WO2022128850A1 - Novel isoquinoline derivatives and pharmaceutical copositions thereof for the treatment of diseases - Google Patents

Novel isoquinoline derivatives and pharmaceutical copositions thereof for the treatment of diseases Download PDF

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Publication number
WO2022128850A1
WO2022128850A1 PCT/EP2021/085377 EP2021085377W WO2022128850A1 WO 2022128850 A1 WO2022128850 A1 WO 2022128850A1 EP 2021085377 W EP2021085377 W EP 2021085377W WO 2022128850 A1 WO2022128850 A1 WO 2022128850A1
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Prior art keywords
compound
pharmaceutically acceptable
independently selected
substituted
acceptable salt
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PCT/EP2021/085377
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French (fr)
Inventor
Christopher Charles Stimson
Olivier Remi BARBEAU
Heather Tye
Elise Lucienne Paulette Gadouleau
Michelle Wing Van SOUTHEY
Claudia Albrecht
Ina Sternberger
Richard Ernest Gilbert
Darren Arthur Vee Yip YUEN
Mathieu Rafaël PIZZONERO
Evelyne QUINTON
Marina Modric
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Galapagos Nv
Mai, Thi Thu Trang
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Publication of WO2022128850A1 publication Critical patent/WO2022128850A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • DDRs discoidin domain receptors
  • RTKs transmembrane receptor tyrosine kinases
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
  • DDRs Discoidin domain receptors
  • RTKs transmembrane receptor tyrosine kinases
  • DDRs contain two discoidin domains in the extracellular region.
  • DDRs are activated by a number of triple-helical collagens which are most abundant components of the extracellular matrix (ECM).
  • ECM extracellular matrix
  • DDR1 is widely expressed in epithelial cells in lung, kidney, colon, brain
  • DDR2 is primarily expressed in mesenchymal cells including fibroblasts, myofibroblasts, smooth muscle, and skeletal in kidney, skin, lung, heart, and connective tissues.
  • DDR1 and DDR2 play crucial roles in fundamental cellular processes, such as proliferation, survival, differentiation, adhesion, and matrix remodeling.
  • Deregulation of DDRs has been implicated in a number of human diseases, including fibrotic disorders, atherosclerosis, and cancer (e.g., pancreatic cancer and melanoma) (Berestjuk et al. 2019; Borza & Pozzi 2014; Ruggeri et al. 2020; Vella et al. 2019).
  • kinase inhibitors imatinib, nilotinib, dasatinib, bafetinib, ponatinib, sorafmib, pazopanib, foretinib, BIRB-796, and LCB 03-0110, are reported to be potent inhibitors of both DDR1 and DDR2.
  • all these inhibitors also potently target many other kinases and cannot be utilized as good pharmacological probes of DDR1 or DDR2 (Li et al. 2015), and for some, showed for example treatment related toxicities (Brunner et al. 2013).
  • DDR inhibitors may show potential promise as therapeutic agents and there is a need for the development of new DDR inhibitors with increased selectivity for DDR receptors, and/or increased safety.
  • the present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • DDRs discoidin domain receptors
  • RTKs transmembrane receptor tyrosine kinases
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
  • Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
  • Li is -O-, or -CR 5a R 5b -;
  • L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R 6 ;
  • heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R 7 ;
  • R 2 is H, C1-4 alkyl, or C1-4 alkoxy, which C1-4 alkyl or C1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
  • R 3a is H or Ci-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
  • R 3b is H, or R 3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
  • R 4 is C1-4 alkyl
  • R 5a and R 5b are independently H or -CH3; each R 6 is independently selected from: halo,
  • each R 7 is independently selected from: halo
  • each R 9 is independently selected from: halo
  • the compounds of the invention are provided for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • the compounds of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention.
  • the further therapeutically active ingredient is an agent for the treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • the compounds of the invention useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
  • this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
  • the present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine.
  • the pharmaceutical composition is for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
  • the articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article.
  • an analogue means one analogue or more than one analogue.
  • Alkyl means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH 2 -C(CH 3 )3), scc-butyl (-CH2-CH(CH3)2), w-pcntyl (-CH2-CH2-CH2-CH2-CH3), w-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3).
  • Particular alkyl groups have between 1 and 4 carbon atoms.
  • Alkylene refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.
  • Alkoxy refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C1-6 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. tert-butoxy, scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Amino refers to the radical -NH2.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified.
  • the term includes groups that include from 6 to 10 ring members.
  • Particular aryl groups include phenyl, and naphthyl.
  • Cycloalkyl refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified.
  • a cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cyano refers to the radical -CN.
  • Halo or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.
  • Heteroaryl means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the aromatic ring structure may have from 5 to 9 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.
  • Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
  • heterocycloalkyl means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified.
  • the heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen.
  • heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g.
  • piperidinyl e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl
  • tetrahydropyranyl e.g. 4- tetrahydropyranyl
  • tetrahydrothiopyranyl e.g. 4-tetrahydrothiopyranyl
  • morpholinyl thiomorpholinyl, dioxanyl, or piperazinyl.
  • heterocycloalkenyl means a ‘heterocycloalkyl’, which comprises at least one double bond.
  • each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
  • fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
  • bridged polycyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH.
  • W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH.
  • spirocyclic rings are shown in the following illustrative examples: wherein each Y is selected from -CH2-, -NH-, -O- and -S-.
  • Haldroxyl refers to the radical -OH.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • substituted with one or more refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • ‘Pharmaceutically acceptable’ refers to compounds of the invention and compositions thereof, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable.
  • such salts may be inorganic or organic acid addition salts and base addition salts
  • pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011).
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid.
  • the compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts.
  • salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases.
  • the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases.
  • Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, /V-alkyhnorpholine esters and the like.
  • Solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding.
  • Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solvate’ encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates and methanolates.
  • Subject includes humans.
  • the terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
  • Effective amount means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • Preventing refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • prophylaxis is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both.
  • “treating” or “treatment” relates to slowing the progression of the disease.
  • fibrotic disease(s) refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • systemic sclerosis renal fibrosis
  • cutaneous fibrosis fibrotic diseases
  • inflammatory disease(s) refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the j oints .
  • allergic airway disease e.g. asthma, rhinitis
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac
  • the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases.
  • the term ‘respiratory disease(s)’ refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves.
  • respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirinsensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • asthma adult respiratory distress syndrome and allergic (extrinsic) asthma
  • non-allergic (intrinsic) asthma acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirinsensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma,
  • autoimmune disease(s) refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • COPD chronic or inveterate asthma
  • bronchitis including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g.
  • autoimmune hepatitis primary sclerosing cholangitis, and primary biliary cirrhosis
  • Sjogren’s syndrome multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • Metabolic diseases refers to disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Metabolic diseases affect the ability to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids).
  • the term refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
  • cardiovascular diseases refers to diseases affecting the heart or blood vessels, or both.
  • cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue. More particularly, the term refers to vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vessel disease, and hypertension.
  • proliferative disease(s) refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis.
  • cancer e.g. uterine leiomyosarcoma or prostate cancer
  • myeloproliferative disorders e.g. polycythemia vera, essential thrombocytosis and myelofibrosis
  • leukemia e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia
  • multiple myeloma psoriasis
  • restenosis scleroderma or fibrosis
  • cancer refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel.
  • a cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain.
  • cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma).
  • metastatic tumour cell types such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma
  • tissue carcinoma such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer,
  • cancer refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, reti
  • leukemia refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding.
  • leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).
  • AML acute myeloid leukemia
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphoblastic leukemia
  • Compound(s) of the invention and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits.
  • reference to intermediates, whether or not they themselves are claimed is meant to embrace their salts, and solvates, where the context so permits.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.
  • the present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), chlorine-37 ( 37 C1), fluorine-18 ( 18 F) iodine-123 ( 123 I), iodine-125 ( 125 I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • an artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( n C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e 2 H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as n C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • positron emitting isotopes such as n C, 18 F, 15 O and 13 N
  • stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
  • the compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
  • DDRs discoidin domain receptors
  • RTKs transmembrane receptor tyrosine kinases
  • the present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
  • Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
  • Li is -O-, or -CR 5a R 5b -;
  • L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R 6 ;
  • heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R 7 ;
  • R 2 is H, C1-4 alkyl, or C1-4 alkoxy, which C1-4 alkyl or C1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
  • R 3a is H or C1-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
  • R 3b is H, or R 3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
  • R 4 is C1-4 alkyl
  • R 5a and R 5b are independently H or -CH3; each R 6 is independently selected from: halo,
  • each R 7 is independently selected from: halo
  • each R 9 is independently selected from: halo
  • the compound of the invention is according to Formula I, wherein R 4 is C1-4 alkyl.
  • R 4 is -CH3, -CH2CH3, or -C H(CH ,)2.
  • R 4 is -CH3 or -CH2CH3.
  • R 4 is -CH3.
  • the compound of the invention is according to Formula II:
  • the compound of the invention is according to Formula I or II, wherein Het is 8-10 membered fused bicyclic heteroaryl comprising one, two, or three N.
  • Het is l,4-dihydropyrrolo[3,2-b]pyrrolyl, l,6-dihydropyrrolo[2,3-b]pyrrolyl, pyrrolo[l,2-a]imidazolyl, pyrrolo[l,2-b]pyrazolyl, l,4-dihydropyrrolo[2,3-d]imidazolyl, l,4-dihydropyrrolo[3,2-c]pyrazolyl, 1,6- dihydropyrrolo [2,3 -c]pyrazolyl, 3 ,4-dihydropyrrolo [2,3 -d]imidazolyl, imidazo [ 1 ,2-a] imidazolyl, imidazo[l,2-b]pyrazolyl,
  • the compound of the invention is according to Formula Illa, IHb, or IIIc:
  • the compound of the invention is according to Formula I or II, wherein Het is 6 membered monocyclic heteroaryl comprising one, two, or three N.
  • Het is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl.
  • Het is pyridinyl.
  • the compound of the invention is according to Formula IVa or IVb:
  • the compound of the invention is according to Formula Va or Vb: wherein R 1 , R 2 , R 3a , R 3b , Li, L3, and the subscript n are as described previously.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 2 is H.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 2 is C1-4 alkyl.
  • R 2 is -CH3, -CH2CH3, or -CH(CH3)2.
  • R 2 is -CH3 or -CH2CH3.
  • R 2 is -CH3.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 2 is C1-4 alkyl substituted with one or more independently selected halo.
  • R 2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one or more independently selected halo.
  • R 2 is C1-4 alkyl substituted with one, two, or three independently selected halo.
  • R 2 is C1-4 alkyl substituted with one or more independently selected F, Cl, or Br.
  • R 2 is -CH3, -CH2CH3, or -CH(CH 3 )2, each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 2 is -CF3 or -CH2CF3. In a most particular embodiment, R 2 is -CF3.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 2 is C1-4 alkoxy.
  • R 2 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2.
  • R 2 is -O-CH3.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein R 2 is C1-4 alkoxy substituted with one or more independently selected halo.
  • R 2 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2, each of which is substituted with one or more independently selected halo.
  • R 2 is C1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 2 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 2 is -O-CH3, - O-CH2CH3, or -O-C H(CH ,)2.
  • R 2 is -O-CH3 substituted with one, two, or three F.
  • R 2 is -O-CF3.
  • the compound of the invention is according to Formula Via, VIb, Vic, Vid, or Vie:
  • the compound of the invention is according to any one of Formulae I- Vie, wherein n is 0.
  • the compound of the invention is according to any one of Formulae I- Vie, wherein n is 1 and Li is -O-.
  • the compound of the invention is according to any one of Formulae I- Vie, wherein n is 1, Li is -CR 5a R 5b -, and R 5a and R 5b are independently H or -CH3. In a particular embodiment, R 5a and R 5b are both H. In another particular embodiment, one of R 5a and R 5b is H, and the other is -CH3. In yet another particular embodiment, R 5a and R 5b are both -CH3. In a most particular embodiment, Li is -CH 2 -. [0095] In one embodiment, the compound of the invention is according to Formula Vila, Vllb, Vile, Vlld,
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl.
  • R 1 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 1 is cyclopropyl or cyclopentyl.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 .
  • R 1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is C3-6 cycloalkyl substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one or more independently selected R 7 .
  • R 1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one R 7 .
  • R 1 is
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C2-6 alkenyl.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is Ci-4 alkyl.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 .
  • R 1 is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is Ci-4 alkyl substituted with one or more independently selected halo.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo.
  • R 1 is Ci-4 alkyl substituted with one, two, or three independently selected halo.
  • R 1 is Ci-4 alkyl substituted with one or more independently selected F, Cl, or Br.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , each of which is substituted with one, two, or three F.
  • R 1 is -CHF 2 , -CF 3 , -C(CH 3 ) 2 F, -CH 2 CF 3 , or - CF 2 CH 2 CH 3 .
  • R 1 is -CH 2 CF 3 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O.
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl.
  • R 1 is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, or morpholinyl. In a most particular embodiment, R 1 is . In another most particular embodiment, the compound of the invention is according to any one of Formulae I-VIIe, wherein R 1 is , , or .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIe, wherein
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O.
  • R 1 is 1- azabicyclo[2.1.1]hexanyl, 3 -azabicyclo [2.
  • R 1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2. l]octanyl.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is l-azabicyclo[2.1.1]hexanyl, 3- azabicyclo [2. 1. l]hexanyl, 5 -azabicyclo [2.1.1 ]hexanyl, 3 -oxabicyclo [2. 1. l]hexanyl, 5- oxabicyclo[2. 1.
  • l]heptanyl 4-oxa-l -azabicyclo [3. 1. l]heptanyl, 6-oxa-3-azabicyclo[3.1. l]heptanyl, 1- azabicyclo [3.2.1] octanyl, 1 -azabicyclo [4.1.1] octanyl, 2-azabicyclo[2.2.2]octanyl, 2- azabicyclo[4. 1. l]octanyl, 3 -azabicyclo [3.2.1] octanyl, 3 -azabicyclo [4.1.
  • R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is l-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5- azabicyclo[2. 1. l]hexanyl, 3 -oxabicyclo [2.1.
  • R 1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2.1]octanyl, each of which is substituted with one R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O.
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2- azabicyclo [2.2.0]hexanyl, 1 -azabicyclo [2.2.0]hexanyl, 2-oxa-5 -azabicyclo [2.2.0] hexanyl, 2,5- diazabicyclo [2.2.0] hexanyl, 2,5 -di oxabicyclo [2.2.0]hexanyl, 6-oxabicyclo [3.2.0] heptanyl, 6- azabicyclo[3 ,2.0]heptanyl, 3 -oxabicyclo [3.2.0] heptanyl, 3 -azabicyclo [3.2.0]heptanyl, 2- oxabicyclo[3 ,2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, l-azabicyclo[3.2.0]heptanyl, 6-oxa-3- azabicyclo[3 ,2.0]heptanyl, 3 ,
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, 1- azabicyclo [2.2.0]hexanyl, 2-oxa-5-azabicyclo [2.2.0]hexanyl, 2,5 -diazabicyclo [2.2.0]hexanyl, 2,5- dioxabicyclo [2.2.0]hexanyl, 6-oxabicyclo[3 ,2.0]heptanyl, 6-azabicyclo [3.2.0] heptanyl, 3- oxabicyclo[3 ,2.0]heptanyl, 3 -azabicyclo [3.2.0] heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2- azabicyclo[3 ,2.0]heptanyl, 1 -azabicyclo [3.2.0] heptanyl, 6-oxa-3 -azabicyclo [3.2.0] heptanyl, 3,6- dioxabicyclo
  • R 1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R 7 .
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, 1- azabicyclo [2.2.0]hexanyl, 2-oxa-5-azabicyclo [2.2 ,0]hexanyl, 2,5 -diazabicyclo [2.2.0]hexanyl, 2,5- dioxabicyclo [2.2.0]hexanyl, 6-oxabicyclo[3 ,2.0]heptanyl, 6-azabicyclo [3.2.0] heptanyl, 3- oxabicyclo[3 ,2.0]heptanyl, 3 -azabicyclo [3.2.0] heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2- azabicyclo[3 ,2.0]heptanyl, 1 -azabicyclo [3.2.0] heptanyl, 6-oxa-3 -azabicyclo [3.2.0] heptanyl, 3,6- dioxabi
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R 7 . In an even further more particular embodiment, R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is halo.
  • R 7 is F, Cl, or Br.
  • R 7 is F.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is Ci-6 alkyl.
  • R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , - CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , -CH(CH 3 )C(CH 3 ) 3 , or - C(CH 3 ) 2 C(CH 3 ) 2 .
  • R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 )CH 2 CH 3 . In a most particular embodiment, R 7 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is Ci-6 alkyl substituted with one or more independently selected R 9 .
  • R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 ) 2 , - C(CH 3 ) 2 CH 2 CH 3 , -CH(CH 3 )C(CH 3 ) 3 , or -C(CH 3 ) 2 C(CH 3 ) 2 , each of which is substituted with one or more independently selected R 9 .
  • R 7 is Ci-6 alkyl substituted with one, two, or three independently selected R 9 .
  • R 7 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one or more independently selected R 9 .
  • R 7 is - CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , - CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , -CH(CH 3 )C(CH 3 ) 3 , or -C(CH 3 ) 2 C(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R 9 .
  • R 7 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one, two, or three independently selected R 9 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is Ci-6 alkyl substituted with one or more independently selected R 9 , and R 9 is halo, -OH, or -CN.
  • R 9 is F, Cl, Br, -OH, or -CN.
  • R 9 is F, -OH, or -CN.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is Ci-6 alkyl substituted with one or more independently selected R 9 , and R 9 is C 3 -6 cycloalkyl.
  • R 9 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 9 is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is C1-6 alkyl substituted with one or more independently selected R 9 , and R 9 is C1-4 alkoxy.
  • R 9 is -O- CH3, -O-CH2CH3, or -O-CH(
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is C1-6 alkyl substituted with one or more independently selected R 9 , and R 9 is C1-4 alkoxy substituted with one or more independently selected halo.
  • R 9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo.
  • R 9 is C1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 9 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 9 is -O-CH3, -O-CH2CH3, or -O-C H(CH,)2. each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 9 is -O-CH3, - O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 9 is -O-CH3 substituted with one, two, or three F.
  • R 9 is -O-CF3.
  • R lla and R llb are both H.
  • R lla and R llb are both independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R lla and R llb are both -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is Ci-4 alkoxy.
  • R 7 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R 7 is -O- CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is C 3 -6 cycloalkyl.
  • R 7 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 7 is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C 3 -6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , R 7 is -NR 10a R 10b , and R 10a and Riot) are i n d e p en d en tly H or Ci-4 alkyl.
  • R 10a and R 10b are both H. In another particular embodiment, one of R 10a and R 10b is H, and the other is Ci-4 alkyl. In yet another particular embodiment, R 10a and R 10b are both independently Ci-4 alkyl. In a more particular embodiment, one of R 10a and R 10b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In another more particular embodiment, R 10a and R 10b are both independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a most particular embodiment, R 10a and R 10b are both -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIf, wherein R 1 is C3-6 cycloalkyl substituted with one or more independently R 7 , or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R 7 , and R 7 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O.
  • R 7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R 7 is morpholinyl.
  • the compound of the invention is according to Formula Villa or Vlllb:
  • the compound of the invention is according to any one of Formulae I-VIIIb, wherein L3 is C3-6 cycloalkyl.
  • L3 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • L3 is cyclobutyl.
  • L3 is
  • the compound of the invention is according to any one of Formulae I-VIIIb, wherein L3 is C1-6 alkylene.
  • L3 is -CH2-, -CH(CH3)-, -C(CH3) 2 -, -CH(CH 2 CH3)- -C(CH3)(CH 2 CH 3 )-, -CH(CH 2 CH 2 CH3)-, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-
  • L3 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 2 CH 3 )-
  • the compound of the invention is according to any one of Formulae I-VIIIb, wherein L 3 is Ci-6 alkylene substituted with one or more independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -C(CH 3 )(CH 2 CH 3 )-, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH(CH(CH 3 )CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH 2 CH 2 -, - CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH
  • L 3 is Ci-6 alkylene substituted with one, two, or three independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 )CH 3 )-, -CH 2 CH 2 - , or -CH(CH 3 )CH 2 -, each of which is substituted with one or more independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -C(CH 3 )(CH 2 CH 3 )-
  • L 3 is Ci-6 alkylene substituted with one R 6 .
  • L 3 is -CH 2 - or -CH 2 CH 2 -, each of which is substituted with one or more independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )- , -CH(CH 2 CH(CH 3 )CH 3 )-, -CH 2 CH 2 -, or -CH(CH 3 )CH 2 -, each of which is substituted with one, two, or three independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 3 )- , -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -C(CH 3 )(CH 2 CH 3 )-, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 ) 2 )-
  • L 3 is -CH 2 - or -CH 2 CH 2 -, each of which is substituted with one, two, or three independently selected R 6 .
  • L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )- , -CH(CH 2 CH(CH 3 )CH 3 )-, -CH 2 CH 2 -, or -CH(CH 3 )CH 2 -, each of which is substituted with one R 6 .
  • L 3 is -CH 2 - or -CH 2 CH 2 -, each of which is substituted with one R 6 .
  • the compound of the invention is according to any one of Formulae I-VIIIb, wherein R 3b is H.
  • the compound of the invention is according to any one of Formulae I-VIIIb, wherein R 3b together with L 3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N.
  • R 3b together with L 3 and the atoms onto which they are attached form a piperidinyl.
  • the compound of the invention is according to Formula IXa, IXb, IXc, IXd, IXe, or IXf:
  • the compound of the invention is according to Formula Xa, Xb, Xc, Xd, Xe, or Xf:
  • the compound of the invention is according to any one of Formulae I-Xf, wherein R 3a is H.
  • the compound of the invention is according to any one of Formulae I-Xf, wherein R 3a is Ci-4 alkyl.
  • R 3a is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2.
  • R 3a is -CH3 or -CH2CH3.
  • the compound of the invention is according to any one of Formulae I-Xf, wherein R 3a is Ci-4 alkyl substituted with one -OH or C3-6 cycloalkyl.
  • R 3a is - CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH 3 )2, each of which is substituted with one -OH or C3-6 cycloalkyl.
  • R 3a is C1-4 alkyl substituted with one -OH, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 3a is -CH3, -CH2CH3, -CH2CH2CH3, or -C H(CH,)2. each of which is substituted with one -OH, cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 3a is -CH3 or -CH2CH3, each of which is substituted with one -OH or cyclopropyl. In a most particular embodiment, R 3a is -CH2-cyclopropyl or -CH2CH2OH.
  • the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R 6 is halo or -OH.
  • R 6 is F, Cl, Br, or -OH.
  • R 6 is F or -OH.
  • one of R 8a and R 8b is H, and the other is -CH3, -CH2CH3, or -CH(CH3)2.
  • one of R 8a and R 8b is H, and the other is -CH3.
  • the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R 6 is C1-4 alkoxy.
  • R 6 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2.
  • R 6 is -O-CH3.
  • the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R 6 is C1-4 alkoxy substituted with one or more independently selected halo.
  • R 6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo.
  • R 6 is C1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 6 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 6 is — O-CH2CH3 substituted with one, two, or three F.
  • R 6 is -O-CH2CF3.
  • the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R 6 is C3-6 cycloalkyl.
  • R 6 is independently cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 6 is independently cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R 6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O.
  • R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4- dioxanyl.
  • R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl .
  • R 6 is 1,3-dioxolanyl substituted with two -CH3.
  • the compound of the invention is according to Formula I, wherein the compound is selected from:
  • the compound of the invention is according to Formula I, wherein the compound is (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
  • the compound of the invention is according to Formula I, wherein the compound is not (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7 -carboxamide .
  • the compound of the invention is according to Formula I, wherein the compound is (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(trifluoromethoxy)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
  • the compound of the invention is according to Formula I, wherein the compound is not (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(trifluoromethoxy)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
  • the compounds of the invention are provided in a natural isotopic form.
  • the compounds of the invention are provided in an unnatural variant isotopic form.
  • the unnatural variant isotopic form is a form in which deuterium (i.e. 2 H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention.
  • the atoms of the compounds of the invention are in an isotopic form which is not radioactive.
  • one or more atoms of the compounds of the invention are in an isotopic form which is radioactive.
  • radioactive isotopes are stable isotopes.
  • the unnatural variant isotopic form is a pharmaceutically acceptable form.
  • a compound of the invention whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms.
  • unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.
  • a compound of the invention according to any one of the embodiments herein described is present as the free base.
  • a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
  • a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.
  • a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
  • a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
  • the present invention provides prodrugs and derivatives of the compounds according to the formulae above.
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo.
  • Such examples include, but are not limited to, choline ester derivatives and the like, A-alkylmorpholinc esters and the like.
  • Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Particularly useful are the Ci to Cx alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
  • a compound of the invention When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal.
  • a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the compound of the invention according to Formula I is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art.
  • the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • a compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • a compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington’s Pharmaceutical Sciences.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio.
  • the mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
  • a compound of the invention according to Formula I may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
  • a compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate may be added as a lubricant.
  • the mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
  • a compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of fibrotic diseases.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a fibrotic diseases treatment agent.
  • fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of inflammatory diseases.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an inflammatory diseases treatment agent.
  • inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise - induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of respiratory diseases.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • asthma adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a respiratory diseases treatment agent.
  • respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirinsensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoimmune diseases.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is an autoimmune diseases treatment agent.
  • autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of metabolic diseases.
  • metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of metabolic diseases.
  • metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a metabolic diseases treatment agent.
  • metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of cardiovascular diseases.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arte
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a cardiovascular diseases treatment agent.
  • cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
  • the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
  • the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of proliferative diseases.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
  • this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
  • the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent.
  • the other therapeutic agent is a proliferative diseases treatment agent.
  • proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
  • Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
  • the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance.
  • one to four (1-4) regular doses daily especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens.
  • dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
  • each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • a compound of the invention When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described previously.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • a compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration.
  • co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
  • a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament.
  • said pharmaceutical composition additionally comprises a further active ingredient.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation
  • agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate, mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
  • immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate, mofetil, muromonab-CD3 (
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).
  • NSAIDS non-steroidal anti-inflammatory drugs
  • DMARDS for example but without limitation methotrexate, leflunom
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders
  • therapeutic agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g.
  • the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery.
  • the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases
  • agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g.
  • anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies monoclonal antibodies, Atgam® and Thymoglobuline®
  • cyclosporin tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-J3), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin.
  • IFN-J3 interferons
  • TNF binding proteins e.g. infliximab, etanercept, or adalimumab
  • mycophenolate fingolimod and myriocin.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection
  • agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: beta2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled).
  • beta2 -adrenoceptor agonists e.g. salbutamol, levalbuterol, terbutaline and bitolterol
  • epinephrine inhaled or tablets
  • anticholinergics e.g. ipratropium bromide
  • glucocorticoids oral or inhaled.
  • Long-acting [32 -agonists e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol
  • combinations of inhaled steroids and long-acting bronchodilators e.g. fluticasone/sahneterol, budesonide/formoterol
  • leukotriene antagonists and synthesis inhibitors e.g. montelukast, zafirlukast and zileuton
  • inhibitors of mediator release e.g. cromoglycate and ketotifen
  • biological regulators of IgE response e.g. omalizumab
  • antihistamines e.g. ceterizine, cinnarizine, fexofenadine
  • vasoconstrictors e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline.
  • a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g.
  • oxygen or heliox administration ebulized salbutamol or terbutaline
  • an anticholinergic e.g. ipratropium
  • systemic steroids oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone
  • intravenous salbutamol e.g. pred
  • epinephrine isoetharine, isoproterenol, metaproterenol
  • anticholinergics IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium
  • methylxanthines theophylline, aminophylline, bamiphylline
  • inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
  • glucocorticoids e.g. prednisone, budesonide
  • immunomodulatory agents e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE
  • particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
  • DMARDs disease-modifying antirheumatic drugs
  • antimalarials e.g. plaquen
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis
  • particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (TopicortTM), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as AmeviveTM, EnbrelTM, Humir
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction
  • therapeutic agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
  • antihistamines e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine
  • glucocorticoids e.g. prednisone, betamethasone, beclomethasone, dexamethasone
  • epinephrine epin
  • any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person.
  • the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential.
  • the agents may be administered in different formulations and at different times.
  • Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
  • Li is -O-, or -CR 5a R 5b -;
  • L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R 6 ;
  • heterocycloalkyl unsubstituted or substituted with one or more independently selected halo, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R 7 ;
  • R 2 is H, Ci-4 alkyl, or Ci-4 alkoxy, which Ci-4 alkyl or Ci-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
  • R 3a is H or Ci-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
  • R 3b is H, or R 3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
  • R 4 is C1-4 alkyl
  • R 5a and R 5b are independently H or -CH3; each R 6 is independently selected from: halo,
  • each R 7 is independently selected from: halo
  • each R 9 is independently selected from: halo
  • Het is l,4-dihydropyrrolo[3,2-b]pyrrolyl, l,6-dihydropyrrolo[2,3-b]pyrrolyl, pyrrolo[l,2-a] imidazolyl, pyrrolo [ 1 ,2-b]pyrazolyl, 1 ,4-dihydropyrrolo [2,3 -d] imidazolyl, 1 ,4-dihydropyrrolo [3 ,2-c]pyrazolyl, 1 ,6-dihydropyrrolo [2,3 -c]pyrazolyl, 3 ,4-dihydropyrrolo [2,3 -d] imidazolyl, imidazo [ 1 ,2-a]imidazolyl, imidazo[l,2-b]pyrazolyl, imidazo [1, 5 -a]imidazolyl, imidazo[l,5-b]pyrazolyl, pyrazolo[l,5- b]pyrazo
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-6, wherein Het is benzimidazolyl or indazolyl.
  • a compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-14, wherein L 2 is -NHC( O)-.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-17, wherein R 2 is C1-4 alkyl substituted with one or more independently selected halo.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-17, wherein R 2 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo.
  • R 2 is C1-4 alkyl substituted with one, two, or three independently selected halo.
  • R 2 is Ci-4 alkoxy substituted with one or more independently selected halo.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-17, wherein R 2 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo.
  • R 2 is C1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 2 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-17, wherein R 2 is -O-CH3, -O-CH2CH3, or -O-C H(CH ,)2. each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-17, wherein R 2 is -O-CH3 substituted with one, two, or three F.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-17, wherein R 2 is -O-CF3.
  • R 1 is C3-6 cycloalkyl substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one or more independently selected R 7 .
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one, two, or three independently selected R 7 .
  • R 1 is cyclopropyl substituted with one R 7 .
  • R 1 is Ci-4 alkyl substituted with one or more independently selected halo.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, wherein R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo.
  • R 1 is Ci-4 alkyl substituted with one, two, or three independently selected halo.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is Ci-4 alkyl substituted with one or more independently selected F, Cl, or Br.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, wherein R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -C(CH 3 ) 3 , or -CH 2 CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , each of which is substituted with one, two, or three F.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, wherein R 1 is -CHF 2 , -CF 3 , -C(CH 3 ) 2 F, -CH 2 CF 3 , or -CF 2 CH 2 CH 3 .
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is -CH 2 CF 3 .
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl.
  • R 1 is A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R 1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R 7 .
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R 7 .
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, wherein R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 7 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R 7 .
  • R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O.
  • R 1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5 -oxabicyclo [2. l.l]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4- azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1.
  • R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R 7 .
  • R 1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo [2.1. l]hexanyl, 5 -oxabicyclo [2.1.1 ]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1- azabicyclo[3.1. l]heptanyl, 3 -azabicyclo [2.2. l]heptanyl, 3 -azabicyclo [3.1.1] heptanyl, 4- azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1.
  • R 1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R 7 .
  • R 1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2. l]octanyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2. l]octanyl, each of which is substituted with one or more independently selected R 7 .
  • R 1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1. l]hexanyl, 5 -oxabicyclo [2.1.1 ]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1 azabicyclo[3.1. l]heptanyl, 3 -azabicyclo [2.2. l]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4 azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1.
  • R 1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3, 8 -diazabicyclo [3.2.1] octanyl, each of which is substituted with one, two, or three independently selected R 7 .
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein R 1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which is substituted with one R 7 .
  • R 1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O.
  • a compound or pharmaceutically acceptable saltthereof according to any one of clauses 1-48, wherein
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2-oxa-5- azabicyclo [2.2.0] hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5 -dioxabicyclo [2.2.0] hexanyl, 6- oxabicyclo [3 ,2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3 -oxabicyclo [3.2.0] heptanyl, 3- azabicyclo[3 ,2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2 -azabicyclo [3.2 ,0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-dioxabicyclo[3.
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2- oxa-5 -azabicyclo [2.2.0]hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5-dioxabicyclo[2.2.0]hexanyl, 6- oxabicyclo[3.2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-oxabicyclo[3.2.0]heptanyl, 3- azabicyclo[3.2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-di
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R 7 ..
  • R 1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2- oxa-5 -azabicyclo [2.2.0]hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5-dioxabicyclo[2.2.0]hexanyl, 6- oxabicyclo[3.2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-oxabicyclo[3.2.0]heptanyl, 3- azabicyclo[3.2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-di
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is F, Cl, or Br. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is F.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is Ci- 6 alkyl. .
  • R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , -CH(CH 3 )C(CH 3 ) 3 , or -C(CH 3 ) 2 C(CH 3 ) 2 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -CH 3 , CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , or -CH(CH 3 )CH 2 CH 3 .
  • R 7 is -CH 3 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is Ci-6 alkyl substituted with one or more independently selected R 9 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , - CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 )C(CH 3 ) 3 , or -C(CH 3 ) 2 C(CH 3 ,
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is Ci-6 alkyl substituted with one, two, or three independently selected R 9 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one or more independently selected R 9 . .
  • R 7 is -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH 2 CH 3 , - CH 2 CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 C(CH 3 ) 3 , -CH(CH 3 )CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 CH 3 , - CH(CH 3 )C(CH 3 ) 3 , or -C(CH 3 ) 2 C(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected R 9 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one, two, or three independently selected R 9 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is halo, -OH, or -CN. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is F, Cl, Br, -OH, or -CN. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is F, -OH, or -CN.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is C 3-6 cycloalkyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is cyclopropyl, cyclobutyl, or cyclopentyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is cyclopropyl or cyclobutyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is Ci- 4 alkoxy.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is Ci-4 alkoxy substituted with one or more independently selected halo.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one or more independently selected halo. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is Ci-4 alkoxy substituted with one, two, or three independently selected halo. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is Ci- 4 alkoxy substituted with one or more independently selected F, Cl, or Br. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected F, Cl, or Br. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected F, Cl, or Br. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CH 3 substituted with one, two, or three F..
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -O-CF 3 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -NR lla R llb , and R lla and R llb are both H..
  • R 9 is -NR lla R llb
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -NR lla R llb , and R lla and R llb are both independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R 9 is -NR lla R llb , and R lla and R llb are both -CH 3 ..
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is Ci-4 alkoxy. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -O-CH 3 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is C 3 -6 cycloalkyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is cyclopropyl or cyclobutyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are independently H or Ci-4 alkyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both H.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and one of R 10a and R 10b is H, and the other is Ci-4 alkyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both independently Ci-4 alkyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and one of R 10a and R 10b is H, and the other is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both independently -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both -CH 3 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O.
  • R 7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R 7 is morpholinyl. .
  • L 3 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 )2-, -CH(CH 2 CH 3 )-, -C(CH3)(CH 2 CH 3 )-, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH(CH(CH3)CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -,
  • L3 is C1-6 alkylene substituted with one or more independently selected R 6 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, wherein L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -CH(CH 2 CH(CH3)CH 3 )-, -CH 2 CH 2 -, or -CH(CH 3 )CH 2 -, each of which is substituted with one or more independently selected R 6 . .
  • L 3 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -C(CH3)(CH 2 CH 3 )-, -CH(CH 2 CH 2 CH 3 )-, -CH(CH(CH 3 ) 2 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH(CH(CH3)CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 ) 2 )-, -CH 2 CH 2 -, - CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 2 CH 3 )-
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, wherein L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 )CH 3 )-, -CH 2 CH 2 -, or -CH(CH 3 )CH 2 -, each of which is substituted with one, two, or three independently selected R 6 . .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, wherein L 3 is -CH 2 -, -CH(CH 2 CH 2 CH 3 )-, -CH(CH 2 CH(CH 3 )CH 3 )-, -CH 2 CH 2 -, or -CH(CH 3 )CH 2 -, each of which is substituted with one R 6 . .
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -NR 8a R 8b , and R 8a and R 8b are independently H, C1-4 alkyl, or C( O)-O-Ci- 6 alkyl.
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -NR 8a R 8b , and R 8a and R 8b are both independently Ci-4 alkyl or - C( O)-O-Ci- 6 alkyl. .
  • R 6 is -NR 8a R 8b
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -NR 8a R 8b , and one of R 8a and R 8b is H, and the other is -CH3, - CH 2 CH 3 , or -CH(CH 3 ) 2 . .
  • R 6 is -NR 8a R 8b
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -NR 8a R 8b , and one of R 8a and R 8b is H, and the other is -CH3.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is C1-4 alkoxy. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -O-CH3, -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . .
  • R 6 is -O-CH3, -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167,
  • R 6 is -O-CH3.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is Ci-4 alkoxy substituted with one or more independently selected halo.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is C1-4 alkoxy substituted with one, two, or three independently selected halo. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is independently cyclopropyl, cyclobutyl, or cyclopentyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is independently cyclopropyl or cyclobutyl. .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-167, 176-188, and 191-202, wherein R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl. .
  • R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl .
  • R 6 is 1,3-dioxolanyl substituted with two -CH 3 .
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-240.
  • a pharmaceutical composition according to clause 241 comprising a further therapeutic agent.
  • the compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • a compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • Analytical LCMS methods described in the Examples include methods A, B, C, and D.
  • Method A includes Phenomenex Kinetix-XB C18, 2.1 x 100 mm, 1.7 pm colum; eluent A: water + 0.1% formic acid; eluent B: ACN + 0.1% formic acid; gradient: 0.00 min 95% A 5.30 min 100% B 5.80 min 100% B 7.00 min 95% A; column temperature: 40 °C; flow rate 0.6 mL/min; injection volume: 1 pL; and UV-detection range: 200-400 nm.
  • Method B includes Waters Atlantis dC18, 2.1 x 100 mm, 3 pm column; eluent A: water + 0.
  • eluent B ACN + 0.1% formic acid; gradient: 0.00 min 95% A 5.00 min 5.40 min 5.42 min 95% A 7.00 min 95% A; column temperature: 40 °C; flow rate 0.6 mL/min; injection volume: 3 pL; and UV-detection range: 210-420 nm.
  • Method C includes Phenomenex Gemini C18, 2.0 x 100 mm, 3 pm column; eluent A: 2 mM ammonium bicarbonate, buffered to pHlO, eluent B: ACN; gradient 0.00 min 95% A 5.50 min 100% B 5.90 min 100% B 5.92 min 95% 7.00 min 95% A; column temperature: 40 °C; flow rate 0.5 mL/min; injection volume: 3 pL; and UV-detection range: 210-420 nm.
  • Method D includes Supelco Ascentis Express C18, 2.1 x 30 mm, 2.7 pm column; eluent A: water + 0.1% formic acid, eluent B: ACN + 0.1% formic acid; Gradient 0.00 min 95% A 1.5 min 1.6 min 100% B -> 1.61 min 95% A 2.00 min 95% A; column temperature: 40 °C; flow rate 1.0 mL/min; 3 pL; and UV-detection range: 210-420 nm.
  • Purification methods include Biotage IsoleraTM column chromatography system using pre-packed silica and pre-packed modified silica cartridges.
  • Preparative High Performance Liquid Chromatography (HPLC) methods described in the Examples include method 1 and 2.
  • Preparative HPLC method 1 (high pH) includes Waters Xbridge C18, 30 x 100 mm, 10 pm column; solvent A: water + 0.2% ammonium hydroxide, solvent B: ACN + 0.2% ammonium hydroxide; gradient 0.00 min 0.55 min 90% A 14.44 min 95% B 16.55 min 95% B 16.75 90% A; column temperature: RT; flow rate 40 mL/min; injection volume: 1500 pL; and 215 nm UV detection.
  • Preparative HPLC method 2 (low pH) includes Waters Sunfire C18, 30 x 100 mm, 10 pm column; solvent A: water + 0.1% formic acid, solvent B: ACN + 0.1% formic acid; gradient 0.00 min 90% 16.75 90% A; column temperature: RT; flow rate 40 mL/min; injection volume: 1500 pL; and 215 nm UV detection.
  • Methyl 5 -bromopyridine -3 -carboxylate (5.0 g, 23.1 mmol) was dissolved in THF (100 mL) and cooled to -78 °C.
  • Methylmagnesium bromide (23.1 mL of a 3 M soln in Et2O, 69 mmol) was added dropwise over 5 min and the mixture was then allowed to warm to RT and was stirred at this temperature for 1 h. The reaction was quenched via addition of water (50 mL) and the mixture was concentrated at reduced pressure to removed excess THF.
  • EtMgBr (8.9 mL of a 3 M soln in THF, 26.9 mmol) was added dropwise to bis[2-(N,N- dimethylamino)ethyl] ether (5.1 mL, 26.9 mmol) in THF (50 mL) at 0 °C and the resulting mixture was stirred for 10 min. This was added dropwise to 5 -bromopyridine -3 -carbonyl chloride (5.4 g, 24.5 mmol) in THF (50 mL) at -78 °C over 5 min. The resulting mixture was allowed to warm to RT and then stirred for 30 min then quenched by addition of sat. aq.
  • a sealed tube was charged with 5-bromopyridin-3-amine (200 mg, 1.16 mmol), 4, 4,5,5- tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (358 pL, 1.73 mmol), CS2CO3 (1.13 g, 3.47 mmol) in DMF (5 mL) and water (1.5 mL).
  • the reaction mixture was degassed by passing a flow of nitrogen through the mixture for 5 min.
  • Pd(PPh3)4 134 mg, 0.12 mmol
  • Cpd 82 (200 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound.
  • Cpd 85 was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound.
  • Cpd 85 was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound.
  • Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer.
  • the methods are using ACN/H2O or MeOH/water gradients with either 0.1% formic acid in both mobile phases, 0.05% NH3 in both mobile phases, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia).
  • Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XB RIDGE BEH C18 OBD 30 mm ID x 100/150 mm L columns and ACN H2O gradients with either 0.1% formic acid in both mobile phases, 0.1% DEA in both mobile phases, 0.1% formic acid in H2O, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia).
  • Microwave heating is performed with a Biotage® Initiator.
  • the Boc-protected amine (1 eq.) is stirred a RT in an acidic medium (typically 4 to 30 eq. HC1 (4 M in dioxane) in dioxane) for 3 to 18 h.
  • the reaction mixture is concentrated.
  • the residue is purified on a Biotage ISOLUTE® SCX exchange resin eluting with MeOH, then with a 7N ammonia solution in MeOH.
  • the basic fraction is concentrated to afford the desired product.
  • reaction mixture is concentrated or is filtered through Celite®.
  • the filtrate is diluted with water and extracted with EtOAc.
  • the combined organic layers are washed with brine, dried over MgSCE and filtered.
  • the filtrate is concentrated to dryness and used as such or is purified by column chromatography on silica gel to afford the desired product.

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Abstract

The present invention discloses compounds according to Formula (I): Wherein R1, R2, R3a, R3b, R4, Het, L1, L2, L3, and the subscript n are as defined herein. The present invention relates to compounds inhibiting discoidin domain receptors (DDRs), methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering a compound of the invention.

Description

NOVEL ISOQUINOLINE DERIVATIVES AND PHARMACEUTICAL COPOSITIONS THEREOF FOR THE TREATMENT OF DISEASES
FIELD OF THE INVENTION
[0001] The present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. In particular, the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
BACKGROUND OF THE INVENTION
[0002] Discoidin domain receptors (DDRs), including DDR1 and DDR2, are members of transmembrane receptor tyrosine kinases (RTKs) discovered in the early 1990s. Unlike other RTKs, DDRs contain two discoidin domains in the extracellular region. DDRs are activated by a number of triple-helical collagens which are most abundant components of the extracellular matrix (ECM). DDR1 is widely expressed in epithelial cells in lung, kidney, colon, brain, whereas DDR2 is primarily expressed in mesenchymal cells including fibroblasts, myofibroblasts, smooth muscle, and skeletal in kidney, skin, lung, heart, and connective tissues. Studies have demonstrated that both DDR1 and DDR2 play crucial roles in fundamental cellular processes, such as proliferation, survival, differentiation, adhesion, and matrix remodeling. Deregulation of DDRs has been implicated in a number of human diseases, including fibrotic disorders, atherosclerosis, and cancer (e.g., pancreatic cancer and melanoma) (Berestjuk et al. 2019; Borza & Pozzi 2014; Ruggeri et al. 2020; Vella et al. 2019).
[0003] A number of other well-characterized kinase inhibitors, imatinib, nilotinib, dasatinib, bafetinib, ponatinib, sorafmib, pazopanib, foretinib, BIRB-796, and LCB 03-0110, are reported to be potent inhibitors of both DDR1 and DDR2. However, all these inhibitors also potently target many other kinases and cannot be utilized as good pharmacological probes of DDR1 or DDR2 (Li et al. 2015), and for some, showed for example treatment related toxicities (Brunner et al. 2013).
[0004] Nevertheless, DDR inhibitors may show potential promise as therapeutic agents and there is a need for the development of new DDR inhibitors with increased selectivity for DDR receptors, and/or increased safety. SUMMARY OF THE INVENTION
[0005] The present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. In particular, the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
[0006] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:
Figure imgf000003_0001
I wherein,
Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
Li is -O-, or -CR5aR5b-;
L2 is -C(=O)NH- or -NHC(=O)-;
L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6;
R1 is
C3-6 cycloalkyl unsubstituted or substituted with one or more independently R7,
C2-6 alkenyl,
C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or
4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R7;
R2 is H, C1-4 alkyl, or C1-4 alkoxy, which C1-4 alkyl or C1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo; R3a is H or Ci-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
R3b is H, or R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
R4 is C1-4 alkyl;
R5a and R5b are independently H or -CH3; each R6 is independently selected from: halo,
- -OH,
- -NR8aR8b,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo,
C3-6 cycloalkyl, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is unsubstituted or substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl; each R7 is independently selected from: halo,
C1-6 alkyl unsubstituted or substituted with one or more independently selected R9,
C1-4 alkoxy,
- -C(=O)-Ci.4 alkyl,
C3-6 cycloalkyl,
- -NR10aR10b, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R9 is independently selected from: halo,
- -OH,
- -CN,
C3-6 cycloalkyl,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and
- -NRllaRllb; each R10a and R10b is independently H or C1-4 alkyl; and each R8a, R8b, Rlla, and Rllb is independently H, C1-4 alkyl, or -C(=O)-O-Ci-6 alkyl.
[0007] In one aspect, the compounds of the invention are provided for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. In a particular aspect, the compounds of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2.
[0008] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
[0009] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.
[0010] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.
[0011] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
[0012] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.
[0013] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0014] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.
[0015] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.
[0016] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue. [0017] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), scc-butyl (-CH2-CH(CH3)2), w-pcntyl (-CH2-CH2-CH2-CH2-CH3), w-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.
[0018] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), w-propcnyl (-CH2CI7X2H2), isopropenyl (-C(CH3)=CH2) and the like.
[0019] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.
[0020] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-C1-6 alkyl. Particular alkoxy groups are methoxy, ethoxy, w-propoxy. isopropoxy, w-butoxy. tert-butoxy, scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
[0021] ‘ Amino’ refers to the radical -NH2.
[0022] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.
[0023] ‘Cycloalkyl ’refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
[0024] ‘Cyano’ refers to the radical -CN.
[0025] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
[0026] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described previously such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom. [0027] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0028] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0029] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
[0030] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.
[0031] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.
[0032] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.
[0033] Examples of representative heteroaryls include the following:
Figure imgf000007_0001
wherein each Y is selected from >C=O, NH, O and S. [0034] ‘Heterocycloalkyl’ means a non-aromatic fully saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3- pyrrolidinyl), tetrahydrofuranyl (e.g. 1 -tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1 -tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3-tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4- tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.
[0035] As used herein, the term ‘heterocycloalkenyl’ means a ‘heterocycloalkyl’, which comprises at least one double bond. Particular examples of heterocycloalkenyl groups are shown in the following illustrative examples:
Figure imgf000008_0001
wherein each W is selected from CEE, NH, O and S; each Y is selected from NH, O, C(=O), SO2, and S; and each Z is selected from N or CH.
[0036] Particular examples of monocyclic rings are shown in the following illustrative examples:
Figure imgf000008_0002
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0037] Particular examples of fused bicyclic rings are shown in the following illustrative examples:
Figure imgf000008_0003
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S-.
[0038] Particular examples of bridged polycyclic rings are shown in the following illustrative examples:
Figure imgf000008_0004
wherein each W and Y is independently selected from -CH2-, -NH-, -O- and -S- and each Z is selected from N or CH. [0039] Particular examples of spirocyclic rings are shown in the following illustrative examples:
Figure imgf000009_0001
wherein each Y is selected from -CH2-, -NH-, -O- and -S-.
[0040] ‘Hydroxyl’ refers to the radical -OH.
[0041] ‘ Oxo’ refers to the radical =0.
[0042] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
[0043] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.
[0044] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
[0045] ‘Pharmaceutically acceptable’ refers to compounds of the invention and compositions thereof, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
[0046] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011). The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
[0047] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. [0048] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, /V-alkyhnorpholine esters and the like.
[0049] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
[0050] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.
[0051] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
[0052] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
[0053] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
[0054] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.
[0055] As used herein the term ‘fibrotic disease(s)’ refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; tubulointerstitium fibrosis; glomerular nephritis; diabetic nephropathy, focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport syndrome; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic/drug induced liver fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis; infection induced liver fibrosis; viral induced liver fibrosis; and autoimmune hepatitis; comeal scarring; hypertrophic scarring; Dupuytren disease, keloids, cutaneous fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury/fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD) associated musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, or chronic lymphocytic. More particularly, the term ‘fibrotic diseases’ refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
[0056] As used herein the term ‘inflammatory disease(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the j oints . Particularly the term refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases.
[0057] As used herein , the term ‘respiratory disease(s)’ refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, related muscles (e.g., diaphram and intercostals), and nerves. In particular, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirinsensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
[0058] As used herein the term ‘autoimmune disease(s)’ refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperreponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g. autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis), Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. Particularly the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[0059] As used herein the term ‘metabolic diseases’ refers to disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Metabolic diseases affect the ability to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). In particular, the term refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
[0060] As used herein the term ‘cardiovascular diseases’ refers to diseases affecting the heart or blood vessels, or both. In particular, cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, insufficiency limited to a single organ or tissue. More particularly, the term refers to vascular disease, atherosclerosis, coronary heart disease, cerebrovascular disease, heart failure and peripheral vessel disease, and hypertension.
[0061] As used herein the term ‘proliferative disease(s)’ refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular the term refers to cancer, leukemia, multiple myeloma and psoriasis. [0062] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasise) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumour cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term ‘cancer’ refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. In a more particular embodiment, the cancer is pancreatic cancer and/or melanoma.
[0063] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). [0064] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.
[0065] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.
[0066] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.
[0067] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
[0068] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulfur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
[0069] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as nC, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
[0070] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.
[0071] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.
[0072] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
[0073] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
[0074] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.
THE INVENTION
[0075] The present invention relates to compounds that may be useful in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. In particular, the compound of the invention may inhibit discoidin domain receptors (DDRs), more particularly DDR1 and/or DDR2, a family of transmembrane receptor tyrosine kinases (RTKs) that are involved in fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases. The present invention also provides methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases by administering the compound of the invention.
[0076] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:
Figure imgf000016_0001
I wherein,
Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
Li is -O-, or -CR5aR5b-;
L2 is -C(=O)NH- or -NHC(=O)-;
L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6;
R1 is
C3-6 cycloalkyl unsubstituted or substituted with one or more independently R7,
C2-6 alkenyl,
C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or
4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R7;
R2 is H, C1-4 alkyl, or C1-4 alkoxy, which C1-4 alkyl or C1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
R3a is H or C1-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
R3b is H, or R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
R4 is C1-4 alkyl;
R5a and R5b are independently H or -CH3; each R6 is independently selected from: halo,
- -OH, - -NR8aR8b,
Ci-4 alkoxy unsubstituted or substituted with one or more independently selected halo,
C3-6 cycloalkyl, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is unsubstituted or substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl; each R7 is independently selected from: halo,
C1-6 alkyl unsubstituted or substituted with one or more independently selected R9,
C1-4 alkoxy,
- -C(=O)-Ci-4 alkyl,
C3-6 cycloalkyl,
- -NR10aR10b, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R9 is independently selected from: halo,
- -OH,
- -CN,
C3-6 cycloalkyl,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and
- -NRllaRllb; each R10a and R10b is independently H or C1-4 alkyl; and each R8a, R8b, Rlla, and Rllb is independently H, C1-4 alkyl, or -C(=O)-O-Ci-6 alkyl.
[0077] In one embodiment, the compound of the invention is according to Formula I, wherein R4 is C1-4 alkyl. In a particular embodiment, R4 is -CH3, -CH2CH3, or -C H(CH ,)2. In a more particular embodiment, R4 is -CH3 or -CH2CH3. In a most particular embodiment, R4 is -CH3.
[0078] In one embodiment, the compound of the invention is according to Formula II:
Figure imgf000017_0001
II wherein R1, R2, R3a, R3b, Het, Li, L2, L3, and the subscript n are as described previously.
[0079] In one embodiment, the compound of the invention is according to Formula I or II, wherein Het is 8-10 membered fused bicyclic heteroaryl comprising one, two, or three N. In a particular embodiment, Het is l,4-dihydropyrrolo[3,2-b]pyrrolyl, l,6-dihydropyrrolo[2,3-b]pyrrolyl, pyrrolo[l,2-a]imidazolyl, pyrrolo[l,2-b]pyrazolyl, l,4-dihydropyrrolo[2,3-d]imidazolyl, l,4-dihydropyrrolo[3,2-c]pyrazolyl, 1,6- dihydropyrrolo [2,3 -c]pyrazolyl, 3 ,4-dihydropyrrolo [2,3 -d]imidazolyl, imidazo [ 1 ,2-a] imidazolyl, imidazo[l,2-b]pyrazolyl, imidazo[l,5-a]imidazolyl, imidazo[l,5-b]pyrazolyl, pyrazolo[l,5-b]pyrazolyl, pyrrolo[l,2-b][l,2,4]triazolyl, pyrrolo[l,2-c]triazolyl, pyrrolo[2,l-c][l,2,4]triazolyl, indolizinyl, indolyl, isoindolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo[l,5-a]pyridinyl, indazolyl, pyrazolo[l,5- a]pyridinyl, pyrrolo[l,2-a]pyrazinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[l,2-b]pyridazinyl, pyrrolo[l,2- c]pyrimidinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4- b]pyridinyl, pyrrolo [3 ,4-c]pyridinyl, [ 1 ,2,4]triazolo [ 1 ,5 -a]pyridinyl, [ 1 ,2,4]triazolo [4,3 -a]pyridinyl, benzotriazolyl, imidazo [l,2-a]pyrazinyl, imidazo [l,2-a]pyrimidinyl, imidazo [l,2-b]pyridazinyl, imidazo [l,2-c]pyrimidinyl, imidazo[l,5-a]pyrazinyl, imidazo[l,5-a]pyrimidinyl, imidazo[l,5- b]pyridazinyl, imidazo [1, 5 -c]pyrimidinyl, imidazo[4,5-c]pyridinyl, pyrazolo[l,5-a]pyrazinyl, pyrazolo[l,5-a]pyrimidinyl, pyrazolo[l,5-b]pyridazinyl, pyrazolo[l,5-c]pyrimidinyl, pyrazolo[3,4- b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-b]pyridinyl, pyrazolo[4,3-c]pyridinyl, pyrrolo[l,2- a][l,3,5]triazinyl, pyrrolo [1,2-b] [1, 2, 4]triazinyl, pyrrolo[l,2-c]triazinyl, pyrrolo [ 1,2-d] [ 1,2, 4]triazinyl, pyrrolo[2,l-c][l,2,4]triazinyl, pyrrolo[2,l-f][l,2,4]triazinyl, pyrrolo[2,3-d]pyridazinyl, pyrrolo[3,2- c] pyridazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[3,4-b]pyrazinyl, pyrrolo [3, 4-d]pyridazinyl, pyrrolo[3,4- d]pyrimidinyl, triazolo[l,5-a]pyridinyl, isoquinolinyl, quinolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, pyrido[2,3-b]pyrazinyl, pyrido[2,3- c] pyridazinyl, pyrido[2,3-d]pyridazinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-c]pyridazinyl, pyrido[3,2- d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[3,4-c]pyridazinyl, pyrido[3,4-d]pyridazinyl, pyrido[3,4- d]pyrimidinyl, pyrido[4,3-c]pyridazinyl, or pyrido[4,3-d]pyrimidinyl. In a more particular embodiment, Het is benzimidazolyl or indazolyl.
[0080] In one embodiment, the compound of the invention is according to Formula Illa, IHb, or IIIc:
Figure imgf000018_0001
IIIc wherein R1, R2, R3a, R3b, Li, L2, L3, and the subscript n are as described previously.
[0081] In one embodiment, the compound of the invention is according to Formula I or II, wherein Het is 6 membered monocyclic heteroaryl comprising one, two, or three N. In a particular embodiment, Het is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl. In a more particular embodiment, Het is pyridinyl. [0082] In one embodiment, the compound of the invention is according to Formula IVa or IVb:
Figure imgf000019_0001
IVa IVb wherein R1, R2, R3a, R3b, Li, L2, L3, and the subscript n are as described previously.
[0083] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein L2 is -C(=O)NH-.
[0084] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein L2 is -NHC(=O)-.
[0085] In one embodiment, the compound of the invention is according to Formula Va or Vb:
Figure imgf000019_0002
wherein R1, R2, R3a, R3b, Li, L3, and the subscript n are as described previously.
[0086] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R2 is H.
[0087] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R2 is C1-4 alkyl. In a particular embodiment, R2 is -CH3, -CH2CH3, or -CH(CH3)2. In a more particular embodiment, R2 is -CH3 or -CH2CH3. In a most particular embodiment, R2 is -CH3.
[0088] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R2 is C1-4 alkyl substituted with one or more independently selected halo. In a particular embodiment, R2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one or more independently selected halo. In another particular embodiment, R2 is C1-4 alkyl substituted with one, two, or three independently selected halo. In yet another particular embodiment, R2 is C1-4 alkyl substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further more particular embodiment, R2 is -CF3 or -CH2CF3. In a most particular embodiment, R2 is -CF3.
[0089] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R2 is C1-4 alkoxy. In a particular embodiment, R2 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2. In a more particular embodiment, R2 is -O-CH3.
[0090] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein R2 is C1-4 alkoxy substituted with one or more independently selected halo. In a particular embodiment, R2 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2, each of which is substituted with one or more independently selected halo. In another particular embodiment, R2 is C1-4 alkoxy substituted with one, two, or three independently selected halo. In yet another particular embodiment, R2 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R2 is -O-CH3, - O-CH2CH3, or -O-C H(CH ,)2. each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further more particular embodiment, R2 is -O-CH3 substituted with one, two, or three F. In a most particular embodiment, R2 is -O-CF3.
[0091] In one embodiment, the compound of the invention is according to Formula Via, VIb, Vic, Vid, or Vie:
Figure imgf000020_0001
Vie wherein R1, R3a, R3b, Li, L3, and the subscript n are as described previously.
[0092] In one embodiment, the compound of the invention is according to any one of Formulae I- Vie, wherein n is 0.
[0093] In one embodiment, the compound of the invention is according to any one of Formulae I- Vie, wherein n is 1 and Li is -O-.
[0094] In one embodiment, the compound of the invention is according to any one of Formulae I- Vie, wherein n is 1, Li is -CR5aR5b-, and R5a and R5b are independently H or -CH3. In a particular embodiment, R5a and R5b are both H. In another particular embodiment, one of R5a and R5b is H, and the other is -CH3. In yet another particular embodiment, R5a and R5b are both -CH3. In a most particular embodiment, Li is -CH2-. [0095] In one embodiment, the compound of the invention is according to Formula Vila, Vllb, Vile, Vlld,
Vile, or Vllf:
Figure imgf000021_0001
Vile Vllf wherein R1, R3a, R3b, and L3 are as described previously.
[0096] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl. In a particular embodiment, R1 is cyclopropyl, cyclobutyl, or cyclopentyl. In a most particular embodiment, R1 is cyclopropyl or cyclopentyl.
[0097] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7. In a particular embodiment, R1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R1 is C3-6 cycloalkyl substituted with one, two, or three independently selected R7. In a more particular embodiment, R1 is cyclopropyl substituted with one or more independently selected R7. In another more particular embodiment, R1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R1 is cyclopropyl substituted with one, two, or three independently selected R7. In an even further more particular embodiment, R1 is cyclopropyl substituted with one R7. In a most
Figure imgf000021_0002
particular embodiment, R1 is
[0098] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C2-6 alkenyl. In a particular embodiment, R1 is -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, -C(CH3)=C(CH3)2, -CH=C(CH3)2, -CH2CH
=CH2, -CH(CH3)CH=CH2, -CH2C(CH3)=CH2, -CH2CH=CHCH3, -C(CH3)2CH=CH2, -CH(CH3)C(CH3)= CH2, -CH(CH3)CH=CHCH3, -CH2C(CH3)=CH(CH3), -CH2CH=C(CH3)2, -C(CH3)2C(CH3)=CH2, -C(CH3) 2CH=CHCH3, -CH(CH3)C(CH3)=CH(CH3), -CH(CH3)CH=C(CH3)2, -CH2C(CH3)=C(CH3)2, -CH(CH3)C( CH2CH3)=CH2, -CH2C(CH2CH3)=CHCH3, -CH2CH2CH=CH2, -CH(CH3)CH2CH=CH2, -CH2CH(CH3)C H=CH2, -CH2CH2C(CH3)=CH2, -C(CH3)2CH2CH=CH2, -CH(CH3)CH(CH3)CH=CH2, -CH(CH3)CH2C(C H3)=CH2, -CH(CH3)CH(CH3)CH=CH2, -CH2C(CH3)2CH=CH2, -CH2CH(CH3)C(CH3)=CH2, -CH(CH3)C H2C(CH3)=CH2, -CH2CH(CH3)C(CH3)=CH2. In a more particular embodiment, R1 is -CH=CHCH3, -C(CH3)=C(CH3)2, -C(CH3)=CHCH3, -CH=C(CH3)2, -CH2CH=CH2, -CH(CH3)CH=CH2, -CH2C(CH3)=CH2, -C(CH3)2CH=CH2, -CH(CH3)C(CH3)=CH2, or -C(CH3)2C(CH3)=CH2. In a most particular embodiment, R1 is -CH=C(CH3)2.
[0099] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is Ci-4 alkyl. In a particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2. In a more particular embodiment, R1 is -CH(CH3)2, -C(CH3)3, or -CH2CH(CH3)2.
[0100] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is Ci-4 alkyl substituted with one or more independently selected halo. In a particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2, each of which is substituted with one or more independently selected halo. In another particular embodiment, R1 is Ci-4 alkyl substituted with one, two, or three independently selected halo. In yet another particular embodiment, R1 is Ci-4 alkyl substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further more particular embodiment, R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, each of which is substituted with one, two, or three F. In yet a further more particular embodiment, R1 is -CHF2, -CF3, -C(CH3)2F, -CH2CF3, or - CF2CH2CH3. In a most particular embodiment, R1 is -CH2CF3.
[0101] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. In a particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R1 is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, or morpholinyl. In a most
Figure imgf000022_0001
particular embodiment, R1 is . In another most particular embodiment, the compound of the invention is according to any one of Formulae I-VIIe, wherein R1 is
Figure imgf000022_0002
, , or .
[0102] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. In a particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. In a more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R7. In another more particular embodiment, R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. In an even further more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R7. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIIe, wherein
Figure imgf000023_0001
[0103] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. In a particular embodiment, R1 is 1- azabicyclo[2.1.1]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, l-azabicyclo[2.2.1]heptanyl, 1- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4- azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 1,4- diazabicyclo[2.2. l]heptanyl, l,4-diazabicyclo[3.1. l]heptanyl, 2,5-diazabicyclo[2.2. l]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3 -oxabicyclo [3. l. l]heptanyl, 4- oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo [2.2. l]heptanyl, 3-oxa-6-azabicyclo[3.1. l]heptanyl, 4-oxa-l -azabicyclo [3. 1. l]heptanyl, 6-oxa-
3 -azabicyclo [3.1.1 ]heptanyl, l-azabicyclo[3.2. l]octanyl, 1 -azabicyclo [4.1.1] octanyl, 2- azabicyclo [2.2.2] octanyl, 2-azabicyclo [4.1.1] octanyl, 3-azabicyclo[3.2.1]octanyl, 3 azabicyclo[4. 1. l]octanyl, 4-azabicyclo [3.2.1] octanyl, 6-azabicyclo[3.2.1]octanyl, 7 azabicyclo[4.1.1]octanyl, 8-azabicyclo[3.2.1]octanyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, 1,4- diazabicyclo[3.2. l]octanyl, 1.4-diazabicyclo[4.1. l]octanyl. 1.5 -diazabi cyclo [4.1. l]octanyl, 2,5- diazabicyclo [2.2.2] octanyl, 2.5-diazabicyclo[4.1. l]octanyl. 2.6-diazabicyclo[3.2. l]octanyl, 3,6- diazabicyclo[3.2. l]octanyl, 3,7-diazabicyclo[4.1. 1] octanyl. 3,8-diazabicyclo[3.2.1]octanyl, 4,7- diazabicyclo[3.2. l]octanyl, 2-oxabicyclo [2.2.2] octanyl, 2-oxabicyclo[3.2.1]octanyl, 2- oxabicyclo[4. 1. l]octanyl, 3 -oxabicyclo [3.2. l]octanyl, 3 -oxabicyclo [4.1.1] octanyl, 6- oxabicyclo[3.2. l]octanyl, 7 -oxabicyclo [4.1. l]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-oxa-5- azabicyclo[2.2.2]octanyl, 2-oxa-5-azabicyclo[4.1. l]octanyl, 2-oxa-6-azabicyclo[3.2. l]octanyl, 3-oxa-6- azabicyclo[3.2. l]octanyl, 3 -oxa-7 -azabicyclo [4.1. l]octanyl, 3 -oxa-8-azabicyclo[3.2.1] octanyl, 4-oxa- 1 - azabicyclo [3.2. l]octanyl, 4-oxa-l-azabicyclo[4.1. l]octanyl, 4-oxa-7 -azabicyclo[3.2.1] octanyl, 5 -oxa- 1 - azabicyclo[4. 1. l]octanyl, 6-oxa-2-azabicyclo[3.2. l]octanyl, 6-oxa-3 -azabicyclo[3.2.1] octanyl, 7 -oxa-3 - azabicyclo[4. 1. l]octanyl, or 8-oxa-3-azabicyclo[3.2. l]octanyl. In a more particular embodiment, R1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2. l]octanyl.
[0104] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. In a particular embodiment, R1 is l-azabicyclo[2.1.1]hexanyl, 3- azabicyclo [2. 1. l]hexanyl, 5 -azabicyclo [2.1.1 ]hexanyl, 3 -oxabicyclo [2. 1. l]hexanyl, 5- oxabicyclo[2. 1. l]hexanyl, 1 -azabicyclo [2.2.1 ]heptanyl, 1 -azabicyclo[3.1. l]heptanyl, 3- azabicyclo [2.2. l]heptanyl, 3 -azabicyclo [3. 1. l]heptanyl, 4-azabicyclo[3. 1. l]heptanyl, azabicyclo [3. 1. l]heptanyl, 7-azabicyclo[2.2. l]heptanyl, l,4-diazabicyclo[2.2. l]heptanyl, diazabicyclo [3. 1. l]heptanyl, 2,5 -diazabicyclo [2.2.1 ]heptanyl, 3,6-diazabicyclo[3.1. l]heptanyl, oxabicyclo [2.2. l]heptanyl, 3 -oxabicyclo [3. 1. l]heptanyl, 4-oxabicyclo[3. 1. l]heptanyl, 6- oxabicyclo [3. 1. l]heptanyl, 7-oxabicyclo[2.2. l]heptanyl, 2-oxa-5-azabicyclo[2.2. l]heptanyl, 3-oxa-6- azabicyclo [3. 1. l]heptanyl, 4-oxa-l -azabicyclo [3. 1. l]heptanyl, 6-oxa-3-azabicyclo[3.1. l]heptanyl, 1- azabicyclo [3.2.1] octanyl, 1 -azabicyclo [4.1.1] octanyl, 2-azabicyclo[2.2.2]octanyl, 2- azabicyclo[4. 1. l]octanyl, 3 -azabicyclo [3.2.1] octanyl, 3 -azabicyclo [4.1. l]octanyl, 4- azabicyclo [3.2.1] octanyl, 6-azabicyclo [3.2.1] octanyl, 7-azabicyclo[4.1. l]octanyl, 8- azabicyclo[3.2.1]octanyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, l,4-diazabicyclo[3.2.1]octanyl, l,4-diazabicyclo[4.1. 1] octanyl, l,5-diazabicyclo[4. 1. l]octanyl, 2,5 -diazabicyclo [2.2.2] octanyl, 2,5- diazabicyclo [4. 1.1] octanyl, 2,6-diazabicyclo[3.2. l]octanyl, 3,6-diazabicyclo[3.2. l]octanyl, 3,7- diazabicyclo [4. 1.1] octanyl, 3 , 8 -diazabicyclo [3.2.1] octanyl , 4,7 -diazabicyclo [3.2.1] octanyl, 2- oxabicyclo [2.2.2] octanyl, 2-oxabicyclo[3.2. l]octanyl, 2-oxabicyclo[4. 1.1] octanyl, 3- oxabicyclo[3.2. l]octanyl, 3 -oxabicyclo [4.1. 1 ]octanyl, 6-oxabicyclo [3.2.1] octanyl, 7- oxabicyclo[4. 1. l]octanyl, 8 -oxabicyclo [3.2.1] octanyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 2-oxa-5- azabicyclo[4. 1. l]octanyl, 2-oxa-6-azabicyclo[3.2. l]octanyl, 3 -oxa-6-azabicyclo[3.2.1] octanyl, 3 -oxa-7 - azabicyclo[4. 1. l]octanyl, 3-oxa-8-azabicyclo[3.2. l]octanyl, 4-oxa- 1 -azabicyclo[3.2.1] octanyl, 4-oxa- 1 - azabicyclo[4. 1. l]octanyl, 4-oxa-7-azabicyclo[3.2. l]octanyl, 5-oxa-l-azabicyclo[4. 1. l]octanyl, 6-oxa-2- azabicyclo[3.2.1]octanyl, 6-oxa-3-azabicyclo[3.2.1]octanyl, 7-oxa-3 -azabicyclo [4.1.1] octanyl, or 8-oxa-3- azabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. In a more particular embodiment, R1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R7. In another more particular embodiment, R1 is l-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5- azabicyclo[2. 1. l]hexanyl, 3 -oxabicyclo [2.1. l]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1 azabicyclo [2.2. l]heptanyl, 1 -azabicyclo [3. 1. 1 ]heptanyl, 3-azabicyclo[2.2.1]heptanyl, 3 azabicyclo [3. 1. l]heptanyl, 4-azabicyclo[3. 1. l]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 7 azabicyclo [2.2. l]heptanyl, l,4-diazabicyclo[2.2. l]heptanyl, l,4-diazabicyclo[3.1. l]heptanyl, 2,5 diazabicyclo [2.2.1] heptanyl, 3,6-diazabicyclo[3. 1. l]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3- oxabicyclo [3. 1. l]heptanyl, 4-oxabicyclo[3. 1. l]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7 oxabicyclo [2.2. l]heptanyl, 2-oxa-5-azabicyclo[2.2. l]heptanyl, 3-oxa-6-azabicyclo[3. 1. l]heptanyl, 4-oxa- 1 -azabicyclo [3.1. l]heptanyl, 6-oxa-3 -azabicyclo [3.1. l]heptanyl, 1 -azabicyclo [3.2. l]octanyl, 1- azabicyclo[4. 1. l]octanyl, 2-azabicyclo[2.2.2]octanyl, 2-azabicyclo[4.1. l]octanyl, 3- azabicyclo [3.2.1] octanyl, 3 -azabicyclo [4.1. l]octanyl, 4-azabicyclo[3.2. l]octanyl, 6- azabicyclo[3.2.1]octanyl, 7 -azabicyclo [4.1.1] octanyl, 8-azabicyclo[3.2.1]octanyl, quinuclidinyl, 1.4- diazabicyclo [2.2.2] octanyl, l,4-diazabicyclo[3.2. l]octanyl, 1.4-diazabicyclo[4.1. l]octanyl, 1.5- diazabicyclo [4. 1.1] octanyl, 2,5 -diazabicyclo [2.2.2] octanyl, 2.5 -diazabi cyclo [4.1. l]octanyl, 2.6- diazabicyclo[3.2. l]octanyl, 3,6-diazabicyclo[3.2. l]octanyl, 3,7-diazabicyclo[4.1. l]octanyl, 3,8- diazabicyclo[3.2. l]octanyl, 4,7-diazabicyclo [3.2.1] octanyl, 2-oxabicyclo [2.2 ,2]octanyl, 2- oxabicyclo[3.2. l]octanyl, 2 -oxabicyclo [4.1. l]octanyl, 3 -oxabicyclo [3.2.1] octanyl, 3- oxabicyclo[4. 1. l]octanyl, 6-oxabicyclo[3.2. l]octanyl, 7 -oxabicyclo [4.1.1] octanyl, 8- oxabicyclo[3.2. l]octanyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 2-oxa-5 -azabicyclo [4.1. l]octanyl, 2-oxa-6- azabicyclo[3.2.1]octanyl, 3-oxa-6-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[4.1.1]octanyl, 3-oxa-8- azabicyclo[3.2.1]octanyl, 4-oxa-l-azabicyclo[3.2.1]octanyl, 4-oxa-l-azabicyclo[4.1.1]octanyl, 4-oxa-7- azabicyclo[3.2. l]octanyl, 5 -oxa- 1 -azabicyclo [4.1. l]octanyl, 6-oxa-2-azabicyclo[3.2. l]octanyl, 6-oxa-3- azabicyclo[3.2.1]octanyl, 7-oxa-3-azabicyclo[4.1.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5- diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R7. In an even further more particular embodiment, R1 is 3,6- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8- diazabicyclo[3.2.1]octanyl, each of which is substituted with one R7.
[0105] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. In a particular embodiment, R1 is 2-oxabicyclo[2.2.0]hexanyl, 2- azabicyclo [2.2.0]hexanyl, 1 -azabicyclo [2.2.0]hexanyl, 2-oxa-5 -azabicyclo [2.2.0] hexanyl, 2,5- diazabicyclo [2.2.0] hexanyl, 2,5 -di oxabicyclo [2.2.0]hexanyl, 6-oxabicyclo [3.2.0] heptanyl, 6- azabicyclo[3 ,2.0]heptanyl, 3 -oxabicyclo [3.2.0] heptanyl, 3 -azabicyclo [3.2.0]heptanyl, 2- oxabicyclo[3 ,2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, l-azabicyclo[3.2.0]heptanyl, 6-oxa-3- azabicyclo[3 ,2.0]heptanyl, 3 ,6-dioxabicyclo [3.2.0]heptanyl, 3 ,6-diazabicyclo [3.2 ,0]heptanyl, 3 -oxa-6- azabicyclo[3 ,2.0]heptanyl, 6-oxa-2-azabicyclo[3.2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6- diazabicyclo [3.2.0] heptanyl, 2-oxa-6-azabicyclo [3.2.0] heptanyl, hexahydro- 1 H-cyclopenta[c] furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro[3 ,4-b] furanyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro [3 ,4-c] furanyl, hexahydrofuro [3 ,2-b]furanyl, octahydropyrrolo [3 ,4-c]pyrrolyl, octahydropyrrolo [3 ,2-b]pyrrolyl, hexahydro-2H-furo [2,3 -c]pyrrolyl, hexahydro- 1 H-furo [3 ,4-c] pyrrolyl, hexahydro- lH-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro- IH-indolyl, octahydroindolizinyl, octahydro- lH-cyclopenta[b]pyridinyl, octahydro-lH-cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2- c]pyranyl, hexahydro-2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- IH-furo [3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][l,4]dioxinyl, octahydro- lH-pyrrolo[3,4-b]pyridinyl, octahydro- lH-pyrrolo[3,4-c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro- lH-pyrrolo[3,2-c]pyridinyl, octahydro- lH-pyrrolo[2,3 -c]pyridinyl, octahydropyrrolo [ 1 ,2-a]pyrazinyl, octahydro- 1H- cyclopenta[b]pyrazinyl, octahydropyrano [3, 2-b]pyrrolyl, hexahydro- lH-pyrrolo[2,l-c][l,4]oxazinyl, octahydrocycl opcnta| b | [1,4] oxazinyl, octahydrofuro [2,3 -c]pyridinyl, octahydropyrano [2,3 -c]pyrrolyl, octahydropyrano [4,3 -b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro [3 ,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro [3 ,4-b]pyridinyl, octahydrofuro [3 ,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro- IH-quinolizinyl, octahydropyrano [4,3 - b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano [3 ,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2- a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3-c]pyridinyl, octahydro-lH-pyrano[3,4- c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1,5-naphthyridinyl, decahydro- 1 , 7-naphthyridinyl, octahydro-2H-benzo [b] [ 1 ,4]oxazinyl, octahydro-2H-pyrano [3 ,2- b]pyridinyl, octahydro-lH-pyrano[4,3-b]pyridinyl, octahydro- lH-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,l-c][l,4]oxazinyl. In a more particular embodiment, R1 is octahydropyrrolo [1,2- a]pyrazinyl.
[0106] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. In a particular embodiment, R1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, 1- azabicyclo [2.2.0]hexanyl, 2-oxa-5-azabicyclo [2.2.0]hexanyl, 2,5 -diazabicyclo [2.2.0]hexanyl, 2,5- dioxabicyclo [2.2.0]hexanyl, 6-oxabicyclo[3 ,2.0]heptanyl, 6-azabicyclo [3.2.0] heptanyl, 3- oxabicyclo[3 ,2.0]heptanyl, 3 -azabicyclo [3.2.0] heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2- azabicyclo[3 ,2.0]heptanyl, 1 -azabicyclo [3.2.0] heptanyl, 6-oxa-3 -azabicyclo [3.2.0] heptanyl, 3,6- dioxabicyclo [3 ,2.0]heptanyl, 3,6-diazabicyclo[3 ,2.0]heptanyl, 3-oxa-6-azabicyclo[3 ,2.0]heptanyl, 6-oxa- 2-azabicyclo[3.2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, 2-oxa-6- azabicyclo[3 ,2.0]heptanyl, hexahydro-lH-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro [3 ,4-b] furanyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro [3 ,4-c]furanyl, hexahydrofuro [3 ,2-b] furanyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, hexahydro-2H-furo[2,3-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro-lH-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro-lH- indolyl, octahydroindolizinyl, octahydro-lH-cyclopenta[b]pyridinyl, octahydro-lH- cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2-c]pyranyl, hexahydro- 2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- lH-furo[3,4-c]pyranyl, hexahydro- 2H-cyclopenta[b] [1,4] dioxinyl, octahydro- IH-pyrrolo [3 ,4-b]pyridinyl, octahydro- IH-pyrrolo [3,4- c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro-lH-pyrrolo[3,2-c]pyridinyl, octahydro-lH- pyrrolo[2,3-c]pyridinyl, octahydropyrrolof l,2-a]pyrazinyl, octahydro-lH-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro- lH-pyrrolo[2, 1 -c] [ 1 ,4]oxazinyl, octahydrocycl opcnta| b | [1,4] oxazinyl, octahydrofuro [2,3 -c]pyridinyl, octahydropyrano [2,3 -c]pyrrolyl, octahydropyrano [4,3 -b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro [3 ,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro [3 ,4-b]pyridinyl, octahydrofuro [3 ,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro- IH-quinolizinyl, octahydropyrano [4,3 - b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano [3 ,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2- a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3-c]pyridinyl, octahydro-lH-pyrano[3,4- c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1,5-naphthyridinyl, decahydro- 1 , 7-naphthyridinyl, octahydro-2H-benzo [b] [ 1 ,4]oxazinyl, octahydro-2H-pyrano [3 ,2- b]pyridinyl, octahydro-lH-pyrano[4,3-b]pyridinyl, octahydro- lH-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,l-c][l,4]oxazinyl, each of which is substituted with one or more independently selected R7. In another particular embodiment, R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. In a more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R7. In another more particular embodiment, R1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, 1- azabicyclo [2.2.0]hexanyl, 2-oxa-5-azabicyclo [2.2 ,0]hexanyl, 2,5 -diazabicyclo [2.2.0]hexanyl, 2,5- dioxabicyclo [2.2.0]hexanyl, 6-oxabicyclo[3 ,2.0]heptanyl, 6-azabicyclo [3.2.0] heptanyl, 3- oxabicyclo[3 ,2.0]heptanyl, 3 -azabicyclo [3.2.0] heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2- azabicyclo[3 ,2.0]heptanyl, 1 -azabicyclo [3.2.0] heptanyl, 6-oxa-3 -azabicyclo [3.2.0] heptanyl, 3,6- dioxabicyclo [3 ,2.0]heptanyl, 3,6-diazabicyclo[3 ,2.0]heptanyl, 3-oxa-6-azabicyclo[3 ,2.0]heptanyl, 6-oxa- 2-azabicyclo[3.2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, 2-oxa-6- azabicyclo[3 ,2.0]heptanyl, hexahydro- lH-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro [3 ,4-b] furanyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro [3 ,4-c]furanyl, hexahydrofuro [3 ,2-b] furanyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,2-b]pyrrolyl, hexahydro-2H-furo[2,3-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro-lH-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro-lH- indolyl, octahydroindolizinyl, octahydro-lH-cyclopenta[b]pyridinyl, octahydro-lH- cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2-c]pyranyl, hexahydro- 2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- lH-furo[3,4-c]pyranyl, hexahydro- 2H-cyclopenta[b] [1,4] dioxinyl, octahydro- IH-pyrrolo [3 ,4-b]pyridinyl, octahydro- IH-pyrrolo [3,4- c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro-lH-pyrrolo[3,2-c]pyridinyl, octahydro-lH- pyrrolo[2,3-c]pyridinyl, octahydropyrrolof l,2-a]pyrazinyl, octahydro-lH-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro- lH-pyrrolo[2, 1 -c] [ 1 ,4]oxazinyl, octahydrocycl opcnta| b | [1,4] oxazinyl, octahydrofuro [2,3 -c]pyridinyl, octahydropyrano [2,3 -c]pyrrolyl, octahydropyrano [4,3 -b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro [3 ,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro [3 ,4-b]pyridinyl, octahydrofuro [3 ,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro- IH-quinolizinyl, octahydropyrano [4,3- b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2- a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3-c]pyridinyl, octahydro-lH-pyrano[3,4- c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1,5-naphthyridinyl, decahydro- 1 , 7-naphthyridinyl, octahydro-2H-benzo [b] [ 1 ,4]oxazinyl, octahydro-2H-pyrano [3 ,2- b]pyridinyl, octahydro-lH-pyrano[4,3-b]pyridinyl, octahydro- lH-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,l-c][l,4]oxazinyl, each of which is substituted with one, two, or three independently selected R7. In a further more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R7. In an even further more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R7.
[0107] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is halo. In a particular embodiment, R7 is F, Cl, or Br. In a more particular embodiment, R7 is F.
[0108] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is Ci-6 alkyl. In a particular embodiment, R7 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, - CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or - C(CH3)2C(CH3)2. In a more particular embodiment, R7 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R7 is -CH3.
[0109] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is Ci-6 alkyl substituted with one or more independently selected R9. In a particular embodiment, R7 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, - C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2, each of which is substituted with one or more independently selected R9. In another particular embodiment, R7 is Ci-6 alkyl substituted with one, two, or three independently selected R9. In a more particular embodiment, R7 is -CH3 or -CH2CH3, each of which is substituted with one or more independently selected R9. In another more particular embodiment, R7 is - CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, - CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2, each of which is substituted with one, two, or three independently selected R9. In a most particular embodiment, R7 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected R9.
[0110] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is Ci-6 alkyl substituted with one or more independently selected R9, and R9 is halo, -OH, or -CN. In a particular embodiment, R9 is F, Cl, Br, -OH, or -CN. In a more particular embodiment, R9 is F, -OH, or -CN.
[oni] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is Ci-6 alkyl substituted with one or more independently selected R9, and R9 is C3-6 cycloalkyl. In a particular embodiment, R9 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R9 is cyclopropyl or cyclobutyl. [0112] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is C1-6 alkyl substituted with one or more independently selected R9, and R9 is C1-4 alkoxy. In a particular embodiment, R9 is -O- CH3, -O-CH2CH3, or -O-CH(CH3)2. In a particular embodiment, R9 is -O-CH3.
[0113] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is C1-6 alkyl substituted with one or more independently selected R9, and R9 is C1-4 alkoxy substituted with one or more independently selected halo. In a particular embodiment, R9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. In another particular embodiment, R9 is C1-4 alkoxy substituted with one, two, or three independently selected halo. In yet another particular embodiment, R9 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R9 is -O-CH3, -O-CH2CH3, or -O-C H(CH,)2. each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further more particular embodiment, R9 is -O-CH3, - O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. In an even further more particular embodiment, R9 is -O-CH3 substituted with one, two, or three F. In a most particular embodiment, R9 is -O-CF3.
[0114] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, R7 is C1-6 alkyl substituted with one or more independently selected R9, R9 is -NRllaRllb, and Rllaand Rllb are independently H, C1-4 alkyl, or -C(=O)-O-Ci-6 alkyl. In a particular embodiment, Rlla and Rllb are both H. In another particular embodiment, one of Rlla and Rllb is H, and the other is C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In yet another particular embodiment, Rlla and Rllb are both independently C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In a more particular embodiment, one of Rlla and Rllb is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O- CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O- CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, - C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In another more particular embodiment, Rlla and Rllb are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O- CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, - C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In a further more particular embodiment, one of Rlla and Rllb is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O- CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. In another further more particular embodiment, Rlla and Rllb are both independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, one of Rlla and Rllb is H, and the other is -CH3 or -C(=O)-O-C(CH3)3. In another most particular embodiment, Rlla and Rllb are both -CH3.
[0115] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is Ci-4 alkoxy. In a particular embodiment, R7 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a particular embodiment, R7 is -O- CH3.
[0116] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is -C(=O)-Ci-4 alkyl. In a particular embodiment, R7 is -C(=O)-CH3, -C(=O)-CH2CH3, or -C(=O)-CH(CH3)2. In a particular embodiment, R7 is -C(=O)-CH3.
[0117] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is C3-6 cycloalkyl. In a particular embodiment, R7 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R7 is cyclopropyl or cyclobutyl.
[0118] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, R7 is -NR10aR10b, and R10aand Riot) are independently H or Ci-4 alkyl. In a particular embodiment, R10a and R10b are both H. In another particular embodiment, one of R10a and R10b is H, and the other is Ci-4 alkyl. In yet another particular embodiment, R10a and R10b are both independently Ci-4 alkyl. In a more particular embodiment, one of R10a and R10b is H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another more particular embodiment, R10a and R10b are both independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, R10a and R10b are both -CH3. [0119] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIf, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is substituted with one or more independently selected R7, and R7 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. In a particular embodiment, R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R7 is morpholinyl.
[0120] In one embodiment, the compound of the invention is according to Formula Villa or Vlllb:
Figure imgf000032_0001
Villa Vlllb wherein R3a, R3b, and L3 are as described previously.
[0121] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, wherein L3 is C3-6 cycloalkyl. In a particular embodiment, L3 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, L3 is cyclobutyl. In a most particular embodiment, L3 is
Figure imgf000032_0002
Figure imgf000032_0003
[0122] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, wherein L3 is C1-6 alkylene. In a particular embodiment, L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)- -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-
, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, - CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, -CH2CH(CH2CH2CH3)-, -
CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -CH(CH3)CH(CH2CH3)-, -
CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, -CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, - CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, -CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, - CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-, -CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, - CH(CH2CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, CH2CH(CH2CH3)CH(CH3)-, -CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or - CH(CH3)CH(CH3)CH(CH3)-. In a more particular embodiment, L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH2CH3)-
, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-. In a most particular embodiment, L3 is -CH2-. [0123] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, wherein L3 is Ci-6 alkylene substituted with one or more independently selected R6. In a particular embodiment, L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)- , -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, - CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, - CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -
CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, -CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, - CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, -CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, - CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-, -CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, - CH(CH2CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, CH2CH(CH2CH3)CH(CH3)-, -CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or - CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one or more independently selected R6. In another particular embodiment, L3 is Ci-6 alkylene substituted with one, two, or three independently selected R6. In a more particular embodiment, L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2- , or -CH(CH3)CH2-, each of which is substituted with one or more independently selected R6. In another more particular embodiment, L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-
-CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-
, -CH(CH2CH(CH3)2)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -
CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, -CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -
CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, - CH(CH(CH3)2)CH(CH3)-, -CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -
CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-, - CH2CH2CH(CH2CH3)-, -CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, - CH(CH(CH3)2)CH2CH2-, -CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-,
CH(CH2CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-,
CH2CH(CH2CH3)CH(CH3)-, -CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or - CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one, two, or three independently selected R6. In yet another more particular embodiment, L3 is Ci-6 alkylene substituted with one R6. In a further more particular embodiment, L3 is -CH2- or -CH2CH2-, each of which is substituted with one or more independently selected R6. In another further more particular embodiment, L3 is -CH2-, -CH(CH2CH2CH3)- , -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one, two, or three independently selected R6. In yet another further more particular embodiment, L3 is -CH2-, -CH(CH3)- , -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-
, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, -CH(CH3)CH2-, - CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, -CH2CH(CH2CH2CH3)- , -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -CH(CH3)CH(CH2CH3)-, - CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, -CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, - CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, -CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, - CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-, -CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, - CH(CH2CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, CH2CH(CH2CH3)CH(CH3)-, -CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or - CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one R6. In an even further more particular embodiment, L3 is -CH2- or -CH2CH2-, each of which is substituted with one, two, or three independently selected R6. In another even further more particular embodiment, L3 is -CH2-, -CH(CH2CH2CH3)- , -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one R6. In a most particular embodiment, L3 is -CH2- or -CH2CH2-, each of which is substituted with one R6.
[0124] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, wherein R3b is H.
[0125] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, wherein R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N. In a particular embodiment, R3b together with L3 and the atoms onto which they are attached form a piperidinyl.
[0126] In one embodiment, the compound of the invention is according to Formula IXa, IXb, IXc, IXd, IXe, or IXf:
Figure imgf000034_0001
IXc IXd
Figure imgf000035_0001
IXe IXf wherein R3a and R6 are as described previously.
[0127] In one embodiment, the compound of the invention is according to Formula Xa, Xb, Xc, Xd, Xe, or Xf:
Figure imgf000035_0002
Xe Xf wherein R3a and R6 are as described previously.
[0128] In one embodiment, the compound of the invention is according to any one of Formulae I-Xf, wherein R3a is H.
[0129] In one embodiment, the compound of the invention is according to any one of Formulae I-Xf, wherein R3a is Ci-4 alkyl. In a particular embodiment, R3a is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. In a more particular embodiment, R3a is -CH3 or -CH2CH3. [0130] In one embodiment, the compound of the invention is according to any one of Formulae I-Xf, wherein R3a is Ci-4 alkyl substituted with one -OH or C3-6 cycloalkyl. In a particular embodiment, R3a is - CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2, each of which is substituted with one -OH or C3-6 cycloalkyl. In another particular embodiment, R3a is C1-4 alkyl substituted with one -OH, cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R3a is -CH3, -CH2CH3, -CH2CH2CH3, or -C H(CH,)2. each of which is substituted with one -OH, cyclopropyl, cyclobutyl, or cyclopentyl. In a further more particular embodiment, R3a is -CH3 or -CH2CH3, each of which is substituted with one -OH or cyclopropyl. In a most particular embodiment, R3a is -CH2-cyclopropyl or -CH2CH2OH.
[0131] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is halo or -OH. In a particular embodiment, R6 is F, Cl, Br, or -OH. In a more particular embodiment, R6 is F or -OH.
[0132] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is -NR8aR8b, and R8a and R8b are independently H, C1-4 alkyl, or -C(=O)- O-C1-6 alkyl. In a particular embodiment, R8a and R8b are both H. In another particular embodiment, one of R8a and R8b is H, and the other is C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In yet another particular embodiment, R8a and R8b are both independently C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In a more particular embodiment, one of R8a and R8b is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, - C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O- CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, - C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In another more particular embodiment, R8a and R8b are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)- O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O- CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, - C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In a further more particular embodiment, one of R8a and R8b is H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another further more particular embodiment, R8a and R8b are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O- CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. In a most particular embodiment, one of R8a and R8b is H, and the other is -CH3. In another most particular embodiment, one of R8a and R8b is -CH3, and the other is -C(=O)-O-C(CH3)3.
[0133] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is C1-4 alkoxy. In a particular embodiment, R6 is -O-CH3, -O-CH2CH3, or -O-CH( 013)2. In a more particular embodiment, R6 is -O-CH3.
[0134] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is C1-4 alkoxy substituted with one or more independently selected halo. In a particular embodiment, R6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. In another particular embodiment, R6 is C1-4 alkoxy substituted with one, two, or three independently selected halo. In yet another particular embodiment, R6 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. In a further more particular embodiment, R6 is — O-CH2CH3 substituted with one, two, or three F. In a most particular embodiment, R6 is -O-CH2CF3.
[0135] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is C3-6 cycloalkyl. In a particular embodiment, R6 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R6 is independently cyclopropyl or cyclobutyl.
[0136] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. In a particular embodiment, R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4- dioxanyl. In a more particular embodiment, R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl .
[0137] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIb, IXe, IXf, Xe and Xf, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In a particular embodiment, R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4- dioxanyl, each of which is substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In another particular embodiment, R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O- C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O- CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In yet another particular embodiment, R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. In a more particular embodiment, R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one, two, or three -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)- O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O- CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. In a further more particular embodiment, R6 is azetidinyl, pyrrolidinyl, 1,3- dioxolanyl, or piperidinyl, each of which is substituted with one, two, or three -CH3, -C(=O)-O-CH3, - C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. In a most particular embodiment, R6 is azetidinyl or pyrrolidinyl, each of which is substituted with -C(=O)-O-C(CH3)3. In another most particular embodiment, R6 is 1,3-dioxolanyl substituted with two -CH3. [0138] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from:
4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[l-methyl-7-(trifluoromethyl)benzimidazol-5-yl]-3,4- dihydro- lH-isoquinoline-7-carboxamide,
4-methyl-N-(l-methylindazol-3-yl)-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
2-(2-amino-2-oxo-ethyl)-4-methyl-N- [5 -(trifluoromethyl) -3 -pyridyl] -3 ,4-dihydro- lH-isoquinoline-7 - carboxamide,
2-(2-amino-2-oxo-ethyl)-N-(5-isopropyl-3-pyridyl)-4-methyl-3,4-dihydro-lH-isoquinoline-7- carboxamide,
(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
2-(2-amino-2-oxo-ethyl)-N-(5-cyclopentyl-3-pyridyl)-4-methyl-3,4-dihydro-lH-isoquinoline-7- carboxamide,
2-(2-amino-2-oxo-ethyl)-4-methyl-N-(5-pyrrolidin-l-yl-3-pyridyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
2-(2-amino-2-oxo-ethyl)-4-methyl-N-[6-morpholino-4-(trifluoromethyl)-2-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
2-(2-amino-2-oxo-ethyl)-4-methyl-N-[6-(trifluoromethyl)-3H-benzimidazol-4-yl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
2-[2-(2-hydroxyethylamino)-2-oxo-ethyl]-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
2-(3-amino-3-oxo-propyl)-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline-7- carboxamide,
2-(3-amino-3-oxo-propyl)-N-(5-isopropyl-3-pyridyl)-4-methyl-3,4-dihydro-lH-isoquinoline-7- carboxamide,
(4R)-2-(3-amino-3-oxo-propyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
2-(3 -amino-3 -oxo-propyl)-N- [5 -( 1 -fluoro- 1 -methyl -ethyl)-3-pyridyl] -4-methyl-3 ,4-dihydro- 1H- isoquinoline -7 -carboxamide ,
2-(3 -amino-3 -oxo-propyl)-N- [5 -(1,1 -difluoropropyl) -3 -pyridyl] -4-methyl-3 ,4-dihydro- lH-isoquinoline-7- carboxamide,
2-(3-amino-3-oxo-propyl)-N-(5-cyclopropyl-3-pyridyl)-4-methyl-3,4-dihydro-lH-isoquinoline-7- carboxamide,
2-(3-amino-2-methyl-3-oxo-propyl)-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline- 7-carboxamide, 2-(l-ethyl-2-oxo-4-piperidyl)-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline-7- carboxamide, 2-[l-(cyclopropylmethyl)-2-oxo-4-piperidyl]-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide,
N-(5-isopropyl-3-pyridyl)-4-methyl-2-(2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7-carboxamide,
N-(5-isopropyl-3-pyridyl)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
N-(5-tert-butyl-3-pyridyl)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide, 4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
N-[5-(l-fluoro-l-methyl-ethyl)-3-pyridyl]-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
N-[5 -( 1 , 1 -difluoropropyl)-3 -pyridyl] -4-methyl-2-( 1 -methyl-2-oxo-4-piperidyl)-3,4-dihydro- 1H- isoquinoline -7 -carboxamide , 4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[5-(2-methylprop-l-enyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
N-(5-isobutyl-3-pyridyl)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
N-(5-cyclopropyl-3-pyridyl)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide, 4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-(5-pyrrolidin-l-yl-3-pyridyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-(5-morpholino-3-pyridyl)-3,4-dihydro-lH-isoquinoline-7- carboxamide,
4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[6-(trifluoromethyl)-3H-benzimidazol-4-yl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
N-(6-isopropyl-lH-benzimidazol-4-yl)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH- isoquinoline -7 -carboxamide , 4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[3-methyl-6-(trifluoromethyl)benzimidazol-4-yl]-3,4- dihydro- lH-isoquinoline-7-carboxamide,
2-[l-(2-hydroxyethyl)-2-oxo-4-piperidyl]-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , czs-2-(3-carbamoylcyclobutyl)-4-methyl-N-[5-(trifluoromethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline- 7-carboxamide,
/ram-2-(3-carbamoylcyclobiityl)-4-mcthyl-N-|5-(trifliioromcthyl)-3-pyridyl ]-3,4-dihydro-l H- isoquinoline -7 -carboxamide , (4R)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-N-[5-[l-(difluoromethyl)cyclopropyl]-3-pyridyl]-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4- dihydro- lH-isoquinoline-7-carboxamide,
(4R)-2-[l-(2-hydroxyethyl)-2-oxo-4-piperidyl]-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7-carboxamide,
N-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH- isoquinoline -7 -carboxamide , N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5- (trifluoromethyl)pyridine -3 -carboxamide ,
N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5-(2,2,2- trifluoroethyl)pyridine -3 -carboxamide, N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5-isopropyl-pyridine-3- carboxamide,
N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-6-(trifluoromethyl)-3H- benzimidazole-4-carboxamide,
N-[(4R)-2-(3-amino-3-oxo-propyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5- (trifluoromethyl)pyridine -3 -carboxamide , N-[(4R)-2-(3-amino-3-oxo-propyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5-(2,2,2- trifluoroethyl)pyridine -3 -carboxamide,
N-[(4R)-2-(3-amino-3-oxo-propyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5-isopropyl-pyridine-3- carboxamide,
N-[(4R)-4-methyl-2-(2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinolin-7-yl]-5-(trifluoromethyl)pyridine-3- carboxamide,
N-[(4R)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinolin-7-yl]-5- (trifluoromethyl)pyridine -3 -carboxamide , N-[(4R)-2-(l-ethyl-2-oxo-4-piperidyl)-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5- (trifluoromethyl)pyridine -3 -carboxamide , 5-isopropyl-N-[(4R)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinolin-7-yl]pyridine- 3 -carboxamide,
N-[(4R)-4-methyl-2-(l-methyl-2-oxo-4-piperidyl)-3,4-dihydro-lH-isoquinolin-7-yl]-5-(2,2,2- trifluoroethyl)pyridine -3 -carboxamide,
N-[(4R)-2-[l-(2-hydroxyethyl)-2-oxo-4-piperidyl]-4-methyl-3,4-dihydro-lH-isoquinolin-7-yl]-5-(2,2,2- trifluoroethyl)pyridine -3 -carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(trifluoromethyl)-2-pyridyl]-3,4-dihydro-lH-isoquinoline- 7-carboxamide,
(4R)-2-(2-amino-2-oxo-ethyl)-N-[5-(3-fluoropyrrolidin-l-yl)-3-pyridyl]-4-methyl-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(trifluoromethoxy)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-(2-amino-l,l-dimethyl-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[5-(azetidin-l-yl)-3-pyridyl]-4-methyl-3,4-dihydro-lH-isoquinoline-7- carboxamide,
(4R)-2-(2-amino-l-methyl-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-[2-amino-l-(methoxymethyl)-2-oxo-ethyl]-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-3,4-dihydro-lH-isoquinoline- 7-carboxamide,
(4R)-2-(l-carbamoylcyclobutyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-(5-tetrahydrofuran-3-yloxy-3-pyridyl)-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethoxy)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[6-[(4-methylpiperazin-l-yl)methyl]-5-(trifluoromethyl)-3- pyridyl]-3,4-dihydro-lH-isoquinoline-7-carboxamide, (4R)-2-[(2R)-3-amino-2-hydroxy-3-oxo-propyl]-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7-carboxamide, (4R)-2-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7-carboxamide,
(4R)-2-(3-amino-2-methyl-3-oxo-propyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide,
(4R)-2-(l-carbamoyl-3-hydroxy-propyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide , (4R)-2-(2-amino-2-oxo-l-tetrahydrofuran-3-yl-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7-carboxamide, (4R)-2-(l-carbamoyl-3-methoxy-propyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH- isoquinoline -7 -carboxamide ,
(4R)-2-(3-amino-l-methyl-3-oxo-propyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide,
(4R)-2-[3-amino-l-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-3-oxo-propyl]-4-methyl-N-[5-(2,2,2- trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline-7 -carboxamide, (4R)-2-[3-amino-3-oxo-l-(2,2,2-trifluoroethoxymethyl)propyl]-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3- pyridyl]-3,4-dihydro-lH-isoquinoline-7-carboxamide, and (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-[(4-methylpiperazin-l-yl)methyl]-4-(trifluoromethyl)-2- pyridyl]-3,4-dihydro-lH-isoquinoline-7-carboxamide.
[0139] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
[0140] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is not (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4- dihydro- lH-isoquinoline-7 -carboxamide .
[0141] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(trifluoromethoxy)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
[0142] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is not (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[5-(trifluoromethoxy)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide.
[0143] In one embodiment, the compounds of the invention are provided in a natural isotopic form.
[0144] In one embodiment, the compounds of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.
[0145] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.
[0146] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.
[0147] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.
[0148] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.
[0149] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.
[0150] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound. [0151] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.
[0152] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.
[0153] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.
[0154] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, A-alkylmorpholinc esters and the like.
[0155] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the Ci to Cx alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.
PHARMACEUTICAL COMPOSITIONS
[0156] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. [0157] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
[0158] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
[0159] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.
[0160] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
[0161] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
[0162] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety. [0163] The above -de scribed components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.
[0164] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.
[0165] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.
Formulation 1 - Tablets
[0166] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.
Formulation 2 - Capsules
[0167] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).
Formulation 3 - Liquid
[0168] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
[0169] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.
Formulation 5 - Injection
[0170] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL. Formulation 6 - Topical
[0171] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.
METHODS OF TREATMENT
[0172] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.
[0173] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
[0174] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
[0175] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
[0176] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a fibrotic diseases treatment agent. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), Dupuytren disease, nonalcoholic steatohepatitis (NASH), systemic sclerosis, renal fibrosis, and cutaneous fibrosis.
[0177] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). [0178] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
[0179] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
[0180] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an inflammatory diseases treatment agent. In particular, the term inflammatory diseases refers to rheumatoid arthritis, osteoarthritis, allergic airway disease (e.g. asthma), chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis). More particularly the term refers to rheumatoid arthritis, chronic obstructive pulmonary disease (COPD) and inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis).
[0181] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise - induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
[0182] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
[0183] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
[0184] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a respiratory diseases treatment agent. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirinsensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adult-onset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway inflammation, cystic fibrosis, and hypoxia.
[0185] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of autoimmune diseases. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[0186] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of autoimmune diseases. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[0187] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[0188] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is an autoimmune diseases treatment agent. In particular, the term autoimmune diseases refers to COPD, asthma, bronchitis, systemic lupus erythematosus (SLE), cutaneous lupus erythrematosis (CLE), lupus nephritis, dermatomyositis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More particularly, the term refers to COPD, asthma, systemic lupus erythematosis, type I diabetes mellitus and inflammatory bowel disease.
[0189] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of metabolic diseases. In particular, the term metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
[0190] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of metabolic diseases. In particular, the term metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
[0191] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
[0192] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a metabolic diseases treatment agent. In particular, the term metabolic diseases refers to obesity, diabetes mellitus, especially type 2 diabetes, hyperinsulinemia, glucose intolerance, metabolic syndrome X, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hyperlipoproteinemia, combined hyperlipidemia, and hepatic steatosis (fatty liver disease), including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH.
[0193] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
[0194] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
[0195] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
[0196] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a cardiovascular diseases treatment agent. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.
[0197] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and/or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
[0198] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and/or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma. [0199] In additional method of treatment aspects, this invention provides methods of prophylaxis and/or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
[0200] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a proliferative diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. More particularly, the term refers to cancer, leukemia, multiple myeloma and psoriasis. Most particularly, the term refers to pancreatic cancer and melanoma.
[0201] Injection dose levels range from about 0.1 mg/kg/h to at least 10 mg/kg/h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g/day for a 40 to 80 kg human patient.
[0202] For the prophylaxis and/or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.
[0203] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.
[0204] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
[0205] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described previously. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
[0206] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.
[0207] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.
[0208] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate, mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.
[0209] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, tofacitinib, baricitinib, fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).
[0210] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leukovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin™), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva™, Erbitux™), VEGF inhibitors (e.g. Avastin™), proteasome inhibitors (e.g. Velcade™), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukaemia.
[0211] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-J3), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin.
[0212] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of transplant rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)). [0213] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of asthma and/or rhinitis and/or COPD, particular agents include but are not limited to: beta2 -adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled). Long-acting [32 -agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/sahneterol, budesonide/formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. ceterizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline).
[0214] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and/or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.
[0215] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).
[0216] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of SLE, particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta)), disease-modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. plaquenil, hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.
[0217] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort™), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive™, Enbrel™, Humira™, Remicade™, Raptiva™ and ustekinumab (a IL- 12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).
[0218] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of allergic reaction, particular agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or antileukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
[0219] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.
CLAUSES
1. A compound according to formula I:
Figure imgf000055_0001
I wherein,
Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
Li is -O-, or -CR5aR5b-;
L2 is -C(=O)NH- or -NHC(=O)-;
L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6;
R1 is
C3-6 cycloalkyl unsubstituted or substituted with one or more independently R7,
C2-6 alkenyl,
C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R7;
R2 is H, Ci-4 alkyl, or Ci-4 alkoxy, which Ci-4 alkyl or Ci-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
R3a is H or Ci-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
R3b is H, or R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
R4 is C1-4 alkyl;
R5a and R5b are independently H or -CH3; each R6 is independently selected from: halo,
- -OH,
- -NR8aR8b,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo,
C3-6 cycloalkyl, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is unsubstituted or substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl; each R7 is independently selected from: halo,
C1-6 alkyl unsubstituted or substituted with one or more independently selected R9,
C1-4 alkoxy,
- -C(=O)-Ci.4 alkyl,
C3-6 cycloalkyl,
' -NR10aR10b, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R9 is independently selected from: halo,
- -OH,
- -CN,
C3-6 cycloalkyl,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and
- -NRllaRllb; each R10a and R10b is independently H or C1-4 alkyl; and each R8a, R8b, Rlla, and Rllb is independently H, C1-4 alkyl, or -C(=O)-O-Ci-6 alkyl; or a pharmaceutically acceptable salt, or a solvate, or the salt of the solvate thereof.
2. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R4 is Ci-4 alkyl.
3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R4 is -CH3, CH2CH3, or -CH(CH3)2.
4. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R4 is -CH3 or -CH2CH3.
5. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R4 is -CH3.
6. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula II:
Figure imgf000057_0001
7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein Het is 8-10 membered fused bicyclic heteroaryl comprising one, two, or three N.
8. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein
Het is l,4-dihydropyrrolo[3,2-b]pyrrolyl, l,6-dihydropyrrolo[2,3-b]pyrrolyl, pyrrolo[l,2-a] imidazolyl, pyrrolo [ 1 ,2-b]pyrazolyl, 1 ,4-dihydropyrrolo [2,3 -d] imidazolyl, 1 ,4-dihydropyrrolo [3 ,2-c]pyrazolyl, 1 ,6-dihydropyrrolo [2,3 -c]pyrazolyl, 3 ,4-dihydropyrrolo [2,3 -d] imidazolyl, imidazo [ 1 ,2-a]imidazolyl, imidazo[l,2-b]pyrazolyl, imidazo [1, 5 -a]imidazolyl, imidazo[l,5-b]pyrazolyl, pyrazolo[l,5- b]pyrazolyl, pyrrolo[l,2-b][l,2,4]triazolyl, pyrrolo[l,2-c]triazolyl, pyrrolo[2,l-c][l,2,4]triazolyl, indolizinyl, indolyl, isoindolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo [1,5 -a] pyridinyl, indazolyl, pyrazolo[l,5-a]pyridinyl, pyrrolo[l,2-a]pyrazinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[l,2- b]pyridazinyl, pyrrolo[l,2-c]pyrimidinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo [3, 2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,4-c]pyridinyl, [l,2,4]triazolo[l,5- a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, benzotriazolyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2- a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-c]pyrimidinyl, imidazo[l,5-a]pyrazinyl, imidazo[l,5-a]pyrimidinyl, imidazo[l,5-b]pyridazinyl, imidazo[l,5-c]pyrimidinyl, imidazo[4,5- c]pyridinyl, pyrazolo[l,5-a]pyrazinyl, pyrazolo[l,5-a]pyrimidinyl, pyrazolo[l,5-b]pyridazinyl, pyrazolo[l,5-c]pyrimidinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3- b]pyridinyl, pyrazolo [4,3 -c]pyridinyl, pyrrolo [ 1 ,2-a] [ 1 ,3 ,5]triazinyl, pyrrolo [ 1 ,2-b] [ 1 ,2,4]triazinyl, pyrrolo [ 1 ,2-c]triazinyl, pyrrolo [ 1 ,2-d] [ 1 ,2,4]triazinyl, pyrrolo[2, 1 -c] [ 1 ,2,4]triazinyl, pyrrolo[2, 1 - f][l,2,4]triazinyl, pyrrolo[2,3-d]pyridazinyl, pyrrolo [3, 2-c]pyridazinyl, pyrrolo [3, 2-d]pyrimidinyl, pyrrolo [3, 4-b]pyrazinyl, pyrrolo[3,4-d]pyridazinyl, pyrrolo[3,4-d]pyrimidinyl, triazolo[l,5- a]pyridinyl, isoquinolinyl, quinolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8- naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, pyrido[2,3-b]pyrazinyl, pyrido[2,3- c]pyridazinyl, pyrido[2,3-d]pyridazinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,2-c]pyridazinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrido[3,4-c]pyridazinyl, pyrido[3,4-d]pyridazinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-c]pyridazinyl, or pyrido[4,3-d]pyrimidinyl. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein Het is benzimidazolyl or indazolyl. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Illa, IHb, or IIIc:
Figure imgf000058_0001
IIIc A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein Het is 6 membered monocyclic heteroaryl comprising one, two, or three N. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein Het is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, or 1,3,5-triazinyl. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-6, wherein Het is pyridinyl. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IVa or IVb:
Figure imgf000058_0002
IVa IVb A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-14, wherein L2 is -C(=O)NH-. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-14, wherein L2 is -NHC(=O)-. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Va or Vb:
Figure imgf000059_0001
Va Vb A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is H. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is Ci-4 alkyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -CH3, -CH2CH3, or -CH(CH3)2. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is -CH3 or -CH2CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -CH3. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkyl substituted with one or more independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one or more independently selected halo. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkyl substituted with one, two, or three independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkyl substituted with one or more independently selected F, Cl, or Br. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is -CF3 or -CH2CF3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -CF3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkoxy. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -O-CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is Ci-4 alkoxy substituted with one or more independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkoxy substituted with one, two, or three independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -O-CH3, -O-CH2CH3, or -O-C H(CH ,)2. each of which is substituted with one, two, or three independently selected F, Cl, or Br. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-17, wherein R2 is -O-CH3 substituted with one, two, or three F. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-17, wherein R2 is -O-CF3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound
Figure imgf000060_0001
Vie A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -40, wherein n is 0. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-40, wherein n is 1 and Li is -O-. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -40, wherein n is 1, Li is -CR5aR5b-, and R5a and R5b are independently H or -CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-40, wherein n is 1, Li is -CR5aR5b-, and R5a and R5b are both H. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -40, wherein n is 1, Li is -CR5aR5b-, and one of R5a and R5b is H, and the other is -CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-40, wherein n is 1, Li is -CR5aR5b-, and R5a and R5b are both -CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-40, wherein n is 1, and Li is CH2-. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Vila, Vllb, Vile, Vlld, Vile, or Vllf:
Figure imgf000061_0001
Vile Vllf A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is C3-6 cycloalkyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl, cyclobutyl, or cyclopentyl. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl or cyclopentyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is C3-6 cycloalkyl substituted with one or more independently R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is C3-6 cycloalkyl substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl substituted with one or more independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is cyclopropyl substituted with one R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
Figure imgf000062_0001
A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is C2-6 alkenyl. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein
R1 is -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, -C(CH3)=C(CH3)2, -CH=C(CH3)2, -CH2CH=CH2, -CH(CH3)CH=CH2, -CH2C(CH3)=CH2, -CH2CH=CHCH3, -C(CH3)2CH=CH2, -CH(CH3)C(CH3)=CH2, -CH(CH3)CH=CHCH3, -CH2C(CH3)=CH(CH3), -CH2CH=C(CH3)2,
-C(CH3)2C(CH3)=CH2, -C(CH3)2CH=CHCH3, -CH(CH3)C(CH3)=CH(CH3), -CH(CH3)CH=C(CH3)2, -CH2C(CH3)=C(CH3)2, -CH(CH3)C(CH2CH3)=CH2, -CH2C(CH2CH3)=CHCH3, -CH2CH2CH=CH2, -CH(CH3)CH2CH=CH2, -CH2CH(CH3)CH=CH2, -CH2CH2C(CH3)=CH2, -C(CH3)2CH2CH=CH2, -CH(CH3)CH(CH3)CH=CH2, -CH(CH3)CH2C(CH3)=CH2, -CH(CH3)CH(CH3)CH=CH2, -CH2C(CH3)2CH=CH2, -CH2CH(CH3)C(CH3)=CH2, -CH(CH3)CH2C(CH3)=CH2,
-CH2CH(CH3)C(CH3)=CH2. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
R1 is -CH=CHCH3, -C(CH3)=C(CH3)2, -C(CH3)=CHCH3, -CH=C(CH3)2, -CH2CH=CH2, - CH(CH3)CH=CH2, -CH2C(CH3)=CH2, -C(CH3)2CH=CH2, -CH(CH3)C(CH3)=CH2, or
-C(CH3)2C(CH3)=CH2. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is -CH=C(CH3)2. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is Ci-4 alkyl. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is -CH(CH3)2, -C(CH3)3, or -CH2CH(CH3)2. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is Ci-4 alkyl substituted with one or more independently selected halo. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2, each of which is substituted with one or more independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is Ci-4 alkyl substituted with one, two, or three independently selected halo. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is Ci-4 alkyl substituted with one or more independently selected F, Cl, or Br. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH(CH3)CH2CH3, -C(CH3)3, or -CH2CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, each of which is substituted with one, two, or three F. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is -CHF2, -CF3, -C(CH3)2F, -CH2CF3, or -CF2CH2CH3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is -CH2CF3. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, or morpholinyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
Figure imgf000063_0001
R1 is A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
Figure imgf000064_0001
A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
Figure imgf000064_0002
A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
R1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5 -oxabicyclo [2. l.l]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4- azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1. l]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 1,4- diazabicyclo [2.2. l]heptanyl, 1 ,4-diazabicyclo[3.1. 1 ]heptanyl, 2, 5 -diazabicyclo [2.2. l]heptanyl, 3,6- diazabicyclo [3.1. l]heptanyl, 3 -oxabicyclo [2.2. l]heptanyl, 3 -oxabicyclo [3. l. l]heptanyl, 4- oxabicyclo [3.1. l]heptanyl, 6-oxabicyclo[3.1. l]heptanyl, 7-oxabicyclo[2.2. l]heptanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 3-oxa-6-azabicyclo[3. 1. l]heptanyl, 4-oxa-l -azabicyclo [3. 1. l]heptanyl, 6- oxa-3 -azabicyclo [3.1. l]heptanyl, l-azabicyclo[3.2. l]octanyl, 1 -azabicyclo [4. 1. l]octanyl, 2- azabicyclo[2.2.2]octanyl, 2 -azabicyclo [4.1. l]octanyl, 3 -azabicyclo [3.2. l]octanyl, azabicyclo[4.1. l]octanyl, 4-azabicyclo[3.2. l]octanyl, 6-azabicyclo[3.2. l]octanyl, 7- azabicyclo[4.1.1]octanyl, 8-azabicyclo[3.2.1]octanyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo [3.2.1] octanyl, l,4-diazabicyclo[4.1.1]octanyl, l,5-diazabicyclo[4.1.1]octanyl, 2,5- diazabicyclo [2.2.2] octanyl, 2,5-diazabicyclo[4.1. l]octanyl, 2,6-diazabicyclo[3.2. l]octanyl, 3.6- diazabicyclo [3.2. l]octanyl, 3,7-diazabicyclo[4.1. l]octanyl, 3 , 8 -diazabicyclo [3.2.1] octanyl, 4.7- diazabicyclo [3.2. l]octanyl, 2-oxabicyclo [2.2.2] octanyl, 2-oxabicyclo [3.2.1] octanyl, 2- oxabicyclo [4.1. l]octanyl, 3 -oxabicyclo [3.2.1] octanyl, 3 -oxabicyclo [4.1. l]octanyl, oxabicyclo [3.2. l]octanyl, 7-oxabicyclo[4. 1. l]octanyl, 8 -oxabicyclo [3.2.1] octanyl, 2-oxa-5 - azabicyclo[2.2.2]octanyl, 2-oxa-5 -azabicyclo [4.1. l]octanyl, 2-oxa-6-azabicyclo[3.2. l]octanyl, 3-oxa- 6-azabicyclo[3.2. l]octanyl, 3-oxa-7-azabicyclo[4. 1. l]octanyl, 3-oxa-8-azabicyclo[3.2. l]octanyl, 4- oxa- 1 -azabicyclo [3.2. 1 ]octanyl, 4-oxa- 1 -azabicyclo [4.1.1] octanyl, 4-oxa-7 -azabicyclo [3.2.1 ]octanyl, 5 -oxa- 1 -azabicyclo [4.1. l]octanyl, 6-oxa-2-azabicyclo[3.2. l]octanyl, 6-oxa-3- azabicyclo[3.2.1]octanyl, 7-oxa-3-azabicyclo[4.1.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3 , 8 -diazabicyclo [3.2.1] octanyl . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
R1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo [2.1. l]hexanyl, 5 -oxabicyclo [2.1.1 ]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1- azabicyclo[3.1. l]heptanyl, 3 -azabicyclo [2.2. l]heptanyl, 3 -azabicyclo [3.1.1] heptanyl, 4- azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1. l]heptanyl, 7-azabicyclo[2.2. l]heptanyl, 1,4- diazabicyclo [2.2. l]heptanyl, 1 ,4-diazabicyclo[3.1. 1 ]heptanyl, 2,5 -diazabicyclo [2.2.1 ]heptanyl, 3,6- diazabicyclo [3.1. l]heptanyl, 3 -oxabicyclo [2.2. l]heptanyl, 3 -oxabicyclo [3.1. 1] heptanyl, 4- oxabicyclo [3.1. l]heptanyl, 6-oxabicyclo[3.1. l]heptanyl, 7-oxabicyclo[2.2. l]heptanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 3-oxa-6-azabicyclo[3. 1. l]heptanyl, 4-oxa-l -azabicyclo [3. 1. l]heptanyl, 6- oxa-3 -azabicyclo [3. l. l]heptanyl, l-azabicyclo[3.2.1]octanyl, l-azabicyclo[4.1.1]octanyl, 2- azabicyclo[2.2.2]octanyl, 2-azabicyclo[4.1.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3- azabicyclo[4.1. l]octanyl, 4-azabicyclo[3.2. l]octanyl, 6-azabicyclo[3.2.1]octanyl, 7- azabicyclo[4.1.1]octanyl, 8-azabicyclo[3.2.1]octanyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, l,4-diazabicyclo[3.2.1]octanyl, l,4-diazabicyclo[4.1.1]octanyl, l,5-diazabicyclo[4.1.1]octanyl, 2,5- diazabicyclo [2.2.2] octanyl, 2,5-diazabicyclo[4.1. l]octanyl, 2,6-diazabicyclo[3.2. l]octanyl, 3.6- diazabicyclo [3.2. l]octanyl, 3,7-diazabicyclo[4.1. l]octanyl, 3 , 8 -diazabicyclo [3.2.1] octanyl, 4.7- diazabicyclo [3.2. l]octanyl, 2-oxabicyclo [2.2.2] octanyl, 2-oxabicyclo [3.2.1] octanyl, 2- oxabicyclo [4.1. l]octanyl, 3 -oxabicyclo [3.2.1] octanyl, 3 -oxabicyclo [4.1. l]octanyl, 6- oxabicyclo [3.2. l]octanyl, 7-oxabicyclo[4. 1. l]octanyl, 8 -oxabicyclo [3.2.1] octanyl, 2-oxa-5 - azabicyclo[2.2.2]octanyl, 2-oxa-5 -azabicyclo [4.1. l]octanyl, 2-oxa-6-azabicyclo[3.2. l]octanyl, 3-oxa- 6-azabicyclo[3.2. l]octanyl, 3-oxa-7-azabicyclo[4. 1. l]octanyl, 3-oxa-8-azabicyclo[3.2. l]octanyl, 4- oxa- 1 -azabicyclo [3.2. 1 ]octanyl, 4-oxa- 1 -azabicyclo [4.1.1] octanyl, 4-oxa-7 -azabicyclo [3.2.1 ]octanyl, 5 -oxa- 1 -azabicyclo [4.1. l]octanyl, 6-oxa-2-azabicyclo[3.2. l]octanyl, 6-oxa-3- azabicyclo[3.2.1]octanyl, 7-oxa-3-azabicyclo[4.1.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl, each of which is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2. l]octanyl, each of which is substituted with one or more independently selected R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein
R1 is 1 -azabicyclo [2. 1.1 ]hexanyl, 3 -azabicyclo [2. l.l]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1. l]hexanyl, 5 -oxabicyclo [2.1.1 ]hexanyl, 1 -azabicyclo [2.2. l]heptanyl, 1 azabicyclo[3.1. l]heptanyl, 3 -azabicyclo [2.2. l]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 4 azabicyclo[3.1. l]heptanyl, 6-azabicyclo[3.1. l]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 1,4 diazabicyclo [2.2. l]heptanyl, 1 ,4-diazabicyclo[3.1. 1 ]heptanyl, 2, 5 -diazabicyclo [2.2. l]heptanyl, 3,6 diazabicyclo [3.1. l]heptanyl, 3 -oxabicyclo [2.2. l]heptanyl, 3 -oxabicyclo [3. l. l]heptanyl, 4 oxabicyclo [3.1. l]heptanyl, 6-oxabicyclo[3.1. l]heptanyl, 7-oxabicyclo[2.2. l]heptanyl, 2-oxa-5- azabicyclo[2.2. l]heptanyl, 3-oxa-6-azabicyclo[3. 1. l]heptanyl, 4-oxa- 1 -azabicyclo [3. 1. l]heptanyl, 6- oxa-3 -azabicyclo [3. l. l]heptanyl, l-azabicyclo[3.2.1]octanyl, l-azabicyclo[4.1.1]octanyl, 2- azabicyclo[2.2.2]octanyl, 2-azabicyclo[4.1.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 3- azabicyclo[4.1.1]octanyl, 4-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 7- azabicyclo[4.1.1]octanyl, 8-azabicyclo[3.2.1]octanyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo [3.2.1] octanyl, l,4-diazabicyclo[4.1.1]octanyl, l,5-diazabicyclo[4.1.1]octanyl, 2,5- diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[4.1.1]octanyl, 2,6-diazabicyclo[3.2.1]octanyl, 3,6- diazabicyclo[3.2.1]octanyl, 3,7-diazabicyclo[4.1.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 4,7- diazabicyclo[3.2.1]octanyl, 2-oxabicyclo[2.2.2]octanyl, 2-oxabicyclo[3.2.1]octanyl, 2- oxabicyclo[4.1.1]octanyl, 3 -oxabicyclo [3.2. l]octanyl, 3-oxabicyclo[4.1.1]octanyl, 6- oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[4.1.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 2-oxa-5- azabicyclo[2.2.2]octanyl, 2-oxa-5 -azabicyclo [4.1. l]octanyl, 2-oxa-6-azabicyclo[3.2. l]octanyl, 3-oxa- 6-azabicyclo[3.2. l]octanyl, 3-oxa-7-azabicyclo[4. 1. l]octanyl, 3-oxa-8-azabicyclo[3.2. l]octanyl, 4- oxa- 1 -azabicyclo [3.2. 1 ]octanyl, 4-oxa- 1 -azabicyclo [4.1.1] octanyl, 4-oxa-7 -azabicyclo [3.2.1 ]octanyl, 5 -oxa- 1 -azabicyclo [4.1. l]octanyl, 6-oxa-2-azabicyclo[3.2. l]octanyl, 6-oxa-3- azabicyclo[3.2.1]octanyl, 7-oxa-3-azabicyclo[4.1.1]octanyl, or 8-oxa-3-azabicyclo[3.2.1]octanyl, each of which is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3, 8 -diazabicyclo [3.2.1] octanyl, each of which is substituted with one, two, or three independently selected R7. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein R1 is 3,6-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, or 3,8-diazabicyclo[3.2.1]octanyl, each of which is substituted with one R7. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. A compound or pharmaceutically acceptable saltthereof, according to any one of clauses 1-48, wherein
R1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2-oxa-5- azabicyclo [2.2.0] hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5 -dioxabicyclo [2.2.0] hexanyl, 6- oxabicyclo [3 ,2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3 -oxabicyclo [3.2.0] heptanyl, 3- azabicyclo[3 ,2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2 -azabicyclo [3.2 ,0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-dioxabicyclo[3.2.0]heptanyl, 3,6- diazabicyclo[3 ,2.0]heptanyl, 3-oxa-6-azabicyclo[3 ,2.0]heptanyl, 6-oxa-2 -azabicyclo [3 ,2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, 2-oxa-6-azabicyclo[3.2.0]heptanyl, hexahydro-lH-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro[3,4-b]furanyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro[3,4-c]furanyl, hexahydrofuro [3 ,2-b]furanyl, octahydropyrrolo [3 ,4-c]pyrrolyl, octahydropyrrolo [3 ,2-b]pyrrolyl, hexahydro-2H-furo[2,3-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro- lH-furo[3, 4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro- IH-indolyl, octahydroindolizinyl, octahydro-lH-cyclopenta[b]pyridinyl, octahydro-lH- cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2-c]pyranyl, hexahydro-2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- lH-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][l,4]dioxinyl, octahydro-lH-pyrrolo[3,4-b]pyridinyl, octahydro-lH-pyrrolo[3,4-c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro-lH- pyrrolo[3,2-c]pyridinyl, octahydro-lH-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydro-lH-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4] oxazinyl, octahydrocyclopenta[b] [1,4] oxazinyl , octahydrofuro [2, 3 -c] pyridinyl , octahydropyrano[2,3-c]pyrrolyl, octahydropyrano[4,3-b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro[3,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro[3,4-b]pyridinyl, octahydrofuro[3,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-lH-quinolizinyl, octahydropyrano [4,3 -b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano [3 ,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo [b] [l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2-a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3- c]pyridinyl, octahydro-lH-pyrano[3,4-c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1, 5 -naphthyridinyl, decahydro- 1, 7-naphthyridinyl, octahydro-2H- benzofb] [ l,4]oxazinyl, octahydro-2H-pyrano[3,2-b]pyridinyl, octahydro- lH-pyrano[4,3-b]pyridinyl, octahydro- IH-pyrano [3 ,4-b]pyridinyl, or octahydropyrido [2, 1 -c] [ 1 ,4] oxazinyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is octahydropyrrolo[l,2-a]pyrazinyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more independently selected R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2- oxa-5 -azabicyclo [2.2.0]hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5-dioxabicyclo[2.2.0]hexanyl, 6- oxabicyclo[3.2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-oxabicyclo[3.2.0]heptanyl, 3- azabicyclo[3.2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-dioxabicyclo[3.2.0]heptanyl, 3,6- diazabicyclo[3 ,2.0]heptanyl, 3-oxa-6-azabicyclo[3 ,2.0]heptanyl, 6-oxa-2 -azabicyclo [3 ,2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, 2-oxa-6-azabicyclo[3.2.0]heptanyl, hexahydro-lH-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro[3,4-b]furanyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro[3,4-c]furanyl, hexahydrofuro [3 ,2-b]furanyl, octahydropyrrolo [3 ,4-c]pyrrolyl, octahydropyrrolo [3 ,2-b]pyrrolyl, hexahydro-2H-furo[2,3-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro- lH-furo[3, 4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro- IH-indolyl, octahydroindolizinyl, octahydro-lH-cyclopenta[b]pyridinyl, octahydro-lH- cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2-c]pyranyl, hexahydro-2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- lH-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][l,4]dioxinyl, octahydro-lH-pyrrolo[3,4-b]pyridinyl, octahydro-lH-pyrrolo[3,4-c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro-lH- pyrrolo[3,2-c]pyridinyl, octahydro-lH-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydro-lH-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4] oxazinyl, octahydrocyclopenta[b] [1,4] oxazinyl , octahydrofuro [2, 3 -c] pyridinyl , octahydropyrano[2,3-c]pyrrolyl, octahydropyrano[4,3-b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro[3,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro[3,4-b]pyridinyl, octahydrofuro[3,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-lH-quinolizinyl, octahydropyrano [4,3 -b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano [3 ,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo [b] [l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2-a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3- c]pyridinyl, octahydro-lH-pyrano[3,4-c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1, 5 -naphthyridinyl, decahydro- 1, 7-naphthyridinyl, octahydro-2H- benzofb] [ l,4]oxazinyl, octahydro-2H-pyrano[3,2-b]pyridinyl, octahydro- lH-pyrano[4,3-b]pyridinyl, octahydro-lH-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,l-c][l,4]oxazinyl, each of which is substituted with one or more independently selected R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three independently selected R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R7.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is 2-oxabicyclo[2.2.0]hexanyl, 2-azabicyclo[2.2.0]hexanyl, l-azabicyclo[2.2.0]hexanyl, 2- oxa-5 -azabicyclo [2.2.0]hexanyl, 2,5-diazabicyclo[2.2.0]hexanyl, 2,5-dioxabicyclo[2.2.0]hexanyl, 6- oxabicyclo[3.2.0]heptanyl, 6-azabicyclo[3.2.0]heptanyl, 3-oxabicyclo[3.2.0]heptanyl, 3- azabicyclo[3.2.0]heptanyl, 2-oxabicyclo[3.2.0]heptanyl, 2-azabicyclo[3.2.0]heptanyl, 1- azabicyclo[3.2.0]heptanyl, 6-oxa-3-azabicyclo[3.2.0]heptanyl, 3,6-dioxabicyclo[3.2.0]heptanyl, 3,6- diazabicyclo[3 ,2.0]heptanyl, 3-oxa-6-azabicyclo[3 ,2.0]heptanyl, 6-oxa-2 -azabicyclo [3 ,2.0]heptanyl, 2,6-dioxabicyclo[3.2.0]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, 2-oxa-6-azabicyclo[3.2.0]heptanyl, hexahydro-lH-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro- IH-pyrrolizinyl, hexahydrofuro[3,4-b]fiiranyl, octahydropyrrolo[3,4-b]pyrrolyl, hexahydrofuro[3,4-c]furanyl, hexahydrofuro [3 ,2-b]furanyl, octahydropyrrolo [3 ,4-c]pyrrolyl, octahydropyrrolo [3 ,2-b]pyrrolyl, hexahydro-2H-furo[2,3-c]pyrrolyl, hexahydro-lH-furo[3,4-c]pyrrolyl, hexahydro- lH-furo[3, 4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- IH-isoindolyl, octahydro- IH-indolyl, octahydroindolizinyl, octahydro-lH-cyclopenta[b]pyridinyl, octahydro-lH- cyclopenta[c]pyridinyl, hexahydro-2H-furo[2,3-c]pyranyl, hexahydro-2H-furo[3,2-c]pyranyl, hexahydro-2H-furo[3,2-b]pyranyl, hexahydro-2H-furo[3,4-b]pyranyl, hexahydro- lH-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][l,4]dioxinyl, octahydro-lH-pyrrolo[3,4-b]pyridinyl, octahydro-lH-pyrrolo[3,4-c]pyridinyl, octahydro-lH-pyrrolo[3,2-b]pyridinyl, octahydro-lH- pyrrolo[3,2-c]pyridinyl, octahydro-lH-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[l,2-a]pyrazinyl, octahydro-lH-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-lH-pyrrolo[2,l- c] [ 1 ,4] oxazinyl, octahydrocyclopenta[b] [1,4] oxazinyl , octahydrofuro [2, 3 -c] pyridinyl , octahydropyrano[2,3-c]pyrrolyl, octahydropyrano[4,3-b]pyrrolyl, octahydrofuro[3,2-b]pyridinyl, octahydrofuro[3,4-c]pyridinyl, octahydropyrano[3,4-c]pyrrolyl, octahydropyrano[3,4-b]pyrrolyl, octahydrofuro[3,4-b]pyridinyl, octahydrofuro[3,2-c]pyridinyl, octahydro- IH-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-lH-quinolizinyl, octahydropyrano [4,3 -b]pyranyl, octahydropyrano [4,3 -c]pyranyl, octahydropyrano [3 ,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo [b] [l,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-lH-pyrido[l,2-a]pyrazinyl, decahydro- 1,6-naphthyridinyl, decahydro-2, 6-naphthyridinyl, decahydro-2, 7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro- lH-pyrano[4,3- c]pyridinyl, octahydro-lH-pyrano[3,4-c]pyridinyl, octahydro-2H-pyrano[2,3-c]pyridinyl, decahydroquinoxalinyl, decahydro- 1, 5 -naphthyridinyl, decahydro- 1, 7-naphthyridinyl, octahydro-2H- benzofb] [ l,4]oxazinyl, octahydro-2H-pyrano[3,2-b]pyridinyl, octahydro- lH-pyrano[4,3-b]pyridinyl, octahydro-lH-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,l-c][l,4]oxazinyl, each of which is substituted with one, two, or three independently selected R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R7. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is F. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3, CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is Ci-6 alkyl substituted with one or more independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, - CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2, each of which is substituted with one or more independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is Ci-6 alkyl substituted with one, two, or three independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3 or -CH2CH3, each of which is substituted with one or more independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2CH2CH3, - CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2C(CH3)3, -CH(CH3)CH(CH3)2, -C(CH3)2CH2CH3, - CH(CH3)C(CH3)3, or -C(CH3)2C(CH3)2, each of which is substituted with one, two, or three independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected R9. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is halo, -OH, or -CN. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is F, Cl, Br, -OH, or -CN. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is F, -OH, or -CN. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is cyclopropyl or cyclobutyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is Ci-4 alkoxy. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is Ci-4 alkoxy substituted with one or more independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is Ci-4 alkoxy substituted with one, two, or three independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is Ci-4 alkoxy substituted with one or more independently selected F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CH3 substituted with one, two, or three F.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -O-CF3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rllaand Rllb are independently H, Ci-4 alkyl, or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rlla and Rllb are both H.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and one of Rlla and Rllb is H, and the other is Ci-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rlla and Rllb are both independently Ci-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and one of Rlla and Rllb is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, - C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, - C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O- CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52-
59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rlla and Rllb are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O- CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O- CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-
C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and one of Rlla and Rllb is H, and the other is -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rlla and Rllb are both independently -CH3, -CH2CH3, or -CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and one of Rlla and Rllb is H, and the other is -CH3 or -C(=O)-O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, 101-108, and 115-120, wherein R9 is -NRllaRllb, and Rlla and Rllb are both -CH3.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is Ci-4 alkoxy. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -O-CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -C(=O)-Ci-4 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -C(=O)-CH3, -C(=O)-CH2CH3, or -C(=O)-CH(CH3)2.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -C(=O)-CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is cyclopropyl or cyclobutyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and R10aand R10b are independently H or Ci-4 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and R10a and R10b are both H. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and one of R10a and R10b is H, and the other is Ci-4 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and R10a and R10b are both independently Ci-4 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and one of R10a and R10b is H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and R10aand R10b are both independently -CH3, -CH2CH3, or -CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is -NR10aR10b, and R10a and R10b are both -CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-48, 52- 59, 80-87, 91-97, and 101-108, wherein R7 is morpholinyl. . A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Villa or Vlllb:
Figure imgf000075_0001
Villa Vlllb. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is cyclobutyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167,
Figure imgf000075_0002
. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is C1-6 alkylene. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, -CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-,
-CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-,
-CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-,
-CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-,
-CH(CH(CH3)2)CH2CH2-, -CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-,
-CH(CH2CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-,
-CH2CH(CH2CH3)CH(CH3)-, -CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or
-CH(CH3)CH(CH3)CH(CH3)-. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH2CH3)- , -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is C1-6 alkylene substituted with one or more independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, - CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, - CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -
CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-,
CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, - CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-
-CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, -CH(CH2CH3)CH(CH3)CH2-,
CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, -CH2CH(CH2CH3)CH(CH3)-,
CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or -CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one or more independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is C1-6 alkylene substituted with one, two, or three independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one or more independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, - CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, - CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, -
CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-,
CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, - CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-
-CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, -CH(CH2CH3)CH(CH3)CH2-,
CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, -CH2CH(CH2CH3)CH(CH3)-,
CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or -CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one, two, or three independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is C1-6 alkylene substituted with one R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one or more independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one, two, or three independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH2CH3)-, -C(CH3)(CH2CH3)-, -CH(CH2CH2CH3)-, -CH(CH(CH3)2)-, -CH(CH2CH(CH3)2)-, -CH(CH(CH3)CH2CH3)-, -CH(CH2CH(CH3)2)-, -CH2CH2-, - CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH3)CH2-, -CH2CH(CH2CH3)-, -CH(CH2CH2CH3)CH2-, - CH2CH(CH2CH2CH3)-, -CH(CH3)CH(CH3)-, -CH(CH(CH3)2)CH2-, -CH2CH(CH(CH3)2)-, - CH(CH3)CH(CH2CH3)-, -CH(CH2CH3)CH(CH3)-, -CH(CH(CH3)2)CH(CH3)-, CH(CH3)CH(CH(CH3)2)-, -CH2CH2CH2-, -CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, CH2CH2CH(CH3)-, -CH(CH2CH3)CH2CH2-, -CH2CH(CH2CH3)CH2-, -CH2CH2CH(CH2CH3)-, - CH(CH3)CH(CH3)CH2-, -CH2CH(CH3)CH(CH3)-, -CH(CH3)CH2CH(CH3)-, -CH(CH(CH3)2)CH2CH2-
-CH2CH(CH(CH3)2)CH2-, -CH2CH2CH(CH(CH3)2)-, -CH(CH2CH3)CH(CH3)CH2-,
CH2CH(CH3)CH(CH2CH3)-, -CH(CH3)CH(CH2CH3)CH2-, -CH2CH(CH2CH3)CH(CH3)-,
CH(CH2CH3)CH2CH(CH3)-, -CH(CH3)CH2CH(CH2CH3)-, or -CH(CH3)CH(CH3)CH(CH3)-, each of which is substituted with one R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one, two, or three independently selected R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one R6. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-187, wherein R3b is H. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-187, wherein R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-187, wherein R3b together with L3 and the atoms onto which they are attached form a piperidinyl. . A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IXa, IXb, IXc, IXd, IXe, or IXf:
Figure imgf000078_0001
. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Xa, Xb, Xc, Xd, Xe, or Xf:
Figure imgf000078_0002
Xc
Figure imgf000079_0001
Xe Xf . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is H. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is C1-4 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH3, -CH2CH3, -CH2CH2CH3, or -CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH3 or -CH2CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is C1-4 alkyl substituted with one -OH or C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH3, -CH2CH3, -CH2CH2CH3, or -CH( CH ,) 2. each of which is substituted with one -
OH or C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is C1-4 alkyl substituted with one -OH, cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH3, -CH2CH3, -CH2CH2CH3, or -C H(CH ,)2. each of which is substituted with one - OH, cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH3 or -CH2CH3, each of which is substituted with one -OH or cyclopropyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-192, wherein R3a is -CH2-cyclopropyl or -CH2CH2OH. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is halo or -OH. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is F, Cl, Br, or -OH. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is F or -OH. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and R8a and R8b are independently H, C1-4 alkyl, or C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and R8a and R8b are both H. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and one of R8a and R8b is H, and the other is Ci-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and R8a and R8b are both independently Ci-4 alkyl or - C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167,
176-188, and 191-202, wherein R6 is -NR8aR8b, and one of R8a and R8b is H, and the other is -CH3, - CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O-
CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-
CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and R8a and R8b are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)- O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, - C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)- O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and one of R8a and R8b is H, and the other is -CH3, - CH2CH3, or -CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and R8a and R8b are both independently -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and one of R8a and R8b is H, and the other is -CH3.. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -NR8aR8b, and one of R8a and R8b is -CH3, and the other is -C(=O)- O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is C1-4 alkoxy. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167,
176-188, and 191-202, wherein R6 is -O-CH3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is Ci-4 alkoxy substituted with one or more independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is C1-4 alkoxy substituted with one, two, or three independently selected halo. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected F, Cl, or Br. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is --O-CH2CH3 substituted with one, two, orthree F. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is -O-CH2CF3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is C3-6 cycloalkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is independently cyclopropyl, cyclobutyl, or cyclopentyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is independently cyclopropyl or cyclobutyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl . . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, 1,3- dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one or more Ci-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one or more -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, - C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)-O-CH(CH3)CH2CH3, - C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-C(CH3)2CH2CH3, -C(=O)-O- CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is substituted with one, two, or three Ci-4 alkyl or -C(=O)-O-Ci-6 alkyl. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167,
176-188, and 191-202, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, 1,3- dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one, two, or three -CH3, -CH2CH3, -CH(CH3)2, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, - C(=O)-O-CH(CH3)2, -C(=O)-O-C(CH3)3, -C(=O)-O-CH2CH2CH3, -C(=O)-O-CH2CH(CH3)2, -C(=O)- O-CH(CH3)CH2CH3, -C(=O)-O-CH2C(CH3)3, -C(=O)-O-CH(CH3)CH(CH3)2, -C(=O)-O-
C(CH3)2CH2CH3, -C(=O)-O-CH(CH3)C(CH3)3, or -C(=O)-O-C(CH3)2C(CH3)2. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is azetidinyl, pyrrolidinyl, 1,3-dioxolanyl, or piperidinyl, each of which is substituted with one, two, or three -CH3, -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O- CH(CH3)2, or -C(=O)-O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is azetidinyl or pyrrolidinyl, each of which is substituted with - C(=O)-O-C(CH3)3. . A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-167, 176-188, and 191-202, wherein R6 is 1,3-dioxolanyl substituted with two -CH3. . A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is selected from Table III. . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-240. . A pharmaceutical composition according to clause 241 comprising a further therapeutic agent. 243. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1 -240, or a pharmaceutical composition according to clause 241 or 242 for use in medicine.
244. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-240, or a pharmaceutical composition according to clause 241 or 242 for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
245. A compound or pharmaceutically acceptable salt thereof for use according to clause 243 or 244, wherein said compound or pharmaceutically acceptable salt thereof is administered in combination with a further therapeutic agent.
246. The pharmaceutical composition according to clause 242, or the compound or pharmaceutically acceptable salt thereof for use according to clause 245, wherein the further therapeutic agent is an agent for the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
CHEMICAL SYNTHETIC PROCEDURES
General
[0220] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[0221] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2014).
[0222] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
Table I. List of abbreviations used in the experimental section
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000084_0002
Figure imgf000085_0015
Figure imgf000085_0014
Example 1. Synthesis of Cpd 1-87
[0223] The examples described herein serve to illustrate the present invention, and the invention is not limited to the examples given.
[0224] Analytical LCMS methods described in the Examples include methods A, B, C, and D. Method A includes Phenomenex Kinetix-XB C18, 2.1 x 100 mm, 1.7 pm colum; eluent A: water + 0.1% formic acid; eluent B: ACN + 0.1% formic acid; gradient: 0.00 min 95% A
Figure imgf000085_0001
5.30 min 100% B
Figure imgf000085_0002
5.80 min 100% B
Figure imgf000085_0003
7.00 min 95% A; column temperature: 40 °C; flow rate 0.6 mL/min; injection volume: 1 pL; and UV-detection range: 200-400 nm. Method B includes Waters Atlantis dC18, 2.1 x 100 mm, 3 pm column; eluent A: water + 0. 1% formic acid, eluent B: ACN + 0.1% formic acid; gradient: 0.00 min 95% A 5.00 min
Figure imgf000085_0005
5.40 min
Figure imgf000085_0006
5.42 min 95% A
Figure imgf000085_0004
7.00 min 95% A; column temperature: 40 °C; flow rate 0.6 mL/min; injection volume: 3 pL; and UV-detection range: 210-420 nm. Method C includes Phenomenex Gemini C18, 2.0 x 100 mm, 3 pm column; eluent A: 2 mM ammonium bicarbonate, buffered to pHlO, eluent B: ACN; gradient 0.00 min 95% A
Figure imgf000085_0007
5.50 min 100% B
Figure imgf000085_0008
5.90 min 100% B 5.92 min 95%
Figure imgf000085_0009
7.00 min 95% A; column temperature: 40 °C; flow rate 0.5 mL/min; injection volume: 3 pL; and UV-detection range: 210-420 nm. Method D includes Supelco Ascentis Express C18, 2.1 x 30 mm, 2.7 pm column; eluent A: water + 0.1% formic acid, eluent B: ACN + 0.1% formic acid; Gradient 0.00 min 95% A
Figure imgf000085_0012
1.5 min
Figure imgf000085_0011
1.6 min 100% B -> 1.61 min 95% A
Figure imgf000085_0010
2.00 min 95% A; column temperature: 40 °C; flow rate 1.0 mL/min; 3 pL; and UV-detection range: 210-420 nm.
[0225] Purification methods include Biotage Isolera™ column chromatography system using pre-packed silica and pre-packed modified silica cartridges.
Preparative High Performance Liquid Chromatography (HPLC) methods described in the Examples include method 1 and 2. Preparative HPLC method 1 (high pH) includes Waters Xbridge C18, 30 x 100 mm, 10 pm column; solvent A: water + 0.2% ammonium hydroxide, solvent B: ACN + 0.2% ammonium hydroxide; gradient 0.00 min
Figure imgf000085_0013
0.55 min 90% A 14.44 min 95% B 16.55 min 95% B 16.75 90% A; column temperature: RT; flow rate 40 mL/min; injection volume: 1500 pL; and 215 nm UV detection. Preparative HPLC method 2 (low pH) includes Waters Sunfire C18, 30 x 100 mm, 10 pm column; solvent A: water + 0.1% formic acid, solvent B: ACN + 0.1% formic acid; gradient 0.00 min 90%
Figure imgf000086_0001
16.75 90% A; column temperature: RT; flow rate 40 mL/min; injection volume: 1500 pL; and 215 nm UV detection.
1.1. Synthesis of Intermediates i-4 to i-193
[0226] Chemical naming of the example Compounds and Intermediates was performed using Marvin software by ChemAxon. Reaction times are either specified explicitly in the protocols of the experimental section, or reactions were run until completion. Chemical reactions were monitored and their completion was judged using methods well known to the person skilled in the art, such as thin layer chromatography, e.g. on plates coated with silica gel, or by liquid chromatography-mass spectrometry (LCMS) methods.
Figure imgf000086_0002
[0227] A solution of methyl 4-(cyanomethyl)benzoate (25.5 g, 146.6 mmol) in dry THF (600 mL) was cooled to -78 °C and LiHMDS (146 mL of a 1 M solution in THF, 146 mmol) was added over 30 min giving a cloudy solution. This was stirred at this temperature for 15 min and iodomethane (9.1 mL, 146 mmol) was then added dropwise over 5 min. The solution was then allowed to warm to RT giving a dark purple solution. This was then quenched via addition of a sat. aq. ammonium chloride solution (50 mL). The mixture was then concentrated at reduced pressure to remove excess THF and diluted with EtOAc (500 mL). The mixture was washed with brine (3 x 150 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The mixture was purified in batches via Biotage Isolera™ column chromatography (5 x 340 g KP-Sil columns, using a gradient of eluents; 92:8 to 70:30 heptane:MTBE) giving the title compound (12.4 g, 45% yield) as a pale yellow oil. ’H NMR (500 MHz, DMSO-t/6) 5 8.03 - 7.97 (m, 2H), 7.60 - 7.53 (m, 2H), 4.44 (q, J= 7.2 Hz, 1H), 3.86 (s, 3H), 1.56 (d, J= 7.3 Hz, 3H). LCMS (Method D) rt = 1.10 min, the product did not ionize.
Figure imgf000086_0003
[0228] To a solution of methyl 4-(l-cyanoethyl)benzoate (Int i-4, 12.4 g, 65.5 mmol) in EtOH (100 mL) was added concentrated HCI (20 mL). 10% Pd/C (3.4 g) was added and the resulting mixture was stirred under a hydrogen atmosphere overnight. The mixture was then filtered over Celite® and further 10% Pd/C (3.4 g) was added and the mixture was again stirred overnight under a hydrogen atmosphere. The process of filtration over Celite®, retreatment with 10% Pd/C and hydrogenation was repeated twice more until complete reaction was observed. The mixture was then filtered over Celite® and concentrated at reduced pressure. The residue obtained was slurried in MTBE (200 mL) with rapid stirring for 1 h. The solids obtained were filtered and dried giving the title compound (10.2 g, 68% yield) as a white solid. LCMS (Method D) rt = 0.72 min, MS (ESIPos) m/z=194 (M+H)+.
Figure imgf000087_0001
[0229] To methyl 4-(l-aminopropan-2-yl)benzoate hydrochloride (Int i-5, 8.8 g, 38.4 mmol) was added TFAA (45 mL). The mixture was stirred at RT for 3 h. The mixture was then quenched by adding ice water (100 mL) and then stirred for 1 h. This mixture was then partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was further extracted with EtOAc (100 mL). The organics were combined and then dried (Na2SO4), filtered and concentrated at reduced pressure to obtain the title compound (14.2 g, quantitative yield) as a colourless oil. XH NMR (250 MHz, chloroform- ) 5 8.01 (m, 2H), 7.28 (m, 2H), 6.16 (s, 1H), 3.92 (s, 3H), 3.70 (m, 1H), 3.41 (m, 1H), 3.18 - 3.01 (m, 1H), 1.34 (m, 3H). LCMS (Method D) rt = 1.12 min, the product did not ionize.
1.1.4. Int i-7: Methyl 4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate
Figure imgf000087_0002
[0230] To methyl 4-[l-(2,2,2-trifluoroacetamido)propan-2-yl]benzoate (Int i-6, 660 mg, 2.28 mmol) and paraformaldehyde (343 mg) was added concentrated sulfuric acid (5 mL) with ice cooling. The mixture was then stirred at RT for 2 h. The mixture was then poured onto ice (300 mL) and then extracted with EtOAc (300 mL). The organic extract was then washed with sat. aq. NaiCCh (300 mL), then water (300 mL) dried (Na2SO4), filtered and concentrated to obtain the title compound (9.53 g, 90% yield) as a colourless oil. LCMS (Method D) rt = 1.20 min, MS (ESIPos): m/z = 302.1 (M+H)+.
Figure imgf000087_0003
[0231] To a solution of methyl 4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate (Int i-7, 3.00 g, 9.96 mmol) in MeOH (25 mL) and water (12.5 mL) was added K2CO3 (2.06 g, 14.9 mmol). The resulting suspension was stirred at RT for 3 h. The mixture was then treated with K2CO3 (2.06 g, 14.94 mmol) followed by di-tert-butyl dicarbonate (2.39 g, 10.95 mmol) and stirred at RT for a further 1 h. The mixture was then diluted with water (200 mL), extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated at reduced pressure to obtain the title compound (3.3 g, quantitative yield) as a yellow viscous oil. This was used without further purification. LCMS (Method D) rt = 1.30 min, MS (ESIPos): m/z = 249.9 (M-t-Bu+H)+.
1.1.6. Int i-9: 2-[(tert-butoxy)carbonyl]-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid
Figure imgf000088_0001
[0232] 2-tert-butyl 7-methyl 4-methyl-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate (Int i-8, 3.04 g, 9.96 mmol) was dissolved in THF (20 mL) and LiOH (5.47 mL of a 2 M aq. solution, 10.94 mmol) was added. The resulting mixture was stirred at 60 °C for 18 h. The mixture then cooled to RT and diluted with HC1 (12 mL of 1 M aq. solution, 12 mmol) and then extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated at reduced pressure giving the title compound (2.79 g, 96% yield) as an off-white powder. This was used without further purification. LCMS (Method D) rt = 1.13 min, MS (ESIPos) m/z= 235.90 [M-t-Bu+H]+
Figure imgf000088_0002
[0233] (2R)-2-phenylpropan-l -amine (52.6 mL, 0.37 mol) was dissolved in DCM (540 mL) and cooled to 0 °C. TFAA (17.8 mL, 0.13 mol) was then added dropwise and on complete addition the mixture was allowed to warm to RT and left to stir overnight. The mixture was diluted with brine (2 x 240 mL), the organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (87.4 g, quantitative yield) as an off-white solid. ’H NMR (500 MHz, chloroform- ) 5 7.38 - 7.33 (m, 2H), 7.30 - 7.26 (m, 1H), 7.22 - 7.18 (m, 2H), 6.11 (m, 1H), 3.74 - 3.66 (m, 1H), 3.36 (m, 1H), 3.06 - 2.97 (m, 1H), 1.33 (d, J = 7.0 Hz, 3H).
Figure imgf000088_0003
[0234] 2,2,2-trifluoro-N-[(2R)-2-phenylpropyl]acetamide (Int i-10, 60 g, 252 mmol) was dissolved in DCM (600 mL) and cooled to -10 °C. Methanesulfonic acid (41.4 mL, 638 mmol) was added followed by portionwise addition of l,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (35.99 g, 125.9 mmol). The reaction was stirred at -10 °C for 1 h then allowed to warm to RT. After 18 h the reaction mixture was diluted with water (300 mL) and the organic layer was separated. The aqueous layer extracted with DCM (600 mL) and the combined organic layers were then washed with brine (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica (using DCM) and purified in 6 batches via Biotage Isolera™ column chromatography (eluting with a gradient eluents; 0 - 40% MTBE:heptane) giving the title compound (27.6 g, 34% yield) as a white solid. LCMS (Method B) rt = 3.55 min, MS (ESINeg) m/z= 310.1 [M-H]’.
Figure imgf000089_0001
[0235] Pd(OAc)2 (1.97 g, 8.79 mmol) was added to a degassed mixture of N-[(2R)-2-(4- bromophenyl)propyl]-2,2,2-trifluoro-acetamide (Int i-11, 11.4 g, 35.2 mmol), propane-1, 3- diylbis(diphenylphosphane) (2.18 g, 5.27 mmol) and N,N-diethylethanamine (8.3 mL, 59.6 mmol) in MeOH (850 mL). The reaction mixture was then placed under a 3 bar atmosphere of carbon monoxide and stirred with heating at 100 °C . After 25 h the reaction mixture was cooled to RT then filtered through Celite® and washed with MeOH (5 x 50 mL) and then concentrated at reduced pressure. The crude mixture was dissolved in DCM (200 mL), acidified with 1 M aq. HC1 (100 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give crude product as a red oil. The crude material was dry loaded onto silica using DCM and purified via Biotage Isolera™ column chromatography (eluting with a gradient eluents; 0 - 40% EtOAc:heptane) giving the title compound (5.36 g, 53% yield) as a white powder. LCMS (Method A) rt = 3.05 min, MS (ESIPos) m/z= 290.1 [M+H]+.
1.1.10. Int i-13: Methyl (4R)-4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline- 7-carboxylate
Figure imgf000089_0002
[0236] To methyl 4-[(lR)-l-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate (Int i-12, 20.6 g, 68.4 mmol) and paraformaldehyde (10.27 g, 342.2 mmol), was added concentrated sulfuric acid (310 mL) with ice cooling. The mixture was then allowed to warm to RT and was then stirred for 3 h. The reaction mixture was then slowly poured onto ice water (1.2 L) maintaining the temperature below 10 °C. The aqueous mixture was extracted with EtOAc (2 x 600 mL). The combined organic extracts were then washed with sat. aq. Na2CC>3 (200 mL), water (250 mL), dried (L^SCL), filtered and concentrated under reduced pressure. The crude material was dry loaded onto silica (using DCM) and purified via Biotage Isolera™ column chromatography (eluting with a gradient of eluents; 0 - 20% EtOAc: heptane) giving the title compound (18.49 g, 87% yield) as a colourless oil. LCMS (Method A) rt: 3.45 min, MS (ESIPos) m/z= 302.1 [M+H]+.
Alternative synthesis:
[0237] A round bottom flask was charged with TFA (1 L), then methyl 4-[(lR)-l-methyl-2-[(2,2,2- trifhioroacetyl)amino]ethyl]benzoate (Int i-12, 500 g, 1729 mmol, 1 eq.) and paraformaldehyde (279 g, 2942 mmol, 1.70 eq.) were added portionwise. The suspension was heated at 40 °C until complete solubilization. Concentrated sulfuric acid (500 mL) was added slowly under water bath cooling. Once the addition was completed, the reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was then poured into cold water (5 L, 10 °C), DCM (2.5 L) was added and the layers were separated. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. The oily residue was filtered on a pad of cellulose, and the pad was washed with DCM. The DCM was concentrated under reduced pressure and the crude residue was purified by filtration on SiO2 (eluting with DCM/EtOAc, 100:0 to 95:5) to afford Int i-13.
1.1.11. Int i-14: 2-tert-butyl 7-methyl (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-2,7- dicarboxylate
Figure imgf000090_0001
[0238] K2CO3 (17.28 g, 125.0 mmol) was added to a methyl (4R)-4-methyl-2-(2,2,2-trifluoroacetyl)-3,4- dihydro-lH-isoquinoline-7-carboxylate (Int i-13, 18.49 g, 59.53 mmol) in MeOH (130 mL) and water (60 mL). The reaction mixture was stirred at RT for 1 h then treated with di-tert-butyl dicarbonate (14.29 g, 65.49 mmol) and stirred at RT for a further 1 h. The reaction mixture was then diluted with water (300 mL), extracted with EtOAc (2 x 300 mL). The combined organic extracts were washed with brine (150 mL), dried (Na2SO4), fdtered and concentrated to give the title compound (18.73 g, quantitative yield) as a colourless oil. LCMS (Method A) rt: 3.99 min; MS (ESIPos) m/z= 306.1 [M+H]+.
1.1.12. Int i-15: (4R)-2-[(tert-butoxy)carbonyl]-4-methyl-l,2,3,4-tetrahydroisoquinoline- 7- carboxylic acid
Figure imgf000090_0002
[0239] 2-tert-butyl 7-methyl (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-2,7-dicarboxylate (Int i-14, 18.73 g, 58.9 mmol) was dissolved in THF (140 mL) and 2 M aq. LiOH (44 mL, 88 mmol) was added. The resulting mixture was stirred with heating at 60 °C for 3 h. The reaction mixture was then cooled to RT and diluted with 2 M aq. HC1 (60 mL) and extracted with EtOAc (2 x 200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound (16.8 g, quantitative yield) as an off-white powder. LCMS (Method A) rt: 3.22 min; MS (ESIPos) m/z= 292.1 [M+H]+. 1.1.13. Int i-37: Methyl 4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
O
[0240] To a solution of methyl 4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate (Int i-7, 3.22 g, 10.69 mmol) in MeOH (30 mL) and water (15 mL) was added K2CO3 (2.21 g, 16.03 mmol). The resulting suspension was stirred at RT for 2 h. The mixture was then concentrated at reduced pressure to remove excess MeOH, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic extracts were dried (Na2SO.0, fdtered and concentrated at reduced pressure to give the title product (1.89 g mg, 78% yield) as a colourless oil. This was used without further purification. LCMS (Method D) rt = 0.67 min, MS (ESIPos): m/z = 206.05 (M+H)+
1.1.14. Int i-52: Methyl 4-methyl-2-(l-methyl-2-oxopiperidin-4-yl)-l, 2,3,4- tetrahydroisoquinoline-7-carboxylate
[0241] To a stirred solution of methyl 4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (Int i-37, 200 mg, 0.97 mmol) and l-methylpiperidine-2, 4-dione (Int i-180, 387 mg, 2.44 mmol) in MeOH (4 mL) was added AcOH (61 pL, 1.07 mmol). The reaction mixture was stirred at RT for 5 min and NaBH3(CN) (153 mg, 2.44 mmol) was added. The reaction mixture was stirred with heating at 80 °C overnight in a sealed tube. The following day the mixture was concentrated at reduced pressure and diluted with sat. aq. NaHCOs (20 mL), extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na2SO.0, filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ column chromatography (KP-Sil cartridge, eluting with a gradient of eluents: 100% DCM to 95:5 DCM:MeOH) giving the title compound (310 mg, quantitative yield) as a yellow oil. The compound was isolated as a mixture of stereoisomers. LCMS (Method D) rt = 0.72 min, MS (ESIPos) m/z = 316.9 [M+H]+
[0242] In analogy to the procedure described for Int i-52, the following intermediates were prepared via reductive amination using the appropriate amine and the appropriately N-substituted piperidine-2, 4-dione.
Figure imgf000091_0001
Figure imgf000092_0002
1.1.15. Int i-53: Lithio 4-methyl-2-(l-methyl-2-oxopiperidin-4-yl)-l, 2,3,4- tetrahydroisoquinoline-7-carboxylate
[0243] Methyl-4-methyl-2-(l-methyl-2-oxopiperidin-4-yl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (Int i-52, 0.31 g, 0.98 mmol) was dissolved in THF (2 mL) and 2 M aq. LiOH (0.73 mL, 1.46 mmol) was added. The resulting mixture was stirred at 60 °C for 6 h. The reaction mixture was cooled to RT, concentrated at reduced pressure and dried to give the title compound (254 mg, 84% yield) as an off-white powder. This was used without further purification. The compound was isolated as a mixture of stereoisomers. ‘H NMR (250 MHz, DMSO-t/6) 5 7.72 - 7.49 (m, 2H), 7.07 (m, 1H), 3.79 - 3.43 (m, 2H), 3.31 - 2.60 (m, 7H), 2.43 - 1.94 (m, 4H), 1.94 - 1.44 (m, 2H), 1.21 (m, 3H).
Figure imgf000092_0001
[0244] Methyl 5 -bromopyridine -3 -carboxylate (5.0 g, 23.1 mmol) was dissolved in THF (100 mL) and cooled to -78 °C. Methylmagnesium bromide (23.1 mL of a 3 M soln in Et2O, 69 mmol) was added dropwise over 5 min and the mixture was then allowed to warm to RT and was stirred at this temperature for 1 h. The reaction was quenched via addition of water (50 mL) and the mixture was concentrated at reduced pressure to removed excess THF. The mixture was diluted with MTBE (100 mL) and the organic layer was extracted then washed with brine (2 x 50 mL), dried (Na2SC>4), fdtered and concentrated at reduced pressure giving the title compound (4.86 g, 86% yield) as a yellow oil. This was used without further purification. LCMS (Method D) rt = 0.81 min, MS (ESIPos) m/z=217.8 & 219.8 [M+H]+.
Figure imgf000093_0001
[0245] EtMgBr (8.9 mL of a 3 M soln in THF, 26.9 mmol) was added dropwise to bis[2-(N,N- dimethylamino)ethyl] ether (5.1 mL, 26.9 mmol) in THF (50 mL) at 0 °C and the resulting mixture was stirred for 10 min. This was added dropwise to 5 -bromopyridine -3 -carbonyl chloride (5.4 g, 24.5 mmol) in THF (50 mL) at -78 °C over 5 min. The resulting mixture was allowed to warm to RT and then stirred for 30 min then quenched by addition of sat. aq. ammonium chloride (50 mL). The mixture was concentrated at reduced pressure to removed excess THF and then diluted with EtOAc (100 mL). The organics were separated and washed with brine (2 x 50 mL), dried (T^SCL), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (2 x 50 g Silica columns, using a gradient of eluents; 95:5 to 6:4 heptane: EtOAc) giving the title compound (2.37 g, 45% yield) as a white solid. LCMS (Method D) rt = 0.98 min, MS (ESIPos) m/z=213.8 & 215.8 [M+H]+.
Figure imgf000093_0002
[0246] To a stirred suspension of 2-(5-bromopyridin-3-yl)acetonitrile (1.0 g, 5.08 mmol) in 50% aq. NaOH (20 mL) was added l-bromo-2 -chloroethane (0.34 mL, 5.33 mmol) followed by N-benzyl-N,N- diethylethanaminium chloride (23.12 mg, 0.1 mmol). The resulting mixture was stirred at 60 °C for 16 h. After this time the mixture was diluted with water (200 mL) and extracted with DCM (2 x 200 mL). The combined organic extracts were dried (MgSOft. filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ column chromatography (50 g KP-Sil column, eluting with a gradient of eluents: 0-40% EtOAc in heptane) to give the title compound (647 mg, 57% yield) as an off-white powder. LCMS (Method D) rt = 0.98 min, MS (ESIPos) m/z=222.8 & 224.75 [M+H]+
Figure imgf000094_0001
[0247] To a stirred solution of Int i-56 (200 mg, 0.9 mmol) in anhydrous DCM (5 mL) at -78 °C under a nitrogen atmosphere was added diisobutylaluminium hydride (DIBAL) (1.08 mL of a 1 M solution in heptane, 1.08 mmol). The mixture was stirred at -78 °C for 3 h, retreated with further DIBAL (0.55 mL of a 1 M solution in heptane, 0.55 mmol), and stirred at -78 °C for a further 1 h. The reaction was then quenched with 1 M aq. HC1 (5 mL) and allowed to warm to RT and then stirred at this temperature for 1 h. The mixture was then basified by addition of sat. aq. NaHCCh (25 mL), extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried (T^SCL), filtered and concentrated at reduced pressure to give the title compound (135 mg, 59% yield) as a white solid. This was used without further purification. LCMS (Method D) rt = 0.91 min, MS (ESIPos) m/z=225.8 & 227.75 [M+H]+
Figure imgf000094_0002
[0248] Int i-54 (1.0 g, 4.63 mmol) was dissolved in DCM (50 mL) and cooled to -78 °C and bis(2- methoxyethyl)aminosulfiir trifluoride (Deoxo-Fluor®) (1.7 mL of a 50% solution in toluene, 4.63 mmol) was added dropwise. The mixture was stirred for 10 min and then allowed to warm to RT. Sat. aq. NaHCCh (50 mL) was added and the mixture was stirred for 10 min until no further gas evolution was observed. The organic layer was then separated and washed with brine (2 x 30 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (50 g KP Sil cartridge, using a gradient of eluents; 99: 1 to 7:3 heptane: EtOAc) giving the title compound (562 mg, 50% yield) as a colourless oil. LCMS (Method D) rt = 1.09 min, MS (ESIPos) m/z=217.8 & 219.8 [M+H]+.
[0249] In analogy to the procedure described for Int i-58, the following intermediates were prepared using the appropriate aldehyde or ketone and Deoxo-Fluor®.
Figure imgf000094_0003
Figure imgf000095_0002
Figure imgf000095_0001
[0250] Int i-58 (562 mg, 2.58 mmol), 1,1-diphenylmethanimine (475 pL, 2.83 mmol), BINAP (240 mg, 0.39 mmol) and NaOtBu (495 mg, 5.15 mmol) were stirred in toluene (10 mL) and nitrogen gas was bubbled through the mixture for 5 min. Pd2(dba); (118 mg, 0.13 mmol) was then added and the resulting mixture was heated in a sealed tube at 100 °C for 2 h. The mixture was then cooled to RT and diluted with EtOAc (75 mL) and filtered over Celite®. The organics were then washed with brine (3 x 30 mL), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (50 g KP Sil cartridge, using a gradient of eluents; 99: 1 to 1: 1 heptane: EtOAc) giving the title compound (800 mg, quantitative yield) as a yellow oil. LCMS (Method D) rt = 1.24 min, MS (ESIPos) m/z=319 [M+H]+
[0251] In analogy to the procedure described for Int i-61, the following intermediates were prepared using the appropriate pyridyl bromide and 1,1-diphenylmethanimine.
Figure imgf000095_0003
Figure imgf000096_0002
Figure imgf000096_0001
[0252] Int i-61 (562 mg, 1.77 mmol) was dissolved in MeOH (20 mL) and 3 M aq. HC1 (5.88 mL, 17.7 mmol) was added. The resulting mixture was stirred rapidly at RT for 2 h. The mixture was then basified via addition of sat. aq. NaHCCf. concentrated at reduced pressure to remove excess MeOH and then diluted with EtOAc (50 mL). The organic layer was separated and then washed with brine (2 x 20 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (25 g KP Sil cartridge, using a gradient of eluents; 9: 1 heptane: EtOAc to 100% EtOAc) giving the title compound (231 mg, 85% yield) as a yellow oil. LCMS (Method D) rt = 0.31 min, MS (ESIPos) m/z=154.9 [M+H]+.
[0253] In analogy to the procedure described for Int i-65, the following intermediates were prepared using the appropriately substituted l,l-diphenyl-N-(pyridin-3-yl)methanimine and aq. HC1.
Figure imgf000096_0003
Figure imgf000097_0002
Figure imgf000097_0001
[0254] A sealed tube was charged with 5-bromopyridin-3-amine (200 mg, 1.16 mmol), 4, 4,5,5- tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (358 pL, 1.73 mmol), CS2CO3 (1.13 g, 3.47 mmol) in DMF (5 mL) and water (1.5 mL). The reaction mixture was degassed by passing a flow of nitrogen through the mixture for 5 min. Pd(PPh3)4 (134 mg, 0.12 mmol) was then added and the mixture was then heated with stirring in a sealed tube at 80 °C for 16 h. The reaction was then cooled to RT, diluted with water (50 mL), extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by Biotage Isolera™ column chromatography (25 g KP-Sil cartridge, eluting with a gradient of eluents: 0-100% EtOAc in heptane). The product obtained was further purified using a Biotage ISOLUTE® SCX-2 column (eluting with 1 M ammonia in MeOH) giving the title compound (122 mg, 71% yield) as a light brown viscous oil. LCMS (Method D) rt = 0.55 min, MS (ESIPos) m/z=148.9 [M+H]+.
[0255] In analogy to the procedure described for Int i-69, the following intermediate was prepared using 3 -bromo-5 -nitropyridine and 2-(cyclopent- 1-en- l-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane.
Figure imgf000097_0003
[0256] In analogy to the procedure described for Int i-69, the following intermediate was prepared using methyl 5 -bromopyridine -3 -carboxylate and 4,4,5,5-tetramethyl-2-(prop-l-en-2-yl)-l,3,2-dioxaborolane.
Figure imgf000098_0002
Figure imgf000098_0001
[0257] To a solution of 5-(2-methylprop-l-en-l-yl)pyridin-3-amine (Int i-69, 100 mg, 0.67 mmol) in EtOH (5 mL) was added 10% Pd/C (36 mg). The reaction mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was then fdtered over Celite®, washed with EtOH and the fdtrate was concentrated at reduced pressure to obtain the title compound (103 mg, quantitative yield) as an off-white powder. LCMS (Method D) rt = 0.56 min, MS (ESIPos) m/z = 150.9 [M+H]+
[0258] In analogy to the procedure described for Int i-71, the following intermediate was prepared using 3-(cyclopent-l-en- l-yl)-5-nitropyridine (Int i-70) as a starting material.
Figure imgf000098_0003
[0259] In analogy to the procedure described for Int i-71, the following intermediate was prepared via hydrogenation using 5-(prop-l-en-2-yl)pyridine-3-carboxylic acid (Int i-155) as a starting material.
Figure imgf000098_0004
1.1.25. Int i-73: 3-nitro-5-(2,2,2-trifluoroethyl)pyridine
Figure imgf000099_0001
[0260] To a solution of l-methyl-3,5-dinitropyridin-2(lH)-one (1.75 g, 8.78 mmol) in EtOH (150 mL) were added 4,4,4-trifluorobutanal (75% purity, 2.96 g, 17.6 mmol) and ammonium acetate (10.0 g, 132 mmol). The resultant mixture was heated at 65 °C with stirring for 24 h. The mixture was concentrated at reduced pressure, diluted with EtOAc (750 mL), washed with water (2 x 30 mL), brine (30 mL), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was purified by flash chromatography using Biotage Isolera™ column chromatography (50 g KP-Sil cartridge; eluting with a gradient of eluents; 9: 1 to 2:8 heptane: EtOAc) giving the title compound (1.1 g, 61% yield) as a yellow solid. JH NMR (250 MHz, DMSO-d6) 5 9.37 (m, 1H), 8.99 (m, 1H), 8.68 (m, 1H), 3.99 (q, J= 11.3 Hz, 2H).
1.1.26. Int i-74: 3-(difluoromethoxy)-5-nitropyridine
Figure imgf000099_0002
[0261] To a solution of 5-nitropyridin-3-ol (0.4 g, 2.86 mmol) and K2CO3 (14.21 g, 102.8 mmol) in ACN:water (1: 1, 12 mL), was added 2-chloro-2,2-difluoro-l -phenylethanone (2.1 mL, 14.3 mmol). The mixture was heated at 80 °C with stirring in a sealed tube for 18 h. The mixture was then cooled to RT, diluted with water (100 mL), extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by Biotage Isolera™ column chromatography (KP-Sil 25 g cartridge, eluting with a gradient of eluents: 0-100% EtOAc in heptane) to obtain the title compound (162 mg, 29% yield) as a yellow oil. LCMS (Method D) rt = 0.96 min, the product did not ionize. ’H NMR (500 MHz, DMSO- 4) 5 9.28 (m, 1H), 8.94 (m, 1H), 8.48 (m, 1H), 7.52 (t, J= 72.6 Hz, 1H)
1.1.27. Int i-77: 2,4-dinitro-6-(trifluoromethyl)aniline
Figure imgf000099_0003
[0262] 2-chloro-l,5-dinitro-3-(trifluoromethyl)benzene (500 mg, 1.85 mmol) was dissolved in 7 M ammonia in MeOH (2.64 mL, 18.5 mmol) and the mixture was left: to stir overnight at RT. The reaction was concentrated at reduced pressure giving the title compound (465 mg, quant, yield) as a yellow powder. This was used without any further purification. [0263] LCMS (Method D) rt = 1. 10 min, MS (ESIPos) m/z=249.9 [M-H]’
[0264] In analogy to the procedure described for Int i-77, the following intermediates were prepared using the appropriately substituted aryl chloride and amine.
Figure imgf000100_0003
1.1.28. Int i-80: 3-nitro-5-(pyrrolidin-l-yl)pyridine
Figure imgf000100_0001
[0265] 3-Fluoro-5-nitropyridine (0.5 g, 3.52 mmol), pyrrolidine (0.35 m , 4.22 mmol) and DIPEA (1.23 mb, 7.04 mmol) were dissolved in DMSO (1 mb) and the resulting mixture was heated at 100 °C for 3 h. The reaction mixture was diluted with EtOAc (50 mb) and washed with water (3 x 20 mb) and brine (20 mb), dried (Na2SC>4), fdtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (50 g KP Sil cartridge, using a gradient of eluents; 95:5 to 1: 1 heptane: EtOAc) giving the title compound (591 mg, 87% yield) as a yellow solid. ECMS (Method A) rt = 1.09 min, MS (ESIPos) m/z=193.9 [M+H]+.
Figure imgf000100_0002
[0266] 6-chloro-4-(trifhioromethyl)pyridin-2-amine (250 mg, 1.27 mmol) was dissolved in morpholine (3.0 mb, 34.7 mmol) and heated at 150 °C for 90 min in a microwave. The reaction was then cooled to RT and concentrated under reduced pressure to give the title compound (354 mg, 96% yield) as an orange solid. This was used without further purification. ECMS (Method D) rt = 0.97 min, MS (ESIPos) m/z=247.9 [M+H]+.
Figure imgf000101_0001
[0267] 3-nitro-5-(2,2,2-trifluoroethyl)pyridine (Int i-73, 3.04 g, 14.75 mmol) was dissolved in EtOH (100 mL) and 10% Pd/C (785 mg) was added. The resulting mixture was stirred under a hydrogen atmosphere for 18 h. The mixture was then filtered over Celite®, washed with EtOH (4 x 50 mL) and the filtrate was concentrated at reduced pressure to give the title compound (2.66 g, quantitative yield) as a brown oil. LCMS (Method D) rt= 1.08 min, MS (ESIPos) m/z= 176.8 [M+H]+
[0268] In analogy to the procedure described for Int i-87, the following intermediates were prepared using the appropriate nitro group containing starting materials.
Figure imgf000101_0002
Figure imgf000102_0002
[0269] In analogy to the procedure described for Int i-87, the following intermediate was prepared using
2-amino-3-nitro-5-(trifluoromethyl)benzoic acid (Int i-157).
Figure imgf000102_0003
Figure imgf000102_0001
[0270] A solution of 6-(trifhioromethyl)benzene-l,2,4-triamine (Int i-89, 350 mg, 1.83 mmol) in 4 M aq. HC1 (7.5 mL) and formic acid (1.5 mL) was stirred at RT for 18 h. The reaction mixture was concentrated at reduced pressure giving the title compound (550 mg, quantitative yield). This was used without further purification. LCMS (Method D) rt = 0.32 min, MS (ESIPos) m/z= 202 [M+H]+
[0271] In analogy to the procedure described for Int i-98, the following intermediates were prepared using the appropriately substituted 1,2-bisaniline starting materials.
Figure imgf000103_0003
[0272] In analogy to the procedure for Int i-98, the following intermediate was prepared using
2,3-diamino-5-(trifluoromethyl)benzoic acid (Int i-158) and formic acid.
Figure imgf000103_0002
1.1.32. Int i-104: 4-methyl-N-[ 5-(trifluoromethyl)pyridin-3-yl]-l,2,3,4-tetrahydroisoquinoline-
7-carboxamide
Figure imgf000103_0001
[0273] Methyl 4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (Int i-7, 750 mg, 2.49 mmol) and 5-(trifhioromethyl)pyridin-3-amine (444 mg, 2.74 mmol) were dissolved in THF (30 mL) and cooled to 0 °C. KOtBu (1.68 g of a 20% wt solution in THF, 2.99 mmol) was added dropwise giving a dark red solution. The mixture was allowed to warm to RT and stirred for 1 h. Sat. aq. K2CO3 solution (30 mL) was then added and the mixture was stirred rapidly for 1 h. The mixture was concentrated at reduced pressure to remove excess THF, diluted with EtOAc (50 mL), washed with brine (3 x 20 mb), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (50 g KP Sil cartridge, using a gradient of eluents; 99: 1 to 7:3 DCM:MeOH) giving the title compound (410 mg, 50% yield) as an off white solid. LCMS (Method D) rt = 0.84 min, MS (ESIPos) m/z=336.0 [M+H]+
[0274] In analogy to the procedure described for Int i-104, the following intermediates were prepared using the appropriately substituted methyl 2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinoline-7- carboxylate and aniline starting materials.
Figure imgf000104_0002
1.1.33. Int i-109: tert-butyl 7-{[5-(2-fluoropropan-2-yl)pyridin-3-yl]carbamoyl}-4-methyl-
Figure imgf000104_0001
[0275] 2-[(tert-butoxy)carbonyl]-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (Int i-9, 150 mg, 0.51 mmol) and 5-(2-fhioropropan-2-yl)pyridin-3-amine (Int i-65, 79 mg, 0.51 mmol) were dissolved in DMF (2 mL) and DIPEA (0.22 mL, 1.24 mmol) and HATU (235 mg, 0.62 mmol) were added. The reaction was stirred at RT overnight. The mixture was then concentrated at reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with brine (3 x 20 mL), dried (Na2SO.0, filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (10 g KP Sil cartridge, using a gradient of eluents; 95:5 heptane :EtO Ac to 100% EtOAc) giving the title compound (190 mg, 86% yield). LCMS (Method D) rt = 1.24 min, MS (ESIPos) m/z=428.1[M+H]+ [0276] In analogy to the procedure described for Int i-109, the following intermediates were prepared using the appropriate 2-[(tert-butoxy)carbonyl]-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and aniline starting materials.
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
1.1.34. Int i-127: N-[5-(2-fluoropropan-2-yl)pyridin-3-yl]-4-methyl-l, 2,3,4- tetrahydroisoquinoline-7-carboxamide
[0277] To a solution of tert-butyl 7-{[5-(2-fluoropropan-2-yl)pyridin-3-yl]carbamoyl}-4-methyl-l, 2,3,4- tetrahydroisoquinoline-2-carboxylate (Int i-109, 190 mg, 0.44 mmol) in 1,4-dioxane (5 mL) was added 4 M HC1 in 1,4-dioxane (3.3 mL, 13.3 mmol). The resulting mixture was stirred at RT for 4 h then concentrated at reduced pressure. The residue was purified using a 2 g Biotage ISOLUTE® SCX-2 column (eluting with 2 M ammonia in MeOH) giving the title compound (105 mg, 72% yield) as a colourless oil. LCMS (Method D) rt = 0.46 min, MS (ESIPos) m/z=328.0
[0278] In analogy to the procedure described for Int i-127, the following intermediates were prepared using the appropriate tert-butyloxycarbonyl (Boc) protected starting materials and a strong acid (i.e. HC1 or TFA). Selected examples were isolated as the acid salts.
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
1.1.35. Int i-142: 4-methyl-N-[5-(trifluoromethyl)-lH-l,3-benzodiazol-7-yl]-l, 2,3,4-
Figure imgf000112_0001
[0279] A solution of tert-butyl 7-{[2,3-diamino-5-(trifluoromethyl)phenyl]carbamoyl}-4-methyl-l, 2,3,4- tetrahydroisoquinoline-2 -carboxylate (Int i-122, 398 mg, 0.86 mmol) in 4 M HC1 (7.5 mb) and formic acid (1.5 mL) was heated at 60 °C and stirred at this temperature for 30 min. The reaction mixture was then cooled to RT and concentrated at reduced pressure. The residue was diluted with sat. aq Na2CC>3 (40 mL) and extracted with EtOAc (2 x 40 mL). The organic extracts were combined, dried over Na2SC>4, filtered and concentrated at reduced pressure. The residue was purified by preparative column chromatography (Method 1) to obtain the title compound (63 mg, 20% yield) as an off-white powder. LCMS (Method D), rt = 0.91 min, MS (ESIPos) m/z = 374.9 [M+H]+
[0280] In analogy to the procedure described for Int i-142, the following intermediate was prepared using tert-butyl 7-{[2,3-diamino-5-(propan-2-yl)phenyl]carbamoyl}-4-methyl-l,2,3,4-tetrahydroisoquinoline-2- carboxylate (Int i-123), HC1 and formic acid.
Figure imgf000112_0003
Figure imgf000112_0002
[0281] 2,2,2-trifluoro-N-[(2R)-2-phenylpropyl]acetamide (Int i-10, 15.7 g, 67.9 mmol) was dissolved in cone, sulfuric acid (50 mL) and cooled to 0 °C. Cone nitric acid (4.4 mL, 63.7 mmol) was then added dropwise and the internal temperature was maintained below 10 °C. On complete addition the mixture was stirred for 30 min at 0 °C. The mixture was then poured onto ice water (250 mL) and then extracted with MTBE (300 mL). The organics were washed with brine (2 x 100 mL), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (340 g Silica column, using a gradient of eluents; 92:8 to 60:40 heptane:MTBE) giving the title compound (10.6 g, 56% yield) as a white solid. LCMS (Method D) rt =1.14 min, MS (ESINeg) m/z=274.9 [M-H]-
1.1.37. Int i-145: 2,2,2-trifluoro-l-[(4R)-4-methyl- 7-nitro- 1,2, 3, 4-tetrahy dr oisoquinolin-2- yl]ethan-l-one
; 6 , o
[0282] 2,2,2-trifluoro-N-[(2R)-2-(4-nitrophenyl)propyl]acetamide (Int i-144, 10.6 g, 38.4 mmol) was dissolved in cone, sulfuric acid (75 mL) and cooled to 0 °C. To this was added paraformaldehyde (5.76 g, 192 mmol). The reaction was allowed to warm to RT and then stirred overnight. The mixture was poured into ice water (400 mL) and then extracted with MTBE (400 mL). The organics were then washed with brine (2 x 100 mL), dried (Na2SC>4), fdltered and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (340 g Silica column, using a gradient of eluents; 92:8 to 60:40 heptane :EtO Ac) giving the title compound (9.6 g, 87% yield) as a pale yellow oil.
‘H NMR (500 MHz, chloroform-d) 5 8.21 - 7.98 (m, 2H), 7.47 - 7.35 (m, 1H), 5.07 - 4.70 (m, 2H), 3.97 - 3.63 (m, 2H), 3.27 - 3.06 (m, 1H), 1.40 - 1.33 (m, 3H).
LCMS (Method D) rt = 1.20 min, the product did not ionize.
1.1.38. Int i-146: l-[(4R)-7-amino-4-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl]-2,2,2- trifluoroethan-l-one
Figure imgf000113_0001
[0283] 2,2,2-trifluoro-l-[(4R)-4-methyl-7-nitro-l,2,3,4-tetrahydroisoquinolin-2-yl]ethan-l-one (Int i- 145, 7.2 g, 25.0 mmol) was stirred in EtOH (100 mL) and 10% Pd/C (1.3 g) was added. The resulting mixture was stirred under a hydrogen atmosphere for 4 h. The mixture was filtered over Celite® and then concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (340 g Silica column, using a gradient of eluents; 90: 10 heptane:MTBE to 100% MTBE) giving the title compound (5.2 g, 81% yield) as an off white solid. LCMS (Method D) rt = 0.84 min, MS (ESIPos) m/z=258.9 [M+H]+
1.1.39. Int i-147: (4R)-4-methyl-7-nitro- 1,2, 3, 4-tetrahy droisoquinoline
Figure imgf000113_0002
[0284] To a solution of 2,2,2-trifhioro-l-[(4R)-4-methyl-7-nitro-l,2,3,4-tetrahydroisoquinolin-2-yl]ethan- 1-one (Int i-145, 1.96 g, 6.81 mmol) in MeOH (20 mL) and water (10 mL) was added K2CO3 (1.41 g, 10.22 mmol). The resulting suspension was left stirring at RT for 4 h. The mixture was then concentrated at reduced pressure to remove excess MeOH then diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried over Na2SC>4, filtered and concentrated at reduced pressure to obtain the title compound (1.07 g, 82% yield) as a pale yellow solid. This was used without further purification. LCMS (Method D) rt = 0.44 min, MS (ESIPos): m/z = 192.85 (M+H)+
Figure imgf000114_0001
[0285] 5 -bromopyridine -3 -carbaldehy de (2.0 g, 10.75 mmol) and CsF (1.6 g, 10.75 mmol) were stirred in THF (50 mL) and cooled to -20 °C. Trimethyl(trifluoromethyl)silane (1.59 mL, 10.75 mmol) was then added dropwise and the internal temperature was maintained below -10 °C. After 30 min the mixture was allowed to warm to RT. 2 M aq. HC1 (50 mL) was added to the mixture and this was rapidly stirred at RT for 10 min. The mixture was concentrated at reduced pressure to remove excess THF. The remaining aqueous layer was extracted with EtOAc (50 mL) and then washed with brine (50 mL), dried (Na2SO.0 and concentrated at reduced pressure to give the title compound (1.52 g, 55% yield) as an off white solid. This was used without further purification. LCMS (Method D) rt = 0.97 min, MS (ESIPos) m/z=255.8 & 257.7 (M+H)+
1.1.41. Int i-151: [l-(5-bromopyridin-3-yl)-2,2,2-trifluoroethoxy](methylsulfanyl)methane thione
Figure imgf000114_0002
[0286] To a stirred solution of l-(5-bromopyridin-3-yl)-2,2,2-trifluoroethan-l-ol (Int i-150, 2.0 g, 7.81 mmol) in dry THF (40 mL) was added sodium hydride (625 mg of a 60% dispersion in mineral oil, 15.62 mmol) portionwise at 0 °C under a nitrogen atmosphere. After stirring at RT for 1 h at this temperature, carbon disulfide (0.94 mL, 15.62 mmol) was added to the reaction mixture dropwise and the mixture was stirred for a further 1 h at 0 °C. To the resulting reaction mixture was then added iodomethane (0.97 mL, 15.62 mmol) at 0 °C. The mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched with ice water and extracted with DCM (2 x 100 mL). The combined organic extracts were dried (Na2S04) and concentrated under reduced pressure to give the title compound (300 mg, quantitative yield). This was used without further purification. LCMS (Method D) rt = 1.37 min, MS (ESIPos): m/z = 345.85 / 347.85 (M+H)+.
Figure imgf000115_0001
[0287] To a stirred solution of [l-(5-bromopyridin-3-yl)-2,2,2- trifluoroethoxy](methylsulfanyl)methanethione (Int i-151, 2.7 g) in dry toluene (20 mL) was added tri-n- butyltin hydride (3.15 mL, 11.72 mmol) followed by AIBN (192 mg, 1.172 mmol) at RT under inert atmosphere. The reaction mixture was gradually heated to 90 °C and stirred for 2 h. The mixture was then cooled to RT, concentrated at reduced pressure and then purified directly via Biotage Isolera™ column chromatography (using a gradient of eluents; 0-10% EtOAc/Hexane) giving the title compound (1.5 g, 72% yield) as a pale-yellow liquid. LCMS (Method D) rt = 1.09 min, MS (ESIPos): m/z = 239.85 / 241.85 (M+H)+.
Figure imgf000115_0002
[0288] 3-bromo-5-(2,2,2-trifluoroethyl)pyridine (Int i-152, 1.5 g, 6.25 mmol) was dissolved in MeOH (100 mL) and TEA (5.2 mL, 37.5 mmol) was added followed by PdC12(dppf) DCM adduct (255 mg, 0.31 mmol). The resulting mixture was heated overnight at 80 °C in a pressurised vessel under an atmosphere of carbon monoxide (100 psi). The mixture was then cooled to RT, concentrated at reduced pressure and the residue was dissolved in EtOAc (150 mL) and passed through a silica plug. The fdtrate was then washed with 1 M aq. HC1 (50 mL), sat. aq. NaHCCL (50 mL), brine (50 mL), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was redissolved in MeOH (100 mL) and TEA (5.2 mL, 37.5 mmol) was added followed by PdC12(dppf) DCM adduct (255 mg, 0.312 mmol). The resulting mixture was heated again overnight at 80 °C in a pressurised vessel under an atmosphere of carbon monoxide (100 psi). The mixture was then cooled to RT, concentrated at reduced pressure and the residue was dissolved in EtOAc (150 mL) and passed through a silica plug. The filtrate was then washed with 1 M aq. HC1 (50 mL), sat. aq. NaHCO; (50 mL), brine (50 mL), dried (Na2SO.0 and concentrated at reduced pressure. The residue was purified via Biotage Isolera™ column chromatography (100 g KP Sil cartridge, using a gradient of eluents; 9: 1 to 3:7 heptane: EtOAc) giving the title compound (918 mg, 65% yield) as a white solid. LCMS (Method D) rt = 0.99 min, MS (ESIPos) m/z= 219.80 [M+H]+
Figure imgf000116_0001
[0289] Methyl 5-(2,2,2-trifluoroethyl)pyridine-3-carboxylate (Int i-153, 918 mg, 0.934 mmol) was dissolved in THF (20 mL) and 2 M aq. LiOH (2.1 mL, 4.26 mmol, 1.05 eq.) was added. The resulting mixture was stirred at 60 °C for 6 h then cooled to RT and concentrated at reduced pressure to give the title compound (857 mg, quantitative yield) as an orange gum. This was used without further purification.
LCMS (Method D) rt = 0.76 min, MS (ESIPos) m/z= 205.85 [Mass of carboxylic acid +H]+
1.1.45. Int i-157: 2-amino-3-nitro-5-(trifluoromethyl)benzoic acid
Figure imgf000116_0002
[0290] 2-chloro-3-nitro-5-(trifluoromethyl)benzoic acid (500 mg, 1.85 mmol) was dissolved in 35% aq. ammonia (2.5 mL, 37 mmol) and the mixture heated in a sealed tube at 120 °C for 1 h. The mixture was then cooled to RT, acidified to pHl using 1 M aq. HC1 and the product precipitated as a pale yellow solid. This was filtered and washed with water. The residue was then dissolved in EtOAc (50 mL), washed with brine (2 x 20 mL), dried (Na2SO4), filtered and concentrated at reduced pressure giving the title compound (410 mg, 88% yield) as a pale yellow soild. This was used in the next step without any further purification. 1H NMR (250 MHz, DMSO-t/6) 5 8.82 (s, 2H), 8.51 (m, 1H), 8.34 (m, 1H).
1.1.46. Int i-160: N-[(4R)-4-methyl-2-(2,2,2-trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin- 7- yl]-5-(trifluoromethyl)pyridine-3-carboxamide
Figure imgf000116_0003
[0291] l-[(4R)-7-amino-4-methyl-l,2,3,4-tetrahydroisoquinolin-2-yl]-2,2,2-trifluoroethan-l-one (Int i- 146, 502 mg, 1.94 mmol) and 5 -(trifluoromethyl)pyridine -3 -carboxylic acid (408 mg, 2.14 mmol) were dissolved in DCM (10 mL) and HATU (813 mg, 2.14 mmol) and DIPEA (1.01 mL, 5.83 mmol) were added. The resulting mixture was stirred at RT overnight. Saturated aq. NazCCL (10 mL) was then added and the aqueous layer was extracted with DCM (2 x 10 mL). The organic layers were combined, dried (MgSCfi). filtered and concentrated at reduced pressure. The residue obtained was purified by flash chromatography on a Biotage Isolera™ 4 system. (50 g KP-Sil cartridge; eluting with 20% EtOAc in heptane (0 to 1 column volume (CV)) then a gradient of eluents: 20% to 100% MeOH in DCM (1 to 11 CV)) to give the title compound (633 mg, 71% yield) as a white solid. LCMS (Method D) rt = 1.26 min, MS (ESIPos): m/z = 431.95 (M+H)+.
[0292] In analogy to the procedure described for Int i-160, the following intermediate was prepared using 1 -[(4R)-7-amino-4-methyl- 1 ,2,3,4-tetrahydroisoquinolin-2-yl] -2,2,2-trifluoroethan- 1 -one (Int i- 146) and the appropriate carboxylic acid starting material.
Figure imgf000117_0002
1.1.47. Int i-164: N-[(4R)-4-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl]-5-
(trifluoromethyl)pyridine-3-carboxamide
Figure imgf000117_0001
[0293] To a solution of N-[(4R)-4-methyl-2-(trifluoroacetyl)-l,2,3,4-tetrahydroisoquinolin-7-yl]-5- (trifluoromethyl)pyridine -3 -carboxamide (Int i-160, 633 mg, 1.47 mmol) in MeOH (20 mL) and water (10 mL), was added K2CO3 (304 mg, 2.20 mmol). The resulting suspension was stirred at RT for 18 h. The mixture was then concentrated at reduced pressure to remove excess MeOH, diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extract was dried (Na2SO.0, fdtered and concentrated at reduced pressure to give the title compound (492 mg, quantitative yield) as a white solid. This was used without further purification.
[0294] LCMS (Method D) rt = 0.84 min, MS (ESIPos): m/z = 335.90 (M+H)+
[0295] In analogy to the procedure described for Int i-164, the following intermediates were prepared using the appropriate trifluoroacetamide containing starting materials.
Figure imgf000118_0002
1.1.48. Int i-173: 2-chloro-N-(2-hydroxyethyl)acetamide
Figure imgf000118_0001
[0296] Chloroacetyl chloride (358 pL, 4.5 mmol) in DCM (1 mL) was added dropwise at 0 °C to a solution of 2-aminoethanol (247 pL, 4.09 mmol) in water (1 mL). Sodium hydroxide (4.5 mL of a 1 M aq. solution, 4.5 mmol) was then added dropwise and the reaction mixture. The reaction mixture was allowed to warm to RT and then stirred for 5 h. Excess DCM was then removed under reduced pressure then the remaining aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried (Na2SC>4), fdtered and concentrated under reduced pressure to give the title compound (236 mg, 42% yield) as a colourless oil. This was used without further purification. ’H NMR (500 MHz, chloroform- ) 5 7.02 (br. s, 1H), 4.08 (s, 2H), 3.78 (m, 2H), 3.53 - 3.48 (m, 2H), 2.19 (br. s, 1H).
[0297] In analogy to the procedure described for Int i-173, the following intermediate was prepared using chloroacetyl chloride and l-(aminomethyl)cyclopropanol.
Figure imgf000119_0003
Figure imgf000119_0001
[0298] Piperidine-2, 4-dione (10.0 g, 88.4 mmol), trimethoxymethane (18.76 g, 176.8 mmol) and 4- methylbenzenesulfonic acid (3.8 g, 22.1 mmol) were stirred in MeOH (440 mL) and the resulting solution was heated at 70 °C for 6 h. After this time, the mixture was concentrated at reduced pressure to give the title compound (16.55 g, quantitative yield) as a thick brown oil. This was used without further purification. 1H NMR (500 MHz, chloroform- ) 5 7.03 (m, 1H), 5.12 (m, 1H), 3.74 (s, 3H), 3.49 (m, 2H), 2.50 (m, 2H).
1.1.50. Int i-176: 4-methoxy-l-methyl-l,2,3,6-tetrahydropyridin-2-one
Figure imgf000119_0002
[0299] Sodium hydride (389 mg of a 60% dispersion in mineral oil, 9.95 mmol) was added to a suspension of 4-methoxy-l,2,5,6-tetrahydropyridin-2-one (Int i-175, 633 mg, 4.98 mmol) in DMF (20 mL) with ice cooling. The reaction mixture was stirred for 5 min then iodomethane (0.34 mL, 5.48 mmol) was added. The reaction mixture was then allowed to warm to RT and stirred for 16 h. The mixture was then diluted with sat. aq. ammonium chloride solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (Na2SO.0, filtered and concentrated. The product was purified via flash chromatography on a Biotage Isolera™ 4 system (50 g KP-Sil column; eluting with a gradient of eluents; 100% DCM to 97:3 DCM:MeOH) to give the title compound (514 mg, 71% yield) as a yellow viscous oil. 1H NMR (500 MHz, chloroform- ) 5 5.10 (m, 1H), 3.66 (s, 3H), 3.38 (m, 2H), 2.95 (s, 3H), 2.47 (m, 2H). [0300] In analogy to the procedure described for Int i-176, the following intermediates were prepared using 4-methoxy-l,2,3,6-tetrahydropyridin-2-one and the appropriate alkylating agent.
Figure imgf000120_0002
Figure imgf000120_0001
[0301] 4-methoxy-l -methyl- 1,2, 5, 6-tetrahydropyridin -2-one (Int i-176, 259 mg, 1.84 mmol) was dissolved in THF (3 mL) and 5 M aq. HC1 (3 mL, 15 mmol) was added. The resulting mixture was stirred at RT for 4 h. The mixture was then basified to pH9 using a sat. aq. NazCCL solution and the aqueous layer was extracted with DCM (3 x 20 mL). The organic layers were combined and dried over MgSCL, filtered and concentrated at reduced pressure to give the title compound (191 mg, 81% yield) as a yellow oil. This was used without further purification. JH NMR (250 MHz, chloroform- ) 5 3.58 (m, 2H), 3.34 (m, 2H), 3.08 (s, 3H), 2.66 (m, 2H).
[0302] In analogy to the procedure described for Int i-180, the following intermediates were prepared using the appropriate N-substituted 4-methoxy-l, 2, 3, 6-tetrahydropyridin-2-one starting materials. WO 2022/128850 lzu PCT/EP2021/085377
Figure imgf000121_0003
1.1.52. Int i-184: 3-(4-methyl-7-{[5-(trifluoromethyl)pyridin-3-yl]carbamoyl}-l, 2,3,4-
Figure imgf000121_0001
[0303] AcOH (14 pL, 0.25 mmol) was added to a solution of 4-methyl-N-[5 -(trifluoromethyl )pyridin-3- yl]-l,2,3,4-tetrahydroisoquinoline-7-carboxamide (Int i-104, 35 mg, 0.104 mmol) and 3-oxocyclobutane- 1-carboxylic acid (64 mg, 0.56 mmol) in MeOH (2 mb). The reaction mixture was stirred at RT for 5 min and NaBH3(CN) (35 mg, 0.56 mmol) was added. The reaction mixture was then stirred and heated at 70 °C overnight in a sealed tube. The following day the mixture was cooled to RT and concentrated at reduced pressure. The residue was purified directly via preparative HPLC (Method 1) giving the title compound (4 mg, 8% yield) as a white solid. The title compound was isolated as a single diastereoisomer (the relative stereochemistry is unknown).
LCMS (Method A) rt = 1.87 min, MS (ESIPos) m/z= 434.2 [M+H]+.
1.1.53. Int i-185: 3-(4-methyl-7-{[5-(trifluoromethyl)pyridin-3-yl]carbamoyl}-l,2,3,4-
Figure imgf000121_0002
[0304] Preparative HPLC (Method 1) purification of the reaction mixture obtained in Example 1.1.52 also gave the title product (2 mg, 4% yield) as a white solid (eluting after Int i-184). The title compound was isolated as a single diastereoisomer (the relative stereochemistry is unknown).
LCMS (Method A) rt = 1.87 min, MS (ESIPos) m/z= 434.2 [M+H]+.
1.2. Synthesis of compounds of the invention
1.2.1. Cpd 1
Figure imgf000122_0001
[0305] To a stirred solution of methyl 4-methyl-2-(l -methyl -2 -oxopiperidin-4-yl)-l, 2,3,4- tetrahydroisoquinoline-7-carboxylate (Int i-52, 64 mg, 0.20 mmol) and l-methyl-7-
(trifluoromethyl)benzimidazol-5-amine (Int i-99, 44 mg, 0.20 mmol) in THF (5.0 mL), potassium tert- butoxide (0.44 mL of a 1 M solution in THF, 0.44 mmol) was added dropwise. The mixture was stirred at RT for 2 h. Water (10 mL) was added to the mixture and 1 M aq. HC1 was added until pH 9 was reached. The aq. layer was extracted with EtOAc (50 mL) and the organics were then washed with brine (2 x 20 mL), dried (Na2SC>4), fdtered, and concentrated at reduced pressure. The product was purified by preparative HPLC (Method 1), giving the desired product (9 mg, 9% yield) as a white solid. LCMS (Method
A) rt = 1.72 min, MS (ESIPos): m/z = 500.4 [M+H]+.
1.2.2. Cpd 2
Figure imgf000122_0002
[0306] To a solution of lithio 4-methyl-2-(l-methyl-2-oxopiperidin-4-yl)-l,2,3,4-tetrahydroisoquinoline- 7-carboxylate (Int i-53, 40 mg, 0.13 mmol) and l-methylindazol-3-amine (19.1 mg, 0.13 mmol) in DMF (1 mL) was added DIPEA (54.24 pL, 0.31 mmol) and HATU (59.2 mg, 0.16 mmol). The resulting mixture was stirred at RT for 64 h, then diluted with water (10 mL), extracted with EtOAc (2 x 10 mL), dried (Na2SO4), filtered, and concentrated at reduced pressure. The crude mixture was purified directly via preparative HPLC (Method 2) to give the title compound (3.2 mg, 5.1% yield) as an off-white solid. LCMS (Method A) rt = 1.6 min, MS (ESIPos): m/z = 432.4 (M+H)+. 1.2.3. Cpd 3
Figure imgf000123_0001
[0307] 4-methyl-N-[5-(trifluoromethyl)pyridin-3-yl]-l,2,3,4-tetrahydroisoquinoline-7-carboxamide
(Int i-104, 100 mg, 0.3 mmol), 2-bromoacetamide (41 mg, 0.3 mmol) and K2CO3 (123 mg, 0.89 mmol) were stirred in ACN (4 mb) and the resulting solution was heated at 50 °C for 4 h. The mixture was then cooled to RT, diluted with EtOAc (30 mb) and washed with water (3 x 10 mb) and brine (10 mb), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was purified via preparative HPLC (Method 1) giving the title compound (70 mg, 59% yield) as a white solid. LCMS (Method D) rt = 1.65 min, MS (ESIPos) m/z=393.2
[0308] In analogy to the procedure described for Cpd 3, the following compounds were prepared using the appropriate amine starting material and alkylating agent.
Figure imgf000123_0002
Figure imgf000124_0002
.2.4. Cpd 5 (alternative synthesis)
Figure imgf000124_0001
[0309] To a solution of Int i-140 as a free base (1.15 g, 3.29 mmol, 1 eq.) in ACN (16.5 mL) were added K2CO3 (910 mg, 6.58 mmol, 2.0 eq.) and 2-bromoacetamide (562 mg, 3.95 mmol, 1.3 eq.). The mixture was stirred at RT for 16 h and was then diluted with DCM and water. Some solids were present between the phases, they were gathered with the organic layer and the mixture was concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH, 10/0 to 9/1) to afford Cpd 5.
1.2.5. Cpd 11
Figure imgf000125_0001
[0310] 4-methyl-N-[5-(trifluoromethyl)pyridin-3-yl]-l,2,3,4-tetrahydroisoquinoline-7-carboxamide (Int i-104, 35 mg, 0.1 mmol) was dissolved in ACN (2 mL) and K2CO3 (15 mg, 0.11 mmol) and 3- chloropropanamide (11 mg, 0.1 mmol) were added and the resulting mixture was heated in a sealed tube at 90 °C for 3 h. The mixture was twice retreated with K2CO3 (15 mg, 0.11 mmol) and 3-chloropropanamide (11 mg, 0. 1 mmol) and heated for a further 6 h at 90 °C after each addition of reagents. The mixture was then cooled to RT, diluted with EtOAc (30 mL), washed with water (3 x 10 mL) and brine (10 mL), dried (Na2SC>4), filtered and concentrated at reduced pressure. The residue was purified via preparative HPLC (Method 1) giving the title compound (10 mg, 22% yield) as a white solid. LCMS (Method A) rt = 1.67 min, MS (ESIPos) m/z=407.2 [M+H]+.
[0311] In analogy to the procedure described for Cpd 11, the following examples was prepared using the appropriate amine starting material and alkylating agent.
Figure imgf000125_0002
Figure imgf000126_0001
Figure imgf000127_0002
1.2.6. Cpd 26
Figure imgf000127_0001
[0312] N-[5-(l,l-difluoropropyl)pyridin-3-yl]-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxamide (Int i-131, 87 mg, 0.25 mmol) and l-methylpiperidine-2, 4-dione (Int i-180, 80 mg, 0.63 mmol) were dissolved in MeOH (5 mL) and AcOH (4 drops) was added. The mixture was stirred at RT for 5 min and NaBHdCN) (40 mg, 0.63 mmol) was added. The mixture was stirred overnight at 70 °C in a sealed tube. The mixture was concentrated at reduced pressure, diluted with EtOAc (30 mL), washed with a sat. aq. NaHCCh solution (10 mL) and brine (2 x 10 mL), dried (Na2SC>4), filtered, and concentrated at reduced pressure. The residue was purified via preparative HPLC (Method 1) giving the title compound (58 mg, 49% yield) as a white solid. The product was isolated as a mixture of stereoisomers. LCMS (Method A) rt = 1.80 min, MS (ESIPos) m/z= 457.3 [M+H]+
[0313] In analogy to the procedure described for Cpd 26, the following compounds were prepared via reductive amination using the appropriate amine and ketone or aldehyde starting materials.
Figure imgf000127_0003
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0002
1.2.7. Cpd 35
Figure imgf000131_0001
[0314] To a solution of 2-[l-(2-methoxyethyl)-2-oxopiperidin-4-yl]-4-methyl-N-[5-
(trifluoromethyl)pyridin-3-yl]-l,2,3,4-tetrahydroisoquinoline-7-carboxamide (Int i-193, 146 mg, 0.30 mmol) in DCM (2 mL) at 0 °C was added boron tribromide (298 pL of a 1 M solution in DCM, 0.30 mmol). The resulting solution was allowed to warm to RT then stirred for 4 h. The mixture was then quenched with water (2 mL), stirred at RT for 18 h then extracted with DCM (3 x 5 mL). The organic layers were combined, dried over MgSCL, filtered and concentrated at reduced pressure. The residue obtained was WO 2022/128850 I J I PCT/EP2021/085377 purified via preparative HPLC (Method 1) giving the title compound (33 mg, 23% yield) as a yellow oil. LCMS (Method B) rt = 2.87 min, MS (ESIPos) m/z= 477.1 [M+H]+.
[0315] In analogy to the procedure described for Cpd 35, the following compounds were prepared using the appropriate ether starting material and boron tribromide.
Figure imgf000132_0002
1.2.8. Cpd 36
Figure imgf000132_0001
[0316] A solution of 3-(4-methyl-7-{[5-(trifluoromethyl)pyridin-3-yl]carbamoyl}-l, 2,3,4- tetrahydroisoquinolin-2-yl)cyclobutane-l -carboxylic acid (a 1:1 mixture of Int i-184 & Int i-185, 253 mg, 0.58 mmol) in EtOAc (2.5 mL) was treated with CDI (122 mg, 0.75 mmol) and stirred at RT for 4 h. After this time the mixture was treated with a 30% aq. ammonia solution (98 mg, 2.889 mmol) and stirred at RT for 18 h. The mixture was concentrated at reduced pressure then purified directly via preparative HPLC (Method 1) to give the title compound (12 mg, 5 % yield) as a white solid.
LCMS (Method B) rt = 3.00 min, MS (ESIPos) m/z= 433.0 [M+H]+. 1.2.9. Cpd 37
Figure imgf000133_0001
[0317] Preparative HPLC (Method 1) purification of the reaction mixture obtained in Example 1.2.8 also gave the title product (80 mg, 32% yield) as a white solid.
LCMS (Method B) rt = 2.96 min, MS (ESIPos) m/z= 433.0 [M+H]+.
1.2.10. Cpd 38
[0318] Cpd 6 (15 mg) was separated into two enantiomers by preparative chiral supercritical fluid chromatography (SFC) (70:30 CO2:MeOH with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound in 60% enantiomeric excess (ee). Chiral SFC analysis: (70:30 CO2:MeOH with Chiralcel OD-H 25 cm column at 4 mL/min) rt = 3.77 min, MS (ESIPos) m/z= 393.2 [M+H]+.
1.2.11. Cpd 39
[0319] Cpd 6 (15 mg) was separated into two enantiomers by preparative chiral supercritical fluid chromatography (SFC) (70:30 CO2:MeOH with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound in 80% ee. Chiral SFC analysis: (70:30 CO2:MeOH with Chiralcel OD-H 25 cm column at 4 mL/min) rt = 5.72 min, MS (ESIPos) m/z= 393.1 [M+H]+ .
1.2.12. Cpd 40
[0320] Cpd 9 (36 mg) was separated into pure enantiomers by preparative chiral SFC (75:25 CO2:MeOH using Chiralpak AS-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:MeOH using Chiralpak AS-H 25 cm column at 4 mL/min) rt = 6.18 min, MS (ESIPos) m/z= 432.1 [M+H]+.
1.2.13. Cpd 41
[0321] Cpd 9 (36 mg) was separated into pure enantiomers by preparative chiral SFC (75:25 CO2:MeOH using Chiralpak AS-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:MeOH using Chiralpak AS-H 25 cm column at 4 mL/min) rt = 11.17 min, MS (ESIPos) m/z= 432.1 [M+H]+.
1.2.14. Cpd 43
[0322] Cpd 42 (60 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (70:30 CC>2:MeOH+0.5% IP Am using Chiralpak IA 5 pm 250 x 20 mm column at 50 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CC>2:MeOH+0.5% IP Am using Chiralpak IA 5 pm 250 x 4.6 mm column at 2.4 mL/min) rt = 15.4 min. 1.2.15. Cpd 44
[0323] Cpd 42 (60 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (70:30 CC>2:MeOH+0.5% IP Am using Chiralpak IA 5 pm 250 x 20 mm column at 50 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CC>2:MeOH+0.5% IP Am using Chiralpak IA 5 pm 250 x 4.6 mm column at 2.4 mL/min) rt = 21.7 min.
1.2.16. Cpd 46
[0324] Cpd 45 (100 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (70:30 CO2:IPA + 0.2% DEA Chiralcel OJ-H at 15 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CO2:IPA + 0.2% DEA Chiralcel OJ-H) rt = 6.66 min, MS (ESIPos) m/z= 469.1 [M+H]+.
1.2.17. Cpd 48
[0325] Cpd 47 (117 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 EtOH:MeOH using Chiralpak AD-H 25 cm column at 18 mL/min) giving the title compound. Chiral LCMS analysis: (50:50 EtOH:MeOH using Chiralpak AD-H 25 cm column at 1 mL/min) rt = 26.03 min, MS (ESIPos) m/z= 491.1 [M+H]+.
1.2.18. Cpd 49
[0326] Cpd 47 (117 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 EtOH:MeOH using Chiralpak AD-H 25 cm column at 18 mL/min) giving the title compound. Chiral LCMS analysis: (50:50 EtOH:MeOH using Chiralpak AD-H 25 cm column at 1 mL/min) rt = 41.41 min, MS (ESIPos) m/z= 491.1 [M+H]+.
1.2.19. Cpd 50
[0327] Cpd 18 (50 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CCLIPA with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CCLIPA with Chiralcel OD-H 25 cm column at 4 mL/min) rt=6.48 min, MS (ESIPos) m/z= 447.0 [M+H]+.
1.2.20. Cpd 51
[0328] Cpd 18 (50 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CO2:IPA with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:IPA with Chiralcel OD-H 25 cm column at 4 mL/min) rt=7.64 min, MS (ESIPos) m/z= 447.0 [M+H]+.
1.2.21. Cpd 52
[0329] Cpd 18 (50 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CO2:IPA with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:IPA with Chiralcel OD-H 25 cm column at 4 mL/min) rt=13.83 min, MS (ESIPos) m/z= 447.0 [M+H]+. 1.2.22. Cpd 53
[0330] Cpd 18 (50 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CChlPA with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:IPA with Chiralcel OD-H 25 cm column at 4 mL/min) rt=15.02 min, MS (ESIPos) m/z= 447.0 [M+H]+.
1.2.23. Cpd 54
[0331] Cpd 22 (17 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=4.44 min, MS (ESIPos) m/z= 421.2 [M+H]+.
1.2.24. Cpd 55
[0332] Cpd 22 (17 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=4.76 min, MS (ESIPos) m/z= 421.2 [M+H]+.
1.2.25. Cpd 56
[0333] Cpd 22 (17 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=6.57 min, MS (ESIPos) m/z= 421.2 [M+H]+.
1.2.26. Cpd 57
[0334] Cpd 22 (17 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=7.22 min, MS (ESIPos) m/z= 421.2 [M+H]+.
1.2.27. Cpd 59
[0335] Cpd 58 (37 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (70:30 CO2:EtOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CO2:EtOH with Chiralpak IC 25 cm column at 4 mL/min) rt=l 1.09 min, MS (ESIPos) m/z= 445.1 [M+H]+.
1.2.28. Cpd 60
[0336] Cpd 58 (37 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (70:30 CO2:EtOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CCL EtOH with Chiralpak IC 25 cm column at 4 mL/min) rt=13.04 min, MS (ESIPos) m/z= 445.1 [M+H]+. 1.2.29. Cpd 61
[0337] Cpd 58 (37 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (70:30 CC>2:EtOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CCF EtOH with Chiralpak IC 25 cm column at 4 mL/min) rt=9.88 min, MS (ESIPos) m/z= 445.1 [M+H]+.
1.2.30. Cpd 62
[0338] Cpd 58 (37 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (70:30 CCF EtOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (70:30 CCF EtOH with Chiralpak IC 25 cm column at 4 mL/min) rt=13.37 min, MS (ESIPos) m/z= 445.1 [M+H]+.
1.2.31. Cpd 63
[0339] Cpd 32 (47 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CC>2:MeOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:MeOH with Chiralpak IC 25 cm column at 4 mL/min) rt= 8.89 min, MS (ESIPos) m/z= 486.2 [M+H]+.
1.2.32. Cpd 64
[0340] Cpd 32 (47 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CC>2:MeOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (75:25 CO2:MeOH with Chiralpak IC 25 cm column at 4 mL/min) rt= 10.52 min, MS (ESIPos) m/z= 486.2 [M+H]+.
1.2.33. Cpd 65
[0341] Cpd 32 (47 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CC>2:MeOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (Analytical Method 1:85: 15 CO2:MeOH + 0.2% DEA with Chiralpak AS-H 25 cm column at 4 mL/min) rt= 11.44 min, MS (ESIPos) m/z= 486.1 [M+H]+.
1.2.34. Cpd 66
[0342] Cpd 32 (47 mg) was separated into enantiomerically pure stereoisomers by preparative chiral SFC (75:25 CC>2:MeOH with Chiralpak IC 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (Analytical Method 1:85: 15 CO2:MeOH + 0.2% DEA with Chiralpak AS-H 25 cm column at 4 mL/min) rt= 14.38 min, MS (ESIPos) m/z= 486.1 [M+H]+. 1.2.35. Cpd 67
Figure imgf000137_0001
[0343] N-[(4R)-4-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl]-5-(trifluoromethyl)pyridine-3-carboxamide (Int i-164, 124 mg, 0.37 mmol), 2-bromoacetamide (51 mg, 0.37 mmol) and K2CO3 (56 mg, 0.41 mmol) were stirred in ACN (2 mb) and the resulting solution was heated at 50 °C for 6 h. The mixture was then cooled to RT and diluted with EtOAc (30 mL) and washed with water (3 x 10 mL) and brine (10 mL), dried (Na2SC>4), filtered and concentrated at reduced pressure. A mixture of ACN and DMSO was added to the residue and the solid product was filtered and dried giving the title compound (32 mg, 22% yield) as a white solid.
LCMS (Method B) rt = 2.94 min, MS (ESIPos) m/z= 393.0 [M+H]+.
[0344] In analogy to the procedure described for Cpd 67, the following compounds were prepared using the appropriate amine starting material and 2-bromoacetamide.
Figure imgf000137_0002
Figure imgf000138_0001
1.2.36. Cpd 71
[0345] N-[(4R)-4-methyl-l,2,3,4-tetrahydroisoquinolin-7-yl]-5-(trifluoromethyl)pyridine-3-carboxamide (Int i-164, 115 mg, 0.34 mmol), 3-chloropropanamide (110 mg, 1.03 mmol) and ICCCh (52 mg, 0.38 mmol) were stirred in ACN (2 mL) and the resulting solution was heated at 50 °C for 6 h. The mixture was then cooled to RT, diluted with EtOAc (30 mL) and washed with water (3 x 10 mL) and brine (10 mL), dried (Na2SC>4), fdtered and concentrated at reduced pressure. The residue was purified directly via preparative HPLC (Method 1) giving the title compound (77 mg, 55% yield) as a colourless glass. LCMS (Method B) rt = 2.94 min, MS (ESIPos) m/z= 407.0 [M+H]+.
[0346] In analogy to the procedure described for Cpd 71, the following compounds were prepared using the appropriate amine starting material and 3-chloropropanamide.
Figure imgf000138_0002
Figure imgf000139_0002
1.2.37. Cpd 74
Figure imgf000139_0001
[0347] AcOH (14 pL, 0.242 mmol) was added to a solution of N-[(4R)-4-methyl-l, 2,3,4- tetrahydroisoquinolin-7-yl]-5-(trifluoromethyl)pyridine-3-carboxamide (Int i-164, 81 mg, 0.24 mmol) and piperidine-2, 4-dione (82 mg, 0.73 mmol) in MeOH (3 mL). The reaction mixture was stirred at RT for 5 min and NaBH3(CN) (30 mg, 0.48 mmol) was added. The reaction mixture was then stirred and heated at 70 °C overnight in a sealed tube. The following day the mixture was cooled to RT, concentrated at reduced pressure and purified directly via preparative HPLC (Method 1) giving the title compound (67 mg, 63% yield) as a white solid.
LCMS (Method B) rt = 2.83 min, MS (ESIPos) m/z= 433.0 [M+H]+.
[0348] In analogy to the procedure described for Cpd 74, the following compounds were prepared using the appropriate amine starting material and N-substituted piperidine-2, 4-dione starting materials.
Figure imgf000139_0003
Figure imgf000140_0001
Figure imgf000141_0001
1.2.38. Cpd 78
[0349] Cpd 75 (104 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 heptane :EtOH + 0.2% v/v ammonia using Lux iC5 column (21.2 x 250 mm, 5 pm) at 21 mL/min) giving the title compound. Chiral HPLC analysis: (20:80 heptane:EtOH + 0.2% v/v ammonia using Lux iC5 column (4.6 x 150 mm, 3 pm) at 1 mL/min) rt= 9.10 min, MS (ESIPos): m/z = 447.0 [M+H]+.
1.2.39. Cpd 79
[0350] Cpd 75 (104 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 heptane :EtOH + 0.2% v/v ammonia using Lux iC5 column (21.2 x 250 mm, 5 pm) at 21 mL/min) giving the title compound. Chiral HPLC analysis: (20:80 heptane:EtOH + 0.2% v/v ammonia using LuxiC5 column (4.6 x 150 mm, 3 pm) at 1 mL/min) rt= 10.2 min, MS (ESIPos): m/z = 447.0 [M+H]+.
1.2.40. Cpd 80
[0351] Cpd 77 (34 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 EtOH:MeOH +0.1% DEA with Chiralpak AS-H column at 6 mL/min) giving the title compound. Chiral HPLC analysis: (50:50 EtOH:MeOH +0.1% DEA with Chiralpak AS-H column at 0.5 mL/min) rt= 12.9 min, MS (ESIPos): m/z = 421.4 [M+H]+.
1.2.41. Cpd 81
[0352] Cpd 77 (34 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral HPLC (50:50 EtOH:MeOH +0.1% DEA with Chiralpak AS-H column at 6 mL/min) giving the title compound. Chiral HPLC analysis: (50:50 EtOH:MeOH +0.1% DEA with Chiralpak AS-H column at 0.5 mL/min) rt= 21.6 min, MS (ESIPos): m/z = 421.4 [M+H]+.
1.2.42. Cpd 83
[0353] Cpd 82 (200 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SLC (85: 15 CO2:MeOH with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SLC analysis: (85: 15 CO2:MeOH with Chiralcel OD-H 25 cm column at 4 mL/min) rt=12.14 min, MS (ESIPos): m/z = 461.1 [M+H]+. 1.2.43. Cpd 84
[0354] Cpd 82 (200 mg) was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH with Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH with Chiralcel OD-H 25 cm column at 4 mL/min) rt=14.46 min, MS (ESIPos): m/z = 461.1 [M+H]+.
1.2.44. Cpd 86
[0355] Cpd 85 was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=14.46 min, MS (ESIPos): m/z = 491.0 [M+H]+.
1.2.45. Cpd 87
Cpd 85 was separated into enantiomerically pure diastereoisomers by preparative chiral SFC (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 15 mL/min) giving the title compound. Chiral SFC analysis: (85: 15 CO2:MeOH using Chiralcel OD-H 25 cm column at 4 mL/min) rt=16.72 min, MS (ESIPos): m/z = 491.0 [M+H]+.
Example 2. Synthesis of Cpd 88-109
[0356] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Biotage® SNAP KP-NH, Biotage® SNAP Ultra, or Interchim® PuriFlash® Si HC flash chromatography cartridges. Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation. 'H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz), a Bruker Avance 300 NMR spectrometer (300 MHz), or a Bruker Avance III HD NMR spectrometer (400 MHz). Chemical shifts (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate residual solvent peak, e.g. CHCI , (5 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class UPLC system coupled to a UV PDA detector and to a Waters SQD or SQD2 mass spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30/50 mm L; Waters Acquity UPLC CSH C18 1.7 pm, 2.1 mm ID x 50/100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 pm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC HSS PFP 1.8 pm, 2.1 mm ID x 100 mm L. The methods are using ACN/H2O or MeOH/water gradients with either 0.1% formic acid in both mobile phases, 0.05% NH3 in both mobile phases, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia). Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XB RIDGE BEH C18 OBD 30 mm ID x 100/150 mm L columns and ACN H2O gradients with either 0.1% formic acid in both mobile phases, 0.1% DEA in both mobile phases, 0.1% formic acid in H2O, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia). Microwave heating is performed with a Biotage® Initiator.
2.1. General methods
2.1.1. General method Al: amide coupling with HATU
Figure imgf000143_0001
[0357] To a solution of carboxylic acid (1 eq.) and aniline (0.8 to 2eq.) in DMF are added HATU (1 to 1.2 eq.) and DIPEA (2.2 to 8 eq.) and the reaction is stirred from RT to 80 °C for 3 h to 24 h. The crude purified by preparative HPLC and optionally further purified by column chromatography on silica gel to give the desired amide.
[0358] Alternative work-up: the crude is partitioned between water and EtOAc. The layers are separated, the aqueous phase is further extracted with EtOAc. The combined organic layers are optionally washed with a LiCl aq. solution (5% w/w) or with brine. They are then dried over MgSO4 and filtered. The filtrate is concentrated and the residue is purified by column chromatography on silica gel or by preparative HPLC to give the desired amide.
2.1.1.1. Illustrative synthesis of Cpd 99
Figure imgf000143_0002
[0359] To a solution of Int i-197 (22 mg, 0.09 mmol, 1.0 eq.) and Int i-201 (123 mg, 0.09 mmol, 1.0 eq.) in DMF (2 mL) were added HATU (38 mg, 0.10 mmol, 1.1 eq.) and DIPEA (36 pL, 0.21 mmol, 2.3 eq.) and the reaction was stirred at RT overnight then at 60 °C for 20 h. The reaction medium was purified by preparative HPLC to give Cpd 99.
2.1.1.2. Illustrative synthesis of Int i-124 (alternative)
Figure imgf000143_0003
[0360] To a solution of Int i-15 (2 g, 6.9 mmol, 1.0 eq.) and Int i-87 (1.4 g, 7.6 mmol, 1.1 eq.) in DMF (25 mL) were added HATU (3.2 g, 8.2 mmol, 1.2 eq) and DIPEA (3 mL, 17 mmol, 2.5 eq.) and the reaction was stirred at RT for 18 h. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with heptane/EtOAc, 10/0 to 3/7) to afford Int i-124. 2.1.2. General method A2: 2 steps procedure saponification and carboxamide formation
Figure imgf000144_0001
[0361] To a solution of the ester (1 eq.) in THF is added Li OH hydrate (2 N in water, 3 to 4 eq.) or NaOH (2 M in water, 2 to 4 eq.) and the mixture is stirred at 50 °C to 65 °C for 1 to 16 h. Then the reaction medium is cooled down to RT and volatiles are removed in vacuo. To a solution of the obtained crude carboxylate in DMF is added HATU (1 to 2 eq.) and the mixture is optionally stirred at RT for 10 min. Then NH4CI or ammonium acetate (2 to 5 eq.) and TEA or DIPEA (2 to 3 eq.) are added and the resulting solution is stirred at RT for 0.75 to 18 h or at 60 °C for 3 h 30 to 16 h. The reaction mixture is directly purified by preparative HPLC or is diluted with a sat. NH4CI solution. The resulting mixture is extracted with EtOAc. The organic layer is filtered through a phase separator and concentrated. The residue is purified either by column chromatography on silica gel or by preparative HPLC, or a combination of both, to afford the desired carboxamide.
2.1.2.1. Illustrative synthesis of Cpd 101
Figure imgf000144_0002
[0362] To a solution of Int i-195 (25 mg, 0.052 mmol, 1 eq.) in THF (1 mL) was added Li OH hydrate (2 N in water, 0.10 mL, 0.21 mmol, 4 eq.) and the mixture was stirred at 65 °C for 1 h. The reaction medium was then cooled down to RT and the volatiles were removed in vacuo. To a solution of the crude lithium carboxylate in DMF (1 mL) was added NH4CI (6 mg, 0.10 mmol, 2 eq.), HATU (40 mg, 0.10 mmol, 2 eq.) and TEA (22 pL, 0.15 mmol, 3 eq.). The resulting solution was stirred at RT for 0.75 h. The reaction mixture was diluted with a sat. NH4CI solution and extracted with EtOAc. The organic layer was fdtered through a phase separator and concentrated. The residue was purified by preparative HPLC then by column chromatography on silica gel (eluting with DCM/MeOH, 100/0 to 90/10) to afford Cpd 101.
2.1.2.2. Illustrative synthesis of Cpd 108
Figure imgf000144_0003
[0363] To a solution of Int i-205 (174 mg, 0.17 mmol, 1 eq.) in THF (2 mL) was added NaOH (2N in water, 0.34 mL, 0.67 mmol, 4 eq.) and the mixture was stirred at 60 °C for 16 h. The solvents were concentrated and the residue was placed in DMF (1.5 mL). HATU (98 mg, 0.25 mmol, 1.5 eq.) was added and the reaction mixture was stirred at RT for 10 min. Ammonium acetate (65 mg, 0.84 mmol, 5 eq.) and DIPEA (73 pL, 0.42 mmol, 2.5 eq.) were added and the reaction mixture was stirred at 60 °C for 16 h. The reaction medium was purified by preparative HPLC to afford the expected product Cpd 108.
2.1.3. General method B: diphenylimine deprotection
Figure imgf000145_0001
[0364] To a solution of the protected amine (1 eq.) in dioxane is added a 2N HC1 aq. solution (2 to 5 eq.) and the mixture is stirred at RT for 18 to 72 h. The reaction medium is concentrated to dryness and the residue is taken up in water and DCM. The pH of the aqueous phase is adjusted to 9.5/10 with a 2N NaOH aq. solution and the phases are separated. The organic phase is concentrated to afford the expected product.
2.1.3.1. Illustrative synthesis of Int i-201
Figure imgf000145_0002
[0365] To a solution of Int i-207 (120 mg, 0.15 mmol, 1 eq.) in dioxane (3 mL) was added a 2N HC1 aq. solution (0.38 mL, 0.75 mmol, 5 eq.) and the mixture was stirred at RT for 72 h. The reaction medium was concentrated to dryness and the residue was taken up in water and DCM. The pH of the aqueous phase was adjusted to 10 with a 2N NaOH aq. solution and the phases were separated. The organic phase was concentrated to afford Int i-201.
2.1.4. General method C: nitro reduction by catalytic hydrogenation
Figure imgf000145_0003
[0366] To a solution of the nitro intermediate (1 eq.) in EtOH or a EtOH/EtOAc 2/1 mixture, is added 10% Pd/C (0.02 to 0.2 eq) and the suspension is stirred at RT under hydrogen atmosphere (1 atm) until complete reduction (2 to 18 h). The reaction mixture is filtered through a phase separator or on Celite® and the solids are washed with EtOAc and MeOH. The filtrate is concentrated, and the residue is used as such.
2.1.4.1. Illustrative synthesis of Int i-198
Figure imgf000145_0004
[0367] To a solution of Int i-206 (40 mg, 0.16 mmol, 1 eq.) in EtOH (1.5 mL) was added Pd/C 10% (34 mg, 0.032 mmol, 0.2 eq). The reaction mixture was placed under hydrogen atmosphere and stirred for 2 h at RT. The reaction medium was filtered through Celite®, washed with EtOH and the filtrate was evaporated in vacuo to afford Int i-198. 2.1.5. General method D: Boc removal
Figure imgf000146_0001
[0368] The Boc-protected amine (1 eq.) is stirred a RT in an acidic medium (typically 4 to 30 eq. HC1 (4 M in dioxane) in dioxane) for 3 to 18 h. The reaction mixture is concentrated. The residue is purified on a Biotage ISOLUTE® SCX exchange resin eluting with MeOH, then with a 7N ammonia solution in MeOH. The basic fraction is concentrated to afford the desired product.
[0369] Alternative work-up 1: the reaction medium is neutralized with a sat. NaHCO; aq. solution and is then extracted with DCM. The phases are filtered on a phase separator and the filtrate is concentrated to afford the desired product.
[0370] Alternative work-up 2: Et2O is added to the reaction medium and the mixture is stirred at RT for 30 min. The precipitate is filtered, rinsed with Et2O and dried to afford the expected product.
2.1.5.1. Illustrative synthesis of Int i- 140
Figure imgf000146_0002
[0371] To a solution of Int i-124 (2.28 g, 5.07 mmol, 1 eq.) in 1,4-dioxane (20 mb) was added a 4 N HCI solution in 1,4-dioxane (5.07 mb, 20.3 mmol, 4 eq.) and the reaction was stirred at RT for 15 h. Et2O was added to the reaction medium and the mixture stirred at RT for 30 min. The precipitate was filtered, rinsed with Et2O and dried to afford Int i- 140.
2.1.6. General method E: (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline N-alkylation
Figure imgf000146_0003
[0372] To a solution of (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline derivative (1 eq.) in ACN are added K2CO3 (1.5 to 3 eq.) and the corresponding alkylating agent (1 to 2 eq). The reaction is stirred at a temperature between RT and 90 °C until completion (1 h to 3 days). If necessary, more alkylating agent (up to 2 eq.) is added. The reaction mixture is filtered and concentrated. The residue is purified by column chromatography on silica gel, or slurred in water and filtered, to give the desired product.
[0373] Alternative work-up: the reaction mixture is concentrated or not, then is partitioned between water and EtOAc or DCM. The layers are separated, and the organic layer is washed or not with brine before being dried on MgSCL, filtered and concentrated, or filtered on a phase separator and concentrated. The residue is purified by column chromatography on silica gel and/or preparative HPLC. 2.1.6.1. Illustrative synthesis of Cpd 91
Figure imgf000147_0001
[0374] To a solution of Int i- 140 as a free base (40 mg, 0. 14 mmol, 1 eq.) in ACN (1.4 m ) were added K2CO3 (30 mg, 0.21 mmol, 1.5 eq.) and 2-bromo-2-methylpropanamide (CAS# 7462-74-0; 24 mg, 0.14 mmol, 1 eq). The suspension was stirred at RT for 15 h and at 90 °C for 2 h. 2-bromo-2-methylpropanamide (CAS# 7462-74-0; 24 mg, 0.14 mmol, 1 eq) was added and the mixture was stirred at 90 °C for 2.25 h. The reaction mixture was then partitioned between water and DCM. The layers were separated, and the organic layer was washed with brine before being filtered on a phase separator and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH, 100/0 to 9/1) to afford Cpd 91.
2.1. 7. General method F: Strecker reaction and cyano hydrolysis
Figure imgf000147_0002
[0375] To a solution of (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline derivative (1 eq.) in a mixture of ACN and water (3/2) are added the aldehyde (3 eq.), NaCN (6 eq.) and AcOH (4.5 eq.), and the mixture is stirred at RT for 16 h to 2 days. Then the reaction medium is poured into water, extracted with DCM, and the combined organic phases are fdtered on a phase separator. The filtrate is concentrated and purified by column chromatography on silica gel to give the cyano intermediate.
[0376] To a solution of the cyano intermediate (1 eq.) dissolved in DMSO, are added K2CO3 (5 eq.) and H2O2 (30% in water, 5 eq.). The mixture is stirred at RT for 1 to 2 h. Then the reaction medium is purified by preparative HPLC to afford the expected product or is quenched with water and extracted with EtOAc. The combined organic phases are dried on a phase separator and concentrated. The residue is purified by column chromatography on silica gel to afford the expected product.
2.1.7.1. Illustrative synthesis of Cpd 105
Figure imgf000147_0003
[0377] To a solution of Int i-140 (50 mg, 0.13 mmol, 1 eq.) in an ACN/water mixture (0.3 mL/0.2 m ) were added 3-methoxypropanal (CAS# 2806-84-0; 34 mg, 0.39 mmol, 3 eq.), NaCN (39 mg, 0.78 mmol, 6 eq.) and AcOH (34 pb, 0.58 mmol, 4.5 eq.). The reaction mixture was stirred at RT for 16 h. The reaction medium was then poured in water, extracted with DCM and the combined organic phases were filtered on a phase separator. The filtrate was concentrated and purified on column chromatography on silica gel (eluting with DCM/MeOH, 100/0 to 95/5) to give the cyano intermediate. This intermediate (12 mg, 0.026 mmol, 1 eq.) was dissolved in DMSO (1.5 mL), and K2CO3 (18 mg, 0.13 mmol, 5 eq.) and hydrogen peroxide (30% in water, 13 pL, 0.13 mmol, 5 eq.) were added. The reaction mixture was stirred at RT for 1 h and the reaction medium was purified by preparative HPLC to afford Cpd 105.
2.1.8. General method J: Michael addition
Figure imgf000148_0001
[0378] To a solution of tetrahydroisoquinoline derivative (1 eq.) in MeOH is added benzyltrimethylammonium hydroxide (40 mass% in MeOH, 1.0 eq.) and the mixture is stirred at RT for 30 min. The corresponding alkene (10 eq.) is then added, and the reaction mixture is stirred at 60 °C for 16 h. If needed, additional benzyltrimethylammonium hydroxide (40 mass% in MeOH, 1.0 eq.) is added and the mixture is stirred at RT for 30 min. Then, the corresponding alkene (10 eq.) is added and the reaction mixture is stirred at 60 °C for 2 days. The reaction medium is quenched with water. The aqueous layer is extracted with DCM and the combined organic phases are filtered on a phase separator. The filtrate is concentrated to dryness and purified by column chromatography on silica gel to afford the desired product.
2.1.8.1. Illustrative synthesis of Int i-205
Figure imgf000148_0002
[0379] To a solution of Int i-140 (150 mg, 0.34 mmol, 1 eq.) in MeOH (1 mL) was added a solution of benzyltrimethylammonium hydroxide (CAS# 100-85-6; 40% in MeOH, 0.18 mL, 0.34 mmol, 1 eq.) and the mixture was stirred at RT for 30 min. Then methyl-4-(2,2,2-trifluoroethoxy)but-2-enoate (CAS# 1864760-24-6; 750 mg, 3.60 mmol, 10 eq.) was added and the reaction mixture was stirred at 60 °C for 16 h. Benzyltrimethylammonium hydroxide (CAS# 100-85-6; 40% in MeOH, 0.18 mL, 0.34 mmol, 1 eq.) was added and the mixture was stirred at RT for 30 min. Then methyl-4-(2,2,2-trifluoroethoxy)but-2-enoate (CAS# 1864760-24-6; 750 mg, 3.60 mmol, 10 eq.) was added and the reaction mixture was stirred at 60 °C for 2 days. The reaction medium was quenched with water and DCM. The aqueous layer was extracted with DCM and the combined organic phases were filtered on a phase separator. The filtrate was concentrated to dryness and purified by column chromatography on silica gel (eluting with DCM/MeOH, 100/0 to 95/5) to afford Int i-205. 2.1.9. General method M: Buchwald reaction
Figure imgf000149_0001
[0380] To a suspension of the pyridine derivative (1 eq.), Xantphos (0.1 to 0.2 eq.), Pd2dba3 (0.04 eq.) or Pd(OAc)2 (0.1 eq.) and CS2CO3 (2 to 3 eq.) in dioxane under argon is added the corresponding amine (1.5 to 3.5 eq.) and the mixture is stirred at 100 °C for 1 h under conventional heating, or 150 °C for 20 to 30 min under microwave irradiation. If needed additional amine (1.8 eq.) is added and the mixture is stirred at 150 °C for 20 min under microwave irradiation. Then the reaction mixture is concentrated or is filtered through Celite®. The filtrate is diluted with water and extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSCE and filtered. The filtrate is concentrated to dryness and used as such or is purified by column chromatography on silica gel to afford the desired product.
2.1.9.1. Illustrative synthesis of Int i-206
Figure imgf000149_0002
[0381] To a suspension of 3 -bromo-5 -nitro-pyridine (CAS# 15862-30-3; 115 mg, 0.57 mmol, 1 eq.), Xantphos (33 mg, 0.057 mmol, 0.1 eq.), Pd2dba3 (13 mg, 0.040 mmol, 0.04 eq.) and CS2CO3 (369 mg, 1.1 mmol, 2 eq.) in dioxane (2.3 mb) under argon was added 3 -fluoropyrrolidine (CAS#116574-74-4; 177 mg, 2.0 mmol, 3.5 eq.) and the mixture was stirred at 150 °C for 30 min under microwave irradiation. The reaction mixture was then fdtered through Celite®, the filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated to dryness and purified by column chromatography on silica gel (eluting with cyclohexane/EtOAc, 100/0 to 70/30) to afford Int i-206.
2.1.9.2. Illustrative synthesis of Int i-207
Figure imgf000149_0003
[0382] Int i-208 (94 mg, 0.28 mmol, 1 eq.), diphenyhnethanimine (CAS# 1013-88-3; 76 mg, 0.42 mmol, 1.5 eq.), XantPhos (32 mg, 0.056 mmol, 0.2 eq.) and Pd(OAc)2 (6.2 mg, 0.028 mmol, 0.1 eq.) were dissolved in dioxane (5 m ). The solution was purged with argon for 5 min and CS2CO3 (272 mg, 0.83 mmol, 3 eq.) was added. The reaction was heated at 100 °C for 1 h. The reaction mixture was then concentrated in vacuo, quenched with water, and extracted with EtOAc. The combined organic layers were evaporated to yield Int i-207. 2.2. Synthesis of Intermediates i-194 to i-210
2.2.1. Int i-194
Figure imgf000150_0001
[0383] To a solution of Int i-140 as a free base (100 mg, 0.27 mmol, 1 eq.) in DMF (3.9 mL) were added TEA (77 pL, 0.55 mmol, 2 eq.) and ethyl (2R)-2,3-epoxypropanoate (CAS# 111058-33-4; 64 mg, 0.55 mmol, 2 eq.). The mixture was stirred at 150 °C for 30 min under microwave irradiation. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were filtered through a phase separator and the filtrate was concentrated. The residue was taken up in DCM, the suspension was filtered, and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel (eluting with DCM/MeOH, 10/0 to 9/1) to afford Int i-194.
2.2.2. Int i-195
Figure imgf000150_0002
[0384] To a solution of Int i-140 as a free base (100 mg, 0.23 mmol, 1 eq.) in DMF (4.6 mL) were added TEA (64 pL. 0.46 mmol, 2 eq.) and methyl (2S)-oxirane-2-carboxylate (CAS# 118712-39-3; 47 mg, 0.46 mmol, 2 eq.). The mixture was stirred at 150 °C for 20 min under microwave irradiation. Water was added and the reaction mixture was extracted with EtOAc. The combined organic layers were filtered through a phase separator and the filtrate was concentrated. The residue was taken up in DCM, the suspension was filtered and the filtrate was concentrated. The crude material was purified by column chromatography on silica gel (eluting with DCM/MeOH, 10/0 to 9/1) to afford Int i-195.
2.2.3. Int i-197
Figure imgf000150_0003
2.2.3.1. Step i: ethyl (R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
Figure imgf000150_0004
[0385] To a flask charged with EtOH (34 mL) cooled to 0 °C was added acetyl chloride (2.4 mL, 34 mmol, 10 eq.). The mixture was stirred at 0 °C for 30 min, then Int i-15 (1 g, 3.4 mmol, 1 eq.) was added at 0 °C. The mixture was heated at 70 °C for 15 h and then cooled to RT. The volatiles were concentrated to afford ethyl (R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate.
LCMS: MW (calcd): 219.3; m/z MW (obsd): 220.6 (M+H)
2.2.3.2. Step it: ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7- carhoxylate
Figure imgf000151_0001
[0386] To a solution of ethyl (R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (750 mg, 3.4 mmol, 1 eq.) in ACN (8 mL) were added K2CO3 (1.4 g, 10 mmol, 3 eq.) and 2-bromoacetamide (CAS#683- 57-8; 591 mg, 4.25 mmol, 1.25 eq). The reaction mixture was stirred at 50 °C for 4 h and was then concentrated. The residue was partitioned between water and DCM. The organic layer was dried over MgSC>4, fdtered, and concentrated to give ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-l, 2,3,4- tetrahydroisoquinoline -7 -carboxylate .
LCMS: MW (calcd): 291.3; m/z MW (obsd): 290.2 (M-H)
2.2.3.3. Step Hi: Int i-197
Figure imgf000151_0002
[0387] To a solution of ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7- carboxylate (200 mg, 0.67 mmol, 1 eq.) in EtOH (14 mL) was added a IN aq. NaOH solution (2.7 mL, 2.7 mmol, 4 eq.). The reaction was stirred at RT for 2.5 days and concentrated. The residue was taken up in water and then a IN aq. HC1 solution was added to adjust pH to 4.9. The aqueous solution was thoroughly extracted with a 1: 1 DCM/iPrOH mixture, the organic layers were combined, dried over MgSC>4, filtered, and concentrated to give Int i- 197.
2.2.4. Int i-202
Figure imgf000151_0003
2.2.4.1. Step i: methyl (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate
Figure imgf000151_0004
[0388] To a solution of Int i-13 (122 g, 384.72 mmol, 1 eq.) in MeOH (700 mL) and H2O (350 mL) was added K2CO3 (106.34 g, 769.43 mmol, 2 eq.). The mixture was stirred at RT for 2 h and the reaction mixture was concentrated. The residue was partitioned between water (50 mL) and DCM (500 mL). The layers were separated, the aqueous layer was further extracted with DCM (2 L). The combined organic layers were washed with water (1 L), dried over MgSCL. filtered, and concentrated under reduced pressure to afford methyl (4R)-4-methyl- 1 ,2,3 ,4-tetrahydroisoquinoline-7 -carboxylate .
Alternative synthesis:
[0389] To a suspension of Int i-13 (464 g, 1539 mmol, 1 eq.) in degassed 2-propanol (1.5 L) was added dropwise a freshly prepared solution of NaOH in water (6 mol/L, 244 mL, 1464 mmol, 0.95 eq.) over 1 h 20 min. The reaction temperature was maintained below 25 °C during the addition. After 1 h 15 min at RT, an NaOH solution (6 mol/L in water, 10.3 mL, 61.8 mmol, 0.040 eq.) was added dropwise over 3 min and the reaction mixture was stirred at RT for 15 min. Then HC1 (37 mass% in water, 341 mL, 4080 mmol, 2.65 eq.) was added dropwise, maintaining the reaction temperature below 25 °C. The suspension was stirred at RT for 2 h and then MTBE (6 L) was added. The mixture was stirred at RT overnight. The suspension was filtered on a glass filter and the solid was washed with MTBE. The solid was then taken up in chloroform and the resulting mixture was stirred at RT for 2 h before being filtered on a pad of cellulose. The pad was washed with chloroform and the filtrate was partially concentrated under reduced pressure (to the 1/7 V). A solvent exchange was performed with EtOAc. The resulting suspension was filtered on a glass filter funnel, the solid was washed with EtOAc and dried to afford methyl (4R)-4-methyl-l, 2,3,4- tetrahydroisoquinoline-7-carboxylate, hydrochloride.
2.2.4.2. Step ii: Int i-202
Figure imgf000152_0001
[0390] To a solution of methyl (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate (26 g, 127 mmol, 1 eq.) in ACN (630 mL) was added K2CO3 (35 g, 253 mmol, 2 eq.) and 2-bromoacetamide (CAS#683-57-8; 21.6 g, 152 mmol, 1.2 eq.). The reaction mixture was stirred at RT for 1.25 h. Precipitation occurred and the solid was filtered. The obtained solid was then washed with water and dried to afford Int i-202.
Alternative synthesis:
[0391] To a suspension of methyl (4R)-4-methyl-l,2,3,4-tetrahydroisoquinoline-7-carboxylate hydrochloride (343 g , 1419 mmol, 1 eq.) and potassium phosphate tribasic (768 g , 3546 mmol, 2.5 eq.) in ACN (3.43 L) was added 2-bromoacetamide (294 g, 2131 mmol, 1.5 eq.) by portion over 5 min while maintaining the temperature below 25 °C. The reaction mixture was then stirred at 20 °C for 3 h. The reaction mixture was poured into water (8.5 L). The suspension was filtered and the solid was washed with water. The solid was dried and was then suspended in ACN. The suspension was stirred at RT for 1 h and filtered on a glass filter funnel. The solid was washed with ACN and dried to afford Int i-202. 2.2.5. Int i-203
Figure imgf000153_0001
2.2.5.1. Step i: N-[5-bromo-4-(trifluoromethyl)-2-pyridyl] -2, 2-dimethyl-propanamide
Figure imgf000153_0002
[0392] To a solution of 5-bromo-4-(trifluoromethyl)pyridin-2-amine (CAS# 944401-56-3; 1 g, 4.0 mmol, 1 eq.) and TEA (0.73 mL, 5.2 mmol, 1.3 eq.) in DCM (6 mL) at 0 °C was added dropwise trimethylacetyl chloride (0.54 mL, 4.4 mmol, 1.1 eq.) and the reaction mixture was stirred at RT for 5 h. Water was added and the mixture was stirred at RT for 10 min. The organic layer was collected, dried over Na2SC>4, fdtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with cyclohexane/EtOAc, 10/0 to 9/1) to afford N-[5-bromo-4-(trifluoromethyl)-2-pyridyl]-2,2-dimethyl- propanamide.
2.2.5.2. Step it: N-[5-formyl-4-(trifluoromethyl)-2-pyridyl ]-2, 2-dimethyl-propanamide
Figure imgf000153_0003
[0393] To a solution ofN-[5-bromo-4-(trifluoromethyl)-2-pyridyl]-2, 2-dimethyl-propanamide (1.22 g, 3.6 mmol, 1 eq.) in dry THF (28 mL) at -78 °C was slowly added n-butyllithium (2.5 M in hexanes, 3.6 mL, 9.1 mmol, 2.5 eq.) under N2 atmosphere. The reaction mixture was stirred at -78 °C for 1 h, DMF (1.1 mL, 15 mmol, 4 eq.) was added dropwise and the mixture was stirred at -78 °C for another 2 h. A 1 N HC1 aq. solution (10 mL) was added and the medium was stirred for 10 min. The mixture was extracted with EtOAc, the combined organic layers were dried over Na2SC>4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluting with cyclohexane/EtOAc, 10/0 to 8/2) to afford N-[5- formyl-4-(trifluoromethyl)-2 -pyridyl] -2, 2-dimethyl-propanamide.
LCMS: MW (calcd): 274.2; m/z MW (obsd): 275.1 2. .5.3. Step Hi: 2, 2-dimethyl-N-[5-[(4-methylpiperazin-l-yl)methyl ]-4-( trifluoromethyl)-2- pyridyl propancimide
Figure imgf000154_0001
[0394] To a solution of N- [5 -formyl -4-(trifluoromethyl)-2 -pyridyl] -2, 2-dimethyl-propanamide (200 mg, 0.51 mmol, 1 eq.) and 1 -methylpiperazine (0.068 mL, 0.61 mmol, 1.2 eq.) in MeOH (5 mL) was added AcOH (0.15 mL, 2.6 mmol, 5 eq.) and the mixture was stirred at RT for 8 h. NaBH3(CN) (80 mg, 1.3 mmol, 2.5 eq.) was then added, the mixture was stirred at RT for 16 h before being concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH, 15/1) to afford 2,2-dimethyl- N-[5-[(4-methylpiperazin-l-yl)methyl]-4-(trifluoromethyl)-2-pyridyl]propanamide.
LCMS: MW (calcd): 358.4; m/z MW (obsd): 359.2
2.2.5.4. Step iv: Int i-203
Figure imgf000154_0002
[0395] To a solution of 2,2-dimethyl-N-[5-[(4-methylpiperazin-l-yl)methyl]-4-(trifluoromethyl)-2- pyridyl]propanamide (135 mg, 0.26 mmol, 1 eq.) in MeOH (4.5 mL) was added KOH (1 M in water, 1.3 mL, 1.3 mmol, 5 eq.), the mixture was stirred at RT for 4 h before being concentrated. The residue was taken up in water and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated to afford Int i-203.
2.2.6. Int i-204
Figure imgf000154_0003
2.2.6.1. Step i: 3-nitro-5-tetrahydrofuran-3-yloxy-pyridine
Figure imgf000154_0004
[0396] A mixture of 5-nitropyridin-3-ol (CAS# 186593-26-0; 50 mg, 0.357 mmol, 1 eq.), 3- iodotetrahydrofuran (84.8 mg, 0.43 mmol, 1.2 eq.), and K2CO3 (118 mg, 0.86 mmol, 2.4 eq.) in DMF (1 mL) was stirred at 80 °C for 18 h. More 3 -iodotetrahydrofuran (42 mg, 0.21 mmol, 0.6 eq.) was then added and the mixture was stirred at 80 °C for another 4 h. Water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with a 5% LiCl aq. solution and concentrated to afford 3 -nitro-5 -tetrahydrofuran-3-yloxy-pyridine . LCMS: MW (calcd): 210.2; m/z MW (obsd): 211.5
2. .6.2. Step it: Int i-204
Figure imgf000155_0001
[0397] Int i-204 was prepared from 3-nitro-5-tetrahydrofuran-3-yloxy-pyridine using General Method C (Ex. 2.1.4).
2.2. 7. Int i-208
Figure imgf000155_0002
2.2. 7.1. Step i: [5-bromo-3-(trifluoromethyl)-2-pyridyl]methyl me thane sulfonate
Figure imgf000155_0003
[0398] To a solution of [5-bromo-3-(trifluoromethyl)-2-pyridyl]methanol (CAS# 932390-36-8; 100 mg, 0.37 mmol, 1 eq.) and TEA (0.16 mL, 1.1 mmol, 3 eq.) in DCM (3 mL) at 0 °C was added methanesulfonylchloride (34 pL, 0.45 mmol, 1.2 eq.) and the reaction mixture was stirred at 0 °C for 1 h. A sat. aq. NaHCCh solution was added and the mixture was extracted with DCM. The organic layers were combined, dried over MgSCL, filtered, and concentrated to afford [5-bromo-3-(trifluoromethyl)-2- pyridyl] methyl methane sulfonate.
2.2. 7.2. Step it: Int i-208
Figure imgf000155_0004
[0399] To a solution of [5-bromo-3-(trifluoromethyl)-2-pyridyl]methyl methanesulfonate (110 mg, 0.32 mmol, 1 eq.) in ACN (3 mL) were added K2CO3 (137 mg, 0.65 mmol, 2 eq.) and 1 -methylpiperazine (39 mg, 0.39 mmol, 1.2 eq.). The reaction mixture was stirred at 50 °C for 1 h. Then water and DCM were added, the layers were separated and the organic phase was washed with a sat. aq. NaHCCh solution. The layers were fdtered on a phase separator and the filtrate was concentrated to afford Int i-208. 2.2.8. Int i-209
Figure imgf000156_0001
2.2.8.1. Step i: tert-butyl (4R)-7-chlorocarbonyl-4-methyl-3,4-dihydro-lH-isoquinoline-2- carboxylate
Figure imgf000156_0002
[0400] To a suspension of Int i-15 (50 mg, 0.17 mmol, 1 eq.) in ACN (3 mL) at 0 °C were added dry DMF (7 pL, 0.009 mmol, 0.5 eq.) and oxalyl chloride (0.088 mL, 1.0 mmol, 6 eq.). The reaction mixture was stirred at 0 °C for 1 h before being concentrated to dryness. The residue was co-evaporated with toluene (2 x 3 mL). The solvents were evaporated in vacuo to afford tert-butyl (4R)-7-chlorocarbonyl-4-methyl-3,4- dihydro- lH-isoquinoline-2 -carboxylate .
2.2.8.2. Step ii: Int i-209
Figure imgf000156_0003
[0401] To a solution of (4R)-7-chlorocarbonyl-4-methyl-3,4-dihydro-lH-isoquinoline-2-carboxylate (53 mg, 0.17 mmol, 1 eq.) and 5 -(trifluoromethoxy )pyridin-3 -amine dihydrochloride salt (CAS# 2197057-53- 5; 43 mg, 0.17 mmol, 1 eq.) in DCM (3 mL) was added TEA (0.095 m , 0.68 mmol, 4 eq.) and the reaction mixture was stirred at RT for 3 h. The reaction was concentrated to dryness and the residue was taken up in EtOAc and water. Layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were concentrated in vacuo and the crude material was purified by column chromatography on silica gel (eluting with cyclohexane/EtOAc, 10/0 to 1/1) to afford Int i-209.
2.2.9. Int i-210
Figure imgf000156_0004
[0402] A suspension of 5-nitropyridin-3-ol (CAS# 186593-26-0; 50 mg, 0.36 mmol, 1 eq.), 1,1,1-trifluoro- 2-iodo-ethane (90 mg, 0.43 mg, 1.2 eq.) and K2CO3 (118 mg, 0.86 mmol, 2.4 eq.) in DMF (1 mL) was stirred overnight at 80 °C. Then more l,l,l-trifluoro-2 -iodo-ethane (90 mg, 0.43 mg, 1.2 eq.) was added and the mixture was stirred at 80 °C for 5 h. More l,l,l-trifluoro-2 -iodo-ethane (90 mg, 0.43 mg, 1.2 eq.) was added and the mixture was stirred at 80 °C for 3 h. More l,l,l-trifluoro-2 -iodo-ethane (90 mg, 0.43 mg, 1.2 eq.) was added and the reaction mixture was stirred at 80 °C under microwave irradiation for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic phases were washed with a 5% LiCl aq solution and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (eluting with cyclohexane/EtOAc, 10/0 to 7/3) to afford Int i-210.
2.3. Synthesis of compounds of the invention
2.3.1. Cpd 94
Figure imgf000157_0001
[0403] To a solution of Int i-140 as a free base (75 mg, 0.21 mmol, 1 eq.) in ACN (2 mL) were added TEA (57 pL. 0.41 mmol, 2 eq.) and methyl 2-bromo-3-methoxypropanoate (CAS# 27704-96-7; 51 mg, 0.25 mmol, 1.2 eq). The mixture was stirred at RT for 1 h and at 80 °C for 1.5 h. The reaction medium was diluted at RT with DCM and washed with brine. The organic layer was filtered through a phase separator and concentrated. The residue was dissolved in ammonia (2 M in MeOH, 10 mL, 20 mmol, 97 eq.) and the solution was stirred at 75 °C for 48 h. The reaction mixture was concentrated, the residue was dissolved in ammonium hydroxide (21 mass% in water, 10 mL, 50 mmol, 300 eq.) and the mixture was heated at 90 °C for 2.25 h. The reaction medium was diluted at RT with DCM and water. The organic layer was filtered through a phase separator and concentrated to afford a crude product that was kept aside.
[0404] The aqueous layer was concentrated to dryness and the obtained carboxylic acid (47 mg, 0.10 mmol, 1 eq.) was dissolved in DML (3 mL). Ammonium chloride (55 mg, 1.03 mmol, 10 eq.), TEA (43 pL, 0.31 mmol, 3 eq.) and HATU (40 mg, 0.10 mmol, 1 eq.) were added. The mixture was stirred at RT for 2 h and was then diluted with EtOAc and washed with brine. The organic layer was dried (Na2SC>4), filtered and concentrated. This residue was gathered with the crude product kept aside and the combined crude material was purified by column chromatography on silica gel (eluting with DCM/MeOH, 10/0 to 9/1) followed by preparative HPLC to afford Cpd 94.
Figure imgf000157_0002
2.3.2.1. Step i: (4R)-4-methyl-2-(2-oxotetrahydrofuran-3-yl)-N-[5-(2,2,2-trifluoroethyl)-3- pyridyl J-3, 4-dihydro-lH-isoquinoline- 7 -carb oxamide
Figure imgf000158_0001
[0405] To a suspension of Int i-140 (50 mg, 0.13 mmol, 1 eq.) in dry ACN (1 mL) were added dry K2CO3 (90 mg, 0.65 mmol, 5 eq.) and tetramethylammonium bromide (0.0013 mmol, 0.2 mg, 0.01 eq.) and the mixture was stirred at 0 °C for 1.5 h. Then 3-bromotetrahydrofiiran-2-one (12 pL, 0.13 mmol, 1 eq.) was added and the reaction mixture was stirred at RT for 16 h. More 3-bromotetrahydrofiiran-2-one (12 pL. 0.13 mmol, 1 eq.) was added and the mixture was stirred at RT for 16 h. The solid was filtered off, rinsed with ACN and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH, 100/0 to 95/5) to afford (4R)-4-methyl-2-(2-oxotetrahydrofuran-3- yl)-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro-lH-isoquinoline-7-carboxamide.
LCMS: MW (calcd): 433.4; m/z MW (obsd): 434.4 (M+H)
2.3.2.2. Step ii: Cpd 103
[0406] (4R)-4-methyl-2-(2-oxotetrahydrofuran-3-yl)-N-[5-(2,2,2-trifluoroethyl)-3-pyridyl]-3,4-dihydro- lH-isoquinoline-7-carboxamide (32 mg, 0.073 mmol, 1 eq.) was mixed with ammonia (0.4 M in dioxane, 1 mL, 0.4 mmol, 5 eq.) and the reaction mixture was heated at reflux for 16 h. Then ammonia (23 mass% in water, 0.5 mL, 6.1 mmol, 82 eq.) was added and the mixture was stirred at reflux for 24 h. The solvents were concentrated to dryness and the residue was partitioned between a sat. NH4CI aq. solution and EtOAc. The aqueous layer was washed with EtOAc and was concentrated. The residue was purified by preparative HPLC to afford Cpd 103.
2.3.3. Cpd 109
Figure imgf000158_0002
[0407] A tube was charged with Int i-202 (25 mg, 0.10 mmol, 1.0 eq.) and Int i-203 (31 mg, 0.11 mmol, 1.2 eq.), and placed under a positive pressure of argon. Toluene (0.30 mL) and a LiHMDS solution (1.3 M in THF, 0.15 mL, 0.19 mmol, 2 eq.) were sequentially added with vigorous stirring and the reaction mixture was stirred at RT for 1.5 h. The reaction mixture was quenched with a sat. NH4CI solution and diluted with EtOAc. The organic layer was washed with water and brine, dried, filtered and concentrated. The residue was purified by preparative HPLC to afford Cpd 109. Table II. Intermediates used towards the compounds of the invention.
SM = Starting Material, Mtd = Method, MS Mes’d = Mesured mass
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Table III. Illustrative compounds of the invention
SM = Starting Material, Mtd = Method, MS Mes’d = Mesured mass
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Table IV. NMR data of illustrative compounds of the invention
Figure imgf000183_0002
Figure imgf000184_0001
SEQUENCE LISTING
[0408] SEQ ID 1: pcDNA3.1 hsDDRl (Uniprot# Q08345-2) plasmid.
[0409] SEQ ID 2: pcDNA3.1 hsDDR2 (Uniprot# Q16832) plasmid.
BIOLOGICAL EXAMPLES
Example 3. In vitro assays
3.1. DDR1 and DDR2 LanthaScreen® Eu Kinase Binding Assay
[0410] The effects of the compounds were tested on DDR1 and DDR2 kinases in a LanthaScreen® Eu kinase binding assay at Invitrogen. Compounds were tested in concentration response ranging from 0.0005- 10 pM. Compound, 5 nM kinase protein, 2 nM Eu-Anti GST antibody and 20 nM kinase tracer 178 were mixed and incubated for 1 h at RT. Binding of an inhibitor to DDR1 and DDR2 kinase domain was measured by TR-FRET and reported as an IC50 (nM) as shown in Table V.
Table V. IC50 (nM) values of examples in DDR1 & DDR2 binding assay
Figure imgf000185_0001
Figure imgf000185_0002
Figure imgf000186_0002
Figure imgf000186_0001
3.2. DDR1 ADP-Glo™ Kinase Assay
3.2.1. Overview
[0411] The ADP-Glo™ kinase assay is a luminescent technology assay which measures the ADP formed from a kinase reaction. In this specific study, the kinase reaction consists of phosphorylation of Axltide substrate by DDR1 (cytoplasmic domain (aa444-876), N-terminal GST). This kinase reaction is terminated in the second step and all the remaining ATP is depleted. In the final step the ADP is converted into ATP and this newly synthesized ATP is measured by using a luciferase/luciferin reaction. The generated light is measured using an Envision plate reader, wherein the luminescent signal obtained positively correlates with the kinase activity.
3.2.2. Protocol
[0412] The test compounds were prepared as a serial dilution of 10-point dose concentrations with 1/5 dilution steps in 100% DMSO starting from 2 mM highest concentration. These compounds were further diluted (1/20) in water and 1 pL was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290).
[0413] 1% DMSO and 10 pM staurosporine final concentrations were used respectively as negative and positive controls respectively. 2 pL enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT.
[0414] The reaction was started by adding 2 pL diluted ATP (final concentration 1/10 Km ATP) on the assay plates. Plates were centrifuged for 30 seconds at 1000 rpm and gently shaken for 2 min followed by an incubation at RT for 120 min.
[0415] The reactions were stopped and the unconsumed ATP was depleted by adding 5 pL ADP-Glo Reagent (Promega, Cat# V9103) to the reaction. The plates were centrifuged for 30 seconds at 1000 rpm and incubated at RT for 40 min.
[0416] The ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 pL Kinase Detection Reagent (Promega, Cat# V9103) to the reaction. The plates were centrifuged for 30 seconds at 1000 rpm and incubated at RT for 30 min. Luminescence was measured on an Envision plate reader (PerkinElmer, Inc.).
Table VI. Conditions for DDR1 kinase ADP-Glo™ assay (final concentration)
Figure imgf000187_0002
3.2.3. Data analysis and results
[0417] Following the read-out performed on the Envision, percentage inhibition (PIN) was calculated based on the equation below and concentration response curves were plotted. Average half maximal inhibitory concentration (IC50) for DDR1 are reported in the table below. 100
Figure imgf000187_0001
n: negative control; p: positive control; RLU: Relative Light Unit and t: test compound
3.3. DDR2 ADP-Glo™ Kinase Assay
3.3.1. Overview
[0418] The ADP-Glo™ kinase assay is a luminescent technology assay which measures the ADP formed from a kinase reaction. In this specific study, the kinase reaction consists of the phosphorylation of Axltide substrate by DDR2, cytoplasmic domain (aa422-855), N-terminal GST. This kinase reaction is terminated in the second step and all the remaining ATP is depleted. In the final step the ADP is converted into ATP and this newly synthesized ATP is measured by using a luciferase/luciferin reaction. The generated light is measured using an Envision plate reader, wherein the luminescent signal obtained positively correlates with the kinase activity.
3.3.2. Protocol
[0419] The test compounds were prepared as a serial dilution of 10-point dose concentrations with 1/5 dilution steps in 100% DMSO starting from 2 mM highest concentration. These compounds were further diluted (1/20) in water and 1 pL was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290). [0420] 1% DMSO and 10 pM staurosporine final concentrations were used respectively as negative and positive controls respectively. 2 pL enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT.
[0421] The reaction was started by adding 2 pL diluted ATP (final concentration 1/10 Km ATP) on the assay plates. Plates were centrifuged for 30 seconds at 1000 rpm and gently shaken for 2 min followed by an incubation at RT for 120 min.
[0422] The reactions were stopped and the unconsumed ATP was depleted by adding 5 pL ADP-Glo Reagent (Promega, Cat# V9103) to the reaction. The plates were centrifuged for 30 seconds at 1000 rpm and incubated at RT for 40 min.
[0423] The ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 pL Kinase Detection Reagent (Promega, Cat# V9103) to the reaction. The plates were centrifuged for 30 seconds at 1000 rpm and incubated at RT for 30 min. Luminescence was measured on an Envision plate reader (PerkinEhner, Inc.).
Table VII. Conditions for DDR2 kinase ADP-Glo™ assay (final concentration)
Figure imgf000188_0002
3.3.3. Data analysis and results
[0424] Following the read-out performed on the Envision, percentage inhibition (PIN) was calculated based on the equation below and concentration response curves were plotted. Average half maximal inhibitory concentration (IC50) for DDR2 are reported in the table below. 100
Figure imgf000188_0001
n: negative control; p: positive control; RLU: Relative Light Unit and t: test compound
Table VIII. ADP-Glo™ DDR kinase assay IC50 of illustrative compounds of the invention.
* > 500 nM
** > 100 - 500 nM
*** > 10 - 100 nM
**** 0.01 - lO nM
NA not measured
Figure imgf000189_0001
Figure imgf000189_0002
Example 4. Cellular assays
4.1. In vitro screening: Kinase Cellular Assay (P-DDR1 Tyr792, IF Imaging)
[0425] Selected examples were tested in a DDR1 kinase cellular assay evaluating the inhibition of autophosphorylation (Tyr792) by immunofluorescence imaging read out. Compounds were tested in concentration response ranging from 0.0005-10 pM. HEK293 cells were seeded in 384 well plates and transfected with human DDR1 for transient over-expression. Compounds were added to serum-deprived cells and DDR1 receptors were stimulated with collagen I. Cells were fixed with PFA, blocked, and stained with Phospho-DDRl (Tyr792) primary antibody (CellSignaling) and Goat anti -Rabbit IgG Alexa-Fluor488 labelled secondary antibody. Hoechst 33342 was used to label cell nuclei. Immunofluorescence signals were measured by Opera Phenix and images were analysed using Acapella script based algorithms, developed at Evotec. The ratio of total phospho vs. background signal was calculated. Kinase activity (inhibition of DDR1 auto-phosphorlyation indicated by IF signal decrease) was reported as an IC50 (nM) as shown in Table 2.
Table IX. IC50 (nM) values of selected examples in DDR1 cellular assay
Figure imgf000190_0002
Figure imgf000190_0001
4.2. DDR1 Hek293T nanobret assay
4.2.1. Overview
[0426] The aim of this assay is to evaluate compounds fortheir binding characteristics to discoidin domaincontaining receptor 1 (DDR1) within intact cells, in this case Human Embryonic Kidney T (HEK293T) cells (originally referred to as 293tsA1609neo, a highly transfectable derivative of human embryonic kidney 293 cells containing the SV40 T-antigen) using bioluminescence resonance energy transfer (BRET) technology. A cell-permeable fluorescent tracer is used in a competitive binding format to quantify drug engagement with the target protein fused to NanoLuc luciferase. The key players of this proximity based assays are HEK293T cells transiently expressing NanoLuc -DDR1, NanoBRET Kinase Tracer-04 and NanoGio substrate. NanoLuc-DDRl will convert the NanoGio substrate to a biolumine scent protein (=BRET donor). If Kinase Tracer-04 (= BRET acceptor) binds NanoLuc-DDRl, donor and acceptor are in close proximity and upon NanoGio substrate addition, this will result in an energy transfer. A DDR1 inhibitor will go in competition with the Kinase Tracer-04 for binding to NanoLuc-DDRl and will thereby block the energy transfer between donor and acceptor. The acceptor and donor emission are measured at 610-630 nm and 450 nm respectively.
4.2.2. Protocol
[0427] Fourteen million HEK293T cells were transiently transfected using 70 pL JetPei, 2.33 pg DDR1- NanoLuc® Fusion Vector and 21 pg pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175).
[0428] After an overnight incubation at 37 °C, 5% CO2, 10 point serial dilutions of compounds were prepared in DMSO and diluted further in PBS (30 pM highest final concentration, 1/3 dilution steps). Four pL of the serial dilution was transferred to non-binding surface plates (2 copies).
[0429] The transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.04 pM NanoBRET Tracer-04 for DDR1.
[0430] Cells were seeded on top of the compounds at 8,000 cells per well in 36 pL
[0431] After 2 h incubation at 37 °C, 5 % CO2, 20 pL of the readout mix was added, containing Opti- MEM medium with 1/332 diluted NanoBRET Nano-Gio substrate and 1/2000 diluted extracellular NanoLuc inhibitor.
[0432] BRET was read out on the Envision within 10 min after addition of the substrate by recording donor (450 nm) and acceptor (610-630 nm) emissions.
Table X. Conditions for DDR1 HEK293T nanobret assay (final concentrations)
Figure imgf000191_0001
4.2.3. Data analysis and results
[0433] The ratio of the acceptor/donor emission was calculated and multiplied by 1000 to obtain data in mBRET units. These raw data were used to calculate percentage inhibition (PIN) relative to control wells, and creation of concentration-response curves. 4.3. DDR2 Hek293T nanobret assay
4.3.1. Overview
[0434] The aim of the two assays described in this protocol is to evaluate compounds for their binding characteristics to discoidin domain-containing receptor 2 (DDR2) within intact cells, in this case Human Embryonic Kidney T (HEK293T) cells (originally referred to as 293tsA1609neo, a highly transfectable derivative of human embryonic kidney 293 cells containing the SV40 T-antigen) using bioluminescence resonance energy transfer (BRET) technology. A cell-permeable fluorescent tracer is used in a competitive binding format to quantify drug engagement with the target protein fused to NanoLuc luciferase. The key players of this proximity based assays are HEK293T cells transiently expressing NanoLuc -DDR2, NanoBRET Kinase Tracer-04 and NanoGio substrate. NanoLuc-DDR2 will convert the NanoGio substrate to a bioluminescent protein (=BRET donor). If Kinase Tracer-04 (= BRET acceptor) binds NanoLuc - DDR2, donor and acceptor are in close proximity and upon NanoGio substrate addition, this will result in an energy transfer. A DDR2 inhibitor will go in competition with the Kinase Tracer-04 for binding to NanoLuc-DDR2 and will thereby block the energy transfer between donor and acceptor. The acceptor and donor emission are measured at 610-630 nm and 450 nm respectively.
4.3.2. Protocol
[0435] Fourteen million HEK293T cells were transiently transfected using 70 pL JetPei, 2.33 pg DDR2- NanoLuc® Fusion Vector and 21 pg pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175).
[0436] After an overnight incubation at 37 °C, 5% CO2, 10 point serial dilutions of compounds were prepared in DMSO and diluted further in PBS (30 pM highest final concentration, 1/3 dilution steps). Four pL of the serial dilution was transferred to non-binding surface plates (2 copies).
[0437] The transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.4 pM NanoBRET Tracer-04 for DDR2.
[0438] Cells were seeded on top of the compounds at 8,000 cells per well in 36 pL
[0439] After 2 h incubation at 37 °C, 5 % CO2, 20 pL of the readout mix was added, containing Opti- MEM medium with 1/332 diluted NanoBRET Nano-Gio substrate and 1/2000 diluted extracellular NanoLuc inhibitor.
[0440] BRET was read out on the Envision within 10 min after addition of the substrate by recording donor (450 nm) and acceptor (610-630 nm) emissions.
Table XI. Conditions for DDR2 HEK293T nanobret assay (final concentrations)
Figure imgf000192_0001
Figure imgf000193_0001
4.3.3. Data analysis and results
[0441] The ratio of the acceptor/donor emission was calculated and multiplied by 1000 to obtain data in mBRET units. These raw data were used to calculate percentage inhibition (PIN) relative to control wells, and creation of concentration-response curves.
Table XII. NANOBRET DDR kinase assay IC50 of illustrative compounds of the invention.
* > 5000 nM
** > 1000 - 5000 nM
*** > 100 - 1000 nM
**** 0.01 - 100 nM
NA not measured
Figure imgf000193_0002
Figure imgf000193_0003
Figure imgf000194_0002
Figure imgf000194_0001
4.4. Phospho-DDR Hek293T cell assay
4.4.1. Overview
[0442] The phospho-DDR assay is based on the immunofluorescent staining of the phosphorylated DDR1 and 2 isoforms after triggering human embryonic kidney 293T cells (HEK293T) cells with collagen.
4.4.2. Protocol
[0443] At day 1, 96-well plates were coated with 50 pL poly-D-lysine dissolved in PBS and incubated for 1 h at 37 °C. After removal of the coating, the plates were washed once with PBS and dried for 1 h.
[0444] HEK293T cells were harvested and transfected with wild type pcDNA3.1 hsDDRl (Uniprot# Q08345-2, SEQ ID 1) or hsDDR2 (Uniprot# Q16832, SEQ ID 2) plasmids. The cell suspension was prepared with the plasmid mix in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. 60,000 cells were seeded in 100 pL in the 96-well plates and cultured at 37 °C 5 % CO2 for 1 day.
[0445] The same day, serial dilutions of compounds were prepared in DMSO (30 pM highest final concentration, 1/5 or 1/3 dilution steps). 900 nL of the compounds were spotted in 96-well dilution plate.
[0446] The next day, the cells were refreshed with 30 pL of fresh medium. The compounds were diluted with 150 pL of medium. When adding the compounds onto the cells, 50 pL medium was added on top of the 30 pL already present in the plate.
[0447] After an incubation of 1 h at 37 °C, 5% CO2, 20 pL of collagen II (Chondrex Inc., Cat# 20022; final concentration: 50 ng/mL in 0.025 M AcOH; positive control) or vehicle (0.025 M AcOH; negative control) were added to the assay plates which were then further incubated for 1 day at 37 °C 5% CO2.
[0448] For immunofluorescent staining, fixation was performed with 3.7% paraformaldehyde for 30 min at RT. After incubation, the plates were washed 3 times with PBS to remove the paraformaldehyde.
[0449] Plates were blocked for 1 h with 50 pL blocking buffer containing 0.2% Triton X-100, 2% heat- inactivated FBS, 3% bovine serum albumin and 1% milk dissolved in PBS.
[0450] Next, 50 pL primary antibody solution in blocking buffer was added with rabbit anti-pDDRl Tyr792 antibody (Cell Signaling Technology, Inc., Cat# 11994S; 1/250 dilution) and mouse monoclonal anti-phosphotyrosine (anti-pDDR2), clone 4G10® (Millipore, Cat# 05-321; 1/250 dilution). Plates were incubated for 1 h at RT, protected from light. [0451] After the plates were washed twice with PBS-Tween 20 (PBS-T) and once with PBS, 50 pL secondary antibody mix was added with Alexa Fluor® 488 goat anti-mouse IgG (Thermo Fisher Scientific, Cat# Al 1029; 1/500 dilution), Alexa Fluor® 488 goat anti-rabbit IgG (Thermo Fisher Scientific, Cat# Al 1008; 1/500 dilution) and Hoechst 33342 (Thermo Fisher Scientific, Cat# H3570; 1/1000 dilution). Plates were incubated for 1 h at RT, protected from light.
[0452] Plates were then washed twice with PBS-T and once with PBS after which they were imaged on a GE Healthcare IN Cell Analyzer 2200.
[0453] After imaging for pDDR, plates were kept in the fridge until the staining for the total DDR (tDDR) . [0454] The PBS was removed from the plates and 50 pL primary antibody solution in blocking buffer was added with rabbit anti-DDRl antibody (Cell Signaling Technology, Inc., Cat# 5583S; 1/250 dilution) and goat anti DDR2 antibody (R&D Systems, Inc., Cat# AF2538; 1/250 dilution). Plates were incubated for 1 h at RT, protected from light.
[0455] After the plates were washed twice with PBS-T and once with PBS, 50 pL secondary antibody mix was added with Alexa Fluor® 647 conjugate goat anti -rabbit IgG (Thermo Fisher Scientific, Cat# A21245; 1/500 dilution), and Alexa Fluor® 647 conjugate chicken anti-goat IgG (Thermo Fisher Scientific, Cat# A21469; 1/500 dilution). Plates were incubated for 1 h at RT, protected from light.
[0456] Plates were then washed twice with PBS-T and once with PBS after which they were imaged on a GE Healthcare IN Cell Analyzer 2200.
4.4.3. Data analysis and results
[0457] Phospho-DDR staining was quantified using the GE Healthcare IN Cell Developer software. Data were imported in the Phaedra software (Open Analytics NV) for automated calculation of percentage (%) inhibition using the controls and creation of concentration response curves. These raw data were used to calculate percentage inhibition (PIN) relative to control wells, and creation of concentration-response curves. Average half maximal inhibitory concentration (IC50) for DDR1 and DDR2 are reported in the table below.
Table XIII. Phospho DDR kinase assay IC50 of illustrative compounds of the invention.
* > 5000 nM
** > 1000 - 5000 nM
*** > 100 - 1000 nM
**** 0.01 - 100 nM
NA not measured
Figure imgf000195_0001
Example 5. ADME assays
5.1. Liver microsomal stability
[0458] A 10 mM stock solution of compound in DMSO was diluted three-fold in DMSO. This pre-diluted compound solution was then diluted to 2 pM in a 100 mM phosphate buffer (pH 7.4) and pre-warmed at 37 °C. This compound dilution was mixed with an equal volume of microsomal/cofactor mix at 37 °C under shaking at 300 rpm.
[0459] Final reaction conditions are: 100 pL incubation volume, 1 pM of test compound (n=2), 0.2% DMSO, 0.5 mg/mL microsomes (Xeno-Tech, Cat# H0620), 0.6 U/mL glucose-6-phosphate-dehydrogenase (G6PDH, Roche, Cat# 10127671001), 3.3 mM MgChCSigma, Cat# M2670), 3.3 mM glucose-6-phosphate (Sigma, Cat# G-7879) and 1.3 mM NADPt (Sigma, Cat# N-0505).
[0460] After 30 min of incubation at 300 rpm and 37 °C, the reaction was stopped with 600 pL of STOP solution (acetonitrile with diclofenac as internal standard). For the zero time point, 600 pL of STOP solution was added to the compound dilution before the microsome mix was added.
[0461] The samples of both time points were centrifuged, filtered and the supernatant analyzed by LC- MS/MS.
[0462] Verapamil (1 pM) and warfarin (1 pM) were used as unstable and stable reference compounds respectively. If the microsomal stability values for these controls were not in the historical ranges, the assay was not validated.
[0463] The data on microsomal stability are expressed as a percentage of the total amount of compound remaining after 30 min incubation.
[0464] The solubility of the compound in the final test concentration in 100 mM phosphate buffer pH 7.4 was checked by microscope to indicate whether precipitation was observed or not. If a precipitate was observed, no microsomal stability data was generated.
Table XIV. Microsomal stability of illustrative compounds of the invention
Figure imgf000196_0001
Figure imgf000196_0002
5.2. Metabolic stability in hepatocytes
[0465] The aim of this assay is to determine the metabolic stability of the compound in hepatocytes (cryopreserved) of different species. Low hepatocyte stability may result in the formation of unwanted metabolites, high clearance, and therefore is not desirable.
[0466] The decrease in parent was assessed by measuring the percentage remaining by LC-MS/MS analysis. [0467] A 10 mM stock solution of test compound in DMSO was first diluted in DMSO to 3 mM, and then in modified Krebs-Henseleit buffer (Sigma, Cat# K3753) to 5 pM. This compound dilution was added to a suspension of pooled cryopreserved hepatocytes (BioreclamationIVT) at 37 °C under gentle shaking.
[0468] Final reaction conditions were: 1 pM of test compound, 0.03% DMSO, 0.5 million viable hepatocytes/mL, and 75 pL incubation volume.
[0469] Testosterone (1 pM) and 7-hydroxycoumarin (1 pM) were used, respectively as phase I and phase II metabolic reaction controls.
[0470] After 0, 10, 20, 45, 90, 120 and 180 min of incubation, the reaction was terminated with 225 pL of ACN:MeOH (2: 1) containing 100 ng/mL of diclofenac as analytical internal standard. Samples were mixed, centrifuged and the supernatant analyzed by LC-MS/MS.
[0471] The instrument responses (ratios of test compound and internal standard peak areas) were referenced to the zero time point samples (considered as 100%) in order to determine the percentage of compound remaining.
Table XV. Hepatocyte stability of illustrative compounds of the invention
Figure imgf000197_0001
Figure imgf000197_0002
Example 6. In vivo assays
6.1. Radiation induced fibrosis mouse model
6.1.1. Study overview
[0472] Pneumonitis and lung fibrosis are the major radiation-induced complications following thoracic radiotherapy, which is one of the major treatment of lung and breast cancers, lymphomas and hematopoietic transplant conditioning. The objective of this model is to evaluate the effect of a compound of the invention in lung fibrosis induced by radiation in mice (Favaudon et al. 2014), in particular on lung functionality and fibrosis marker (Collagen I).
6.1.2. Animals
[0473] 7 weeks old (18-22 g) albinos female C57BL/6J mice from Charles River (Ecully, France) were maintained on 12 h light/dark cycle at 22 °C with ad libitum access to tap water and food.
6.1.3. Materials
[0474] The test compounds were dissolved/suspended in appropriate vehicle prior to using and kept light- free, under agitation at RT.
[0475] An aliquot of the formulation (-200 pL) was frozen at TO (day of preparation) and all the formulations were checked (daily) for any change in aspect. [0476] The dose volume administered was 10 mL/kg and the volume was adapted following mean (body weight (BW) of the group as follows: 200 pL if mean BW < 22.5 g, 250 pL if mean BW > 22.5 g; 300 pL if mean BW > 27.5 g.
6.1.4. In vivo experimental procedure
[0477] On day 1 of week 1, the animals were exposed at the thorax to a 17 Gray irradiation dose, under isoflurane anesthesia.
[0478] At the beginning of week 13 post radiation (DI), animals were randomized into 4 study groups (15 subjects per group): 1) sham (dosed p.o. b.i.d. with vehicle: PEG200/methylcellulose (MC) 0.5% (25/75)), 2) diseased (dosed p.o. b.i.d. with vehicle: PEG200/methylcellulose (MC) 0.5% (25/75)), 3) positive control (dosed p.o. q.d. with nintedanib 60 mg/kg in 0.1% Natrosol™), and 4) test compound (dosed p.o. b.i.d. with 10 mg/kg test compound in Captisol®/acetate buffer pH 4.6 (20/80)), and dosed daily from D23 until D43 (week 19).
[0479] Body weight was recorded on D23, D27, D30, D33, D36, and D41.
[0480] On D43, the mice were sacrificed, and the lungs collected, wheighed, and fixed in 4% formaldehyde for 24 h before embedding in paraffin. 4 pm thick sections were immunostained with anti-collagen I antibody (LifeSpan BioSciences, Inc., Cat# LS-343921). The sections were deparaffmized and processed by heat antigen retrieval before incubation for 1 h with the primary antibody. The anti-collagen I antibody was detected and amplified by ImmPress kit (Vector Laboratories, Ltd., Cat# MP-7401). The immunostained sections were then scanned (Nanozoomer, Hamamatsu Photonics K.K.) before quantification by image analysis (CaloPix software, TRIBVN Healthcare SAS). Data are expressed as percentage collagen I area per area of lung tissue.
[0481] Values of all mice from the same group are averaged. Data are expressed as mean ± sem and are compared with a one-way ANOVA on the arcsinh(log) -transformed data and Dunnett’s post-hoc test. Significance levels are defined as * (p<0.05), ** (p<0.01), or *** (p<0.001) versus irradiated control group.
6.1.5. Results
[0482] When subjected to this protocol, Cpd 5 dosed at 10 mg/kg p.o. b.i.d. showed a statistically significant decrease of the percentage collagen I area per area of lung tissue, compared to the vehicle group.
6.2. Therapeutic bleomycin induced pulmonary fibrosis 21-day mice model
6.2.1. Study overview
[0483] The aim of the study is to test the efficacy of a test compound at three different doses in a 21-day model of bleomycin induced pulmonary fibrosis in mice.
6.2.2. Animals
[0484] This study was carried out on C57BL/6 male mice (Charles River, Italy), which were acclimatized for at least 5 days in an environment maintained at 22 °C, at 55% relative humidity, with 15-20 air changes per hour under light cycles of 12 h. Mice pelleted food and water were provided ad libitum. [0485] At least one day prior to start of experiment, all animals were allocated randomly into groups as indicated in the table below.
Table XVI. Study groups
Figure imgf000199_0001
6.2.3. Materials
[0486] The solvent for the test solutions was prepared by adding 50 g of Captisol® (CyDex Pharmaceuticals, Inc., USA, Cat# RC-0C7) into 250 mL acetate buffer 50 mM, pH 4.6, and mixing under magnetic stirring at RT for 2 to 3 h.
[0487] To prepare a solution for intranasal (i.n.) challenge, 10 mg of bleomycin (Cat# BML-AP302-0010, Enzo Life Sciences, Inc., USA) were dissolved with 16.7 mL of saline resulting in a 0.6 mg/mL stock solution. The solution was aliquoted (1 mL aliquots) and stored at -20 °C until thawed for application. The volume for the challenge was 50 qL/mousc. Prior to i.n. administration, mice were anesthetized i.p..
[0488] A fresh nintedanib formulation was prepared daily in 0. 1% Natrosol™ to a final concentration of 6 mg/mL. Before dosing, animals were weighed and the nintedanib amount administered was adjusted accordingly to individual weights corresponding to 10 mL/kg body weight, once daily p.o..
[0489] finally, test compound solutions were prepared by dissolving the suitable amount of said test compound in Captisol ®/acetate buffer 50 mM, pH 4.6 solution, and sonicating for 5 min, to reach final concentrations of 1 mg/mL and 5 mg/mL, thus yielding compound for doses of 10 mg/kg and 50 mg/kg. Prior to dosing, animals were weighed and the amount administered adjusted accordingly to individual weights.
6.2.4. Study
[0490] Animals were examined clinically twice daily. Animals were weighed on DO, D3 and daily from D6 until D21.
[0491] On D21, 2 h post dosing with vehicle, nintedanib or test compound, mice were sacrificed. [0492] The lungs were excised and weighed individually. For all groups: the whole superior right lung lobe was cut in half. One part was quickly placed into Eppendorf safe lock tubes (2 m round bottom) with 1 m of RNA/a r® solution (ThermoFischer Scientific, Cat# AM7020) and stored at 4 °C for 24 h, then frozen at -80 °C. The other part was quickly snap frozen in liquid nitrogen.
[0493] All remaining lungs were placed into marked bottles containing 10% buffered formalin for further histopathological evaluation.
6.2.5. Sample analysis, data processing and statistical evaluation
[0494] Body weight data and lung weight data were processed using MS Excel. Statistical analysis and graphical presentation were performed using GraphPad Prism software. A Mann-Whitney test was employed for lung weights. A two-way ANOVA was employed for body weight changes. Differences between groups were considered statistically significant when p<0.05.
[0495] For histopathological evaluation, whole lungs (except sampled superior right lung) were embedded in paraffin and stained with Crossman's trichrome for muscle and collagen.
[0496] Pulmonary histological changes were assessed using Matsuse’s modification of Ashcroft score (Ashcroft et al. 1988; Matsuse et al. 1999). Statistical analysis and graphical presentation were performed using GraphPad Prism software. A Mann-Whitney test was employed. Differences between groups were considered statistically significant when p<0.05.
Figure imgf000200_0001
6.2.6. Results
[0497] When subjected to this protocol, Cpd 5 dosed at 10 mg/kg p.o. b.i.d. showed a statistically significant increase of the bodyweight, decrease of the lung weight, and decrease of the Ashcroft score compared to the vehicle group.
6.3. Murine sclerodermatous chronic graft-versus host disease (cGvHD)
6.3.1. General overview
[0498] In this cGvHD model, fibrosis is induced in BAEB/c (H2d) mice by allogeneic transplantation of bone marrow cells and splenocytes from B10.D2 (H2d) donor mice (minor HLA mismatch). The recipient mice develop inflammation-driven dermal and pulmonary fibrosis resembling patients with rapidly progressive diffuse cutaneous systemic sclerosis (Zerr et al. 2012).
[0499] The treatment is provided only after the onset of first clinical symptoms of sclerodermatous cGvHD.
6.3.2. Study groups
[0500] The following groups with each eight mice are used in this study
Syngeneically transplanted, placebo-treated control group:
Syngeneic bone marrow and splenocyte transplantation (BALB/c (H2d) BALB/c (H2d)). Application of methyl cellulose 0.5% from day 21 to day 56 post transplantation.
Vehicle-treated fibrosis group:
Allogeneic bone marrow and splenocyte transplantation (B10.D2 (H2d)
Figure imgf000201_0001
BALB/c (H2d)).
Application of methyl cellulose 0.5% from day 21 to day 56 post transplantation
Control group to assess pretreatment levels of fibrosis induced by allogeneic transplantation: Allogeneic bone marrow and splenocyte transplantation (B10.D2 (H2d) BALB/c (H2d)). Sacrifice at day 21, before treatment is initiated in the other groups.
Treatment group:
Allogeneic bone marrow and splenocyte transplantation (B10.D2 (H2d)
Figure imgf000201_0002
BALB/c (H2d)).
Application of a test compound of the invention from day 21 to day 56 post transplantation.
Positive control group:
Allogeneic bone marrow and splenocyte transplantation (B10.D2 (H2d)
Figure imgf000201_0003
BALB/c (H2d)). Application of 50 mg/kg qd nintedanib from day 21 to day 56 post transplantation.
6.3.3. Steady state PK
[0501] On D20, for the groups receiving test compounds, blood is collected from the tail vein from 2 animals per timepoint, at the following timepoints: pre-dose, 1, 3 and 6 h with anticoagulant Li-heparin.
[0502] The blood samples are kept on ice and centrifuged at approx. 3500 x g. for 10 min at +4 °C, within 1 h after blood sampling; plasma is transferred in polypropylene tubes and stored at -20 °C.
6.3.4. Sampling and analysis
[0503] Animals are sacrificed 2 h post last dose, and samples of skin (3 mm punch biopsies), lung, spleen and blood are collected for histology and gene expression analysis.
6.3.5. Main readouts
[0504] The anti-fibrotic effects on skin are analysed by determination of dermal thickness, quantification of lesional collagen and staining for myofibroblasts.
[0505] In case of positive effects on skin fibrosis, effects on pulmonary fibrosis are analysed by Ashcroft scoring, hydroxyproline content, and quantification of the collagen covered area using Sirius red staining. 6.3.6. Analysis
[0506] Based on individual animal raw data, the means for each group are determined and percent change from disease controls is calculated. Treatment groups are compared to disease controls using a one-way analysis of variance (1-way ANOVA) with a Dunnett’s post-hoc analysis for measured (parametric) data or a Kruskal -Wallis test with a Dunn’s post-hoc analysis for scored (non-parametric) data.
6.4. Surgical destabilization of the medial meniscus (DMM) mouse model of osteoarthritis
[0507] The experiment assesses disease-modifying osteoarthritis drug (DMOAD) effect by prophylactic treatment of compounds that inhibits the structural disease progression of OA and ideally also improves symptoms and/or function.
[0508] DMM surgery is performed in the right knees of 10-week old male C57BL/6 mice. For the prophylactic study, systemic (p.o.) treatment starts at the time of surgery. Mice are sacrificed 8 weeks after surgery, and another group are sacrificed 12 weeks after surgery. Knees are harvested for detailed histopathological assessment (Glasson et al. 2007). Thus, the DMM model uniquely captures the chronic progressive nature of OA and associated sensitization and pain-related behaviours. Knees are collected for histology, following standard methods (Miller et al. 2016).
FINAL REMARKS
[0509] It will be appreciated by those skilled in the art that the foregoing descriptions are exemplary and explanatory in nature, and intended to illustrate the invention and its preferred embodiments. Through routine experimentation, an artisan will recognize apparent modifications and variations that may be made without departing from the spirit of the invention. All such modifications coming within the scope of the appended claims are intended to be included therein. Thus, the invention is intended to be defined not by the above description, but by the following claims and their equivalents.
[0510] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication are specifically and individually indicated to be incorporated by reference herein as though fully set forth.
[0511] It should be understood that factors such as the differential cell penetration capacity of the various compounds can contribute to discrepancies between the activity of the compounds in the in vitro biochemical and cellular assays.
[0512] At least some of the chemical names of compound of the invention as given and set forth in this application, may have been generated on an automated basis by use of a commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc., the Marvin software sold by ChemAxon Ltd., and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control. REFERENCES
Ashcroft T, Simpson JM, Timbrell V. 1988. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J. Clin. Pathol. 41, 467-470.
Berestjuk I et al. 2019. Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy. bioRxtv, 857896.
Borza CM, Pozzi A. 2014. Discoidin domain receptors in disease. Matrix Biol. 34, 185-192.
Brunner AM et al. 2013. Treatment-related Toxi cities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung: A Brief Report. J. Thorac. Oncol. Off. Puhi. Int. Assoc. Study Lung Cancer 8, 1434-1437.
Bundgaard H. 1985. Design of prodrugs, Elsevier.
Favaudon V et al. 2014. Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci. Transl. Med. 6, 245ra93.
Glasson SS, Blanchet TJ, Morris EA. 2007. The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 15, 1061-1069.
Li Y et al. 2015. Small Molecule Discoidin Domain Receptor Kinase Inhibitors and Potential Medical Applications: Miniperspective. J. Med. Chem. 58, 3287-3301.
Matsuse T et al. 1999. ICAM-1 mediates lung leukocyte recruitment but not pulmonary fibrosis in a murine model of bleomycin-induced lung injury. Eur. Respir. J. 13, 1\-T1.
Miller RE et al. 2016. Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthritis Cartilage 24, 299-306.
Ruggeri JM et al. 2020. Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma. Am. J. Pathol. 190, 1735-1751.
Stahl PH, Wermuth CG eds. 2011. Handbook of Pharmaceutical Salts: Properties, Selection, and Use 2nd revised edition., Wiley-VCH Verlag GmbH & Co. KGaA.
Vella V et al. 2019. Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection. Biochim. Biophys. Acta BBA - Mol. Cell Res. 1866, 118522.
Wuts PGM, Greene TW. 2014. Greene ’s protective groups in organic synthesis Fifth edition., Wiley, Hoboken, NJ.
Zerr P et al. 2012. Combined Inhibition of c-Abl and PDGF Receptors for Prevention and Treatment of Murine Sclerodermatous Chronic Graft-versus-Host Disease. Am. J. Pathol. 181, 1672-1680.

Claims

1. A compound according to Formula I:
Figure imgf000204_0001
I wherein,
Het is 6 membered monocyclic heteroaryl or 8-10 membered fused bicyclic heteroaryl, which heteroaryl comprises one, two, or three N; n is 0 or 1;
Li is -O-, or -CR5aR5b-;
L2 is -C(=O)NH- or -NHC(=O)-;
L3 is C3-6 cycloalkyl or C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6;
R1 is
C3-6 cycloalkyl unsubstituted or substituted with one or more independently R7,
C2-6 alkenyl,
C1-4 alkyl unsubstituted or substituted with one or more independently selected halo, or
4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged polycyclic heterocycloalkyl, or 6-10 membered fused bicyclic heterocycloalkyl, which heterocycloalkyl comprises one, two, or three heteroatoms independently selected from N and O, and is unsubstituted or substituted with one or more independently selected R7;
R2 is H, C1-4 alkyl, or C1-4 alkoxy, which C1-4 alkyl or C1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
R3a is H or C1-4 alkyl unsubstituted or substituted with one -OH or C3-6 cycloalkyl;
R3b is H, or R3b together with L3 and the atoms onto which they are attached form a 5-6 membered monocyclic heterocyloaklyl comprising one N;
R4 is C1-4 alkyl;
R5a and R5b are independently H or -CH3; each R6 is independently selected from: halo,
- -OH,
- -NR8aR8b,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo,
C3-6 cycloalkyl, and 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O, which heterocycloalkyl is unsubstituted or substituted with one or more C1-4 alkyl or -C(=O)-O-Ci-6 alkyl; each R7 is independently selected from: halo,
C1-6 alkyl unsubstituted or substituted with one or more independently selected R9,
C1-4 alkoxy,
- -C(=O)-Ci.4 alkyl,
C3-6 cycloalkyl,
' -NR10aR10b, and
4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R9 is independently selected from: halo,
- -OH,
- -CN,
C3-6 cycloalkyl,
C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and
- -NRllaRllb; each R10a and R10b is independently H or C1-4 alkyl; each R8a, R8b, Rlla, and Rllb is independently H, C1-4 alkyl, or -C(=O)-O-Ci-6 alkyl; or a pharmaceutically acceptable salt, or a solvate, or the salt of the solvate thereof.
2. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein R4 is -CH3.
3. A compound or pharmaceutically acceptable salt thereof, according to claim 1 or 2, wherein Het is benzimidazolyl, indazolyl, or pyridinyl.
4. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula Illa, Illb, or IIIc:
Figure imgf000205_0001
IIIc A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula Va or Vb:
Figure imgf000206_0001
Va Vb
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein R2 is H, CH3, or CF3.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein Li is -O- or -CH2-.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, wherein L3 is cyclobutyl, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH(CH3)CH2-, -CH2CH(CH3)-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein R1 is C1-4 alkyl unsubstituted or substituted with one or more independently selected halo.
A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula IXa, IXb, IXc, IXd, IXe, or IXf:
Figure imgf000206_0002
IXc IXd
Figure imgf000207_0001
IXe IXf
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein R3a is H, CH3, -CH2CH3, -CFb-cyclopropyl or -CH2CH2OH.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-11, wherein R6 is -OH, -O-CH3, -O-CH2CF3, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, or a pharmaceutical composition according to claim 13 for use in medicine.
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, or a pharmaceutical composition according to claim 13 for use in the prophylaxis and/or treatment of fibrotic diseases, inflammatory diseases, respiratory diseases, autoimmune diseases, metabolic diseases, cardiovascular diseases, and/or proliferative diseases.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180022730A1 (en) * 2014-10-22 2018-01-25 The Board Of Regents Of The University Of Texas System Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof
WO2022008383A1 (en) * 2020-07-08 2022-01-13 Galapagos Nv Isoquinoline derivatives and pharmaceutical compositions thereof for the treatment of diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180022730A1 (en) * 2014-10-22 2018-01-25 The Board Of Regents Of The University Of Texas System Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof
WO2022008383A1 (en) * 2020-07-08 2022-01-13 Galapagos Nv Isoquinoline derivatives and pharmaceutical compositions thereof for the treatment of diseases

Non-Patent Citations (17)

* Cited by examiner, † Cited by third party
Title
"Handbook of Pharmaceutical Salts: Properties, Selection, and Use 2nd revised edition.", 2011, WILEY-VCH VERLAG GMBH & CO. KGAA
ASHCROFT TSIMPSON JMTIMBRELL V: "Simple method of estimating severity of pulmonary fibrosis on a numerical scale", J. CLIN. PATHOL., vol. 41, 1988, pages 467 - 470
BERESTJUK I ET AL.: "Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy", BIORXIV, 2019, pages 857896
BORZA CMPOZZI A: "Discoidin domain receptors in disease", MATRIX BIOL, vol. 34, 2014, pages 185 - 192, XP055357838, DOI: 10.1016/j.matbio.2013.12.002
BRUNNER AM ET AL.: "Treatment-related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung: A Brief Report", J. THORAC. ONCOL. OFF. PUBL. INT. ASSOC. STUDY LUNG CANCER, vol. 8, 2013, pages 1434 - 1437
BUNDGAARD H.: "Remington's Pharmaceutical Sciences", 1985, MACK PUBLISHING COMPANY
FAVAUDON V ET AL.: "Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice", SCI. TRANSL. MED., vol. 6, 2014
GLASSON SSBLANCHET TJMORRIS EA: "The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse", OSTEOARTHRITIS CARTILAGE, vol. 15, 2007, pages 1061 - 1069, XP022237886, DOI: 10.1016/j.joca.2007.03.006
LI Y ET AL.: "Small Molecule Discoidin Domain Receptor Kinase Inhibitors and Potential Medical Applications: Miniperspective", J. MED. CHEM., vol. 58, 2015, pages 3287 - 3301, XP055558686, DOI: 10.1021/jm5012319
MATSUSE T ET AL.: "ICAM-1 mediates lung leukocyte recruitment but not pulmonary fibrosis in a murine model of bleomycin-induced lung injury", EUR. RESPIR. J., vol. 13, 1999, pages 71 - 77
MILLER RE ET AL.: "Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis", OSTEOARTHRITIS CARTILAGE, vol. 24, 2016, pages 299 - 306, XP029388361, DOI: 10.1016/j.joca.2015.09.005
RUGGERI JM ET AL.: "Discoidin Domain Receptor 1 (DDR1) Is Necessary for Tissue Homeostasis in Pancreatic Injury and Pathogenesis of Pancreatic Ductal Adenocarcinoma", AM. J. PATHOL., vol. 190, 2020, pages 1735 - 1751
VELLA V ET AL.: "Insulin/IGF signaling and discoidin domain receptors: An emerging functional connection", BIOCHIM. BIOPHYS. ACTA BBA - MOL. CELL RES, vol. 1866, 2019, pages 118522, XP085763121, DOI: 10.1016/j.bbamcr.2019.118522
WUTS PGMGREENE TW: "Greene's protective groups in organic synthesis", 2014, WILEY
Z. WANG ET. AL.: "Tetrahydroisoquinoline-7-carboxamide Derivatives as New Selective Discoidan Domain Receptor 1 (DDR1) Inhibitors.", ACS MEDICINAL CHEMISTRY LETTERS, vol. 8, no. 3, 9 February 2017 (2017-02-09), pages 327 - 332, XP055553533, DOI: 10.1021/acsmedchemlett.6b00497 *
Z. WANG ET. AL.: "Tetrahydroisoquinoline-7-carboxamides as Selective Discoidan Domain Receptor 1 (DDR1) Inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 12, 24 May 2016 (2016-05-24), pages 5911 - 5916, XP055335989, DOI: 10.1021/acs.jmedchem.6b00140 *
ZERR P ET AL.: "Combined Inhibition of c-Abl and PDGF Receptors for Prevention and Treatment of Murine Sclerodermatous Chronic Graft-versus-Host Disease. Am", J. PATHOL., vol. 181, 2012, pages 1672 - 1680

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