WO2022008383A1 - Isoquinoline derivatives and pharmaceutical compositions thereof for the treatment of diseases - Google Patents

Isoquinoline derivatives and pharmaceutical compositions thereof for the treatment of diseases Download PDF

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Publication number
WO2022008383A1
WO2022008383A1 PCT/EP2021/068377 EP2021068377W WO2022008383A1 WO 2022008383 A1 WO2022008383 A1 WO 2022008383A1 EP 2021068377 W EP2021068377 W EP 2021068377W WO 2022008383 A1 WO2022008383 A1 WO 2022008383A1
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Prior art keywords
compound
pharmaceutically acceptable
methyl
acceptable salt
azabicyclo
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PCT/EP2021/068377
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French (fr)
Inventor
Agnès Marie JONCOUR
Mathieu Rafaël PIZZONERO
Thi Thu Trang Mai
Marina Modric
Evelyne Martine QUINTON
Christopher Charles Stimson
Olivier Remi BARBEAU
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Galapagos Nv
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Publication of WO2022008383A1 publication Critical patent/WO2022008383A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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; Rugged 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).
  • 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.
  • 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.
  • DDRs discoidin domain receptors
  • the compounds of the invention may exhibit good metabolic stability, which may result in lower dosage regimen.
  • the compounds of the invention show good stability in hepatocytes, which may result in low hepatic clearance.
  • 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.
  • 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 [0015] 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.
  • 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 (-CH 3 ), ethyl (-CH 2 -CH 3 ), n-propyl (-CH 2 -CH 2 -CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (- CH 2 -CH 2 -CH 2 -CH 3 ), tert-butyl (-CH 2 -C(CH 3 ) 3 ), sec-butyl (-CH 2 -CH(CH 3 ) 2 ), n-pentyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), n-hexyl (-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 ), and 1,2-dimethylbutyl (-CHCH 3 )-C(CH 3 )H 2 -CH 2 -CH 3 ).
  • 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 (-CH 2 -), ethylene (-CH 2 -CH 2 -), or -CH(CH 3 )- 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-C 1-6 alkyl.
  • alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 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. 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.
  • 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.
  • 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.
  • 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.
  • 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. 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.
  • heterocycloalkenyl means a ‘heterocycloalkyl’, which comprises at least one double bond.
  • each W and Y is independently selected from -CH 2 -, -NH-, -O- and –S-.
  • Particular examples of fused bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH 2 -, -NH-, -O- and –S-.
  • Particular examples of bridged bicyclic rings are shown in the following illustrative examples: wherein each W and Y is independently selected from -CH 2 -, -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 -CH 2 -, -NH-, -O- and –S-.
  • ‘Hydroxyl’ 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).
  • term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents.
  • ‘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.
  • ‘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, N-alkylmorpholine 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, EtOH, 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’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e.
  • prophylactic measures are 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.
  • 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.
  • endotoxin-driven disease states e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure
  • related diseases involving cartilage such as that of the joints.
  • 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, 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 onset
  • 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
  • Sjögren’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.
  • 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.
  • the term ‘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.
  • arrhythmia atrial or ventricular or both
  • atherosclerosis and its sequelae angina
  • cardiac rhythm disturbances myocardial ischemia
  • myocardial infarction cardiac or vascular aneurysm
  • vasculitis stroke
  • 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 le
  • cancer refers to cancer, leukemia, multiple myeloma and psoriasis.
  • 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
  • the cancer is pancreatic cancer and/or melanoma.
  • 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
  • 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.
  • 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”).
  • 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 ( 11 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 Cl), chlorine-37 ( 37 Cl), 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.
  • 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 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • 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 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.
  • compounds of the invention may be metabolized to yield biologically active metabolites.
  • 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.
  • the compound of the invention is according to Formula I, wherein R 3 is C 1-4 alkyl. In a particular embodiment, R 3 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 . In a more particular embodiment, R 3 is -CH 3 or -CH 2 CH 3 . In a most particular embodiment, R 3 is -CH 3 . [0079] In one embodiment, the compound of the invention is according to Formula II: wherein R 1 , R 2 , L 1 , L 2 , and L 3 are as described previously.
  • the compound of the invention is according to any one of Formulae I-IVb, wherein R 2 is C 1-4 alkyl.
  • R 2 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 .
  • R 2 is -CH 3 or -CH 2 CH 3 .
  • R 2 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVb, wherein R 2 is C 1-4 alkyl substituted with one or more independently selected halo.
  • 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 C 1-4 alkyl substituted with one, two, or three independently selected halo.
  • R 2 is C 1-4 alkyl substituted with one or more independently selected F, Cl, or Br.
  • R 2 is -CH 3 , -CH 2 CH 3 , or -CH(CH 3 ) 2 , each of which is substituted with one, two, or three independently selected F, Cl, or Br.
  • R 2 is -CF 3 or -CH 2 CF 3 . In a most particular embodiment, R 2 is -CF 3 .
  • the compound of the invention is according to any one of Formulae I-IVb, wherein R 2 is C 1-4 alkoxy. In a particular embodiment, R 2 is –O-CH 3 , –O-CH 2 CH 3 , or –O-CH(CH 3 ) 2 . In a more particular embodiment, R 2 is –O-CH 3 .
  • the compound of the invention is according to any one of Formulae I-IVb, wherein R 2 is C 1-4 alkoxy substituted with one or more independently selected halo.
  • R 2 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.
  • R 2 is C 1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 2 is C 1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 2 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.
  • R 2 is -O-CH 3 substituted with one, two, or three F. In a most particular embodiment, R 2 is -O-CF 3 .
  • the compound of the invention is according to Formula Va or Vb: wherein R 1 , L1, and L3 are as described previously.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein L 1 is –O-.
  • the compound of the invention is according to any one of Formulae I-Vb, wherein L1 is –CR 4a R 4b -, and R 4a and R 4b are as previously described. In a particular embodiment, R 4a and R 4b are both H.
  • R 4a and R 4b are H, and the other is –CH 3 . In yet another particular embodiment, R 4a and R 4b are both –CH 3 . [0091] In one embodiment, the compound of the invention is according to Formula VIa, VIb, or VIc:
  • the compound of the invention is according to any one of Formulae I-VIc, wherein L 3 is C 1-6 alkylene.
  • 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(CH 2 CH(CH 3 ) 2 )-, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 -, -
  • L3 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 -. In a most particular embodiment, L3 is -CH 2 -.
  • the compound of the invention is according to any one of Formulae I-VIc, wherein L3 is C 1-6 alkylene substituted with one or more independently selected R 6 .
  • L3 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 C 1-6 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 )- , -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 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH
  • L3 is C 1-6 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 .
  • L3 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 .
  • L3 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
  • 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 Formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf: wherein R 1 , and R 6 are as described previously.
  • the compound of the invention is according to Formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe, or VIIIf: wherein R 1 , and R 6 are as described previously.
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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 pyrrolidinyl, piperidinyl, or morpholinyl.
  • the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R 1 is , , or .
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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 5 .
  • 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 5 .
  • 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 5 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R 5 .
  • 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 5 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R 5 .
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R 5 .
  • the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R 1 is or .
  • the compound of the invention is according to any one of Formulae Formulae I-VIIIf, wherein R 1 is [0098]
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-
  • 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.
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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 5 .
  • R 1 is 1-azabicyclo[2.1.1]hexanyl, 3- azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-oxabicyclo[2.1.1]hexanyl, 5- oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl,
  • 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 5 .
  • 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 5 .
  • R 1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5- azabicyclo[2.1.1]hexanyl, 3-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1- 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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl,
  • 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 5 .
  • 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 5 .
  • the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R 1 is [0100]
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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-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-di
  • R 1 is octahydropyrrolo[1,2- a]pyrazinyl.
  • the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R 1 is [0101]
  • the compound of the invention is according to any one of Formulae I-VIIIf, 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 5 .
  • 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[3.2.0]heptanyl, 3,6-diazabic
  • 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 5 .
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R 5 .
  • 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[3.2.0]heptanyl, 3,6-diazabic
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R 5 .
  • R 1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R 5 .
  • the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R 1 is .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , and R 5 is C 1-6 alkyl.
  • R 5 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 5 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 5 is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , and R 5 is C 1-6 alkyl substituted with one or more independently selected R 7 .
  • R 5 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 7 .
  • R 5 is C 1-6 alkyl substituted with one, two, or three independently selected R 7 .
  • R 5 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one or more independently selected R 7 .
  • R 5 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 7 .
  • R 5 is -CH 3 or -CH 2 CH 3 , each of which is substituted with one, two, or three independently selected R 7 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , R 5 is C 1-6 alkyl substituted with one or more independently selected R 7 , and R 7 is halo, -OH, or -CN.
  • R 7 is F, Cl, Br, -OH, or -CN. In a more particular embodiment, R 7 is F, -OH, or -CN.
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , R 5 is C 1-6 alkyl substituted with one or more independently selected R 7 , and R 7 is C3-6 cycloalkyl.
  • R 7 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 7 is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , R 5 is C 1-6 alkyl substituted with one or more independently selected R 7 , and R 7 is C 1-4 alkoxy.
  • R 7 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . In a particular embodiment, R 7 is -O-CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , R 5 is C 1-6 alkyl substituted with one or more independently selected R 7 , and R 7 is C 1-4 alkoxy substituted with one or more independently selected halo.
  • R 7 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.
  • R 7 is C 1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 7 is C 1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 7 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.
  • R 7 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.
  • R 7 is -O-CH 3 substituted with one, two, or three F.
  • R 7 is -O-CF 3 .
  • R 10a and R 10b are both H.
  • R 10a and R 10b are both independently -CH 3 , –CH 2 CH 3 , or –CH(CH 3 ) 2 .
  • R 10a and R 10b are both -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , and R 5 is C 1-4 alkoxy.
  • R 5 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 .
  • R 5 is -O-CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , and R 5 is C3-6 cycloalkyl.
  • R 5 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 5 is cyclopropyl or cyclobutyl.
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , R 5 is -NR 8a R 8b , and R 8a and R 8b are independently H or C 1-4 alkyl.
  • R 8a and R 8b are both H. In another particular embodiment, one of R 8a and R 8b is H, and the other is C 1-4 alkyl. In yet another particular embodiment, R 8a and R 8b are both independently C 1-4 alkyl. In a more particular embodiment, one of R 8a and R 8b is H, and the other is -CH 3 , –CH 2 CH 3 , or –CH(CH 3 ) 2 . In another more particular embodiment, R 8a and R 8b are both independently -CH 3 , –CH 2 CH 3 , or –CH(CH 3 ) 2 . In a most particular embodiment, R 8a and R 8b are both -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIIIf, wherein R 1 is 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 5 , and R 5 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O.
  • R 5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R 5 is morpholinyl.
  • the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R 6 is halo, or -OH.
  • R 6 is F, Cl, Br, or -OH.
  • R 6 is F or -OH.
  • one of R 9a and R 9b is H, and the other is -CH 3 , –CH 2 CH 3 , or –CH(CH 3 ) 2 .
  • one of R 9a and R 9b is H, and the other is -CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R 6 is C 1-4 alkoxy.
  • R 6 is -O- CH 3 , -O-CH 2 CH 3 , or –O-CH(CH 3 ) 2 .
  • R 6 is -O-CH 3 .
  • the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R 6 is C 1-4 alkoxy substituted with one or more independently selected halo.
  • R 6 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.
  • R 6 is C 1-4 alkoxy substituted with one, two, or three independently selected halo.
  • R 6 is C 1-4 alkoxy substituted with one or more independently selected F, Cl, or Br.
  • R 6 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.
  • R 6 is --O-CH 2 CH 3 substituted with one, two, or three F.
  • R 6 is -O-CH 2 CF 3 .
  • the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R 6 is C3-6 cycloalkyl.
  • R 6 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R 6 is independently cyclopropyl or cyclobutyl. [0119] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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.
  • the compound of the invention is according to Formula I, wherein the compound is selected from: (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5- (trifluoromethyl)phenyl]-3,4-
  • the compound of the invention is according to Formula I, wherein the compound is selected from: (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5- (trifluoromethyl)phenyl]-3,4-
  • the compound of the invention is according to Formula I, wherein the compound is (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-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-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. [0135] 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. [0136] 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, N-alkylmorpholine esters and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • a minor component from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight
  • 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 corn 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 corn starch
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin
  • a flavoring agent such as
  • 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.
  • the active ingredients may be formulated in a cream with, for example an oil-in-water cream base.
  • 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.
  • the above-described components for orally administrable, injectable or topically administrable compositions are merely representative.
  • 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.
  • 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 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 [0149] 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
  • 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.
  • Formulation 5 - Injection 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
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75oC 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 [0154]
  • 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.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • systemic sclerosis idiopathic pulmonary fibrosis
  • renal fibrosis fibrosis
  • cutaneous fibrosis fibrotic diseases.
  • 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.
  • IPF idiopathic pulmonary fibrosis
  • NASH nonalcoholic steatohepatitis
  • 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.
  • the term 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).
  • 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.
  • 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).
  • 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.
  • 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
  • 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, 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 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, Sjögren’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 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, Sjögren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus, atopic dermatitis, thyroiditis, contact dermatitis, eczematous dermatitis, inflammatory bowel disease (e.g.
  • 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, Sjögren’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 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, Sjögren’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 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 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g.
  • a compound of the invention is co-administered with another therapeutic agent for the treatment and/or prophylaxis of arthritis (e.g.
  • 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).
  • NAIDS non-steroidal anti-inflammatory drugs
  • DMARDS for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, aza
  • 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.
  • 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-2R ⁇ receptor antibodies, basiliximab, daclizumab
  • polyclonal anti-T-cell antibodies e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)
  • 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 ⁇ 2-agonists e.g.
  • salmeterol, formoterol, bambuterol, and sustained-release oral albuterol combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, 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.
  • 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.
  • emergency therapies for asthma and/or COPD 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.
  • 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.
  • 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 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.
  • 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 biologics such as AmeviveTM, EnbrelTM, HumiraTM
  • 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)).
  • 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 anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.
  • co-administration 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 CLAUSES 1.
  • R 1 is 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 5 ;
  • R 2 is C 1-4 alkyl or C 1-4 alkoxy, which C 1-4 alkyl or C 1-4 alkoxy is unsubstituted or substituted with one or more independently selected halo;
  • R 3 is C 1-4 alkyl;
  • a compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R 3 is C 1-4 alkyl. 3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R 3 is -CH 3 , - CH 2 CH 3 , or -CH(CH 3 ) 2 . 4. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R 3 is -CH 3 or -CH 2 CH 3 . 5. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R 3 is -CH 3 . 6. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula II: 7. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IIIa or IIIb: 8.
  • R 2 is -CF 3 .
  • 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 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 2 CH
  • 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 3 )-, -CH(CH 2 CH 3 )CH 2 -, -CH 2 CH(CH 2 CH
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-45, wherein L3 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 . 58.
  • R 1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl.
  • 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 5 . 71.
  • 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 5 . 72.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 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 5 . 73.
  • R 1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R 5 . 74.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 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 5 . 75.
  • 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[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6
  • 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 5 .
  • R 1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- di
  • 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 5 .
  • 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 5 . 86.
  • R 1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- di
  • 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 5 . 88.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 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 5 . 89.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-63, wherein R 1 is , , , , , or . 90.
  • R 1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. 91.
  • 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, 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 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, 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 R 5 .
  • 101 is a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-44, 46- 62, and 64, wherein R 1 is 102.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 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 5 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 5 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 7 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is F, Cl, Br, -OH, or -CN.
  • R 7 is F, Cl, Br, -OH, or -CN.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is F, -OH, or -CN.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is cyclopropyl, cyclobutyl, or cyclopentyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is cyclopropyl or cyclobutyl.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is C 1-4 alkoxy. 119.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . 120.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is C 1-4 alkoxy substituted with one or more independently selected halo. 122.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 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.
  • R 7 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 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is C 1-4 alkoxy substituted with one, two, or three independently selected halo. 124.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is C 1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. 125.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 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. 126.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 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. 127.
  • R 7 is -O-CH 3 substituted with one, two, or three F. 128.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is -O-CF 3 . 129.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both H. 132.
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R 7 is -NR 10a R 10b , and R 10a and R 10b are both independently C 1- 4 alkyl or -C( O)-O-C 1-6 alkyl. 134.
  • R 7 is -NR 10a R 10b
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, 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 . 138.
  • R 7 is -NR 10a R 10b
  • R 10a and R 10b are both -CH 3 .
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -O-CH 3 , -O-CH 2 CH 3 , or -O-CH(CH 3 ) 2 . 142.
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -C( O)-C 1-4 alkyl. 144.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -NR 8a R 8b , and R 8a and R 8b are independently H or C 1-4 alkyl. 151.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -NR 8a R 8b , and one of R 8a and R 8b is H, and the other is C 1-4 alkyl. 153.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -NR 8a R 8b , and one of R 8a and R 8b is H, and the other is -CH 3 , – CH 2 CH 3 , or –CH(CH 3 ) 2 . 155.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is -NR 8a R 8b , and R 8a and R 8b are both -CH 3 . 157.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R 5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl.
  • R 5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl.
  • R 5 is morpholinyl.
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R 6 is -NR 9a R 9b , and one of R 9a and R 9b is H, and the other is C 1-4 alkyl or -C( O)-O-C 1-6 alkyl.
  • R 6 is -NR 9a R 9b
  • R 6 is -NR 9a R 9b
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-159, wherein R 6 is -NR 9a R 9b , and one of R 9a and R 9b is H, and the other is -CH 3 , –CH 2 CH 3 , or –CH(CH 3 ) 2 . 170.
  • R 6 is -NR 9a R 9b
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R 6 is -NR 9a R 9b , and one of R 9a and R 9b is -CH 3 , and the other is -C( O)-O-C(CH 3 ) 3 . 173.
  • R 6 is C 1-4 alkoxy substituted with one or more independently selected halo. 177.
  • R 6 is C 1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. 180.
  • a compound or pharmaceutically acceptable salt thereof according to any one of clauses 1-159, wherein R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl. 188. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R 6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl. 189.
  • a compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R 6 is azetidinyl or pyrrolidinyl, each of which is substituted with -C( O)-O-C(CH 3 ) 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 1-195.
  • a pharmaceutical composition according to clause 196 comprising a further therapeutic agent. 198.
  • 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 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.
  • 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).
  • 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.
  • Biotage ® ISOLUTE ® phase separators (e.g., Cat# 120-1907-E) are used for aqueous phase separation.
  • 1 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 ( ⁇ ) for 1 H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane ( ⁇ 0.00) or the appropriate residual solvent peak, e.g. CHCl3 ( ⁇ 7.27), as internal reference.
  • 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 XBRIDGE BEH C18 OBD 30 mm ID ⁇ 100/150 mm L columns and ACN/H2O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine in both mobile phases, 0.1% formic acid in H2O, or 10 mM NH4HCO3 in H2O (adjusted to pH 10 with ammonia).
  • HATU (0.22 g, 0.56 mmol, 2 eq.) and 4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline (CAS# 630125-91-6; 80 mg, 0.28 mmol, 1 eq.) were added and the mixture was stirred at 55 °C for 16 h.
  • the reaction medium was concentrated to dryness and the residue was purified by preparative HPLC to afford 1.2.4.
  • reaction medium is poured in water, extracted with DCM and the combined organic phases are filtered on a phase separator. The filtrate is concentrated to give the cyano intermediate.
  • This intermediate is dissolved in DMSO and K 2 CO 3 (5 eq.) and H 2 O 2 (30% in water, 5 eq.) are added. The mixture is stirred at RT for 16 h. If needed more K 2 CO 3 (5 eq.) and H 2 O 2 (30% in water, 5 eq.) are added and the mixture is stirred at 50 °C for 1 to 4 h or at RT for 16 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 aqueous phase is extracted with DCM.
  • the combined organic phases are washed or not with brine, dried over MgSO4 or Na2SO4, filtered and concentrated to dryness.
  • the residue is used as such or purified by column chromatography on silica gel to afford the desired product. 1.2.15.1.
  • reaction mixture is quenched by addition of water at 0 °C or by addition of ice at RT.
  • the phases are separated and the aqueous layer is extracted with DCM.
  • the combined organic layers are washed or not with brine, dried over Na2SO4 or MgSO4, filtered and concentrated under reduced pressure.
  • the residue is used as such, or is purified by column chromatography on silica gel, or is suspended in pentane and filtered, to afford the expected product. 1.2.17.1.
  • Example 2 Pre iparation of the compounds of the invention ii iii 2.1.1. Step i: N-[(2R)-2-(4-bromophenyl)propyl]-2,2,2-trifluoro-acetamide [0256] A solution of Int 1 (158 g, 615 mmol, 1.0 eq.) in DCM (2.5 L) was cooled to -10 °C.
  • Methane sulfonic acid 131 mL, 1.85 mol, 3.0 eq. was added, followed by portion wise addition of 1,3-dibromo- 5,5-dimethyl-imidazolidine-2,4-dione (CAS# 77-48-5; 105 g, 369 mmol, 0.6 eq.). The resulting mixture was stirred at RT for 15 h. The reaction mixture was quenched by addition water (8 L) at 10 °C and was then extracted with DCM (8 L). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure.
  • Step ii methyl 4-[(1R)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate
  • N-[(2R)-2-(4-bromophenyl)propyl]-2,2 N,2-trifluoro-acetamide 100 g, 290 mmol H (500 mL) and DM FF (5 O00 mL) and C tOheM , 1.0 eq.
  • MeO 2ne TEA 121 mL, 870 mmol, 3.0 eq.
  • Pd(dppf)Cl2 CAS# 72287-26-4; 10.6 g, 14.5 mmol, 0.05 eq.
  • Step iii Int 4 (alternative synthesis) [0259] A round bottom flask was charged with TFA (1 L), then methyl 4-[(1R)-1-methyl-2-[(2,2,2- trifluoroacetyl)amino]ethyl]benzoate (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.
  • 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 MgSO 4 , 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 SiO 2 (eluting with DCM/EtOAc, 100:0 to 95:5) to afford Int 4. 2.2.
  • Int 6 To a solution of Int 5 (78 g, 380 mmol, 1 eq.) and TEA (106 mL, 760.04 mmol, 2 eq.) in DCM (800 mL) was added Boc2O (91.2 g, 418 mmol, 1.1 eq.) portion wise. The mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (eluting with petroleum ether/DCM 7/3) to give Int 6. 2.3.
  • Int 10 [0262] To a solution of Int 5 (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 occured and the solid was filtered. The obtained solid was then washed with water and dried to afford Int 10. 2.5. Int 10 (alternative synthes iis) ii 2.5.1.
  • Step i Int 5, hydrochloride
  • a suspension of Int 4 (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.
  • 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.
  • Step i ethy il (R)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7- iiciarboxylate [0265] To a flask charged with EtOH (34 mL) cooled to 0 °C was added acetyl chloride (2.4 mL, 34 mmol, 10 eq.).
  • Step ii ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7- carboxylate
  • acetonitrile 8 mL
  • K2CO3 1.25 mmol, 1 eq.
  • 2-bromoacetamide 2-bromoacetamide
  • Step i tert-butyl i 4-[[4-[[(4R)-2-(2-amino-2-oxo-eth iyil)-4-methyl-3,4-dihydro-1H- isoquinoline-7-carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate [0269] To Int 10 (108 mg, 0.37 mmol, 1 eq.) in EtOH (2.15 mL) was added NaOH (1 M in water, 0.75 mL, 0.75 mmol, 2 eq.) and the solution was stirred at 55 °C for 2 h.
  • Step ii: Int 62 [0270] Int 62 was obtained from tert-butyl 4-[[4-[[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro- 1H-isoquinoline-7-carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate using general method D with HCl (4 N in dioxane). 2.9.
  • Int 75 [0271] To a solution of Int 76 (45 mg, 0.15 mmol, 1 eq.) in formic acid (1.5 mL) was added formaldehyde (13.3 M in water, 37 ⁇ L, 0.5 mmol, 3.3 eq.) and the mixture was heated under microwave irradiation at 150 °C for 5 min. The reaction medium was directly loaded on a Biotage ® Isolute ® SCX cation exchange column eluting with MeOH and then with a 7 N solution of NH 3 in MeOH. The basic phase was concentrated to afford Int 75. 2.10.
  • Step i methyl 4-(1-cyanopropyl)benzoate
  • a solution of methyl 4-(cyanomethyl)benzoate (CAS# 76469-88-0; 20 g, 114 mmol, 1 eq.) in THF (500 mL) was cooled down to -78 °C and LiHMDS (1 M in THF, 114 mL, 114 mmol, 1 eq.) was added dropwise over 30 min.
  • the mixture was then stirred for 5 min at -78 °C and iodoethane (9.1 mL, 114 mmol, 1 eq.) was added dropwise.
  • the reaction mixture was stirred at -78 °C for 30 min and at RT for 3 h.
  • the reaction was quenched with a sat. aq. NH 4 Cl solution (250 mL) and stirred at RT for 16 h.
  • the organic solvents were removed under reduced pressure.
  • the mixture was diluted with EtOAc (300 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure.
  • Step i N i-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethoxy)phenyl]-1,1- diphenyl-methanimine [0276]
  • Int 122 390 mg, 0.06 mmol, 1 eq.
  • diphenylmethanimine CAS# 1013-88-3; 261 mg, 1.4 mmol, 1.5 eq.
  • Xantphos 56 mg, 0.096 mmol, 0.1 eq.
  • palladium acetate 17. mg, 0.077 mmol, 0.08 eq.
  • Step ii Int 120 [0277] To a solution of N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethoxy)phenyl]-1,1- diphenyl-methanimine (606 mg, 0.57 mmol, 1 eq.) in dioxane (5 mL) was added HCl (2 M in water, 1.4 mL, 2.8 mmol, 5 eq.) and the mixture was stirred at RT for 16 h. The reaction medium was concentrated to dryness, the residue was taken up in water and the pH was adjusted to 10 with a 2 N aq. NaOH solution. The aqueous phase was extracted with DCM, the layers were separated and the organic layer was concentrated.
  • Step ii [acetoxy-[2-(bromomethyl)-5-nitro-phenyl]methyl] acetate
  • [acetoxy-(2-methyl-5-nitro-phenyl)methyl] acetate 300 mg, 1.0 mmol, 1 eq.) was dissolved in tetrachloromethane (5 mL), and NBS (294 mg, 1.7 mmol, 1.7 eq.) and AIBN (0.022 mL, 0.01 mmol, 0.01 eq.) were added. The reaction mixture was stirred at 80 °C for 4 h. The reaction medium was concentrated in vacuo.
  • Step iii [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate
  • [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate was obtained from [acetoxy-[2-(bromomethyl)-5-nitro-phenyl]methyl] acetate using general method B2 with N- methylpiperazine (CAS# 109-01-3).
  • LCMS MW (calcd): 365.4; m/z MW (obsd): 366.1 (M+H) 2.15.4.
  • Step iv 2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde [0283] To a solution of [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate (105 mg, 0.26 mmol, 1 eq.) in EtOH (5 mL) was added concentrated sulfuric acid (0.028 mL, 0.53 mmol, 2 eq.) and the reaction mixture was stirred at reflux for 3.5 h. Then concentrated sulfuric acid (0.028 mL, 0.53 mmol, 2 eq.) was added and the mixture was stirred at reflux for 2 h.
  • Step v (1E)-2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde hydrazone
  • 2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde (465 mg, 1.6 mmol, 1 eq.) in EtOH (10 mL)
  • NH2NH2.H2O (0.78 mL, 16 mmol, 10 eq.
  • Step vi Int 131 [0285] To a solution of (1E)-2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde hydrazone (429 mg, 0.97 mmol, 1 eq.) in ACN (20 mL) were added 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (Togni’s reagent, CAS# 887144-94-7; 847 mg, 1.7 mmol, 1.1 eq.) and water (20 mL).
  • Step ii 4-[(1S)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoyl chloride [0287] To a solution of AlCl3 (329 mL, 6.03 mol, 3 eq.) in DCM (2.79 L) was added oxalyl chloride (528 mL, 6.03 mol, 3 eq.) dropwise over 30 min while keeping the temperature between 0 and 5 °C.
  • Step ii methyl (4S)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate, hydrochloride salt
  • the reaction mixture was concentrated in vacuo and DCM and water were added. The water layer was washed again with DCM, the organic layers were combined and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry THF (1.25 L) and HCl (5-6 M in 2-propanol, 134 mL, 671 mmol, 1 eq.) was added. The suspension (pH: 1-2) was stirred RT for 2 h. Then the mixture was cooled to 4 °C and stirred overnight. The solids were filtered off over a P2 glass filter under nitrogen flow.
  • the reaction mixture was cooled to 12 °C and water (3.9 L) was added dropwise over 50 min. The layers were separated and the aq. layer was extracted 3 times with DCM. The combined organic layers were evaporated under reduced pressure until approximately 80% of the solvent was removed. A solvent exchange was performed with ACN (3.9 L). The suspension was filtered on a glass filter funnel and the solid was washed with ACN. The collected solid was taken up in 2-propanol (4V) and the mixture was heated at reflux. When reflux was reached, 2-propanol was added until total solubilization of the reaction mixture. The mixture was cooled down to RT overnight and stirred at 20 °C for 2 h. The suspension was filtered and the solid washed with 2-propanol and MTBE.
  • Step ii methyl (R)-2-(4-methyl-7-((4-((4-methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate
  • Step iv Cpd 1 [0297] 2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]- 3,4-dihydro-1H-isoquinolin-2-yl]acetic acid (30 mg, 0.055 mmol, 1 eq.), ammonium acetate (29 mg, 0.38 mmol, 8 eq.) and HATU (31 mg, 0.080 mmol, 1.5 eq.) were dissolved in DMF (0.9 mL).
  • Step i meth iyl 3-methoxy-2-[(4R)-4-methyl-7-[[4 ii-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate [0301] Methyl 3-methoxy-2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate was obtained from Int 43 following general method E1 with methyl 2-bromo-3-methoxypropanoate (CAS# 27704-96-7).
  • Step iv methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate
  • Methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate was obtained from methyl 4- methyl-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate using general method H.
  • Step v methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7- carboxylate
  • Methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxylate was obtained from methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate using general method E1 with 2-bromoacetamide (CAS# 683-57-8).
  • LCMS MW (calcd): 262.3; m/z MW (obsd): 263.1 (M+H) 2.25.6.
  • Step vi Cpd 18 [0308] Methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxylate (0.6 g, 2.29 mmol, 1 eq.) and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (CAS# 694499-26-8; 0.77 g, 2.74 mmol, 1.2 eq.) were mixed in THF (12 mL).
  • Step i (4R)-2- i[cyano(tetrahydrofuran-3-yl)methyl]- ii4-methyl-N-[4-[(4-methylpiperazin- 1-yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide
  • Step i 1-isop 3 iropyl-4-[[4-ni iitro-2-(trif .42 mm iiliuoromethyl)phenyl]methyl]piperidine
  • Int 76 60 mg, 0.21 mmol, 1 eq.
  • acetone 77 ⁇ L, 1.04 mmol, 5 eq.
  • acetic acid 6 ⁇ L, 0.10 mmol, 0.5 eq.
  • the mixture was stirred at RT for 10 min and NaBH(OAc) was added portionwise (88 mg, 0 ol, 2 eq.).
  • the reaction mixture was stirred at RT for 20 h and at 60 °C for 5 h. Then at RT more acetone (77 ⁇ L, 1.04 mmol, 5 eq.), acetic acid (6 ⁇ L, 0.10 mmol, 0.5 eq.) and NaBH(OAc) 3 (44 mg, 0.21 mmol, 1 eq.) were added. The mixture was stirred at RT for 16 h. The volatiles were concentrated and the residue was taken up in DCM and water. A sat. NaHCO3 aq. solution was added and the layers were separated. The aqueous phase was extracted with DCM.
  • Step ii 4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)aniline
  • 4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)aniline was obtained from 1-isopropyl-4- [[4-nitro-2-(trifluoromethyl)phenyl]methyl]piperidine using general method C1.
  • LCMS MW (calcd): 300.4; m/z MW (obsd): 301.1 (M+H) 2.27.3.
  • DIPEA 34 ⁇ L, 0.20 mmol, 2.2 eq.
  • Step i methyl i (2S)-2-hydroxy-3-[(4R)-4-methyl-7-[[4-[( ii4-methylpiperazin-1-yl)methyl]- 3-(trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate [0315] To a solution of Int 43 (300 mg, 0.65 mmol, 1 eq.) in DMF (10 mL) were added TEA (182 ⁇ L, 1.30 mmol, 2 eq.) and (S)-methylglycidate (CAS# 118712-39-3; 136 mg, 1.3 mmol, 2 eq.) and the mixture was stirred at 150 °C for 45 min under microwaves irradiation.
  • HATU (162 mg, 0.42 mmol, 2 eq.) and DIPEA (73 ⁇ L, 0.42 mmol, 2 eq.) were added and the mixture was stirred at 55 °C for 20 h.
  • the reaction medium was purified by preparative LCMS to afford Cpd 75. 2.33.
  • Cpd 76 [0320] Int 10 (100 mg, 0.38 mmol, 1 eq.) and Int 137 (228 mg, 0.76 mmol, 2 eq.) were placed in toluene (1.3 mL) under argon atmosphere and LiHMDS (1.3 M in THF, 0.88 mL, 1.1 mmol, 3 eq.) was added under vigorous stirring.
  • Step i i 4-[(6-methyl i-i3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline [0321] To a solution of Int 140 (273 mg, 0.85 mmol, 1 eq.) in EtOH (15 mL) was added Pd/C 10% (45 mg, 0.042 mmol, 0.05 eq.) and the reaction mixture was stirred under hydrogen pressure (2 atm) at RT for 5 h. Then additional Pd/C 10% (25 mg, 0.02 mmol, 0.02 eq.) was added and the hydrogenation was continued under 2 atm of H2 for 16 h.
  • Step ii Cpd 77 [0322] Int 10 (40 mg, 0.15 mmol, 1 eq.) and 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline (52 mg, 0.18 mmol, 1.2 eq.) were placed in toluene (3 mL) under argon atmosphere and LiHMDS (1.3 M in THF, 0.23 mL, 0.30 mmol, 2 eq.) was added under vigorous stirring.
  • LiHMDS 1.3 M in THF, 0.23 mL, 0.30 mmol, 2 eq.
  • More LiHMDS (1.3 M in THF, 0.23 mL, 0.30 mmol, 2 eq.) was added and the mixture was stirred for 3 h at RT before 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3-(trifluoromethyl)aniline (4 mg, 0.015 mmol, 0.1 eq.) and LiHMDS (1.3 M in THF, 150 ⁇ L, 0.2 mmol, 1.3 eq.) were added. The reaction mixture was stirred again at RT for 1.5 h. A sat. NH 4 Cl aq. solution was added and the solution was extracted with EtOAc.
  • Step i methyl 4-methoxy- i3-[(4R)- i4ii-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate [0323] Methyl-4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate was obtained from Int 43 using general method J with
  • Step ii 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoic acid [0324] To a solution of methyl 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate (105 mg, 0.18 mmol, 1 eq.) in THF (2 mL) was added NaOH (2 N in water, 360 ⁇ L, 0.73 mmol, 4 eq.) and the mixture was stirred at 60 °C for 16 h.
  • 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. 3.1.2.
  • 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 ⁇ L was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290). [0331] 1% DMSO and 10 ⁇ M staurosporine final concentrations were used respectively as negative and positive controls respectively.2 ⁇ L enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT. [0332] The reaction was started by adding 2 ⁇ L diluted ATP (final concentration 1/10 Km ATP) on the assay plates.
  • the ADP-Glo TM kinase assay is a luminescent technology assay which measures the ADP formed from a kinase reaction.
  • 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.
  • 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.
  • 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 ⁇ L was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290). [0338] 1% DMSO and 10 ⁇ M staurosporine final concentrations were used respectively as negative and positive controls respectively.2 ⁇ L enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT. [0339] The reaction was started by adding 2 ⁇ L diluted ATP (final concentration 1/10 Km ATP) on the assay plates.
  • the aim of this assay is to evaluate compounds for their binding characteristics to discoidin domain- containing 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.
  • HEK293T Human Embryonic Kidney T
  • 293tsA1609neo a highly transfectable derivative of human embryonic kidney 293 cells containing the SV40 T-antigen
  • BRET bioluminescence resonance energy transfer
  • a DDR1 inhibitor will go in competition with the Kinase Tracer-04 for binding to NanoLuc-DDR1 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. 4.1.2.
  • HEK293T cells Fourteen million HEK293T cells were transiently transfected using 70 ⁇ L JetPei, 2.33 ⁇ g DDR1- NanoLuc ® Fusion Vector and 21 ⁇ g pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175). [0344] 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 ⁇ M highest final concentration, 1/3 dilution steps). Four ⁇ L of the serial dilution was transferred to non-binding surface plates (2 copies).
  • the transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.04 ⁇ M NanoBRET Tracer-04 for DDR1.
  • Cells were seeded on top of the compounds at 8,000 cells per well in 36 ⁇ L
  • 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. 4.1.3. Data analysis and results [0349] 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. 4.2. DDR2 Hek293T nanobret assay 4.2.1.
  • 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.
  • BRET bioluminescence resonance energy transfer
  • a cell-permeable fluorescent tracer is used in a competitive binding format to quantify drug engagement with the target protein fused to NanoLuc luciferase.
  • 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. 4.2.2.
  • HEK293T cells Fourteen million HEK293T cells were transiently transfected using 70 ⁇ L JetPei, 2.33 ⁇ g DDR2- NanoLuc ® Fusion Vector and 21 ⁇ g pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175). [0352] 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 ⁇ M highest final concentration, 1/3 dilution steps). Four ⁇ L of the serial dilution was transferred to non-binding surface plates (2 copies).
  • the transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.4 ⁇ M NanoBRET Tracer-04 for DDR2.
  • Cells were seeded on top of the compounds at 8,000 cells per well in 36 ⁇ L
  • 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 IX Conditions for DDR2 HEK293T nanobret assay (final concentrations) 4.2.3. Data analysis and results [0357] 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 X NANOBRET DDR kinase assay IC50 of illustrative compounds of the invention.
  • Phospho-DDR Hek293T cell assay 4.3.1. Overview [0358] 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. 4.3.2. Protocol [0359] At day 1, 96-well plates were coated with 50 ⁇ L poly-D-lysine dissolved in PBS and incubated for 1 h at 37 °C.
  • HEK293T cells were harvested and transfected with wild type pcDNA3.1 hsDDR1 (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 ⁇ L in the 96-well plates and cultured at 37 °C 5 % CO2 for 1 day.
  • FBS fetal bovine serum
  • 60,000 cells were seeded in 100 ⁇ L in the 96-well plates and cultured at 37 °C 5 % CO2 for 1 day.
  • 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. [0369] After imaging for pDDR, plates were kept in the fridge until the staining for the total DDR (tDDR). [0370] The PBS was removed from the plates and 50 ⁇ L primary antibody solution in blocking buffer was added with rabbit anti-DDR1 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 hour at RT, protected from light.
  • rabbit anti-DDR1 antibody Cell Signaling Technology, Inc., Cat# 5583S; 1/250 dilution
  • goat anti DDR2 antibody R&D Systems, Inc., Cat# AF2538; 1/250 dilution
  • 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 XI. Phospho DDR kinase assay IC50 of illustrative compounds of the invention.
  • microsomal stability are expressed as a percentage of the total amount of compound remaining after 30 min incubation.
  • 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 XII Microsomal stability of illustrative compounds of the invention 5.2. Metabolic stability in hepatocytes
  • 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.
  • Testosterone (1 ⁇ M) and 7-hydroxycoumarin (1 ⁇ M) were used, respectively as phase I and phase II metabolic reaction controls. [0386] After 0, 10, 20, 45, 90, 120 and 180 min of incubation, the reaction was terminated with 225 ⁇ L 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. [0387] 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 XIII. Hepatocyte stability of illustrative compounds of the invention Example 6.
  • mice 7 weeks old (18-22 g) albinos female C57BL/6J mice from Charles River (Écully, 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 [0390] The test compounds were dissolved/suspended in appropriate vehicle prior to using and kept light- free, under agitation at RT. [0391] An aliquot of the formulation ( ⁇ 200 ⁇ L) was frozen at T0 (day of preparation) and all the formulations were checked (daily) for any change in aspect.
  • the dose volume administered is 10 mL/kg and the volume is adapted following mean body weight (BW) of the group as follows: 200 ⁇ L if mean BW ⁇ 22.5 g, 250 ⁇ L if mean BW ⁇ 22.5 g; 300 ⁇ L if mean BW > 27.5 g. 6.1.4.
  • BW mean body weight
  • lungs were collected, wheighed, and fixed in 4% formaldehyde for 24 h before embedding in paraffin.
  • 4 ⁇ m thick sections were immunostained with anti-collagen I antibody (LifeSpan BioSciences, Inc., Cat# LS-343921). The sections were deparaffinized and processed by heat antigen retrieval before incubation for one hour 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).
  • a fresh nintedanib formulation was prepared daily in 0.1% NatrosolTM to a final concentration of 5 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.. [0405] Finally, test compound solutions were prepared by dissolving the suitable amount of said test compound in Solutol® (CAS# 70142-34-6; 2% of the final volume) then MC 0.5% (98% of the final volume) with 1 eq.
  • cGvHD Murine sclerodermatous chronic graft-versus host disease
  • 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.

Abstract

The present invention discloses compounds according to Formula (I) wherein R1, R2, R3, L1, L2, and L3 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

ISOQUINOLINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS 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; Rugged 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: wherein,
Figure imgf000003_0001
L1 is –O- or –CR4aR4b-; L2 is –C(=O)NH- or –NHC(=O)-; L3 is C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6; R1 is 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 R5; R2 is 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; R3 is C1-4 alkyl; R4a and R4b are independently H or –CH3; each R5 is independently selected from - C1-6 alkyl unsubstituted or substituted with one or more independently selected R7, - C1-4 alkoxy, - -C(=O)-C1-4 alkyl, - C3-6 cycloalkyl, - -NR8aR8b, and - 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R6 is independently selected from - halo, - -OH, - -NR9aR9b, - 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 -C(=O)-O-C1-6 alkyl; each R7 is independently selected from: - halo, - -OH, - –CN, - C3-6 cycloalkyl, - C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and - -NR10aR10b; each R8a and R8b is independently H or C1-4 alkyl; each R9a, R9b, R10a, and R10b is independently H, C1-4 alkyl, or -C(=O)-O- C1-6 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 compounds of the invention may exhibit good metabolic stability, which may result in lower dosage regimen. In a particular aspect, the compounds of the invention show good stability in hepatocytes, which may result in low hepatic clearance. [0009] 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. [0010] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used. [0011] 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. [0012] 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. [0013] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein. [0014] 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 [0015] 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. [0016] 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. [0017] 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. [0018] ‘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), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-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. [0019] ‘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), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like. [0020] ‘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. [0021] ‘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, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 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. [0022] ‘Amino’ refers to the radical -NH2. [0023] ‘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. [0024] ‘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. [0025] ‘Cyano’ refers to the radical -CN. [0026] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro. [0027] ‘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. [0028] ‘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. [0029] 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. [0030] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. [0031] 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. [0032] 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. [0033] 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. [0034] Examples of representative heteroaryls include the following: wherein each Y is selected from >C=O, NH, O and S. [0035] ‘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. [0036] 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 CH2, 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. [0037] 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-. [0038] 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-. [0039] Particular examples of bridged bicyclic 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. [0040] Particular examples of spirocyclic rings are shown in the following illustrative examples:
Figure imgf000008_0005
wherein each Y is selected from -CH2-, -NH-, -O- and –S-. [0041] ‘Hydroxyl’ refers to the radical -OH. [0042] ‘Oxo’ refers to the radical =O. [0043] ‘Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). [0044] 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. [0045] 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. [0046] ‘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. [0047] ‘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. [0048] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered. [0049] ‘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, N-alkylmorpholine esters and the like. [0050] ‘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, EtOH, 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. [0051] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein. [0052] ‘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. [0053] ‘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. [0054] 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. [0055] ‘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. [0056] 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; corneal 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. [0057] 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 joints. 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. [0058] 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, 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. [0059] 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), Sjögren’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. [0060] 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. [0061] 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. [0062] 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. [0063] 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, Waldenström 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. [0064] 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). [0065] ‘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. [0066] When ranges are referred to herein, for example but without limitation, C1-8 alkyl, the citation of a range should be considered a representation of each member of said range. [0067] 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 C1-8 alkyl, C2-8 alkenyl, C6-10 optionally substituted aryl, and (C6-10 aryl)-(C1-4 alkyl) esters of the compounds of the invention. [0068] 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. [0069] 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 (11C), 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 (36Cl), chlorine-37 (37Cl), 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. [0070] 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 11C, 18F, 15O and 13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. [0071] 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’. [0072] 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’. [0073] 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. [0074] 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. [0075] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites. THE INVENTION [0076] 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. [0077] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I: wherein,
Figure imgf000016_0001
L1 is –O- or –CR4aR4b-; L2 is –C(=O)NH- or –NHC(=O)-; L3 is C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6; R1 is 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 R5; R2 is 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; R3 is C1-4 alkyl; R4a and R4b are independently H or –CH3; each R5 is independently selected from - C1-6 alkyl unsubstituted or substituted with one or more independently selected R7, - C1-4 alkoxy, - -C(=O)-C1-4 alkyl, - C3-6 cycloalkyl, - -NR8aR8b, and - 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R6 is independently selected from - halo, - -OH, - -NR9aR9b, - 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 -C(=O)-O-C1-6 alkyl; each R7 is independently selected from: - halo, - -OH, - –CN, - C3-6 cycloalkyl, - C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and - -NR10aR10b; each R8a and R8b is independently H or C1-4 alkyl; each R9a, R9b, R10a, and R10b is independently H, C1-4 alkyl, or -C(=O)-O-C1-6 alkyl. [0078] In one embodiment, the compound of the invention is according to Formula I, wherein R3 is C1-4 alkyl. In a particular embodiment, R3 is -CH3, -CH2CH3, or -CH(CH3)2. In a more particular embodiment, R3 is -CH3 or -CH2CH3. In a most particular embodiment, R3 is -CH3. [0079] In one embodiment, the compound of the invention is according to Formula II:
Figure imgf000017_0001
wherein R1, R2, L1, L2, and L3 are as described previously. [0080] In one embodiment, the compound of the invention is according to Formula IIIa or IIIb:
Figure imgf000017_0002
wherein R1, R2, L1, L2, and L3 are as described previously. [0081] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIb, wherein L2 is –C(=O)NH-. [0082] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIb, wherein L2 is –NHC(=O)-. [0083] In one embodiment, the compound of the invention is according to Formula IVa or IVb:
Figure imgf000017_0003
wherein R1, R2, L1, and L3 are as described previously. [0084] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, 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. [0085] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, 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. [0086] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein R2 is C1-4 alkoxy. In a particular embodiment, R2 is –O-CH3, –O-CH2CH3, or –O-CH(CH3)2. In a more particular embodiment, R2 is –O-CH3. [0087] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, 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(CH3)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-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 -O-CH3 substituted with one, two, or three F. In a most particular embodiment, R2 is -O-CF3. [0088] In one embodiment, the compound of the invention is according to Formula Va or Vb:
Figure imgf000018_0001
wherein R1, L1, and L3 are as described previously. [0089] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein L1 is –O-. [0090] In one embodiment, the compound of the invention is according to any one of Formulae I-Vb, wherein L1 is –CR4aR4b-, and R4a and R4b are as previously described. In a particular embodiment, R4a and R4b are both H. In another particular embodiment, one of R4a and R4b is H, and the other is –CH3. In yet another particular embodiment, R4a and R4b are both –CH3. [0091] In one embodiment, the compound of the invention is according to Formula VIa, VIb, or VIc:
Figure imgf000019_0001
wherein R1, and L3 are as described previously. [0092] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, 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(CH2CH2CH3)- , -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-. In a most particular embodiment, L3 is -CH2-. [0093] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, wherein L3 is C1-6 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 C1-6 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 C1-6 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. [0094] In one embodiment, the compound of the invention is according to Formula VIIa, VIIb, VIIc, VIId, VIIe, or VIIf:
Figure imgf000021_0001
wherein R1, and R6 are as described previously. [0095] In one embodiment, the compound of the invention is according to Formula VIIIa, VIIIb, VIIIc, VIIId, VIIIe, or VIIIf:
Figure imgf000021_0002
Figure imgf000022_0001
wherein R1, and R6 are as described previously. [0096] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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 pyrrolidinyl, piperidinyl, or morpholinyl. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R1 is , , or . [0097] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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 R5. 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 R5. 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 R5. In a more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R5. 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 R5. In a further more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R5. In an even further more particular embodiment, R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R5. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R1 is or
Figure imgf000022_0002
Figure imgf000023_0001
. In another most particular embodiment the compound of the invention is according to any one of Formulae Formulae I-VIIIf, wherein R1 is
Figure imgf000023_0002
[0098] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 4- oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4-oxa-1-azabicyclo[3.1.1]heptanyl, 6-oxa- 3-azabicyclo[3.1.1]heptanyl, 1-azabicyclo[3.2.1]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[4.1.1]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, 1,4-diazabicyclo[2.2.2]octanyl, 1,4- diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5-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[3.2.1]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[4.1.1]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-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[4.1.1]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. 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. [0099] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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 R5. In a particular embodiment, R1 is 1-azabicyclo[2.1.1]hexanyl, 3- azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3-oxabicyclo[2.1.1]hexanyl, 5- oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4- diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3- oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 4-oxabicyclo[3.1.1]heptanyl, 6- oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6- azabicyclo[3.1.1]heptanyl, 4-oxa-1-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1- azabicyclo[3.2.1]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[4.1.1]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, 1,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5-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[3.2.1]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[4.1.1]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-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[4.1.1]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 R5. 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 R5. 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 R5. In another more particular embodiment, R1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5- azabicyclo[2.1.1]hexanyl, 3-oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1- 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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5- diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3- oxabicyclo[3.1.1]heptanyl, 4-oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7- oxabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4-oxa- 1-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1-azabicyclo[3.2.1]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[4.1.1]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, 1,4- diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5- 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[3.2.1]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[4.1.1]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-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[4.1.1]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, two, or three independently selected R5. 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 R5. 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 R5. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R1 is
Figure imgf000025_0001
[0100] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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-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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro- 1H-isoindolyl, octahydro-1H-indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H-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-1H-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro- 1H-pyrrolo[3,4-c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H- cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1-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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3- b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2- a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3-c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl. In a more particular embodiment, R1 is octahydropyrrolo[1,2- a]pyrazinyl. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R1 is
Figure imgf000026_0001
[0101] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, 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 R5. 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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro-1H-isoindolyl, octahydro-1H- indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H- 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-1H-furo[3,4-c]pyranyl, hexahydro- 2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4- c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, octahydro-1H- pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1-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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3- b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2- a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3-c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl, each of which is substituted with one or more independently selected R5. 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 R5. In a more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R5. 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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro-1H-isoindolyl, octahydro-1H- indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H- 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-1H-furo[3,4-c]pyranyl, hexahydro- 2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4- c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, octahydro-1H- pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1-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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3- b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3- c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2- a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3-c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl, each of which is substituted with one, two, or three independently selected R5. In a further more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R5. In an even further more particular embodiment, R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R5. In a most particular embodiment, the compound of the invention is according to any one of Formulae I-VIb, VIIa-VIId, and VIIIa-VIIId, wherein R1 is
Figure imgf000028_0001
. [0102] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is C1-6 alkyl. In a particular embodiment, R5 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, R5 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. In a most particular embodiment, R5 is -CH3. [0103] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is C1-6 alkyl substituted with one or more independently selected R7. In a particular embodiment, R5 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 R7. In another particular embodiment, R5 is C1-6 alkyl substituted with one, two, or three independently selected R7. In a more particular embodiment, R5 is -CH3 or -CH2CH3, each of which is substituted with one or more independently selected R7. In another more particular embodiment, R5 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 R7. In a most particular embodiment, R5 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected R7. [0104] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is C1-6 alkyl substituted with one or more independently selected R7, and R7 is halo, -OH, or -CN. In a particular embodiment, R7 is F, Cl, Br, -OH, or -CN. In a more particular embodiment, R7 is F, -OH, or -CN. [0105] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is C1-6 alkyl 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. [0106] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is C1-6 alkyl substituted with one or more independently selected R7, and R7 is C1-4 alkoxy. In a particular embodiment, R7 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a particular embodiment, R7 is -O-CH3. [0107] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is C1-6 alkyl substituted with one or more independently selected R7, and R7 is C1-4 alkoxy substituted with one or more independently selected halo. In a particular embodiment, R7 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, R7 is C1-4 alkoxy substituted with one, two, or three independently selected halo. In yet another particular embodiment, R7 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. In a more particular embodiment, R7 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, R7 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, R7 is -O-CH3 substituted with one, two, or three F. In a most particular embodiment, R7 is -O-CF3. [0108] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is C1-6 alkyl substituted with one or more independently selected R7, R7 is -NR10aR10b, and R10a and R10b are independently H, C1-4 alkyl, or -C(=O)-O-C1-6 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 C1-4 alkyl or -C(=O)-O-C1-6 alkyl. In yet another particular embodiment, R10a and R10b are both independently C1-4 alkyl or -C(=O)-O-C1-6 alkyl. In a more particular embodiment, one of R10a and R10b 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, R10a and R10b 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 R10a and R10b 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, R10a and R10b are both independently -CH3, –CH2CH3, or –CH(CH3)2. In a most particular embodiment, one of R10a and R10b is H, and the other is -CH3 or -C(=O)-O-C(CH3)3. In another most particular embodiment, R10a and R10b are both -CH3. [0109] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is C1-4 alkoxy. In a particular embodiment, R5 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a particular embodiment, R5 is -O-CH3. [0110] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is -C(=O)-C1-4 alkyl. In a particular embodiment, R5 is -C(=O)-CH3, -C(=O)-CH2CH3, or -C(=O)-CH(CH3)2. In a particular embodiment, R5 is -C(=O)-CH3. [0111] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is C3-6 cycloalkyl. In a particular embodiment, R5 is cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R5 is cyclopropyl or cyclobutyl. [0112] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, R5 is -NR8aR8b, and R8a and R8b are independently H or C1-4 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. In yet another particular embodiment, R8a and R8b are both independently C1-4 alkyl. In a more particular embodiment, one of R8a and R8b is H, and the other is -CH3, –CH2CH3, or –CH(CH3)2. In another more particular embodiment, R8a and R8b are both independently -CH3, –CH2CH3, or –CH(CH3)2. In a most particular embodiment, R8a and R8b are both -CH3. [0113] In one embodiment, the compound of the invention is according to any one of Formulae I-VIIIf, wherein R1 is 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 R5, and R5 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. In a particular embodiment, R5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. In a more particular embodiment, R5 is morpholinyl. [0114] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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. [0115] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R6 is -NR9aR9b, and R9a and R9b are independently H, C1-4 alkyl, or -C(=O)-O-C1-6 alkyl. In a particular embodiment, R9a and R9b are both H. In another particular embodiment, one of R9a and R9b is H, and the other is C1-4 alkyl or -C(=O)-O-C1-6 alkyl. In yet another particular embodiment, R9a and R9b are both independently C1-4 alkyl or -C(=O)-O-C1-6 alkyl. In a more particular embodiment, one of R9a and R9b 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, R9a and R9b 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 R9a and R9b is H, and the other is -CH3, –CH2CH3, or –CH(CH3)2. In another further more particular embodiment, R9a and R9b 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 R9a and R9b is H, and the other is -CH3. In another most particular embodiment, one of R9a and R9b is -CH3, and the other is -C(=O)-O-C(CH3)3. [0116] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, wherein R6 is C1-4 alkoxy. In a particular embodiment, R6 is -O- CH3, -O-CH2CH3, or –O-CH(CH3)2. In a more particular embodiment, R6 is -O-CH3. [0117] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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. [0118] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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. [0119] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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. [0120] In one embodiment, the compound of the invention is according to any one of Formulae I-VIc, VIIb, VIId, VIIf, VIIIb, VIIId, and VIIIf, 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 -C(=O)-O-C1-6 alkyl. In a particular embodiment, R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one -C(=O)-O-C1-6 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 -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 more particular embodiment, R6 is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with -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, or piperidinyl, each of which is substituted with -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. [0121] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from: (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(1-methyl-4-piperidyl)oxy]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(1-methylpyrrolidin-3-yl)oxy-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[3-[[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-5- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[3-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-5- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(1-piperidylmethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-methoxy-1-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(morpholinomethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(methoxymethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[1-(4-methylpiperazin-1-yl)ethyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, 2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(1-methyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinolin-7-yl]-4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)benzamide, 2-(2-amino-2-oxo-ethyl)-4-ethyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethoxy)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-tetrahydrofuran-3-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-methoxyethyl)-4-piperidyl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-1-cyclopropyl-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-tetrahydropyran-4-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl 3-[2-amino-1-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]azetidine-1- carboxylate, tert-butyl 3-[2-amino-1-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]pyrrolidine-1- carboxylate, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-hydroxyethyl)-4-piperidyl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(azetidin-3-yl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-pyrrolidin-3-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-methoxy-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-4,4,4-trifluoro-butyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-1-cyclobutyl-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(oxetan-3-yl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl N-[3-amino-2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-oxo-propyl]-N-methyl- carbamate, (4R)-2-[2-amino-1-(methylaminomethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]- 3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-hydroxy-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-methyl-butyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoylbutyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(aminomethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-morpholinopyrrolidin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-2-methyl-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-1-methyl-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-propylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-isopropylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-cyclobutylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-sec-butylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-isobutylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2,2-difluoroethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(dimethylamino)-1-piperidyl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-N-[4-[(1-acetyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-2-(2-amino-2-oxo-ethyl)-4-methyl- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-cyanoethyl)-4-piperidyl]methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2,2-difluoroethyl)-4-piperidyl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[[4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl N-[2-[4-[[4-[[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7- carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]ethyl]carbamate, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-fluoroethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-cyclopropylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(2,2,3,3,5,5,6,6-octadeuterio-4-methyl-piperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-N-[4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-3-(trifluoromethyl)phenyl]-2- (2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[3-amino-3-oxo-1-(2,2,2-trifluoroethoxymethyl)propyl]-4-methyl-N-[4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(2,2,2- trifluoroethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(cyclobutylmethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[3-amino-1-(methoxymethyl)-3-oxo-propyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, and (4S)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide. [0122] In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from: (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[3-[(4-methylpiperazin-1-yl)methyl]-5- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(1-methyl-4-piperidyl)oxy]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(1-methylpyrrolidin-3-yl)oxy-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[3-[[(3R)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-5- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[3-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-5- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(1-piperidylmethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-methoxy-1-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-(morpholinomethyl)-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(2-methyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(methoxymethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[1-(4-methylpiperazin-1-yl)ethyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, 2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(1-methyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, N-[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinolin-7-yl]-4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)benzamide, 2-(2-amino-2-oxo-ethyl)-4-ethyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3,4- dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethoxy)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-tetrahydrofuran-3-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-methoxyethyl)-4-piperidyl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-1-cyclopropyl-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-tetrahydropyran-4-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl 3-[2-amino-1-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]azetidine-1- carboxylate, tert-butyl 3-[2-amino-1-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-2-oxo-ethyl]pyrrolidine-1- carboxylate, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-hydroxyethyl)-4-piperidyl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(azetidin-3-yl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-1-pyrrolidin-3-yl-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-methoxy-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-4,4,4-trifluoro-butyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-1-cyclobutyl-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(oxetan-3-yl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl N-[3-amino-2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-oxo-propyl]-N-methyl- carbamate, (4R)-2-[2-amino-1-(methylaminomethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]- 3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-hydroxy-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(cyclopropylmethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoyl-3-methyl-butyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(1-carbamoylbutyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[2-amino-1-(aminomethyl)-2-oxo-ethyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-morpholinopyrrolidin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-2-methyl-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(3-amino-1-methyl-3-oxo-propyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4-methyl- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-propylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-isopropylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-cyclobutylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-sec-butylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(cyclopropylmethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-isobutylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2,2-difluoroethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(dimethylamino)-1-piperidyl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-N-[4-[(1-acetyl-4-piperidyl)methyl]-3-(trifluoromethyl)phenyl]-2-(2-amino-2-oxo-ethyl)-4-methyl- 3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2-cyanoethyl)-4-piperidyl]methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[1-(2,2-difluoroethyl)-4-piperidyl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2- yl]methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[[4-[2-(trifluoromethoxy)ethyl]piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, tert-butyl N-[2-[4-[[4-[[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7- carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]ethyl]carbamate, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-hydroxyethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(2-fluoroethyl)piperazin-1-yl]methyl]-3-(trifluoromethyl)phenyl]- 4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[(4-cyclopropylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-4- methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(2,2,3,3,5,5,6,6-octadeuterio-4-methyl-piperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-N-[4-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-3-(trifluoromethyl)phenyl]-2- (2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-[3-amino-3-oxo-1-(2,2,2-trifluoroethoxymethyl)propyl]-4-methyl-N-[4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(2,2,2- trifluoroethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-N-[4-[[4-(cyclobutylmethyl)piperazin-1-yl]methyl]-3- (trifluoromethyl)phenyl]-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, (4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-N-[4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide, and (4R)-2-[3-amino-1-(methoxymethyl)-3-oxo-propyl]-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide. [0123] 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-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide. [0124] 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-[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide. [0125] In one embodiment, the compounds of the invention are provided in a natural isotopic form. [0126] 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. [0127] 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. [0128] 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. [0129] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base. [0130] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt. [0131] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound. [0132] 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. [0133] 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. [0134] 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. [0135] 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. [0136] 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, N-alkylmorpholine esters and the like. [0137] 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 C1 to C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention. PHARMACEUTICAL COMPOSITIONS [0138] 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. [0139] 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. [0140] 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. [0141] 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 corn 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. [0142] 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. [0143] 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. [0144] 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. [0145] The above-described 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. [0146] 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. [0147] 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 [0148] 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 [0149] 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 [0150] 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 [0151] 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 [0152] 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 [0153] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75ºC 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 [0154] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. [0155] 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. [0156] 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. [0157] 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. [0158] 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. [0159] 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). [0160] 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). [0161] 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). [0162] 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). [0163] 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. [0164] 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. [0165] 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. [0166] 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, 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. [0167] 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, Sjögren’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. [0168] 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, Sjögren’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. [0169] 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, Sjögren’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. [0170] 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, Sjögren’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. [0171] 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. [0172] 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. [0173] 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 non- alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). More particularly, the term refers to type 2 diabetes, hyperlipidemia, and NASH. [0174] 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. [0175] 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. [0176] 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. [0177] 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. [0178] 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. [0179] 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. [0180] 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. [0181] 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. [0182] 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. [0183] 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. [0184] 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. [0185] 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. [0186] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses. [0187] 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. [0188] 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. [0189] 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. [0190] 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, mycophenolate, mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam. [0191] 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). [0192] 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. HerceptinTM), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. lressa®, 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. [0193] 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-β), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fingolimod and myriocin. [0194] 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-2Rα receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti-lymphocyte globulin (ALG)). [0195] 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 β2-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone/salmeterol, 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). [0196] 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. [0197] 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). [0198] 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. [0199] 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 biologics 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)). [0200] 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 anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants. [0201] 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
wherein, L1 is –O- or –CR4aR4b-; L2 is –C(=O)NH- or –NHC(=O)-; L3 is C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6; R1 is 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 R5; R2 is 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; R3 is C1-4 alkyl; R4a and R4b are independently H or –CH3; each R5 is independently selected from - C1-6 alkyl unsubstituted or substituted with one or more independently selected R7, - C1-4 alkoxy, - -C(=O)-C1-4 alkyl, - C3-6 cycloalkyl, - -NR8aR8b, and - 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R6 is independently selected from - halo, - -OH, - -NR9aR9b, - 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 -C(=O)-O-C1-6 alkyl; each R7 is independently selected from: - halo, - -OH, - –CN, - C3-6 cycloalkyl, - C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and - -NR10aR10b; each R8a and R8b is independently H or C1-4 alkyl; each R9a, R9b, R10a, and R10b is independently H, C1-4 alkyl, or -C(=O)-O-C1-6 alkyl; or a pharmaceutically acceptable salt, solvate, or salt of the solvate thereof. 2. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R3 is C1-4 alkyl. 3. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R3 is -CH3, - CH2CH3, or -CH(CH3)2. 4. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R3 is -CH3 or -CH2CH3. 5. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein R3 is -CH3. 6. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula II:
Figure imgf000056_0001
7. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IIIa or IIIb:
Figure imgf000057_0001
8. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, wherein L2 is –C(=O)NH-. 9. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-7, wherein L2 is –NHC(=O)-. 10. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula IVa or IVb:
Figure imgf000057_0002
11. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is –O-. 12. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is –CR4aR4b- and R4a and R4b are independently H or –CH3. 13. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is –CR4aR4b- and R4a and R4b are both H. 14. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is –CR4aR4b- and one of R4a and R4b is H, and the other is –CH3. 15. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is –CR4aR4b- and R4a and R4b are both –CH3. 16. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-10, wherein L1 is -CH2-. 17. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkyl. 18. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CH3, -CH2CH3, or -CH(CH3)2. 19. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CH3 or -CH2CH3. 20. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CH3. 21. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkyl substituted with one or more independently selected halo. 22. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one or more independently selected halo. 23. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkyl substituted with one, two, or three independently selected halo. 24. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkyl substituted with one or more independently selected F, Cl, or Br. 25. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, 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. 26. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CF3 or -CH2CF3. 27. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -CF3. 28. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkoxy. 29. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is –O-CH3, –O-CH2CH3, or –O-CH(CH3)2. 30. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is –O-CH3. 31. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkoxy substituted with one or more independently selected halo. 32. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is –O-CH3, –O-CH2CH3, or –O-CH(CH3)2, each of which is substituted with one or more independently selected halo. 33. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkoxy substituted with one, two, or three independently selected halo. 34. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. 35. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 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. 36. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -O-CH3 substituted with one, two, or three F. 37. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-16, wherein R2 is -O-CF3. 38. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula Va or Vb:
Figure imgf000059_0001
39. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-38, wherein L1 is –O-. 40. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-38, wherein L1 is –CR4aR4b-. 41. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-38, wherein L1 is –CR4aR4b-, and R4a and R4b are both H. 42. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-38, wherein L1 is –CR4aR4b-, and one of R4a and R4b is H, and the other is –CH3. 43. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-38, wherein L1 is –CR4aR4b-, and R4a and R4b are both –CH3. 44. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIa or VIb:
Figure imgf000059_0002
45. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIc:
Figure imgf000059_0003
46. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is C1-6 alkylene. 47. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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)-. 48. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-. 49. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2-. 50. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is C1-6 alkylene substituted with one or more independently selected R6. 51. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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. 52. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is C1-6 alkylene substituted with one, two, or three independently selected R6. 53. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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. 54. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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. 55. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is C1-6 alkylene substituted with one R6. 56. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one or more independently selected R6. 57. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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. 58. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, 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. 59. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one, two, or three independently selected R6. 60. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2-, -CH(CH2CH2CH3)-, -CH(CH2CH(CH3)CH3)-, -CH2CH2-, or -CH(CH3)CH2-, each of which is substituted with one R6. 61. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-45, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one R6. 62. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIa, VIIb, VIIc, or VIId:
Figure imgf000062_0001
63. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIe or VIIf:
Figure imgf000062_0002
64. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIIa, VIIIb, VIIIc, or VIIId:
Figure imgf000062_0003
Figure imgf000063_0001
65. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is according to Formula VIIIe or VIIIf:
Figure imgf000063_0002
66. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 4-7 membered monocyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. 67. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, oxazolidinyl, morpholinyl, dioxanyl, or piperazinyl. 68. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is pyrrolidinyl, piperidinyl, or morpholinyl. 69. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-44, 46-62, and 64, wherein R1 is
Figure imgf000063_0003
70. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 71. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 72. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 73. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one or more independently selected R5. 74. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 75. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R5. 76. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is pyrrolidinyl, piperidinyl, or piperazinyl, each of which is substituted with one R5. 77. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-44, 46-62, and 64, wherein R1 is
Figure imgf000064_0001
, , , , o . 78. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is
Figure imgf000064_0002
79. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 6-10 membered bridged polycyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. 80. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 4- oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4-oxa-1-azabicyclo[3.1.1]heptanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, 1-azabicyclo[3.2.1]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[4.1.1]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, 1,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5-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[3.2.1]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[4.1.1]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-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[4.1.1]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. 81. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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. 82. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 83. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 4- oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4-oxa-1-azabicyclo[3.1.1]heptanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, 1-azabicyclo[3.2.1]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[4.1.1]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, 1,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5-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[3.2.1]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[4.1.1]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-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[4.1.1]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 R5. 84. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 85. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 or more independently selected R5. 86. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 1-azabicyclo[2.1.1]hexanyl, 3-azabicyclo[2.1.1]hexanyl, 5-azabicyclo[2.1.1]hexanyl, 3- oxabicyclo[2.1.1]hexanyl, 5-oxabicyclo[2.1.1]hexanyl, 1-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[2.2.1]heptanyl, 1,4-diazabicyclo[3.1.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6- diazabicyclo[3.1.1]heptanyl, 3-oxabicyclo[2.2.1]heptanyl, 3-oxabicyclo[3.1.1]heptanyl, 4- oxabicyclo[3.1.1]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, 4-oxa-1-azabicyclo[3.1.1]heptanyl, 6- oxa-3-azabicyclo[3.1.1]heptanyl, 1-azabicyclo[3.2.1]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[4.1.1]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, 1,4-diazabicyclo[2.2.2]octanyl, 1,4-diazabicyclo[3.2.1]octanyl, 1,4-diazabicyclo[4.1.1]octanyl, 1,5-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[3.2.1]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[4.1.1]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-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[4.1.1]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, two, or three independently selected R5. 87. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 88. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 89. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-63, wherein R1 is
Figure imgf000067_0001
, , , , , or . 90. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is 6-10 membered fused bicyclic heterocycloalkyl comprising one, two, or three heteroatoms independently selected from N and O. 91. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein 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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro-1H-isoindolyl, octahydro- 1H-indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H- 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-1H-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H- pyrrolo[3,2-c]pyridinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1- 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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3-b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3- c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl. 92. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is octahydropyrrolo[1,2-a]pyrazinyl. 93. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-44, 46-62, and 64, wherein R1 is
Figure imgf000068_0001
. 94. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 95. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein 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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro-1H-isoindolyl, octahydro- 1H-indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H- 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-1H-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H- pyrrolo[3,2-c]pyridinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1- 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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3-b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3- c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl, each of which is substituted with one or more independently selected R5. 96. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 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 R5. 97. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one or more independently selected R5. 98. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein 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-1H-cyclopenta[c]furanyl, hexahydro-2H-cyclopenta[b]furanyl, octahydrocyclopenta[c]pyrrolyl, octahydrocyclopenta[b]pyrrolyl, hexahydro-1H-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-1H-furo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4- b]pyrrolyl, hexahydro-2H-furo[3,2-b]pyrrolyl, octahydrobenzofuranyl, octahydroisobenzofuranyl, octahydrocyclopenta[b]pyranyl, octahydrocyclopenta[c]pyranyl, octahydro-1H-isoindolyl, octahydro- 1H-indolyl, octahydroindolizinyl, octahydro-1H-cyclopenta[b]pyridinyl, octahydro-1H- 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-1H-furo[3,4- c]pyranyl, hexahydro-2H-cyclopenta[b][1,4]dioxinyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, octahydro-1H-pyrrolo[3,2-b]pyridinyl, octahydro-1H- pyrrolo[3,2-c]pyridinyl, octahydro-1H-pyrrolo[2,3-c]pyridinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-cyclopenta[b]pyrazinyl, octahydropyrano[3,2-b]pyrrolyl, hexahydro-1H-pyrrolo[2,1- 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-1H-isochromenyl, octahydro-2H-chromenyl, decahydroisoquinolinyl, decahydroquinolinyl, octahydro-1H-quinolizinyl, octahydropyrano[4,3-b]pyranyl, octahydropyrano[4,3-c]pyranyl, octahydropyrano[3,4-c]pyranyl, octahydropyrano[2,3-c]pyranyl, octahydrobenzo[b][1,4]dioxinyl, octahydropyrano[3,2-b]pyranyl, octahydro-1H-pyrido[1,2-a]pyrazinyl, decahydro-1,6-naphthyridinyl, decahydro-2,6-naphthyridinyl, decahydro-2,7-naphthyridinyl, octahydro-2H-pyrano[3,2-c]pyridinyl, octahydro-1H-pyrano[4,3- c]pyridinyl, octahydro-1H-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-1H-pyrano[4,3-b]pyridinyl, octahydro-1H-pyrano[3,4-b]pyridinyl, or octahydropyrido[2,1-c][1,4]oxazinyl, each of which is substituted with one, two, or three independently selected R5. 99. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one, two, or three independently selected R5. 100. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, wherein R1 is octahydropyrrolo[3,4-c]pyrrolyl substituted with one R5. 101. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-44, 46- 62, and 64, wherein R1 is
Figure imgf000070_0001
102. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is C1-6 alkyl. 103. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 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. 104. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, or -CH(CH3)CH2CH3. 105. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -CH3. 106. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is C1-6 alkyl substituted with one or more independently selected R7. 107. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 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 R7. 108. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is C1-6 alkyl substituted with one, two, or three independently selected R7. 109. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -CH3 or -CH2CH3, each of which is substituted with one or more independently selected R7. 110. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 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 R7. 111. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -CH3 or -CH2CH3, each of which is substituted with one, two, or three independently selected R7. 112. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is halo, -OH, or -CN. 113. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is F, Cl, Br, -OH, or -CN. 114. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is F, -OH, or -CN. 115. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is C3-6 cycloalkyl. 116. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is cyclopropyl, cyclobutyl, or cyclopentyl. 117. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is cyclopropyl or cyclobutyl. 118. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is C1-4 alkoxy. 119. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. 120. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -O-CH3. 121. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is C1-4 alkoxy substituted with one or more independently selected halo. 122. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo. 123. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is C1-4 alkoxy substituted with one, two, or three independently selected halo. 124. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. 125. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 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. 126. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 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. 127. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -O-CH3 substituted with one, two, or three F. 128. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -O-CF3. 129. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b. 130. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b are independently H, C1-4 alkyl, or -C(=O)-O-C1-6 alkyl. 131. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b are both H. 132. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b is H, and the other is C1-4 alkyl or -C(=O)-O-C1-6 alkyl. 133. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b are both independently C1- 4 alkyl or -C(=O)-O-C1-6 alkyl. 134. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and one of R10a and R10b 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. 135. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b 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. 136. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and one of R10a and R10b 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. 137. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b are both independently -CH3, –CH2CH3, or –CH(CH3)2. 138. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and one of R10a and R10b is H, and the other is -CH3 or -C(=O)-O-C(CH3)3. 139. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, 94-101, and 106-111, wherein R7 is -NR10aR10b, and R10a and R10b are both -CH3. 140. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is C1-4 alkoxy. 141. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. 142. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -O-CH3. 143. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -C(=O)-C1-4 alkyl. 144. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -C(=O)-CH3, -C(=O)-CH2CH3, or -C(=O)-CH(CH3)2. 145. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -C(=O)-CH3. 146. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is C3-6 cycloalkyl. 147. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is cyclopropyl, cyclobutyl, or cyclopentyl. 148. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is cyclopropyl or cyclobutyl. 149. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b. 150. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and R8a and R8b are independently H or C1-4 alkyl. 151. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and R8a and R8b are both H. 152. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and one of R8a and R8b is H, and the other is C1-4 alkyl. 153. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and R8a and R8b are both independently C1-4 alkyl. 154. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and one of R8a and R8b is H, and the other is -CH3, – CH2CH3, or –CH(CH3)2. 155. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and R8a and R8b are both independently -CH3, –CH2CH3, or –CH(CH3)2. 156. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is -NR8aR8b, and R8a and R8b are both -CH3. 157. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. 158. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, dioxanyl, or piperazinyl. 159. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-65, 70- 78, 82-89, and 94-101, wherein R5 is morpholinyl. 160. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is halo, or -OH. 161. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is F, Cl, Br, or -OH. 162. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is F or -OH. 163. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b. 164. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and R9a and R9b are both H. 165. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and one of R9a and R9b is H, and the other is C1-4 alkyl or -C(=O)-O-C1-6 alkyl. 166. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and R9a and R9b are both independently C1-4 alkyl or -C(=O)-O-C1-6 alkyl. 167. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and one of R9a and R9b 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. 168. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and R9a and R9b 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. 169. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and one of R9a and R9b is H, and the other is -CH3, –CH2CH3, or –CH(CH3)2. 170. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and R9a and R9b 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. 171. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and one of R9a and R9b is H, and the other is -CH3. 172. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -NR9aR9b, and one of R9a and R9b is -CH3, and the other is -C(=O)-O-C(CH3)3. 173. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is C1-4 alkoxy. 174. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -O-CH3, -O-CH2CH3, or –O-CH(CH3)2. 175. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -O-CH3. 176. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is C1-4 alkoxy substituted with one or more independently selected halo. 177. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is –O-CH3, –O-CH2CH3, or –O-CH(CH3)2, each of which is substituted with one or more independently selected halo. 178. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is C1-4 alkoxy substituted with one, two, or three independently selected halo. 179. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is C1-4 alkoxy substituted with one or more independently selected F, Cl, or Br. 180. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, 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. 181. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is --O-CH2CH3 substituted with one, two, or three F. 182. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is -O-CH2CF3. 183. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is C3-6 cycloalkyl. 184. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is independently cyclopropyl, cyclobutyl, or cyclopentyl. 185. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is independently cyclopropyl or cyclobutyl. 186. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O. 187. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl. 188. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, or tetrahydropyranyl. 189. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, 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 -C(=O)-O-C1-6 alkyl. 190. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or 1,4-dioxanyl, each of which is substituted with one -C(=O)-O-C1-6 alkyl. 191. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, 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 -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. 192. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with -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. 193. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with -C(=O)-O-CH3, -C(=O)-O-CH2CH3, -C(=O)-O-CH(CH3)2, or -C(=O)-O-C(CH3)3. 194. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-159, wherein R6 is azetidinyl or pyrrolidinyl, each of which is substituted with -C(=O)-O-C(CH3)3. 195. A compound or pharmaceutically acceptable salt thereof, according to clause 1, wherein the compound is selected from Table III. 196. 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 1-195. 197. A pharmaceutical composition according to clause 196 comprising a further therapeutic agent. 198. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-195, or a pharmaceutical composition according to clause 196 or 197 for use in medicine. 199. A compound or pharmaceutically acceptable salt thereof, according to any one of clauses 1-195, or a pharmaceutical composition according to clause 196 or 197 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. 200. A compound or pharmaceutically acceptable salt thereof for use according to clause 198 or 199, wherein said compound or pharmaceutically acceptable salt thereof is administered in combination with a further therapeutic agent. 201. The pharmaceutical composition according to clause 197, or the compound or pharmaceutically acceptable salt thereof for use according to clause 200, 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 [0202] 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. [0203] 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). [0204] 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. [0205] 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 µm) 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.1H 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 (δ) for 1H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, e.g. CHCl3 (δ 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 C181.7 µm, 2.1 mm ID × 30/50 mm L; Waters Acquity UPLC CSH C181.7 μm, 2.1 mm ID × 50/100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 μm, 2.1 mm ID × 100 mm L; Waters Acquity UPLC HSS PFP 1.8 μm, 2.1 mm ID × 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 XBRIDGE BEH C18 OBD 30 mm ID × 100/150 mm L columns and ACN/H2O gradients with either 0.1% formic acid in both mobile phases, 0.1% diethylamine 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. Table I. List of abbreviations used in the experimental section
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0002
SYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTION Example 1. General synthetic methods 1.1. Synthetic methods overview General method A1: amide coupling with HATU General method A2: direct amidation of ester General method A3: one-pot procedure saponification and amide coupling General method B1: nucleophilic aromatic substitution by alcohols General method B2: nucleophilic substitution by amines General method C1: nitro reduction by catalytic hydrogenation General method C2: nitro reduction with Zn/NH4Cl General method C3: nitro reduction with Fe/AcOH General method D: Boc removal General method E1: alkylation of tetrahydroisoquinoline core General method E2: alkylation of a piperidine General method F: Strecker reaction and cyano hydrolysis General method G: saponification and carboxamide formation General method H: trifluoroacetyl cleavage General method I: reductive amination General method J: Michael addition General method K: trifluoroacetyl protection General method L: Pictet-Spengler cyclization with sulfuric acid 1.2. General methods 1.2.1. General method A1: amide coupling with HATU
Figure imgf000080_0001
[0206] To a solution of carboxylic acid (1 eq.) and aniline (0.75 to 1.2 eq.) in DMF are added HATU (1 to 1.5 eq.) and DIPEA (2 to 10 eq.) and the reaction is stirred at RT to 55 °C for 1 to 24 h. The crude is concentrated and purified either by column chromatography on silica gel or by preparative HPLC to give the desired amide. [0207] Alternative work-up: the crude is partitioned between water and EtOAc. The layers are separated, the aqueous layer is further extracted with EtOAc. The combined organic layers are washed with a LiCl solution (5% w/w) or washed with water and brine. They are then dried over MgSO4 and filtered, or filtered on a phase separator. The filtrate is concentrated. The residue is purified by column chromatography on silica gel or by preparative HPLC to give the desired amide. 1.2.1.1. Illustrative synthesis of Cpd 3
Figure imgf000081_0001
[0208] To a solution of Int 11 (30 mg, 0.12 mmol, 1.0 eq.) and 3-[(4-methylpiperazin-1-yl)methyl]-5- (trifluoromethyl)aniline (CAS# 853296-94-3; 33 mg, 0.12 mmol, 1 eq.) in DMF (1.5 mL) were added HATU (55 mg, 0.14 mmol, 1.2 eq.) and DIPEA (51 µL, 0.29 mmol, 2.5 eq.). The reaction was stirred at RT for 15 h. The reaction medium was concentrated and purified by preparative HPLC to give Cpd 3. 1.2.1.2. Illustrative synthesis of Cpd 19
Figure imgf000081_0002
[0209] To a solution of Int 74 (37 mg, 0.11 mmol, 1.0 eq.) and Int 11 (34 mg, 0.13 mmol, 1.2 eq.) in DMF (1 mL) were added HATU (55 mg, 0.14 mmol, 1.3 eq.) and DIPEA (42 µL, 0.24 mmol, 2.2 eq.). The mixture was stirred at RT for 20 h. The reaction medium was diluted with EtOAc and quenched with water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and brine, filtered on a phase separator and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 95/5 to 9/1 then DCM + 10% NH37N in MeOH) to afford Cpd 19. 1.2.2. General method A2: direct amidation of ester
Figure imgf000081_0003
[0210] To a solution or suspension of the ester (1 eq.) and the amine derivative (1 to 2 eq.) in toluene or THF is added dropwise a LiHMDS solution (1 M to 1.3 M in THF, 2 to 4 eq.) and the mixture is stirred at RT for 1 h 30 to 16 h. The reaction mixture is quenched with MeOH, concentrated and purified by preparative HPLC to afford the expected product. [0211] Alternative work-up: the reaction mixture is quenched with water or a saturated aqueous NH4Cl solution and extracted with DCM or EtOAc. The combined organic layers are washed with water, brine, filtered on a phase separator and concentrated. The residue is purified by preparative HPLC or column chromatography on silica gel to afford the expected product. 1.2.2.1. Illustrative synthesis of Cpd 70
Figure imgf000082_0001
[0212] To a suspension of Int 10 (80 mg, 0.28 mmol, 1.0 eq.) and Int 72 (113 mg, 0.36 mmol, 1.3 eq.) in toluene (1.5 mL) was added dropwise a LiHMDS solution (1 M in THF, 1.12 mL, 1.12 mmol, 4 eq.) and the mixture was stirred at RT for 16 h. The reaction medium was quenched with MeOH and concentrated to dryness. The residue was purified by preparative HPLC to afford Cpd 70. 1.2.3. General method A3: one-pot procedure saponification and amide coupling
Figure imgf000082_0002
[0213] To a solution of the ester (1 eq.) in EtOH is added NaOH (2 N in water, 2 eq.) and the mixture is stirred at 55 °C for 1 to 2 h. Then the reaction medium is cooled down to RT and the amine (1 eq.) and HATU (2 eq.) are added. The mixture is stirred at 55 °C for 1 h 30 to 16 h. The reaction medium is either concentrated and purified by preparative HPLC to give the expected product, or quenched with water. The aqueous phase is extracted with DCM, the combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by preparative HPLC to afford the expected product. 1.2.3.1. Illustrative synthesis of Cpd 48
Figure imgf000082_0003
[0214] To a solution of Int 10 (80 mg O, 0.28 mmol, 1.0 eq.) in Et OOH (2 m NL) was added NaOH (2 M in water, 0.28 mL, 0.56 mmol, 2 eq.) and the reaction mixture was stirFreFd at 55 °C for 1.5 h. Then HATU (0.22 g, 0.56 mmol, 2 eq.) and 4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline (CAS# 630125-91-6; 80 mg, 0.28 mmol, 1 eq.) were added and the mixture was stirred at 55 °C for 16 h. The reaction medium was concentrated to dryness and the residue was purified by preparative HPLC to afford 1.2.4. General method B1: nucleophilic aromatic substitution by alcohols
Figure imgf000083_0001
[0215] The fluoronitrophenyl derivative (1 eq.), the alcohol (1.1 eq.) and Cs2CO3 (2.3 eq.) are combined in DMF and then heated at 100 °C for 16 h. The solvents are concentrated and the residue is partitioned between water and EtOAc. The layers are separated and the aqueous phase is further extracted with EtOAc. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to give the desired product. 1.2.4.1. Illustrative synthesis of Int 146
Figure imgf000083_0002
[0216] 1-Fluoro-4-nitro-2-(trifluoromethyl)benzene (CAS# 400-74-8; 500 mg, 2.4 mmol, 1 eq.), 1- methylpyrrolidin-3-ol (CAS# 13220-33-2; 266 mg, 2.6 mmol, 1.1 eq.) and Cs2CO3 (1.79 g, 5.5 mmol, 2.3 eq.) were combined in DMF (25 mL) in a sealed tube and then heated at 100 °C for 15 h. The reaction medium was concentrated and partitioned between water and EtOAc. The layers were separated and the aqueous phase was further extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM to DCM/MeOH 9:1) to give Int 146. 1.2.5. General method B2: nucleophilic substitution by amines
Figure imgf000083_0003
[0217] To the substituted benzyl bromide (1 eq.) in DCM, THF or DMF are added the amine (0.95 to 2.3 eq.) and TEA or K2CO3 (1 to 5 eq.). The mixture is stirred at RT for 1.5 to 16 h, then a sat. NaHCO3 aq. solution is added and the layers are separated. The organic layer is washed with water, brine, dried over MgSO4, filtered and concentrated to give the desired product. [0218] Alternative work-up 1: the obtained suspension is filtered, the solid is dried and collected to afford the expected product. [0219] Alternative work-up 2: the reaction is quenched with water and the aqueous phase is extracted with DCM. The combined organic phases are filtered on a phase separator, washed or not with a saturated aqueous NH4Cl solution, and concentrated. The residue is purified by column chromatography on silica gel to afford the expected product. 1.2.5.1. Illustrative synthesis of Int 16
Figure imgf000084_0001
[0220] To a solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (CAS# 694499-22-4; 100 mg, 0.35 mmol, 1 eq.) in DCM (2 mL) were added (3S)-N,N-dimethyl-3-pyrrolidinamine (CAS# 132883- 44-4; 92 mg, 0.81 mmol, 2.3 eq.) and TEA (0.13 mL, 0.92 mmol, 2.6 eq.). The mixture was stirred at RT for 15 h, then a sat. NaHCO3 aq. solution was added and the layers were separated. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated to give Int 16. 1.2.5.2. Illustrative synthesis of Int 88
Figure imgf000084_0002
[0221] To a suspension of 1-propylpiperaz .iner dihydrobromide salt (700 mg, 2.41 mmol, 1 eq.) in DCM (10 mL) was added TEA (0.84 mL, 6.03 mmol, 2.5 eq.) and the mixture was stirred at RT for 30 min. Then 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (CAS# 694499-22-4; 722 mg, 2.41 mmol, 1 eq.) and TEA (0.51 mL, 3.62 mmol, 1.5 eq.) were added and the reaction mixture was stirred at RT for 15 h. The reaction medium was quenched with water and the aqueous phase extracted with DCM. The combined organic phases were filtered on a phase separator and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to afford the expected product Int 88. 1.2.6. General method C1: nitro reduction by catalytic hydrogenation
Figure imgf000084_0003
[0222] 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 0.5 eq.) and the suspension is stirred at 20 °C under hydrogen atmosphere (1 to 2.5 bar) for 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 or purified by column chromatography on silica gel to obtain the expected product. 1.2.6.1. Illustrative synthesis of Int 145
Figure imgf000084_0004
[0223] To a solution of Int 146 (140 mg, 0.48 mmol, 1 eq.) in EtOH (6 mL) was added Pd/C (10 w%, 10 mg, 0.064 mmol, 0.02 eq.). The suspension was stirred at RT under hydrogen atmosphere (1 bar) for 2 h. The reaction mixture was filtered through a phase separator, the solids were washed with EtOAc and the filtrate was concentrated to afford Int 145. 1.2.7. General method C2: nitro reduction with Zn/NH4Cl [0224] To a solution of the nitro compound (1 eq.) in MeOH or EtOH is added Zn (powder, 10 eq.) and the mixture is stirred at RT for 5 to 30 min before ammonium chloride (10 eq.) is added. The reaction mixture is stirred at RT for 1 to 18 h and the solids are removed by filtration. The filtrate is concentrated and used as such. [0225] Alternative work-up: the reaction mixture is filtered, the filtrate is concentrated and the residue is taken up in water or a sat. NaHCO3 aq. solution. If a solid precipitates, it is filtered off and used as such. If not, the aqueous phase is extracted with a DCM/ i-PrOH mixture (9/1), the combined organic phases are filtered on a phase separator and the filtrate is concentrated to afford the expected product. 1.2.7.1. Illustrative synthesis of Int 57
Figure imgf000085_0001
[0226] To a solution of Int 89 (1.69 g, 5.1 mmol, 1 eq.) in MeOH (20 mL) was added Zn powder (3.34 g, 51 mmol, 10 eq.) and the suspension was stirred at RT for 30 min. Then ammonium chloride (2.73 g, 51 mmol, 10 eq.) was added and the mixture was stirred at RT for 2 h. The reaction medium was filtered and the solids washed with MeOH. The filtrate was concentrated in vacuo to afford the expected product Int 57. 1.2.7.2. Illustrative synthesis of Int 72
Figure imgf000085_0002
[0227] To a solution of Int 105 (660 mg, 2.01 mmol, 1 eq.) in EtOH was added zinc powder (1.32 g, 20.14 mmol, 10 eq.) and the suspension was stirred at RT for 5 min. Then ammonium chloride (1.08 g, 20.14 mmol, 10 eq.) was added and the mixture was stirred at RT for 2 h. The reaction medium was filtered, the solid was rinsed with MeOH and DCM and the filtrate was concentrated. The residue was taken up in water and extracted with DCM/i-PrOH 9/1. Then combined organic phases were filtered on a phase separator and concentrated to afford Int 72. 1.2.8. General method C3: nitro reduction with Fe/AcOH [0228] To a solution of the nitrophenyl derivative (1 eq.) in AcOH at 0 °C is added iron powder (1 eq. w/w) and the mixture is heated at 80 °C for 3 to 5 h. The crude is partitioned between water and EtOAc and the pH adjusted to 8 by addition of a sat. NaHCO3 aq. solution. The layers are separated, the aqueous phase is further extracted with EtOAc. The combined organic layers are washed with water and brine, then filtered through phase separator and concentrated to afford the desired product. 1.2.8.1. Illustrative synthesis of Int 23
Figure imgf000086_0001
[0229] To a solution of Int 22 (78 mg, 0.22 mmol, 1 eq.) in AcOH (1 mL) at 0 °C was added iron powder (78 mg) and the mixture was stirred at RT for 2 h then at 80 °C for 3 h. The reaction mixture was partitioned between water and EtOAc and the pH adjusted to 8 by addition of a sat. NaHCO3 aq. solution. The layers were separated, the aqueous phase was further extracted with EtOAc. The combined organic layers were washed with water and brine, then filtered through phase separator and concentrated to afford Int 23. 1.2.9. General method D: Boc removal
Figure imgf000086_0002
[0230] The Boc-protected amine (1 eq.) is stirred at RT in an acidic medium (typically 2:1 DCM/TFA or 4 to 30 eq. HCl (4M in dioxane) in dioxane or MeOH) for 3 to 18 h. The reaction mixture is concentrated. The residue is used as such or undergoes a purification technique such as elution on a cation exchange column, preparative HPLC, or trituration with Et2O to afford the desired product. 1.2.9.1. Illustrative synthesis of Int 143
Figure imgf000086_0003
[0231] To a solution of Int 144 (105 mg, 0.2 mmol, 1 eq.) in 1,4-dioxane (2 mL) was added a 4 N HCl solution in 1,4-dioxane (1.5 mL, 6 mmol, 30 eq.). The reaction mixture was stirred at RT for 15 h. The solvents were concentrated and the residue was purified on a Biotage® Isolute® SCX cation exchange column, eluting with a 7 N ammonia solution in MeOH to give Int 143. 1.2.9.2. Illustrative synthesis of Int 76
Figure imgf000086_0004
[0232] To a solution of Int 42 (65 mg, 0.17 mmol, 1 eq.) in DCM (2 mL) was added TFA (1 mL) and the mixture was stirred at RT overnight. The reaction mixture was concentrated and the residue was purified on a Biotage® Isolute® SCX cation exchange column eluting with a 7 N ammonia solution in MeOH to give Int 76. 1.2.10. General method E1: alkylation of tetrahydroisoquinoline core
Figure imgf000087_0001
[0233] To a solution of the central core (1 eq.) in acetonitrile are added TEA, K3PO4 or 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 80 °C for 1 to 15 h. 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. [0234] Alternative work-up: the reaction mixture is concentrated or not, then is partitioned between water and EtOAc or DCM. The layers are separated. The organic layer is washed or not with brine before being dried over MgSO4, 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. 1.2.10.1. Illustrative synthesis of Cpd 5
Figure imgf000087_0002
[0235] To a solution of Int 143 (82 mg, 0.19 mmol, 1 eq.) in ACN (3 mL) were added K2CO3 (78 mg, 0.56 mmol, 3 eq.) and 2-bromoacetamide (CAS# 683-57-8; 26 mg, 0.19 mmol, 1 eq.). The suspension was stirred at 50 °C for 15 h. The reaction mixture was filtered, concentrated and the residue was purified by column chromatography on silica gel (eluting with DCM to DCM/MeOH/NH380:20:1) to afford Cpd 5. 1.2.10.2. Illustrative synthesis of Cpd 13
Figure imgf000087_0003
[0236] To a solution of Int 43 (250 mg, 0.48 mmol, 1 eq.) in ACN (4.8 mL) was added K2CO3 (132 mg, 0.95 mmol, 2 eq.) and 3-bromopropionamide (145 mg, 0.95 mmol, 2 eq.) and the reaction mixture was stirred at 70 °C for 4 h. The mixture medium was partitioned between water and EtOAc. The layers were separated and the organic layer was 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 then DCM/(NH37 N in MeOH) 9/1) to afford Cpd 13. 1.2.11. General method E2: alkylation of a piperidine
Figure imgf000088_0001
[0237] To a solution or suspension of the piperidine derivative (1 eq.) in ACN or THF are added TEA or DIPEA (1.5 to 4 eq.) and the alkylating agent (1.5 to 4 eq.). The mixture is stirred at 70 °C for 6 to 16 h. The reaction medium is concentrated and the residue is purified by cation exchange column or by column chromatography on silica gel to afford the expected product. 1.2.11.1. Illustrative synthesis of Cpd 58
Figure imgf000088_0002
[0238] To a suspension of Int 62 (50 mg, 0.089 mmol, 1 eq.) in ACN (2 mL) were added TEA (49 µL, 0.35 mmol, 4 eq.) and 3-bromopropane nitrile (CAS# 2417-90-5; 11 µL, 0.13 mmol, 1.5 eq.) and the mixture was stirred at 70 °C for 16 h. The reaction medium was concentrated and the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to afford the expected product Cpd 58. 1.2.12. General method F: Strecker reaction and cyano hydrolysis
Figure imgf000088_0003
[0239] To a solution of the central core (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.). The mixture is stirred at RT for 16 h. If needed additional aldehyde (3 eq.), NaCN (6 eq.) and AcOH (4.5 eq.) are added and the mixture is stirred for another 24 h. Then the reaction medium is poured in water, extracted with DCM and the combined organic phases are filtered on a phase separator. The filtrate is concentrated to give the cyano intermediate. [0240] This intermediate is dissolved in DMSO and K2CO3 (5 eq.) and H2O2 (30% in water, 5 eq.) are added. The mixture is stirred at RT for 16 h. If needed more K2CO3 (5 eq.) and H2O2 (30% in water, 5 eq.) are added and the mixture is stirred at 50 °C for 1 to 4 h or at RT for 16 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 over MgSO4, filtered and concentrated. The residue is purified by preparative HPLC to afford the expected product. 1.2.12.1. Illustrative synthesis of Cpd 36
Figure imgf000088_0004
[0241] To a solution of Int 43 (150 mg, 0.27 mmol, 1 eq.) in a ACN/water mixture (1.2 mL / 0.8 mL) was added oxetane-3-carbaldehyde (CAS# 1305207-52-6; 70 mg, 0.81 mmol, 3 eq.), NaCN (82 mg, 1.62 mmol, 6 eq.) and acetic acid (70 µL, 1.21 mmol, 4.5 eq.). The reaction mixture was stirred at RT for 16 h. Then the reaction medium was poured in water, extracted with DCM and the combined organic phases were filtered on a p Rhase separator. The filtrate was concentrated to give the cyano intermediate. This intermediate was dissolved in DMSO (1.5 mL) and K2CO3 (188 mg, 1.34 mmol, 5 eq.) and hydrogen peroxide (30% in water, 138 µL, 1.34 mmol, 5 eq.) were added. The reaction mixture was stirred at RT for 16 h and the reaction medium was purified by preparative HPLC to afford Cpd 36. 1.2.13. General method G: saponification and carboxamide formation
Figure imgf000089_0001
[0242] To a solution of the ester (1 eq.) in THF is added NaOH (2 M in water, 4 eq.) and the mixture is stirred at 60 °C for 16 h. The solvents are concentrated in a4tt =e M vacuo to afford the carboxylate intermediate. [0243] The l re i onr E dtissolved in DMF, HATU (2 to 4 eq.) is added and the mixture is stirred at RT for 5 min. Then ammonium acetate (3 to 7 eq.) and DIPEA (2 to 4 eq.) are added and the reaction mixture is stirred at 60 °C for 5 to 72 h. The reaction medium is purified by preparative HPLC to afford the expected product. 1.2.13.1. Illustrative synthesis of Cpd 72
Figure imgf000089_0002
[0244] To a solution of Int 73 (44 mg, 0.07 mmol, 1 eq.) in THF (0.5 mL) was added NaOH (2 N in water, 0.14 mL, 0.27 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 mL). HATU (40 mg, 0.10 mmol, 1.5 eq.), ammonium acetate (21 mg, 0.27 mmol, 4 eq.) and DIPEA (24 µL, 0.14 mmol, 2 eq.) were added and the reaction mixture was stirred at 60 °C for 5 h. The reaction medium was purified by preparative HPLC to afford the expected product Cpd 72. 1.2.14. General method H: trifluoroacetyl cleavage
Figure imgf000089_0003
[0245] To a solution of the trifluoroacetyl-protected intermediate in a MeOH/H2O mixture (2/1 to 14/1) is added K2CO3 (2.0 eq.). The mixture is stirred at RT for 1 to 16 h. The solvents are concentrated and the residue is partitioned between a sat. NaHCO3 aq. solution and DCM. The layers are separated, the aqueous phase is further extracted with DCM. The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure to give the expected product. [0246] Alternative work-up: the reaction medium is quenched with water and extracted with DCM. The combined organic layers are dried over MgSO4, filtered and concentrated under reduced pressure to give the expected product. 1.2.14.1. Illustrative synthesis of Int 5
Figure imgf000090_0001
[0247] To a solution of Int 4 (122 g, 385 mmol, 1 eq.) in MeOH (700 mL) and H2O (350 mL) was added K2CO3 (106.3 g, 769 mmol, 2 eq.). The mixture was stirred at RT for 2 h and the reaction medium 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 MgSO4, filtered and concentrated under reduced pressure to afford Int 5. 1.2.15. General method I: reductive amination
Figure imgf000090_0002
[0248] To a solution of the ketone or the aldehyde derivative (1 eq.) in DCM, DCE or MeOH at RT is added the corresponding amine (1.1 to 1.5 eq.). AcOH (5 eq.) or titanium(IV) isopropoxide (2 eq.) may also be added. The mixture is stirred at RT to 45 °C for 30 min to 72 h. Then at RT the reducing agent (NaBH3(CN) or NaBH(OAc)3, 2.5 to 8 eq.) is added and the reaction mixture is again stirred at RT to 45 °C for 3 to 16 h. Water and DCM are added and the layers separated. The aqueous phase is extracted with DCM. The combined organic phases are washed or not with brine, dried over MgSO4 or Na2SO4, filtered and concentrated to dryness. The residue is used as such or purified by column chromatography on silica gel to afford the desired product. 1.2.15.1. Illustrative synthesis of Int 40
Figure imgf000090_0003
[0249] To a solution of 1-[4-nitro-2-(trifluoromethyl)phenyl]ethanone (CAS# 1314777-65-5; 100 mg, 0.43 mmol, 1 eq.) in DCM (4 mL) at RT were added 1-methylpiperazine (CAS# 109-01-3; 0.071 mL, 0.64 mmol, 1.5 eq.) and titanium(IV) isopropoxide (CAS# 546-68-9; 0.26 mL, 0.86 mmol, 2 eq.). The reaction was stirred at 45 °C for 72 h and NaBH3(CN) (216 mg, 3.4 mmol, 8 eq.) was added at RT. The reaction was again stirred at 45 °C for 3 h and cooled to RT. Water and DCM were added and the layers were separated. The organic phase was concentrated and the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 10:0 to 9:1) to give Int 40. 1.2.16. General method J: Michael addition
Figure imgf000091_0001
[0250] To a solution of tetrahydroisoquinoline (1 eq.) in MeOH is added benzyltrimethylammonium hydroxide (CAS# 100-85-6; 40 mass% in MeOH, 1.0 eq.) and the responding alkene (10 eq.) is added and the reaction mixtu = m reeixture is stirred at RT for 30 min. Then the cor i,s sttirred at 60 °C for 16 h. The solvents are concentrated in vacuo and the residue is taken up in water and DCM. 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. 1.2.16.1. Illustrative synthesis of Int 73
Figure imgf000091_0002
[0251] To a solution of Int 43 (200 mg, 0.36 mmol, 1 eq.) in MeOH (2 mL) was added a solution of benzyltrimethylammonium hydroxide (CAS# 100-85-6; 40% in MeOH, 0.19 mL, 0.17 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. The solvents were concentrated in vacuo and the residue was taken up in 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 90/10) to afford Int 73. 1.2.17. General method K: trifluoroacetyl protection
Figure imgf000091_0003
[0252] A solution of the starting amine (1.0 eq.) in DCM is cooled to 0 °C and TFAA (1.0 to 3 eq.) is added dropwise. The mixture is stirred at RT for 1 to 15 h. The reaction mixture is quenched by addition of water at 0 °C or by addition of ice at RT. The phases are separated and the aqueous layer is extracted with DCM. The combined organic layers are washed or not with brine, dried over Na2SO4 or MgSO4, filtered and concentrated under reduced pressure. The residue is used as such, or is purified by column chromatography on silica gel, or is suspended in pentane and filtered, to afford the expected product. 1.2.17.1. Illustrative synthesis of Int 1
Figure imgf000092_0001
[0253] A solution of (R)-2-phenylpropan-1-amine (CAS# 28163-64-6; 105 mL, 739 mmol, 1.0 eq.) in DCM (1.0 L) was cooled to 0 °C and TFAA (102 mL, 739 mmol, 1.0 eq.) was added dropwise. The mixture was stirred at RT for 15 h. The reaction mixture was quenched by addition of water (1.0 L) at 0 °C. The phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give Int 1. 1.2.18. General method L: Pictet-Spengler cyclization with sulfuric acid
Figure imgf000092_0002
[0254] The starting open amide (1.0 eq.) is placed in concentrated sulfuric acid at 0 °C and paraformaldehyde (5.0 eq.) is added. The mixture is stirred at RT for 8 to 16 h. Then the reaction medium is poured into ice-water and extracted with DCM, EtOAc or MTBE. The combined organic layers are washed with brine or a sat. NaHCO3 aq. solution, dried over MgSO4 or Na2SO4, filtered and concentrated. The residue is purified by column chromatography on silica gel to afford the expected product. 1.2.18.1. Illustrative synthesis of Int 114
Figure imgf000092_0003
[0255] Paraformaldehyde (7.64 g, 254.5 mmol, 5 eq.) was added to a suspension of Int 115 (25.7 g, 50.9 mmol, 1 eq.) in concentrated sulfuric acid (200 mL) at 0 °C. The reaction mixture was stirred at RT overnight. The mixture was poured into ice water (900 mL) and then diluted with EtOAc (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (500 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (eluting with Heptane/ EtOAc 10/0 to 8/2) to afford Int 114. Example 2. Pre iparation of the compounds of the invention
Figure imgf000092_0004
ii iii 2.1.1. Step i: N-[(2R)-2-(4-bromophenyl)propyl]-2,2,2-trifluoro-acetamide
Figure imgf000093_0001
[0256] A solution of Int 1 (158 g, 615 mmol, 1.0 eq.) in DCM (2.5 L) was cooled to -10 °C. Methane sulfonic acid (131 mL, 1.85 mol, 3.0 eq.) was added, followed by portion wise addition of 1,3-dibromo- 5,5-dimethyl-imidazolidine-2,4-dione (CAS# 77-48-5; 105 g, 369 mmol, 0.6 eq.). The resulting mixture was stirred at RT for 15 h. The reaction mixture was quenched by addition water (8 L) at 10 °C and was then extracted with DCM (8 L). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with of petroleum ether/MTBE 9/1) to afford N-[(2R)-2-(4-bromophenyl)propyl]-2,2,2-trifluoro- acetamide. 2.1.2. Step ii: methyl 4-[(1R)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate
Figure imgf000093_0002
[0257] N-[(2R)-2-(4-bromophenyl)propyl]-2,2 N,2-trifluoro-acetamide (100 g, 290 mmol H (500 mL) and DM FF (5 O00 mL) and C tOheM , 1.0 eq.) was dissolved in MeO 2ne TEA (121 mL, 870 mmol, 3.0 eq.) and Pd(dppf)Cl2 (CAS# 72287-26-4; 10.6 g, 14.5 mmol, 0.05 eq.) were added. The reactor was sealed under 50 Psi of CO and heated to 80 °C for 48 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with petroleum ether/MTBE 9/1) to give methyl 4-[(1R)-1-methyl-2-[(2,2,2- trifluoroacetyl)amino]ethyl]benzoate. 2.1.3. Step iii: Int 4
Figure imgf000093_0003
[0258] Int 4 was prepared from methyl 4-[(1R)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate using General Method L. 2.1.4. Step iii: Int 4 (alternative synthesis) [0259] A round bottom flask was charged with TFA (1 L), then methyl 4-[(1R)-1-methyl-2-[(2,2,2- trifluoroacetyl)amino]ethyl]benzoate (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 4. 2.2. Int 6
Figure imgf000094_0001
[0260] To a solution of Int 5 (78 g, 380 mmol, 1 eq.) and TEA (106 mL, 760.04 mmol, 2 eq.) in DCM (800 mL) was added Boc2O (91.2 g, 418 mmol, 1.1 eq.) portion wise. The mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure to give a residue that was purified by flash chromatography on silica gel (eluting with petroleum ether/DCM 7/3) to give Int 6. 2.3. Int 7
Figure imgf000094_0002
[0261] A solution of Int 6 (1.6 g, 5.2 mmol, 1 eq.) in THF (20 mL) was treated with lithium hydroxide hydrate (2 M in water, 5.2 mL, 10.4 mmol, 2.0 eq.). The resulting mixture was stirred at 65 °C for 4 h and then cooled to RT. The reaction medium was acidified by addition of a 1 N aq. HCl solution and extracted with DCM. The combined organic layers were filtered through a phase separator and the filtrate was concentrated to afford Int 7. 2.4. Int 10
Figure imgf000094_0003
[0262] To a solution of Int 5 (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 occured and the solid was filtered. The obtained solid was then washed with water and dried to afford Int 10. 2.5. Int 10 (alternative synthes iis)
Figure imgf000094_0004
ii 2.5.1. Step i: Int 5, hydrochloride
Figure imgf000095_0001
[0263] To a suspension of Int 4 (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 HCl (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 Int 5, hydrochloride. LCMS: MW (calcd): 205.3; m/z MW (obsd): 206.1 (M+H) 2.5.2. Step ii: Int 10
Figure imgf000095_0002
[0264] To a suspension of methyl (4R)-4-methyl-1,2,3,4-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 10. 2.6. Int 11
Figure imgf000095_0003
2.6.1. Step i: ethy il (R)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7- iiciarboxylate
Figure imgf000095_0004
[0265] 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 7 (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-1,2,3,4-tetrahydroisoquinoline-7-carboxylate. LCMS: MW (calcd): 219.3; m/z MW (obsd): 220.6 (M+H) 2.6.2. Step ii: ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7- carboxylate
Figure imgf000096_0001
[0266] To a solution of ethyl (R)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (750 mg, 3.4 mmol, 1 eq.) in acetonitrile (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 h for 4 h and was then concentrated. The residue was partitioned between water and DCM. The organic layer was dried over MgSO4, filtered and concentrated to give ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-1,2,3,4- tetrahydroisoquinoline-7-carboxylate. LCMS: MW (calcd): 291.3; m/z MW (obsd): 290.2 (M-H) 2.6.3. Step iii: Int 11
Figure imgf000096_0002
[0267] To a solution of ethyl (R)-2-(2-amino-2-oxoethyl)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7- carboxylate (200 mg, 0.67 mmol, 1 eq.) in EtOH (14 mL) was added a 1 N 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 1 N aq. HCl solution was added to adjust pH to 4.9. The aqueous solution was thoroughly extracted a 1:1 DCM/i-PrOH mixture, the organic layers were combined, dried over MgSO4, filtered and concentrated to give Int 11. 2.7. Int 42
Figure imgf000096_0003
[0268] 1-bromo-4-nitro-2-(trifluoromethyl)benzene (CAS# 367-67-9; 350 mg, 1.29 mmol, 1 eq.), tert- butyl-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]piperidine-1-carboxylate (CAS# 1048970- 17-7; 843 mg, 2.59 mmol, 2 eq.), K2CO3 (537 mg, 3.89 mmol, 3 eq.), Ag2O (751 mg, 3.24 mmol, 2.5 eq.) and Pd(dppf)Cl2 (CAS# 72287-26-4; 100 mg, 0.13 mmol, 0.1 eq.) were combined in a dry vial and flushed with argon. The vial was sealed and dry THF (7 mL) was added. The mixture was heated in a pre-heated bath at 80 °C for 6 h, at RT for 15 h and again at 80 °C for 1 h. The mixture was then cooled to RT, filtered through a pad of Celite®, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with Hept/EtOAc 95/5 to 8/2) to afford Int 42. 2.8. Int 62
Figure imgf000097_0001
2.8.1. Step i: tert-butyl i 4-[[4-[[(4R)-2-(2-amino-2-oxo-eth iyil)-4-methyl-3,4-dihydro-1H- isoquinoline-7-carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate
Figure imgf000097_0002
[0269] To Int 10 (108 mg, 0.37 mmol, 1 eq.) in EtOH (2.15 mL) was added NaOH (1 M in water, 0.75 mL, 0.75 mmol, 2 eq.) and the solution was stirred at 55 °C for 2 h. Then HATU (0.28 g, 0.75 mmol, 2 eq.) and Int 95 (0.14 g, 0.37 mmol, 1.0 eq.) in EtOH (1 mL) were added. The mixture was stirred at 55 °C for 1 h and at RT overnight. The suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 9/1) to afford tert- butyl 4-[[4-[[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carbonyl]amino]-2- (trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate. LCMS: MW (calcd): 588.7; m/z MW (obsd): 589.3 (M+H) 2.8.2. Step ii: Int 62
Figure imgf000097_0003
[0270] Int 62 was obtained from tert-butyl 4-[[4-[[(4R)-2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro- 1H-isoquinoline-7-carbonyl]amino]-2-(trifluoromethyl)phenyl]methyl]piperidine-1-carboxylate using general method D with HCl (4 N in dioxane). 2.9. Int 75
Figure imgf000097_0004
[0271] To a solution of Int 76 (45 mg, 0.15 mmol, 1 eq.) in formic acid (1.5 mL) was added formaldehyde (13.3 M in water, 37 µL, 0.5 mmol, 3.3 eq.) and the mixture was heated under microwave irradiation at 150 °C for 5 min. The reaction medium was directly loaded on a Biotage® Isolute® SCX cation exchange column eluting with MeOH and then with a 7 N solution of NH3 in MeOH. The basic phase was concentrated to afford Int 75. 2.10. Int 105
Figure imgf000098_0001
[0272] 4-nitro-2-(trifluoromethyl)benzaldehyde (638 mg, 2.91 mmol, 1.05 eq.) was dissolved in DCM (7 mL), then 2,2,3,3,5,5,6,6-octadeuterio-1-methyl-piperazine (0.33 mL, 2.77 mmol, 1 eq.) and NaBH(OAc)3 (1.76 g, 8.31 mmol, 3 eq.) were added. The mixture was stirred at RT overnight. The reaction mixture was quenched with water, DCM was added and the mixture was stirred at RT for 1 h. After filtration on a phase separator, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 9/1) to afford Int 105. 2.11. Int 112
Figure imgf000098_0002
[0273] To a solution of Int 1 (1 g, 4.32 mmol, 1 eq.) in concentrated sulfuric acid (10 mL) was added concentrated nitric acid (277 µL, 4.32 mmol, 1 eq.) dropwise while keeping the internal temperature below 10 °C. On complete addition, the mixture was stirred at 0 °C for 30 min and was then poured into water. The aqueous phase was extracted with MTBE. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with heptane/MTBE 92/8 to 60/40) to afford Int 112. 2.12. Int 116
Figure imgf000098_0003
2.12.1. Step i: methyl 4-(1-cyanopropyl)benzoate
Figure imgf000098_0004
[0274] A solution of methyl 4-(cyanomethyl)benzoate (CAS# 76469-88-0; 20 g, 114 mmol, 1 eq.) in THF (500 mL) was cooled down to -78 °C and LiHMDS (1 M in THF, 114 mL, 114 mmol, 1 eq.) was added dropwise over 30 min. The mixture was then stirred for 5 min at -78 °C and iodoethane (9.1 mL, 114 mmol, 1 eq.) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min and at RT for 3 h. The reaction was quenched with a sat. aq. NH4Cl solution (250 mL) and stirred at RT for 16 h. The organic solvents were removed under reduced pressure. The mixture was diluted with EtOAc (300 mL), the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with EtOAc/Heptane 0/100 to 20/80) to afford methyl 4-(1-cyanopropyl)benzoate. LCMS: MW (calcd): 203.2; m/z MW (obsd): no ionization 2.12.2. Step ii: Int 116
Figure imgf000099_0001
[0275] To solution of methyl 4-(1-cyanopropyl)benzoate (14.07 g, 69.2 mmol, 1 eq.) in EtOH (300 mL) was added concentrated HCl (30 mL). Pd/C (10%, 3.68 g, 3.46 mmol, 0.05 eq.) was added and the reaction mixture was stirred under hydrogen atmosphere at 40 °C for 16 h. Then the mixture was filtered through Celite®. To the filtrate fresh Pd/C (10%, 3.68 g, 3.46 mmol, 0.05 eq.) was added and the reaction mixture was stirred under hydrogen atmosphere at 40 °C for 24 h. The whole operation was performed another time and after 24 h the mixture was filtered through Celite®, washed with MeOH and then concentrated under vacuum to obtain Int 116. 2.13. Int 120
Figure imgf000099_0002
2.13.1. Step i: N i-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethoxy)phenyl]-1,1- diphenyl-methanimine
Figure imgf000099_0003
[0276] To a solution of Int 122 (390 mg, 0.06 mmol, 1 eq.), diphenylmethanimine (CAS# 1013-88-3; 261 mg, 1.4 mmol, 1.5 eq.), Xantphos (56 mg, 0.096 mmol, 0.1 eq.) and palladium acetate (17 mg, 0.077 mmol, 0.08 eq.) in dioxane (12 mL) was added cesium carbonate (939 mg, 2.9 mmol, 3 eq.) and the mixture was stirred at 100 °C for 2 h. Then the volatiles were removed in vacuo and the residue was taken up in EtOAc and water. The layers were separated, the organic layer was concentrated to afford N-[4-[(4- methylpiperazin-1-yl)methyl]-3-(trifluoromethoxy)phenyl]-1,1-diphenyl-methanimine. 2.13.2. Step ii: Int 120
Figure imgf000100_0001
[0277] To a solution of N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethoxy)phenyl]-1,1- diphenyl-methanimine (606 mg, 0.57 mmol, 1 eq.) in dioxane (5 mL) was added HCl (2 M in water, 1.4 mL, 2.8 mmol, 5 eq.) and the mixture was stirred at RT for 16 h. The reaction medium was concentrated to dryness, the residue was taken up in water and the pH was adjusted to 10 with a 2 N aq. NaOH solution. The aqueous phase was extracted with DCM, the layers were separated and the organic layer was concentrated. The crude residue was purified by column chromatography on silica gel (eluting with DCM/MeOH/(NH37M in MeOH) 90/9/0.5) to give Int 120. 2.14. Int 125
Figure imgf000100_0002
2.14.1. Step i: 1-[[4-[(4 i-methoxyphenyl)methylamino]-2-(trifluo iiromethyl)phenyl]methyl]-N,N- dimethyl-piperidin-4-amine
Figure imgf000100_0003
[0278] Int 127 (120 mg, 0.33 mmol, 1 eq.), (4-methoxyphenyl)methanamine (68 mg, 0.49 mmol, 1.5 eq.), palladium acetate (0.8 mg, 0.0033 mmol, 0.01 eq.), BINAP (4.1 mg, 0.0066 mmol, 0.02 eq.) and potassium tert-butoxide (55 mg, 0.49 mmol, 1.5 eq.) were placed in a vial and toluene (0.3 mL) was added. The mixture was stirred at 140 °C for 5 min under microwaves irradiation. The reaction mixture was filtered trought Celite® and the filtrate was concentrated. To the residue was added water and the aqueous phase was extracted with EtOAc. The combined organic phases were filtered through a phase separator and the filtrate was concentrated. The crude product was purified by column chromatography on silica gel (eluting with DCM/MeOH/(NH37M in MeOH) 90/9/0.5) to afford 1-[[4-[(4-methoxyphenyl)methylamino]-2- (trifluoromethyl)phenyl]methyl]-N,N-dimethyl-piperidin-4-amine. LCMS: MW (calcd): 421.5; m/z MW (obsd): 422.3 (M+H) 2.14.2. Step ii: Int 125
Figure imgf000101_0001
[0279] 1-[[4-[(4-methoxyphenyl)methylamino]-2-(trifluoromethyl)phenyl]methyl]-N,N-dimethyl- piperidin-4-amine (66 mg, 0.16 mmol, 1 eq.) was dissolved in HCl (4 N in dioxane, 0.39 mL, 1.6 mmol, 10 eq.) and the mixture was stirred at 100 °C for 3 h. The reaction medium was extracted with DCM. The pH of the aqueous layer was then adjusted to 10 with a 5 N aq. NaOH solution and the basic aqueous phase was extracted with DCM. The combined organic phases were filtered through a phase separator and the filtrate was concentrated to afford Int 125
Figure imgf000101_0002
2.15.1. To a iv Step i: [a solution of 2 i. cetoxy-(2-methyl- -methyl-5-nitro-b v5-nitro-phenyl)methyl] acetat enzaldehyde (CAS# 16634-91 iie
Figure imgf000101_0003
[0280] vi-i6; 412 mg, 2.4 mmol, 1 eq.) in acetic anhydride (2 mL) was added toluene-4-sulfonic acid (47 mg, 0.24 mmol, 0.1 eq.) and the reaction mixture was stirred at RT for 3 h. The mixture was diluted with a sat. NaHCO3 aq. solution and was extracted with Et2O. The aqueous layer was then extracted with DCM, the combined organic phases were filtered through a phase separator and the filtrate was concentrated to give [acetoxy-(2-methyl-5-nitro- phenyl)methyl] acetate. LCMS: MW (calcd): 267.2; m/z MW (obsd): no ionization 2.15.2. Step ii: [acetoxy-[2-(bromomethyl)-5-nitro-phenyl]methyl] acetate
Figure imgf000101_0004
[0281] [acetoxy-(2-methyl-5-nitro-phenyl)methyl] acetate (300 mg, 1.0 mmol, 1 eq.) was dissolved in tetrachloromethane (5 mL), and NBS (294 mg, 1.7 mmol, 1.7 eq.) and AIBN (0.022 mL, 0.01 mmol, 0.01 eq.) were added. The reaction mixture was stirred at 80 °C for 4 h. The reaction medium was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with Cyclohexane / EtOAc 3/1) to afford [acetoxy-[2-(bromomethyl)-5-nitro-phenyl]methyl] acetate. LCMS: MW (calcd): 346.1; m/z MW (obsd): no ionization 2.15.3. Step iii: [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate
Figure imgf000102_0001
[0282] [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate was obtained from [acetoxy-[2-(bromomethyl)-5-nitro-phenyl]methyl] acetate using general method B2 with N- methylpiperazine (CAS# 109-01-3). LCMS: MW (calcd): 365.4; m/z MW (obsd): 366.1 (M+H) 2.15.4. Step iv: 2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde
Figure imgf000102_0002
[0283] To a solution of [acetoxy-[2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-phenyl]methyl] acetate (105 mg, 0.26 mmol, 1 eq.) in EtOH (5 mL) was added concentrated sulfuric acid (0.028 mL, 0.53 mmol, 2 eq.) and the reaction mixture was stirred at reflux for 3.5 h. Then concentrated sulfuric acid (0.028 mL, 0.53 mmol, 2 eq.) was added and the mixture was stirred at reflux for 2 h. The reaction medium was concentrated in vacuo and the residue was taken up in a sat. NaHCO3 aq. solution. The pH was adjusted to 8.5 and the aqueous phase was extracted with EtOAc. The organic phase was concentrated to afford 2-[(4- methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde. LCMS: MW (calcd): 263.3; m/z MW (obsd): 264.1 (M+H) 2.15.5. Step v: (1E)-2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde hydrazone
Figure imgf000102_0003
[0284] To a solution of 2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde (465 mg, 1.6 mmol, 1 eq.) in EtOH (10 mL) was added NH2NH2.H2O (0.78 mL, 16 mmol, 10 eq.) and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo, water was added and the aqueous phase was extracted with DCM. The combined organic phases were filtered through a phase separator and the filtrate was concentrated to afford (1E)-2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde hydrazone. LCMS: MW (calcd): 277.3; m/z MW (obsd): 278.2 (M+H) 2.15.6. Step vi: Int 131
Figure imgf000103_0001
[0285] To a solution of (1E)-2-[(4-methylpiperazin-1-yl)methyl]-5-nitro-benzaldehyde hydrazone (429 mg, 0.97 mmol, 1 eq.) in ACN (20 mL) were added 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (Togni’s reagent, CAS# 887144-94-7; 847 mg, 1.7 mmol, 1.1 eq.) and water (20 mL). Then under stirring were added a solution of CsF (44 mg, 0.29 mmol, 0.3 eq.) in water (400 µL) and a solution of KOH (164 mg, 2.9 mmol, 3 eq.) in water (400 µL). The reaction mixture was stirred at RT for 10 min and then water was added. The aqueous phase was extracted with DCM, the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified twice by column chromatography on silica gel (eluting with DCM/(DCM:MeOH:NH3) 1/(9:4:1), and then DCM/MeOH 95/5) to afford Int 131. 2.16. Int 164
Figure imgf000103_0002
2.16.1. Ste ip i: 2,2,2-trifluoro-N-[(2S)- ii2-phenylpropyl]acetamide
Figure imgf000103_0003
[0286] To a solution of (2S)-2-phenylpropan-1-amine (CAS#17596-79-1, 41 ii3i mL, 2.88 mol, 1 eq.) in DCM (1.95 L) was added TFAA (401 mL, 2.88 mol, 1 eq.) keeping the temperature below 10 °C, then the mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched with water (1.56 L) at 10-20 °C and stirred for 30 min. The layers were separated, and the aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2,2,2-trifluoro-N-[(2S)-2-phenylpropyl]acetamide. 2.16.2. Step ii: 4-[(1S)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoyl chloride
Figure imgf000103_0004
[0287] To a solution of AlCl3 (329 mL, 6.03 mol, 3 eq.) in DCM (2.79 L) was added oxalyl chloride (528 mL, 6.03 mol, 3 eq.) dropwise over 30 min while keeping the temperature between 0 and 5 °C. The mixture was stirred at 0 to 5 °C for 30 min and a solution of 2,2,2-trifluoro-N-[(2S)-2- phenylpropyl]acetamide (465 g, 2.01 mol, 1 eq.) in DCM (930 mL) was added dropwise at 0 to 5 °C over 2 h. The reaction mixture was stirred at 0 to 5 °C for 1 h and was then poured into water (4.65 L) at 0 to 5 °C. The resulting mixture was stirred for 2 h, then DCM (1 L) was added and the mixture was stirred for an additional hour. The phases were separated, the organic layer was washed with brine, dried over Na2SO4, concentrated under reduced pressure to afford 4-[(1S)-1-methyl-2-[(2,2,2- trifluoroacetyl)amino]ethyl]benzoyl chloride. 2.16.3. Step iii: Int 164
Figure imgf000104_0001
[0288] To a solution of 4-[(1S)-1-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoyl chloride (550 g, 1.87 mol, 1 eq) in DCM (1 L) was added MeOH (1.1 L) over 30 min while keeping the temperature between 0 and 5°C, then the mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with MTBE (2.5 L) at 65 °C for 1 h. The suspension was filtered and the filtrate was washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude material. This crude was placed in diisopropylether (2.5 L) at 68 °C for 1 h, the suspension was filtered and the solid collected to afford Int 164. 2.17. Int 165
Figure imgf000104_0002
2.17.1. Step i: m iethyl (4S)-4-methyl-2-(2,2,2-trifluoroacetyl)-3,4-di ihiiydro-1H-isoquinoline-7- carboxylate
Figure imgf000104_0003
[0289] To a solution of Int 164 (195 g, 674 mmol, 1 eq.) in DCM (780 mL) was added slowly paraformaldehyde (33.7 g, 1079 mmol, 1.6 eq.) under stirring. The mixture was cooled to 3 °C and conc. sulfuric acid (150 mL, 2764 mmol, 4 eq.) was added over a 40 min period, keeping the temperature under 25 °C. After addition, the mixture was allowed to stir overnight at RT. The mixture was poured into 1.2 L of ice water and DCM (780 mL) was added. The mixture was stirred for 30 min before separation of the layers. The aq. phase was extracted with DCM twice. The combined organic layers were washed with a sat. aq. NaHCO3 solution (water layer pH: 8) and water, then dried over Na2SO4 and filtered over a silica plug (30 g silica, plug was first washed with dichloromethane). The filtrate was concentrated in vacuo to afford methyl (4S)-4-methyl-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate. LCMS: MW (calcd): 301.3; m/z MW (obsd): 302.0 (M+H) 2.17.2. Step ii: methyl (4S)-4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate, hydrochloride salt
Figure imgf000105_0001
[0290] To a solution of methyl (S)-4-methyl-2-(2,2,2-trifluoroacetyl)- 1,2,3,4-tetrahydroisoquinoline-7- carboxylate (192 g, 639 mmol, 1 eq.) in methanol (1 L) at 0°C was added dropwise over 60 min a NaOH solution (6M in water, 102 mL, 613 mmol, 0.96 eq.), keeping the temperature between 0 and 5 °C. At the end of the addition the mixture was allowed to warm to RT and was stirred overnight. The reaction mixture was concentrated in vacuo and DCM and water were added. The water layer was washed again with DCM, the organic layers were combined and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry THF (1.25 L) and HCl (5-6 M in 2-propanol, 134 mL, 671 mmol, 1 eq.) was added. The suspension (pH: 1-2) was stirred RT for 2 h. Then the mixture was cooled to 4 °C and stirred overnight. The solids were filtered off over a P2 glass filter under nitrogen flow. Subsequently, the solids were washed on the filter with Et2O and pentane to afford methyl (4S)-4- methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate, hydrochloride salt. LCMS: MW (calcd): 241.7; m/z MW (obsd): 206.1 (M+H) 2.17.3. Step iii: Int 165
Figure imgf000105_0002
[0291] To a solution of (4S)-4-methyl-1,2,3, O4-tetrahydroisoquinoline-7-carboxyl 530 mmol, 1 eq.) and 2-bromoacetamid N Oate, hydrochloride salt (132 g, H Ne (95 g, 689 m Omol, 1.3 eq.) in MeOH (660 mL) was added TEA (162 mL, 1165 mmol, 2.2 eq.) over 30 min, keeping the temperature under 22 °C. The reaction mixture was stirred for 2 h at RT and subsequently the reaction medium was cooled to 0 °C. Cold water (660 mL) was added and the mixture was stirred at -5 °C for 1 h. The solids were filtered off, washed twice with cold water and dried afford Int 165. 2.18. Cpd 1
Figure imgf000105_0003
[0292] To a solution of Int 10 (1.1 g, 4 mmol, 1 eq.) and 4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)aniline (CAS# 694499-26-8; 1.4 g, 5.1 mmol, 1.3 eq.) in THF (20 mL) at 5 °C was added dropwise LiHMDS (1 M in THF, 8 mL, 8 mmol, 2 eq.). The mixture was stirred at RT for 1 h and then at 5 °C more LiHMDS (1 M in THF, 4 mL, 4 mmol, 1 eq.) was added. The reaction mixture was stirred at RT for 25 min and was poured into water (200 mL). The aqueous layer was extracted with DCM (150 mL), the organic phase was dried over MgSO4, filtered and concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with EtOAc/TEA/MeOH 100/4/3 then 90/5/5) to afford Cpd 1. 2.19. Cpd 1 (alternative synthesis)
Figure imgf000106_0001
[0293] To a mixture of Int 10 (387 g, 1475 mmol, 1 eq.) and 4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)aniline (CAS# 694499-26-8; 484 g, 1769 mmol, 1.2 eq.) in THF (1.9 L) at 0 to 3 °C was added dropwise LiHMDS in THF (1.3 mol/L, 3.4 L, 4400 mmol, 3 eq.) over 2 h 40 min keeping the temperature below 5 °C. The reaction mixture was warmed to RT and stirred for 2.5 h. The reaction mixture was cooled to 12 °C and water (3.9 L) was added dropwise over 50 min. The layers were separated and the aq. layer was extracted 3 times with DCM. The combined organic layers were evaporated under reduced pressure until approximately 80% of the solvent was removed. A solvent exchange was performed with ACN (3.9 L). The suspension was filtered on a glass filter funnel and the solid was washed with ACN. The collected solid was taken up in 2-propanol (4V) and the mixture was heated at reflux. When reflux was reached, 2-propanol was added until total solubilization of the reaction mixture. The mixture was cooled down to RT overnight and stirred at 20 °C for 2 h. The suspension was filtered and the solid washed with 2-propanol and MTBE. The solid was collected and dried to afford Cpd 1. 2.20. Cpd 1 (alternative synthesi
Figure imgf000106_0002
2.20.1. iii Step i is) : (4R)- iv4-methyl-N-(4-((4 ii-methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide
Figure imgf000106_0003
[0294] Int 5 hydrochloride (cf. Ex.2.5.1; 1 g, 4.14 mmol, 1 eq.) and 4-[(4-methylpiperazin-1-yl)methyl]- 3-(trifluoromethyl)aniline (CAS# 694499-26-8; 1.357 g, 4.97 mmol, 1.2 eq.) were dissolved in THF (20 mL) under a nitrogen atmosphere. The reaction mixture was cooled down to 0-3 °C. Then, LiHMDS (1 mol/L in THF, 16.55 mL, 4 eq.) was added dropwise and the reaction mixture was stirred at RT for 1 h. The mixture was diluted with water and then concentrated under reduced pressure to remove the THF phase. The aq. layer was extracted 3 times with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired product. LCMS: MW (calcd): 446.5; m/z MW (obsd): 447.4 (M+H) 2.20.2. Step ii: methyl (R)-2-(4-methyl-7-((4-((4-methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)acetate
Figure imgf000107_0001
[0295] (4R)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-1,2,3,4- tetrahydroisoquinoline-7-carboxamide (2.12 g, 4.27 mmol, 1 eq.) was dissolved in THF (46 mL). Sodium carbonate (679 mg, 6.41 mmol, 1.5 eq.) was added and the reaction mixture was stirred for 5 min. Then, methyl bromoacetate (0.404 mL, 4.28 mmol, 1 eq.) was added slowly and the reaction mixture was stirred at RT for 24 h. Brine was added and the reaction mixture was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (eluent: 90:10 DCM/MeOH) to afford the desired product. LCMS: MW (calcd): 518.6; m/z MW (obsd): 519.4 (M+H) 2.20.3. Step iii: 2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]acetic acid
Figure imgf000107_0002
[0296] Methyl 2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl]acetate (864 mg, 1.67 mmol, 1 eq.) was dissolved in MeOH (16.7 mL). Sodium hydroxyde (2 mol/L in water, 3.33 mL, 4 eq.) was added and the reaction mixture was stirred at RT for 1 h. Hydrochloric acid (1 mol/L in Et2O, 6.66 mL, 4 eq.) was added. The reaction was stirred at RT for 30 min and then concentrated under reduced pressure. The crude was purified by preparative HPLC to afford the desired product. LCMS: MW (calcd): 504.5; m/z MW (obsd): 505.4 (M+H) 2.20.4. Step iv: Cpd 1 [0297] 2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]- 3,4-dihydro-1H-isoquinolin-2-yl]acetic acid (30 mg, 0.055 mmol, 1 eq.), ammonium acetate (29 mg, 0.38 mmol, 8 eq.) and HATU (31 mg, 0.080 mmol, 1.5 eq.) were dissolved in DMF (0.9 mL). DIPEA (19 μL, 0.11 mmol, 2 eq.) was added and the reaction mixture was stirred at 60 °C fro 18 h. The reaction medium was purified by preparative HPLC to afford the desired product.
Figure imgf000108_0001
[0298] To a solution of Int 11 (27 mg, 0.11 mmol, 1 eq.) and Int 157 (26 mg, 0.11 mmol, 1 eq.) in DMF (1 mL) were added COMU (CAS# 1075198-30-9; 51 mg, 0.12 mmol, 1.1 eq.) and TEA (33 µL, 0.24 mmol, 2.2 eq.). The mixture was stirred at RT overnight and then the volatiles were concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH/NH4OH 90/4/1) and by preparative HPLC to afford Cpd 11.
Figure imgf000108_0002
[0299] To a solution of Int 159 (30 mg, 0.07 mmol, 1 eq.) in ACN (0.4 mL) were added 2-bromoacetamide (9 mg, 0.07 mmol, 1 eq.) and TEA (27 µL, 0.2 mmol, 3 eq.) and the mixture was stirred at RT for 2 h. Then more 2-bromoacetamide (1.8 mg, 0.013 mmol, 0.2 eq.) was added and the reaction mixture was stirred for another 2 h at RT. The solvents were concentrated and the residue was taken up in DCM and water. The phases were separated and the organic phase was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH/NH4OH 90/4/1) to afford Cpd 12.
Figure imgf000108_0003
[0300] To a solution of Int 149 (16 mg, 0.037 mmol, 1 eq.) in ACN (0.3 mL) were added 2- bromoacetamide (5.1 mg, 0.037 mmol, 1 eq.) and TEA (0.015 mL, 0.11 mmol, 3 eq.) and the mixture was stirred at RT for 2 h. Then more 2-bromoacetamide (1 mg, 0.007 mmol, 0.2 eq.) was added and the reaction mixture was stirred for another 1 h at RT. The solvents were concentrated and the residue was taken up in DCM and water. The phases were separated and the organic phase was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH/NH4OH 90/4/1) to afford Cpd 14. 2.24. Cpd 16
Figure imgf000109_0001
2.24.1. Step i: meth iyl 3-methoxy-2-[(4R)-4-methyl-7-[[4 ii-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate
Figure imgf000109_0002
[0301] Methyl 3-methoxy-2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate was obtained from Int 43 following general method E1 with methyl 2-bromo-3-methoxypropanoate (CAS# 27704-96-7). LCMS: MW (calcd): 562.6; m/z MW (obsd): 563.4 (M+H) 2.24.2. Step ii: Cpd 16
Figure imgf000109_0003
[0302] To a solution of 3-methoxy-2-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate (70 mg, 0.12 mmol, 1 eq.) in THF (3 mL) was added lithium hydroxide hydrate (2 N in water, 0.28 mL, 0.46 mmol, 4 eq.) and the resulting mixture was stirred at 65 °C for 2 h. Then the reaction medium was cooled down to RT and the volatiles were concentrated to afford a carboxylate intermediate. This residue was dissolved in DMF (1 mL) and ammonium chloride (1 w% in water, 12 µL, 0.23 mmol, 2 eq.), TEA (32 µL, 0.23 mmol, 2 eq.) and HATU (45 mg, 0.12 mmol, 1 eq.) were added. The mixture was stirred at RT for 3 h and more ammonium chloride (1 w% in water, 12 µL, 0.23 mmol, 2 eq.) and HATU (45 mg, 0.12 mmol, 1 eq.) were added. The reaction mixture was stirred at RT for 1 h 15 and was then diluted with water. The aqueous layer was extracted with EtOAc, the combined organic layers were concentrated and the residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 10/0 to 9/1) to afford Cpd 16. 2.25. Cpd 18
Figure imgf000110_0001
2.25.1. Step i: 2,2,2-trifluoro-N-(2-phenylpropyl)acetamide
Figure imgf000110_0002
[0303] 2.2.2-trifluoro-/V-(2-phenylpropyl)acetamide was obtained from 2-phenylpropan- 1 -amine (CAS# 582-22-9) using general method K.
LCMS: MW (calcd): 231.2; m/z MW (obsd): 232.0 (M+H)
2.25.2. Step ii: methyl 4-[l-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate
Figure imgf000110_0003
[0304] To a suspension of AlCh (32.5 g, 239 mmol, 1.5 eq.) in DCM (400 mL) was added dropwise at - 10 °C oxalyl chloride (21 mL, 240 mmol, 1.5 eq.). Then 2.2.2-trifluoro-A-(2-phcnylpropyl)acctamidc (36.8 g, 159 mmol, 1 eq.) was added in 5 portions at -10 °C and the mixture was stirred at 0 °C for 1 h. The reaction medium was slowly poured into MeOH under ice cooling and the mixture was stirred at RT for 2 h. The mixture was poured into water (500 mL) and the aqueous layer was extracted with DCM (300 mL). The organic phase was dried over MgSCL, filtered and concentrated. The crude material was purified by column chromatography on silica gel (eluting with Hept/EtOAc 7/3) to give a residue that was recrystallized in Hept/EtOAc 10/1 to afford methyl 4-[l-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate.
LCMS: MW (calcd): 289.3; m/z MW (obsd): 288.1 (M-H)
2.25.3. Step Hi: methyl 4-methyl-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-lH-isoquinoline-7- carboxylate
Figure imgf000110_0004
[0305] Methyl 4-[l-methyl-2-[(2,2,2-trifluoroacetyl)amino]ethyl]benzoate (6.4 g, 22 mmol, 1 eq.) and paraformaldehyde (3.5 g, 37 mmol, 1.7 eq.) were placed in TFA (13 mL) and the mixture was warmed to 40 °C. Then concentrated sulfuric acid (6.4 mL) was added slowly and the reaction was stirred at 40 °C for 1 h. The reaction medium was poured in ice water (400 mL), the aqueous phase was extracted with EtOAc and the organic phase was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluting with Hept/EtOAc 7/3) to afford methyl 4-methyl-2-(2,2,2- trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate. LCMS: MW (calcd): 301.3; m/z MW (obsd): 302.0 (M+H) 2.25.4. Step iv: methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate
Figure imgf000111_0001
[0306] Methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate was obtained from methyl 4- methyl-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-1H-isoquinoline-7-carboxylate using general method H. LCMS: MW (calcd): 205.3; m/z MW (obsd): 206.0 (M+H) 2.25.5. Step v: methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7- carboxylate
Figure imgf000111_0002
[0307] Methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxylate was obtained from methyl 4-methyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylate using general method E1 with 2-bromoacetamide (CAS# 683-57-8). LCMS: MW (calcd): 262.3; m/z MW (obsd): 263.1 (M+H) 2.25.6. Step vi: Cpd 18
Figure imgf000111_0003
[0308] Methyl 2-(2-amino-2-oxo-ethyl)-4-methyl-3,4-dihydro-1H-isoquinoline-7-carboxylate (0.6 g, 2.29 mmol, 1 eq.) and 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (CAS# 694499-26-8; 0.77 g, 2.74 mmol, 1.2 eq.) were mixed in THF (12 mL). The mixture was cooled down to 5 °C, LiHMDS (1 M in THF, 5.8 mL, 5.8 mmol, 1.5 eq.) was added slowly and the mixture was stirred at RT for 30 min. LiHMDS (1 M in THF, 0.6 mL, 0.6 mmol, 0.1 eq.) was added and the reaction mixture was stirred for another 30 min at RT. The reaction medium was poured in water (200 mL), the aqueous phase was extracted with EtOAc and the organic phase was dried over MgSO4, filtered and concentrated. The residue was triturated in ACN (20 mL), filtered and washed with 20 mL of ACN to afford Cpd 18. 2.26. Cpd 23
Figure imgf000112_0001
2.26.1. Step i: (4R)-2- i[cyano(tetrahydrofuran-3-yl)methyl]- ii4-methyl-N-[4-[(4-methylpiperazin- 1-yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide
Figure imgf000112_0002
[0309] To a solution of Int 43 (100 mg, 0.22 mmol, 1 eq.) in ACN (0.6 mL) and water (0.4 mL) were added tetrahydrofurane-3-carbaldehyde (CAS# 79710-86-4; 122 µL, 0.67 mmol, 3 eq.), NaCN (68 mg, 1.34 mmol, 6 eq.) and acetic acid (58 µL, 1.01 mmol, 4.5 eq.). The mixture was stirred at RT for 16 h. More tetrahydrofurane-3-carbaldehyde (CAS# 79710-86-4; 122 µL, 0.67 mmol, 3 eq.) was added and the reaction mixture was stirred at RT for 20 h. The reaction medium was poured into water and the mixture was extracted with DCM. The combined organic layers were filtered on a phase separator and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH: 100/0 to 95/5) to afford (4R)-2-[cyano(tetrahydrofuran-3-yl)methyl]-4-methyl-N-[4-[(4-methylpiperazin-1- yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide. LCMS: MW (calcd): 555.6; m/z MW (obsd): 556.2 (M+H) 2.26.2. Step ii: Cpd 23
Figure imgf000112_0003
[0310] To a solution of 4R)-2-[cyano(tetrahydrofuran-3-yl)methyl]-4-methyl-N-[4-[(4-methylpiperazin- 1-yl)methyl]-3-(trifluoromethyl)phenyl]-3,4-dihydro-1H-isoquinoline-7-carboxamide (70 mg, 0.088 mmol, 1 eq.) in DMSO (1 mL) were added K2CO3 (61 mg, 0.44 mmol, 5 eq.) and H2O2 (30% in water, 45 µL, 0.44 mmol, 5 eq.) were added. The reaction mixture was stirred at RT for 16 h, water was added and the precipitate was filtered and collected. The solid was purified by column chromatography on silica gel (eluting with DCM/MeOH: 100/0 to 97/3) to afford Cpd 23. 2.27. Cpd 24
Figure imgf000113_0001
2.27.1. Step i: 1-isop 3 iropyl-4-[[4-ni iitro-2-(trif .42 mm iiliuoromethyl)phenyl]methyl]piperidine
Figure imgf000113_0002
[0311] Int 76 (60 mg, 0.21 mmol, 1 eq.) was placed in THF (1.5 mL) and acetone (77 µL, 1.04 mmol, 5 eq.) and acetic acid (6 µL, 0.10 mmol, 0.5 eq.) were added. The mixture was stirred at RT for 10 min and NaBH(OAc) was added portionwise (88 mg, 0 ol, 2 eq.). The reaction mixture was stirred at RT for 20 h and at 60 °C for 5 h. Then at RT more acetone (77 µL, 1.04 mmol, 5 eq.), acetic acid (6 µL, 0.10 mmol, 0.5 eq.) and NaBH(OAc)3 (44 mg, 0.21 mmol, 1 eq.) were added. The mixture was stirred at RT for 16 h. The volatiles were concentrated and the residue was taken up in DCM and water. A sat. NaHCO3 aq. solution was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, filtered on a phase separator and concentrated to afford 1-isopropyl-4-[[4-nitro-2-(trifluoromethyl)phenyl]methyl]piperidine. LCMS: MW (calcd): 330.3; m/z MW (obsd): 331.0 (M+H) 2.27.2. Step ii: 4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)aniline
Figure imgf000113_0003
[0312] 4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)aniline was obtained from 1-isopropyl-4- [[4-nitro-2-(trifluoromethyl)phenyl]methyl]piperidine using general method C1. LCMS: MW (calcd): 300.4; m/z MW (obsd): 301.1 (M+H) 2.27.3. Step iii: Cpd 24
Figure imgf000113_0004
[0313] To a solution of 4-[(1-isopropyl-4-piperidyl)methyl]-3-(trifluoromethyl)aniline (41 mg, 0.089 mmol, 1 eq.), Int 11 (31 mg, 0.12 mmol, 1.3 eq.) and HATU (48 mg, 0.12 mmol, 1.4 eq.) in DMF (1 mL) was added DIPEA (34 µL, 0.20 mmol, 2.2 eq.) and the mixture was stirred at RT for 16 h. Then more Int 11 (10 mg, 0.04 mmol, 0.5 eq.) and HATU (12 mg, 0.03 mmol, 0.4 eq.) were added and the mixture was stirred again at RT for 16 h. The reaction medium was diluted with EtOAc and quenched with water. The layers were separated, the aqueous phase was extracted with EtOAc and the combined organic layers were washed with water and brine. Then they were filtered on a phase separator and concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 95/5 to 8/2) followed by preparative HPLC to afford Cpd 24. 2.28. Cpd 37
Figure imgf000114_0001
[0314] To a solution of Int 43 (200 mg, 0.36 mmol, 1 eq.) in ACN (1.2 mL) and water (0.8 mL) were added tert-butyl N-methyl-N-(2-oxoethyl)carbamate (CAS# 123387-72-4 ;187 mg, 1.08 mmol, 3 eq.), NaCN (109 mg, 2.16 mmol, 6 eq.) and acetic acid (94 µL, 1.62 mmol, 4.5 eq.). The mixture was stirred at RT for 16 h. Then more tert-butyl N-methyl-N-(2-oxoethyl)carbamate (187 mg, 1.08 mmol, 3 eq.), NaCN (109 mg, 2.16 mmol, 6 eq.) and acetic acid (94 µL, 1.62 mmol, 4.5 eq.) were added and the mixture was again stirred at RT for 24 h. The reaction medium was poured into water and the mixture was extracted with DCM. The combined organic layers were filtered on a phase separator and concentrated. The residue was dissolved in DMSO (1.5 mL) and K2CO3 (251 mg, 1.80 mmol, 5 eq.) and H2O2 (30% in water, 184 µL, 1.80 mmol, 5 eq.) were added. The mixture was stirred at 50 °C for 4 h and the reaction medium was purified by preparative HPLC to afford Cpd 37. 2.29. Cpd 43
Figure imgf000114_0002
2.29.1. Step i: methyl i (2S)-2-hydroxy-3-[(4R)-4-methyl-7-[[4-[( ii4-methylpiperazin-1-yl)methyl]- 3-(trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate
Figure imgf000114_0003
[0315] To a solution of Int 43 (300 mg, 0.65 mmol, 1 eq.) in DMF (10 mL) were added TEA (182 µL, 1.30 mmol, 2 eq.) and (S)-methylglycidate (CAS# 118712-39-3; 136 mg, 1.3 mmol, 2 eq.) and the mixture was stirred at 150 °C for 45 min under microwaves irradiation. The reaction medium was then diluted with a sat. NH4Cl aq. solution and the aqueous phase was extracted with EtOAc. The combined organic layers were filtered on a phase separator and concentrated to afford methyl (2S)-2-hydroxy-3-[(4R)-4-methyl-7- [[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin- 2-yl]propanoate. LCMS: MW (calcd): 548.6; m/z MW (obsd): 549.2 (M+H) 2.29.2. Step ii: Cpd 43
Figure imgf000115_0001
[0316] To a solution of (2S)-2-hydroxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]propanoate (125 mg, 0.22 mmol, 1 eq.) in THF (2.2 mL) was added lithium hydroxide hydrate (2 M in water, 216 µL, 0.43 mmol, 2 eq.) and the mixture was stirred at 65 °C for 30 min. The volatiles were then concentrated and the residue was dissolved in DMF (2 mL). Ammonium chloride (1 w% in water, 58 µL, 1.08 mmol, 5 eq.), TEA (90 µL, 0.65 mmol, 3 eq.) and HATU (100 mg, 0.26 mmol, 1.2 eq.) were added. The mixture was stirred at RT for 1 h, at 70 °C for 3 h and at RT for 16 h. Then the reaction medium was diluted with water and DCM, the organic layer was filtered on a phase separator and concentrated. The residue was dissolved in DCM (2 mL) and ammonium chloride (1 w% in water, 58 µL, 1.08 mmol, 5 eq.), TEA (90 µL, 0.65 mmol, 3 eq.) and HATU (100 mg, 0.26 mmol, 1.2 eq.) were added. The mixture was stirred at RT for 1 h and was then diluted with water. The aqueous layer was extracted with DCM, the combined organic layers were filtered on a phase separator and concentrated. The residue was purified by preparative HPLC followed by preparative TLC plate (eluting with DCM/MeOH 9/1) to afford Cpd 43. 2.30. Cpd 57
Figure imgf000115_0002
[0317] To aH s Nu Ospen Nsion of I OntHN 6F2 (5 F0 mg, ide (10 N 0 µH.09 mmol, 1 e L, 0.05 mmoHq. l, N) i 1. On D 2 eq NCM (1.5 .) and the O m mH NL) were add ixture was s Ned ti O TEA (49 µL, 0.36 mmol, 4 eq.) and acetic anhy Fdr F F Frred at RT for 5 h. The reaction was quenched with water, the medium was filtered on a phase separator and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH 100/0 to 95/5) to afford Cpd 57. 2.31. Cpd 74
Figure imgf000116_0001
[0318] To a solution of Int 10 (0.84 g, 2.93 mmol, 1.0 eq.) in EtOH (8 mL) was added NaOH (2 N in water, 5.85 mL, 11.7 mmol, 4 eq.) and the mixture was stirred at 55 °C for 1 h 30. Then 1.2 mL of the obtained solution was sampled and Int 106 (117 mg, 0.23 mmol, 1.1 eq.) and HATU (162 mg, 0.42 mmol, 2 eq.) were added. The mixture was stirred at 55 °C for 16 h. The solvents were concentrated and the residue was taken up in DMF (1 mL). HATU (162 mg, 0.42 mmol, 2 eq.) and DIPEA (73 µL, 0.42 mmol, 2 eq.) were added and the mixture was stirred at 55 °C for 20 h. The reaction medium was purified by preparative LCMS to afford Cpd 74. 2.32. Cpd 75
Figure imgf000116_0002
[0319] To a solution of Int 10 (0.84 g, 2.93 mmol, 1.0 eq.) in EtOH (8 mL) was added NaOH (2 N in water, 5.85 mL, 11.7 mmol, 4 eq.) and the mixture was stirred at 55 °C for 1 h 30. Then 1.2 mL of the obtained solution was sampled and Int 155 (111 mg, 0.23 mmol, 1.1 eq.) and HATU (162 mg, 0.42 mmol, 2 eq.) were added. The mixture was stirred at 55 °C for 16 h. The solvents were concentrated and the residue was taken up in DMF (1 mL). HATU (162 mg, 0.42 mmol, 2 eq.) and DIPEA (73 µL, 0.42 mmol, 2 eq.) were added and the mixture was stirred at 55 °C for 20 h. The reaction medium was purified by preparative LCMS to afford Cpd 75. 2.33. Cpd 76
Figure imgf000116_0003
[0320] Int 10 (100 mg, 0.38 mmol, 1 eq.) and Int 137 (228 mg, 0.76 mmol, 2 eq.) were placed in toluene (1.3 mL) under argon atmosphere and LiHMDS (1.3 M in THF, 0.88 mL, 1.1 mmol, 3 eq.) was added under vigorous stirring. The reaction mixture was stirred at RT for 16 h then Int 137 (115 mg, 0.38 mmol, 1 eq.) and LiHMDS (1.3 M in THF, 0.44 mL, 0.55 mmol, 1.5 eq.) were added. The reaction mixture was stirred again at RT for 5 h. A sat. NH4Cl aq. solution was added and the solution was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (eluting with DCM/MeOH/NH4OH 90/15/1.5) and then by preparative HPLC to afford Cpd 76. 2.34. Cpd 77
Figure imgf000117_0001
2.34.1. Step i i: 4-[(6-methyl i-i3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline
Figure imgf000117_0002
[0321] To a solution of Int 140 (273 mg, 0.85 mmol, 1 eq.) in EtOH (15 mL) was added Pd/C 10% (45 mg, 0.042 mmol, 0.05 eq.) and the reaction mixture was stirred under hydrogen pressure (2 atm) at RT for 5 h. Then additional Pd/C 10% (25 mg, 0.02 mmol, 0.02 eq.) was added and the hydrogenation was continued under 2 atm of H2 for 16 h. The reaction mixture was filtered through Celite® and to the filtrate was added fresh Pd/C 10% (70 mg, 0.07 mmol, 0.07 eq.). The reaction was stirred under 2 atm of H2 for 3 d. The reaction medium was filtered through Celite®, the solid was washed with EtOAc and the filtrate was concentrated to afford 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline. LCMS: MW (calcd): 285.3; m/z MW (obsd): 286.2 (M+H) 2.34.2. Step ii: Cpd 77
Figure imgf000117_0003
[0322] Int 10 (40 mg, 0.15 mmol, 1 eq.) and 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline (52 mg, 0.18 mmol, 1.2 eq.) were placed in toluene (3 mL) under argon atmosphere and LiHMDS (1.3 M in THF, 0.23 mL, 0.30 mmol, 2 eq.) was added under vigorous stirring. The reaction mixture was stirred at RT for 2 h then 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3- (trifluoromethyl)aniline (8.5 mg, 0.03 mmol, 0.2 eq.) was added and the stirring was prolonged for 16 h. More LiHMDS (1.3 M in THF, 0.23 mL, 0.30 mmol, 2 eq.) was added and the mixture was stirred for 3 h at RT before 4-[(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl]-3-(trifluoromethyl)aniline (4 mg, 0.015 mmol, 0.1 eq.) and LiHMDS (1.3 M in THF, 150 µL, 0.2 mmol, 1.3 eq.) were added. The reaction mixture was stirred again at RT for 1.5 h. A sat. NH4Cl aq. solution was added and the solution was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC to afford Cpd 77. 2.35. Cpd 78
Figure imgf000118_0001
2.3 ii5.1. Step i: methyl 4-methoxy- i3-[(4R)- i4ii-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate
Figure imgf000118_0002
[0323] Methyl-4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate was obtained from Int 43 using general method J with methyl (E)-4-methoxybut-2-enoate (CAS# 13168-99-5). 2.35.2. Step ii: 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoic acid
Figure imgf000118_0003
[0324] To a solution of methyl 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoate (105 mg, 0.18 mmol, 1 eq.) in THF (2 mL) was added NaOH (2 N in water, 360 μL, 0.73 mmol, 4 eq.) and the mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated and the residue was dissolved in DMF (1 mL). HATU (137 mg, 0.36 mmol, 4 eq.) was added and the mixture was stirred at RT for 10 min. Then ammonium acetate (55 mg, 0.72 mmol, 5 eq.) and DIPEA (0.046 mL, 0.2 mmoL, 1.1 eq.) were added and the reaction mixture was stirred at 60 °C for 16 h. Additional HATU (66.5 mg, 0.175 mmol, 1 eq.), ammonium acetate (27 mg, 0.35 mmol, 2 eq.) and DIPEA (0.023 mL, 0.175 mmoL, 1 eq.) were added and the mixture was stirred at 60 °C for 16 h more. The reaction medium was purified by preparative HPLC to give 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoic acid. 2.35.3. Step iii: Cpd 78
Figure imgf000119_0001
[0325] To a solution of 4-methoxy-3-[(4R)-4-methyl-7-[[4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)phenyl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]butanoic acid (10 mg, 0.017 mmol, 1 eq.) in DMF (0.2 mL) was added HATU (13 mg, 0.035 mmol, 2 eq.) and the mixture was stirred at RT for 10 min. Then ammonium acetate (5.3 mg, 0.069 mmol, 4 eq.) and DIPEA (0.009 mL, 0.052 mmoL; 3 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 Cpd 78. 2.36. Cpd 79
Figure imgf000119_0002
Figure imgf000119_0003
[0326] To a solution of Int 162 (52 mg, 0.088 mmol, 1 eq.) in DCM (5 mL) was added HCl (4 M in dioxane, 0.22 mL, 0.88 mmol, 10 eq.) and the reaction mixture was stirred at RT for 5 h. Then ammonia (7N in MeOH, 1 mL) was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with (DCM + 0.5% TEA) / MeOH, 10/0 to 9/1) and by preparative HPLC to afford the expected product Cpd 79. 2.37. Cpd 80
Figure imgf000119_0004
[0327] To a suspension of Int 165 (118 g, 450 mmol, 1 eq.) and 4-[(4-methylpiperazin-1-yl)methyl]-3- (trifluoromethyl)aniline (CAS# 694499-26-8; 129 g, 472 mmol, 1.05 eq.) in THF (1 L) under stirring was added NaHMDS (2M in THF, 675 mL, 1350 mmol, 3 eq.) keeping the temperature below 25 °C. The reaction mixture was then stirred at RT for 1.5 h. Water (500 mL) was then slowly added under cooling to maintain the internal temperature below 25 °C, followed by 500 mL of isopropyl acetate. The phases were stirred for 10 min. The water layer was removed, and water and isopropyl acetate were added. The phases were stirred, and the layers were separated. The organic phase was then washed another time with water, the phases were separated, the organic layer was diluted with isopropyl acetate and filtered over a glass filter. THF was evaporated under reduced pressure while isopropyl acetate (10V) was added. The resulting mixture was then stirred at 20 °C for 30 min and filtered. The collected solid was dried to afford Cpd 80. Table II. Intermediates used towards the compounds of the invention. SM = Starting Material, Mtd = Method, MS Mes’d = Mesured mass
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
+
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Table IV. NMR data of illustrative compounds of the invention
Figure imgf000155_0001
Figure imgf000156_0001
SEQUENCE LISTING [0328] SEQ ID 1: pcDNA3.1 hsDDR1 (Uniprot# Q08345-2) plasmid. [0329] SEQ ID 2: pcDNA3.1 hsDDR2 (Uniprot# Q16832) plasmid. BIOLOGICAL EXAMPLES Example 3. In vitro assays 3.1. DDR1 ADP-GloTM Kinase Assay 3.1.1. Overview Compound 1: The ADP-GloTM 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. 3.1.2. Protocol [0330] 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 µL was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290). [0331] 1% DMSO and 10 µM staurosporine final concentrations were used respectively as negative and positive controls respectively.2 µL enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT. [0332] The reaction was started by adding 2 µL 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. [0333] The reactions were stopped and the unconsumed ATP was depleted by adding 5 µL 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. [0334] The ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 µL 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.).
Figure imgf000157_0002
3.1.3. Data analysis and results [0335] 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.
Figure imgf000157_0001
n: negative control; p: positive control; RLU: Relative Light Unit and t: test compound 3.2. DDR2 ADP-GloTM Kinase Assay 3.2.1. Overview [0336] The ADP-GloTM 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. 3.2.2. Protocol [0337] 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 µL was transferred to the assay plates (PerkinElmer Inc., Cat# 6007290). [0338] 1% DMSO and 10 µM staurosporine final concentrations were used respectively as negative and positive controls respectively.2 µL enzyme-substrate mixture was added to the assay plates and incubated for 30 min at RT. [0339] The reaction was started by adding 2 µL 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. [0340] The reactions were stopped and the unconsumed ATP was depleted by adding 5 µL 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. [0341] The ADP was converted to ATP and luciferase and luciferin was introduced to detect ATP by adding 10 µL 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 DDR2 kinase ADP-GloTM assay (final concentration)
Figure imgf000158_0002
3.2.3. Data analysis and results [0342] 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. ^^ ^^ ^^ ^^ ^^ ^^ ^^ ^^
Figure imgf000158_0001
n: negative control; p: positive control; RLU: Relative Light Unit and t: test compound Table VII. ADP-GloTM DDR kinase assay IC50 of illustrative compounds of the invention. * > 500 nM ** > 100 - 500 nM *** > 10 - 100 nM **** 0.01 - 10 nM NA not measured
Figure imgf000159_0001
Figure imgf000160_0001
Example 4. Cellular assays 4.1. DDR1 Hek293T nanobret assay 4.1.1. Overview The aim of this assay is to evaluate compounds for their binding characteristics to discoidin domain- containing 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 NanoGlo substrate. NanoLuc-DDR1 will convert the NanoGlo substrate to a bioluminescent protein (=BRET donor). If Kinase Tracer-04 (= BRET acceptor) binds NanoLuc-DDR1, donor and acceptor are in close proximity and upon NanoGlo 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-DDR1 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. 4.1.2. Protocol [0343] Fourteen million HEK293T cells were transiently transfected using 70 µL JetPei, 2.33 µg DDR1- NanoLuc® Fusion Vector and 21 µg pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175). [0344] 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 µM highest final concentration, 1/3 dilution steps). Four µL of the serial dilution was transferred to non-binding surface plates (2 copies). [0345] The transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.04 µM NanoBRET Tracer-04 for DDR1. [0346] Cells were seeded on top of the compounds at 8,000 cells per well in 36 µL [0347] After 2 hours incubation at 37 °C, 5 % CO2, 20 µL of the readout mix was added, containing Opti- MEM medium with 1/332 diluted NanoBRET Nano-Glo substrate and 1/2000 diluted extracellular NanoLuc inhibitor. [0348] 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.
Figure imgf000161_0001
4.1.3. Data analysis and results [0349] 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. 4.2. DDR2 Hek293T nanobret assay 4.2.1. Overview [0350] 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 NanoGlo substrate. NanoLuc-DDR2 will convert the NanoGlo 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 NanoGlo 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. 4.2.2. Protocol [0351] Fourteen million HEK293T cells were transiently transfected using 70 µL JetPei, 2.33 µg DDR2- NanoLuc® Fusion Vector and 21 µg pBluescript. The transfected cells were re-seeded in a culture flask (14E06 cells/T175). [0352] 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 µM highest final concentration, 1/3 dilution steps). Four µL of the serial dilution was transferred to non-binding surface plates (2 copies). [0353] The transfected HEK293T cells were harvested by trypsinization and re-suspended in Opti-MEM medium without phenol red containing 0.4 µM NanoBRET Tracer-04 for DDR2. [0354] Cells were seeded on top of the compounds at 8,000 cells per well in 36 µL [0355] After 2 hours incubation at 37 °C, 5 % CO2, 20 µL of the readout mix was added, containing Opti- MEM medium with 1/332 diluted NanoBRET Nano-Glo substrate and 1/2000 diluted extracellular NanoLuc inhibitor. [0356] 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 IX. Conditions for DDR2 HEK293T nanobret assay (final concentrations)
Figure imgf000162_0001
4.2.3. Data analysis and results [0357] 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 X. 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 imgf000163_0001
Figure imgf000164_0001
4.3. Phospho-DDR Hek293T cell assay 4.3.1. Overview [0358] 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. 4.3.2. Protocol [0359] At day 1, 96-well plates were coated with 50 µL 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. [0360] HEK293T cells were harvested and transfected with wild type pcDNA3.1 hsDDR1 (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 µL in the 96-well plates and cultured at 37 °C 5 % CO2 for 1 day. [0361] The same day, serial dilutions of compounds were prepared in DMSO (30 µM highest final concentration, 1/5 or 1/3 dilution steps).900 nL of the compounds were spotted in 96-well dilution plate. [0362] The next day, the cells were refreshed with 30 µL of fresh medium. The compounds were diluted with 150 µL of medium. When adding the compounds onto the cells, 50 µL medium was added on top of the 30 µL already present in the plate. [0363] After an incubation of 1 h at 37 °C, 5% CO2, 20 µL 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. [0364] 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. [0365] Plates were blocked for 1 h with 50 µL blocking buffer containing 0.2% Triton X-100, 2% heat- inactivated FBS, 3% bovine serum albumin and 1% milk dissolved in PBS. [0366] Next, 50 µL primary antibody solution in blocking buffer was added with rabbit anti-pDDR1 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. [0367] After the plates were washed twice with PBS-Tween 20 (PBS-T) and once with PBS, 50 µL secondary antibody mix was added with Alexa Fluor® 488 goat anti-mouse IgG (Thermo Fisher Scientific, Cat# A11029; 1/500 dilution), Alexa Fluor® 488 goat anti-rabbit IgG (Thermo Fisher Scientific, Cat# A11008; 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. [0368] 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. [0369] After imaging for pDDR, plates were kept in the fridge until the staining for the total DDR (tDDR). [0370] The PBS was removed from the plates and 50 µL primary antibody solution in blocking buffer was added with rabbit anti-DDR1 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 hour at RT, protected from light. [0371] After the plates were washed twice with PBS-T and once with PBS, 50 µL 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 hour at RT, protected from light. [0372] 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. 4.3.3. Data analysis and results [0373] 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 XI. 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 imgf000166_0001
Example 5. ADME assays 5.1. Liver microsomal stability [0374] 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 µM 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. [0375] Final reaction conditions are: 100 µL incubation volume, 1 µM 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 MgCl2 (Sigma, Cat# M2670), 3.3 mM glucose-6-phosphate (Sigma, Cat# G-7879) and 1.3 mM NADP+ (Sigma, Cat# N-0505). [0376] After 30 min of incubation at 300 rpm and 37 °C, the reaction was stopped with 600 µL of STOP solution (acetonitrile with diclofenac as internal standard). For the zero time point, 600 µL of STOP solution was added to the compound dilution before the microsome mix was added. [0377] The samples of both time points were centrifuged, filtered and the supernatant analyzed by LC- MS/MS. [0378] Verapamil (1 µM) and warfarin (1 µM) 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. [0379] The data on microsomal stability are expressed as a percentage of the total amount of compound remaining after 30 min incubation. [0380] 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 XII. Microsomal stability of illustrative compounds of the invention
Figure imgf000166_0002
Figure imgf000167_0001
5.2. Metabolic stability in hepatocytes [0381] 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. [0382] The decrease in parent was assessed by measuring the percentage remaining by LC-MS/MS analysis. [0383] 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 µM. This compound dilution was added to a suspension of pooled cryopreserved hepatocytes (BioreclamationIVT) at 37 °C under gentle shaking. [0384] Final reaction conditions were: 1 µM of test compound, 0.03% DMSO, 0.5 million viable hepatocytes/mL, and 75 µL incubation volume. [0385] Testosterone (1 µM) and 7-hydroxycoumarin (1 µM) were used, respectively as phase I and phase II metabolic reaction controls. [0386] After 0, 10, 20, 45, 90, 120 and 180 min of incubation, the reaction was terminated with 225 µL 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. [0387] 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 XIII. Hepatocyte stability of illustrative compounds of the invention
Figure imgf000167_0002
Figure imgf000168_0001
Example 6. In vivo assays 6.1. Radiation induced fibrosis mouse model 6.1.1. Study overview [0388] 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 [0389] 7 weeks old (18-22 g) albinos female C57BL/6J mice from Charles River (Écully, 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 [0390] The test compounds were dissolved/suspended in appropriate vehicle prior to using and kept light- free, under agitation at RT. [0391] An aliquot of the formulation (~200 µL) was frozen at T0 (day of preparation) and all the formulations were checked (daily) for any change in aspect. [0392] The dose volume administered is 10 mL/kg and the volume is adapted following mean body weight (BW) of the group as follows: 200 µL if mean BW < 22.5 g, 250 µL if mean BW ≥ 22.5 g; 300 µL if mean BW > 27.5 g. 6.1.4. In vivo experimental procedure [0393] On day 1 of week 1, the animals were exposed at the thorax to a 17 Gray irradiation dose, under isoflurane anesthesia. [0394] At the beginning of week 13 post radiation (D1), animals were randomized into 6 study groups (15 subjects per group): 1) sham (vehicle: methylcellulose (MC) 0.5%), 2) diseased (vehicle: methylcellulose (MC) 0.5%), 3) positive control (nintedanib dosed 60 mg/kg in 0.1% NatrosolTM), and 4) 3 groups of test compound (3, 10, and 30 mg/kg in Solutol®/methylcellulose (MC) 0.5% (2/98)), and dosed p.o. q.d. until D42 (week 18). [0395] Body weight was recorded once a week. [0396] After 6 weeks of treatment, lungs were collected, wheighed, and fixed in 4% formaldehyde for 24 h before embedding in paraffin. 4 µm thick sections were immunostained with anti-collagen I antibody (LifeSpan BioSciences, Inc., Cat# LS-343921). The sections were deparaffinized and processed by heat antigen retrieval before incubation for one hour 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. [0397] 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 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 [0398] When subjected to this protocol, Cpd 1 dosed at 3 mg/kg p.o. q.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 [0399] 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 [0400] This study was carried out on C57BL/6N male mice (Charles River, Germany), 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. [0401] At least one day prior to start of experiment, all animals were allocated randomly into groups as indicated in the table below. Table XIV. Study groups
Figure imgf000169_0001
Figure imgf000170_0001
6.2.3. Materials [0402] The solvent for the test solutions was prepared by adding 0.5 g of hydroxyethylcellulose (NatrosolTM) into 500 mL aqua distillate (0.1%) under continuous stirring without heating for 5 h on a magnetic stirrer. [0403] To prepare a solution for intranasal (i.n.) challenge, 0.8 mg/mL stock solutions of bleomycin (Cat# BML-AP302-0010, Enzo Life Sciences, Inc., USA) was thawed and diluted in 330 µL of saline. Prior to i.n. administration, mice were anesthetized i.p.. [0404] A fresh nintedanib formulation was prepared daily in 0.1% NatrosolTM to a final concentration of 5 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.. [0405] Finally, test compound solutions were prepared by dissolving the suitable amount of said test compound in Solutol® (CAS# 70142-34-6; 2% of the final volume) then MC 0.5% (98% of the final volume) with 1 eq. hydrochloric acid, to reach final concentrations of 3 mg/mL, 1 mg/mL and 0.3 mg/mL, thus yielding compound for a doses of 30 mg/kg, 10 mg/kg and 3 mg/kg. Prior to dosing, animals were weighed and the amount administered adjusted accordingly to individual weights. 6.2.4. Study [0406] Animals were examined clinically twice daily. Animals were weighed daily starting from D0. [0407] On day 21, 2 h post dosing with vehicle, nintedanib or test compound, mice were sacrificed. [0408] The lungs were excised and weighed individually. For all groups: the whole superior right lung lobe was placed into a Precellys® tube containing silica beads and immediately snap frozen in liquid nitrogen and subjected to gene expression analysis. [0409] 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 [0410] Body weight data and lung weight data were processed using MS Excel. Statistical analysis and graphical presentation were performed using GraphPad Prism software. One-way ANOVA or Mann- Whitney test were employed for lung weights. Two-way ANOVA were employed for body weight changes. Differences between groups were considered statistically significant when p<0.05. [0411] For histopathological evaluation, whole lungs (except sampled superior right lung) were embedded in paraffin and stained with Mallory’s trichrome. [0412] 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 was performed using GraphPad Prism software. A Mann-Whitney test was employed. Differences between groups were considered statistically significant when p<0.05.
Figure imgf000171_0001
6.2.6. Results [0413] When subjected to this protocol, Cpd 1 dosed at 10 mg/kg p.o. q.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 [0414] In this cGvHD model, fibrosis is induced in BALB/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). [0415] The treatment is provided only after the onset of first clinical symptoms of sclerodermatous cGvHD. 6.3.2. Study groups [0416] The following groups with each eight mice were 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) ^ 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 was initiated in the other groups. - Treatment group: Allogeneic bone marrow and splenocyte transplantation (B10.D2 (H2d) ^ 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) ^ BALB/c (H2d)). Application of 50 mg/kg qd nintedanib from day 21 to day 56 post transplantation. 6.3.3. Steady state PK [0417] On D20, for the groups receiving test compounds, blood was 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. [0418] The blood samples were kept on ice and centrifuged at approx.3500 × g, for 10 min at +4 °C, within 1 h after blood sampling; plasma was transferred in polypropylene tubes and stored at -20 °C. 6.3.4. Sampling and analysis [0419] Animals were sacrificed 2 h post last dose, and samples of skin (3 mm punch biopsies), lung, spleen and blood were collected for histology and gene expression analysis. 6.3.5. Main readouts [0420] The anti-fibrotic effects on skin were analysed by determination of dermal thickness, quantification of lesional collagen and staining for myofibroblasts. [0421] In case of positive effects on skin fibrosis, effects on pulmonary fibrosis were analysed by Ashcroft scoring, hydroxyproline content, and quantification of the collagen covered area using Sirius red staining. 6.3.6. Analysis [0422] Based on individual animal raw data, the means for each group were determined and percent change from disease controls was calculated. Treatment groups were 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. 6.3.7. Results [0423] When subjected to this protocol, Cpd 1 dosed at 30 mg/kg p.o. q.d. in Solutol®/methyl cellulose 0.5% (2/98) showed a statistically significant reduction of dermal thickness, myofibroblast count, Ashcroft score, and collagen-covered lung area compared to the vehicle group. 6.4. Surgical destabilization of the medial meniscus (DMM) mouse model of osteoarthritis [0424] 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. [0425] DMM surgery was performed in the right knees of 10-week old male C57BL/6 mice. For the prophylactic study, systemic (p.o.) treatment started at the time of surgery. Mice were sacrificed 8 weeks after surgery, and another group was sacrificed 12 weeks after surgery. Knees were 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 were collected for histology, following standard methods (Miller et al.2016). 6.4.1. Results [0426] When subjected to this protocol, Cpd 1 dosed at 30 mg/kg p.o. b.i.d. in methyl cellulose 0.5% showed a statistically significant decrease in the total knee joint score, a statistically significant decrease in the medial compartment cartilage degeneration score, and a statistically significant decrease in tibial and femoral substantial knee cartilage degeneration width compared to the vehicle group, at 8 weeks post DMM surgery. FINAL REMARKS [0427] 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. [0428] 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. [0429] 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. [0430] 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. 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. bioRxiv, 857896. Borza CM, Pozzi A.2014. Discoidin domain receptors in disease. Matrix Biol.34, 185–192. Brunner AM et al.2013. 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 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, 71–77. 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

CLAIMS 1. A compound according to Formula I: wherein,
Figure imgf000175_0001
L1 is –O- or –CR4aR4b-; R1 is 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 R5; L2 is –C(=O)NH- or –NHC(=O)-; R2 is 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; L3 is C1-6 alkylene, which alkylene is unsubstituted or substituted with one or more independently selected R6; R3 is C1-4 alkyl; R4a and R4b are independently H or –CH3; each R5 is independently selected from - C1-6 alkyl unsubstituted or substituted with one or more independently selected R7, - C1-4 alkoxy, - -C(=O)-C1-4 alkyl, - C3-6 cycloalkyl, - -NR8aR8b, and - 4-6 membered monocyclic heterocycloalkyl comprising one, two or three heteroatoms independently selected from N and O; each R6 is independently selected from - halo, - -OH, - -NR9aR9b, - 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 -C(=O)-O-C1-6 alkyl; each R7 is independently selected from: - halo, - -OH, - –CN, - C3-6 cycloalkyl, - C1-4 alkoxy unsubstituted or substituted with one or more independently selected halo, and - -NR10aR10b; each R8a and R8b is independently H or C1-4 alkyl; each R9a, R9b, R10a, and R10b is independently H, C1-4 alkyl, or -C(=O)-O-C1-6 alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein R3 is -CH3.
3. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula IIIa or IIIb:
Figure imgf000176_0001
4. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein L1 is –O-.
5. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-3, wherein L1 is -CR4aR4b- and R4a and R4b are independently H or –CH3.
6. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein R2 is C1-4 alkyl substituted with one or more independently selected halo.
7. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein R2 is -CF3 or -CH2CF3.
8. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula VIa or VIb:
Figure imgf000176_0002
9. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein L3 is -CH2- or -CH2CH2-, each of which is substituted with one R6.
10. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-9, wherein R6 is -OH, -O-CH3, -O-CH2CF3, cyclopropyl, cyclobutyl, oxetanyl, or tetrahydrofuranyl.
11. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-8, wherein L3 is -CH2-, -CH2CH2-, or -CH(CH3)CH2-.
12. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-11, wherein R1 is piperidinyl or piperazinyl, each of which is substituted with one -CH3 or -CH2CH3.
13. 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.
14. 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.
15. 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.
ABSTRACT The present invention discloses compounds according to Formula I: I Wherein R1, R2, R3, L1, L2, and L3 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.
ernational application No CT / EPCT/EP2021/068377
C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT
Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.
A GUO JING ET AL: "A patent review of 1-15 discoidin domain receptor 1 (DDR1) modulators (2014-present)",
EXPERT OPINION ON THERAPEUTIC PATENTS, vol . 30, no. 5, 3 May 2020 (2020-05-03), pages 341-350, XP055827937,
GB
ISSN: 1354-3776, D0I:
10.1080/13543776.2020.1732925
Retrieved from the Internet:
URL: ttps : //www. tandfonl i ne . com/doi /pdf/10 .1080/13543776.2020.1732925?needAccess=tru e> page 345; figure 5
A W0 2016/064970 A1 (UNIV TEXAS [US]; 1-15
GUANGZHOU INST BI0MED & HEALTH [CN] )
28 April 2016 (2016-04-28) page 1, line 19 - line 20; claim 1
A ZHEN WANG ET AL: "Structure-Based Design 1-15 of Tetrahydroi soquinol ine-7-carboxamides as Selective Discoidin Domain Receptor 1 (DDR1) Inhibitors",
JOURNAL OF MEDICINAL CHEMISTRY, vol. 59, no. 12, 23 June 2016 (2016-06-23)
, pages 5911-5916, XP055335989,
ISSN: 0022-2623, D0I:
10.1021/acs. jmedchem.6b00140 page 5913; table 1
A W0 2013/070657 A1 (ARENA PHARM INC [US]) 1-15
16 May 2013 (2013-05-16)
STN discloses 2 compounds which would fall within the scope of claim 1. These are
1436422-25-1 which is
2H-i soquinol inepropanamide,
7- [ [ [4-chl oro-2- [4-(3,3,3-trifluoropropyl )
- 1-pi perazinyl] ami no] carbonyl] -
3.4-dihydro and 1436422-8 which is
2H-i soquinol ineacetamide,
7- [[[4-chl oro-2- [4-(3,3,3-trifluoropropyl )
- 1-pi perazinyl] phenyl] ami no] carbonyl] -
3.4-dihydro; page 1, line 5 - line 7; claim 1
Form PCT/ISA/210 (continuation of second sheet) (April 2005) page 2 of 2 ernational application No CT / EPCT/EP2021/068377
Patent document Publication Patent family Publication cited in search report date member(s) date
WO 2016064970 A1 28-04-2016 AU 2015335980 A1 18-05-2017
CA 2965336 A1 28-04-2016
CN 107206004 A 26-09-2017
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JP 2018502900 A 01-02-2018
US 2018022730 A1 25-01-2018
WO 2016064970 A1 28-04-2016
WO 2013070657 A1 16-05-2013 AR 088810 A1 10-07-2014 AU 2012335978 A1 22-05-2014 BR 112014011163 A2 09-05-2017 CA 2853833 A1 16-05-2013 CN 104105691 A 15-10-2014 CO 6970607 A2 13-06-2014 DO P2014000096 A 15-07-2014 EA 201490941 A1 30-10-2014 EP 2776407 A1 17-09-2014 JP 2015501788 A 19-01-2015 KR 20140083058 A 03-07-2014 SG 11201401743R A 29-05-2014 TW 201326143 A 01-07-2013 US 2014309192 A1 16-10-2014 WO 2013070657 A1 16-05-2013
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WO2022216680A1 (en) 2021-04-05 2022-10-13 Halia Therapeutics, Inc. Nek7 inhibitors
WO2022226182A1 (en) 2021-04-22 2022-10-27 Halia Therapeutics, Inc. Nek7 inhibitors
WO2024059200A1 (en) 2022-09-14 2024-03-21 Halia Therapeutics, Inc. Nek7 inhibitors

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