different (e.g., R is independently at each occurrence hydrogen, halo (e.g., F, Cl), cyano, -NH2, hydroxy, =0, alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkyl (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl), perhaloalkyl (e.g., C1-C4 perhaloalkyl such as C1-C4 perfluoroalkyl including perfluoromethyl), aryl (e.g., C6-C10 aryl), heteroaryl (e.g., 5-10 membered heteroaryl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyd), or heterocycloalkyl (e.g., C3-C10 heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl), wherein R may be optionally substituted (e.g., from one to three times) with halo (e.g., F, Cl), hydroxy, cyano, -NH2, alkyl (e.g., C1-C8 alky l, lower alkyl such as C1-C4 alkyl, methyl) and/or alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy)).
Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.
The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.
Any compound, compositions, or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. DETAILED DESCRIPTION
Compounds of the present disclosure may exhibit activity to inhibit C3aR (and affect the Complement cascade typically reducing activity thereof) and administration thereof may result in the ability to decrease diseases, disorders, or conditions as described herein. Typically, the compounds of the present disclosure are C3aR inhibitors.
Complement inhibitors
The C3aR inhibitors of the present disclosure may be a compound having the structure of formula (I): wherein A is C, CR, CR2, aryl (e.g., C6-C10 ary l), heteroaryl (e.g.. 5-10 membered heteroaryl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyl, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g., 3 to 10 membered heterocycloalkyl, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl);
Xi is CR or N;
X2 is CR or N;
X3 1S CR2 or NR;
Li is absent (i.e., it is a bond) or -C=C-;
L2 is absent (i.e., it is a bond), -C=C-, -(C(R)2)I-4 — NR-, or -O-; n is an integer from 0-16 (e.g.. 1, 2, 3. 4. 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16);
Ri and R2 are independently hydrogen or alkyl (e.g., C1-C8 alkyl, C1-C4 alkyl, methyl), and wherein Ri and R2 may together (with X3) form an optionally aromatic five or six membered fused ring (e.g. cycloalkyl (e.g., C-Ce membered cycloalkyl ring)), aryl (e.g., phenyl), heterocycloalkyl or heteroaryl ring (e.g., 3 to 6 membered heterocycloalkyl ring), 5 to 6 membered heteroaryl ring)), wherein Ri, R2, and the fused ring may be optionally substituted (e.g.. from one to three times) with, for example, -R, -C(O)R, -C(O)OR. -NHC(O)R. - NRR, -(CRR)i-NRCOR, -(CRR)I-4NRS(O)2R, heteroaryl (e.g., 5-10 membered heteroaryl such as triazolyl) optionally substituted with R, heterocycloalkyl (e.g., 5-10 membered heterocycloalkyl) optionally substituted with R;
R3 is independently at each occurrence hydrogen or R, and two R3 groups may together form an optionally substituted spiro, fused, or bridged ring (e.g., 3 to 6 membered cycloalkyd ring), wherein R3 and the spiro, fused, or bridged ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR, -NHC(O)R. -NRR, and/or - (CRR)I-4NHCOR;
R4 is hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), aryl (e.g., C6-C10 aryl), heteroaryl (e.g., 5-10 membered heteroary l), cycloalkyl (e.g., C3-C10 cycloalkyd, saturated cycloalkyl, saturated Cs- C10 cycloalkyd, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g.. C3-C10 heterocycloalkyl. saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl), wherein Ri may be optionally substituted (e.g., from one to three times) with, for example, - R, C(O)R, C(O)OR, NHC(O)R, NRR, and/or (CRR)I-4NHC(O)R; and
R is independently independently at each occurrence hydrogen, halo (e.g., F, Cl), cyano, - NH2, hydroxy, =0, alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkyl (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl) perhaloalkyl (e.g., C1-C4 perhaloalkyl such as C1-C4 perfluoroalkyl including perfluoromethyl), wherein R may be optionally substituted (e.g., from one to three times) with halo (e.g., F, Cl), hydroxy, cyano, - NH2, alkyd (e.g., C1-C8 alkyl, lower alkyd such as C1-C4 alkyd, methyl) or alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy); or a pharmaceutically acceptable salt thereof (e.g, p-toluenesulfonic acid salt, hydrochloride salt, dihydrochloride salt, methylbenzenesulfonate salt, lithium salt). In some embodiments, the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-43 W02007034278A2, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-43. In some embodiments, the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-166 W02007034282A2. which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-166. In some embodiments, the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-51 W02007034277A1, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-51. In some embodiments, the compound or pharmaceutically acceptable salt thereof is not any of Examples 1-47 W02007034279A2, which is hereby incorporated by reference in its entirety and particularly in relation to Examples 1-47.
Cycloalkyl or cycloalkylene groups described may refer to cyclic aliphatic hydrocarbon radical of 3-15 carbon atoms (e.g., 3-12 carbon atoms. 3-8 carbon atoms, 3-6 carbon atoms, or 3-5 carbon atoms, 3-4 carbon atoms). In some embodiments, the cycloalkyl group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein. Cycloalkyl groups may have from 3-12 carbon atoms in the carbon ring. Cycloalkyl groups include monocyclic and multicyclic ring systems such as bicyclic and tricyclic groups. In other embodiments, cyclalkyl groups will have from 3-8 or from from 3-6 or from 3-4 or 3 carbon atoms, including for example, embodiments having three, four, five, six, seven, eight, nine, or ten carbon atoms. Any cycloalkyl or cycloalkydene group may be substituted or unsubstituted. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy l, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Multicyclic groups include, for example, bridged and/or fused ring systems, such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclofl. l. l]pentan-l-yl, adamantyl, norbomyl, decalinyl, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Heterocycloalky l groups or heterocycloalkylene may to cycloalkyl groups (e.g., saturated aliphatic hydrocarbon radicals) with one or more heteroatoms (e.g., N, O. S) in the ring. Heterocycloalkyl groups or heterocycloalkylene groups may have 3-15 atoms in the ring (e.g., 3-12 atoms, 3-8 atoms, 3-6 atoms, or 3-5 atoms, 3-4 atoms). In some embodiments, the hetercyclooalkyl group or heterocycloalkylene group may be substituted with 1, 2, 3, or 4 substituent groups as defined herein.
Aryl or aryelene groups may be aromatic mono-or polycyclic radicals of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalyl, 1,2-dihydronaphthalyl, indanyl, and IH-indenyl. Typically, heteroaryls or heteroary clones include mono-or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing one, two, or three ring heteroatoms selected from N, O. and S, with the remaining ring atoms being C. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, benzooxazolyl, benzoimidazolyl, and benzothiazolyl.
Exemplary heterocycloalkyl or heteroaryl groups include: These groups may include one or more substituents as described herein (e.g., R substituted, alkyl substituted, halogen substituted, hydroxy substituted, amino substituted, alkoxysubstituted, each of which may be further substituted one or more times).
A substituted hydrocarbon group may have as a substituent one or more hydrocarbon radicals, substituted hydrocarbon radicals, or may comprise one or more heteroatoms. Examples of substituted hydrocarbon radicals include, without limitation, heterocycles, such as heteroaryls. Unless otherwise specified, a hydrocarbon substituted with one or more heteroatoms will comprise from 1-20 heteroatoms. In other embodiments, a hydrocarbon substituted with one or more heteroatoms will comprise from 1-12 or from 1-8 or from 1-6 or from 1-4 or from 1-3 or from 1-2 heteroatoms. Examples of heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorous, halogen (e.g, F, Cl, Br, I), boron, or silicon. In some embodiments, heteroatoms will be selected from the group consisting of oxygen, nitrogen, sulfur, phosphorous, and halogen (e.g., F. Cl. Br. I). In some embodiments, a heteroatom or group may substitute a carbon (e.g., substituted alkyl may include heteroalkyl). In some embodiments, a heteroatom or group may substitute a hydrogen. In some embodiments, a substituted hydrocarbon may comprise one or more heteroatoms in the backbone or chain of the molecule (e.g.. interposed between two carbon atoms, as in "oxa'’). In some embodiments, a substituted hydrocarbon may comprise one or more heteroatoms pendant from the backbone or chain of the molecule (e.g., covalently bound to a carbon atom in the chain or backbone, as in "oxo").
Unless otherwise noted, all groups described herein (e.g., alkyl, cycloalkyd, heteroalkyl, heterocycloalkyl, aryl, heteroaryl, alkylene, heteroalkylene, cylcoalkylene, heterocycloalkylene. R1-R4, R. A, Li, L2) may optionally contain one or more substituents, to the extent permitted by valency. Substituents include halogen (e.g., F, Cl), C1-12 straight chain or branched chain alky l, C2-12 alkeny l, C2-i2 alkynyl, C3-12 cycloalky l, Ce-naryl, C3-12 heteroaryl, C3-i2heterocyclyl, C1-12 alkylsulfony l, nitro, cyano, -COOR, -C(O)NRR’, -OR, - SR, -NRR’, and oxo, such as mono-or di-or tri-substitutions with moieties such as halogen, fluoroalkyl, perfluoroalkyl, perfluroalkoxy, trifluoromethoxy, chlorine, bromine, fluorine, methyl, methoxy, pyridyl, furyl, triazyd, piperazinyl, pyrazoyl, imidazoyl, and the like, each optionally containing one or more heteroatoms such as halo, N, O, S, and P. R and R’ are independently hydrogen. C1-12 alkyd, C 1-12 haloalky 1. C2-12 alkenyl, C2-12 alkynyl, C3-12 cycloalkyd. C4-24 cycloalkylalkyl, Ce-naryl, C7-24 aralkyl, Cs-nheterocyclyl. C3-24 heterocyclylalkyl, C3-12 heteroaryl, or C4-24 heteroarylalkyl. Further, as used herein, the phrase optionally substituted indicates the designated hydrocarbon group may be unsubstituted (e.g. substituted with H) or substituted. Typically, substituted hydrocarbons are hydrocarbons with a hydrogen atom removed and replaced by a substituent (e.g., a common substituent). Any hydrocarbon in the present disclosure may be considered substituted or “optionally substituted” with, for example, alky l (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, ethyl, propyl including isopropyl ('Pr). deuterated alkyl or deuterated lower alkyl such as -CD3,). heteroalkyl (e.g., C1-C8 heteroalkyl, lower heteroalkyl such as C1-C4 heteroalkyl), alkoxy substituted alkyl (e.g., Ci-Ce alkyl substituted with Ci-Ce alkoxy such as methoxy), cycloalkyl (e.g., C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkoxy substituted with, for example, aryl (e.g.. benzyloxy), spiro cycloalkyl (C3-C9 cycloalkyl, C3-C5 cycloalkyl, cyclopropyl), haloalkyl (e.g., C1-C8 haloalkyl, lower haloalkyl such as C1-C4 haloalkyl, halomethyl, C1-C8 fluoroalkyl, lower fluoroalkyl such as C1-C4 fluoroalkyl, fluoromethyl, difluoromethy l, perfluoroalky l, C1-C8 perfluoroalkyl, lower perfluoroalkyl such as C1-C4 perfluoroalkyl, perfluoromethyl), halogen (e.g., F, Cl, Br). oxo (=0), amino (e.g.. - NH2, NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl), amide (e.g., -NHC(0)R, -C(0)NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyd), hydroxy, cyano, nitroso, carboxylic acid (-C00H), ester (e.g., -COOR’, where R’ is selected at each occurrence from C1-C8 alkyl, lower alkyl). -C(0)NR’R”, where R’ and R” are independently selected at each occurrence from H and lower alkyl). In some embodiments, a group described herein may be substituted with a protecting group such as tert-butyloxy carbonyl (Boc).
It is understood by one of ordinary skill in the chemistry art that substitution at a given atom is limited by valency. Typically, the use of a substituent (radical) prefix names such as alkyl or alkylene without the modifier optionally substituted or substituted is understood to mean that the particular substituent is unsubstituted unless otherwise indicated. However, the use of haloalkyl without the modifier optionally substituted or substituted is still understood to mean an alkyl group, in which at least one hydrogen atom is replaced by halo. Where a group may be substituted by one or more of a number of substituents, such substitutions are selected so as to comply with principles of chemical bonding with regard to valencies, and to give compounds which are not inherently unstable. For example, any carbon atom will be bonded to two, three, or four other atoms, consistent with the four valence electrons of carbon. Additionally, when a structure has less than the required number of functional groups indicated, those carbon atoms without an indicated functional group are bonded to the requisite number of hydrogen atoms to satisfy the valency of that carbon unless otherwise indicated.
Compounds provided herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbent or eluant). That is, certain of the disclosed compounds may exist in various stereoisomeric forms including stereoisomers, enantiomers, diastereomers, or racemates (z.e., the compound exists as a mixture containing two enantiomers and does not rotate polarized light). Enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well- known techniques and methods, such as chiral chromatography and separation methods based thereon. The appropriate technique and/or method for separating an enantiomer of a compound described herein from a racemic mixture can be readily determined by those of skill in the art.
The compound provided herein may also be present as geometric isomer which differ in the orientation of substituent atoms (e.g, to a carbon-carbon double bond, to a cycloalkyl ring, to a bridged bicyclic system). Atoms (other than H) on each side of a carbon-carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and "‘trans,” indicate configurations relative to the core molecule and may be used to indicate the geometric configuration of the presently disclosed compounds. Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. When a compound having a stereocenter is provided without indication of its chirality, it will be understood that all specific configurations (e.g., (R), (S)) are included as well as mixtures thereof (e.g., racemates).
The compounds disclosed herein may be prepared as individual isomers by either isomer-specific synthesis or resolved from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer may be typically more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is more than 50% (e.g.. at least 55%. 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) optically pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is more than 50% (e.g., at least 55%, 60%, 70%, 80%, 90%, 99%, or 99.9%) by weight (or mole fraction) pure. Percent optical purity is the ratio of the weight of the enantiomer or over the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer or over the weight of all the diastereomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer or over the moles of the enantiomer plus the moles of its optical isomer. Similarly, percent purity by moles fraction is the ratio of the moles of the diastereomer or over the moles of the diastereomer plus the moles of its isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The disclosure embraces all of these forms. Solvates of the compounds described herein may form the aggregate of the compound or an ion of the compound with one or more solvents. Such solvents may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.
The compounds described herein may be present as a pharmaceutically acceptable salt. Typically, salts are composed of a related number of cations and anions (at least one of which is formed from the compounds described herein) coupled together (e.g., the pairs may be bonded ionically) such that the salt is electrically neutral. Pharmaceutically acceptable salts may retain or have similar activity to the parent compound (e.g.. an ED50 within 10%) and have a toxicity profile within a range that affords utility in pharmaceutical compositions. For example, pharmaceutically acceptable salts may be suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19. 1977 and in Pharmaceutically acceptable salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley -VCH, 2008. Salts may be prepared from pharmaceutically acceptable nontoxic acids and bases including inorganic and organic acids and bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, dichloroacetate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glycerophosphate, hemisulfate, heptonate, hexanoate, hippurate, hydrobromide, hydrochloride, hydroiodide. 2-hydroxy -ethanesulfonate, isethionate, lactobionate. lactate, laurate, lauryl sulfate, malate, maleate, malonate. mandelate, methanesulfonate, mucate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pantothenate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and valerate salts. Representative basic salts include alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium, aluminum salts, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, caffeine, and ethylamine.
Pharmaceutically acceptable acid addition salts of the disclosure can be formed by the reaction of a compound of the disclosure with an equimolar or excess amount of acid. Alternatively, hemi -salts can be formed by the reaction of a compound of the disclosure with the desired acid in a 2: 1 ratio, compound to acid. The reactants are generally combined in a mutual solvent such as diethyl ether, tetrahydrofuran, methanol, ethanol, /.so-propanol. benzene, or the like. The salts normally precipitate out of solution within, e.g. one hour to ten days and can be isolated by filtration or other conventional methods.
The compounds of the present invention include the compounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an anion (e.g., halide such as chloride, fluoride, bromide, optionally substituted phosphate, optionally substituted sulfonate, optionally substituted acetate) and a positively charged substituent (e.g., optionally substituted ammonium) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion. magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. A prodrug generally converts into an active compound following administration to a subject, for example through in vivo hydrolysis. Examples of prodrugs include Ci-e alkyl esters of carboxylic acid groups, which, upon administration to a subject, are typically capable of providing active compounds.
The identified hydrocarbon groups in the compounds of the present disclosure (e.g., Ri, R2, R3, R4, R, A, Li, L2) may be optionally substituted one or more times with a substituent as described herein. For example, in some embodiments. R4 is aryl optionally substituted one or more times with a substituent selected from alkyl, alkoxy, halogen, -NRR, -C(O)R, -NRC(O)R, and -C(O)NRR; and any two vicinal substituents may together form a five or six membered ring. Additionally, when the identified group is alkyl, the alkyl group may be optionally unsaturated (e.g., alkenyl).
The compound may be any one of Compounds 1-170 as disclosed in Table 1. or pharmaceutically acceptable salts and/or prodrugs thereof.
Table 1 "Where the stereoconfiguration of any chiral center is not provided, it will be understood that both stereoisomeric configurations (e.g., (R), (S)) are disclosed as well as mixtures thereof (including racemic mixtures). When the stereoconfiguration having multiple chiral centers is not provided, it will be understood that all possible stereoconfigurations are disclosed as well as mixtures of the various enantiomers and/or diastereomers (including racemic mixtures thereof).
In some embodiments, the compound is any Compound in Table 1 including a compound selected from Compounds 1-170, or a pharmaceutically salt or prodrug thereof. Tautomeric, enantiomeric, and diastereomic forms of these compounds, as well as mixtures thereof, are included within the disclosure.
Pharmaceutical Compositions
The compounds described herein (e.g.. C3aR agonists, C3aR inhibitors. Compounds having the structure of Formula (I), (la), (lai), (Ia2) (lb), (Ic), (Id), one or more of Compounds 1-170) are useful for the treatment of a disease, disorder, or condition in a subject in need thereof. The compounds described herein may also be compounds for use in the preparation of a medicament for the treatment of (e.g., a disease caused by) in a subject in need thereof.
Pharmaceutical dosage forms are provided as well, which may comprise a compound of the present disclosure (e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170) and one or more pharmaceutically acceptable carriers, diluents, or excipients.
Unit dosage forms, also referred to as unitary dosage forms, often denote those forms of medication supplied in a manner that does not require further weighing or measuring to provide the dosage (e.g.. tablet, capsule, caplet). The compositions of the present disclosure may be present as unit dosage forms. For example, a unit dosage form may refer to a physically discrete unit suitable as a unitary7 dosage for human subjects and other species, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients. Exemplary, non-limiting unit dosage forms include a tablet (e.g., a chewable tablet), caplet, capsule (e.g., a hard capsule or a soft capsule), lozenge, film, strip, and gel cap. In certain embodiments, the compounds described herein, including crystallized forms, polymorphs, and solvates thereof, may be present in a unit dosage form. Useful pharmaceutical carriers, excipients, and diluents for the preparation of the compositions hereof, can be solids, liquids, or gases. These include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The pharmaceutically acceptable carrier or excipient does not destroy the pharmacological activity of the disclosed compound and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. Thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enterically coated or other protected formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained release formulations, solutions, suspensions, elixirs, and aerosols. The carrier can be selected from the various oils including those of petroleum, animal, vegetable or synthetic origin, e.g.. peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, aqueous dextrose, and glycols are examples of liquid carriers, particularly (when isotonic with the blood) for injectable solutions. For example, formulations for intravenous administration comprise sterile aqueous solutions of the active ingredient(s) which are prepared by dissolving solid active ingredient(s) in water to produce an aqueous solution and rendering the solution sterile. Suitable pharmaceutical excipients include starch, cellulose, chitosan, talc, glucose, lactose, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The compositions may be subjected to conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, and buffers. Suitable pharmaceutical carriers and their formulation are described in Remington’s Pharmaceutical Sciences by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable carrier so as to prepare the proper dosage form for administration to the recipient.
Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate: powdered tragacanth; malt; gelatin; talc; cocoa butter and suppository' waxes; oils such as peanut oil, cottonseed oil, safflower oil. sesame oil. olive oil, com oil and soybean oil; glycols, such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate; coloring agents; releasing agents: coating agents; sweetening, flavoring and perfuming agents; preservatives; antioxidants; ion exchangers; alumina; aluminum stearate; lecithin; self-emulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethyleneglycol 1000 succinate; surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices; serum proteins such as human serum albumin; 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, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; poly acrylates; waxes; and polyethylene-polyoxypropylene-block polymers. Cyclodextrins such as a-, fy, and y-cyclodextrin. or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2-and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of the compounds described herein.
In various embodiments, the compositions of the invention are formulated in pellets or tablets for an oral administration. According to this type of formulation, they comprise lactose monohydrate, cellulose microcrystalline, crospovidone/povidone, aroma, compressible sugar and magnesium stearate as excipients. When the compositions are in the form of pellets or tablets, they are for instance 1 mg, 2 mg, or 4 mg pellets or tablets. Such pellets or tablets are divisible so that they can be cut to suit the posology according to the invention in one or two daily takes. In a further embodiment, the compositions of the disclosure are formulated in injectable solutions or suspensions for a parenteral administration. The injectable compositions are produced by mixing therapeutically efficient quantity of torasemide with a pH regulator, a buffer agent, a suspension agent, a solubilization agent, a stabilizer, a tonicity agent and/or a preservative, and by transformation of the mixture into an intravenous, sub-cutaneous, intramuscular injection or perfusion according to a conventional method. Possibly, the injectable compositions may be lyophilized according to a conventional method. Examples of suspension agents include methylcellulose, polysorbate 80. hydroxy ethylcellulose, xanthan gum, sodic carboxymethylcellulose and poly ethoxylated sorbitan monolaurate. Examples of solubilization agent include polyoxy ethylene- solidified castor oil, polysorbate 80, nicotinamide, poly ethoxylated sorbitan monolaurate, macrogol and ethyl ester of caste oil fatty acid. Moreover, the stabilizer includes sodium sulfite, sodium metalsulfite and ether, while the preservative includes methyl p-hydroxy benzoate, ethyl p- hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. An example of tonicity agent is mannitol. When preparing injectable suspensions or solutions, it is desirable to make sure that they are blood isotonic.
In some embodiments, the pharmaceutical composition further comprises a viscosity enhancing agent. In some embodiments, the viscosity enhancing agent includes methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose and smart hydrogel. In some embodiments, the viscosity enhancing agent is hydroxyethylcellulose. In some embodiments, the pharmaceutical composition comprises 0.01-1.0% (w/v) viscosity enhancing agent. In other embodiments, the intranasal pharmaceutical composition comprises 0.05% (w/v) hydroxyethylcellulose.
In some embodiments, the pH of the pharmaceutical composition is from 4.0 to 7.5. In other embodiments, the pH of the pharmaceutical composition is from 4.0 to 6.5. In another embodiment the pharmaceutical composition has a pH of from 5.5 to 6.5. In further embodiments, the pharmaceutical composition has a pH of from 6.0 to 6.5. In various implementations, the pH of said aqueous solution or liquid formulation is from pH 3 to pH 7, from pH 3 to pH 6. from pH 4 to pH 6, or from pH 5 to pH 6. These pH ranges may be achieved through the incorporation of one or more pH modifying agents, buffers, and the like. In some embodiments, a pH modifier such as acetic acid, is present in a final concentration of at least 0.001%, preferably at least 0.01%, more preferably between 0.01%- 0.2% by weight of the composition.
In terms of their form, compositions of this invention may include solutions, emulsions (including microemulsions), suspensions, creams, lotions, gels, powders, or other typical solid or liquid compositions used for application to skin and other tissues where the compositions may be used. Such compositions may contain: antimicrobials, moisturizers and hydration agents, penetration agents, preservatives, emulsifiers, natural or synthetic oils, solvents, surfactants, detergents, gelling agents, emollients, antioxidants, fragrances, fillers, thickeners, waxes, odor absorbers, dyestuffs, coloring agents, powders, viscosity -controlling agents and water, and optionally including anesthetics, anti-itch actives, botanical extracts, conditioning agents, darkening or lightening agents, glitter, humectants, mica, minerals, polyphenols, silicones or derivatives thereof, sunblocks, vitamins, and phytomedicinals. In certain embodiments, the composition of the invention is formulated with the above ingredients so as to be stable for a long period of time, as may be beneficial where continual or long-term treatment is intended.
Methods for Treatment
Typically, the treatment of a disease, disorder, or condition (e.g., the conditions described herein such as those associated with excessive Complement activation such as schizophrenia or Alzherimer’s Disease) is an approach for obtaining beneficial or desired results, such as clinical results. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing spread of disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. A disease, disorder, or condition may be palliated which includes that the extent and/or undesirable clinical manifestations of the disease, disorder, or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.
The method of treatment of a subject in need thereof may comprise administration to the subject a compound (e.g., C3aR agonists, C3aR inhibitors, Compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), (Id), one or more of Compounds 1-170) or composition of the present disclosure.
The compounds of the present disclosure may selectively modulate C3aR (and produce a decreased Complement cascade).
In order to treat, prevent, or prevent recurrence of diseases, disorders, or conditions (e.g., Alzheimer’s disease, multiple sclerosis. Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory' disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory conditions) as discussed herein, the compounds or compositions of the present disclosure may be administered at least once a day for at least one week. In various embodiments, the composition is administered at least twice a day for at least two days. In certain embodiments, the composition is administered approximately daily, at least daily, twice a week, weekly, or for once a month. In certain embodiments, the composition of the invention is administered for several months, such as at least two months, six months, or one year or longer. The invention is further suited for long-term use, which may be particularly beneficial for preventing recurring infection, or for preventing infection or conditions in at-risk or susceptible patients, including immune compromised patients. Such long-term use may involve treatment for at least two years, three years, four years, or even five or more years.
Examples of other drugs to combine with the compounds described herein include pharmaceuticals for the treatment of schizophrenia or conditions or disorders associated therewith. Combination methods can involve the use of the two (or more) agents formulated together or separately, as determined to be appropriate. In one example, two or more drugs are formulated together for the simultaneous or near simultaneous administration of the agents.
Kits
In another aspect, the composition of the invention is a kit, which contains the compositions of the present disclosure packaged to facilitate dispensing and/or administration of the compositions disclosed herein (e.g., compositions comprising one or more C3aR inhibitors, compositions comprising one or more compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), or (Id), compositions comprising one or more of Compounds 1-170). The packaging or dispenser may include a bottle, tube, spray bottle, or other dispenser. In certain embodiments of the invention, the composition is packaged in a concentrated form, and diluted to a desired concentration upon use by the end user. Typically, in these aspects, the composition may be formulated and packaged in a manner suitable for long-term storage to maintain efficacy of the composition. The kits may include instructions for using the compounds (e.g., for treatment of a disease disorder or condition) or include an internet link to such instructions (e g., which may be a pharmaceutical label).
Syntheses
The present disclosure also provides synthetic methods for preparing the active compounds of the present disclosure (e.g., compounds having the structure of Formula (I), (la), (lai), (Ia2), (lb), (Ic), or (Id), Compounds 1-170) as well as compounds useful as intermediates in those synthetic methods. The method for producing a compound of Formula (I) may comprise reacting a first compound having a boron containing coupling moiety (e.g., dioxaborolanes, dioxaborinanes), or boronic acid or boronic ester such as a group selected from: with a second compound having a halide (e.g., Cl, Br, I); to produce a compound coupling the first and second compound. For example, the coupling may involve reacting a compound having the structure of formula (II):
(ID with a compound having the structure of formula (III): wherein one of Z1 and Z2 is a boron containing coupling moiety and the other of Z1 and Z2 is a halide to form a compound having the structure of Formula (I). In some embodiments, the method may involve reacting a compound having the structure of formula (IV): with a compound having the structure of formula (V):
Z2 R4 (V) wherein one of Z1 and Z2 is a boron containing coupling moiety7 and the other of Z1 and Z2 is a halide to form a compound having the structure of Formula (I).
In some embodiments (particularly embodiments where Li and/or L2 are -C=C-), the coupling may involve a Sonagashira type coupling. This may involve reacting a compound having the structure of formula (IV): with a compound having the structure of formula (VII): wherein one of Z1 and Z2 is a halide and the other of Z1 and Z2 is -C=CH to form a compound having the structure of Formula (I). In some embodiments, the method may involve reacting a compound having the structure of formula (VIII): with a compound having the structure of formula (IX):
Z2 R4 (IX) wherein one of Z1 and Z2 is a halide and the other of Z1 and Z2 is -C=CH to form a compound having the structure of Formula (I) (Procedure B). In some embodiments, the method may involve the removal of a protecting group. For example, Z1 or Z2 may be - C=C-Pg. w here Pg is a protecting group and, prior to contacting the compounds or while contacting the compounds, deprotection occurs. In certain instances. Pg is a silyl ether such as trimethysilyl (which may be deprotected with, for example. Procedure A).
In some embodiments, the coupling (particularly those embodiments where L2 is O or NR) may occur via Chan-Lam, Ullman, or Buchwal-Hartwig reactions. For example, the method may involve reacting a compound having the structure of formula (X): with a compound having the structure of formula (XI):
Z2 R4 (XI)
Wherein one of Z1 and Z2 is boronic acid (-B(OH)2) or halide and the other of Z1 and Z2 is hydroxy or amine to form a compound having the structure of Formula (I). In some embodiments, the coupling (particularly those embodiments where L2 is - C(R2)-) may occur via Grignard or organolithium addition to an aldehyde, each of which may be followed by alcohol hydrogenation with H2 and suitable catalyst (e.g., Pd/C) reactions. For example, the method may involve reacting a compound having the structure of formula (X): with a compound having the structure of formula (XI):
Z2 R4 (XI)
Wherein one of Z1 and Z2 is a ketone (e.g., -C(O)R) and the other of Z1 and Z2 is a Grignard coupling agent such as magnesium halide (e.g., MgCl) or an Organolithium Li to form a compound having the structure of Formula (XII): Compounds having the structure of Formula (XII) may be subsequently dehydrogenated (e.g., with H2 and a catalyst such as Pd/C) to form compounds having the structure of Formula (I) (or intermediates useful for production of compounds having the structure of Formula (I).
In some embodiments, the coupling (particularly those embodiments where R4 is aromatic such as aryl or heteroaryl) may occur via aromatic substitution (e.g., nucleophilic aromatic substitution (SxAr). electrophilic aromatic substation (Si: Ar)). For example, the coupling may involve reacting a compound having the structure of formula (XIII) wherein A is ring comprising a nucleophilic moiety (e.g. the hydrogen of -NH- in heterocycloalkyl groups such as azetidnyl); with a compound having the structure of formula (XIV) z2— R4 (XIV) wherein R4 is aromatic (e.g., aryl, heteroaryl), and Z2 is an electron withdrawing group such as halogen (e.g., F. Cl).
The coupling may occur under transmateal catalyzed coupling conditions such as Buchwald- Hartwig couplings (e.g., with tBuXPhos, Pd2(dba)s. CuO. and combinations thereof), Negishi couplings, Suzuki couplings, Kumada coupldings, or Stille couplings. For example, the intermediates may be reacted under alkaline conditions (e.g., basic conditions as produced from an organic base or inorganic base in solvent) in the presence of a metal catalyst. In some embodiments the metal catalyst may be Pd(dppf)ChCH2C12, Pd(OAc)2, Pd(PPhs)4, Ni(cod2), or Ni(dppf)C12. The coupling may occur in a solvent seletcted from toluene, tetrahydrofuran, N,N-dimethylformamide, dioxane, water, and mixtures thereof. The alkaline conditions may be established through the use of a base dissolved in the solvent, where the base may be, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium carbonate, sodium hydroxide, barium hydroxide, potassium fluoride, cesium fluoride, and sodium tert-butoxide. Exemplary chemical synthetic steps include:
X = Br, I In various embodiments, the syntheses and intermediates associated therewith may include one or more reaction additional steps. For example, compounds having the structures of Formulas (I), (II), (IV), (VI), (VIII), (X), (XII), or (XIII), wherein Ri and R2 together form a fused ring may be formed by amidine cyclization and/or Pd/C reduction, to result in the substitution groups for compounds having the structure of Formula (I). The method may involve modifications involving the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, or substitution. These transformations include those which introduce a functionality which allows for further interconversion of substituents. For example, the method may comprise alkylation (e.g., amine alky lation), acetyl deprotection (e.g., conversion of an -OAc to -OH), deoxygenation (e.g., removal of a hydroxyl group), carbonyl reduction (e.g., conversion of a -C(O)OR group to -CH2-OH), tetrazole installation (e.g., via a cyano group), sulfonylation, or saponification. Exemplary modifications and reactions may be found in the Examples (e.g., General Procedures provided in the Examples).
Additionally, the syntheses may proceed in a manner similar to as disclosed in W02007034278A2, W02007034282A2, W02007034277A1, W02007034279A2, each of which are hereby incorporated by reference in their entirety and particularly in relation to the synthetic schema provided therein.
The following examples are put forth to provide those of ordinary skill in the art with disclosure and description of how to make and use the assay, screening, compounds, intermediates, syntheses, and therapeutic methods of the invention, and are not intended to limit the scope of the present disclosure.
EXAMPLES
Example 1: C3aR Inhibition Measurements
High-throughput assays able to identify inhibitors of C3aR were employed to screen compounds. In brief, C3aR activity was measured by the detection of the interaction of P- arrestin with C3aR, using enzyme fragment complementation, in mammalian cells. C3aR was fused to a small, optimized alpha fragment peptide derived from beta-galactosidase, while P- arrestin was fused to an N-terminal deletion mutant of beta-galactosidase (the enzyme acceptor). Upon activation of the receptor, P-arrestin recruitment to C3aR drives enzyme fragment complementation, resulting in an active beta-galactosidase enzyme. C3aR activation can then be determined by quantifying beta-galactosidase activity. An exemplary assay is also disclosed in U.S. Pub. No. 2008/0274913, which is hereby incorporated by reference in its entirey. P-arrestin recruitment may be induced using human or mouse C3aR and enzy me activity can be measured using chemiluminescent detection reagents. Activation of C3aR can be driven by a small molecule agonist of C3aR (BR103, CAS No. : 1434873-26-3) or C3a peptide. Compounds of the present disclosure were applied to the cells 1-2 minutes prior to application of C3aR agonist.
In addition to P-arrestin recruitment assays, C3aR activity was also measured by calcium flux detection in primary mouse brain-derived macrophages (microglia) similarly to the assays described in Hansen, Kasper B., and Hans Brauner-Osbome. "FLIPR® assays of intracellular calcium in GPCR drug discovery ." G Protein-Coupled Receptors in Drug Discovery (2009): 269-278, which is hereby incorporated by reference in its entirety and particularly in relation to intracellular calcium assays. Briefly, microglia endogenously express C3aR and are the main target cell type for C3aR inhibition in neurodegenerative conditions such as Alzheimer’s. Mouse microglia were obtained by7 dissociating early postnatal (P0-P5) mouse brains and culturing mixed glia for two weeks in DMEM supplemented with heat-inactivated 10% fetal bovine serum (Thermo Fisher Scientific). Microglia were then detached from the astrocyte monolayer by shaking for 4 hours, re-seeded at 15,000 cells/well in 384-well plates, and cultured for a further 1-3 days in NbActiv4 media (Fisher Scientific) supplemented with mouse macrophage colony-stimulating factor (MCSF, 40 ng/rnL). Calcium flux assays were then performed using a high-throughput fluorometric imaging plate reader (Molecular Devices). In brief, cells were loaded with a synthetic fluorescent calcium indicator dye (Fluo-4AM, 4 pM) for 1.5 hours at room temperature, excess indicator dye was then washed out, and compounds of interest were added for 2 minutes, followed by BR103 (small molecule C3aR agonist, at ECso) or mouse C3a peptide (at ECso) for 3 minutes. C3aR-induced calcium transient peak amplitude from baseline was determined using the ScreenWorks software (Molecular Devices) and compared across conditions.
Table 2 lists the ICso for various compounds of the present disclosure as measured by C3aR P-arrestin recruitment assays. The ICso and Emax, expressed as a percentage reduction of the maximum value of the agonist effect, were determined for inhibtion of both human (h C3aR) and mouse (m C3aR) C3aR for Compounds as well as the similar values determined for the mouse Calcium flux assay (m C3aR Ca Flux) . As can be seen, compounds of the present disclosure are able to inhibit agonist-driven interaction of P-arrestin with C3aR. Table 2 tit will be understood that in the event of any inconsistency in the smiles string, compound number, compound structure or 1UPAC nomenclature, each compound will be embraced by the disclosure. Unless otherwise indicated, the data in Table 2 relates to the compound having the indicated smiles string (and any specific stereoisomeric forms associated such structure).
Example 2: Compound Synthesis
Procedure A - General Sonagashira coupling (w/ TMS deprotection) To the mixture of 2-(3-fluoro-4-methyl-phenyl)ethynyl-trimethyl-silane (250 mg, 1.21 mmol, 1.00 eq) and 2-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[1.2-a]pyridine (432 mg, 1.33 mmol, 1.10 eq) in DMF (6 mL) was added Cui (46 mg, 0.242 mmol, 0.200 eq) and TEA (.87 mL, 6.06 mmol, 5.00 eq) and degassed for 10 min and then added Pd(PPhs)2C12 (85 mg, 0.121 mmol, 0.100 eq) and TBAF (632 mg, 2.42 mmol, 2.00 eq) and then reaction mixture was stirred at 80 °C for 16 hrs.
After completion of the reaction the solvent in the reaction mixture was evaporated under reduced pressure to obtain the crude compound which was purified by preparative HPLC to COMPOUND 21, (17 mg, 0.0493 mmol, 98.73% purity, 4% yield) as light brown solid.
1H NMR (400 MHz, DMSO-d6): δ 7.76-7.74 (d, J= 8 Hz, 2H), 7.57 (s,lH) 7.50-7.48 (d, J= 8 Hz, 2H), 7.35-7.27 (m, 3H), 3.98-3.96 (t, J= 52 Hz, 2H), 2.78-3.75 (t, J= 8Hz, 2H), 2.26 (s, 3H), 1.91-1.85 (m, 4H).
LCMS (m/z) = 331.2 [M+H],
Procedure B - General sonagashira coupling (without TMS deprotection)
To a stirred solution of 2-(4-iodophenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine (200 mg, 0.617 mmol, 1.00 eq) in triethylamine (8 mL), was added 2-ethynyl-l,4-dimethyl-benzene (96 mg, 0.740 mmol, 1.20 eq) and copper iodide (12 mg, 0.0617 mmol, 0.100 eq) at RT, degassed using nitrogen gas for 5 min. PdChdppf (45 mg, 0.0617 mmol, 0.100 eq) was added into the reaction, and the mixture was degassed for another 5 min. The resulted suspension was stirred for 16 hrs at 100°C in a sealed vessel. The progress of the reaction was monitored by TLC & LCMS. The reaction mixture was cooled to RT, filtered over celite bed, washed with DCM (30 mL), then concentrated under reduced vacuum. The crude material was purified by flash column chromatography followed by prep HPLC to afford 2-[4-[2-(2.5- dimethylphenyl)ethynyl]phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine. COMPOUND 21, (21 mg, 99.54% purity, 10% yield) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, J= 8.4 Hz. 2H), 7.56 (s, 1H), 7.48 (d, J= 8.4 Hz, 2H), 7.31 (s, 1H), 7.20 (d, J= 7.6 Hz, 1H), 7.11 (d, J= 7.6 Hz, 1H), 3.97 (1, J= 5.4 Hz, 2H). 2.76 (t, J= 6.2 Hz, 2H), 2.41 (s, 3H), 2.27 (s, 3H), 1.91-1.87 (m, 4H).
LCMS (ESI, m/z) = 327.55 [M+H],
COMPOUND 23
Synthesized according to procedure B, the title compound was afforded as a pale yellow solid (21 mg, 99.82% purity, 7% yield).
1H NMR (400MHz, DMSO-d6) δ 7.85 (s,lH), 7.39 (s,l), 7.32 (d, J= 7.6 Hz,lH), 7.22 (d, J= 7.2 Hz,lH), 4.03 (t, J= 5.2 Hz, 2H). 2.78 (t, J= 5.6 Hz. 2H), 2.26 (d, J= 6.4 Hz. 6H), 1.92-
1.89 (m, 4H).
LCMS (ESI, m/z) = 329.45 [M+H],
COMPOUND 29 Synthesized according to procedure B, title compound was afforded as a light brown solid (70 mg, 30% yield) as a racemic mixture.
Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 21 mm) 5p. Operating at ambient temperature and flow rate is 21.0 mL/min. Mobile phase was mixture of 50% Hexane, 25% Ethyl Acetate, 25% EtOH and 0.1% IP Amine held this isocratic mixture run up to 20 min with wavelength of 294nm.
Isomer 1 :
1H NMR (400 MHz, DMSO-d6) d 7.67 (d, J= 8.4 Hz, 2H), 7.51 (s, 1H), 7.32 (d, J= 8.4 Hz, 2H), 3.95 (t, J= 5.2 Hz, 2H). 3.43-3.38 (m ,1H), 3.31 (m, 1H, merged with DMSO water peak), 3.17-3.15 (m , 1H), 2.83 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 2.58-2.54 (m , 1H), 2.34-2.28 (m ,1H), 2.07-2.04 (m, 1H), 1.90-1.86 (m, 5H).
UPLC (m/z) = 334.2 [M+H],
Enantiomeric excess: 99.58%
SOR : Optical Rotation : 0.034°
Solvent: MeOH
Sample Cell Temperature: 25 °C
Specific Rotation : 27.788°, C=0.1224
Isomer 2:
1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, J= 8.4 Hz, 2H), 7.51 (s, 1H), 7.32 (d, J= 8.4 Hz, 2H), 3.95 (t, J= 5.2 Hz, 2H), 3.43-3.38 (m ,1H), 3.31 (m, 1H, merged with DMSO water peak), 3.17-3.15 (m ,1H), 2.83 (s, 3H), 2.74 (t, J=5.6 Hz, 2H), 2.58-2.54 (m , 1H), 2.34-2.28 (m ,1H), 2.07-2.04 (m. 1H), 1.90-1.86 (m. 5H).
UPLC (m/z) = 334.2 [M+H],
Enantiomeric excess: 98.30%
SOR : Optical Rotation : -0.049°
Solvent: MeOH
Sample Cell Temperature: 25 °C
Specific Rotation : -40.636°, C=0.1206
Synthesized according to procedure B to yield title compound as an off-white solid (29 mg, 99.75% purity, 15% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, J= 8.4 Hz, 2H), 7.50 (s, 1H), 7.33 (d, J= 8 Hz, 2H), 3.96 (t, J= 10.8 Hz, 2H), 3.82 - 3.79 (m, 2H), 3.44 (t, J= 9.2 Hz, 2H), 2.89 (m, 1H), 2.75 (t, J= 6.4 Hz, 2H), 1.90 - 1.83 (m, 6H), 1.61 - 1.57 (m, 2H). LCMS (ESI, m/z) = 307.0 [M+H],
COMPOUND 47
Racemate: Synthesized according to procedure B, title compound was afforded as a light brown solid (18 mg, 96.62% purity, 10% yield).
1H NMR (400 MHz, DMSO-d6) : δ 7.69 (d, J= 8.0 Hz, 2H). 7.52 (s, 1H); 7.36 (d, J= 7.6 Hz, 2H), 7.28 ( s, 1H), 7.23 (d. J= 7.2 Hz. 1H), 7.13 (d. J= 7.6 Hz. 1H), 6.00 (d. J= 5.6 Hz. 1H),
5.50 (d, J= 5.2Hz, 1H), 3.95 (br s, 2H), 2.76 (br s, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.89-1.86 (m, 4H).
LCMS (ESI, m/z) = 357.29 [M+l],
COMPOUND 47 (ISOMER 1 )
Isomer 1 : Synthesized according to procedure B, title compound was afforded as an off white solid. (31 mg, 96.09% purity, 14% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.70 (d, J= 8.0 Hz, 2H); 7.53 (s, 1H); 7.37 (d, J= 7.6 Hz, 2H); 7.29 (s, 1H); 7.24 (d, J = 7.2 Hz, 1H); 7.14 (d, J = 7.6 Hz, 1H); 6.00 (d, J = 5.6 Hz. 1H);
5.50 (d, .7 = 5.2 Hz, 1H); 3.95 (br 2H); 2.76 (br 2H); 2.24(s, 3H); 2.21 (s, 3H); 1.89-1.86 (m, 4H).
LCMS (ESI, m/z): 357.49 (M+l).
COMPOUND 47 (ISOMER 2)
Isomer 2: Synthesized according to procedure B, title compound was afforded as an off white solid (44 mg. 99.02% purity. 20% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.70 (d, J= 8.0 Hz. 2H), 7.53 (s, 1H), 7.37 (d, J= 7.6 Hz, 2H), 7.29 (s, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7. 14 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 5.6 Hz, 1H),
5.50 (d, .7 = 5.2 Hz, 1H), 3.95 (br s, 2H), 2.76 (br s, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.89-1.86 (m, 4H).
LCMS (ESI, m/z) = 357.39 [M+l], General procedure: amine alky lation
COMPOUND 34
To the solution of 3-[2-[6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)-3- pyridyl]ethynyl]pyrrolidin-3-ol (120 mg, 0.389 mmol, 1.00 eq) in DCM (5 mL) and DMF (1 mL) solvent mixture, ELN (.33 mL, 2.33 mmol. 6.00 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (.22 mL, 1.17 mmol, 3.00 eq) were added sequentially' at 0 °C under inert atmoshphere and allowed to stir for 2 hrs. Aqueous NaHCCh solution was added to reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to get crude. Combiflash column purification of resultant crude afforded 3-[2-[6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)-3- pyridyl]ethynyl]-l-(2,2,2-trifluoroethyl)pyrrolidin-3-ol, (90 mg, 59% yield) as yellow solid. Isomers were separated and characterized.
Chiral separation was done on Agilent 1200 series instrument. Column name : CHIRALPAK IG (250 X21 mm) 5p. Operating at ambient temperature and flow rate is 21.0 mL/min. Mobile phase was mixture of 70% Hexane, 15% Ethyl acetate, 15% Ethanol and 0. 1 % IP Amine held this isocratic mixture run up to 26 min with wavelength of 318 nm.
COMPOUND 34 (Isomer 1):
1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.79-7.75 (m, 2H), 7.60 (m,lH), 5.81 (s. 1H), 3.99 (t, J = 5.4 Hz, 2H), 3.38-3.32 (m, 2H), 3.15 (d, J= 10.2 Hz, 1H), 2.99-2.91 (m, 3H), 2.77 (d, J= 6.28 Hz, 2H), 2.20-2.17 (m , 1H), 2.10-2.07 (m , 1H), 1.91-1.86 (m, 4H).
19F NMR (376 MHz, DMSO-d6): δ -69.23 (t).
UPLC (m/z) = 391.2 | M+H|.
Enantiomeric excess: 100%
SOR : Optical Rotation : 0.022°
Solvent: MeOH Sample Cell Temperature: 25 °C
Specific Rotation : 21.999°, C=0.1000
COMPOUND 34 (Isomer 2):
1H NMR (400 MHz, DMSO-d6): δ 8.48 (s, 1H), 7.79-7.75 (m, 2H), 7.60 (m ,1H), 5.81 (s, 1H), 3.99 (t, J= 5.4 Hz, 2H), 3.38-3.32 (m, 2H), 3.15 (d, J= 10.2 Hz, 1H), 2.99-2.91 (m, 3H), 2.77 (d, J= 6.28 Hz, 2H), 2.20-2.17 (m, 1H), 2.10-2.07 (m, 1H), 1.91-1.86 (m, 4H).
19F NMR (376 MHz, DMSO-d,): δ -69.23 (t).
UPLC (m/z) = 391.2 [M+H],
Enantiomeric excess: 99.82%
SOR : Optical Rotation : -0.022°
Solvent: MeOH
Sample Cell Temperature: 25 °C
Specific Rotation : -21.999°. C=0.1000
COMPOUND 75
Following the amine alkylation procedure, the title compound was afforded as a brown solid (55 mg, 36% yield). After chiral separation, each isomer was characterized individually.
COMPOUND 75 (Isomer 1): white solid (11.1 mg, 99.55% purity, 22% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H). 7.77-7.73 (m, 2H). 7.59 (s. 1H), 3.99 (t, 5.6 Hz, 2H), 3.38-3.36 (m, 1H, overlapped with water), 3.29-3.19 (m, 2H), 3.12 (t, J= 8.0 Hz, 1H), 2.85-2.69 (m, 5H), 2.24-2.19 (m, 1H), 1.89-1.85 (m, 5H).
19F (376 MHz, DMSO-d6): δ -68.7344 (t, J= 10.41 Hz). UPLC (m/z) = 375.2 [M+H],
Enantiomeric excess: 99.84%
SOR : Optical Rotation : +0.025°
Solvent: MeOH
Sample Cell Temperature: 25 °C
Specific Rotation : +24.875°, C=0. 1005
COMPOUND 75 (Isomer 2): white solid (13 mg, 99.55% purity, 26% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.77-7.73 (m, 2H), 7.59 (s. 1H), 3.99 (t, 5.6 Hz. 2H), 3.38-3.36 (m. 1H, overlapped with dmso water). 3.29-3. 19 (m, 2H). 3. 12 (t. J= 8.0 Hz, 1H), 2.85-2.69 (m, 5H), 2.24-2.19 (m, 1H), 1.89-1.85 (m, 5H).
19F (376 MHz, DMSO-d6): δ -68.7347 (t, J= 9.024 Hz).
UPLC (m/z) = 375.2 [M+H],
Enantiomeric excess: 93.06%
SOR : Optical Rotation : -0.018°
Solvent: MeOH
Sample Cell Temperature: 25 °C
Specific Rotation : -17.733°, C=0.1015
COMPOUND 35
Synthesized according to procedure B, title compound was afforded as an off white solid (22 mg, 98.7% purity. 9% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s,lH) 8.07-8.04 (dd, J= 2 Hz, 1H),7.7O (s,lH), 7.57-7.55 (d, J= 8 Hz. 1H), 7.38 (s, 1H) 7.32-7.30 (d. J= 8 Hz, 1H), 7.22-7.20 (d, J= 8Hz, 1H), 4.00-3.97 (t, J= 8 Hz, 2H), 2.79-2.76 (t, J = 4 Hz, 2H), 2.26-2.24 (d, J= 8 Hz, 6H), 1.92-1.86 (m, 4H). LCMS (ESI, m/z) = 328.2 [M+H],
COMPOUND 36
Synthesized according to procedure B afforded title compound as an off white solid (55 mg. 97.4% purify, 23% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J= 7.2 Hz, 2H), 7.53 (s, 1H), 7.31 (d, J= 4 Hz, 2H), 3.97 (s, 2H), 2.79 (s, 2H), 2.63 (s, 1H), 1.90 - 1.85 (m, 6H), 1.69 (s, 2H), 1.50 - 1.46 (m, 3H), 1.34 (s, 3H).
LCMS (ESI, m/z) = 305.22 [M+H], COMPOUND 42
Synthesized according to procedure B afforded title compound as an off white solid (16 mg, 99.9% purity, 22% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.75-7.69 (m, 2H), 7.58 (s, 1H), 3.98 (t, J = 5.36 Hz, 2H), 2.90-2.87 (m, 1H), 2.76 (t, J= 6.24 Hz. 2H), 2.00-1.97 (m. 2H), 1.90-1.85 (m. 4H), 1.72-1.70 (m, 2H), 1.63-1.56 (m, 4H).
Synthesized according to procedure B, title compound was afforded as an off white solid (21 mg, 99.4% purity, 4% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J= 8.4 Hz, 2H), 7.55 (s, 1H), 7.46 (d, J= 8.4 Hz, 2H), 7.33 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7. 18 (d, J = 7.6 Hz, 1H), 3.97 (t, J = 5.6 Hz, 2H).
2.76 (t. J= 6.4 Hz. 2H), 2.24 (s, 3H), 2.23 (s. 3H), 1.91-1.85 (m, 4H). Synthesized according to procedure B, title compound was afforded as a pale yellow solid (15 mg, 99.5% purity, 6% yield). 1H NMR (400 MHz, DMSO-d6+D2O): δ 7.74 (d, J= 8.4 Hz, 2H), 7.55 (s, 1H), 7.48 (d, J = 8.4 Hz. 2H), 7.37 (d. J = 8 Hz. 1H), 7.14 (s, 1H), 7.04 (d. J = 7.6 Hz, 1H), 3.97 (t, J= 5.2 Hz, 2H), 2.76 (t, J = 5.2 Hz, 2H), 2.42 (s, 3H), 2.30 (s, 3H), 1.90-1.85 (m, 4H).
Synthesized according to general procedure B, title compound was afforded as an off white solid (21 mg, 99.53% purity. 5% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.67 (d, J= 7.6 Hz, 2H), 7.52-7.49 (m, 3H), 7.42-7.40 (m, 2H), 7.23 (d, J= 7.6 Hz, 1H), 3.94 (t, 5.8 Hz, 2H), 2.71 (t, J= 6.0 Hz, 2H), 2.29 (s. 3H),
2.58 (s. 3H), 1.90-1.84 (m. 4H).
COMPOUND 52 Synthesized according to general procedure B, the title compound was afforded as a pale yellow solid (12 mg, 99.48% purity, 5% yield). 1H NMR (400 MHz, DMSO-d6+D2O): δ 7.78 (d, J= 8.4 Hz, 2H), 7.59 (s, 1H), 7.54-7.50 (m, 3H), 7.46-7.43 (m, 1H), 7.28-7.26 (m. 1H), 3.97 (t, J= 4.4 Hz, 2H), 2.76 (t, J= 4.4 Hz, 2H). 1.91-1.85 (m, 4H).
COMPOUND 53
Synthesized according to procedure B, title compound was afforded as an off white solid (21 mg, 98.2% purity, 7% yield).
1H NMR (400MHz, DMSO-d6): δ 9.75 (s, 1H), 8.08 (s, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.69 (d, J= 8.0 Hz, 2H), 7.22 (t, J= 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.84 (d, J= 8 Hz, 1 H), 4.12 (br s, 2H), 3.01 (br s, 2H), 1.99 -1.94 (m, 4H). Synthesized according to general procedure B, title compound was afforded as a light brown solid (18.7 mg, 95.7% purity, 7.4% yield). 1HNMR (400MHz, DMSO-d6): δ .76 (d, J= 8.4 Hz, 2H), 7.56 (s.lH), 7.50 (d, J= 8.0 Hz, 2H), 7.34 (d, J= 7.60 Hz,lH), 7.19 (d, J = 7.2 Hz, 1H), 7.13 (d, J = 7.60 Hz, 1H), 3.98 (t, J = 5.6 Hz, 2H), 2.77 (t, J = 6.40 Hz, 2H), 2.42 (s, 3H), 2.27 (s, 3H), 1.91 (m, 4H).
LCMS (ESI, m/z) = 327.10 [M+H],
COMPOUND 57
Synthesized according to general procedure B, title compound was afforded as an off white solid (20 mg, 96.7% purity, 7% yield).
1H NMR (400MHz, DMSO-d6): δ 7.75 (d, J= 8.4 Hz, 2H), 7.56 (s, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.37 (s, 1H), 7.32-7.28 (m, 2H), 7.22 (d, J= 6.4 Hz, 1H), 3.97 (t, J= 5.4 Hz, 2H), 2.76 (t, J= 6.2 Hz, 2H). 2.32 (s, 3H), 1.91-1.85 (m, 4H).
LCMS (ESI, m/z) = 313.21 [M+H],
COMPOUND 59
Synthesized according to procedure B, the title compound was afforded as an off white solid (15 mg, 99.75% purity, 19% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.78-7.72 (m, 2H), 7.59 (s, 1H), 5.34 (s, 1H), 3.99 (t. J= 5.6 Hz. 2H), 2.77 (t, J= 5.6 Hz, 2H), 1.91-1.86 (m, 8H), 1.76-1.68 (m, 4H).
UPLC (m/z) = 308.2 [M+H],
Synthesized according to procedure B, title compound was afforded as a grey solid (18 mg, 90.8% purity, 5% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 7.90-7.80 (m, 2H), 7.69-7.55 (m, 1H), 7.41 (s, 1H), 7.35(d, J= 7.60 Hz, 1H), 7.20 (d, J= 7.60 Hz, 1H), 4.05-3.95 (m, 2H), 2.85-2.75 (m,
2H), 2.26-2.23 (m, 6H), 1.95-1.85 (m, 4H).
LCMS (ESI, m/z): 328.2 [M+H],
Synthesized according to procedure A, the title compound was afforded as an off white solid (22 mg, 98.99% purity, 6% yield). 1H NMR (400 MHz , DMSO-d6): δ ppm 7.84 (d, J= 8.0 Hz, 1H), 7.76 (d, J= 8.4 Hz, 2H), 7.58 (s, 1H), 7.52-7.50 (m. 3H), 7.46 (d. J= 8.4 Hz. 1H), 3.98-3.95 (m. 2H), 3.83 (s, 3H), 2.77-2.74 (m, 2H), 2.52 (s, 3H), 1.91-1.84 (m, 4H).
LCMS (m/z) = 371.2 [M+H],
Synthesized according to procedure B, the title compound was afforded as an off-white solid (18 mg, 99.48% purity, 9% yield).
1H NMR (400MHz, DMSO-d6): δ 7.77 (d. J= 8 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J= 7.6 Hz, 2H), 7.18 - 7.13 (m, 3H), 3.97 (t, J = 5.2 Hz, 2H). 2.77 (t. J= 11.6 Hz, 2H), 2.46 (s, 6H). 1.91 - 1.87 (m, 4H).
LCMS (m/z) = 327.23 [M+H],
COMPOUND 76
Synthesized according to procedure B, the title compound was afforded as a light brown solid (20 mg, 95.07% purity, 6% yield). 1H NMR (400MHz, DMSO-d6): δ 7.76 (d. J= 8.0 Hz. 2H), 7.58 (s, 1H), 7.51 (d, J= 7.6 Hz, 2H), 7.48 (s, 1H), 7.34 - 7.21 (m, 3H). 3.98 (t. J= 5.6 Hz. 2H), 2.77 (t, J = 6 Hz, 2H), 2.47 (s, 3H), 1.92 - 1.86 (m, 4H).
LCMS (m/z) = 313.10 [M+H] .
COMPOUND 78
Synthesized according to procedure A, the title compound was afforded as an off white solid (25 mg, 99.66% purity, 5% yield). JH NMR (400MHZ, DMSO-d6): δ 7.55 (s, 1H), 7.35 (s, 1H), 7.30-7.28 (d, J= 8 Hz, 1H), 7.18-7.16 (d, J= 7.8 Hz,l H), 3.93 (t, 2H), 2.70-2.65 (t, 2H), 2.24 (s, 3H), 2.21 (s, 3H), 1.87- 1.81 (m, 4H).
LCMS (m/z) = 275.2 [M+H],
COMPOUND 2
Synthesizsed according to procedure B, title compound was afforded as an off-white solid (20 mg, 99.36% purity, 9% yield). 1H NMR (400MHz, DMSO-d6): δ 7.64 (d. J= 8.0 Hz, 2H), 7.48 (s, 1H), 7.28 (d, J= 8.0 Hz, 2H), 3.96-3.93 (m. 1H), 2.74 (t, J= 6.0 Hz, 2H). 1.90-1.85 (m, 4H). 1.54-1.50 (m, 1H). 0.89- 0.86 (m, 2H), 0.71-0.70 (m, 2H).
LCMS (ESI, m/z) = 263.2 [M+H],
COMPOUND 86
Synthesized according to procedure B, the title compound was afforded as a white solid (5.4 mg, 95.4% purity, 2% yield).
1H NMR (400MHz, DMSO-d6) : δ 7.74 (d, J= 8.4 Hz, 2H), 7.55 (s, 1H), 7.47 (d, J= 8.4 Hz, 2H), 7.43 (d, J= 8.0 Hz, 2H), 7.23 (d, J= 7.6 Hz, 2H), 3.97 (t, J= 5.4 Hz, 2H), 2.76 (t, J = 6.2 Hz, 2H), 2.33 (s, 3H), 1.92-1.84 (m, 4H).
LCMS (ESI, m/z) = 313.21 [M+H],
COMPOUND 87
Synthesized according to procedure B, the title compound was afforded as a pale yellow solid (810 mg, 99.08% purity, 61% yield). 1H NMR (400MHz, DMSO-d6): δ 7.74 (d. J= 8.0 Hz. 2H), 7.68 (t. J= 8.8 Hz, 1H), 7.57 (s, 1H), 7.54-7.47 (m. 3H), 7.42 (br, 1H). 3.97 (br, 2H), 2.77-2.74 (m, 2H), 1.90-1.86 (m, 4H).
LCMS (ESI, m/z) = 335.10 [M+H],
COMPOUND 88
Synthesized according to procedure A, the title compound was afforded as a light brown solid (32 mg, 98.7% purity, 7% yield).
1H NMR (400MHz, DMSO-d6): δ 7.77-7.75 (d, J= 8 Hz, 2H), 7.57 (s,lH). 7.50-7.48 (d. J= 8.4 Hz, 2H), 7.23 (s,lH), 7.19-7.17 (d, J= 8.8 Hz, 1H), 7.11-7.09 (d, .7= 8.4 Hz, 1H), 3.98-
3.96 (t, J= 5.6Hz, 2H), 2.78-2.75 (t, J= 5.6 Hz, 2H), 2.34 (s, 3H), 1.91-1.85 (m,4H).
LCMS (ESI, m/z) = 335.10 [M+H], COMPOUND 89
Synthesized according to procedure B, the title compound was afforded as an off white solid (18 mg, 98.5% purity. 4% yield). 1H NMR (400MHz, DMSO-d6): δ 7.16 (s, 1H), 6.94 (d, J= 8.4 Hz, 1H), 6.75 (s, 1H), 6.65 (d, J= 8.0 Hz. 1H), 3.88-3.85 (m. 2H), 3.39-3.72 (m. 2H), 2.86 (t, J= 9.4 Hz, 2H), 2.74-2.70 (m, 1H), 2.64 (t, J= 6.0 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.85-1.79 (m, 6H), 1.68-1.61 (m, 2H). LCMS (ESI, m/z) = 334.10 [M+H],
COMPOUND 91
Synthesized according to procedure B, the title compound was afforded as a white solid (14 mg, 98.82% purity, 19% yield).
1H NMR (400MHz, DMSO-d6): δ 8.44 (s, 1H), 7.76-7.70 (m, 2H), 7.58 (s, 1H), 3.99 (t, J
= 5.6 Hz, 2H), 2.85-2.80 (m, 1H), 2.76 (t, J= 6.4 Hz, 2H), 1.91-1.86 (m, 4H), 1.22 (d, J= 7.2
Hz. 6H).
UPLC (ESI, m/z) = 266.2 [M+H],
COMPOUND 93
Synthesized according to procedure B, the title compound was afforded as a pale yellow solid (19 mg, 99.14% purity, 19% yield). 1H NMR (400MHz, DMSO-d6): δ 8.48 (d. J= 5.2 Hz. 1H), 7.78 (d. J= 8.4 Hz. 2H), 7.59 (s, 1H), 7.54 (d, J= 8.4 Hz. 2H), 7.39 (s, 1H), 7.30 (d, J= 4.8 Hz, 1H), 3.97 (t, J= 5.6 Hz, 2H). 2.76 (t, J= 5.6 Hz, 2H), 2.50-2.48 (br s, 3H), 1.91-1.85 (m, 4H).
LCMS (ESI, m/z) = 314.38 [M+H],
COMPOUND 95
Synthesized according to procedure B, title compound was afforded as a light brown solid (29 mg, 99% purity, 17% yield).
1H NMR (400MHz, DMSO-:d6)δ 7.76 (d, J= 8.0 Hz, 2H), 7.57-7.47 (m, 6H), 7.18(t, J = 54.8 Hz, 1H), 3.97(t, J= 5.4 Hz, 2H), 2.76 (t, J = 5.6 Hz, 2H), 2.41(s, 3H); 1.90-1.87 (m, 4H).
19F (400 MHz, DMSO:-d 86 -)113.297-113.445 (d, J= 59.2 Hz, 2F).
LCMS (ESI, m/z) = 363.24 [M+H], COMPOUND 38
Synthesized according to procedure B, title compound was afforded as an off white solid (20 mg, 97.17% purity, 8% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J= 8 Hz, 2H), 7.64 (s, 1H), 7.50 (t, J= 7.6 Hz, 3H), 7.34-7.22 (m, 3H), 4.25-4.21 (m, 1H), 4.15-4.09 (m, 1H), 3.68 (s, 3H), 3.2-3.18 (m. 1H),
2.82-2.81 (m, 2H), 2.47 (s, 3H), 2.24-2.22(m, 1H), 2.08-2.01 (m, 1H).
LCMS (ESI. m/z) = 371.45 [M+l],
COMPOUND 43 Synthesized according to procedure B, title compound was afforded as a white solid (7.0 mg, 99.27% purity, 3% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.70 (d, J= 8.2 Hz, 2H), 7.68 (s, 1H), 7.59 (s, 1H), 7.41 (d, J= 8.2 Hz, 2H), 4.23-4.20 (m, 1H), 4.13-4.05 (m, 3H). 3.68 (s, 3H), 3.19- 3.17 (m, 1H), 2.81-2.79 (m, 2H), 2.21-2.19 (m, 1H), 2.04-2.02 (m, 1H), 1.81-1.76 (m, 2H), 0.82 (t. J= 7.36 Hz, 3H).
UPLC (m/z) = 389.2 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (32 mg, 99.2% purity, 14% yield). 1H-NMR (400 MHz, DMSO4+D2O): δ 8.47 (d, J= 12.8 Hz, 2H), 7.98 (d, J= 8.4 Hz, 2H), 7.59-7.50 (m, 3H), 7.37-7.35 (m, 2H), 7.30-7.18 (m, 2H), 5.27 (s, 1H), 2.24 (d, J = 4.4 Hz, 6H), 1.48 (s, 6H).
LCMS (ESI, m/z) = 381.7 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (8.4 mg, 97.6% purity, 8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.50 (d, J= 7.2 Hz, 2H), 8.01 (d, J= 7.6 Hz, 2H), 7.66(t, J = 6.0 Hz. 1H), 7.60 (d. J= 7.6 Hz. 3H), 7.37 (s, 1H), 7.30-7.25 (m, 2H), 7.20 (d, J= 8.0 Hz, 1H), 4.19 (d, J = 5.6 Hz, 2H), 2.94 (s, 3H), 2.25 (s,6H).
LCMS (ESI, m/z) = 430.15 [M+H],
COMPOUND 71
Synthesized according to procedure B, title compound was afforded as an off white solid (37 mg, 98.3% purity, 17% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.40 (s, 2H), 8.00 (d, J= 8.0 Hz, 2H), 7.57 (t, J= 8.0 Hz, 3H), 7.36 (s, 1H), 7.29 (d, J= 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 2H), 4.26 (d, J
= 6.0 Hz. 2H), 2.25 (d. J = 4.8 Hz. 6H), 1.88 (s, 3H).
LCMS (ESI, m/z) = 394.50 [M+l],
COMPOUND 1 Synthesized according to procedure B, title compound was afforded as a sticky yellow solid (21 mg, 97.9% purity, 10% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.64 (d, J= 8.0 Hz, 2H), 7.31 (d, J= 8.0 Hz, 2H), 5.78 (s, 1H), 5.56 - 5.54 (m, 1H), 3.54 (s, 3H). 2.70 (d, J= 5.2 Hz, 3H). 1.55-1.51 (m, 1H). 0.90-0.85 (m, 2H), 0.74-0.70 (m, 2H).
LCMS (ESI, m/z) = 252.2 [M+l],
COMPOUND 80
Synthesized according to procedure B, title compound was afforded as a light yellow solid (63 mg, 99.8% purity, 32% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.91 (d, J= 11.04 Hz, 1H), 7.75 (d, J= 8.24 Hz, 2H), 7.63 (s, 1H), 7.50 (d, J= 8.24 Hz, 2H), 4.25-4.21 (m, 1H), 4.14-4.09 (m, 1H), 3.99 (s, 3H), 3.68 (s, 3H). 3.19-3.17 (m, 1H). 2.83-2.79 (m, 2H). 2.24-2.20 (m, 1H). 2.06-2.00 (m, 1H).
19F NMR (376 MHz. DMSO-d6): δ -139.30 (d, J= 52.35 Hz). UPLC (m/z) = 406.2 [M+H],
Synthesized according to procedure B, title compound was afforded as a brow n solid (20 mg, 96.3% purity, 6% yield).
1H NMR (400 MHz, DMSO-d6): δ 9.68 (s, 1H), 7.74 (d, J= 7.6 Hz, 2H), 7.63 (s, 1H), 7.50 (d, J= 7.6 Hz, 2H), 7.21 (t, J= 8.0 Hz, 1H). 6.95 (d, J= 8.4 Hz, 1H). 6.89 (s, 1H), 6.80 (d, J = 8.0 Hz. 1H), 4.23-4.09 (m. 2H), 3.68(s, 3H), 3.17(br, 1H), 2.82(br, 2H), 3.17 (br. 1H), 2.24- 2.21(m, 1H), 2.04(br, 1H).
LCMS (ESI, m/z) = 373.40 [M+l],
COMPOUND 48
To a solution of [2-[2-[4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2- yl)phenyl]ethynyl]phenyl] acetate (100 mg, 0.281 mmol, 1.00 eq) in MeOH (5 rnL), THF (5 mL) was added K2CO3 (80 mg, 0.580 mmol, 1.50 eq). The reaction was stirred at 25 °C for 0.25 h (15 min) . The reaction progress was monitored bv LCMS and TLC (5% DCM/MeOH). After completion of the reaction, the reaction mixture was diluted with DCM . The combined organic layer was filtered and washed with MeOH. then concentrated under reduced pressure to get crude (100 mg). The crude was column purified by reverse phase preparative HPLC method (Column: X bridge; ABC in H2O: ACN;Flow rate: 18mL/min) to get 2-[2-[4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl]ethynyl]phenol, COMPOUND 48, (14 mg, 0.0446 mmol, 99.4% purity, 16% yield) as off white solid.
1H NMR (400MHz, DMSO-d6): δ 9.93 (s, 1H); 7.73 (d, J = 8.0 Hz, 2H); 7.54 (s, 1H); 7.45 (d, J= 7.6 Hz, 2H); 7.36 (d, J= 8.1 Hz, 2H); 7.20 (t, J= 5.6 Hz, 1H). 6.91(d. J= 7.6 Hz. 1H), 6.81(t, J= 5.6 Hz, 1H), 3.92 (t, 2H), 2.76 (t, 2H), 1.90-1.87 (m, 4H).
LCMS (ESI, m/z): 315.16 [M+l],
COMPOUND 26
Synthesized according to procedure Ac dep, title compound was afforded as an off white solid (26 mg. 98.9% purity, 22% yield).
1H NMR (400MHz, DMSO-d6): δ 9.94 (s, 1H); 7.73 (d, J= 8 Hz, 2H), 7.60 (s, 1H), 7.46 (d, J = 8 Hz. 2H), 7.36 (d. J= 7.8 Hz. 1H), 7.20 (t, J= 5.9 Hz, 1H), 6.91 (d, J= 8 Hz, 1H), 6.81 (t, J = 5.6 Hz. 1H), 4.23-4.12 (m. 2H), 3.68 (s. 3H), 3.17 (br, 1H). 2.81 (t. J = 5.6 Hz. 2H), 2.21 (br, 1H); 2.04 (br, 1H).
LCMS (ESI, m/z) = 373.37 [M+l],
General procedure: Deoxygenation
COMPOUND 27
To rac-(3 S)-3 - [2- [4-(5 ,6,7,8-tetrahy droimidazo [ 1 ,2-a]pyridin-2- yl)phenyl]ethynyl]tetrahydropyran-3-ol (50 mg, 0.155 mmol, 1.00 eq), trifluoroacetic acid (1 mL) and triethylsilane (.6 mL, 0.155 mmol, 1.00 eq) was added under nitrogen atmosphere at 0°C. The reaction was warmed to 25°C and continued the reaction for further 16 hrs. The reaction progress was monitored by LCMS and TLC (5% MeOH/DCM), after completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution, diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate, fdter and concentrated under reduced pressure to get crude. The crude was purified by using 230-400 mesh silica gel and eluted with MeOH/DCM (0-5%) to get 88% pure compound, which was further purified by reverse phase preparative HPLC method (column- Innert cell; Flow rate: 18 mL/min; Mobile phase: ABC/ACN) to get 2-[4-[2-[rac- (3 R)-tetrahydropyran-3-yl |ethynyl | phenyl |-5.6.7.8-tetrahydroimidazo| 1,2-alpyridine, COMPOUND 27, (15 mg, 0.0491 mmol, 99.69% purity, 32% yield) as a white solid.
1H NMR (400 MHz, DMSO-d6): δ (d, J= 8 Hz, 2H), 7.49 (s, 1H), 7.31 (d, J= 8 Hz, 2H), 3.96-3.94 (m, 2H), 3.87-3.84 (m, 1H), 3.74-3.71 (m, 1H), 3.42-3.35 (m, 2H), 2.76-2.75 (m, 3H), 1.89-1.86 (m, 5H), 1.67-1.62 (m, 3H).
LCMS (ESI, m/z) = 307.13 [M+H],
General procedure: Chan lam coupling
COMPOUND 69
To a stirred solution of 2-[4-[2-(azetidin-3-yl)ethynyl]phenyl]-5,6,7,8-tetrahydroimidazo[l,2- a] pyridine (150 mg, 0.541 mmol, 1.00 eq) in DCM (10 mL) was added (3,4- dimethylphenyl)boronic acid (243 mg, 1.62 mmol, 3.00 eq), copper acetate (246 mg, 1.35 mmol, 2.50 eq), and pyridine (.11 mL, 1.35 mmol, 2.50 eq) at RT, and stirred for 24 hrs under air atmosphere. The progress of the reaction was monitored by TLC & LCMS.
Upon completion, the reaction mixture was diluted with water (20 mL) and extracted using DCM (10 mL x 2). The combined organic layer was washed with water (10 mL x 2). brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced vacuum to afford crude. The crude material was purified by flash column chromatography using silica gel column and the product eluted at 2-4% MeOH in DCM, again repurified by Prep HPLC purification to afford 2-[4-[2-[l-(3,4-dimethylphenyl)azetidin-3- yl]ethynyl]phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine. COMPOUND 69, (20 mg. 0.0521 mmol, 99.36% purity, 10% yield) as pale brown solid.
1H NMR (400MHz, DMSO-d6): δ 7.67 (d, J= 7.6 Hz, 2H), 7.51 (s, 1H), 7.35 (d, J= 8.0 Hz, 2H), 6.93 (d, J= 8.0 Hz, 1H), 6.29 (s, 1H), 6.21 (d, J= 8.4 Hz, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.96-3.94 (m, 2H), 3.78-3.76 (m, 1H), 3.71-3.69 (m, 2H), 2.74 (t, J= 5.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.90-1.84 (m, 4H).
LCMS(ESI, m/z) = 382.50 [M+H],
Synthesized following procedure Chan-lam, title compound was afforded as an off white solid (16 mg. 95.5% purity, 2% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J= 6.4 Hz, 1H), 7.72 (s, 1H), 7.46 (d, J= 8.8 Hz, 1H), 7.17 (t, J= 6.8 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 6.83 - 6.79 (m, 2H). 6.69 (d, J= 8 Hz, 1H), 3.68 (d, J= 12.4 Hz, 2H), 2.85 - 2.73 (m, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 2.07 (d, J= 14 Hz, 2H), 1.80 (q, J= 11.6 Hz, 2H), 1.24 (s, 1H).
LCMS (ESI, m/z) = 306.2 [M+H],
COMPOUND 79 To a stirred solution of 2-t2-(azetidin-3-yl)ethynyl]-5,6,7,8-tetrahydroimidazotl,2-aJpyridine hydrochloride (220 mg, 0.925 mmol, 1.00 eq) and methyl 4-fluoro-2-methyl-benzoate (311 mg, 1.85 mmol, 2.00 eq) in DMSO (5 mL) was added DIPEA (.48 mL, 2.78 mmol, 3.00 eq) then the resulting reaction mixture was heated at 100°C for 16 h. TLC and LCMS was showed the desired compound was formed. Reaction mixture was diluted with ethyl acetate (30mL). Combine organic layers were washed with cold water (lOmL) and brine solution (lOmL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a crude compound.
Crude compound was purified by Prep HPLC (mobile phase - 5% MeOH/DCM :Rf=0.3 ) to give COMPOUND 79, (12 mg, 99.86% purity, 4% yield) as a brown solid.
1H NMR (400MHz, DMSO-d6): δ 7.75 (d, J= 8.8 Hz, 1H), 7.23 (s, 1H), 6.33-6.30 (m, 2H), 4.25-4.22 (m, 2H), 3.89-3.86 (m, 2H), 3.84-3.81 (m, 3H), 3.73 (s, 3H), 2.66-2.65 (m, 2H), 2.47 (s, 3H), 1.86-1.80 (m, 4H).
LCMS (m/z) = 350.2 [M+H],
General procedure - Carbonyl reduction (carb red)
COMPOUND 24
Methyl rac-(6S)-2-[4-[2-[2-fluoro-5-(trifluoromethyl)phenyl]ethynyl]phenyl]-5,6,7,8- tetrahydroimidazo[l,2-a]pyridine-6-carboxylate (320 mg, 0.723 mmol, 1.00 eq) was taken in THF (15 mL), after that DIBAL (IM in toluene) (.52 mL, 2.89 mmol, 4.00 eq) was added at 0°C, reaction was stirred for 16 hrs at 25 °C, LC showed that near about 60 % desired product was formed, then again 2 eq of DIBAL (I M in THF ), was added to the reaction mixture. After full conversion of starting material, reaction was quenched by saturated ammonium chloride solution. Reaction was extracted with ethyl acetate, organic solvent was dried over Na2SO4 and reduced under rotary evaporator, crude was purified by prep-HPLC purification. After purification, title compound was afforded as a white solid (52 mg, 99.67% purity, 17% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.10-8.03 (m, 1H). 7.90-7.82 (m, 1H), 7.79 (d, J= 8.4 Hz, 2H), 7.64-7.53 (m. 4H), 4.79 (t, J= 5.2 Hz, 1H), 4.17-4.08 (m, 1H), 3.71-3.61 (m, 1H), 3.55- 3.47 (m, 1H), 3.45-3.37 (m, 1H), 2.92-2.81 (m, 1H), 2.78-2.67 (m, 1H), 2.12-2.05 (m, 1H), 2.01-1.93 (m, 1H), 1.65-1.50 (m, 1H). LCMS (m/z) = 415 [M+H] .
Synthesized using procedure carb red, the title compound was afforded as an off white solid (38 mg, 99.68% purity, 16% yield).
1H NMR (400MHz, DMSO-d6): δ 9.71 (s, 1H), 7.74 (d, J= 7.6 Hz, 2H), 7.58 (s, 1H), 7.48 (d, J= 7.6 Hz, 2H), 7.21(t, J= 8.0 Hz, 1H), 6.95 (d, J= 8.4 Hz, 1H), 6.89 (s, 1H), 6.80 (d, J = 8.0 Hz. 1H), 4.78 (bs, 1H). 4.13-4.09 (m, 1H). 3.68 (t. J= 10.8 Hz, 1H), 3.49 (br, 1H), 3.42 (br, 1H), 2.88-2.50 (m, 2H), 2.09 (br, 1H), 1.96(br, 1H), 1.60-1.55 (m, 1H).
LCMS (ESI, m/z) = 345.15 [M+l] Synthesized according to procedure carb red, title compound was afforded as an off white solid (10 mg. 99.73% purity. 24% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 4.8 Hz, 1H). 7.77 (d, J = 7.6 Hz, 2H). 7.61 (s, 1H), 7.54 (d. J= 8 Hz. 2H), 7.06 (d. J= 4.8 Hz. 1H), 6.90 (s, 1H), 4.77 (t, J= 5 Hz, 1H). 4.31 (m, 2H), 4. 12-4.09 (m, 1H), 3.65 (t, ,7 = 10.8 Hz, 1H), 3.49-3.47 (m, 1H), 3.43-3.38 (m, 1H),
2.88-2.83 (m, 1H), 2.75-2.71 (m, 1H), 2.09 (br s, 1H), 1.98-1.95 (m, 1H), 1.58-1.55 (m, 1H), 1.32 (t, .7= 7.2 Hz, 3H).
UPLC (m/z) = 374.2 [M+H], COMPOUND 31
Synthesized according to procedure carb red, title compound was afforded as an off white solid (66 mg. 99.7% purity, 64% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J= 8.28 Hz. 2H), 7.60-7.52 (m. 6H), 7.43 (d, J=
7.12 Hz, 1H), 4.78 (t, J = 5.2 Hz, 1H). 4.14-4.09 (m, 1H). 3.65 (t. J = 10.36 Hz, 1H). 3.52- 3.47 (m, 1H), 3.45-3.39 (m, 1H), 2.89-2.83 (m, 1H), 2.75-2.67 (m, 1H), 2.11-2.02 (m, 1H),
1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ d -56.795 (s).
UPLC (m/z) = 413.1 [M+H],
Synthesized according to procedure carb red, title compound was afforded as an off white solid (53 mg, 99.64% purity, 52% yield).
1H NMR (400 MHz. DMSO-d6): δ 8.21 (d, J= 5.2 Hz, 1H). 7.77 (d, J= 8.12 Hz. 2H), 7.62 (s, 1H), 7.54 (d, J= 8.12 Hz, 2H), 7.10 (d, J= 5.08 Hz, 1H), 6.95 (s, 1H), 4.79 (t, J= 5 Hz, 1H), 4.10 (dd, J= 12.1, 4.8 Hz, 1H), 3.87 (s, 3H), 3.65 (t, J= 10.8 Hz, 1H), 3.51-3.47 (m, 1H), 3.45-3.39 (m, 1H), 2.89-2.84 (m, 1H), 2.76-2.67 (m, 1H), 2.10-2.08 (m, 1H), 1.98-1.96 (m. 1H), 1.61-1.55 (m. 1H). UPLC (m/z) = 360.2 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a light yellow solid (47 mg, 98.2% purity, 55% yield).
1H NMR (400 MHz. DMSO-d6): δ 8.81 (d, J = 4.8 Hz, 1H). 8.05 (s, 1H). 7.84 (d, J = 4.2 Hz, 1H), 7.81 (d, J = 8 Hz, 2H), 7.64 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 4.79 (t, J= 52 Hz, 1H), 4.11 (dd, J= 12.4, 5.2 Hz, 1H), 3.66 (t, J= 10 Hz, 1H), 3.52-3.47 (m, 1H), 3.45-3.39 (m, 1H), 2.89-2.83 (m, 1H), 2.76-2.67 (m, 1H), 2.10-2.07 (m, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m. 1H).
19F NMR (376 MHz. DMSO-d6): δ -66.767(s).
UPLC (m/z) = 398.2 [M+H],
Synthesized according to procedure carb red, the title compound was afforded as an off white solid (25 mg. 99.7% purity, 12% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J= 4.80 Hz. 1H), 7.77 (d. J= 8.00 Hz, 2H), 7.60 (s, 1H), 7.53 (d, J= 8.40 Hz, 2H), 6.73 (s, 1H), 6.65 (d, J= 5.20 Hz, 1H), 4.77 (t, J= 5.00
Hz, 1H), 4.12 (dd, J= 4.80, 12.40 Hz, 1H), 3.66 (t, J= 11.0 Hz, 1H), 3.53-3.47 (m, 1H), 3.45-3.39 (m, 1H), 3.04 (s, 6H), 2.88-2.83 (m, 1H), 2.76-2.67 (m, 1H), 2.12-2.05 (m, 1H), 1.99-1.94 (m, 1H), 1.60-1.54 (m, 1H).
LCMS (ESI, m/z) = 373.2 [M+H], Synthesized according to procedure carb red, title compound was afforded as a white solid (80 mg, 98.65% purity, 68% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.75 (d, J= 8.0 Hz, 2H). 7.59 (s, 1H), 7.50 (d, J= 8.2 Hz, 2H), 7.33 (t, J= 8.0 Hz, 1H), 7.13-7.09 (m, 2H), 6.98 (dd, J= 8.36. 1.92 Hz, 1H), 4.78 (t, J = 5.16 , 1H), 4.1 1 (dd, .7 = 12.36, 4.96 Hz, 1H), 3.79 (s, 3H), 3.68-3.63 (m, 1H), 3.53-3.47 (m,
1H), 3.45-3.39 (m, 1H), 2.88-2.84 (m, 1H), 2.76-2.67 (m, 1H), 2.10-2.08 (m, 1H), 1.98-1.95 (m, 1H), 1.59-1.55 (m, 1H).
UPLC (m/z) = 359.2 [M+H], COMPOUND 40
Synthesized according to procedure carb red, title compound was afforded as an off white solid (20 mg. 99.82% purity. 28% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J= 5.2 Hz, 1H). 7.78 (d, J = 8 Hz, 2 Hz, 1H), 7.62 (s. 1H), 7.54 (d. J = 8 Hz. 2H), 7.09 (d. J = 5.2 Hz. 1H), 6.94 (s, 1H). 4.79 (t. J= 5.2 Hz, 1H), 4.39 (t, J = 4.8 Hz, 2H), 4. 11 (dd, J = 12.4, 5.2 Hz, 1H), 3.68-3.63 (m, 3H), 3.51- 3.47 (m, 1H), 3.44-3.40 (m, 1H), 3.30 (s, 3H), 2.88-2.83 (m, 1H), 2.74-2.71 (m, 1H), 2.09- 2.08 (m, 1H), 1.98-1.95 (m, 1H), 1.59-1.56 (m, 1H).
UPLC (m/z) = 404.2 [M+H],
COMPOUND 41
Synthesized according to procedure carb red, title compound was afforded as an off white solid (70 mg. 99.8% purity, 34% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 7.84 (dd, J= 8.4 Hz, 1H), 7.74 (d, J= 8.4 Hz. 2H), 7.57 (s, 1H), 7.48 (d, J= 8.0 Hz, 2H), 6.88 (d, J= 8.8 Hz, 1H), 4.9-4.87 (m, 1H), 4.13-4.09 (m, 3H). 3.68-3.62 (m, 1H). 3.51-3.47 (m, 1H). 3.44-3.39 (m, 1H). 2.88-2.86 (m, 1H), 2.75-2.66 (m, 1H), 2.09 (s, 1H), 1.98-1.94 (m, 1H), 1.61-1.48 (m, 1H), 1.27-1.19 (m, 1H), 0.57-0.53 (m, 2H), 0.35-0.31 (m, 2H). LCMS (ESI, m/z) = 400.2 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a white solid (48 mg, 99.64% purity, 57% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J= 8.2 Hz, 2H), 7.72 (d, J= 7.52 Hz, 1H), 7.60 (s, 1H), 7.57-7.45 (m, 5H), 4.79 (t, J= 5.12 Hz, 1H), 4.10 (dd, J= 12.32, 4.88 Hz. 1H), 3.65 (t, J= 10.4 Hz, 1H), 3.52-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.88-2.84 (m, 1H), 2.76-2.67 (m, 1H), 2.10-2.09 (m. 1H), 1.98-1.95 (m. 1H), 1.61-1.55 (m. 1H).
19F NMR (376 MHz. DMSO-d6): δ -56.58 (s).
UPLC (m/z) = 413.2 [M+H],
COMPOUND 45
Synthesized according to procedure carb red, title compound was afforded as a white solid (24 mg, 99.11% purity, 39% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J= 2 Hz, 1H), 7.86 (dd, J= 8.4, 2 Hz, 1H), 7.74 (d, 8 Hz, 2H), 7.59 (s, 1H), 7.49 (d, 8.4 Hz, 2H), 6.88 (d, 8.4 Hz, 1H), 4.79 (t, J =
5.2 Hz. 1H), 4.11 (dd, J= 12.4, 4.8 Hz, 1H), 3.89 (s, 3H). 3.65 (t. J=10.8 Hz, 1H). 3.53-3.47 (m, 1H), 3.43-3.39 (m, 1H), 2.88-2.83 (m, 1H), 2.75-2.67 (m, 1H), 2.10-2.08 (m, 1H), 1 .98- 1.95 (m, 1H), 1.62-1.53 (m, 1H). UPLC (m/z) = 360.2 [M+H], COMPOUND 49
Synthesized according to procedure carb red, title compound was afforded as a light brow n solid (15 mg. 99.07% purity. 7% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.78 (s, 1H), 8.13 (s, 1H), 7.79 (d, J= 8.28 Hz. 2H), 7.62 (s, 1H), 7.56 (d. J= 8.28 Hz, 2H), 7.18 (t, J= 55.00 Hz, 1H), 4.79 (t, J= 5.16 Hz, 1H), 4.12 (dd, J = 5.00 & 12.30 Hz, 1H), 3.66 (t, J= 12.20 Hz, 1H), 3.50-3.46 (m, 1H), 3.44-3.39 (m, 1H), 2.76-2.68 (m, 1H), 2.86-2.82 (m 1H), 2.12-2.07 (m, 1H), 2.02-1.93 (m, 1H), 1.62-1.52 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -112.09 (d).
LCMS (ESI, m/z) = 380.1 [M+H],
COMPOUND 50
Synthesized according to procedure carb red, title compound was afforded as an off white solid (30 mg, 99.88% purity, 38% yield).
1H NMR (400 MHz, DMSO-rty): 8 7.76 (d, J= 8 Hz, 2H), 7.63-7.60 (m, 2H), 7.52 (d, J= 8.4 Hz, 2H), 7.37 (s, 1H), 7.23 (d, J= 8 Hz, 1H), 4.79 (t, J= 5.2 Hz, 1H), 4.11 (dd, J= 12.4, 5.2 Hz. 1H), 3.68-3.62 (m. 1H), 3.51-3.47 (m. 1H), 3.45-3.40 (m. 1H), 2.88-2.84 (m. 1H), 2.76- 2.71 (m, 1H), 2.10-2.07 (m, 1H), 1.98-1.95 (m, 1H), 1.59-1.55 (m, 1H).
1H NMR (400 MHz, MeOD): δ 7.71 (d, J= 8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8 Hz, 2H), 7.39 (s, 1H), 7.19 (s, 1H), 7.10 (d, J = 8 Hz, 1H), 4.21 (dd, J= 12.4, 4.8 Hz, 1H), 3.78-3.73 (m, 1H), 3.69-3.65 (m, 1H), 3.61-3.57 (m, 1H), 3.03-2.96 (m, 1H), 2.86-2.78 (m, 1H), 2.53 (s, 3H), 2.23-2.22 (m, 1H), 2.12-2.08 (m, 1H), 1.75-1.64 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -56.58 (s). UPLC (m/z) = 427.2 [M+H],
COMPOUND 55
Synthesized according to procedure carb red, title compound was afforded as an off white solid (25 mg. 98.6% purity, 19% yield).
1H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H); 7.74-7.69 (m, 2H), 7.56 (s. 1H), 7.53-7.35
(m. 2H). 7.18 (t. J = 5.2 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.81 (t, J= 5.2 Hz, 1H). 4.78 (br.
1H), 4.13-4.09 (m, 1H), 3.65 (t, J= 5.2 Hz, 1H), 3.52-3.40 (m, 2H), 2.89-2.67 (m, 2H), 2.09 (br, 1H), 1.97 (br, 1H), 1.60-1.54 (m, 1H). LCMS (ESI, m/z) = 345.15 [M+l],
COMPOUND 56
Synthesized according to procedure carb red, title compound was afforded as a white solid (48 mg, 99.6% purity, 46% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.78 (d, J= 8 Hz, 2H), 7.72-7.69 (m, 2H), 7.61-7.54 (m, 4H), 4.79 (t, J= 5.04 Hz, 1H), 4.10 (dd, J= 12.44, 4.88 Hz. 1H), 3.65 (t, J= 10.96 Hz. 1H), 3.51-3.47 (m, 1H). 3.44-3.33 (m, 1H). 2.88-2.84 (m, 1H). 2.74-2.67 (m, 1H). 2.55 (s. 3H), 2.11-2.09 (m, 1H), 1.98-1.95 (m, 1H), 1.61-1.55 (m, 1H). 19F NMR (376 MHz, DMSO-d6): δ -61.16 (s).
UPLC (m/z) - 41 1.2 [M+H],
COMPOUND 58 Synthesized according to procedure carb red, title compound was afforded as a white solid (42 mg, 99.78% purity, 18% yield).
>H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.19 (dd, J= 8.0 Hz, 1H), 7.77 (d, J= 8.0 Hz. 2H), 7.60 (s, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 8.0 Hz, 1H), 4.79-4.76 (m, 1H), 4.13-4.09 (m, 1H). 3.68-3.62 (m, 1H). 3.52-3.47 (m, 1H). 3.44-3.39 (m, 1H). 2.88-2.83 (m, 1H), 2.75-2.67 (m, 1H), 2.08 (s, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H).
LCMS (ESI, m/z) = 414. 1 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a white solid (38 mg, 99.57%, 19% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J= 8.0 Hz, 2H), 7.60 (s, 1H), 7.52 (d, J= 8.4 Hz, 2H), 7.28 (s, 1H), 7.09 (s, 1H), 4.79-4.76 (m, 1H), 4.12 (dd, J= 6.0 Hz, 1H), 3.68-3.65 (m, 1H), 3.49-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.88-2.82 (m, 1H), 2.75-2.71 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 2.09 (s, 1H), 1.98-1.95 (m, 1H), 1.59-1.54 (m, 1H). LCMS (ESI, m/z)= 358.2 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a white solid (105 mg. 99.87%, 38% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J= 8.0 Hz, 2H), 7.57 (s, 1H), 7.46 (d, J= 8.4 Hz, 2H), 7.33 (s, 1H), 7.26 (d, J= 8.4 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 4.80-4.77 (m, 1H), 4.11 (dd, J= 6.0 Hz, 1H), 3.67-3.62 (m, 1H), 3.51-3.47 (m, 1H), 3.44-3.38 (m, 1H), 2.83-2.81 (m, 1H), 2.73-2.67 (m, 1H), 2.38 (s, 3H), 2.08 (s, 1H), 1.97-1.92 (m, 1H), 1.59-1.54 (m, 1H), LCMS (ESI, m/z) = 383.2 [M+H], COMPOUND 65
Synthesized according to procedure carb red, title compound was afforded as an off white solid (54 mg. 99.62% purity. 55% yield).
'H NMR (400 MHz, DMSO-d6): δ 8.17 (d, J= 5.6 Hz, 1H), 7.78 (d, J= 8.4 Hz, 2H), 7.62 (s, 1H), 7.54 (d, J= 8.4 Hz, 2H), 7.06 (dd, J= 5.2, 1.2 Hz, 1H), 6.93 (s, 1H), 4.79 (t. J= 5.2 Hz,
1H), 4.14-4.09 (m, 3H), 3.80-3.63 (m, 1H), 3.52-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.89-2.83 (m, 1H), 2.76-2.69 (m, 1H), 2.09-2.08 (m, 1H), 1.99-1.95 (m, 1H), 1.61-1.54 (m, 1H), 1.26- 1.21 (m, 1H), 0.57-0.53 (m, 2H), 0.34-0.31 (m, 2H).
UPLC (m/z) = 400.2 [M+H],
COMPOUND 68
Synthesized according to procedure carb red, title compound was afforded (55 mg, 99.12% purity, 19% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.88 - 7.71 (m, 4H), 7.63 (s, 1H), 7.57 (t, J= 8.5 Hz, 3H), 4.79 (t, J= 5.2 Hz, 1H), 4.12 (dd, J= 12.5, 5.2 Hz, 1H), 3.71 - 3.61 (m, 1H), 3.54 - 3.46 (m,
1H), 3.46 - 3.37 (m, 1H), 2.91 - 2.82 (m, 1H), 2.78 - 2.67 (m, 1H), 2. 12 - 2.07 (m, 1H). 2.01 - 1.93 (m, 1H), 1.65 - 1.50 (m, 1H).
LCMS (ESI. m/z) = 415.1 [M+H],
COMPOUND 72
Synthesized according to procedure carb red, title compound was afforded as an off white solid (21 mg, 98. 1% purity, 7% yield).
1H NMR (400 MHz. DMSO-d6): δ 7.76 (d, J = 8 Hz, 2H): 7.59 (s, 1H): 7.50 (d, J = 6.8 Hz, 3H); 7.31-7.30 (m, 2H); 7.25-7.23 (m, 1H); 4.78 (s, 1H); 4.11 (d, J= 8 Hz, 1H); 3.66 (t, J = 11.2 Hz, 1H); 3.50-3.49 (m, 1H); 3.44 (bs, 1H); 2.88-2.84 (m, 1H); 2.73-2.67 (m, 1H); 2.47 (s, 3H); 2.09 (bs, 1H); 1.96 (bs, 1H); 1.58-1.57 (m, 1H).
LCMS (ESI, m/z) = 343.45 [M+l],
Synthesized according to procedure carb red, title compound was afforded as a white solid (32 mg, 99.69% purity, 86% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.21 (d, J= 1.6 Hz, 1H), 7.92 (dd, J= 11.2, 1.6 Hz, 1H), 7.76 (d, J= 8.4 Hz, 2H), 7.59 (s, 1H), 7.50 (d, J= 8.4 Hz, 2H), 4.78 (t, J= 5.2Hz. 1H), 4.14-
4.09 (m, 1H), 3.98 (s, 3H), 3.68-3.52 (m, 1H), 3.52-3.47 (m, 1H), 3.45-3.41 (m, 1H), 2.87- 2.83 (m, 1H), 2.75-2.69 (m, 1H), 2.08 (br s, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H). 19F NMR (376 MHz, DMSO-d6) : δ -139.32 (d, J=10.98 Hz).
UPLC (m/z) = 378.2 [M+H], Synthesized according to procedure carb red, title compound was afforded as a white solid (48 mg, 97.77% purity, 42% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J= 5.2 Hz, 1H). 7.78 (d, J= 8 Hz, 2H). 7.62 (s, 1H), 7.55 (d. J= 8.4 Hz. 2H), 7.23 (dd, J= 5.6, 0.8 Hz, 1H), 7.13 (s, 1H), 5.02 (m. 2H), 4.79 (t, J= 5.2 Hz, 1H), 4.11 (dd, J= 12.4, 5.2 Hz, 1H), 3.68-3.62 (m, 1H), 3.52-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.89-2.83 (m, 1H), 2.76-2.67 (m, 1H), 2.08 (br m, 1H), 1.98-1.95 (m, 1H),
1.62-1.52 (m, 1H).
19F NMR (376 MHz,DMSO-d6) : δ -72.272 (t).
UPLC (m/z) = 428.2 [M+H], Synthesized according to procedure carb red, title compound was afforded as an off white solid (18 mg. 99.83% purity. 32% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J= 7.6 Hz, 2H). 7.57 (s, 1H), 7.49-7.45 (m, 4H), 6.98 (d, J= 8.0 Hz, 2H). 4.78-4.76 (m, 1H). 4. 11 (dd. J= 12.0, 4.4 Hz, 1H), 3.79 (s, 3H), 3.65 (t, .7= 1 1.2 Hz, 1H), 3.51 -3.48 (m, 1H), 3.45-3.42 (m, 1H), 2.88-2.84 (m, 1H), 2.75-2.71
(m, 1H), 2.09-2.08 (m, 1H), 1.98-1.95 (m, 1H), 1.59-1.55 (m, 1H).
UPLC (m/z) = 359.2 [M+H],
COMPOUND 82 Synthesized according to procedure carb red, title compound was afforded as a white solid (14 mg, 99.11% purity, 53% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J= 8 Hz, 2H), 7.68 (d, J= 8.4 Hz, 2H), 7.60 (s, 1H), 7.52 (d, .7=8 Hz, 2H), 7.43 (d, .7=8 Hz, 2H), 4.79 (t, .7=5.2 Hz, 1H), 4.11 (dd, J= 12, 4.8 Hz. 1H), 3.65 (t, .7=10.8 Hz, 1H), 3.52-3.47 (m, 1H), 3.44-3.33 (m, 1H), 2.88-2.83 (m, 1H), 2.75-2.67 (m, 1H). 2.10-2.08 (m, 1H). 1.98-1.95 (m, 1H). 1.62-1.52 (m, 1H).
19F NMR (376 MHz. DMSO-d6): δ -56.74.
UPLC (m/z) = 413.1 [M+H],
COMPOUND 83
Synthesized according to procedure carb red, title compound was afforded as a white solid (37 mg, 99.22% purity, 16% yield).
1H NMR (400 MHz. DMSO-d6): δ 8.08-8.04 (m, 1H). 7.81-7.78 (m, 3H). 7.70 (d, J=8.0 Hz. 1H), 7.62-7.58 (m, 3H), 7.12-6.84 (m, 1H), 4.78-4.76 (m, 1H), 4.12 (dd, J= 6.0 Hz, 1H), 3.66 (t, J= 12.0 Hz, 1H), 3.52-3.47 (m, 1H), 3.45-3.39 (m, 1H), 2.88-2.84 (m, 1H), 2.76-2.66 (m, 1H), 2.10 (s, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H).
19F NMR (376 MHz, DMSO: - δd -65)6.74 (d, J= 54.5 Hz). LCMS (ESI, m/z)= 380.1 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a white solid (70 mg, 98.96% purity, 70% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.81 (d, J= 7.6 Hz, 1H), 7.78 (d, J= 8.0 Hz, 2H), 7.71 (d, J= 8.0 Hz. 1H), 7.61 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 8.0 Hz, 1H). 4.79 (t, J = 5.2 Hz, 1H), 4.11 (dd, J= 12.4, 5.2 Hz, 1H), 3.68-3.62 (m, 1H), 3.52-3.47 (m, 1H), 3.45-3.39 (m, 1H), 2.89-2.83 (m, 1H), 2.78-2.67 (m, 1H), 2.62 (s, 3H), 2.09-2.08 (m, 1H), 1.98-1.95 (m. 1H), 1.62-1.52 (m. 1H).
19F NMR (376 MHz. DMSO-d6): δ -59.931.
UPLC (m/z) = 411.2 [M+H],
COMPOUND 90
Synthesized according to the procedure carb red, title compound was afforded as an off white solid (15 mg. 99.66% purity. 7% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.69 (br s, 1H), 7.96 (d, J= 8.4 Hz, 1H), 7.81-7.78 (m, 3H), 7.62 (s, 1H), 7.57 (d, J= 8.4 Hz, 2H), 4.79-4.76 (m, 1H), 4. 14-4.09 (m, 1H), 3.69-3.63
(m, 1H), 3.52-3.47 (m, 1H), 3.45-3.41 (m, 1H), 2.89-2.83 (m, 1H), 2.76-2.66 (m, 1H), 2.09 (s, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -57.125(s).
LCMS (m/z)= 414.1 [M+H], Synthesized according to procedure carb red, title compound was afforded as an off white solid (38 mg. 99.6% purity, 12% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.27 (d, J= 8.4 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 8.80 (d. J = 8.4 Hz. 2H), 7.64-7.59 (m. 3H), 4.80-4.77 (m. 1H), 4.14-4.10 (M. 1H), 3.66 (t, .7=1 1.2 Hz, 1H), 3.52-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.88-2.84 (m, 1H), 2.76-2.69 (m,
1H), 2.09 (s, 1H), 1.98-1.95 (m, 1H), 1.59-1.55 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -60.943 (s).
LCMS (ESI, m/z) = 398.1 [M+HJ. COMPOUND 94
Synthesized according to procedure carb red, title compound was afforded as a white solid (70 mg, 98.2% purity, 57% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.74 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.47-7.44 (m, 3H), 7.38 (t, .7= 8.0 Hz, 1H), 7.08 (d, .7= 8.0 Hz, 1H), 6.97 (t, .7= 7.6 Hz, 1H), 4.78 (t, J= 5.04 , 1H), 4.11 (dd, <7= 12.32. 4.96 Hz, 1H), 3.86 (s, 3H), 3.68-3.62 (m, 1H), 3.53-3.47 (m, 1H),
3.45-3.39 (m, 1H). 2.89-2.84 (m, 1H). 2.76-2.67 (m, 1H). 2. 11-2.09 (m, 1H). 1.98-1.95 (m, 1H), 1.62-1.53 (m, 1H).
UPLC (m/z) = 359.2 [M+HJ.
Synthesized according to procedure carb red, title compound was afforded as an off white solid (57 mg. 99.88% purity. 21% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.26 ( 3.6 Hz, 1H). 8.18 (t. J = 8.0 Hz, 1H). 7.782
(d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.537 (d, J= 8.0 Hz, 2H), 7.45-7.42 (m, 1H), 7.82 (t, J= 5.2 Hz, 1H), 4.13-4.09 (m, 1H), 3.68-3.62 (m, 1H), 3.52-3.47 (m, 1H), 3.44-3.38 (m, 1H), 2.89- 2.82 (m, 1H), 2.75-2.67 (m, 1H), 2.08-2.07 (m, 1H), 1.97-1.94 (m, 1H), 1.61-1.53 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -65.650 (d, J= 9.3 Hz). LCMS (m/z)= 348.2 [M+H],
Synthesized according to procedure carb red, title compound was afforded as a white solid (65 mg, 99.3% purity, 30% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.73 (d, J= 8.4 Hz, 2H), 7.48 (d, J= 8.4 Hz, 2H), 7.33 (s, 1H), 7.26 (d, J= 7.6 Hz. 1H), 7.17 (d, J= 7.6 Hz, 1H), 5.82 (s, 1H), 5.56-5.55 (m, 1H), 3.56 (s, 3H), 2.71 (d, J= 5.2 Hz, 3H), 2.24 (s, 3H), 2.23 (s, 3H).
LCMS (ESI, m/z) = 316.2 [M+H],
COMPOUND 119
Synthesized according to procedure carb red, title compound was afforded as an off white solid (10 mg. 99.25% purity. 18% yield).
1H NMR (400 MHz, DMSO-d6): δ 13.76 (s, 1H), 10.29 (s, 1H). 8.23 (d, J = 8.08 Hz, 1H), 7.85 (d, J = 8.64 Hz. 2H), 7.69-7.65 (m. 3H), 7.48-7.43 (m. 2H), 7.29 (t, J = 7.6 Hz, 1H). 4.78 (t, J = 5.32 Hz, 1H), 4.10 (dd, J = 12.4 , 5.2 Hz, 1H), 3.64 (t, J = 11.9 Hz, 1H), 3.52-3.40 9m, 2H), 2.87-2.83 (m, 1H), 2.75-2.71 (m, 1H), 2.08 (brs, 1H), 1.99-1.95 (m, 1H), 1.62-1.53 (m, 1H). UPLC (m/z) = 388.2 (M+H)+ Synthesized according to procedure carb red, title compound was afforded as an off white solid (25 mg. 98.33% purity. 35% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 7.68-7.62 (m, 5H), 7.45 (s, 1H), 7.15 (s, 1H), 7.03 (d. J = 8.8 Hz. 1H), 4.76 (t, J = 5.2 Hz, 2H). 4.08 (dd. J = 1.24. 4.8 Hz. 1H), 3.89 (s, 3H), 3.65-3.59 (m, 1H), 3.49-3.44 (m, 1H), 3.42-3.36 (m, 1H), 2.86-2.82 (m, 1H), 2.75-2.70 (m, 1H), 2.07-2.04 (m, 1H), 1.95-1.92 (m, 1H), 1.58-1.51 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -56.55
LC-MS: m/z = 462.2 (M+H)+
COMPOUND 135
Synthesized according to procedure carb red to furnish the title compound as a white solid (26 mg, 99.58% purity, 15% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, J = 8 Hz, 2H); 7.41 (s, 1H): 7. 17 (d, J= 8 Hz, 3H); 7. 12 - 7.08 (m, 3H); 4.77 (t, .7=5.2 Hz, 1H); 4. 11 - 4.07 (m, 1H); 3.66 - 3.60 (m, 1H); 3.51 - 3.47 (m, 1H); 3.45 - 3.39 (m, 1H); 2.83 - 2.77 (m, 5H); 2.74 - 2.65 (m, 1H); 2.26 (s, 3H); 2.07 (bs, 1H):1.98 - 1.94 (br s, 1H); 1.58 - 1.54 (m, 1H).
LCMS (ESI, m/z): 347.40 (M+H)+
General procedure - tetrazole
COMPOUND 77
To the mixture of 2-[4-[2-(3,4-dimethylphenyl)ethynyl]phenyl]imidazo[l,2-a]pyridine-6- carbonitrile (500 mg, 1.44 mmol, 1.00 eq) and dibutyltin oxide (72 mg, 0.288 mmol, 0.200 eq) in toluene (10 ml) was added trimethylsilyl azide (248 mg, 2.16 mmol, 1.50 eq) the reaction mixture was stirred at 80°C for 16 hrs. After completion of the reaction (monitored by TLC, 0. 1=2 rf value in 10% MeOH-DCM), the solvent in the reaction mixture was evaporated under reduced pressure to obtain the crude compound, which was purified by preparative HPLC to afford the title compound as an off white solid (44 mg, 99.29% purity, 8% yield).
'H NMR (400 MHz, DMSO-d6): δ 9.27 (s,lH), 8.65 (s,lH), 8.04-8.02 (d, J= 8 Hz, 2H), 7.84-7.76 (m, 2H), 7.63-7.60 (d, J= 12Hz, 2H), 7.36 (s. 1H), 7.30-7.28 (d, J= 8 Hz, 1H), 7.20-7. 18 (d. J = 8 Hz. 1H), 2.25 (s.3H). 2.24 (s, 3H).
LCMS (ESI, m/z) = 391.2 [M+H], Synthesized according to procedure tetrazole, title compound was afforded as a grey solid (38 mg, 99.87% purity, 19% purity).
*H NMR (400 MHz, DMSO-d6): δ 9.44 (s, 1H), 8.66 (s. 1H), 8.48 (s, 1H), 8.17 (d, J= 8.7
Hz. 1H), 7.83 (s, 2H), 7.63 - 7.56 (m, 1H), 6.89 (d, J= 9.7 Hz, 1H), 6.84 (d, J = 10.2 Hz, 1H), 6.79 (s, IH), 2.32 (s, 3H).
LCMS (ESI, m/z) = 388.0 [M+H],
COMPOUND 152
Synthesized according to procedure tetrazole, title compound was afforded as a white solid (14 mg, 99.88% purity, 12% yield).
'H NMR (400 MHz, DMSO-d6): δ 9.30 (s, IH), 8.57 (s, IH), 8.01 (d, J = 8.4 Hz, 2H), 7.80 (s, 2H), 7.15 (d, J= 8.8 Hz, 2H). 6.84 (d, J= 9.2 Hz, IH), 6.72 (s, 2H), 2.30 (s. 3H).
LCMS (ESI, m/z) = 387.2 [M+H], Synthesized according to procedure tetrazole, title compound was afforded as an off white solid (31 mg. 95.71% purity. 61% yield).
'H-NMR (400 MHz, DMSO-d6) : δ 10.64 (s. 1H), 9.00 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 8.08 (d, J= 7.6 Hz, 1H). 8.01-7.84 (m, 5H). 7.58 (d, J= 9.2 Hz. 1H), 2.43 (s, 3H).
LCMS (ESI, m/z) = [M+H]=397.10, RT= 2.09 mm Synthesized according to a modified procedure of Pd/C red using Pd(OH)2 as a catalyst, title compound was afforded as a white solid (80 mg, 99.65% purity, 21% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.00 (d, J= 8 Hz, 2H), 6.93 (d, J= 8Hz, 1H), 6.70 (s, 1H), 4.13-3.95 (m, 2H), 3.66 (s, 3H), 3.10 (br, 1H), 2.71 (br, 2H), 2.50-2.33 (m, 2H), 2.18- 2.02 (m, 7H), 2.02-1.92 (m, 3H), 1.80 (d, 2H), 1.70 (d, 1H), 1.58-1.38 (m, 4H). LCMS (ESI, m/z) = 367.5 [M+H], Synthesized according to procedure Pd/C, title compound was afforded as an off white solid (21 mg, 99.45% purity, 7% yield).
1H NMR (400 MHz, DMSO-d6): δ 6.94 (d, J= 8 ,4Hz, 1H), 6.75 (s, 1H), 6.65 (d, J= 6.4 Hz, 2H), 3.85 (t, J= 5.2 Hz, 2H), 3.62 (d, J= 12.4 Hz, 2H), 2.69 - 2.64 (m, 4H), 2.16 (s, 3H), 2.10 (s, 3H), 1.93 - 1.81 (m, 6H), 1.59 (d, J= 9.6 Hz, 2H).
LCMS (ESI, m/z) = 310.1 [M+H],
COMPOUND 148
Synthesized according to procedure Pd/C, title compound was afforded as an off white solid (30 mg, 98.4% purity, 8% yield).
>H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 7.41 (s, 1H), 7.29 (d, J= 8.0 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 6.94 (d, J= 8.4 Hz, 2H), 3.93 (t, J = 6 Hz ,2H), 2.71 (s, 2H), 2.30 (s, 3H), 1.88-1.84 (m, 4H).
LCMS (ESI, m/z) = 305.2 [M+H],
COMPOUND 10
Synthesized according to procedure Pd/C. title compound was afforded as an off white solid (20 mg, 99.08% purity, 12% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.67(d, J= 8.8 Hz. 2H), 7.38 (s, 1H), 7.15 (d, J = 8.0 Hz.lH), 6.90 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 2.4 Hz,lH). 6.75 (dd. J= 6.0 Hz. 1H), 3.94 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 6.4 Hz, 2H), 2.20 (s, 6H), 1.90-1.84 (m, 4H).
LCMS (ESI, m/z) = 319.25 [M+H],
COMPOUND 149
Synthesized according to procedure Pd/C, title compound was afforded as an off white solid (81 mg, 99.25% purity, 23% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 7.41 (d, J= 7.2 Hz, 1H), 7.31-7.27 (m, 2H),
7.15 (d, J= 8.0 Hz,lH), 6.85 (d, J= 2 Hz, 1H), 6.76 (d, J= 8.4 Hz, 2H), 3.93 (t, J= 5.6 Hz, 2H), 2.71 (t, J= 6.4 Hz, 2H), 2.19 (s, 6H). 1.89-1.83 (m, 4H).
LCMS (ESI, m/z) = 319.20 [M+H], COMPOUND 151
Synthesized according to procedure Pd/C red, title compound was afforded as an off white solid (20 mg. 99.37% purity. 11% yield). 1H NMR (400 MHz, DMSO-d6): δ 6.99 (d, J= 8.0 Hz, 1H), 6.73 (br s, 1H), 6.69 (s, 1H). 6.64 (dd, J= 8.2 Hz, 2.7 Hz, 1H). 3.95 (s, 2H), 3.83 (t, J= 5.6 Hz, 2H), 2.63 (t, J= 6.2 Hz, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.88-1.77 (m, 10H).
LCMS (ESI, m/z) = 323.2 [M+H],
COMPOUND 116
Synthesized according to a modified version of procedure Pd/C red using Pd(OH)2/C to furnish the title compound as an off-white solid (25 mg. 99.51% purity, 6% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.35 (s, 1H), 9.03 (s, 1H), 8.28-8.25 (m, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 7.60 (d, J=8.0 Hz. 1H), 7.10 (d. J=8.4 Hz, 1H). 4.01 (t, J=5.2 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.22 (s, 3H). 2.19 (s, 3H). 1.934-1.886 (m, 4H).
LCMS (ESI, m/z): 347.24 (M+l)
COMPOUND 121
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a light brown solid (51 mg, 99.24% purity. 25% yield). ’HNMR (400MHz, DMSO-d: 6 δ) 10.12 (bs, 1H), 7.70 (s, 1H), 7.64 (m, J=8.0Hz, 3H), 7.50 (s, 1H), 7.43 (d, J=8.0Hz, 1H). 7.08 (d, J=7.6Hz, 1H). 3.99 (1. J=5.6Hz. 2H), 2.53 (t, J=6.0Hz, 2H), 2.20 (d, J=8.4Hz, 6H), 1.92 (m, J=4.0Hz, 4H).
LCMS (ESI, m/z): 364.20 [M+H]+
COMPOUND 8
Synthesized according to a modified version of Pd/C red using catalytic TFA to furnish the title compound as an off-white solid (31 mg, 99.64% purity , 13% yield).
1H NMR (400MHz, DMSO-d6): δ 7.58 (d, J=7.6 Hz, 2H), 7.36 (s, 1H), 7. 13 (d, J=7.6 Hz, 2H), 7.13 (d, J=7.6 Hz, 2H), 7.06-6.99 (m, 2H), 6.93 (d, J=7.6Hz, 1H), 3.94-3.92 (m, 2H), 3.81 (s, 2H), 2.73 (t, 2H), 2.16 (s, 6H), 1.88-1.85 (m, 4H).
LCMS (ESI, m/z): 317.20 (M+H)+
COMPOUND 132
Synthesized according to a modified version of Pd/C red using Pd(OH)2/C to furnish the title compound as an off-white solid (35 mg, 99.88% purity7, 14% yield).
1H NMR (400MHz, DMSO-d6): δ 7.61 (d, J= 7.4 Hz, 2H); 7.37 (s, 1H); 7.29 (d, J=7.8 Hz, 2H); 3.94 (s, 2H); 2.74 (s, 2H); 2.05 (s, 3H); 1.86 (s, 10H), 1.73 (s, 6H) LCMS (ESI, m/z): 333.28 (M+H)
COMPOUND 139
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (14 mg, 99.21% purity, 55% yield).
1H NMR (400 MHz, DMSO-d6): d 7.61 (d, J= 8 Hz, 2H), 7.50 (s, 1H), 7.45-7.42 (m. 2H), 7.36 (d, J = 8 Hz, 1H), 7.18 (d, J = 8 Hz, 2H), 4.78 (t, J = 4.8 Hz, 1H), 4.08 (dd, J= 12, 4.8 Hz, 1H), 3.63 (t, J= 10.4 Hz, 1H), 3.49-3.47 (m, 1H), 3.44-3.39 (m, 1H), 2.95-2.78 (m, 5H), 2.73-2.67 (m, 1H), 2.34 (s, 3H), 2.07 (br s, 1H), 1.97-1.94 (m, 1H), 1.58-1.53 (m, 1H).
19F NMR (376 MHz, DMSO-^): δ -60.586 (s).
UPLC (m/z) = 415.2 )M+HJ+ (Rt = 2.35 mins, 5 mins run, TFA in CH3CN)
COMPOUND 11
Synthesized according to a modified version of Pd/C red omitting catalytic HC1 to furnish the title compound (157.9 mg, 98.65% purity, 28.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.89 (s,lH), 7.52 (d, J= 8.4 Hz, 2H), 7.24 (s, 1H), 6.79- 6.99 (m, 5H), 3.92 (d, J= 5.62 Hz, 2H), 2.73 (t, J= 5.6 Hz,2H), 2.14 (d. J= 10.4 Hz, 6H). 1.86 (t, J= 6.4 Hz, 4H).
LCMS: m/z= 319.20 [M+H], RT= 3.171 min
COMPOUND 7
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound (74 mg, 97.43% purity, 19% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.04 (s,lH), 7.56 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7. 10 (t, J = 7.6 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 7.6 Hz, 2H), 6.62 (d, J = 7.6 Hz, 1H), 3.93 (t, J = 5.6 Hz, 2H), 2.74 (t, J = 6 Hz, 2H), 2.24 (s, 3H), 1.90-1.84 (m, 4H).
LCMS (m/z) = 304.20 [M+H]’ RT=2.34 min
COMPOUND 6
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as an off-white solid (88 mg, 97.97% purity, 35% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.53 (d, J=8.4Hz, 2H), 7.25 (s, 1H), 7.04 (d, J=8.0Hz, 2H), 6.97 (d, J~8.0Hz. 4H), 3.92 (d, J~5 2Hz. 2H), 2.73 (t, J=5.6Hz, 2H), 2.22 (s, 3H), 1.89-1.85 (m, 4H).
LCMS (m/z) = 304.20 [M+H]’, RT= 2.28 min.
COMPOUND 5
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a pale yellow solid (61.7 mg, 98.62% purity. 30.4% yield).
1H NMR (400 MHz, DMSO-d6): δ 8. 13 (s, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.04 (t, J = 7.2 Hz, 4H), 6.79 (t, J = 7.2Hz, 1H), 3.94 (t, J = 5.2 Hz, 2H), 2.74 (t, J = 5.6 Hz, 2H), 1.90-1.84 (m, 4H).
LCMS (m/z) = 290.20 [M+H]’, RT= 2.23 mm.
COMPOUND 13
Synthesized according to a modified procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a light brown solid (14 mg, 97.84% purity, 5% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 6.97-7.13 (m, 6H), 6.80 (d, J= 7.6 Hz, 1H), 3.94 (t, J= 5.6 Hz, 2H), 2.73 (t, J= 5.6 Hz, 2H). 2.23 (s, 3H), 1.87 (t, J= 6.8 Hz. 4H).
LCMS (m/z) = 304.20 | M+H | , RT= 2.393 min.
COMPOUND 14
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as an off-white solid (20 mg, 96.05% purity, 7% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 7.41 (s, 1H), 7.34 (s, 1H), 6.98-7.12 (m, 3H), 6.79-6.86 (m, 3H), 3.94 (t, J= 5.2 Hz, 2H), 2.73 (t, J= 6.0 Hz, 2H), 2.15 (d, J= 8.0 Hz, 6H), 1.85-1.90 (m, 4H).
LCMS (m/z) = 318.25 [M+Hty, RT= 2.462 min
COMPOUND 15
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as an off-white solid (24 mg, 99. 13% purity, 9% yield).
*H NMR (400 MHz, DMSO-d6): δ 8.04 (s, 1H). 7.46 (s. 1H), 7.36 (s. 1H), 7.08-7.17 (m. 3H), 6.86 (s, 3H), 6.63 (d, J= 7.2 Hz, 1H), 3.94 (d, J= 5.6 Hz, 2H), 2.73 (t, J= 5.6 Hz, 2H), 2.24 (s,
3H), 1.87 (t, J= 6.8 Hz, 4H).
LCMS (m/z) = 304.20 [M+H]’, RT= 2.362 mm
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (29 mg, 99.37% purity, 9% yield). >H NMR (400 MHz, DMSO-d6): δ 7.61 (d, J= 7.6 Hz, 2H), 7.40 (s, 1H), 7.18 (d, J= 7.6 Hz, 3H), 7.11 (d, J= 11.2 Hz, 3H), 3.95 - 3.94 (m, 2H), 2.82 - 2.75 (m, 6H), 2.26 (s, 3H), 1.90 - 1.86 (m, 4H).
LCMS: m/z= 317.20[M+H]+
Synthesized according to a modified version of procedure Pd/C red using Pd(OH)2/C to furnish the title compound as a brown solid (18 mg, 95.79% purity, 5% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.60 (d, J= 8 Hz, 2H); 7.45 (s, 1H): 7. 19-7.09 (m, 6H): 4.23 - 4.18 (m, 1H); 4.12-4.07 (m, 1H); 3.68 (s, 3H); 3.17-3.16 (bs, 1H); 2.89-2.79 (m, 6H);
2.26-2.20 (m, 4H); 2.05-1.99 (m, 1H).
LCMS (ESI, m/z): 375.10 (M+H)+
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a yellow solid (71 mg, 99.66% purity, 24% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.59 (d, J=7.6Hz, 2H), 7.39 (s, 1H), 7.13 (d, J=8.4Hz, 2H), 3.95 (t, J=5.6Hz, 2H), 3.77 (t, J=12.0Hz, 2H), 3.23 (m, J=8.4Hz, 2H), 3.00 (t, J=11.2Hz, 2H), 2.75 (t, J=6.0Hz, 2H), 2.56 (m, J=6.4Hz, 2H), 1.90 (m, J=3.6Hz, 5H), 1.53 (m, J=13.2Hz, 4H), 1.14 (d, J=11.2Hz, 1H).
LCMS (ESI, m/z) : 311.40 (M+H)+
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as an off-white solid (16 mg, 99.44% purity, 45% yield).
1H NMR (400 MHz, DMSO-d6): δ d 7.93 (s, 1H), 7.59 (d, J= 7.92 Hz, 2H). 7.53 (dd. J= 8.4, 1.96 Hz, 1H), 7.41 (s, 1H). 7. 14 (d, J= 7.96 Hz, 2H), 6.68 (d, J= 8.92 Hz. 1H), 4.77 (t. J=
4.96 Hz, 1H), 4.26-4.21 (m, 2H), 4.07 (dd, J= 12.3, 4.9 Hz, 1H), 3.62 (t, J= 10.8 Hz, 1H), 3.51-3.47 (m, 1H), 3.44-3.41 (m, 1H), 2.87-2.84 (m, 5H), 2.71-2.67 (m, 1H), 2.08-2.06 (m, 1H), 1.98-1.94 (m, 1H), 1.56-1.54 (m, 1H), 1.28 (t, J= 7 Hz, 1H).
UPLC (m/z) = 378.2 [M+H]+ (Rt = 1.57 mins, 5 mins run, TFA in CH3CN)
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (38 mg, 96.28% purity, 72% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.59 (d, J= 7.6 Hz, 2H), 7.41-7.38 (m, 2H), 7.27 (d, J = 7.6 Hz. 1H), 7.22 (s, 1H), 7. 17-7. 15 (m, 3H), 4.77 (t, J = 4.8 Hz, 1H). 4.08 (dd. J= 12.4, 4.8 Hz, 1H), 3.62 (t, J= 10.4 Hz, 1H), 3.50-46 (m, 1H), 3.44-3.40 (m, 1H), 2.95-2.81 (m, 5H), 2.72-2.69 (m, 1H), 2.07 (br s, 1H), 1.97-1.94 (m, 1H), 1.57-1.53 (m, 1H).
19F NMR (376 MHz, DMSO-d6) d -56.588 (s). UPLC (m/z) = 417.2 [M+H]+ (Rt = 2.31 mins, 5 mins run, TFA in CH3CN)
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (10 mg, 98.96% purity, 30% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.02 (d, J= 4.8 Hz. 1H), 7.59 (d. J= 7.6 Hz, 2H), 7.45 (s, 1H), 7.16 (d, J= 7.2 Hz, 2H), 6.86 (d, J= 4.8 Hz, 1H), 6.65 (s, 1H), 4.77-4.75 (m, 1H), 4.08 (dd, J= 12, 4.4 Hz, 1H), 3.80 (s, 3H), 3.62 (t, J= 10.8 Hz, 1H), 3.49-3.47 (m, 1H), 3.44-3.41 (m, 1H), 2.85-2.81 (m, 5H), 2.73-2.67 (m, 1H), 2.08 (br s, 1H), 1.97-1.94 (m, 1H), 1.58-1.53 (m. 1H).
UPLC (m/z) = 364.2 [M+H]+ (Rt = 1.45 mins, 5 mins run, TFA in CH3CN)
COMPOUND 141
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (25 mg, 98.85% purity, 76% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, J= 7.6 Hz, 2H), 7.40 (s, 1H), 7.15-7.11 (m, 4H), 6.81 (d, J = 8.4 Hz, 2H), 4.77 (t, J = 4.8 Hz, 1H), 4.08 (dd, J= 12, 4.8 Hz, 1H), 3.70 (s, 3H), 3.62 (t, J= 10.4 Hz, 1H), 3.49-3.41 (m, 2H), 2.85-2.80 (m, 5H), 2.73-2.67 (m, 1H), 2.08 (br s, 1H), 1.97-1.94 (m, 1H), 1.60-1.54 (m, 1H).
UPLC (m/z) = 363.2 [M+H]+ (Rt = 2.01 mins, 5 mins run, TFA in CH3CN)
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (18 mg, 98.76% purity, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J= 8.8 Hz, 2H), 7.79 (s, 1H), 7.61-7.57 (m, 3H), 7.42 (s, 1H), 7.17 (d. J= 8.04 Hz, 2H). 4.78 (t. J= 5.24 Hz, 1H). 4.08 (dd, J= 12.3, 4.8 Hz, 1H), 3.51-3.38 (m, 2H), 3.06-3.02 (m, 2H), 2.91-2.80 (m, 3H), 2.73-2.65 (m, 1H), 2.08 (br s, 1H), 1.97-1.94 (m, 1H), 1.62-1.52 (m, 1H). 19F NMR (376 MHz, DMSO-d6): δ -55.92 (s).
UPLC (m/z) = 402.2 [M+H]+ (Rt = 1.91 mins, 5 mins run, TFA in CH3CN) Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (28 mg, 99.43% purity. 92% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.99 (d, J= 5. 12 Hz, 2H), 7.59 (d, J= 7.92 Hz, 2H), 7.41 (s, 1H), 7.17 (d, J= 7.96 Hz, 2H), 6.84 (d, J= 5.04 Hz, 1H), 6.66 (s, 1H), 4.77 (t, J= 5.08 Hz, 1H), 4.10-4.03 (m, 3H), 3.62 (t, J= 10.68 Hz, 1H), 3.50-3.40 (m, 2H), 2.85-2.82 (m, 6H), 2.73-2.66 (m, 1H), 2.08 (br s, 1H), 1.97-1.94 (m, 1H), 1.58-1.53 (m, 1H), 1.23-1.19 (m, 1H),
0.53-0.50 (m, 2H), 0.29-0.28 (m, 2H).
UPLC (m/z) = 404.2 [M+H]+ (Rt = 1.75 mins, 5 mins run, TFA in CH3CN) COMPOUND 144
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (22 mg, 98.9% purity, 60% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J= 4.8 Hz, 1H), 7.59 (d, J= 8 Hz 2H), 7.41 (s. 1H), 7.17 (d, J= 8 Hz, 2H), 6.99 (d, J = 4.8Hz, 1H), 6.86 (s. 1H), 4.92-4.98 (m. 2H), 4.77 (t, J= 5.2 Hz, 1H), 4.10-4.06 (m, 1H), 3.62 (t, J= 10.4 Hz, 1H), 3.51-3.46 (m, 1H), 3.44-3.38 (m, 1H), 2.92-2.81 (m, 5H), 2.73-2.65 (m, 1H), 2.08 (brm, 1H), 1.97-1.94 (brm, 1H), 1.61-1.50 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -72.35 (t).
UPLC (m/z) = 432.2 [M+H]+ (Rt = 2. 12 mins, 5 mins run, TFA in CH3CN).
Synthesized according to a modified version of procedure Pd/C red omitting catalytic HC1 to furnish the title compound as a white solid (10 mg, 98.68% purity, 48% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.78 (s, 1H), 7.60-7.56 (m, 3H), 7.41 (s. 1H), 7.14 (d. J= 8.0 Hz, 2H), 4.79-4.76 (m, 1H), 4.08 (dd, J= 12.32, 4.96 Hz, 1H), 3.89 (s, 3H), 3.62 (t, J= 11.2 Hz, 1H), 3.50-3.48 (m, 1H), 3.44-3.38 (m, 1H), 2.84-2.81 (m, 5H), 2.73-2.64 (m, 1H), 2.09-2.07 (brm, 1H), 1.97-1.90 (m, 1H), 1.59-1.53 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -140.96 (d, J = 11.47 Hz).
UPLC (m/z) = 382.2 [M+H]+ (Rt = 1.91 mins, 5 mins run, TFA in CH3CN).
COMPOUND 9
Synthesized according to procedure XX, title compound was afforded as an off white solid (26 mg, 99.09% purity, 4% yield).
1H NMR (400 MHz, DMSO-:d 66) 8.52 (d, J= 7.2 Hz,lH), 8.33 (s, 1H), 7.94 (d, J= 9.2 Hz, 2H), 7.56 (d, J= 9.2 Hz, 1H), 7.25-7.21(m, 1H), 7.17 (d, J= 8.4Hz,lH), 7.01 (d, J= 8.4 Hz, 2H), 6.90-6.88 (m, 2H), 6.82-6.79 (m, 1H), 2.21 (s, 6H).
LCMS (ESI, m/z) = 315.20 [M+H],
General procedure: Reductive amination
COMPOUND 101
To a stirred solution of 4-(5,6,7,8-tetrahydroimidazotl,2-aJpyridin-2-yl)aniline (60 mg, 0.281 mmol, 1.00 eq) in MeOH (0.50 mL) were added 4-methylbenzaldehyde (41 mg, 0.338 mmol, 1.20 eq) and AcOH (1.7 mg, 0.0281 mmol, 0.100 eq) at 25°C. Resulting mixture was allowed to stir at 25 °C for 3 hrs and then NaBHsCN (27 mg. 0.422 mmol, 1.50 eq) was added and stirred for another 24 hrs at 25°C . Reaction mixture was diluted with water and extracted with 5% (MeOH/DCM). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude. Crude product was purified in reverse phase prep HPLC to afford JV-(4-methylbenzyl)-4-(5,6,7,8-tetrahydroimidazo[l,2- a]pyridin-2-yl)aniline, (36.1 mg. 0.114 mmol. 98.13% purity. 40.5% yield).
LCMS (m/z) = 318.3 [M+H]+
COMPOUND 98
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (19.5 mg, 98.59% purity, 25.9% yield).
LCMS (m/z) = 268.2 [M+H]+
COMPOUND 99
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (8.2 mg, 99.17% purity, 9.8% yield).
LCMS (m/z) = 284.3 [M+H]+
COMPOUND 100
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (12.6 mg, 99.22% purity7, 15.2% yield). LCMS (m/z) = 296.3 [M+H]
COMPOUND 102 Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (25.4 mg, 98.13% purity, 28.4% yield).
LCMS (m/z) = 318.2 [M+H]+
COMPOUND 103 Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (26.3 mg, 96.16% purity, 29.4% yield).
LCMS (m/z) = 318.2 [M+H]+ Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (23.9 mg, 99.55% purity, 27.5% yield).
LCMS (m/z) = 310.3 [M+H]+
COMPOUND 105
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (39.0 mg, 99.77% purity, 41.4% yield).
LCMS (m/z) = 336.2 [M+H]+
COMPOUND 106
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (13.7 mg, 91.08% purity, 14.7% yield). LCMS (m/z) = 332.3 [M+H]+ COMPOUND 107
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (13.9 mg, 98.39% purity, 15.2% yield).
LCMS (m/z) = 324.3 [M+H]+
COMPOUND 108
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (24.8 mg, 98.18% purity, 24.4% yield). LCMS (m/z) = 362.3 [M+H]+
COMPOUND 109
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (10.8 mg, 95.63% purity, 10.6% yield).
LCMS (m/z) = 362.4 [M+H]+
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (5.6 mg, 91.6% purity, 5.6% yield).
LCMS (m/z) = 362.2 [M+H]+
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (14.2 mg, 97.35% purity, 13. 1% yield).
LCMS (m/z) = 388.2 [M+H]
COMPOUND 113
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (10.5 mg, 98.79% purity, 11.5% yield).
LCMS (m/z) = 326.3 [M+H]+
COMPOUND 114
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (4.8 mg, 98.45% purity, 3.7% yield). LCMS (m/z) = 459.3 [M+H]+
COMPOUND 115
Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (20.3 mg, 98.7% purity', 16.3% yield).
LCMS (m/z) = 445.3 [M+H] Synthesized according to reductive amination procedure to furnish the title compound as an off-white solid (5.0 mg, 99.09% purity’, 4.6% yield).
LCMS (m/z) = 388.3 [M+H]+
COMPOUND 97
Synthesized according to reductive amination procedure to furnish the title compound as an off white solid (33 mg. 98.29% purity, 13% yield).
1H NMR (400 MHz, DMSO-:d δ6) 7.41 (d, J=8.0 Hz, 2H); 7.13 ( s, 1H); 6.56 (d, J=8.4Hz, 2H); 5.24 (d. J=8.4Hz. 1H); 3.90 (t, J=5.2Hz, 2H); 3.72-371(m. 1H); 2.71 (t, J=5.2Hz, 2H); 1.90-1.84 (m, 6H); 1.29 (s, 6H): 1.12-1.04 (m, 8H)
LCMS (ESI. m/z): 354.35 [M+H]+
COMPOUND 111
Synthesized according to procedure boc depr utilizing HC1. the title compound was afforded as a light orange salt (38.5 mg, 98.26% purity, 24.7% yield) as an HC1 salt.
LCMS (m/z) = 388.2 [M+H]+
General procedure: Buchwald-Hartwig
COMPOUND 11
To a stirred solution of 2-(4-bromophenyl)imidazo[l,2-a]pyridine (500 mg, 1.83 mmol, 1.00 eq), 3,4-dimethylaniline (333 mg, 2.75 mmol, 1.50 eq) and CS2CO3 (1789 mg, 5.49 mmol, 3.00 eq) were dissolved in 1,4-Dioxane (10 mL). This solution was purged with nitrogen for 20 min. Pd G3 X-Phos (154.9 mg, 0.18 mmol, 0.100 eq) was added and the reaction was place in a micro wave reactor and heated to 120 °C for 2 hours. Reaction mixture was cooled to ambient temperature, filtered through celite, and washed with methanol (50 mL). The solvent was removed under reduced pressure and obtained residue was dissolved in water (30 mL) and extracted with EtOAc (30x3 mL). The organic layers were combined and dried over sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography using 230-400 mesh size silica (Column size; 50 g, Flow rate; 40 mL/min, UV; 254 nm) and 0 to 60% EtOAc in hexane as a mobile phase to give title compound N-(4- imidazo[l,2-a]pyridin-2-ylphenyl)-3,4-dimethyl-aniline, (450 mg, 1.37 mmol, 95.71% purity, 75% yield) as an off-white solid.
1H NMR (400 MHz, CDCI3): δ 8.10 (d, 1H), 7.83 (d, 2H), 7.77 (s, 1H), 7.61 (d, 1H), 7.15- 7.12 (m, 1H), 7.08-7.05 (m, 3H), 6.94-6.90 (m, 2H), 6.77-6.74 (m, 1H), 5.71 (s, 1H). 2.24 (d, 6H).
LCMS; m/z= 314.25 [M+H], RT= 2.408 min
General procedure: Buchwald-Hartwig Procedure 2 3-bromo-2-methoxypyridine (53 mg, 0.281 mmol, 1.00 eq), CS2CO3 (275 mg, 0.844 mmol, 3.00 eq), RuPhos (26 mg, 0.0563 mmol, 0.200 eq) and Pd2(dba)3 (26 mg, 0.0281 mmol, 0.100 eq) were sequentially added to a stirred degassed solution of 4-(5, 6,7,8- tetrahydroimidazo[l,2-a]pyridin-2-yl)aniline (60 mg, 0.281 mmol, 1.00 eq) in 1,4-Dioxane (1.5 mL). The resulting mixture was allowed to stir at 100 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude. Crude material was purified by reverse phase prep HPLC to afford the desired product 2-methoxy- JV-(4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl)pyridin-3-amine, (10 mg, 97.73% purity, 11.2% yield).
LCMS (m/z) = 321.2 [M+H]+
COMPOUND 154
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (26.2 mg, 98.05% purity, 30.4% yield).
LCMS (m/z) = 308.2 [M+H]+
COMPOUND 155
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (33 mg, 98.51% purity, 36.1% yield). LCMS (m/z) = 326.2 [M+H]
COMPOUND 157 Synthesized according to Buchwald-Hartwig procedure 2_to furnish the title compound (27.5 mg, 99.23% purity, 28.7% yield).
LCMS (m/z) = 341.2 [M+H]
COMPOUND 158 Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (27.3 mg, 99.26% purity, 28% yield).
LCMS (m/z) = 348.2 [M+H]+ COMPOUND 159
Synthesized according to Buchwald-Hartwig procedure 2_to furnish the title compound (21.7 mg, 99.33% purity, 22.2% yield).
LCMS (m/z) = 347.3 [M+H]+
COMPOUND 160
Synthesized according to Buchwald-Hartwig procedure 2_to furnish the title compound (38.3 mg, 99.48% purity, 41.9% yield). LCMS (m/z) = 326.2 [M+H]+
COMPOUND 161
Synthesized according to Buchwald-Hartwig procedure 2_to furnish the title compound (32 mg, 98.89% purity, 32.9% yield).
LCMS (m/z) = 346.2 [M+H]+
COMPOUND 162
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (29 mg, 99.15% purity, 31.63% yield). LCMS (m/z) = 326.2 [M+H]+
COMPOUND 163
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (42.2 mg, 99.12% purity, 47% yield).
LCMS (m/z) = 320.2 [M+H]+
COMPOUND 164
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (28.8 mg, 99.35% purity, 33.3% yield).
LCMS (m/z) = 308.2 [M+H]+
COMPOUND 165
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (37.9 mg, 98.61% purity, 41.4% yield). LCMS (m/z) = 326.2 [M+H]+
COMPOUND 166
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (41.7 mg, 95.49% purity, 38.22% yield).
LCMS (m/z) = 388.2 [M+H]+
COMPOUND 167
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (37.9 mg, 98.67% purity, 34.5% yield).
LCMS (m/z) = 392.1 [M+H]+ 1HNMR (400MHz, DMSO-d6): δ.56 (s, 1H), 7.64-7.62 (m, 2H), 7.36-7.32 (m, 2H), 7.11-7.09 (m. 2H), 6.96-6.92 (m. 1H), 6.86-6.84 (m. 1H), 3.96-3.93 (m. 2H), 2.76-2.73 (m. 2H), 1.90- 1.84 (m, 4H)
COMPOUND 168
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (12 mg, 98.38% purity, 13.1% yield).
LCMS (m/z) = 326.2 [M+H]+
COMPOUND 169
Synthesized according to Buchwald-Hartwig procedure 2 to furnish the title compound (28. 1 mg, 96.39% purity, 25.56% yield). LCMS (m/z) = 392.2 [M+H] 1
General HATU procedure
COMPOUND 117
HATU (160 mg, 0.420 mmol, 1.50 eq), DIPEA (0.15 mL, 0.841 mmol, 3.00 eq) and 2- methoxy-5-(trifluoromethoxy)benzoic acid (66 mg, 0.280 mmol, 1.00 eq) were sequentially added to a stirred solution of 4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2- yl)aniline:hydrochloride (70 mg, 0.280 mmol, 1.00 eq) in DMF (1 mL) under inert atmosphere at ambient temperature. The resulting mixture stirred for 16h. The reaction mixture was concentrated under reduced pressure and purified directly by prep HPLC to afford the title compound, (52 mg. 0. 120 mmol, 99.89% purity. 43% yield) as white solid.
'H NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 7.67 (br s. 4H), 7.58-7.56 (m. 1H), 7.54- 7.51 (m, 1H), 7.40 (s, 1H). 7.28 (d, J = 8.8 Hz, 1H). 3.9-3.95 (m, 2H), 3.92 (s, 3H), 2.75 (t, J = 6.0 Hz, 2H), 1.89-1.87 (m, 4H).
19F NMR (376 MHz. DMSO-d6): δ -57.29
LC-MS: m/z = 432.2 (M+H)+
COMPOUND 120
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (91 mg, 99.93% purity, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.31 (s, 1H), 8.07 (d, J= 8.8 Hz, 2H), 7.73-7.67 (m, 4H), 7.53 (d, J= 8.4 Hz, 2H), 7.40 (s, 1H), 3.96 (t, J= 5.2 Hz. 2H), 2.75 (t, J= 6.4 Hz, 2H). 1.91- 1.85 (m, 4H).
19F NMR (376 MHz. DMSO-d6): δ -56.65 (s). UPLC (m/z) = 402.2 [M+H]+ (Rt = 2. 10 mins, 5 mins run, TFA in CH3CN)
COMPOUND 129
Synthesized according to HATU procedure to furnish the title compound as a white solid (52 mg, 99.87% purity, 53% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 7.70-7.63 (m, 5H), 7.52-7.48 (m, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.75 (t, J = 6.0 Hz, 2H), 1.91-1.85 (m, 4H).
LC-MS (m/z) = 348.2 [M+H]+
COMPOUND 170
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (52 mg, 99.89% purity, 43% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.89 (s, 1H), 10.50 (s, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.71-7.65 (m, 4H). 7.44-7.40 (m, 2H). 6.97-6.91 (m, 2H). 3.95 (t. J = 5.6 Hz, 2H), 2.75 (t, J = 6.0 Hz, 2H), 1.91-1.85 (m, 4H).
LC-MS (m/z) = 334.2 [M+H]+
COMPOUND 122
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (74 mg, 99.89% purity, 61% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 7.68-7.66 (m, 5H), 7.47 (s, 1H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 7.03 (s, 1H), 3.97 (t, J = 5.6 Hz, 2H), 3.86 (s, 3H), 2.79 (t, J = 6.0 Hz, 2H), 1.92-1.86 (m, 4H).
19F NMR (376 MHz, DMSO-d>): δ -56.54
LC-MS (m/z) = 432.2 [M+H]+
COMPOUND 125
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (46 mg, 99.4% purity, 9% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.8 (s, 1H), 8.60 (s, 1H), 8.08 (d, J= 8.0 Hz, Al l). 7.98 (s, 1H), 7.89 (d, J= 7.6 Hz, 1H), 7.72 (d, J= 8.4 Hz, 2H). 4.13 (s, 2H), 3.03 (t, J= 6.0 Hz, 2H), 2.43 (s, 3H), 1.94-2.01 (m, 4H).
LCMS: m/z= 333.15 [M+H]+
COMPOUND 127
Synthesized according to HATU procedure to furnish the title compound as a white solid (35 mg, 99.78% purity, 32% yield).
1H NMR (400 MHz, DMSO-d6) d 10.36 (s, 1H), 8.81 (s, 1H),8.15 (dd, J= 8.52, 2.08 Hz, 1H), 7.80-7.75 (m, 3H), 7.50 (s. 1H), 7.44-7.42 (m. 2H), 3.98 (t, J = 5.0 Hz, 2H), 2.77(t. J=6.1 Hz, 2H), 2.41 (s, 3H), 1.92-1.86 (m, 4H).
UPLC (m/z)= 331.2 [M-H]’
COMPOUND 128
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (44 mg, 98.99% purity, 43% yield).
1H NMR (400 MHz, DMSO-d6): δ 10. 18 (br s, 1H), 9.83 (s, 1H), 7.71-7.63 (m, 5H), 7.39 (s, 1H), 6.54-6.48 (m, 2H), 3.97-3.93 (m, 5H), 2.75 (t, J= 6.2 Hz, 2H), 1.91-1.85 (m, 4H). UPLC (m/z) = 364.2 [M+H]
COMPOUND 129 Synthesized according to HATU procedure to furnish the title compound as a white solid (52 mg, 99.87% purity, 53% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 7.70-7.63 (m, 5H), 7.52-7.48 (m, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.07 (t, J= 7.6 Hz, 1H), 3.95 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.75 (t, J = 6.0 Hz, 2H), 1.91-1.85 (m, 4H). LC-MS: m/z = 348.2 (M+H)+
COMPOUND 130
Synthesized according to HATU procedure to furnish the title compound as an off-white solid (22 mg. 98.05% purity. 25% yield).
1H NMR (400 MHz, DMSO-d6): δ 10.44 (s. 1H), 7.68-7.63 (m. 4H), 7.54 (t, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7. 18 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.97 (t, J = 5.6 Hz, 2H), 3.85 (s, 3H), 2.78 (t, J= 6.0 Hz, 2H), 1.92-1.86 (m, 4H). 19F NMR (376 MHz, DMSO-d6): δ -55.874 (s)
UPLC (m/z) = 432.2 [M+H]+ COMPOUND 118
Synthesized according to HATU procedure to furnish the title compound (33.3 mg, 100% purity, 31.9% yield).
LCMS (m/z) = 372.2 [M+H]+
COMPOUND 124
Synthesized according to HATU procedure to furnish the title compound (30.4 mg, 99.88% purity, 25% yield).
LCMS (m/z) = 432.2 [M+H]+
COMPOUND 131
Synthesized according to HATU procedure to furnish the title compound (19. 1 mg, 99.62% purity, 19% yield).
LCMS (m/z) = 358.2 [M+H]+
Synthesis of starting materials:
General procedure XX for amidine cyclization
The mixture of 2-bromo-l-(4-iodophenyl)ethanone (1.00 g, 3.08 mmol, 1.00 eq). 2, 3,4,5- tetrahydropyridin-6-amine;hydrochloride (829 mg, 6.15 mmol. 2.00 eq) and Sodium carbonate (1305 mg, 12.3 mmol, 4.00 eq) were taken in DMF (20 mL) was allowed to heat at 80 °C for 12 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC &LCMS and found product. Water was added to quench the reaction followed by ethyl acetate extraction. The combined layer was washed well with water, brine dried over anhydrous Na2SO4, concentrated it. The crude was purified by column chromatography on silica gel using 60% ethyl acetate/Hexane as an eluent to give 2-(4-iodophenyl)-5, 6,7,8- tetrahydroimidazo[l,2-a]pyridine, (700 mg, 2.14 mmol, 99.13% purity, 70% yield) as an off- white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, J= 8.4 Hz, 2H), 7.51 (m, 3H), 3.40 (t, J= 8 Hz, 2H), 2.74 (t, J= 6 Hz, 2H), 1.86 (m. 4H). Synthesized according to procedure XX, title compound was afforded as a pale brown solid (860 mg, 89.8% yield).
LCMS (m/z) = 279. 14 [M+H], Synthesized according to procedure XX to yield title compound as an off white solid (450 mg, 20% yield).
LCMS (m/z)= 278.2, 280.2 [M+H],
Synthesized according to procedure XX to yield title compound as a off white solid (150 mg, 94.3% purity, 60.2% yield).
LCMS (m/z) = 278.0 [M+H],
Synthesized according to procedure XX, the title compound was afforded as an off white solid (10.0 g, 83% purity, 82% yield).
LCMS (m/z) = 298.0 [M+H],
Synthesized according to procedure XX, title compound was afforded as a yellow solid (500 mg, 99.5% purity. 31% yield).
LCMS (ESI, m/z) = 314.99 [M+H], Synthesized according to procedure XX, title compound w as afforded as an off w hite solid (1.3 g, 95% purity. 72% yield).
LCMS (ESI, m/z) = 346.6 [M+H],
Synthesized according to procedure XX, title compound was afforded as a brown solid (380 mg, 86.5% purity, 70% yield).
LCMS (ESI, m/z) = 363.20 [M+H],
Synthesized according to procedure XX, title compound was afforded as a brown liquid (0.85 g, 95% purity, 82% yield).
Synthesized according to procedure XX, the title compound was afforded as a pale brown solid (1.8 g, 93.4% yield). Synthesized according to procedure XX, the title compound was afforded as a brown solid (1.2 g, 45% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, J= 6.4 Hz, 1H). 7.77 (s, 1H), 7.46 (d, J= 8.8 Hz, 1H), 7.20 (m, 1H). 6.85 (m, 1H), 3.64 (s, 3H). 2.30 (s, 6H). LCMS (ESI, m/z) = 243.15 [M+H] .
Synthesized according to procedure XX, the title compound was afforded (170 mg, 53.3% yield).
1H NMR (400 MHz, DMSO-d6): δ 9.38 (s, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8. 16 (d, J= 8.6 Hz. 1H), 7.78 (d. J= 9.6 Hz. 1H), 7.59-7.55 (m. 2H), 6.90-6.79 (m. 3H).
Synthesized according to procedure XX, title compound was afforded as an off white solid (200 mg, 42% yield).
LCMS (ESI, m/z) = 344.1 [M+H],
Synthesized according to procedure XX to furnish the title compound (9.00 g, 91.8% yield). LCMS (m/z) = 240.2.
Synthesized according to procedure XX to furnish the title compound as a light red solid (4.2 g, 96% purity, 82% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 1H), 8.45 (s, 1H), 7.92 (d, 2H), 7.63 (d, 2H), 7.58 (d, 1H), 7.26 (m, 1H), 6.91 (m, 1H).
LCMS (m/z) = 273.0 [M+H]+
Synthesized according to procedure XX to furnish the title compound as a grey solid (7.8 g, 99.76% purity. 80% yield).
LCMS: m/z=275.00 [M+H]+
Synthesized according to procedure XX to furnish the title compound as an off-white solid (810 mg, 94.9% purity, 74.8% yield).
LCMS (m/z) = 265.1 [M+H]+
Synthesized according to procedure XX to furnish the title compound as a brown solid (12.0 g, 61% yield).
1H NMR (400 MHz, DMSO-d6): 8.72 (d, J= 2 Hz, 1H), 8.58 (d, J= 6.8 Hz, 1H), 8.50 (s, 1H), 8.13-8.10 (m, 1H), 8.05 (d, J= 8.4 Hz, 1H), 7.60 (d, > 9.2 Hz, 1H), 7.31-7.27 (m, 1H), 6.95- 6.92 (m, 1H).
LCMS (m/z) = 274.1 and 276.1 (bromo pattern) [M+H], (RT=1.69 min).
To a stirred solution of 2-(5-bromo-2-pyridyl)imidazo[l,2-a]pyridine (4.00 g, 14.6 mmol, 1 .00 eq) in Dioxane (50 mL) was added CS2CO3 (14.3 g, 43.8 mmol, 3.00 eq) and diphenylmethanimine (3.97 g, 21.9 mmol, 1.50 eq). The mixture was purged with N2 for 15 mins. Pd2(dba)s (1.34 g, 1.46 mmol, 0. 100 eq) and Ruphos (1362 mg, 2.92 mmol, 0.200 eq) were added to the reaction mixture and stirred for 16 h at 110 °C . Reaction mixture was filtered through cehte and the filtrate was evaporated under reduced pressure to get crude, which was purified with silica gel column chromatography to get N-(6-imidazo[l,2- a] pyri din-2-yl-3 -pyridyl)- 1,1 -di phenyl-methanimine, (2.50 g, 6.68 mmol, 46% yield).
LCMS (m/z) = 375.0 [M+H]+, Rt= 3.89.
To a stirred solution of N-(6-imidazo[l,2-a]pyridin-2-yl-3-pyridyl)-l,l-diphenyl- methanimine (6.00 g, 16.0 mmol, 1.00 eq) in Dioxane (20 mL) was cooled to 0 °C and 4M HC1 in Dioxane (20 mL, 0.009 mmol, 0.100 eq) was added. The reaction was stirred at this temperature for 6 h. The reaction mixture was evaporated under reduced pressure to afford crude, which was washed with DCM. The crude was neutralized on an amberlyst resin to furnish 6-imidazo[l,2-a]pyridin-2-ylpyridin-3-amine, (2.00 g, 6.66 mmol, 70% purity, 59.4% yield).
LCMS (m/z) = 211.2 [M+H]+, Rt=1.91.
To a stirred a solution of 2-(4-nitrophenyl)imidazo[ l,2-a]pyridine-6-carbonitrile (700 mg, 2.65 mmol, 1.00 eq) in Ethanol (18 mL) and Water (6 mL) was added Fe (740 mg, 13.2 mmol, 5.00 eq) followed by2-(4-aminophenyl)imidazo[l,2-a]pyridine-6-carbonitrile, (301 mg, 1.21 mmol, 94.18% purity, 46% yield) and reaction mixture refluxed at 85 °C for 16 h .
Reaction was monitored by LCMS; after completion of reaction, decant upper layer of ethanol and again added ethanol (200 mL * 4) stirred reaction mixture and settle down solid and decant upper layer of ethanol, combined ethanol layer evaporated to obtain 580 mg of crude. Crude compound was treated with aq. NaHCO3 solution and washed with hexane, dried to obtain 301 mg of 2-(4-aminophenyl)imidazo[l,2-a]pyridine-6-carbonitrile, (301 mg, 1.21 mmol, 94.18% purity, 46% yield) as a off white solid.
LCMS (m/z) = 235.2 [M+H]+
To a stirred solution of 2-(4-aminophenyl)imidazo[l,2-a]pyridine-6-carbonitrile (310 mg, 1.32 mmol, 1.00 eq) in DCM (4 mL) and 1,4-Dioxane (2 mL) was added TEA (.06 mL, 0.427 mmol, 2.00 eq) followed by solution of 5-methylpyridine-2-carbonyl chloride (226 mg, 1.46 mmol, 1.10 eq) in DCM (4 mL) at 0 °C, then reaction mixture stirred at 25 °C for 16 h. After completion, w ater w as added to reaction mixture to precipitate the compound and the solid was filtered through filter paper. The residue was washed with water followed by ethyl acetate (8 mL) and dried under line vacuum to obtain N-[4-(6-cyanoimidazo[ L2-a]pyridin-2- yl)phenyl]-5-methyl-pyridine-2-carboxamide, (305 mg, 0.663 mmol, 76.8% purity, 50% yield).
LCMS (m/z) = 254.1 [M+H]+
General procedure XBr for keto-bromination
To a stirred a solution of l-(5-bromopyrimi din-2 -yl)ethanone (900 mg, 4.48 mmol, 1.00 eq) in HBr in AcOH (5 mL) was added Br2 (.24 mL, 4.65 mmol, 1.04 eq) at 0°C. Reaction mixture was heated at 60 °C for 16 hrs. Reaction monitored by TLC (100% ethyl acetate / hexane) and LCMS; after completion of reaction, reaction mixture filtered through celite bed, celite bed washed with ethyl acetate (100 mL * 3) and filtrate was evaporated to get 1.2 g of crude compound. 1.2 g of crude product was purified by column chromatography using 230-400 mesh size silica gel (column size; 25 g. flow rate; 25 ml/min, uv; 254 nm) and 0 to 100 % ethyl acetate / hexane as a mobile phase to afford of 2-bromo-l-(5-bromopyrimidin-2-yl)ethanone, (960 mg, 2.85 mmol, 82.96% purity, 64% yield) as a pale yellow solid. LCMS (m/z) = 280.65 [M+H],
Synthesized according to general procedure XBr to yield title compound as an off white solid (620 mg, 95% purity, 42% yield). GCMS (m/z) = 278.9 [M+],
Synthesized according to procedure XBr, title compound was afforded as a pale brown liquid (1.1 g, 83.7% purity, 62% yield).
LCMS (ESI, m/z) = 309.0 [M+],
Synthesized according to procedure XBr, title compound was afforded as an oily liquid (730 mg, 85% yield).
LCMS (ESI, m/z) = 319.2 [M+H],
Synthesized according to procedure XBr, title compound was afforded as a brown liquid (2.7 g, 68% yield). Used immediately without characterization.
Synthesized according to procedure XBr, title compound was afforded (250 mg, 63% yield).
LCMS (ESI, m/z) = 326.25 [M+2],
Synthesized according to procedure XBr, title compound was afforded as a colorless viscous liquid (120 mg, 36% yield).
LCMS (ESI, m/z) = 323.22 [M+H],
To a stirred solution of 5,6,7,8-tetrahydroimidazo[l,2-a]pyridine (500 mg, 4.09 mmol, 1.00 eq) in DMF (5 mL) was added N-iodosuccinimide (1934 mg, 8.59 mmol, 2.10 eq) under nitrogen atmosphere. The resulted suspension was stirred for 16 hrs at 40°C. The progress of the reaction was monitored by TLC & LCMS. The reaction mixture was diluted with sat. sodium thisulphate solution (20mL) and extracted using DCM (20 mL * 2). The combined organic layer was washed with water (10 mL *2), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced vacuum to afford 2,3-diiodo-5,6,7,8- tetrahydroimidazo[1.2-a] pyridine, (900 mg, 2.41 mmol. 59% yield) as pale yellow solid.
1H NMR (400MHz, CDCI3): δ 3.80-3.78 (m, 2H), 2.89 (br, 2H), 1.99-1.78 (m, 4H).
LCMS (ESI, m/z) = 374.90 [M+H],
To a stirred solution of 2,3-diiodo-5,6.7.8-tetrahydroimidazo[1.2-a]pyridine (0.85 g, 2.27 mmol, 1.00 eq) in THF (20 mL) was added 2-Propylmagnesium bromide (2.9 M in , 1.57 mL, 4.55 mmol, 2.00 eq) at -20°C under nitrogen atmosphere. The resulted suspension was stirred for 2 hrs at -20 °C.
The progress of the reaction was monitored by TLC & LCMS. The reaction mixture was diluted with sat. ammonium chloride solution (10 mL) and extracted using DCM (10 mL * 2). The combined organic layer was washed with water (10 mL *2), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced vacuum to afford 2-iodo- 5,6,7,8-tetrahydroimidazo[l,2-a]pyridine, (400 mg, 1.61 mmol, 71% yield) as brown liquid.
1H NMR (400 MHz, CDCI3): δ 6.86 (s, 1H), 3.93 (t, J= 5.8 Hz, 2H), 2.85 (t, J = 6.4 Hz, 2H), 1.95-1.89 (m, 4H).
LCMS (ESI, m/z) = 249.00 [M+H], To a stirred solution of 4-bromo-l-cyclopropyl-2-methyl-benzene (250 mg, 1.18 mmol, 1.00 eq) in dioxane (5 mL) was degassing for 5 mins then to it was added Cui (11 mg, 0.0592 mmol, 0.0500 eq) and Nal (355 mg, 2.37 mmol, 2.00 eq) followed by the addition ofN,N- dimethyl cyclohexyl 1,2- diamine (17 mg, 0.118 mmol, 0.100 eq). After complication of addition the resulting reaction mixture was stirred for 24 hrs at 110 °C. Reaction mixture was concentrated and diluted with ethyl acetate (30mL). Combine organic layers were washed with water (lOmL) and brine solution (lOmL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a crude compound. Crude compound w as purified by column chromatography to give l-cyclopropyl-4-iodo-2-methyl-benzene, (200 mg, 65% yield) as a colorless liquid.
GCMS (m/z) = 258.1 [M+],
Synthesized according to procedure B, title compound was afforded as a white solid (240 mg, 70% purity, 38% yield).
LCMS (m/z) = 409.2 [M+H],
Synthesized according to procedure B, title compound was afforded as a yellow sticky solid (230 mg. 39.5% yield). LCMS (ESI, m/z) = 378.55 [M+H],
General procedure: Nitrile red/Boc prot
To a stirred solution of 2-(4-iodophenyl)imidazo[l,2-a]pyridine-6-carbonitrile (1.00 g, 2.90 mmol, 1.00 eq) in MeOH (15 mL) was added. Resulting mixture was cooled to 0°C then charged NiCh.SEEO (0.069 g, 0.290 mmol, 0.100 eq). Reaction was stirred at RT for 16hrs. Progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion, the reaction was quenched with sodium bicarbonate solution at 0°C, extracted with ethyl acetate, combined organic layer washed with brine solution, and dried over sodium sulphate. Organic layer was concentrated under reduced pressure. Crude was purified by column chromatography to afford tert-butyl N-[[2-(4-iodophenyl)imidazo[l,2-a]pyridin-6- yl]methyl]carbamate, (0.82 g, 1.83 mmol, 63% yield) as brown liquid.
LCMS (ESI, m/z) = 450.09 [M+H],
A solution of 4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)aniline;hydrochloride (2.00 g, 8.01 mmol, 1.00 eq) in tert-butanol (20 mL) was cooled in an ice bath. TEA (3.35 mL, 24.0 mmol, 3.00 eq) and BOC2O (2.76 mL, 12.0 mmol, 1.50 eq) were added and the reaction was heated to 80 °C for 16 h. Volatiles were evaporated under reduced pressure to afford the crude. This crude was further purified in automated flash chromatography in 0 to 70% ethyl acetate in DCM gradient to afford the pure compound tert-butyl N-[4-(5, 6,7,8- tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl]carbamate, (1.10 g, 44% yield).
1H NMR (400 MHz. DMSO-d6): δ 9.27 (s, 1H). 7.56 (d, J = 8.56, 2H). 7.38(d, J = 8.32.2H), 3.93 (t, J= 5.46, 2H), 2.73 (t, J = 6.00, 2H), 1.88-1.83 (m, 4H), 1.47 (s, 9H).
LCMS(m/z)= 314.0 & RT= 3.28 min.
Synthesized using a modified amine alkylation procedure with NaH as the base, the title compound was afforded (195 mg, 63% yield).
LCMS (m/z) = 488.4 [M+H]+
General procedure: Boc depr
Procedure: To the solution of tert-butyl 3-hydroxy-3-[2-[6-(5.6.7.8-tetrahydroimidazo[1.2- a|pyridin-2-yl)-3-pyridyl]ethynylJpyrrolidine-l-carboxylate (110 mg, 0.269 mmol, 1.00 eq) in DCM (3 mL) was added TFA (.21 mL, 2.69 mmol, 10.0 eq) at 0°C and allowed to stir at 25°C for 3 h. After completion volatiles were removed under reduced pressure, residue was washed with DCM-Ether and diluted with 15% MeOH in DCM, which was treated with amberlyst A21 base to get salt free amine, filtered off and solution was concentrated to afford desired compound 3-[2-[6-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)-3- pyridyl]ethynyl]pyrrolidin-3-ol, (35 mg, 0. 113 mmol, 42% yield) as brownish fluffy solid.
LCMS; m/z = 309.5 [M+H],
Following a modified procedure of Boc-depr utilizing HC1 in dioxane, the title compound was afforded as the HC1 salt (230 mg, 69% yield).
LCMS (ESI, m/z) = 277.95 [M+H],
Following a modified procedure of Boc-depr utilizing HC1 in dioxane, the title compound was afforded as the HC1 salt as a white solid (1.0 g, 96% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.83 (br s, 2H), 3.13 (m, 2H); 3.09 (s, 1H); 2.95 (m, 2H);
2.73 (m, 1H); 1.95 (m, 2H); 1.79 (m, 2H). Following a modified procedure of Boc depr utilizing HC1 in dioxane, the title compound was afforded as a free base as a light green solid (40 mg, 95% punty. 57% yield).
1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J= 6.8 Hz, 1H). 7.65 (s, 1H), 7.44 (d, J= 9.2 Hz, 1H), 7. 15 (t, J= 7.6 Hz, 1H), 6.80 (t, J= 6.4 Hz, 1H). 3.02 (d, J= 11.6 Hz. 2H); 2.74 (m, 1H); 2.62 (t, J = 12 Hz, 2H); 1.92 (d, J= 12.4 Hz, 2H); 1.55 (m, 2H).
LCMS (ESI, m/z) = 202. 1 [M+H],
Synthesized according to Boc depr utilizing HC1, the title compound was afforded as an off white solid (310 mg, 98.29% purity. 66% yield) as an HC1 salt.
LCMS (ESI, m/z) = 350.08 [M+H],
General procedure -sulfonylation
KMSHRUTH 001 440
To a stirred solution of [2-(4-iodophenyl)imidazo[l,2-a]pyridin-6-yl]methanamine hydrochloride (210 mg, 0.545 mmol, 1.00 eq) in DCM (10 mL) was added. Resulting mixture was cooled to 0°C then charged Mesyl chloride (.05 mL. 0.653 mmol, 1.20 eq). Reaction was stirred at RT for 16 hrs. Progress of the reaction was monitored by TLC (10% MeOH in DCM). After completion of the reaction, RM was quenched with sodium bicarbonate solution at 0°C , extracted with DCM. combined organic layer washed with brine solution, dreid over sodium sulphate. Organic layer was concentrated under reduced pressure. Crude was purified by column chromatography to afford N-[[2-(4- iodophenyl)imidazo[l,2-a]pyridin-6-yl]methyl]methanesulfonamide, (150 mg, 98.59% purity, 64% yield) as brown liquid.
LCMS (ESI, m/z) = 427.99 [M+H],
To a solution of ethyl 4-oxocyclohexyl-l -carboxylate (6.00 g, 35.3 mmol, 1.00 eq) in THF (120 rnL) was added LIHMDS (1 M, 38.78 mL, 38.8 mmol, 1.10 eq) under nitrogen atmosphere at -78°C stirred for 1 hr at same temperature. After that added dissolved solution of l.l.l-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (13.22 g, 37.0 mmol, 1.05 eq) in THF (30 mL) slowly for 30 min at -78 °C , then allow to stirred at 25 °C for 16 hrs. The reaction progress was monitored by LCMS and TLC (10% EtOAc/Hexane). After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (500 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude (11.0 g). The crude was column purified by using 230-400 mesh silica gel and eluted with ethyl acetate / hexane (0 to 20%) to get ethyl 4-(trifluoromethylsulfonyloxy)cyclohex-3-ene- 1 -carboxylate, (8.00 g, 20.1 mmol, 76% purity, 57% yield) as colorless liquid.
JH NMR (400 MHz, DMSO-d6): δ 5.89 (s, 1H), 4.08 (q, J= 7.2 Hz, 2H), 2.64 (m, 1H), 2.44- 2.34 (m, 4H), 2.04 (m, 1H), 1.82 (m, 1H), 1.18 (t, J= 7.6 Hz, 3H).
A stirred solution of |2-(4-bromophenyl)imidazo| l .2-a|pyridin-6-yl |nielhanamine (500 mg, 1.65 mmol, 1.00 eq) in THF (10 mL) was cooled to 0°C then charged TEA (.35 mL, 2.48 mmol, 1.50 eq) followed by acetic anhydride (.17 mL, 1.82 mmol, 1.10 eq) slowly. Reaction was stirred at RT for 1 hr. Progress of the reaction was monitored by TLC (5% methanol in DCM). Upon completion of reaction, reaction mixture was diluted with ice cold water, extracted with ethyl acetate, combined organic layer was washed with water and brine solution. Organic layer was concentrated under reduced pressure to give N-[[2-(4- bromophenyl)imidazo[l,2-a]pyridin-6-yl]methyl]acetamide, (520 mg, 92% yield).
LCMS (ESI, m/z) = 345.02 [M+H],
General procedure - carbonyl additions
To a stirred solution of bromo(ethynyl)magnesium (0.5 M in THF, 5 mL. 2.50 mmol, 1.85 eq) was added tert-butyl 3-oxopyrrolidine-l -carboxylate (250 mg, 1.35 mmol, 1.00 eq) at ice cooled condition and stirred for 0.40 hrs. TLC looks formation of a new polar spot (KMNo4 active). Reaction mixture was quenched with sat. NH4CI and extracted with EtOAc and dried over Na2SO4, concentrated under reduced pressure to get tert-butyl 3-ethynyl-3-hydroxy- pyrrolidine-1 -carboxylate, (170 mg, 0.805 mmol, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 5.81 (s, 1H), 3.61-3.58 (m, 1H), 3.45 (s. 1H), 3.40-3.35 (m. 2H), 3.82-3.25 (m. 1H), 2.02-1.98 (m. 1H), 1.77-1.74 (m. 1H), 1.38 (s, 9H).
Synthesized according to procedure carbonyl additions, title compound was afforded as a colorless liquid (580 mg, 90.5% purity, 73% yield).
1H NMR (400 MHz. DMSO-d6): δ 7.20 (s, 1H). 7. 15 (d, J= 8 Hz, 1H). 7. 10 (d, J= 8 Hz, 1H), 5.89 (d, .7= 6 Hz, 1H), 3.43 (d, .7= 2.4 Hz, 1H), 2.21 (s, 3H), 2.20 (s, 3H).
To a stirred solution of 2-(4-ethynylphenyl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine (100 mg, 0.450 mmol, 1.00 eq) in tetrahydrofuran (2 mL) was added n-butyllithium (1.6 M in hexane, 0.53 mL, 0.855 mmol, 1.90 eq) at -78 °C under nitrogen atmosphere. The resulting solution was stirred at -78 °C for 0.50 h. Then tetrahydropyran-3-one (90 mg, 0.900 mmol, 2.00 eq) in THF (0.5mL) was added slowly at -78°C to the above reaction mixture. The reaction was stirred at the same temperature for further 0.50 h and then at 25°C for 1 h. Progress of the reaction was monitored by LCMS and TLC (5% MeOH/DCM) found desired product. After completion of the reaction, the reaction mixture was quenched with ammonium chloride solution, diluted with water and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get a crude. Crude was purified by column chromatography to give rac- (3S)-3-[2-[4-(5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl]ethynyl]tetrahydropyran- 3-ol, (70 mg. 98.93% purity. 48% yield) as a brown liquid. LCMS (ESI, m/z) = 323.4 [M+l],
To stirred solution of l-[2-(4-bromophenyl)imidazo[l,2-a]pyridin-6-yl] ethanone (290 mg, 0.920 mmol, 1.00 eq) in Dry' THF (5 mL) cooled reaction mixture to 0°C, was added MeMgBr (3M in DEE) (3 M, 1.23 mL, 3.68 mmol. 4.00 eq) at 0°C dropwise to reaction mixture and stirred reaction mixture for 16 hrs at 25 °C. Reaction monitored by LCMS; after completion of reaction, reaction mixture quenched with saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (200 mL * 2), organic layer dried over sodium sulfate and evaporated under reduced vacuum to obtain 310 mg crude product. The crude product was purified by column chromatography to give 200 mg of 2- [2- (4-bromophenyl)imidazo[l,2-a]pyridin-6-yl]propan-2-ol, (200 mg, 97.15% purity, 64% yield) as a pale yellow solid.
LCMS (ESI, m/z) = 331.08 [M+H],
To a solution of 4-(3,4-dimethylphenyl)-N-methoxy-N-methyl-cyclohexanecarboxamide (1.40 g, 5.08 mmol, 1.00 eq) in THF (40 mL) was added MeMgBr in Et20 (3 M in Et20, 6.95 mL. 20.8 mmol, 4.10 eq) under nitrogen atmosphere at 0°C . The reaction was stirred at 25°C for 3 hrs. The reaction progress was monitored by LCMS and TLC (30% EtOAc/Hexanes). After completion, the reaction mixture was diluted by water (20 mL), extracted by EtOAc (3*200 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude (1.2 g). The crude was column purified by using 230-400 mesh silica gel and eluted with ethyl acetate / hexane (10 to 30%) to get 6-(3,4-dimethylphenyl)-3-ethyl-heptan-2-one, (1100 mg, 3.38 mmol, 75.7% purity7, 66% yield) as pale colorless liquid.
1H NMR (400 MHz, CDCI3): δ 7.03 (d, J= 8 Hz, 1H), 6.95-6.90 (m, 2H), 2.62 (br s, 1H), 2.47 (m, 1H), 2.24-2.17 (m, 10H), 1.74-1.63 (m, 7H).
LCMS (ESI, m/z) - not ionizable.
A mixture of 3-methoxycarbonylbicyclo[l. l. l]pentane-l-carboxylic acid (4.00 g, 23.5 mmol, 1.00 eq) and thionyl chloride (20 mL) was stirred for 5 hrs at 80°C. The reaction mixture was cooled to room temp, evaporated directly under rotavapor to afford methyl 3- chlorocarbonylbicyclo[l. l. l]pentane-l-carboxylate, (4.00 g, 21.2 mmol, 90% yield) as pale yellow solid, which was used directly in the next step without further purification or identification.
The next step was performed in 2 separate batches of equal amounts of acid chloride and combined for purification.
To a stirred solution of copper iodide (2.42 g, 12.7 mmol. 1.20 eq) in THF (30 mL) was added methyl lithium (1.6 M in diethyl ether, 13.25 mL, 21.2 mmol, 2.00 eq) at -78°C under argon atmosphere. Methyl 3-chlorocarbonylbicyclo[l. l. l]pentane-l-carboxylate (2.00 g, 10.6 mmol, 1.00 eq) in THF (30 mL) was added in to the reaction mixture slowly and stirred for 2 hrs at -78°C.
The progress of the reaction was monitored by TLC. The reaction mixture was diluted with saturated ammonium chloride solution (20 mL) and extracted using DCM ( 20 mL * 2). The combined organic layer was washed with water (10 mL *2), brine solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced vacuum to afford crude. The crude material was purified by flash column chromatography using silica gel column and the product eluted at 40-50% EtOAc in Hexanes to afford as methyl 3- acetylbicyclo[l.l. l]pentane-l-carboxylate, (2.70 g, 16.1 mmol, 75.8% yield) as a pale yellow solid.
1H NMR (400 MHz, CDCI3): δ 3.70 (s, 3H), 2.29 (s, 6H), 2.14 (s, 3H).
To a solution of 2-bromoimidazo[l,2-a]pyridine (1.50 g, 7.61 mmol, 1.00 eq) and (4- formylphenyl)boronic acid (1.71 g, 11.4 mmol, 1.50 eq) in Dioxane (24 mL) was added K2CO3 (2. 10 g, 15.2 mmol. 2.00 eq) dissolved in water (6 mL) and the mixture was purged under nitrogen atmosphere for 30 min. Pd(PPh?J i (880 mg, 0.761 mmol, 0.100 eq) was added and the reaction was heated to 100 °C for 16 h. After completion, the reaction mixture was diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by automated flash chromatography eluteing with a gradient of ethyl acetate in hexane ( 20 to 40%) to furnish the title compound (750 mg, 86.5% purity, 44.3% yield) as pale yellow solid.
LCMS (ESI, m/z): 223.05 (M+H)+
To a solution of 4-imidazo[l,2-a]pyridin-2-ylbenzaldehyde (400 mg, 1.80 mmol, 1.00 eq) in THF (16 mL) was added bromo-(3,4-dimethylphenyl)magnesium (0.5 M in , 10.8 mL, 5.40 mmol, 3.00 eq) under nitrogen atmosphere at 0°C, The reaction was stirred at 25 °C for 4 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (100 mL x 3). The combined organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure.The crude residue was washed with diethyl ether to get (3,4-dimethylphenyl)-(4-imidazo[l,2-a]pyridin-2-ylphenyl)methanol, (400 mg, 1.15 mmol, 94.1% purity, 64% yield) as an off-white solid.
LCMS (ESI, m/z): 229.15 (M+H)+
General procedure: 3-TMS
To the mixture of 2-fluoro-4-iodo-l-methyl-benzene (1000 mg, 4.24 mmol, 1.00 eq) in DMF (5 mL) was added Cui (161 mg, 0.847 mmol, 0.200 eq) and TEA (2140 mg, 21.2 mmol, 5.00 eq) and trimethylsilylacetylene (1246 mg. 12.7 mmol, 3.00 eq), degassed for 10 min and then added PdC12(PPh3)2 (297 mg, 0.424 mmol, 0. 100 eq) and the reaction mixture was stirred at 80 °C for 16 hrs. After completion of the reaction (monitored by TLC, 0.3 Rf value in 10 ea-hex), the reaction mixture was filtered over celite bed and washed with 20% MeOH-DCM. The filtrate was the evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by combiflash chromatography using 0-100% ethyl acetate-hexane (compound eluted at 05% ethyl acetate-hexane) followed by trituration with diethyl ether and pentane to afford 2-(3-fluoro-4-methyl- phenyl)ethynyl-trimethyl-silane, (670 mg, 3.25 mmol, 77% yield).
GCMS (m/z) =206 [M+],
Synthesized according to procedure 3-TMS, the title compound was afforded as a paleyellow liquid (890 mg, 99.82% purity7, 68% yield). 1H NMR (400 MHz, CDCI3): δ 7.32 (d, J= 8 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J= 8 Hz, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 0.24 (s, 9H). Synthesized according to procedure 3-TMS. the title compound was afforded as a brown liquid (1.0 g. 90% purity, 93% yield).
1H NMR (400 MHz, CDCI3): δ 7.33 (d, J= 8 Hz, 1H), 7.24 (t, J= 7.2 Hz, 1H). 6.94 (d, J = 8Hz, 1H), 6.85 (t, J= 7.2 Hz, 1H), 5.83 (s, 1H), 0.28 (s, 9H).
Synthesized according to procedure 3-TMS, title compound was afforded as a pale-yellow liquid (890 mg, 92.2% purity, 62% yield).
1H NMR (400 MHz, CDCI3): δ 7.21 (m, 1H), 7.12 (m, 1H), 6.99 (m, 1H), 0.27 (s, 9H).
Synthesized according to procedure 3-TMS, title compound was afforded as a brown gum (1.5 g, 46% yield).
GC-MS (m/z} = 246.2 [M+]
Synthesized according to procedure 3-TMS, title compound was afforded as a brown liquid (700 mg, 80% yield).
JH NMR (400 MHz, CDCI3): δ 7.29-7.31 (m, 1H), 7.08-7.11 (m, 1H), 6.99-7.08 (m, 1H), 2.38 (s, 3H), 2.26 (s, 3H), 0.25 (s, 9H).
Synthesized according to procedure 3-TMS, title compound was afforded as a brown liquid (400 mg, 92% yield).
1H NMR (400 MHz, CDC13): δ 7.15-6.93 (m. 3H), 2.42 (s, 6H), 0.26 (s, 9H).
Synthesized using a modified procedure 3-TMS with Pd(PPh?)4 as a catalyst and K2CO3 as the base, title compound was afforded (300 mg, 51.42% yield).
GCMS (m/z) = 226.2 [M+l.
Synthesized using the procedure 3 -TMS, the title compound was afforded (290 mg, 66% yield).
GCMS (m/z) = 206.1 [M+],
Synthesized using the procedure 3 -TMS, the title compound was afforded as a pale yellow liquid (700 mg, 98% purity, 62% yield).
1H NMR (400 MHz, CDCI3): δ 8.43 (d, J= 4.8 Hz, 1H), 7.19 (s, 1H), 7.05 (d, J= 4.8 Hz, 1H), 2.52 (s, 3H), 0.25 (s, 9H).
LCMS (m/z) = 190.0 [M+H],
Synthesized according to procedure 3-TMS, the title compound was afforded (800 mg, 98.8% purity, 94% yield).
Tf NMR (400 MHz, CDCI3): δ 7.44-7.34 (m, 3H), 6.72 (t, J= 55.6 Hz, 1H), 2.39 (s, 3H), 0.25 (s, 9H).
Synthesized according to procedure 3-TMS. the title compound was afforded as an off white solid (4.0 g, 88% purity, 87% yield).
LCMS (m/z) = 353.0 [M+H],
Synthesized according to procedure 3-TMS, the title compound was afforded as a light brown liquid (170 mg, 96% yield).
GCMS (m/z) = 228.2 [M+],
General procedure - Ac prot
To a stirred solution of 2-(2-trimethylsilylethynyl)phenol (500 mg, 2.63 mmol. 1.00 eq) in dichloromethane (13 mL) were added triethylamine (319 mg, 3.15 mmol, 1.20 eq) , DMAP (64 mg, 0.525 mmol, 0.200 eq) and Acetic Anhydride (402 mg, 3.94 mmol, 1.50 eq) under nitrogen atmosphere at RT, the reaction was stirred at RT for 16 hrs. The progress was monitored by LCMS and TLC (5% EtOAc/Hexane). After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get crude. The Crude was purified by column chromatography using 230-400 mesh silica (column size; 25g) Flow rate: (20 mL/min, UV; 254 nm) and 0-5% Ethyl Acetate/Hexane as mobile phase to give [2-(2-trimethylsilylethynyl)phenyl] acetate, (500 mg, 2.07 mmol, 96.18% purity, 79% yield) as a brown liquid.
LCMS (ESI, m/z) = 233.1 [M+H]
General procedure - TMS deprotection (TMS-depr)
To a stirred solution of 2-(2,4-dimethylphenyl)ethynyl-trimethyl-silane (890 mg, 4.40 mmol, 1.00 eq) in Methanol (4.1667 mL) and diethyl ether (6.6667 mL) was added K2CO3 (728 mg, 5.28 mmol, 1.20 eq) and reaction stirred at 25 °C for 16 h . Reaction was monitored by LCMS; after completion of reaction, reaction mixture was filtered through celite bed and celite bed was washed with diethyl ether (250 mL * 4), filtrate was distilled under vacuum of 100 mbar and water bath temperature 35 °C to get 380 mg of 1 -ethynyl-2,4-dimethyl- benzene, (380 mg, 2.91 mmol, 99.81% purity, 66% yield) as a pale yellow liquid.
1H NMR (400 MHz. CDCI3): δ 7.34 (d, J = 8 Hz, 1H), 7.02 (s, 1H), 6.94 (d, J = 8 Hz, 1H), 3.22 (s, 1H) 2.41 (s, 3H), 2.31 (s, 3H).
Synthesized according to procedure TMS depr, title compound was afforded as a brown liquid (400 mg, 72.85% purity, 60% yield).
LCMS (ESI, m/z) = 160.95 [M+H],
Synthesized according to procedure TMS depr, title compound was afforded as a brown solid (240 mg, 75% yield).
1H NMR (400 MHz, CDC13): δ 7.33 (d, J= 7.2 Hz, 1H), 7.12 (d, J= 7.2 Hz, 1H), 6.99-7.05 (m, 1H), 3.32 (s, 1H), 2.40 (s, 3H), 2.27 (s, 3H).
Synthesized according to TMS-depr, title compound was afforded as a pale-yellow liquid (400 mg, 71% purity, 49% yield).
1H NMR (400 MHz, CDCI3): δ 7.18-7.24 (m, 2H), 7.04 (m, 1H), 3.35 (s, 1H).
Synthesized according to procedure TMS-depr, title compound was afforded as a brown liquid (220 mg, 85% yield).
1H NMR (400 MHz. CDCI3): δ 7.00-7. 13 (m, 3H), 3.50 (s, 1H), 2.44 (s, 6H).
Synthesized according to procedure TMS-depr, title compound was afforded as a pale-yellow liquid (316 mg, 98% purity, 71% yield).
1H NMR (400 MHz, CDCI3): δ 8.46 (d, J= 4.4 Hz, 1H), 7.22 (s, 1H), 7.14 (d, J= 4.4 Hz, 1H), 3.24 (s, 1H), 2.54 (s, 3H).
Synthesized according to procedure TMS-depr, title compound was afforded as a colorless liquid (500 mg, 90% purity, 88% yield). 1H NMR (400 MHz, CDCI3): δ 7.46 (d, J =1.6 Hz, 1H), 7.37 (m, 2H), 6.73 (t, J = 55.2 Hz, 1H), 3.11 (s, 1H), 2.41 (s, 3H). Synthesized according to TMS-depr, title compound was afforded as a white solid (4. 1 g, 52% yield). LCMS (ESI, m/z) = 281.2 [M+H],
To a stirred solution of l-methyl-2-oxo-piperidine-4-carbaldehyde (500 mg, 3.54 mmol, 1.00 eq) in MeOH (10 mL) , K2CO3 (1466 mg, 10.6 mmol, 3.00 eq) and Bestmann-Ohira reagent (1.7 mL, 7.08 mmol, 2.00 eq) were added at 0°C and continue the reaction at 25°C for 16 h.
TLC showed SM almost consumed and non-polar spot formed. To RM (diluted with DCM) aqueous NaHCCh solution was added and stirred for 30 mins. DCM part was separated out, dried over Na2SO4, filtered and concentrated to afford crude product which was purified by flash column chromatography using MeOH in DCM to afford 4-ethynyl-l-methyl-piperidin- 2-one, (250 mg, 1.82 mmol, 51% yield).
GCMS (m/z) = 137.0 [M+],
General procedure - Suzuki
To a stirred solution of (3,4-dimethylphenyl)boronic acid (2.07 g, 13.8 mmol, 1.30 eq), 1- bromo-4-iodo-benzene (3.00 g, 10.6 mmol, 1.00 eq) and Pd(PPh?)4 (0.62 g, 0.530 mmol, 0.0500 eq) in toluene (30 mL) and water (5 mL) was added potassium carbonate (4.39 g, 31.8 mmol, 3.00 eq) at RT, degassed using nitrogen for 10 min. The resulted suspension was stirred for 16 hrs at 110 °C.
The progress of the reaction was monitored by TLC . The reaction mixture was cooled to RT, filtered over celite bed , washed with EtOAc (50 mL). Filtrate was concentrated under reduced vacuum to afford crude. The crude material was purified by flash column chromatography using silica gel column and the product eluted at 0-1% EtOAc in Hexanes to afford as 4-(4-bromophenyl)- 1 ,2-dimethyl-benzene, (2.50 g, 9.57 mmol, 90% yield) white solid.
1H NMR (400MHz, CDCI3): δ 7.53 (d, J= 8.8 Hz, 2H), 7.43 (d, J= 8 Hz, 2H), 7.32 (s, 1H), 7.28 (d, J= 8.8 Hz, 1H). 7. 19 (d, J= 8 Hz, 1H). 2.32 (s. 3H), 2.29 (s. 3H).
Synthesized according to procedure Suzuki, title compound was afforded as a pale-yellow liquid (3.9 g, 99.33% purity7, 91% yield).
1H NMR (400MHz, CDCI3): δ 7.14 (s, 1H), 7.10 (d, J= 8 Hz, 1H), 7.06 (d, J= 8 Hz, 1H), 6.04 (br s, 1H). 4.17 (q, J= 7.6 Hz, 2H), 2.60-2.45 (m, 5H). 2.25 (s, 3H), 2.24 (s. 3H), 2.17
(m. 1H), 1.82 (m, 1H). 1.27 (t. J= 7.6 Hz. 3H).
LCMS (ESI, m/z) = 259.1 [M+H], Synthesized according to procedure Suzuki, title compound was afforded as a white solid (900 mg, 97.85% purity, 64% yield).
To a solution of l-(4-bromophenyl)adamantane (500 mg, 1.72 mmol, 1.00 eq) in Dioxane (12 mL) were added Bis(pinacolato)diboron (567 mg, 2.23 mmol, 1.30 eq) and KO Ac (808 mg, 8.23 mmol, 4.80 eq) under nitrogen atmosphere at room temperature. The mixture was purged with N2 for 10 min then Pd(dppf)Ch (125 mg, 0.171 mmol, 0.100 eq) was added. The reaction was stirred at 110 °C for 2 h in a microwave reactor. After completion, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The crude mixture was subjected to column purification by using 230-400 mesh size silica using (5-8%) Ethyl acetate and hexane as eluent. The combined fractions were concentrated to obtained 2-[4-(l-adamantyl)phenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (480 mg, 1.08 mmol, 76% purity, 80% yield) as an off-white solid.
LCMS (ESI, m/z): 339.15 (M+H)+ Synthesized according to a modified version of procedure Suzuki using catalytic Pd(dppf)Ch and Na2COs to furnish the title compound as a light yellow solid (260 mg, 86.22% purity, 69% yield).
LCMS (ESI, m/z): 329.40 (M+H)+ General procedure for aldehyde to diFMe
To a solution of 4-bromo-2-methyl-benzaldehyde (1.50 g, 7.54 mmol, 1.00 eq) in DCM (30 mL) was added DAST (2.49 mL, 18.8 mmol, 2.50 eq) under nitrogen atmosphere at 0°C . The reaction was stirred at 25 °C for 12 h . The reaction progress was monitored by LCMS and TLC (10% EtOAc/Hexane). After completion of the reaction; the reaction mixture was diluted with water and extracted with DCM ( 20 mL x 3). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude (1.4 g). The crude was column purified by using 230-400 mesh silica gel and eluted with ethyl acetate / hexane ( 0 to 10%) to get 4-bromo-l-(difluoromethyl)-2-methyl-benzene, (1.00 g, 4.21 mmol, 93.08% purity, 56% yield) as pale yellow' liquid.
1H NMR (400MHz, CDCI3): δ 7.40 (m, 3H), 6.70 (t, J= 55.2 Hz, 1H), 2.40 (s, 3H), 2.30 (s, 3H).
General procedure: Pd/C reduction (Pd/C red)
SANTRA 003 161
To a stirred solution of methyl 2-(4-nitrophenyl)imidazo[l,2-a]pyridine-6-carboxylate (9000 mg, 30.3 mmol, 1.00 eq) in methanol (900 mL) was added concentrated HC1 (6.3 mL) and the reaction mixture was degassing for 5 minutes. Then to it was added Pd-C (2416 mg, 22.7 mmol, 0.750 eq). After complication of addition the resulting reaction mixture was stirred at 25 °C for 16 hrs under 2068.4 mbar H2 pressure in Parr shaker. TLC and LCMS was showed the desired compound was formed. Reaction mixture was filtered through celite bed and bed was washed with methanol. Filtration was concentrated and diluted with ethyl acetate (200mL). Combine organic layers were washed with saturated sodium bicarbonate solution (50mL) and brine solution (50mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a crude compound. Crude compound was purified by diethyl ether wash to afford the title compound as an off white solid (7.0 g, 78% purity, 85% yield).
LCMS (m/z) = 272.2 [M+H],
Synthesized using a modified procedure of Pd/C red utilizing Pd(OH)2 as a catalyst, the title compound was afforded as a pale brown solid (3.6 g, 97.37% purity, 89% yield).
LCMS (ESI, m/z) = 261.13 [M+H] .
Synthesized according to Pd/C red to furnish the title compound (8.0 g, 89.7% yield). LCMS (m/z)= 214.3, Rt= 1.35 min.
1H NMR (400 MHz. DMSO-d6): δ 7.35 (d, J = 8.36, 2H). 7.11 (s. 1 H). 6.51 (d, J = 8.36, 2H), 4.94 (s, 2H), 3.89 (t, J = 11.04, 2H), 2.70 (t, J = 12.12, 2H), 1.88-1.82 (m, 4H)
Synthesized according to a modified Pd/C procedure utilizing PtCh as a catalyst, the title compound was afforded (3.0 g, 96% purity, 57% yield).
LCMS (m/z) = 215.2 [M+H],
General procedure - Sandmeyer
To a stirred solution of methyl rac-(6S)-2-(4-aminophenyl)-5,6,7,8-tetrahydroimidazo[l,2- a]pyridine-6-carboxylate (9000 mg, 33.2 mmol, 1.00 eq) in H2O (150 mL) was cooled to 0°C and to it was added NaNCO2 (2975 mg, 43.1 mmol, 1.30 eq) in H2O (150 mL) followed by the addition of PTSA (12620 mg, 66.3 mmol, 2.00 eq) in ACN (225 mL). After addition reaction mixture was stirred for 1 hr at 0°C . Then to it was added KJ (16519 mg, 99.5 mmol. 3.00 eq) in H2O (150 mL) at 0°C . After that reaction mixture was allow to 25 °C for 1 hr and monitored by TLC and LCMS. Upon completion, reaction mixture was diluted with ethyl acetate (70mL). Combine organic layers were washed with saturated sodium bicarbonate solution (25mL) and brine solution (25mL). dried over anhydrous sodium sulphate and concentrated under reduced pressure to get a crude compound. Crude compound was purified by silica gel column chromatography (mobile phase - 5% MeOH/DCM ;Rf=0.3) to afford the title compound as a sticky brown solid (6.5 g, 76% purity, 51% yield).
LCMS (m/z) = 383.2 [M+Hl.
Synthesized according to procedure A, title compound was afforded as a white solid (320 mg, 88% purity, 51.4% yield).
LCMS (m/z) = 442.9 [M+],
Synthesized according to procedure B, title compound was afforded as a pale yellow solid
(450 mg, 82.8% purity, 69% yield).
LCMS (ESI, m/z) = 415.5 [M+HJ.
Synthesized according to procedure B, title compound was afforded as an off white solid (45 mg, 89% purity, 14% yield).
LCMS (ESI, m/z) = 402.2 [M+H],
Synthesized according to procedure B, the title compound was afforded as an off white solid (110 mg, 46% yield).
LCMS (ESI, m/z) = 441.3 [M+H],
Synthesized according to procedure B, the title compound was afforded as a white solid (110 mg, 40% yield).
LCMS (ESI, m/z) = 338.2 [M+H],
Synthesized according to procedure B, title compound was afforded as a white solid (90 mg, 84% purity, 25% yield).
LCMS (ESI, m/z) = 426.0 [M+H],
Synthesized according to procedure A, title compound was afforded as a brown solid (350 mg, 90% purity, 55% yield).
LCMS (ESI, m/z) = 401.3 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (140 mg, 77% purity, 51% yield).
LCMS (ESI, m/z) = 387.2 [M+H],
Synthesized according to procedure B, title compound was afforded (75 mg, 32% yield).
LCMS (ESI, m/z) = 432.3 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (240 mg, 40% yield).
LCMS (ESI, m/z) = 428.0 ([M+H],
Synthesized according to procedure B, title compound was afforded as a white solid (110 mg, 35% yield).
LCMS (ESI, m/z) = 441.2 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (66 mg, 32% yield).
LCMS (ESI, m/z) = 388.1 [M+H],
Synthesized according to procedure B, title compound was afforded as a brow n solid (250 mg, 85% purity, 37% yield).
LCMS (ESI, m/z) = 408.3 [M+H],
Synthesized according to procedure B, title compound was afforded (115 mg, 81% purity, 14% yield).
LCMS (ESI, m/z) = 455.2 [M+H],
Synthesized according to procedure B, title compound was afforded as a pale yellow solid
(450 mg, 82.8% purity, 69% yield).
LCMS (ESI, m/z) = 415.5 [M+H],
Synthesized according to procedure B, title compound was afforded (110 mg, 35% yield).
LCMS (ESI, m/z) = 439.2 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (270 mg, 43% yield).
LCMS (ESI, m/z) = 442.0 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (220 mg, 64% yield).
LCMS (ESI, m/z) = 386.2 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (200 mg, 93%).
LCMS (ESI, m/z) = 411.0 [M+H],
Synthesized according to procedure B, title compound was afforded (105 mg, 57% yield).
LCMS (ESI, m/z) = 428.3 [M+H],
Synthesized according to procedure A, title was afforded (125 mg, 39.8% yield).
LCMS (ESI, m/z) = 443.2 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (20 mg, 97.17% purity, 8% yield).
1H NMR (400 MHZ,DMSO-CZ6): δ 7.75 (d, J= 8 Hz, 2H): 7.64 (s, 1H); 7.50 (t, J= 7.6 Hz, 3H); 7.34-7.22(m, 3H); 4.25-4.21 (m, 1H); 4.15-4.09 (m, 1H); 3.68 (s, 3H); 3.2-3.18 (m , 1H); 2.82-2.81 (m, 2H); 2.47 (s, 3H); 2.24-2.22(m, 1H); 2.08-2.01 (m, 1H).
LCMS (ESI, m/z) = 371.45 [M+l],
Synthesized according to procedure B, title compound was afforded (120 mg, 75% yield).
LCMS (ESI, m/z) = 456.1 [M+H],
Synthesized according to procedure B, title compound was afforded (60 mg, 29% yield).
LCMS (ESI, m/z) = 387.2 [M+H],
Synthesized according to procedure B, title compound was afforded (110 mg, 35% yield).
LCMS (ESI, m/z) = 441.2 [M+H], Synthesized according to procedure B, title compound was afforded as an off white solid (250 mg, 54% yield).
LCMS (ESI, m/z) = 407.9 [M+H],
Synthesized according to procedure B, title compound was afforded (105 mg, 44% yield).
LCMS (ESI, m/z) = 439.3 [M+H],
Synthesized according to procedure B, title compound was afforded as an off white solid (250 mg, 53% yield).
LCMS (ESI, m/z) = 442.2 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (350 mg, 83% yield).
LCMS (ESI, m/z) = 425.8 [M+H],
Synthesized according to procedure B, title compound was afforded (130 mg, 100% purity, 47% yield).
LCMS (ESI, m/z) = 387.2 [M+H],
Synthesized according to procedure A, title compound was afforded as an off white solid (300 mg, 94% yield).
LCMS (ESI, m/z) = 376.2 [M+H],
Synthesizsed according to procedure B, title compound was afforded as a light brown solid (250 mg, 43% yield).
LCMS (ESI, m/z) = 373.9 [M+H],
Synthesized according to procedure B to furnish the title compound (320 mg, 51.4% yield).
UPLC (m/z) = 442.9 [M+H]+
Synthesized according to carb red to furnish the title compound as a white solid (44 mg, 99.84% purity, 41% yield).
1H NMR (400 MHz, DMSO-d6): δ 7.83 (s, 1H). 7.78 (d, J= 8 Hz. 2H), 7.65 (d, J= 8.4 Hz, 1H), 7.60 (s, 1H), 7.58-7.54 (m, 3H), 4.78 (t, J = 5.2 Hz, 1H), 4.1 1 (dd, J= 12.4, 5.2 Hz, 1H), 3.66 (t, J=10.8 Hz, 1H), 3.51-3.47 (m, 1H), 3.45-3.41 (m, 1H), 2.88-2.84 (m, 1H), 2.74-2.71
(m, 1H), 2.55 (s, 3H), 2.09 (brm, 1H), 1.98-1.95 (m, 1H), 1.62-1.52 (m, 1H).
19F NMR (376 MHz, DMSO-d6): δ -61.02 (s).
UPLC (m/z) = 411.2 [M+H]+ (Rt = 2.36 mins, 5 mins run, TFA-ACN) General procedure - saponification
To a solution of ethyl 4-(3,4-dimethylphenyl)cyclohexane-l-carboxylate (2.00 g. 7.62 mmol, 1 .00 eq) in THF (5 mL) , MeOH (2 mL) & water (5 mL) was added LiOH (1601 mg, 38.1 mmol, 5.00 eq) under nitrogen atmosphere at 25°C . The reaction was stirred at 25°C for 12 h . The reaction progress was monitored by LCMS and TLC (30% EtOAc/Hexanes). After completion the reaction mixture was concentrated under reduced pressure and acidified with 10% citric acid; solid was precipitated, filtered the solid and washed with water to get 4-(3,4- dimethylphenyl)cyclohexane carboxylic acid, (1.50 g, 5.49 mmol, 85% purity, 72% yield) as an off white solid.
1H NMR (400 MHz, DMSO-d6): δ 12.11 (br s, 1H), 7.01 (d, J= 7.2 Hz, 1H), 6.92 (s, 1H), 6.86 (d, J= 7.2 Hz, 1H), 2.61 (br s, 1H), 2.17 (s, 3H), 2.15 (s, 3H), 2.07 (m, 2H), 1.97 (m, 1H), 1.77 (m, 1H), 1.65-1.52 (m, 4H), 1.43 (m, 1H).
LCMS (ESI, m/z) = not ionized.
Synthesized according to procedure saponification, title compound was afforded as a white solid (350 mg, 98.98% purity, 73% yield).
LCMS (ESI, m/z) = 257.08 [M+H], General procedure - amide coupling
To a solution of 4-(3,4-dimethylphenyl)cyclohexane carboxylic acid (1500 mg, 6.4 mmol, 1.00 eq) in DCM (10 mL) was added CDI (1076 mg, 6.64 mmol, 1.03 eq) under nitrogen atmosphere at 25 °C stirred for Ih. Then added N-methoxymethanamine (443 mg, 7.25 mmol, 1.13 eq) . The reaction was stirred at 25°C for 12 hrs. The reaction progress was monitored by LCMS and TLC (30% EtOAc/Hexanr). After completion the reaction mixture was diluted by water (30 mL), extracted by EtOAc (200*3 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to get crude (450 mg). The crude was column purified by using 230-400 mesh silica gel and eluted with ethyl acetate / hexane (20 to 40%) to get 4-(3.4-dimethylphenyl)-N-methoxy-N-methyl- cyclohexanecarboxamide, (1400 mg, 83.8% purity, 82% yield) as a colorless liquid.
LCMS (ESI. m/z) = 276.0 [M+l],
To a solution of 5-(4-bromophenyl)-2-methyl-pyrazol-3-amine (850 mg, 3.37 mmol, 1.00 eq) in formic acid (8.9 mL, 236 mmol, 70.0 eq) under nitrogen atmosphere at rt . The reaction was heated to 100 °C for 4 h The reaction progress was monitored by LCMS and TLC (5% MeOH/DCM). After completion of the reaction, the reaction mixture was added to water (200 mL) and solid was precipitated, filtered, washed by water, and then dried in vacuum to get N-[5-(4-bromophenyl)-2-methyl-pyrazol-3-yl]formamide, (750 mg, 2.60 mmol, 96.93% purity, 77% yield) as an off-white solid. LCMS (ESI, m/z) = 279.95 [M+],
5-(4-bromophenyl)-2-methyl-pyrazol-3-amine (250 mg, 0.992 mmol. 1.00 eq) was taken in THF (5 mL), then at 0°C, ethyl chloroformate (0.11 mL, 0.992 mmol, 1.00 eq) and pyridine (78 mg, 0.992 mmol, 1.00 eq) were added to the reaction mixture, reaction was stirred for 1 h at 0°C. Afer full conversion of starting reaction was quenched with water, and extracted by ethyl aceate, solvent was removed under vacuum, and crude was purified by column chromatography using 30-70% ethyl acetate/hexanes to afford the title compound (175 mg, 54% yield).
LCMS (ESI, m/z) = 324. 1 [M+H],
To a solution of 3-(4-bromophenyl)-3-oxo-propanenitrile (1.20 g, 5.36 mmol, 1.00 eq) in EtOH (9.6 mL) was added methylhydrazine (1.35 mL, 21.4 mmol, 4.00 eq) under nitrogen atmosphere at rt. The reaction was heated at 80°C for 16 hrs. The reaction progress was monitored by LCMS and TLC (40% EtOAc/Hexane). After completion of the reaction, the reaction mixture was added to water (100 mL) and solid was precipitated, filtered, and washed by water to get pure 5-(4-bromophenyl)-2-methyl-pyrazol-3-amine, (850 mg, 3.29 mmol, 97.7% purity, 62% yield) as off-white solid.
1H NMR (400 MHz, CDCI3): δ 7.59 (d, J= 8.8 Hz, 2H), 7.46 (d, J= 8.8 Hz, 2H); 5.84 (s, 1H); 3.72 (s, 3H); 3.54 (br s, 2H).
LCMS (ESI, m/z) = 253.95 [M+2],
Synthesized according to procedure carb red, title compound was afforded as a pale yellow solid (500 mg, 70% yield). LCMS (ESI, m/z) = 266.05 [M+H] .
Synthesized according to the procedure carb red, title compound was afforded as a viscous pale-yellow liquid (800 mg, 75% yield). LCMS (ESI, m/z) = 215.10 [M+H] .
Synthesized according to the procedure Chan lam, the title compound was afforded as a pale brown liquid (400 mg. 27% yield). LCMS (ESI, m/z) = 214.05 [M+H],
Synthesized according to procedure Chan lam, the title compound was afforded as a colorless liquid (0.37 g, 89.8% purity, 23% yield).
LCMS (ESI, m/z) = 301.10 [M+H],
Synthesized according to procedure Chan lam, the title compound was afforded as a colorless liquid (350 mg, 91.17% purity, 21% yield).
LCMS (ESI, m/z) = 315.20 [M+H],
Synthesized according to procedure Chan lam, the title compound was afforded as a colorless liquid (0.93 g, 97.54% purity, 28% yield).
LCMS (ESI, m/z) = 241.20 [M+H],
Synthesized according to procedure Chan lam, title compound was afforded as a pale-yellow viscous liquid (180 mg, 27% yield).
LCMS (ESI, m/z) = 319.20 [M+H],
Synthesized according to Chan lam, the title compound was afforded as a brown solid (2000 mg, 54% yield).
LCMS (ESI, m/z) = 245.2 [M+H],
Synthesized according to procedure SNAr, the title compound was afforded (400 mg, 32.6% yield).
LCMS (ESI, m/z) = 246.1 [M+H],
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound (380 mg, 99.27% purity, 87.4% yield).
LCMS (m/z) = 300.20 [M+H] , RT=2.43 min
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound as an off-white solid (240 mg, 72% yield).
LCMS (m/z) =300.20 [M+H]+, RT=2.47 mm
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound as a brown solid (200 mg, 60% purity, 62.9% yield).
LCMS (m/z) = 286.20 [M+H]’, RT=2.24 mm
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound as a yellow solid (250 mg, 99.18% purity, 90% yield).
LCMS; m/z=300.20 [M+H]+
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound as a yellow solid (280 mg, 92.59% purity, 90% yield).
LCMS m/z= 314.20 [M+H]+
Synthesized according to procedure Buchwald-Hartwig to furnish the title compound as a pale yellow solid (279 mg, 96.93% purity, 99% yield).
LCMS m/z= 300.20 [M+H]+
Synthesized according to procedure HATU to furnish the title compound as a light yellow solid (60 mg, 88% purity , 20% yield).
LCMS (m/z) = 416.3 (M+H)+
Synthesized according to HATU procedure to furnish the title compound (70 mg, 95% purity, 37% yield).
LCMS (m/z) = 490.4 [M+H]+ (Rt = 1.88 min, 3 mins run, AA in CH3CN). Synthesized according to HATU procedure to furnish the title compound as a pale-yellow oil (200 mg, 96.2% purity, 39% yield).
LCMS (m/z) = 360.19 |M+H|

Claims

1. A compound having the structure of formula (I): wherein A is C, CR, CR2, aryl (e.g., C6-C10 aryl), heteroaryl (e.g., 5-10 membered heteroaryl), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3-C10 cycloalkyd, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g.. 3 to 10 membered heterocycloalkyd, saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyd);
Xi is CR or N;
X2 is CR or N;
X3 is CR2 or NR;
Li is absent (i. e.. it is a bond) or -C=C-;
L2 is absent (i.e.. it is a bond), -C=C- -(C(R)2)I-4 — NR-, or -O-; n is an integer from 0-16 (e.g., 1, 2, 3, 4, 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, 16);
Ri and R2 are independently hydrogen or alkyl (e.g., C1-C8 alkyl, C1-C4 alkyl, methyl), and wherein Ri and R2 may together (with X3) form an optionally aromatic five or six membered fused ring (cycloalkyd (e.g., C-Ce membered cycloalkyl ring), aryl (e.g., phenyl), heterocycloalkyl or heteroaryl ring (e.g., 3 to 6 membered heterocycloalkyl ring), 5 to 6 membered heteroaryl ring)), wherein Ri, R2, and the fused ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR. -NHC(O)R, - NRR, -(CRR)I-4NHCOR, -(CRR)I-4NHS(O)2R, heteroaryl (e.g.. 5-10 membered heteroaryl such as triazolyl) optionally substituted with R, heterocycloalkyl (e.g., 5-10 membered heterocycloalkyl) optionally substituted with R;
R3 is independently at each occurrence hydrogen or R, and two R3 groups may together form an optionally substituted spiro, fused, or bridged ring (e.g., 3 to 6 membered cycloalkyd ring), wherein R3 and the spiro, fused, or bridged ring may be optionally substituted (e.g., from one to three times) with, for example, -R, -C(O)R, -C(O)OR, -NHC(O)R, -NRR, -(CRR)i- 4NHCOR;
R4 is hydrogen, alkyl (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyl, methyl, deuterated alkyl or deuterated lower alkyl such as -CD3,), aryl (e.g., C6-C10 aryl), heteroaryl (e.g., 5-10 membered heteroary l), cycloalkyl (e.g., C3-C10 cycloalkyl, saturated cycloalkyl, saturated C3- C10 cycloalky l, unsaturated cycloalkyl, unsaturated C3-C10 cycloalkyl), or heterocycloalkyl (e.g.. C3-C10 heterocycloalkyL saturated heterocycloalkyl, saturated 3 to 10 membered heterocycloalkyl, unsaturated heterocycloalkyl, unsaturated 3 to 10 membered heterocycloalkyl), wherein R4 may be optionally substituted (e.g., from one to three times) with, for example, - R, -C(O)R, -C(O)OR, -NHC(O)R, -NRR, -(CRR)I-4NHC(O)R; and
R is independently at each occurrence hydrogen, halo (e.g., F, Cl), cyano, -NH2, hydroxy, =0, alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy), alkyl (e.g., Ci- Cs alkyl, lower alkyl such as C1-C4 alkyl, methyl), or perhaloalkyl (e.g., C1-C4 perhaloalkyl such as C1-C4 perfluoroalkyl including perfluoromethyl), wherein R may be optionally substituted (e.g., from one to three times) w ith halo (e.g., F, Cl), hydroxy, cyano, -NH2, alky l (e.g., C1-C8 alkyl, lower alkyl such as C1-C4 alkyd, methyl) and/or alkoxy (e.g., C1-C8 alkoxy, lower alkoxy such as C1-C4 alkoxy, methoxy); or a pharmaceutically acceptable salt thereof (e.g, p-toluenesulfonic acid salt, hydrochloride salt, dihydrochloride salt, methylbenzenesulfonate salt, lithium salt), wherein said compound or pharmaceutically acceptable salt thereof is not
N-[5-(3',4'-Dimethylbiphenyl-4-yl)-2-methyl-2H-pyrazol-3-yl]methylamine,
2-Methyl-5-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-2H-pyrazol-3- ylamine,
6-(3',4'-Dimethylbiphenyl-4-yl)-2,3-dihydro-lH-imidazo[l,2-b]pyrazole,
3-(3',4'-Dimethylbiphenyl-4-yl)-l,5-dimethyl-lH-pyrazole
3-(3',4'-Dimethylbiphenyl-4-yl)-l-methyl-lH-pyrazole 5-(3',4'-Dimethylbiphenyl-4-yl)-2-methyl-2H-pyrazol-3-ylamine
3-(4'-ethyl[l J'-biphenyl]-4-yl)-l-methyl-lH-Pyrazol-5-amine
1-[4-(5,6,7,8-Tetrahydroimidazo[l,2-a]pyridin-2-yl)phenyl]-3-(trifluoromethyl)-lH- pyrazole-4-methanol, ethyl 1 -(4-imidazo[ 1 ,2-a] pyridin-2-ylpheny l)-3 -(trifluoromethyl)- 1 H-pyrazole-4- carboxylate,
(7S)-5,6,7,8-Tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[1.2-a]pyridine-7-methanol.
5.6.7,8-Tetrahydro-2-[4-[4-methyl-3-(trifluoromethyl)-lH-pyrazol-l- yl]phenyl]imidazo[1.2-a]pyridine,
2-[4-[4-Methyl-5-(trifluoromethyl)-2-oxazolyl]phenyl]imidazo[1.2-a]pyridine, l-Methyl-6-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-lH- imidazo[l,2-a]imidazole-2-methanol,
1-methyl-6-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]- 1H- imidazo[ 1 ,2-a] imidazole,
3-Methyl-5-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-3H- imidazo[l,2-b][l,2,4]triazole-2-methanol,
6-(2,5-Dimethyl- IH-pyrrol-l -yl)-2-[4-[ 1 -methyl-5-(trifluoromethyl)- lH-pyrazol-3- yl]phenyl]imidazo[l ,2-a]pyridine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-6-(2H-tetrazol-5- yl)imidazo[ 1 ,2-b] py ridazine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2- b]pyridazine-6-carbonitrile,
3-[2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridin-
6-y 1] - 1 ,2,4-oxadiazol-5 (2H)-one,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-6-(2H-tetrazol-5- yl)imidazo[l,2-a]pyridine,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine-
6-carbonitrile, 2,3-Dihydro-6-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[2,l- b] thiazole, a-Methyl-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[1.2- a]pyridine-7-methanol.
2-[4-[l -Methyl-5-(tri fluoromethyl)- lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine- 7-methanol,
5.6.7.8-Tetrahydro-a-methyl-2-[4-[l-methyl-5-(tri fluoromethyl)- lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridine-6-methanol, a-Methyl-2-t4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2- a]pyridine-6-methanol,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine-
6-carboxaldehyde,
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-b]pyridazin-
6-amine,
6-Chloro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2- b]pyridazine,
5.6.7.8-Tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridine-6-methanol.
2-[4-[l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]imidazo[l,2-a]pyridine-
6-methanol,
2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridine-6- carboxylic acid ethyl ester.
5-(4-(imidazo[l,2-a]pyridin-2-yl)phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester
2-[4-[l-ethyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-5,6,7,8-tetrahydro- imi dazo[ 1 ,2-a] pyridine,
2-[4-[l-ethyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-imidazo[l,2-a]pyridine.
5.6.7.8-Tetrahydro-2-[4-[l -methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-ajpyridine. 2-[4-[5-(Trifluoromethyl)-4-methyloxazol-2-yl]phenyl]-imidazo[l,2-a]pyridine,
2-[4-(5-Methylthien-2-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
2-[4-(5-Ethylthien-2-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
2-[4-(4-Ethylthien-2-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
[l-Methyl-6-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-lH- imidazo[l,2-a]imidazol-2-yl]methanol,
1-Methyl-6-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-lH-imidazo[l,2- a]imidazole,
[3-Methyl-5-[4-(l-methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-3H- imidazo[l,2-b]-[l,2,4]triazol-2-yl]methanol, tetrahydro-N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridin-6-yl]methyl]- 3 -thiopheneacetamide,
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[L2-a]pyridin-6-yl]methyl]- 3-pyridinecarboxamide
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[L2-a]pyridin-6-yl]methyl]-lH-Pyrrole-2-carboxamide, 4- methylbenzenesulfonate (1:2)
N-[[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l ,2-a]pyridin-6-yl]methyl]-cyclopropanecarboxamide,
[[2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5, 6,7,8- tetrahydroimidazo[l,2-a]pyridin-6-yl]methyl]amine,
N-[5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3- yl]phenyl]imidazo[l,2-a]pyridin-6-yl]-acetamide,
5,6,7,8-tetrahydro-2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]- imidazo[l,2-a]pyridin-6-amine,
2-[4-[l-methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl]phenyl]-imidazo[l,2-a]pyridin-6- amine,
N-[2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridin- 6-yl] acetamide [2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridin-7- yl] methanol,
2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5, 6,7,8- tetrahydroimidazof 1.2-b]pyridazine.
2-[4-(l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[1.2-b]pyridazine.
6-Amino-2-[4-(l -methy 1-5 -trifluoromethyl- lH-pyrazol-3-yl)phenyl]imidazo[ 1 ,2- b]pyridazine.
2-[4-(l-Ethyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]-5.6,7,8- tetrahydroimidazol 1 ,2-aJ pyridine,
2-[4-(l-Ethyl-5-trifluoromethyl-lH-pyrazol-3-yl)phenyl]imidazo[l,2-a]pyridine,
2-[4-(l -Methyl-5-trifluoromethyl- lH-pyrazol-3-yl)phenyl]-5, 6,7,8- tetrahydroimidazo[ 1.2-a]pyridine, or
2-[4-[l-Methyl-5-trifluoromethyl-lH-pyrazol-3-yl]phenyl]imidazo[1.2-a]pyridine;
2-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-yl)- 1 H-imidazo [ 1 ,2-a]imidazole,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-5,6.7,8-tetrahydroimidazo[l,2-a]pyridine-6- methanamine,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6.7.8-tetrahydroimidazo[l,2-a]pyridine-6- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6.7.8-tetrahydroimidazo[1.2-a]pyridine-7- methanol,
2-(3'.4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridine-6-carboxamide,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine-7-methanol,
2-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-y l)imidazo[ 1 ,2-a] pyridine-6-methanol,
2- [ 1 , 1 '-Biphenyl] -4-y 1-7 -(methoxy methy l)imidazo [ 1 ,2-a] pyridine,
2-[l,l'-Biphenyl]-4-ylimidazo[l,2-a]pyridine-7-methanol,
2-[l,l'-Biphenyl]-4-yl-7-ethylimidazo[l,2-a]pyridine,
Ethyl 6-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[2,l-b]thiazole-3-acetate,
6-(3',4'-Dimethyl[l,l'-biphenylJ-4-yl)imidazo[2,l-b]thiazole-3-ethanol, 6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-2,3-dihydroimidazo[2,l-b]thi azole,
2-[l,r-Biphenyl]-4-ylimidazo[l,2-a]pyridine-7-carbonitrile,
2- [l,l'-Biphenyl]-4-yl-7-(2H-tetrazol-5-yl)imidazo[l,2-a] pyridine,
3-[2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridin-6-yl]-l,2,4-oxadiazol-
5(2H)-one,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine,
3-Ethyl-6-(4-imidazo[l,2-a]pyridin-2-ylphenyl)-l-methyl-lH-indazole,
2-[4-(3,4-Dihydro-lH-2-benzopyran-7-yl)phenyl]imidazo[l,2-a]pyridine,
2-(3-Fluoro-3'.4'-dimethyl[ 1,1 '-biphenyl]-4-yl)imidazo[1.2-a]pyri dine,
2-[4-(2.3-Dihydro-l,4-benzodioxin-6-yl)phenyl]imidazo[l,2-a]pyridine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-(2H-tetrazol-5-yl)imidazo[1.2-a]pyridine,
2-[l,l'-Biphenyl]-4-yl-6-(2H-tetrazol-5-yl)imidazo[l,2-a]pyridine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridine-6-carbonitrile,
2-[l,r-Biphenyl]-4-ylimidazo[l,2-a]pyridine-6-carbonitrile,
6-Bromo-2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridine,
2-[l,r-Biphenyl]-4-yl-7-(4-morpholinyl)imidazo[l,2-a]pyridine,
2-[(2-[ 1 , r-Biphenyl]-4-ylimidazo[ 1.2-a]pyridin-6-yl)amino] ethanol,
6-( 1 -Aziridinyl)-2-[ 1 , 1 '-bipheny 1] -4-y limidazo[ 1 ,2-a] pyridine,
2-[l, l'-Biphenyl]-4-yl-N-(2 -methoxy ethyl)imidazo[l,2-a]pyridin-6-amine,
2-[l,l'-Biphenyl]-4-yl-6-bromoimidazo[l,2-a]pyridine,
2-[l,r-Biphenyl]-4-yl-6-(4-morpholinyl)imidazo[l,2-a]pyridine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazol-2- amine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- carboxamide.
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- carboxylic acid, 2-[5-(3',4'-Dimethylbiphenyl-4-yl)-3-methyl-377-imidazo[1.2-Z>]-[l,2,4]triazol-2- yl]propan-2-ol.
1-[5-(3',4'-Dimethylbiphenyl-4-yl)-3-methyl-377-imidazo[l,2-6]-[l,2.4]triazol-2- yl] ethanol,
5-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- methanamine,
2-(3-Fluoro-3',4'-dimethyl[ 1,1 '-biphenyl]-4-yl)-a,a-dimethylimidazo[ 1.2- b]pyridazine-7-methanol,
2-[6-(3,4-Dimethylphenyl)-3-pyridazinyl]imidazo[l,2-b]pyridazin-6-amine,
2-[2-(3.4-Dimethylphenyl)-5-pyrimidinyl]imidazo[l,2-b]pyridazin-6-amine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole-2- methanol,
2-(3',4'-Dimethyl[ 1 , 1 '-biphenyl] -4-y l)-a-methylimidazo[ 1 ,2-b]py ridazine-6-methanol,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-(4-methyl-l-piperazinyl)imidazo[l,2- b]pyridazine.
2-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y l)-6-( 1 -piperidiny l)imidazo[ 1 ,2-b] py ridazine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-(4-morpholinyl)imidazo[l,2-b]pyridazine.
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-6-hydrazinylimidazo[l,2-b]pyridazine,
N-[(2,4-Dimethoxyphenyl)methyl]-2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2- b] pyridazin-6-amine,
6-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-l-ethyl-lH-imidazo[l,2-a]imidazole,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyridin-6-amine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[l,2-a]pyridine-6- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- a]pyridine,
2-[3',4'-Bis(trifluoromethyl)[l,r-biphenyl]-4-yl]-5,6,7,8-tetrahydroimidazo[l,2- a]pyridine,
5.6.7.8-Tetrahydro-2-[4'-methyl-3'-(trifluoromethyl)[l,r-biphenyl]-4-yl]imidazo[l,2- a]pyridine,
5.6.7.8-Tetrahydro-2-[3'-methyl-4'-(trifluoromethyl)[l,l'-biphenyl]-4-yl]imidazo[l,2- a]pyridine,
6-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-yl)- 1 -methyl- IH-imidazo [2, 1 -c] - 1 ,2,4-triazole,
2-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro[l,2,4]triazolo[l,5- a]pyridine,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2-b][l,2,4]triazole,
5-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-2,3-dimethyl-3H-imidazo[l,2-b][l,2,4]triazole,
2-[4-(2,3-Dihydro-lH-inden-5-yl)phenyl]-5,6,7,8-tetrahydroimidazo[l,2-a]pyridine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-c]pyrimidin-7-amine,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-a-methylimidazo[l,2-b]pyridazine-7-methanol,
2-(3',4'-Dimethyl[l ,1 '-biphenyl]-4-yl)imidazo[l ,2-b]pyridazine,
2-(3'.4'-Dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[l,2-b]pyridazine-6- methanol,
2-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-a]pyrimidin-7-amine,
2-(3'.4'-Dimethyl[l,r-biphenyl]-4-yl)-a,a-dimethylimidazo[l,2-b]pyridazine-7- methanol,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-7,8-dihydro-6-methylimidazo[l,2-c]pyrimidin-
5(6H)-one,
6-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)imidazo[l,2-b][l,2,4]triazine,
2-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-8-fluoroimidazo[l,2-c]pyrimidin-5(6H)-one,
2-(3-Fluoro-3'.4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[1.2-b]pyridazin-6-amine.
6-Chloro-2-(3 '.4'-dimethyl [1,1 '-biphenyl] -4-y l)imidazo[ 1 ,2-b] pyridazine.
2-(3 ',4'-Dimethy 1 [ 1 , 1 '-biphenyl] -4-y l)imidazo[ 1 ,2-b] py ridazin-6-amine,
6-(3 ',4'-Dimethyl [1,1 '-biphenyl] -4-y 1)- IH-imidazo [ 1 ,2-a] imidazole- 1 -ethanol,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)-5,6-dihydro-3-methylimidazo[5,l-b]oxazole, 6-(3\4'-Dimethyl[ 1 J '-biphenyl] -4-yl)imidazo[2, 1 -b] - 1 ,3, 4-thiadi azole,
6-(3',4'-Dimethyl[l,l'-biphenyl]-4-yl)imidazo[2,l-b]thiazole,
6-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-l-methyl-lH-imidazo[2,l-c]-l,2,4- tri azole,
5-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-2,3-dimethyl-3H-imidazo[l,2- b][l,2,4]triazole,
6-(3-Fluoro-3 ',4'-dimethyl [1,1 '-biphenyl] -4-yl)- 1 -methy 1- lH-imidazo[ 1 ,2- a]imidazole,
5-(3-Fluoro-3',4'-dimethyl[l,l'-biphenyl]-4-yl)-3-methyl-3H-imidazo[l,2- b][l,2,4]triazole,
6-(3',4'-Dimethyl[l,r-biphenyl]-4-yl)-2-methylimidazo[2,l-b]-l,3,4-thiadiazole,
Ethyl 2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)imidazo[l,2-a]pyridine-6-carboxylate,
2-[l,l'-Biphenyl]-4-yl-7-chloroimidazo[l,2-a]pyridine,
N-[[2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-6- y 1] methyl] - Acetami de,
6-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)-imidazo[2,l-b]thiazole-3-ethanol
6-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)-2,3-dihydro-imidazo[2,l-b]thiazole,
2-(3',4'-dimethyl[l,l'-biphenyl]-4-yl)- imidazo[l,2-a]pyridine-6-carboxylic acid,
2-(3'-fluoro-4'-methyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-(2'-fluoro-4'-methyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2-a]pyridine
5,6,7, 8-tetrahydro-2-(3'-methyl[l,l'-biphenyl]-4-yl)-imidazo[l,2-a]pyri dine,
2-(3'-fluoro-4',5'-dimethyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-(4'-chloro-3'-methyl[l,l'-biphenyl]-4-yl)-5,6,7,8-tetrahydro- imidazo[l,2- a]pyridine,
2-[4-(l,3-benzodioxol-5-yl)phenyl]-5,6,7,8-tetrahydro-imidazo[l,2-a]pyridine,
2-(3 '-ethyl [ 1, 1 '-biphenyl]-4-yl)-5,6,7,8-tetrahydro-imidazo[ 1,2-a] pyridine, 2-[2'-fluoro-4'-(l-methylethyl)[l,T-biphenyl]-4-yl]-5,6,7,8-tetrahydro-imidazo[l,2- a]pyridine, or a pharmaceutically acceptable salt (e.g., p-toluenesulfonic acid salt, hydrochloride salt, dihydrochloride salt, methylbenzenesulfonate salt, lithium salt) thereof.
2. The compound according to claim 1 , wherein said compound has the structure of formula (la): wherein the doted circle indicates optional aromaticity; and
X4 is CR or N.
3. The compound according to claim 1, wherein said compound has the structure of formula (lb): wherein the doted circle indicates optional aromaticity; and
X4 is CR or N.
4. The compound according to any one of claims 1-3, wherein said compound has the structure of formula (Ic): wherein the doted circle indicates optional aromaticity,
X4 is CR or N; and optionally R4 is hydrogen, aryl, heterocvcloalkyl, or heteroarvl.
5. The compound according to any one of claims 1-3, wherein said compound has the structure of formula (Id): wherein the dottec circle indicates optional aromaticity.
X4 is CR or N; and optionally R4 is hydrogen, aryl, heterocycloalkyl, or heteroaryl.
6. The compound according to any one of claims 1-3, wherein Ri and R2 are independently alkyl (e.g., lower alkyl such as C1-C4 alkyl, methyl).
7. The compound according to any one of claims 1-6, wherein R4 is cycloalkyl (e.g., C3- C10 cycloalkyl, cyclopropyl, cyclobutyl, cyclopenyl, cycloheptyl) optionally having one. two or three points of alkyl (e.g., lower alkyl substitution such as C1-C4 alkyl, methyl) substitution (e.g., monosubstitution, geminal substitution, vicinal substitution).
8. The compound according to any one of claims 1-6, wherein R4 is aryl (e.g., phenyl) optionally having one, two or three points of alkyl (e.g., lower alkyl such as C1-C4 alkyl, methyl) substitution (e.g., monosubstitution, geminal substitution, vicinal substitution).
9. The compound according to any one of claims 1-8, wherein at least one of Li or L2 is not absent.
10. The compound according to any one of claims 1-9, wherein the fused ring formed by Ri and R2 contains only one N (e.g.. when X3 is NR and the remaining members of the fused ring are all C).
11. The compound according to any one of claims 1-10, wherein said compound has the structure -95Z-
12. The compound according to any one of claims 1-11, wherein said compound has an ICso (e.g., as measured in a P-arrestin assay, as measured in a Calcium Flux assay) of human
Complement Component 3a Receptor (C3aR) and/or mouse C3aR of less than (or from 1 nM to) 20pM (e.g.. less than 10 pM. less than 5 pM, less than 2 pM, less than 1 pM. less than 500 nM, less than 200 nM).
13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical composition according to claim 13, wherein the pharmaceutical composition is an injectable composition or an oral composition.
15. A method of inhibiting the Complement Component 3a Receptor (C3aR) in a cell comprising contacting the cell with the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof.
16. The method according to claim 15, wherein the cell is in vivo.
17. A method of treating the excessive Complement activation in a subject in need thereof comprising administering the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof (or the pharmaceutical composition according to claim 13 or 14) to the subject.
18. The method according to claim 17, wherein the subject has a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s disease, frontotemporal dementia, Guillian Barre syndrome, encephalitis, meningitis, stroke, hemorrhagic stroke, cancer, allergic disease, respiratory' disease, cardiovascular or metabolic disease states, shock, hypertension, hyperlipidemia, hypercholesterolemia, edema, obesity, nephritis. Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory' demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection, or inflammatory' conditions.
19. The method according to claim 17, wherein the subject has a disease disorder or condition selected from Alzheimer’s disease, multiple sclerosis, Huntington’s chorea, Pick’s disease, Guillian Barre syndrome, encephalitis, meningitis, stroke, Schizophrenia, amyotrophic lateral sclerosis, Parkinson's disease, chronic inflammatory demyelinating polyneuropathy, myaesthenia gravis, traumatic brain injury, epilepsy, haemolytic uraemic syndrome, C3 glomerulopathy, and antibody-mediated transplant rejection and hemorrhagic stroke.
20. A method of treating Alzheimer’s disease in a subject in need thereof comprising administering the compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof (or the pharmaceutical composition according to claim 13 or 14) to the subject.
21. The method according to any one of claims 17-20, wherein the compound (or the pharmaceutical composition) is administered by intraperitoneal (IP) injection, intravenous (IV) injection, subcutaneous (SC) injection, or orally (PO).
22. The method according to any one of claims 17-21, wherein the compound is administered in an amount of from 1 mg/kg-40 mg/kg (e.g., from 3 mg/kg to 30 mg/kg, from 5 mg/kg-15 mg/kg).
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